Autonomic imbalance characterized by sustained sympathetic overdrive and by parasympathetic withdrawal is a key maladaptation of the heart failure (HF) state. This autonomic dysregulation has long been recognized as a mediator of increased mortality and morbidity in myocardial infarction and HF.^1,2 Sympathovagal imbalance in HF can lead to increased heart rate, excess release of proinflammatory cytokines, dysregulation of nitric oxide (NO) pathways, and arrythmogenesis. Diminished vagal activity reflected in increased heart rate is a predictor of high mortality in HF.^3,4 Sustained increase of sympathetic activity contributes to progressive left ventricular (LV) dysfunction in HF and promotes progressive LV remodeling.^5,6 Pharmacologic agents that reduce heart rate, such as beta-blockers and, more recently, specific and selective inhibitors of the cardiac pacemaker current If, have been shown to improve survival and prevent or attenuate progressive LV remodeling in animals with HF.^4,5,7,8

During the past two to three decades, the emphasis on modulation of neurohumoral activition for treatment of chronic HF gave rise to angiotensin-converting enzyme inhibitors, beta-adrenergic receptor blockers, and aldosterone antagonists. In recent years, renewed interest has emerged in modulating parasympathetic or vagal activity as a therapeutic target for treating chronic HF. An alteration in cardiac vagal efferent activity through peripheral cardiac nerve stimulation can produce bradycardia and can modify atrial as well as ventricular contractile function.^9,10

Electrical vagus nerve stimulation (VNS) was shown to prevent sudden cardiac death in dogs with myocardial infarction and to improve long-term survival in rats with chronic HF.^11,12 VNS has also been shown to suppress arrhythmias in conscious rats with chronic HF secondary to myocardial infarction.¹³

This article focuses primarily on the effects of chronic VNS on LV dysfunction and remodeling in dogs with HF produced by multiple sequential intracoronary microembolizations¹⁴ or by high-rate ventricular pacing¹⁵ and on the safety, feasibility, and efficacy trends of VNS in patients with advanced HF.¹⁶

VNS IN DOGS WITH MICROEMBOLIZATION-INDUCED HEART FAILURE

Courtesy of BioControl Medical, Ltd., Yehud, Israel

Monotherapy with VNS

Long-term VNS therapy also elicited improvements in indices of LV diastolic function. VNS significantly decreased LV end-diastolic pressure (Table 1), increased deceleration time of rapid mitral inflow velocity, tended to increase the ratio of peak mitral inflow velocity during early LV filling to peak mitral inflow velocity during left atrial contraction (PE/PA), and significantly reduced LV end-diastolic circumferential wall stress, a determinant of myocardial oxygen consumption (Table 1). These measures suggest that VNS can reduce preload, improve LV relaxation and improve LV function without increasing myocardial oxygen consumption.

 

 

VNS in combination with beta-blockade

The effects of VNS in combination with beta-blockade were examined in dogs with HF. Dogs with LV ejection fraction of approximately 35% were randomized to 3 months of therapy with a beta-blocker alone (metoprolol succinate, 100 mg once daily, n = 6) or to metoprolol (100 mg once daily) combined with active VNS with CardioFit (n = 6). As with the monotherapy study, the CardioFit VNS system was operated in the feedback on-demand heart rate responsive mode. Dogs were started on oral metoprolol therapy 2 weeks prior to randomization to VNS therapy. After randomization, all dogs continued to receive metoprolol succinate once daily for the duration of the study.¹⁸

The improvements in LV systolic and diastolic function with combination therapy were associated with important changes in heart rate. Twenty-four–hour ambulatory ECG Holter monitoring studies showed no differences in minimum and average heart rate between dogs treated with metoprolol and those treated with combination therapy with VNS. Maximum heart rate, however, was significantly lower in dogs treated with the combination therapy (114 ± 12 vs 149 ± 8 beats/min, P < .05). These observations suggest that preventing heart rate escape at the high end may further improve LV systolic function compared with beta-blockade alone. This added benefit of the combination of VNS and beta-blockade was likely the result of reducing the adverse impact of increased cardiac workload and increased myocardial oxygen consumption elicited by the heart rate increase.

VNS and left ventricular remodeling

VNS and proinflammatory cytokines, nitric oxide, and gap junction proteins

Nitric oxide (NO) is formed by a family of NO synthases (NOS). The three isoforms of NOS identified to date are endothelin NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS). The three isoforms have differing characteristics and roles:

eNOS. NO produced by eNOS plays an important role in the regulation of cell growth and apoptosis²² and can enhance myocardial relaxation and regulate contractility.^22,23

iNOS. Overexpression of iNOS in cardiomyocytes in mice results in peroxynitrite generation associated with fibrosis, LV hypertrophy, chamber dilation, cardiomyopathic phenotype, heart block, and sudden cardiac death.²⁴

nNOS. nNOS has been shown to be upregulated in the human failing heart and in rats following myocardial infarction.²⁵ In rats with HF, inhibition of nNOS leads to increased sensitivity of the myocardium to beta-adrenergic stimulation,²⁶ suggesting a role for nNOS in the autocrine regulation of myocardial contractility.²⁶

In dogs with coronary microembolization-induced HF, mRNA and protein expression of eNOS in LV myocardium is significantly downregulated compared with normal dogs; therapy with VNS significantly improves the expression of eNOS (Table 3).²⁷ Both iNOS and nNOS are significantly upregulated, and their expression tends to be normalized by long-term VNS therapy.²⁷

Gap junction proteins or connexins are reduced or redistributed from intercalated disks to lateral cell borders in a variety of cardiac diseases, including HF.²⁸ This so-called “gap junction remodeling” is considered highly arrhythmogenic. In mammals, gap junctions exclusively contain connexin-43 (Cx43). Reduced expression of Cx43 occurs in the failing human heart and has been shown to result in slowed transmural conduction and dispersion of action potential duration with increased susceptibility to arrhythmia and sudden cardiac death.^29,30 In dogs with coronary microembolization-induced HF, mRNA and protein expression of Cx43 in LV myocardium was shown to be markedly downregulated compared with normal dogs, and long-term therapy with VNS was associated with a significant increase in the expression of Cx43 in LV myocardium (Table 3).³¹

VNS IN DOGS WITH RAPID PACING–INDUCED HEART FAILURE

Electrical VNS as a potential therapy for HF was examined in dogs with HF secondary to high-rate ventricular pacing using the Cyberonics VNS system (Cyberonics Inc., Houston, TX), which does not operate on a negative feedback mechanism.¹⁵ In this study, VNS therapy was delivered continuously for the duration of the study with a duty cycle of 14 seconds on and 12 seconds off. VNS signals were delivered to the right cervical vagus nerve at a frequency of 20 Hz and a pulse width of 0.5 msec.¹⁵ Dogs were randomized to control (n = 7) or to monotherapy with VNS (n = 8) and followed for 8 weeks. All measurements were made approximately 15 minutes after temporarily turning off the ventricular pacemaker and the vagus nerve stimulator.¹⁵ VNS therapy resulted in a significant decrease in LV end-diastolic and end-systolic volumes and a significant increase in LV ejection fraction compared with controls.¹⁵ This improvement was associated with significant reduction in plasma levels of norepinephrine, angiotensin II, and C-reactive protein. The study also demonstrated the effectiveness of VNS in restoring baroreflex sensitivity, thus improving cardiac autonomic control.¹⁵ Because rapid pacing was maintained throughout the study except for short periods when measurements were made, one can argue that the benefits of VNS therapy in this model of HF are independent of heart rate.¹⁵

SAFETY AND TOLERABILITY OF VNS IN PATIENTS WITH ADVANCED HEART FAILURE

In patients with HF, reduced vagal activity is associated with increased mortality.¹ Vagal withdrawal has also been shown to precede episodes of acute decompensation.³² In a recently published study, De Ferrari et al, on behalf of the CardioFit Multicenter Trial Investigators, examined the safety and tolerability of chronic VNS in 32 patients with symptomatic HF and severe LV dysfunction using the CardioFit system.¹⁶ The CardioFit system used in this study differed from that used in dogs with microembolization-induced HF in that it did not operate on a negative feedback principle. A bradycardia limit causing interruption of VNS was set at 55 beats/min. A 3-week uptitration period was used to maximize current amplitude and duty cycle based on patient sensation. The intensity of the stimulation reached 4.1 ± 1.2 mA at the end of the titration period.¹⁶

This multicenter, open-label, phase 2 trial involved 3 to 6 months of followup with an optional 1 year followup. The results suggested that VNS may be safe and tolerable in HF patients with severe LV dysfunction. Trends for efficacy were also favorable, bearing in mind the nonrandomized and unblinded nature of the study design. The study showed significant improvements in New York Heart Association HF classification, 6-minute walk test, LV ejection fraction, and LV systolic volumes.¹⁶

CONCLUSIONS

A wealth of preclinical and clinical studies supports the concept that electrical VNS can favorably modify the underlying pathophysiology and course of evolving HF. In animals with HF, VNS improves LV function, attenuates LV remodeling and may prevent arrhythmias that provoke sudden cardiac death. VNS derives these potential clinical benefits from multiple mechanisms of action that include reduced heart rate and normalization of sympathetic overdrive. VNS also appears to have a favorable impact on other signaling pathways that are likely to elicit beneficial effects in patients with HF. These include restoration of baroreflex sensitivity, suppression of proinflammatory cytokines, normalization of NO signaling pathways, and suppression of gap junction remodeling. At present, there is no evidence to implicate a single mechanism of action for the benefits derived from VNS. Instead, it is likely that all of the mechanisms listed above act in concert to elicit the global benefit seen with VNS. In humans with HF, VNS may be safe, feasible, and apparently well tolerated. Full appreciation of its efficacy in treating chronic HF must await completion of pivotal randomized clinical trials.

Autonomic imbalance characterized by sustained sympathetic overdrive and by parasympathetic withdrawal is a key maladaptation of the heart failure (HF) state. This autonomic dysregulation has long been recognized as a mediator of increased mortality and morbidity in myocardial infarction and HF.^1,2 Sympathovagal imbalance in HF can lead to increased heart rate, excess release of proinflammatory cytokines, dysregulation of nitric oxide (NO) pathways, and arrythmogenesis. Diminished vagal activity reflected in increased heart rate is a predictor of high mortality in HF.^3,4 Sustained increase of sympathetic activity contributes to progressive left ventricular (LV) dysfunction in HF and promotes progressive LV remodeling.^5,6 Pharmacologic agents that reduce heart rate, such as beta-blockers and, more recently, specific and selective inhibitors of the cardiac pacemaker current If, have been shown to improve survival and prevent or attenuate progressive LV remodeling in animals with HF.^4,5,7,8

During the past two to three decades, the emphasis on modulation of neurohumoral activition for treatment of chronic HF gave rise to angiotensin-converting enzyme inhibitors, beta-adrenergic receptor blockers, and aldosterone antagonists. In recent years, renewed interest has emerged in modulating parasympathetic or vagal activity as a therapeutic target for treating chronic HF. An alteration in cardiac vagal efferent activity through peripheral cardiac nerve stimulation can produce bradycardia and can modify atrial as well as ventricular contractile function.^9,10

Electrical vagus nerve stimulation (VNS) was shown to prevent sudden cardiac death in dogs with myocardial infarction and to improve long-term survival in rats with chronic HF.^11,12 VNS has also been shown to suppress arrhythmias in conscious rats with chronic HF secondary to myocardial infarction.¹³

This article focuses primarily on the effects of chronic VNS on LV dysfunction and remodeling in dogs with HF produced by multiple sequential intracoronary microembolizations¹⁴ or by high-rate ventricular pacing¹⁵ and on the safety, feasibility, and efficacy trends of VNS in patients with advanced HF.¹⁶

VNS IN DOGS WITH MICROEMBOLIZATION-INDUCED HEART FAILURE

Courtesy of BioControl Medical, Ltd., Yehud, Israel

Monotherapy with VNS

Long-term VNS therapy also elicited improvements in indices of LV diastolic function. VNS significantly decreased LV end-diastolic pressure (Table 1), increased deceleration time of rapid mitral inflow velocity, tended to increase the ratio of peak mitral inflow velocity during early LV filling to peak mitral inflow velocity during left atrial contraction (PE/PA), and significantly reduced LV end-diastolic circumferential wall stress, a determinant of myocardial oxygen consumption (Table 1). These measures suggest that VNS can reduce preload, improve LV relaxation and improve LV function without increasing myocardial oxygen consumption.

 

 

VNS in combination with beta-blockade

The effects of VNS in combination with beta-blockade were examined in dogs with HF. Dogs with LV ejection fraction of approximately 35% were randomized to 3 months of therapy with a beta-blocker alone (metoprolol succinate, 100 mg once daily, n = 6) or to metoprolol (100 mg once daily) combined with active VNS with CardioFit (n = 6). As with the monotherapy study, the CardioFit VNS system was operated in the feedback on-demand heart rate responsive mode. Dogs were started on oral metoprolol therapy 2 weeks prior to randomization to VNS therapy. After randomization, all dogs continued to receive metoprolol succinate once daily for the duration of the study.¹⁸

The improvements in LV systolic and diastolic function with combination therapy were associated with important changes in heart rate. Twenty-four–hour ambulatory ECG Holter monitoring studies showed no differences in minimum and average heart rate between dogs treated with metoprolol and those treated with combination therapy with VNS. Maximum heart rate, however, was significantly lower in dogs treated with the combination therapy (114 ± 12 vs 149 ± 8 beats/min, P < .05). These observations suggest that preventing heart rate escape at the high end may further improve LV systolic function compared with beta-blockade alone. This added benefit of the combination of VNS and beta-blockade was likely the result of reducing the adverse impact of increased cardiac workload and increased myocardial oxygen consumption elicited by the heart rate increase.

VNS and left ventricular remodeling

VNS and proinflammatory cytokines, nitric oxide, and gap junction proteins

Nitric oxide (NO) is formed by a family of NO synthases (NOS). The three isoforms of NOS identified to date are endothelin NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS). The three isoforms have differing characteristics and roles:

eNOS. NO produced by eNOS plays an important role in the regulation of cell growth and apoptosis²² and can enhance myocardial relaxation and regulate contractility.^22,23

iNOS. Overexpression of iNOS in cardiomyocytes in mice results in peroxynitrite generation associated with fibrosis, LV hypertrophy, chamber dilation, cardiomyopathic phenotype, heart block, and sudden cardiac death.²⁴

nNOS. nNOS has been shown to be upregulated in the human failing heart and in rats following myocardial infarction.²⁵ In rats with HF, inhibition of nNOS leads to increased sensitivity of the myocardium to beta-adrenergic stimulation,²⁶ suggesting a role for nNOS in the autocrine regulation of myocardial contractility.²⁶

In dogs with coronary microembolization-induced HF, mRNA and protein expression of eNOS in LV myocardium is significantly downregulated compared with normal dogs; therapy with VNS significantly improves the expression of eNOS (Table 3).²⁷ Both iNOS and nNOS are significantly upregulated, and their expression tends to be normalized by long-term VNS therapy.²⁷

Gap junction proteins or connexins are reduced or redistributed from intercalated disks to lateral cell borders in a variety of cardiac diseases, including HF.²⁸ This so-called “gap junction remodeling” is considered highly arrhythmogenic. In mammals, gap junctions exclusively contain connexin-43 (Cx43). Reduced expression of Cx43 occurs in the failing human heart and has been shown to result in slowed transmural conduction and dispersion of action potential duration with increased susceptibility to arrhythmia and sudden cardiac death.^29,30 In dogs with coronary microembolization-induced HF, mRNA and protein expression of Cx43 in LV myocardium was shown to be markedly downregulated compared with normal dogs, and long-term therapy with VNS was associated with a significant increase in the expression of Cx43 in LV myocardium (Table 3).³¹

VNS IN DOGS WITH RAPID PACING–INDUCED HEART FAILURE

Electrical VNS as a potential therapy for HF was examined in dogs with HF secondary to high-rate ventricular pacing using the Cyberonics VNS system (Cyberonics Inc., Houston, TX), which does not operate on a negative feedback mechanism.¹⁵ In this study, VNS therapy was delivered continuously for the duration of the study with a duty cycle of 14 seconds on and 12 seconds off. VNS signals were delivered to the right cervical vagus nerve at a frequency of 20 Hz and a pulse width of 0.5 msec.¹⁵ Dogs were randomized to control (n = 7) or to monotherapy with VNS (n = 8) and followed for 8 weeks. All measurements were made approximately 15 minutes after temporarily turning off the ventricular pacemaker and the vagus nerve stimulator.¹⁵ VNS therapy resulted in a significant decrease in LV end-diastolic and end-systolic volumes and a significant increase in LV ejection fraction compared with controls.¹⁵ This improvement was associated with significant reduction in plasma levels of norepinephrine, angiotensin II, and C-reactive protein. The study also demonstrated the effectiveness of VNS in restoring baroreflex sensitivity, thus improving cardiac autonomic control.¹⁵ Because rapid pacing was maintained throughout the study except for short periods when measurements were made, one can argue that the benefits of VNS therapy in this model of HF are independent of heart rate.¹⁵

SAFETY AND TOLERABILITY OF VNS IN PATIENTS WITH ADVANCED HEART FAILURE

In patients with HF, reduced vagal activity is associated with increased mortality.¹ Vagal withdrawal has also been shown to precede episodes of acute decompensation.³² In a recently published study, De Ferrari et al, on behalf of the CardioFit Multicenter Trial Investigators, examined the safety and tolerability of chronic VNS in 32 patients with symptomatic HF and severe LV dysfunction using the CardioFit system.¹⁶ The CardioFit system used in this study differed from that used in dogs with microembolization-induced HF in that it did not operate on a negative feedback principle. A bradycardia limit causing interruption of VNS was set at 55 beats/min. A 3-week uptitration period was used to maximize current amplitude and duty cycle based on patient sensation. The intensity of the stimulation reached 4.1 ± 1.2 mA at the end of the titration period.¹⁶

This multicenter, open-label, phase 2 trial involved 3 to 6 months of followup with an optional 1 year followup. The results suggested that VNS may be safe and tolerable in HF patients with severe LV dysfunction. Trends for efficacy were also favorable, bearing in mind the nonrandomized and unblinded nature of the study design. The study showed significant improvements in New York Heart Association HF classification, 6-minute walk test, LV ejection fraction, and LV systolic volumes.¹⁶

CONCLUSIONS

A wealth of preclinical and clinical studies supports the concept that electrical VNS can favorably modify the underlying pathophysiology and course of evolving HF. In animals with HF, VNS improves LV function, attenuates LV remodeling and may prevent arrhythmias that provoke sudden cardiac death. VNS derives these potential clinical benefits from multiple mechanisms of action that include reduced heart rate and normalization of sympathetic overdrive. VNS also appears to have a favorable impact on other signaling pathways that are likely to elicit beneficial effects in patients with HF. These include restoration of baroreflex sensitivity, suppression of proinflammatory cytokines, normalization of NO signaling pathways, and suppression of gap junction remodeling. At present, there is no evidence to implicate a single mechanism of action for the benefits derived from VNS. Instead, it is likely that all of the mechanisms listed above act in concert to elicit the global benefit seen with VNS. In humans with HF, VNS may be safe, feasible, and apparently well tolerated. Full appreciation of its efficacy in treating chronic HF must await completion of pivotal randomized clinical trials.

Autonomic imbalance characterized by sustained sympathetic overdrive and by parasympathetic withdrawal is a key maladaptation of the heart failure (HF) state. This autonomic dysregulation has long been recognized as a mediator of increased mortality and morbidity in myocardial infarction and HF.^1,2 Sympathovagal imbalance in HF can lead to increased heart rate, excess release of proinflammatory cytokines, dysregulation of nitric oxide (NO) pathways, and arrythmogenesis. Diminished vagal activity reflected in increased heart rate is a predictor of high mortality in HF.^3,4 Sustained increase of sympathetic activity contributes to progressive left ventricular (LV) dysfunction in HF and promotes progressive LV remodeling.^5,6 Pharmacologic agents that reduce heart rate, such as beta-blockers and, more recently, specific and selective inhibitors of the cardiac pacemaker current If, have been shown to improve survival and prevent or attenuate progressive LV remodeling in animals with HF.^4,5,7,8

During the past two to three decades, the emphasis on modulation of neurohumoral activition for treatment of chronic HF gave rise to angiotensin-converting enzyme inhibitors, beta-adrenergic receptor blockers, and aldosterone antagonists. In recent years, renewed interest has emerged in modulating parasympathetic or vagal activity as a therapeutic target for treating chronic HF. An alteration in cardiac vagal efferent activity through peripheral cardiac nerve stimulation can produce bradycardia and can modify atrial as well as ventricular contractile function.^9,10

Electrical vagus nerve stimulation (VNS) was shown to prevent sudden cardiac death in dogs with myocardial infarction and to improve long-term survival in rats with chronic HF.^11,12 VNS has also been shown to suppress arrhythmias in conscious rats with chronic HF secondary to myocardial infarction.¹³

This article focuses primarily on the effects of chronic VNS on LV dysfunction and remodeling in dogs with HF produced by multiple sequential intracoronary microembolizations¹⁴ or by high-rate ventricular pacing¹⁵ and on the safety, feasibility, and efficacy trends of VNS in patients with advanced HF.¹⁶

VNS IN DOGS WITH MICROEMBOLIZATION-INDUCED HEART FAILURE

Courtesy of BioControl Medical, Ltd., Yehud, Israel

Monotherapy with VNS

Long-term VNS therapy also elicited improvements in indices of LV diastolic function. VNS significantly decreased LV end-diastolic pressure (Table 1), increased deceleration time of rapid mitral inflow velocity, tended to increase the ratio of peak mitral inflow velocity during early LV filling to peak mitral inflow velocity during left atrial contraction (PE/PA), and significantly reduced LV end-diastolic circumferential wall stress, a determinant of myocardial oxygen consumption (Table 1). These measures suggest that VNS can reduce preload, improve LV relaxation and improve LV function without increasing myocardial oxygen consumption.

 

 

VNS in combination with beta-blockade

The effects of VNS in combination with beta-blockade were examined in dogs with HF. Dogs with LV ejection fraction of approximately 35% were randomized to 3 months of therapy with a beta-blocker alone (metoprolol succinate, 100 mg once daily, n = 6) or to metoprolol (100 mg once daily) combined with active VNS with CardioFit (n = 6). As with the monotherapy study, the CardioFit VNS system was operated in the feedback on-demand heart rate responsive mode. Dogs were started on oral metoprolol therapy 2 weeks prior to randomization to VNS therapy. After randomization, all dogs continued to receive metoprolol succinate once daily for the duration of the study.¹⁸

The improvements in LV systolic and diastolic function with combination therapy were associated with important changes in heart rate. Twenty-four–hour ambulatory ECG Holter monitoring studies showed no differences in minimum and average heart rate between dogs treated with metoprolol and those treated with combination therapy with VNS. Maximum heart rate, however, was significantly lower in dogs treated with the combination therapy (114 ± 12 vs 149 ± 8 beats/min, P < .05). These observations suggest that preventing heart rate escape at the high end may further improve LV systolic function compared with beta-blockade alone. This added benefit of the combination of VNS and beta-blockade was likely the result of reducing the adverse impact of increased cardiac workload and increased myocardial oxygen consumption elicited by the heart rate increase.

VNS and left ventricular remodeling

VNS and proinflammatory cytokines, nitric oxide, and gap junction proteins

Nitric oxide (NO) is formed by a family of NO synthases (NOS). The three isoforms of NOS identified to date are endothelin NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS). The three isoforms have differing characteristics and roles:

eNOS. NO produced by eNOS plays an important role in the regulation of cell growth and apoptosis²² and can enhance myocardial relaxation and regulate contractility.^22,23

iNOS. Overexpression of iNOS in cardiomyocytes in mice results in peroxynitrite generation associated with fibrosis, LV hypertrophy, chamber dilation, cardiomyopathic phenotype, heart block, and sudden cardiac death.²⁴

nNOS. nNOS has been shown to be upregulated in the human failing heart and in rats following myocardial infarction.²⁵ In rats with HF, inhibition of nNOS leads to increased sensitivity of the myocardium to beta-adrenergic stimulation,²⁶ suggesting a role for nNOS in the autocrine regulation of myocardial contractility.²⁶

In dogs with coronary microembolization-induced HF, mRNA and protein expression of eNOS in LV myocardium is significantly downregulated compared with normal dogs; therapy with VNS significantly improves the expression of eNOS (Table 3).²⁷ Both iNOS and nNOS are significantly upregulated, and their expression tends to be normalized by long-term VNS therapy.²⁷

Gap junction proteins or connexins are reduced or redistributed from intercalated disks to lateral cell borders in a variety of cardiac diseases, including HF.²⁸ This so-called “gap junction remodeling” is considered highly arrhythmogenic. In mammals, gap junctions exclusively contain connexin-43 (Cx43). Reduced expression of Cx43 occurs in the failing human heart and has been shown to result in slowed transmural conduction and dispersion of action potential duration with increased susceptibility to arrhythmia and sudden cardiac death.^29,30 In dogs with coronary microembolization-induced HF, mRNA and protein expression of Cx43 in LV myocardium was shown to be markedly downregulated compared with normal dogs, and long-term therapy with VNS was associated with a significant increase in the expression of Cx43 in LV myocardium (Table 3).³¹

VNS IN DOGS WITH RAPID PACING–INDUCED HEART FAILURE

Electrical VNS as a potential therapy for HF was examined in dogs with HF secondary to high-rate ventricular pacing using the Cyberonics VNS system (Cyberonics Inc., Houston, TX), which does not operate on a negative feedback mechanism.¹⁵ In this study, VNS therapy was delivered continuously for the duration of the study with a duty cycle of 14 seconds on and 12 seconds off. VNS signals were delivered to the right cervical vagus nerve at a frequency of 20 Hz and a pulse width of 0.5 msec.¹⁵ Dogs were randomized to control (n = 7) or to monotherapy with VNS (n = 8) and followed for 8 weeks. All measurements were made approximately 15 minutes after temporarily turning off the ventricular pacemaker and the vagus nerve stimulator.¹⁵ VNS therapy resulted in a significant decrease in LV end-diastolic and end-systolic volumes and a significant increase in LV ejection fraction compared with controls.¹⁵ This improvement was associated with significant reduction in plasma levels of norepinephrine, angiotensin II, and C-reactive protein. The study also demonstrated the effectiveness of VNS in restoring baroreflex sensitivity, thus improving cardiac autonomic control.¹⁵ Because rapid pacing was maintained throughout the study except for short periods when measurements were made, one can argue that the benefits of VNS therapy in this model of HF are independent of heart rate.¹⁵

SAFETY AND TOLERABILITY OF VNS IN PATIENTS WITH ADVANCED HEART FAILURE

In patients with HF, reduced vagal activity is associated with increased mortality.¹ Vagal withdrawal has also been shown to precede episodes of acute decompensation.³² In a recently published study, De Ferrari et al, on behalf of the CardioFit Multicenter Trial Investigators, examined the safety and tolerability of chronic VNS in 32 patients with symptomatic HF and severe LV dysfunction using the CardioFit system.¹⁶ The CardioFit system used in this study differed from that used in dogs with microembolization-induced HF in that it did not operate on a negative feedback principle. A bradycardia limit causing interruption of VNS was set at 55 beats/min. A 3-week uptitration period was used to maximize current amplitude and duty cycle based on patient sensation. The intensity of the stimulation reached 4.1 ± 1.2 mA at the end of the titration period.¹⁶

This multicenter, open-label, phase 2 trial involved 3 to 6 months of followup with an optional 1 year followup. The results suggested that VNS may be safe and tolerable in HF patients with severe LV dysfunction. Trends for efficacy were also favorable, bearing in mind the nonrandomized and unblinded nature of the study design. The study showed significant improvements in New York Heart Association HF classification, 6-minute walk test, LV ejection fraction, and LV systolic volumes.¹⁶

CONCLUSIONS

A wealth of preclinical and clinical studies supports the concept that electrical VNS can favorably modify the underlying pathophysiology and course of evolving HF. In animals with HF, VNS improves LV function, attenuates LV remodeling and may prevent arrhythmias that provoke sudden cardiac death. VNS derives these potential clinical benefits from multiple mechanisms of action that include reduced heart rate and normalization of sympathetic overdrive. VNS also appears to have a favorable impact on other signaling pathways that are likely to elicit beneficial effects in patients with HF. These include restoration of baroreflex sensitivity, suppression of proinflammatory cytokines, normalization of NO signaling pathways, and suppression of gap junction remodeling. At present, there is no evidence to implicate a single mechanism of action for the benefits derived from VNS. Instead, it is likely that all of the mechanisms listed above act in concert to elicit the global benefit seen with VNS. In humans with HF, VNS may be safe, feasible, and apparently well tolerated. Full appreciation of its efficacy in treating chronic HF must await completion of pivotal randomized clinical trials.

Implantable devices are increasingly used in the treatment of diseases which have historically been targeted only with small molecule and biological therapeutic agents. In addition to well-established products such as subcutaneous insulin pumps and intra-arterial chemotherapy pumps, where the implantable device merely serves as a more efficient means of delivering the drug, there are a number of recently developed therapeutic approaches in which the implanted device itself functions to directly treat the underlying medical condition. One particularly successful example of this strategy is cardiac resynchronization using biventricular pacing devices for congestive heart failure (CHF). These devices were approved for marketing after having been proved to prolong survival in patients whose disease had progressed despite medical management.¹ Implantable device products are now approved or in late-stage development for many other traditional “medical” disorders such as hypertension, obesity, diabetes, Parkinson’s disease, and glaucoma. Recent advances in understanding the interplay between the central nervous system and the immune system have made possible a feasible implantable device approach that may similarly find use in the management of rheumatoid arthritis (RA) and other chronic inflammatory diseases.²

NEUROSTIMULATION OF THE CHOLINERGIC ANTIINFLAMMATORY PATHWAY

The vagus nerve mediates an important neural reflex which senses inflammation both peripherally and in the central nervous system, and downregulates the inflammation via efferent neural outflow to the reticuloendothelial system. The efferent arm of this reflex has been termed the “cholinergic antiinflammatory pathway” (CAP). The CAP serves as a physiological regulator of inflammation by responding to environmental injury, pathogens, and other external threats with an appropriate degree of immune system activation.³ An increasing body of evidence indicates that the CAP can also be harnessed to reduce pathological inflammation. Electrical neurostimulation of the vagus nerve (NCAP) in an appropriate manner with an implantable device is emerging as a novel and potentially feasible means of treating diseases characterized by excessive and dysregulated inflammation.

Our current understanding of the CAP began with the observations of Kevin Tracey and colleagues over a decade ago. They demonstrated that systemic, hepatic, and splenic tumor necrosis factor (TNF) production as well as the physiological manifestations of endotoxemic shock in rodents were worsened by vagotomy and ameliorated by electrical stimulation of the cervical vagus nerve (VNS). Further, based on in vitro experiments they postulated that this effect was mediated directly by acetylcholine acting through specific receptors on macrophages in the reticuloendothelial system.⁴ It was later demonstrated that reducing the response to endotoxemia using NCAP required an intact spleen, and selective anatomical lesion experiments showed that an intact neural pathway to the spleen from the cervical vagus through the celiac ganglion and the splenic nerve was also necessary for this effect.⁵ Within the spleen itself, nerve fiber synaptic vesicles are found in close apposition to TNF-secreting macrophages.⁶ The α-7 nicotinic acetylcholine receptor, expressed on the surface of macrophages, is essential for the NCAP effect as demonstrated by antisense oligonucleotide and targeted disruption experiments.⁷ In the macrophage, the α-7 nicotinic acetylcholine receptor does not appear to transduce signals through ion channels, as is the case in neuronal tissue. Rather, the NCAP effect is mediated at the subcellular level by alterations in the NF-κB and JAK/STAT/SOCS pathways.^8,9

When taken together, these studies show that NCAP has a dual set of immunological effects: it reduces production of systemically active cytokines by resident spleen cells and also causes circulating cells which traverse the spleen to develop an altered phenotype with reduced expression of inflammatory mediators and adhesion molecules upon trafficking to inflamed tissue.

An important characteristic of NCAP delivered by VNS is that very brief episodes of stimulation result in a remarkably prolonged biological effect. Huston et al delivered a single 30-second electrical VNS or sham treatment in rats, and then induced endotoxemia with intraperitoneal lipopolysaccharide (LPS) at varying times after VNS. Interestingly, this brief VNS stimulation reduced production of serum TNF in response to systemic LPS exposure for up to 48 hours. Similarly, after only 60 minutes of exposure to acetylcholine, cultured human macrophages are changed in phenotype such that they become refractory to in vitro LPS stimulation for up to 48 hours thereafter.¹⁵ The consistency of this phenomenon across species is corroborated by preliminary data in a canine model where 60-second VNS treatment results in reduced LPS-inducible TNF production in a whole-blood in vitro release assay for several days after the VNS (M Faltys, personal communication). A duration of biological effect lasting hours to days after periods of stimulation lasting for only seconds to minutes implies that an implantable device will probably only need to operate with very short daily duty cycles to effectively elicit an NCAP response. This will in turn greatly reduce the necessary size and complexity of the device itself, and increase its functional lifespan, with resultant reductions in overall cost of the treatment.

NEUROSTIMULATION OF THE CAP IN ANIMAL MODELS OF DISEASE

In a canine model of CHF induced by rapid ventricular pacing, inflammation and ventricular remodeling with fibrosis are typically accompanied by marked increases in serum C-reactive protein (CRP) levels. In addition to improving the physiological manifestations of CHF, VNS resulted in 60% to 80% reductions in CRP for up to 8 weeks.¹⁷ In another canine CHF model induced by repetitive microembolization, which is similarly associated with systemic and myocardial inflammation, VNS markedly reduced circulating levels of interleukin 6 and TNF for up to 12 weeks.¹⁸ Importantly, both these studies show that rapid tachyphylaxis does not appear to occur with NCAP over periods of time that are relatively chronic by the typical standards of animal models.

VAGAL NERVE STIMULATION FOR EPILEPSY AND DEPRESSION: EXPERIENCE IN HUMANS

VNS delivered using a surgically implanted cuffed cervical vagus nerve lead and pacemaker-style pulse generator device has been approved for the treatment of refractory epilepsy in the United States since the mid-1990s and has more recently been approved for treatment of depression. Over 50,000 patients have been implanted with these devices world wide since that time. The safety profile of both surgical implantation and VNS delivery in this setting is well established.¹⁹ The major tolerability problem is laryngeal and pharyngeal symptoms, such as hoarseness and dysphonia, which are present almost solely during periods of active device stimulation. The frequency and severity of these treatments decreases after receiving treatment for an extended time.²⁰ With growing experience in VNS delivery over the first 5 years of use, it also became apparent that reducing the active stimulation duty cycle from 40% to 10%, and keeping stimulation currents at ≤ 1.5 mA results in a marked reduction in these symptoms.²¹ Of note, the stimulation currents necessary to evoke NCAP in animals are well below the 1.5 mA level, and as above, NCAP is effective even with very brief, once-daily periods of stimulation (ie, a duty cycle of 0.07% if given for 1 min each day). Thus it is likely that the laryngeal and pharyngeal adverse event profile of VNS will not be problematic in the setting of NCAP delivery for inflammation.

A POTENTIAL ROLE FOR THERAPEUTIC NCAP USING IMPLANTABLE DEVICES IN HUMAN INFLAMMATORY DISEASES

Autonomic nervous system activity can be measured indirectly by recording cardiac R-R interval variability and subjecting the data to power spectral analysis. Such heart rate variability (HRV) measurements are influenced by the levels of vagus nerve activity and by balance in cardiac sympathetic–parasympathetic tone. Reduced HRV is indicative of decreased vagal tone, and reductions in HRV have a strong inverse correlation with CRP levels, progression of atherosclerosis, and risk of sudden death.^22,23 HRV is also reduced relative to normal subjects in patients with RA, systemic lupus erythematosus, and Sjögren syndrome, and the extent of reduction in HRV within the patient groups correlates with disease severity.^24–26 Although these associations are only correlative and do not provide firm evidence of causality, they do provide additional epidemiological support for the hypothesis that driving increased vagal activity using implantable devices may have a favorable effect on inflammatory disease.

Implantable neurostimulation devices have not yet been tested in human patients with RA. However, preliminary evidence from a small study carried out in normal volunteers demonstrated that the CAP reflex can be elicited by brief mechanical stimulation of the afferent auricular branch of the vagus nerve, as shown by reduction of in vitro LPS-inducible cytokine production (T van der Poll, personal communication). Clinical testing of NCAP using implantable VNS devices will begin in the near future. The devices to be used for these initial studies will be very similar in design to those currently in use for epilepsy treatment. However, prototype versions of the device which will be used in follow-on studies are miniaturized to the point where they will be directly implantable on the vagus nerve, without the need for a pulse generator unit on the chest and will use a small self-contained battery system which can be recharged using transcutaneous radiofrequency induction. Given the long lifespan, relatively low cost, and potential for increased safety over currently available treatments, NCAP delivered using an implantable device holds great promise as a novel potential therapeutic approach for patients with RA and other inflammatory diseases.

Implantable devices are increasingly used in the treatment of diseases which have historically been targeted only with small molecule and biological therapeutic agents. In addition to well-established products such as subcutaneous insulin pumps and intra-arterial chemotherapy pumps, where the implantable device merely serves as a more efficient means of delivering the drug, there are a number of recently developed therapeutic approaches in which the implanted device itself functions to directly treat the underlying medical condition. One particularly successful example of this strategy is cardiac resynchronization using biventricular pacing devices for congestive heart failure (CHF). These devices were approved for marketing after having been proved to prolong survival in patients whose disease had progressed despite medical management.¹ Implantable device products are now approved or in late-stage development for many other traditional “medical” disorders such as hypertension, obesity, diabetes, Parkinson’s disease, and glaucoma. Recent advances in understanding the interplay between the central nervous system and the immune system have made possible a feasible implantable device approach that may similarly find use in the management of rheumatoid arthritis (RA) and other chronic inflammatory diseases.²

NEUROSTIMULATION OF THE CHOLINERGIC ANTIINFLAMMATORY PATHWAY

The vagus nerve mediates an important neural reflex which senses inflammation both peripherally and in the central nervous system, and downregulates the inflammation via efferent neural outflow to the reticuloendothelial system. The efferent arm of this reflex has been termed the “cholinergic antiinflammatory pathway” (CAP). The CAP serves as a physiological regulator of inflammation by responding to environmental injury, pathogens, and other external threats with an appropriate degree of immune system activation.³ An increasing body of evidence indicates that the CAP can also be harnessed to reduce pathological inflammation. Electrical neurostimulation of the vagus nerve (NCAP) in an appropriate manner with an implantable device is emerging as a novel and potentially feasible means of treating diseases characterized by excessive and dysregulated inflammation.

Our current understanding of the CAP began with the observations of Kevin Tracey and colleagues over a decade ago. They demonstrated that systemic, hepatic, and splenic tumor necrosis factor (TNF) production as well as the physiological manifestations of endotoxemic shock in rodents were worsened by vagotomy and ameliorated by electrical stimulation of the cervical vagus nerve (VNS). Further, based on in vitro experiments they postulated that this effect was mediated directly by acetylcholine acting through specific receptors on macrophages in the reticuloendothelial system.⁴ It was later demonstrated that reducing the response to endotoxemia using NCAP required an intact spleen, and selective anatomical lesion experiments showed that an intact neural pathway to the spleen from the cervical vagus through the celiac ganglion and the splenic nerve was also necessary for this effect.⁵ Within the spleen itself, nerve fiber synaptic vesicles are found in close apposition to TNF-secreting macrophages.⁶ The α-7 nicotinic acetylcholine receptor, expressed on the surface of macrophages, is essential for the NCAP effect as demonstrated by antisense oligonucleotide and targeted disruption experiments.⁷ In the macrophage, the α-7 nicotinic acetylcholine receptor does not appear to transduce signals through ion channels, as is the case in neuronal tissue. Rather, the NCAP effect is mediated at the subcellular level by alterations in the NF-κB and JAK/STAT/SOCS pathways.^8,9

When taken together, these studies show that NCAP has a dual set of immunological effects: it reduces production of systemically active cytokines by resident spleen cells and also causes circulating cells which traverse the spleen to develop an altered phenotype with reduced expression of inflammatory mediators and adhesion molecules upon trafficking to inflamed tissue.

An important characteristic of NCAP delivered by VNS is that very brief episodes of stimulation result in a remarkably prolonged biological effect. Huston et al delivered a single 30-second electrical VNS or sham treatment in rats, and then induced endotoxemia with intraperitoneal lipopolysaccharide (LPS) at varying times after VNS. Interestingly, this brief VNS stimulation reduced production of serum TNF in response to systemic LPS exposure for up to 48 hours. Similarly, after only 60 minutes of exposure to acetylcholine, cultured human macrophages are changed in phenotype such that they become refractory to in vitro LPS stimulation for up to 48 hours thereafter.¹⁵ The consistency of this phenomenon across species is corroborated by preliminary data in a canine model where 60-second VNS treatment results in reduced LPS-inducible TNF production in a whole-blood in vitro release assay for several days after the VNS (M Faltys, personal communication). A duration of biological effect lasting hours to days after periods of stimulation lasting for only seconds to minutes implies that an implantable device will probably only need to operate with very short daily duty cycles to effectively elicit an NCAP response. This will in turn greatly reduce the necessary size and complexity of the device itself, and increase its functional lifespan, with resultant reductions in overall cost of the treatment.

NEUROSTIMULATION OF THE CAP IN ANIMAL MODELS OF DISEASE

In a canine model of CHF induced by rapid ventricular pacing, inflammation and ventricular remodeling with fibrosis are typically accompanied by marked increases in serum C-reactive protein (CRP) levels. In addition to improving the physiological manifestations of CHF, VNS resulted in 60% to 80% reductions in CRP for up to 8 weeks.¹⁷ In another canine CHF model induced by repetitive microembolization, which is similarly associated with systemic and myocardial inflammation, VNS markedly reduced circulating levels of interleukin 6 and TNF for up to 12 weeks.¹⁸ Importantly, both these studies show that rapid tachyphylaxis does not appear to occur with NCAP over periods of time that are relatively chronic by the typical standards of animal models.

VAGAL NERVE STIMULATION FOR EPILEPSY AND DEPRESSION: EXPERIENCE IN HUMANS

VNS delivered using a surgically implanted cuffed cervical vagus nerve lead and pacemaker-style pulse generator device has been approved for the treatment of refractory epilepsy in the United States since the mid-1990s and has more recently been approved for treatment of depression. Over 50,000 patients have been implanted with these devices world wide since that time. The safety profile of both surgical implantation and VNS delivery in this setting is well established.¹⁹ The major tolerability problem is laryngeal and pharyngeal symptoms, such as hoarseness and dysphonia, which are present almost solely during periods of active device stimulation. The frequency and severity of these treatments decreases after receiving treatment for an extended time.²⁰ With growing experience in VNS delivery over the first 5 years of use, it also became apparent that reducing the active stimulation duty cycle from 40% to 10%, and keeping stimulation currents at ≤ 1.5 mA results in a marked reduction in these symptoms.²¹ Of note, the stimulation currents necessary to evoke NCAP in animals are well below the 1.5 mA level, and as above, NCAP is effective even with very brief, once-daily periods of stimulation (ie, a duty cycle of 0.07% if given for 1 min each day). Thus it is likely that the laryngeal and pharyngeal adverse event profile of VNS will not be problematic in the setting of NCAP delivery for inflammation.

A POTENTIAL ROLE FOR THERAPEUTIC NCAP USING IMPLANTABLE DEVICES IN HUMAN INFLAMMATORY DISEASES

Autonomic nervous system activity can be measured indirectly by recording cardiac R-R interval variability and subjecting the data to power spectral analysis. Such heart rate variability (HRV) measurements are influenced by the levels of vagus nerve activity and by balance in cardiac sympathetic–parasympathetic tone. Reduced HRV is indicative of decreased vagal tone, and reductions in HRV have a strong inverse correlation with CRP levels, progression of atherosclerosis, and risk of sudden death.^22,23 HRV is also reduced relative to normal subjects in patients with RA, systemic lupus erythematosus, and Sjögren syndrome, and the extent of reduction in HRV within the patient groups correlates with disease severity.^24–26 Although these associations are only correlative and do not provide firm evidence of causality, they do provide additional epidemiological support for the hypothesis that driving increased vagal activity using implantable devices may have a favorable effect on inflammatory disease.

Implantable neurostimulation devices have not yet been tested in human patients with RA. However, preliminary evidence from a small study carried out in normal volunteers demonstrated that the CAP reflex can be elicited by brief mechanical stimulation of the afferent auricular branch of the vagus nerve, as shown by reduction of in vitro LPS-inducible cytokine production (T van der Poll, personal communication). Clinical testing of NCAP using implantable VNS devices will begin in the near future. The devices to be used for these initial studies will be very similar in design to those currently in use for epilepsy treatment. However, prototype versions of the device which will be used in follow-on studies are miniaturized to the point where they will be directly implantable on the vagus nerve, without the need for a pulse generator unit on the chest and will use a small self-contained battery system which can be recharged using transcutaneous radiofrequency induction. Given the long lifespan, relatively low cost, and potential for increased safety over currently available treatments, NCAP delivered using an implantable device holds great promise as a novel potential therapeutic approach for patients with RA and other inflammatory diseases.

Implantable devices are increasingly used in the treatment of diseases which have historically been targeted only with small molecule and biological therapeutic agents. In addition to well-established products such as subcutaneous insulin pumps and intra-arterial chemotherapy pumps, where the implantable device merely serves as a more efficient means of delivering the drug, there are a number of recently developed therapeutic approaches in which the implanted device itself functions to directly treat the underlying medical condition. One particularly successful example of this strategy is cardiac resynchronization using biventricular pacing devices for congestive heart failure (CHF). These devices were approved for marketing after having been proved to prolong survival in patients whose disease had progressed despite medical management.¹ Implantable device products are now approved or in late-stage development for many other traditional “medical” disorders such as hypertension, obesity, diabetes, Parkinson’s disease, and glaucoma. Recent advances in understanding the interplay between the central nervous system and the immune system have made possible a feasible implantable device approach that may similarly find use in the management of rheumatoid arthritis (RA) and other chronic inflammatory diseases.²

NEUROSTIMULATION OF THE CHOLINERGIC ANTIINFLAMMATORY PATHWAY

The vagus nerve mediates an important neural reflex which senses inflammation both peripherally and in the central nervous system, and downregulates the inflammation via efferent neural outflow to the reticuloendothelial system. The efferent arm of this reflex has been termed the “cholinergic antiinflammatory pathway” (CAP). The CAP serves as a physiological regulator of inflammation by responding to environmental injury, pathogens, and other external threats with an appropriate degree of immune system activation.³ An increasing body of evidence indicates that the CAP can also be harnessed to reduce pathological inflammation. Electrical neurostimulation of the vagus nerve (NCAP) in an appropriate manner with an implantable device is emerging as a novel and potentially feasible means of treating diseases characterized by excessive and dysregulated inflammation.

Our current understanding of the CAP began with the observations of Kevin Tracey and colleagues over a decade ago. They demonstrated that systemic, hepatic, and splenic tumor necrosis factor (TNF) production as well as the physiological manifestations of endotoxemic shock in rodents were worsened by vagotomy and ameliorated by electrical stimulation of the cervical vagus nerve (VNS). Further, based on in vitro experiments they postulated that this effect was mediated directly by acetylcholine acting through specific receptors on macrophages in the reticuloendothelial system.⁴ It was later demonstrated that reducing the response to endotoxemia using NCAP required an intact spleen, and selective anatomical lesion experiments showed that an intact neural pathway to the spleen from the cervical vagus through the celiac ganglion and the splenic nerve was also necessary for this effect.⁵ Within the spleen itself, nerve fiber synaptic vesicles are found in close apposition to TNF-secreting macrophages.⁶ The α-7 nicotinic acetylcholine receptor, expressed on the surface of macrophages, is essential for the NCAP effect as demonstrated by antisense oligonucleotide and targeted disruption experiments.⁷ In the macrophage, the α-7 nicotinic acetylcholine receptor does not appear to transduce signals through ion channels, as is the case in neuronal tissue. Rather, the NCAP effect is mediated at the subcellular level by alterations in the NF-κB and JAK/STAT/SOCS pathways.^8,9

When taken together, these studies show that NCAP has a dual set of immunological effects: it reduces production of systemically active cytokines by resident spleen cells and also causes circulating cells which traverse the spleen to develop an altered phenotype with reduced expression of inflammatory mediators and adhesion molecules upon trafficking to inflamed tissue.

An important characteristic of NCAP delivered by VNS is that very brief episodes of stimulation result in a remarkably prolonged biological effect. Huston et al delivered a single 30-second electrical VNS or sham treatment in rats, and then induced endotoxemia with intraperitoneal lipopolysaccharide (LPS) at varying times after VNS. Interestingly, this brief VNS stimulation reduced production of serum TNF in response to systemic LPS exposure for up to 48 hours. Similarly, after only 60 minutes of exposure to acetylcholine, cultured human macrophages are changed in phenotype such that they become refractory to in vitro LPS stimulation for up to 48 hours thereafter.¹⁵ The consistency of this phenomenon across species is corroborated by preliminary data in a canine model where 60-second VNS treatment results in reduced LPS-inducible TNF production in a whole-blood in vitro release assay for several days after the VNS (M Faltys, personal communication). A duration of biological effect lasting hours to days after periods of stimulation lasting for only seconds to minutes implies that an implantable device will probably only need to operate with very short daily duty cycles to effectively elicit an NCAP response. This will in turn greatly reduce the necessary size and complexity of the device itself, and increase its functional lifespan, with resultant reductions in overall cost of the treatment.

NEUROSTIMULATION OF THE CAP IN ANIMAL MODELS OF DISEASE

In a canine model of CHF induced by rapid ventricular pacing, inflammation and ventricular remodeling with fibrosis are typically accompanied by marked increases in serum C-reactive protein (CRP) levels. In addition to improving the physiological manifestations of CHF, VNS resulted in 60% to 80% reductions in CRP for up to 8 weeks.¹⁷ In another canine CHF model induced by repetitive microembolization, which is similarly associated with systemic and myocardial inflammation, VNS markedly reduced circulating levels of interleukin 6 and TNF for up to 12 weeks.¹⁸ Importantly, both these studies show that rapid tachyphylaxis does not appear to occur with NCAP over periods of time that are relatively chronic by the typical standards of animal models.

VAGAL NERVE STIMULATION FOR EPILEPSY AND DEPRESSION: EXPERIENCE IN HUMANS

VNS delivered using a surgically implanted cuffed cervical vagus nerve lead and pacemaker-style pulse generator device has been approved for the treatment of refractory epilepsy in the United States since the mid-1990s and has more recently been approved for treatment of depression. Over 50,000 patients have been implanted with these devices world wide since that time. The safety profile of both surgical implantation and VNS delivery in this setting is well established.¹⁹ The major tolerability problem is laryngeal and pharyngeal symptoms, such as hoarseness and dysphonia, which are present almost solely during periods of active device stimulation. The frequency and severity of these treatments decreases after receiving treatment for an extended time.²⁰ With growing experience in VNS delivery over the first 5 years of use, it also became apparent that reducing the active stimulation duty cycle from 40% to 10%, and keeping stimulation currents at ≤ 1.5 mA results in a marked reduction in these symptoms.²¹ Of note, the stimulation currents necessary to evoke NCAP in animals are well below the 1.5 mA level, and as above, NCAP is effective even with very brief, once-daily periods of stimulation (ie, a duty cycle of 0.07% if given for 1 min each day). Thus it is likely that the laryngeal and pharyngeal adverse event profile of VNS will not be problematic in the setting of NCAP delivery for inflammation.

A POTENTIAL ROLE FOR THERAPEUTIC NCAP USING IMPLANTABLE DEVICES IN HUMAN INFLAMMATORY DISEASES

Autonomic nervous system activity can be measured indirectly by recording cardiac R-R interval variability and subjecting the data to power spectral analysis. Such heart rate variability (HRV) measurements are influenced by the levels of vagus nerve activity and by balance in cardiac sympathetic–parasympathetic tone. Reduced HRV is indicative of decreased vagal tone, and reductions in HRV have a strong inverse correlation with CRP levels, progression of atherosclerosis, and risk of sudden death.^22,23 HRV is also reduced relative to normal subjects in patients with RA, systemic lupus erythematosus, and Sjögren syndrome, and the extent of reduction in HRV within the patient groups correlates with disease severity.^24–26 Although these associations are only correlative and do not provide firm evidence of causality, they do provide additional epidemiological support for the hypothesis that driving increased vagal activity using implantable devices may have a favorable effect on inflammatory disease.

Implantable neurostimulation devices have not yet been tested in human patients with RA. However, preliminary evidence from a small study carried out in normal volunteers demonstrated that the CAP reflex can be elicited by brief mechanical stimulation of the afferent auricular branch of the vagus nerve, as shown by reduction of in vitro LPS-inducible cytokine production (T van der Poll, personal communication). Clinical testing of NCAP using implantable VNS devices will begin in the near future. The devices to be used for these initial studies will be very similar in design to those currently in use for epilepsy treatment. However, prototype versions of the device which will be used in follow-on studies are miniaturized to the point where they will be directly implantable on the vagus nerve, without the need for a pulse generator unit on the chest and will use a small self-contained battery system which can be recharged using transcutaneous radiofrequency induction. Given the long lifespan, relatively low cost, and potential for increased safety over currently available treatments, NCAP delivered using an implantable device holds great promise as a novel potential therapeutic approach for patients with RA and other inflammatory diseases.

I am fortunate to be the recipient of the 2010 Bakken Institute Pioneer Award and feel especially honored to have my work recognized in this way. When informed that I was this year’s recipient, it prompted me to reflect on the meaning of the term “pioneer,” and how it related to me.

WHAT IS A PIONEER?

According to Merriam-Webster’s Collegiate Dictionary, a pioneer is one who (a) ventures into unknown or unclaimed territory to settle; and (b) opens up new areas of thought, research, or development. One requirement for any pioneer is that there be a frontier to explore. Thirty years ago, my colleagues and I began our investigations into cardiac rehabilitation (CR), which at the time we considered to be a new frontier for behavioral medicine.¹

EXERCISE-BASED CARDIAC REHABILITATION

Historically, patients who suffered an acute myocardial infarction (AMI) were often discouraged from engaging in physical activity; patients were initially prescribed prolonged bed rest and told to avoid strenuous exercise.² In the early 1950s, armchair therapy was proposed³ as an initial attempt to mobilize patients after a coronary event. Over the years, the value of physical exercise has been increasingly recognized and exercise is now considered to be the cornerstone of CR.^4–7 Today, exercise-based CR, involving aerobic exercise supplemented by resistance training, is offered by virtually all CR programs in the United States.⁸ Proper medical management is also emphasized, along with dietary modification and smoking cessation, but exercise is the centerpiece of treatment.

Exercise has been shown to reduce traditional risk factors such as hypertension and hyperlipidemia,⁸ attenuate cardiovascular responses to mental stress,⁹ and reduce myocardial ischemia.^10–12 Although no single study has demonstrated definitively that exercise reduces morbidity in patients with coronary heart disease (CHD), pooling data across clinical trials has shown that exercise may reduce risk of fatal CHD events by 25%.¹³ A recent, comprehensive meta-analysis by Jolliffe et al¹⁴ reported a 27% reduction in all-cause mortality and 31% reduction in cardiac mortality.

Not only is exercise considered beneficial for medical outcomes, but is also recognized as an important factor in improved quality of life. Indeed, there has been increased interest in the value of exercise for improving not just physical health, but also mental health.^15–17 The mental health benefits of exercise are especially relevant for cardiac patients, as there is a growing literature documenting the importance of mental health, and, in particular the prognostic significance of depression, in patients with CHD.

PSYCHOSOCIAL RISK FACTORS: THE ROLE OF DEPRESSION IN CORONARY HEART DISEASE

There has long been an interest in psychosocial factors that contribute to the development and progression of CHD. More than three decades ago, researchers identified the type A behavior pattern as a risk factor for CHD.¹⁸ When subsequent studies failed to confirm the association of type A with adverse health outcomes, researchers turned their attention to other possible psychosocial risk factors, including anger and hostility,¹⁹ low social support,²⁰ and most recently, depression.²¹ Indeed, the most consistent and compelling evidence is that clinical depression or elevated depressive symptoms in the presence of CHD increase the risk of fatal and nonfatal cardiac events and of all-cause mortality.²²

Major depressive disorder (MDD) is a common and often chronic condition. Lifetime incidence estimates for MDD are approximately 12% in men and 20% in women.²³ In addition, MDD is marked by high rates of relapse, with 22% to 50% of patients suffering recurrent episodes within 6 months after recovery.²⁴ Furthermore, MDD is underrecognized and undertreated in older adults,²⁵ CHD patients, and, especially, minorities.^26–28

Cross-sectional studies have documented a higher prevalence of depression in CHD patients than in the general population. Point estimates range from 14% to as high as 47%, with higher rates recorded most often in patients with unstable angina, heart failure (HF), and patients awaiting coronary artery bypass graft (CABG) surgery.^29–36

Depression associated with poor outcomes

A number of prospective studies have found that depression is associated with increased risk for mortality or nonfatal cardiac events in a variety of CHD populations. The most compelling evidence for depression as a risk factor has come from studies in Montreal, Canada. Frasure-Smith and colleagues³¹ assessed the impact of depression in 222 AMI patients, of whom 35 were diagnosed with MDD at the time of hospitalization. There were 12 deaths (six depressed and six nondepressed) over an initial 6-month followup period, representing more than a fivefold increased risk of death for depressed patients compared with nondepressed patients (hazard ratio, 5.7; 95% confidence interval [CI], 4.6 to 6.9). In a subsequent report,³⁶ in which 896 AMI patients were followed for 1 year, the presence of elevated depressive symptoms was associated with more than a threefold increased risk in cardiac mortality after controlling for other multivariate predictors of mortality (odds ratio, 3.29 for women; 3.05 for men).

Studies of patients with stable CHD also have reported significant associations between the presence of depression and worse clinical outcomes. For example, Barefoot et al³⁷ assessed 1,250 patients with documented CHD using the Zung self-report depression scale at the time of diagnostic coronary angiography and followed patients for up to 19.4 years. Results showed that patients with moderate to severe depression were at 69% greater risk for cardiac death and 78% greater risk for all-cause death.

Reprinted from The Lancet (Blumenthal JA, et al. Depression as a risk factor for mortality after coronary artery bypass surgery. Lancet 2003; 362:604–609), copyright © 2003, with permission from Elsevier.

Depression and heart failure outcomes

Patients with HF represent a particularly vulnerable group; a meta-analysis of depression in HF patients suggested that one in five patients are clinically depressed (range, 9% to 60%).⁴¹ Not only is depression in HF patients associated with worse outcomes,^42–46 but recent evidence suggests that worsening of depressive symptoms, independent of clinical status, is related to worse outcomes. Sherwood et al⁴⁶ demonstrated that increased symptoms of depression, as indicated by higher scores on the Beck Depression Inventory (BDI) over a 1-year interval (BDI change [1-point] hazard ratio, 1.07; 95% CI, 1.02 to 1.12; P = .007), were associated with higher risk of death or cardiovascular hospitalization after controlling for baseline depression (baseline BDI hazard ratio, 1.1; 95% CI, 1.06 to 1.14, P < .001) and established risk factors, including HF etiology, age, ejection fraction, N-terminal pro-B-type natriuretic peptides, and prior hospitalizations. Consequently, strategies to reduce depressive symptoms and prevent the worsening of depression may have important implications for improving cardiac health as well as for enhancing quality of life.

CONVENTIONAL APPROACHES TO TREATMENT OF DEPRESSION

Treatment of depression has focused on reduction of symptoms and restoration of function. Antidepressant medications are generally considered the treatment of choice.⁵⁶ In particular, second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are widely prescribed.⁵⁷ Current treatment guidelines suggest 6 to 12 weeks of acute treatment followed by a continuation phase of 3 to 9 months to maintain therapeutic benefit.⁵⁸ However, meta-analyses of antidepressant medications have reported only modest benefits over placebo treatments.^59,60 In particular, active drug–placebo differences in antidepressant efficacy are positively correlated with depression severity: antidepressants are often comparable with placebo in patients with low levels of depression but may be superior to placebo among patients with more severe depression. However, the explanation for this relationship may be that placebo is less effective for more depressed patients rather than antidepressants being more effective for more depressed patients.⁵⁹

For acute treatment of MDD, approximately 60% of patients respond to second-generation antidepressants,⁶¹ with a 40% relapse rate after 1 year.⁶² A recent meta-analysis⁶⁰ of second-generation antidepressants summarized four comparative trials and 23 placebo-controlled trials and found that second-generation antidepressants were generally comparable with each other. Interestingly, despite the modest benefit of antidepressants, the percentage of patients treated for depression in the United States increased from 0.73% in 1987 to 2.33% in 1997. The proportion of those treated who received antidepressants increased from 37.3% in 1987 to 74.5% in 1997.⁶³ The percentage of treated outpatients who used antidepressants has not increased significantly since 1997, but the use of psycho therapy as a sole treatment declined from 53.6% in 1998 to 43.1% in 2007.⁶⁴ Moreover, the national expenditure for the outpatient treatment of depression increased from $10.05 billion in 1998 to $12.45 billion in 2007, primarily driven by an increase in expenditures for antidepressant medications.

Uncertainty about value of antidepressant therapy

Despite compelling reasons for treating depression in cardiac patients, the clinical significance of treating depression remains uncertain. To date, only the Enhancing Recovery in CHD Patients (ENRICHD) trial has examined the impact of treating depression in post-MI patients on “hard” clinical end points.⁶⁵ Although more than 2,400 patients were enrolled in the trial, the results were disappointing. There were only modest differences (ie, two points on the Hamilton Depression Rating Scale [HAM-D]) in reductions of depressive symptoms in the group receiving cognitive behavior therapy (CBT) relative to usual-care controls and there were no treatment group differences in the primary outcome—all-cause mortality and nonfatal cardiac events. By the end of the follow-up period, 28.0% of patients in the CBT group and 20.6% of patients in usual care had received antidepressant medication. Although a subsequent reanalysis of the ENRICHD study revealed that antidepressant use was associated with improved clinical outcomes,⁶⁶ because patients were not randomized to pharmacologic treatment it could not be concluded that SSRI use was responsible for the improved outcomes.

In a randomized trial of patients with acute coronary syndrome (the Sertraline Antidepressant Heart Attack Randomized Trial, or SADHART),⁶⁷ almost 400 patients were treated with the SSRI sertraline or with placebo. Reductions in depressive symptoms were similar for patients receiving sertraline compared with placebo in the full sample, although a subgroup analysis revealed that patients with more severe depression (ie, those patients who reported two or more previous episodes) benefited more from sertraline compared with placebo. Interestingly, patients receiving sertraline tended to have more favorable cardiac outcomes, including a composite measure of both “hard” and “soft” clinical events, compared with placebo controls. These results suggested that antidepressant medication may improve underlying physiologic processes, such as platelet function, independent of changes in depression.⁶⁸ However, because SADHART was not powered to detect differences in clinical events, there remain unanswered questions about the clinical value of treating depression in cardiac patients with antidepressant medication.

In a second sertraline trial, SADHART-HF,⁶⁹ 469 men and women with MDD and chronic systolic HF were randomized to receive either sertraline or placebo for 12 weeks. Participants were followed for a minimum of 6 months. Results showed that while sertraline was safe, its use did not result in greater reductions in depressive symptoms compared with placebo (−7.1 ± 0.5 vs −6.8 ± 0.5) and there were no differences in clinical event rates between patients receiving sertraline compared with those receiving placebo.

In an observational study of patients with HF,⁴⁴ use of antidepressant medication was associated with increased risk of mortality or hospitalization. Although the potential harmful effects of antidepressant medication could not be ruled out, a more likely interpretation is that antidepressant medication use was a marker for individuals with more severe depression, and that the underlying depression may have contributed to their higher risk. Further, patients who are depressed, despite receiving treatment, may represent a subset of treatment-resistant patients who may be especially vulnerable to further cardiac events. Indeed, worsening depression is associated with worse outcomes in HF patients⁴⁶; this is consistent with data from the ENRICHD trial, which showed that patients receiving CBT (and, in some cases, antidepressant medication) who failed to improve with treatment had higher mortality rates compared with patients who exhibited a positive response to treatment.⁷⁰

A fourth randomized trial of CHD patients, the Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial,⁷¹ used a modified “2 by 2” design; 284 CHD patients with MDD and HAM-D rating scores of 20 or greater were randomized to receive 12 weeks of (a) interpersonal therapy (IPT) plus clinical management (CM) or (b) CM only and citalopram or matching placebo. Because the same interventionists delivered the CM and IPT, patients assigned to IPT received IPT plus CM within the same (extended) session. Patients receiving citalopram had greater reductions in depressive symptoms compared with placebo, with a small to medium effect size of 0.33, and better remission rates (35.9%) compared with placebo (22.5%). Unexpectedly, patients who received just CM tended to have greater improvements in depressive symptoms compared with patients who received IPT plus CM (P < .07); no clinical CHD end points were assessed, however.

Alternative approaches needed

Taken together, these data illustrate that antidepressant medications may reduce depressive symptoms for some patients; for other patients, however, medication fails to adequately relieve depressive symptoms and may perform no better than placebo. Adverse effects also may affect a subgroup of patients and may be relatively more common or more problematic in older persons with CHD.⁷² Thus, a need remains to identify alternative approaches for treating depression in cardiac patients. We believe that aerobic exercise, the cornerstone of traditional CR, may be one such approach. Exercise is safe for most cardiac patients,^73,74 including patients with HF,⁷⁵ and, if proven effective as a treatment for depression, exercise would hold several potential advantages over traditional medical therapies: it is relatively inexpensive, improves cardiovascular functioning, and avoids the side effects sometimes associated with medication use.

Some studies of exercise treatment for CHD patients have tracked depressive symptoms and thus have provided information regarding the potential efficacy of exercise as a treatment for depression in this population.^{76 –81} Although most previous studies have reported significant improvements in depression after completion of an exercise program, many studies had important methodologic limitations, including the absence of a control group.

In one of the few controlled studies in this field, Stern et al⁸² randomized 106 male patients who had a recent history of AMI along with elevated depression and anxiety or low fitness to 12 weeks of exercise training, group therapy, or a usual-care control group. At 1-year followup, both the exercise and counseling groups showed improvements in depression relative to controls.

Cross-sectional studies of non-CHD samples have reported that active individuals obtain significantly lower depression scores on self-report measures than sedentary persons.⁸³ Studies also have shown that aerobic exercise may reduce self-reported depressive symptoms in nonclinical populations and in patients diagnosed with MDD.⁸³ In 2001, a meta-analysis evaluating 11 randomized controlled trials of non-CHD patients with MDD⁸⁴ noted that studies were limited because of self-selection bias, absence of control groups or nonrandom controls, and inadequate assessment of exercise training effects; the authors concluded that “the effectiveness of exercise in reducing symptoms of depression cannot be determined because of a lack of good quality research on clinical populations with adequate followup.”

Randomized controlled trials needed

A subsequent meta-analysis⁸⁵ included 25 studies; for 23 trials (907 participants) that compared exercise with no treatment or a control intervention, the pooled standardized mean difference (SMD) was −0.82 (95% CI, −1.12, −0.51), indicating a large effect size. However, when only the three trials (216 participants) with adequate allocation concealment, intention to treat analysis, and blinded outcome assessment were included, the pooled SMD was −0.43 (95% CI, −0.88, 0.03), with a point estimate that was half the size of that with all trials. As a result, the authors concluded that “exercise seems to improve depressive symptoms in people with a diagnosis of depression, but when only the methodologically robust trials are included, the effect size is only moderate.”

To date, no randomized clinical trials (RCTs) have examined the effects of exercise on clinical outcomes in depressed cardiac patients. However, data from the ENRICHD trial suggest that exercise may reduce the rates of mortality and nonfatal reinfarction in patients with depression or in post-MI patients who are socially isolated.⁸⁶ Self-report data were used to categorize participants as exercising regularly or not exercising regularly. After controlling for medical and demographic variables, the magnitude of reduction in risk associated with regular exercise was nearly 40% for nonfatal reinfarction and 50% for mortality. The evidence that exercise mitigates depression, reduces CHD risk factors, and improves CHD outcomes suggests that exercise may be a particularly promising intervention for depressed CHD patients.

COMPARATIVE EFFECTIVENESS OF EXERCISE AND ANTIDEPRESSANT MEDICATION

In 2008, an Institute of Medicine (IOM) report called for a national initiative of research that would provide a basis for better decision-making about how to best treat various medical conditions, including depression. In 2009, the American Reinvestment Recovery Act provided a major boost in funding for comparative effectiveness research (CER). The act allotted $1.1 billion to support this form of research. CER refers to the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition, or to improve the delivery of care. The purpose of CER is to assist consumers, clinicians, purchasers, and policy makers in reaching informed decisions that will improve health care at both the individual and population levels.⁸⁷

Two research categories inform decision-making

Two broad categories of research have been used to inform decision-making:

• Epidemiologic studies provide evidence linking various treatments with patient outcomes. These sources of data are limited because they seldom specify the basis for medical decisions and they fail to consider patient characteristics that affect both clinical decisions and clinical outcomes. Indeed, it has been suggested that “overcoming the limitations of observational research is the most important frontier of research on study methods.”⁸⁸
• RCTs address these limitations by randomly assigning patients to different treatment conditions. While this design may eliminate some of the uncertainty and potential confounders that characterize purely observational studies, most RCTs are efficacy studies; patients are carefully selected and a treatment is usually compared with a placebo or usual care.

The RCT design addresses the question of whether a given treatment is effective, but it does not necessarily address questions that many physicians want answers to: namely, is this treatment better than that treatment? Further, physicians want to know if one treatment is more effective than another for a given patient. For example, Hlatky et al⁸⁹ showed that mortality associated with percutaneous coronary interventions (PCIs) and CABG surgery was comparable; however, mortality with CABG surgery was significantly lower for patients older than 65 years while PCI was superior for patients younger than 55 years. Thus, examination of individual differences may also help to inform clinicians about the optimal therapy for their particular patients.

 

 

Treatment of depression not necessarily a research priority

The IOM committee sought advice from a broad range of stakeholders and prioritized areas for research. The top-ranked topic was comparison of treatment strategies for atrial fibrillation, including surgery, catheter ablation, and pharmacologic treatment. Coming in at #98 was comparison of the effectiveness of different treatment strategies (eg, psychotherapy, antidepressants, combination treatment with case management) for depression after MI and their impact on medication adherence, cardiovascular events, hospitalization, and death.

Reprinted, with permission, from Archives of Internal Medicine (Blumenthal JA, et al. Arch Intern Med 1999 Oct 25; 159:2349–2356), Copyright © 1999 American Medical Association. All rights reserved.

In a second Duke study that compared exercise and antidepressant medication,⁹² 202 adults (153 women; 49 men) diagnosed with MDD were randomly assigned to one of four groups: supervised exercise in a group setting, home-based exercise, antidepressant medication (sertraline, 50 to 200 mg daily), or placebo pill for 16 weeks. Once again, patients underwent the Structured Clinical Interview for Depression and completed the HAM-D. After 4 months of treatment, 41% of participants achieved remission, defined as no longer meeting criteria for MDD and a HAM-D score of less than 8 points. Patients receiving active treatments tended to have higher remission rates than placebo controls: supervised exercise, 45%; home-based exercise, 40%; medication, 47%; placebo, 31% (P = .057). All treatment groups had lower HAM-D scores after treatment; scores for the active treatment groups were not significantly different from the placebo group (P = .23). However, when immediate responders (ie, those patients who reported more than 50% reduction in depressive symptoms after only 1 week of treatment) were excluded from the analysis, patients receiving active treatments (ie, either sertraline or exercise) had greater reductions in depressive symptoms compared with placebo controls (P = .048). There was no difference between the exercise and antidepressant groups. We concluded that the efficacy of exercise appears generally comparable with antidepressant medication and both tend to be better than placebo in patients with MDD. Placebo response rates were high, suggesting that a considerable portion of the therapeutic response could be determined by patient expectations, ongoing symptom monitoring, attention, and other nonspecific factors. Similar to our previous trial, participants who continued to exercise following the completion of the program were less likely to be depressed.⁹³

Another RCT⁹⁴ also demonstrated that exercise was associated with reduced depression, independent of group support. Participants exercised alone in a secluded setting, and the study included a no-treatment control group. Only 53 of 80 patients actually completed the 12-week trial, however, including only five of 13 no-treatment controls. Moreover, there was no active treatment comparison group, so that an estimate of comparative effectiveness could not be determined.

While these results are preliminary and should be interpreted with caution, it appears that exercise may be comparable with conventional antidepressant medication in reducing depressive symptoms, at least for patients who are willing to try it, and maintenance of exercise reduces the risk of relapse.

SUMMARY

Three decades ago, we recognized that CR was a new frontier for behavioral medicine. We now know that successful rehabilitation of patients with CHD involves modification of lifestyle behaviors, including smoking cessation, dietary modification, and exercise. Exercise is no longer considered unsafe for most cardiac patients, and exercise is currently the key component of CR services. Research also has provided strong evidence that depression is an important risk factor for CHD, although there is no consensus regarding the optimal way to treat depression in CHD patients.⁹⁵ Research on comparative effectiveness of established and alternative treatments for depressed cardiac patients is a new frontier for future pioneers in heart-brain medicine.

I am fortunate to be the recipient of the 2010 Bakken Institute Pioneer Award and feel especially honored to have my work recognized in this way. When informed that I was this year’s recipient, it prompted me to reflect on the meaning of the term “pioneer,” and how it related to me.

WHAT IS A PIONEER?

According to Merriam-Webster’s Collegiate Dictionary, a pioneer is one who (a) ventures into unknown or unclaimed territory to settle; and (b) opens up new areas of thought, research, or development. One requirement for any pioneer is that there be a frontier to explore. Thirty years ago, my colleagues and I began our investigations into cardiac rehabilitation (CR), which at the time we considered to be a new frontier for behavioral medicine.¹

EXERCISE-BASED CARDIAC REHABILITATION

Historically, patients who suffered an acute myocardial infarction (AMI) were often discouraged from engaging in physical activity; patients were initially prescribed prolonged bed rest and told to avoid strenuous exercise.² In the early 1950s, armchair therapy was proposed³ as an initial attempt to mobilize patients after a coronary event. Over the years, the value of physical exercise has been increasingly recognized and exercise is now considered to be the cornerstone of CR.^4–7 Today, exercise-based CR, involving aerobic exercise supplemented by resistance training, is offered by virtually all CR programs in the United States.⁸ Proper medical management is also emphasized, along with dietary modification and smoking cessation, but exercise is the centerpiece of treatment.

Exercise has been shown to reduce traditional risk factors such as hypertension and hyperlipidemia,⁸ attenuate cardiovascular responses to mental stress,⁹ and reduce myocardial ischemia.^10–12 Although no single study has demonstrated definitively that exercise reduces morbidity in patients with coronary heart disease (CHD), pooling data across clinical trials has shown that exercise may reduce risk of fatal CHD events by 25%.¹³ A recent, comprehensive meta-analysis by Jolliffe et al¹⁴ reported a 27% reduction in all-cause mortality and 31% reduction in cardiac mortality.

Not only is exercise considered beneficial for medical outcomes, but is also recognized as an important factor in improved quality of life. Indeed, there has been increased interest in the value of exercise for improving not just physical health, but also mental health.^15–17 The mental health benefits of exercise are especially relevant for cardiac patients, as there is a growing literature documenting the importance of mental health, and, in particular the prognostic significance of depression, in patients with CHD.

PSYCHOSOCIAL RISK FACTORS: THE ROLE OF DEPRESSION IN CORONARY HEART DISEASE

There has long been an interest in psychosocial factors that contribute to the development and progression of CHD. More than three decades ago, researchers identified the type A behavior pattern as a risk factor for CHD.¹⁸ When subsequent studies failed to confirm the association of type A with adverse health outcomes, researchers turned their attention to other possible psychosocial risk factors, including anger and hostility,¹⁹ low social support,²⁰ and most recently, depression.²¹ Indeed, the most consistent and compelling evidence is that clinical depression or elevated depressive symptoms in the presence of CHD increase the risk of fatal and nonfatal cardiac events and of all-cause mortality.²²

Major depressive disorder (MDD) is a common and often chronic condition. Lifetime incidence estimates for MDD are approximately 12% in men and 20% in women.²³ In addition, MDD is marked by high rates of relapse, with 22% to 50% of patients suffering recurrent episodes within 6 months after recovery.²⁴ Furthermore, MDD is underrecognized and undertreated in older adults,²⁵ CHD patients, and, especially, minorities.^26–28

Cross-sectional studies have documented a higher prevalence of depression in CHD patients than in the general population. Point estimates range from 14% to as high as 47%, with higher rates recorded most often in patients with unstable angina, heart failure (HF), and patients awaiting coronary artery bypass graft (CABG) surgery.^29–36

Depression associated with poor outcomes

A number of prospective studies have found that depression is associated with increased risk for mortality or nonfatal cardiac events in a variety of CHD populations. The most compelling evidence for depression as a risk factor has come from studies in Montreal, Canada. Frasure-Smith and colleagues³¹ assessed the impact of depression in 222 AMI patients, of whom 35 were diagnosed with MDD at the time of hospitalization. There were 12 deaths (six depressed and six nondepressed) over an initial 6-month followup period, representing more than a fivefold increased risk of death for depressed patients compared with nondepressed patients (hazard ratio, 5.7; 95% confidence interval [CI], 4.6 to 6.9). In a subsequent report,³⁶ in which 896 AMI patients were followed for 1 year, the presence of elevated depressive symptoms was associated with more than a threefold increased risk in cardiac mortality after controlling for other multivariate predictors of mortality (odds ratio, 3.29 for women; 3.05 for men).

Studies of patients with stable CHD also have reported significant associations between the presence of depression and worse clinical outcomes. For example, Barefoot et al³⁷ assessed 1,250 patients with documented CHD using the Zung self-report depression scale at the time of diagnostic coronary angiography and followed patients for up to 19.4 years. Results showed that patients with moderate to severe depression were at 69% greater risk for cardiac death and 78% greater risk for all-cause death.

Reprinted from The Lancet (Blumenthal JA, et al. Depression as a risk factor for mortality after coronary artery bypass surgery. Lancet 2003; 362:604–609), copyright © 2003, with permission from Elsevier.

Depression and heart failure outcomes

Patients with HF represent a particularly vulnerable group; a meta-analysis of depression in HF patients suggested that one in five patients are clinically depressed (range, 9% to 60%).⁴¹ Not only is depression in HF patients associated with worse outcomes,^42–46 but recent evidence suggests that worsening of depressive symptoms, independent of clinical status, is related to worse outcomes. Sherwood et al⁴⁶ demonstrated that increased symptoms of depression, as indicated by higher scores on the Beck Depression Inventory (BDI) over a 1-year interval (BDI change [1-point] hazard ratio, 1.07; 95% CI, 1.02 to 1.12; P = .007), were associated with higher risk of death or cardiovascular hospitalization after controlling for baseline depression (baseline BDI hazard ratio, 1.1; 95% CI, 1.06 to 1.14, P < .001) and established risk factors, including HF etiology, age, ejection fraction, N-terminal pro-B-type natriuretic peptides, and prior hospitalizations. Consequently, strategies to reduce depressive symptoms and prevent the worsening of depression may have important implications for improving cardiac health as well as for enhancing quality of life.

CONVENTIONAL APPROACHES TO TREATMENT OF DEPRESSION

Treatment of depression has focused on reduction of symptoms and restoration of function. Antidepressant medications are generally considered the treatment of choice.⁵⁶ In particular, second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are widely prescribed.⁵⁷ Current treatment guidelines suggest 6 to 12 weeks of acute treatment followed by a continuation phase of 3 to 9 months to maintain therapeutic benefit.⁵⁸ However, meta-analyses of antidepressant medications have reported only modest benefits over placebo treatments.^59,60 In particular, active drug–placebo differences in antidepressant efficacy are positively correlated with depression severity: antidepressants are often comparable with placebo in patients with low levels of depression but may be superior to placebo among patients with more severe depression. However, the explanation for this relationship may be that placebo is less effective for more depressed patients rather than antidepressants being more effective for more depressed patients.⁵⁹

For acute treatment of MDD, approximately 60% of patients respond to second-generation antidepressants,⁶¹ with a 40% relapse rate after 1 year.⁶² A recent meta-analysis⁶⁰ of second-generation antidepressants summarized four comparative trials and 23 placebo-controlled trials and found that second-generation antidepressants were generally comparable with each other. Interestingly, despite the modest benefit of antidepressants, the percentage of patients treated for depression in the United States increased from 0.73% in 1987 to 2.33% in 1997. The proportion of those treated who received antidepressants increased from 37.3% in 1987 to 74.5% in 1997.⁶³ The percentage of treated outpatients who used antidepressants has not increased significantly since 1997, but the use of psycho therapy as a sole treatment declined from 53.6% in 1998 to 43.1% in 2007.⁶⁴ Moreover, the national expenditure for the outpatient treatment of depression increased from $10.05 billion in 1998 to $12.45 billion in 2007, primarily driven by an increase in expenditures for antidepressant medications.

Uncertainty about value of antidepressant therapy

Despite compelling reasons for treating depression in cardiac patients, the clinical significance of treating depression remains uncertain. To date, only the Enhancing Recovery in CHD Patients (ENRICHD) trial has examined the impact of treating depression in post-MI patients on “hard” clinical end points.⁶⁵ Although more than 2,400 patients were enrolled in the trial, the results were disappointing. There were only modest differences (ie, two points on the Hamilton Depression Rating Scale [HAM-D]) in reductions of depressive symptoms in the group receiving cognitive behavior therapy (CBT) relative to usual-care controls and there were no treatment group differences in the primary outcome—all-cause mortality and nonfatal cardiac events. By the end of the follow-up period, 28.0% of patients in the CBT group and 20.6% of patients in usual care had received antidepressant medication. Although a subsequent reanalysis of the ENRICHD study revealed that antidepressant use was associated with improved clinical outcomes,⁶⁶ because patients were not randomized to pharmacologic treatment it could not be concluded that SSRI use was responsible for the improved outcomes.

In a randomized trial of patients with acute coronary syndrome (the Sertraline Antidepressant Heart Attack Randomized Trial, or SADHART),⁶⁷ almost 400 patients were treated with the SSRI sertraline or with placebo. Reductions in depressive symptoms were similar for patients receiving sertraline compared with placebo in the full sample, although a subgroup analysis revealed that patients with more severe depression (ie, those patients who reported two or more previous episodes) benefited more from sertraline compared with placebo. Interestingly, patients receiving sertraline tended to have more favorable cardiac outcomes, including a composite measure of both “hard” and “soft” clinical events, compared with placebo controls. These results suggested that antidepressant medication may improve underlying physiologic processes, such as platelet function, independent of changes in depression.⁶⁸ However, because SADHART was not powered to detect differences in clinical events, there remain unanswered questions about the clinical value of treating depression in cardiac patients with antidepressant medication.

In a second sertraline trial, SADHART-HF,⁶⁹ 469 men and women with MDD and chronic systolic HF were randomized to receive either sertraline or placebo for 12 weeks. Participants were followed for a minimum of 6 months. Results showed that while sertraline was safe, its use did not result in greater reductions in depressive symptoms compared with placebo (−7.1 ± 0.5 vs −6.8 ± 0.5) and there were no differences in clinical event rates between patients receiving sertraline compared with those receiving placebo.

In an observational study of patients with HF,⁴⁴ use of antidepressant medication was associated with increased risk of mortality or hospitalization. Although the potential harmful effects of antidepressant medication could not be ruled out, a more likely interpretation is that antidepressant medication use was a marker for individuals with more severe depression, and that the underlying depression may have contributed to their higher risk. Further, patients who are depressed, despite receiving treatment, may represent a subset of treatment-resistant patients who may be especially vulnerable to further cardiac events. Indeed, worsening depression is associated with worse outcomes in HF patients⁴⁶; this is consistent with data from the ENRICHD trial, which showed that patients receiving CBT (and, in some cases, antidepressant medication) who failed to improve with treatment had higher mortality rates compared with patients who exhibited a positive response to treatment.⁷⁰

A fourth randomized trial of CHD patients, the Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial,⁷¹ used a modified “2 by 2” design; 284 CHD patients with MDD and HAM-D rating scores of 20 or greater were randomized to receive 12 weeks of (a) interpersonal therapy (IPT) plus clinical management (CM) or (b) CM only and citalopram or matching placebo. Because the same interventionists delivered the CM and IPT, patients assigned to IPT received IPT plus CM within the same (extended) session. Patients receiving citalopram had greater reductions in depressive symptoms compared with placebo, with a small to medium effect size of 0.33, and better remission rates (35.9%) compared with placebo (22.5%). Unexpectedly, patients who received just CM tended to have greater improvements in depressive symptoms compared with patients who received IPT plus CM (P < .07); no clinical CHD end points were assessed, however.

Alternative approaches needed

Taken together, these data illustrate that antidepressant medications may reduce depressive symptoms for some patients; for other patients, however, medication fails to adequately relieve depressive symptoms and may perform no better than placebo. Adverse effects also may affect a subgroup of patients and may be relatively more common or more problematic in older persons with CHD.⁷² Thus, a need remains to identify alternative approaches for treating depression in cardiac patients. We believe that aerobic exercise, the cornerstone of traditional CR, may be one such approach. Exercise is safe for most cardiac patients,^73,74 including patients with HF,⁷⁵ and, if proven effective as a treatment for depression, exercise would hold several potential advantages over traditional medical therapies: it is relatively inexpensive, improves cardiovascular functioning, and avoids the side effects sometimes associated with medication use.

Some studies of exercise treatment for CHD patients have tracked depressive symptoms and thus have provided information regarding the potential efficacy of exercise as a treatment for depression in this population.^{76 –81} Although most previous studies have reported significant improvements in depression after completion of an exercise program, many studies had important methodologic limitations, including the absence of a control group.

In one of the few controlled studies in this field, Stern et al⁸² randomized 106 male patients who had a recent history of AMI along with elevated depression and anxiety or low fitness to 12 weeks of exercise training, group therapy, or a usual-care control group. At 1-year followup, both the exercise and counseling groups showed improvements in depression relative to controls.

Cross-sectional studies of non-CHD samples have reported that active individuals obtain significantly lower depression scores on self-report measures than sedentary persons.⁸³ Studies also have shown that aerobic exercise may reduce self-reported depressive symptoms in nonclinical populations and in patients diagnosed with MDD.⁸³ In 2001, a meta-analysis evaluating 11 randomized controlled trials of non-CHD patients with MDD⁸⁴ noted that studies were limited because of self-selection bias, absence of control groups or nonrandom controls, and inadequate assessment of exercise training effects; the authors concluded that “the effectiveness of exercise in reducing symptoms of depression cannot be determined because of a lack of good quality research on clinical populations with adequate followup.”

Randomized controlled trials needed

A subsequent meta-analysis⁸⁵ included 25 studies; for 23 trials (907 participants) that compared exercise with no treatment or a control intervention, the pooled standardized mean difference (SMD) was −0.82 (95% CI, −1.12, −0.51), indicating a large effect size. However, when only the three trials (216 participants) with adequate allocation concealment, intention to treat analysis, and blinded outcome assessment were included, the pooled SMD was −0.43 (95% CI, −0.88, 0.03), with a point estimate that was half the size of that with all trials. As a result, the authors concluded that “exercise seems to improve depressive symptoms in people with a diagnosis of depression, but when only the methodologically robust trials are included, the effect size is only moderate.”

To date, no randomized clinical trials (RCTs) have examined the effects of exercise on clinical outcomes in depressed cardiac patients. However, data from the ENRICHD trial suggest that exercise may reduce the rates of mortality and nonfatal reinfarction in patients with depression or in post-MI patients who are socially isolated.⁸⁶ Self-report data were used to categorize participants as exercising regularly or not exercising regularly. After controlling for medical and demographic variables, the magnitude of reduction in risk associated with regular exercise was nearly 40% for nonfatal reinfarction and 50% for mortality. The evidence that exercise mitigates depression, reduces CHD risk factors, and improves CHD outcomes suggests that exercise may be a particularly promising intervention for depressed CHD patients.

COMPARATIVE EFFECTIVENESS OF EXERCISE AND ANTIDEPRESSANT MEDICATION

In 2008, an Institute of Medicine (IOM) report called for a national initiative of research that would provide a basis for better decision-making about how to best treat various medical conditions, including depression. In 2009, the American Reinvestment Recovery Act provided a major boost in funding for comparative effectiveness research (CER). The act allotted $1.1 billion to support this form of research. CER refers to the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition, or to improve the delivery of care. The purpose of CER is to assist consumers, clinicians, purchasers, and policy makers in reaching informed decisions that will improve health care at both the individual and population levels.⁸⁷

Two research categories inform decision-making

Two broad categories of research have been used to inform decision-making:

• Epidemiologic studies provide evidence linking various treatments with patient outcomes. These sources of data are limited because they seldom specify the basis for medical decisions and they fail to consider patient characteristics that affect both clinical decisions and clinical outcomes. Indeed, it has been suggested that “overcoming the limitations of observational research is the most important frontier of research on study methods.”⁸⁸
• RCTs address these limitations by randomly assigning patients to different treatment conditions. While this design may eliminate some of the uncertainty and potential confounders that characterize purely observational studies, most RCTs are efficacy studies; patients are carefully selected and a treatment is usually compared with a placebo or usual care.

The RCT design addresses the question of whether a given treatment is effective, but it does not necessarily address questions that many physicians want answers to: namely, is this treatment better than that treatment? Further, physicians want to know if one treatment is more effective than another for a given patient. For example, Hlatky et al⁸⁹ showed that mortality associated with percutaneous coronary interventions (PCIs) and CABG surgery was comparable; however, mortality with CABG surgery was significantly lower for patients older than 65 years while PCI was superior for patients younger than 55 years. Thus, examination of individual differences may also help to inform clinicians about the optimal therapy for their particular patients.

 

 

Treatment of depression not necessarily a research priority

The IOM committee sought advice from a broad range of stakeholders and prioritized areas for research. The top-ranked topic was comparison of treatment strategies for atrial fibrillation, including surgery, catheter ablation, and pharmacologic treatment. Coming in at #98 was comparison of the effectiveness of different treatment strategies (eg, psychotherapy, antidepressants, combination treatment with case management) for depression after MI and their impact on medication adherence, cardiovascular events, hospitalization, and death.

Reprinted, with permission, from Archives of Internal Medicine (Blumenthal JA, et al. Arch Intern Med 1999 Oct 25; 159:2349–2356), Copyright © 1999 American Medical Association. All rights reserved.

In a second Duke study that compared exercise and antidepressant medication,⁹² 202 adults (153 women; 49 men) diagnosed with MDD were randomly assigned to one of four groups: supervised exercise in a group setting, home-based exercise, antidepressant medication (sertraline, 50 to 200 mg daily), or placebo pill for 16 weeks. Once again, patients underwent the Structured Clinical Interview for Depression and completed the HAM-D. After 4 months of treatment, 41% of participants achieved remission, defined as no longer meeting criteria for MDD and a HAM-D score of less than 8 points. Patients receiving active treatments tended to have higher remission rates than placebo controls: supervised exercise, 45%; home-based exercise, 40%; medication, 47%; placebo, 31% (P = .057). All treatment groups had lower HAM-D scores after treatment; scores for the active treatment groups were not significantly different from the placebo group (P = .23). However, when immediate responders (ie, those patients who reported more than 50% reduction in depressive symptoms after only 1 week of treatment) were excluded from the analysis, patients receiving active treatments (ie, either sertraline or exercise) had greater reductions in depressive symptoms compared with placebo controls (P = .048). There was no difference between the exercise and antidepressant groups. We concluded that the efficacy of exercise appears generally comparable with antidepressant medication and both tend to be better than placebo in patients with MDD. Placebo response rates were high, suggesting that a considerable portion of the therapeutic response could be determined by patient expectations, ongoing symptom monitoring, attention, and other nonspecific factors. Similar to our previous trial, participants who continued to exercise following the completion of the program were less likely to be depressed.⁹³

Another RCT⁹⁴ also demonstrated that exercise was associated with reduced depression, independent of group support. Participants exercised alone in a secluded setting, and the study included a no-treatment control group. Only 53 of 80 patients actually completed the 12-week trial, however, including only five of 13 no-treatment controls. Moreover, there was no active treatment comparison group, so that an estimate of comparative effectiveness could not be determined.

While these results are preliminary and should be interpreted with caution, it appears that exercise may be comparable with conventional antidepressant medication in reducing depressive symptoms, at least for patients who are willing to try it, and maintenance of exercise reduces the risk of relapse.

SUMMARY

Three decades ago, we recognized that CR was a new frontier for behavioral medicine. We now know that successful rehabilitation of patients with CHD involves modification of lifestyle behaviors, including smoking cessation, dietary modification, and exercise. Exercise is no longer considered unsafe for most cardiac patients, and exercise is currently the key component of CR services. Research also has provided strong evidence that depression is an important risk factor for CHD, although there is no consensus regarding the optimal way to treat depression in CHD patients.⁹⁵ Research on comparative effectiveness of established and alternative treatments for depressed cardiac patients is a new frontier for future pioneers in heart-brain medicine.

I am fortunate to be the recipient of the 2010 Bakken Institute Pioneer Award and feel especially honored to have my work recognized in this way. When informed that I was this year’s recipient, it prompted me to reflect on the meaning of the term “pioneer,” and how it related to me.

WHAT IS A PIONEER?

According to Merriam-Webster’s Collegiate Dictionary, a pioneer is one who (a) ventures into unknown or unclaimed territory to settle; and (b) opens up new areas of thought, research, or development. One requirement for any pioneer is that there be a frontier to explore. Thirty years ago, my colleagues and I began our investigations into cardiac rehabilitation (CR), which at the time we considered to be a new frontier for behavioral medicine.¹

EXERCISE-BASED CARDIAC REHABILITATION

Historically, patients who suffered an acute myocardial infarction (AMI) were often discouraged from engaging in physical activity; patients were initially prescribed prolonged bed rest and told to avoid strenuous exercise.² In the early 1950s, armchair therapy was proposed³ as an initial attempt to mobilize patients after a coronary event. Over the years, the value of physical exercise has been increasingly recognized and exercise is now considered to be the cornerstone of CR.^4–7 Today, exercise-based CR, involving aerobic exercise supplemented by resistance training, is offered by virtually all CR programs in the United States.⁸ Proper medical management is also emphasized, along with dietary modification and smoking cessation, but exercise is the centerpiece of treatment.

Exercise has been shown to reduce traditional risk factors such as hypertension and hyperlipidemia,⁸ attenuate cardiovascular responses to mental stress,⁹ and reduce myocardial ischemia.^10–12 Although no single study has demonstrated definitively that exercise reduces morbidity in patients with coronary heart disease (CHD), pooling data across clinical trials has shown that exercise may reduce risk of fatal CHD events by 25%.¹³ A recent, comprehensive meta-analysis by Jolliffe et al¹⁴ reported a 27% reduction in all-cause mortality and 31% reduction in cardiac mortality.

Not only is exercise considered beneficial for medical outcomes, but is also recognized as an important factor in improved quality of life. Indeed, there has been increased interest in the value of exercise for improving not just physical health, but also mental health.^15–17 The mental health benefits of exercise are especially relevant for cardiac patients, as there is a growing literature documenting the importance of mental health, and, in particular the prognostic significance of depression, in patients with CHD.

PSYCHOSOCIAL RISK FACTORS: THE ROLE OF DEPRESSION IN CORONARY HEART DISEASE

There has long been an interest in psychosocial factors that contribute to the development and progression of CHD. More than three decades ago, researchers identified the type A behavior pattern as a risk factor for CHD.¹⁸ When subsequent studies failed to confirm the association of type A with adverse health outcomes, researchers turned their attention to other possible psychosocial risk factors, including anger and hostility,¹⁹ low social support,²⁰ and most recently, depression.²¹ Indeed, the most consistent and compelling evidence is that clinical depression or elevated depressive symptoms in the presence of CHD increase the risk of fatal and nonfatal cardiac events and of all-cause mortality.²²

Major depressive disorder (MDD) is a common and often chronic condition. Lifetime incidence estimates for MDD are approximately 12% in men and 20% in women.²³ In addition, MDD is marked by high rates of relapse, with 22% to 50% of patients suffering recurrent episodes within 6 months after recovery.²⁴ Furthermore, MDD is underrecognized and undertreated in older adults,²⁵ CHD patients, and, especially, minorities.^26–28

Cross-sectional studies have documented a higher prevalence of depression in CHD patients than in the general population. Point estimates range from 14% to as high as 47%, with higher rates recorded most often in patients with unstable angina, heart failure (HF), and patients awaiting coronary artery bypass graft (CABG) surgery.^29–36

Depression associated with poor outcomes

A number of prospective studies have found that depression is associated with increased risk for mortality or nonfatal cardiac events in a variety of CHD populations. The most compelling evidence for depression as a risk factor has come from studies in Montreal, Canada. Frasure-Smith and colleagues³¹ assessed the impact of depression in 222 AMI patients, of whom 35 were diagnosed with MDD at the time of hospitalization. There were 12 deaths (six depressed and six nondepressed) over an initial 6-month followup period, representing more than a fivefold increased risk of death for depressed patients compared with nondepressed patients (hazard ratio, 5.7; 95% confidence interval [CI], 4.6 to 6.9). In a subsequent report,³⁶ in which 896 AMI patients were followed for 1 year, the presence of elevated depressive symptoms was associated with more than a threefold increased risk in cardiac mortality after controlling for other multivariate predictors of mortality (odds ratio, 3.29 for women; 3.05 for men).

Studies of patients with stable CHD also have reported significant associations between the presence of depression and worse clinical outcomes. For example, Barefoot et al³⁷ assessed 1,250 patients with documented CHD using the Zung self-report depression scale at the time of diagnostic coronary angiography and followed patients for up to 19.4 years. Results showed that patients with moderate to severe depression were at 69% greater risk for cardiac death and 78% greater risk for all-cause death.

Reprinted from The Lancet (Blumenthal JA, et al. Depression as a risk factor for mortality after coronary artery bypass surgery. Lancet 2003; 362:604–609), copyright © 2003, with permission from Elsevier.

Depression and heart failure outcomes

Patients with HF represent a particularly vulnerable group; a meta-analysis of depression in HF patients suggested that one in five patients are clinically depressed (range, 9% to 60%).⁴¹ Not only is depression in HF patients associated with worse outcomes,^42–46 but recent evidence suggests that worsening of depressive symptoms, independent of clinical status, is related to worse outcomes. Sherwood et al⁴⁶ demonstrated that increased symptoms of depression, as indicated by higher scores on the Beck Depression Inventory (BDI) over a 1-year interval (BDI change [1-point] hazard ratio, 1.07; 95% CI, 1.02 to 1.12; P = .007), were associated with higher risk of death or cardiovascular hospitalization after controlling for baseline depression (baseline BDI hazard ratio, 1.1; 95% CI, 1.06 to 1.14, P < .001) and established risk factors, including HF etiology, age, ejection fraction, N-terminal pro-B-type natriuretic peptides, and prior hospitalizations. Consequently, strategies to reduce depressive symptoms and prevent the worsening of depression may have important implications for improving cardiac health as well as for enhancing quality of life.

CONVENTIONAL APPROACHES TO TREATMENT OF DEPRESSION

Treatment of depression has focused on reduction of symptoms and restoration of function. Antidepressant medications are generally considered the treatment of choice.⁵⁶ In particular, second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are widely prescribed.⁵⁷ Current treatment guidelines suggest 6 to 12 weeks of acute treatment followed by a continuation phase of 3 to 9 months to maintain therapeutic benefit.⁵⁸ However, meta-analyses of antidepressant medications have reported only modest benefits over placebo treatments.^59,60 In particular, active drug–placebo differences in antidepressant efficacy are positively correlated with depression severity: antidepressants are often comparable with placebo in patients with low levels of depression but may be superior to placebo among patients with more severe depression. However, the explanation for this relationship may be that placebo is less effective for more depressed patients rather than antidepressants being more effective for more depressed patients.⁵⁹

For acute treatment of MDD, approximately 60% of patients respond to second-generation antidepressants,⁶¹ with a 40% relapse rate after 1 year.⁶² A recent meta-analysis⁶⁰ of second-generation antidepressants summarized four comparative trials and 23 placebo-controlled trials and found that second-generation antidepressants were generally comparable with each other. Interestingly, despite the modest benefit of antidepressants, the percentage of patients treated for depression in the United States increased from 0.73% in 1987 to 2.33% in 1997. The proportion of those treated who received antidepressants increased from 37.3% in 1987 to 74.5% in 1997.⁶³ The percentage of treated outpatients who used antidepressants has not increased significantly since 1997, but the use of psycho therapy as a sole treatment declined from 53.6% in 1998 to 43.1% in 2007.⁶⁴ Moreover, the national expenditure for the outpatient treatment of depression increased from $10.05 billion in 1998 to $12.45 billion in 2007, primarily driven by an increase in expenditures for antidepressant medications.

Uncertainty about value of antidepressant therapy

Despite compelling reasons for treating depression in cardiac patients, the clinical significance of treating depression remains uncertain. To date, only the Enhancing Recovery in CHD Patients (ENRICHD) trial has examined the impact of treating depression in post-MI patients on “hard” clinical end points.⁶⁵ Although more than 2,400 patients were enrolled in the trial, the results were disappointing. There were only modest differences (ie, two points on the Hamilton Depression Rating Scale [HAM-D]) in reductions of depressive symptoms in the group receiving cognitive behavior therapy (CBT) relative to usual-care controls and there were no treatment group differences in the primary outcome—all-cause mortality and nonfatal cardiac events. By the end of the follow-up period, 28.0% of patients in the CBT group and 20.6% of patients in usual care had received antidepressant medication. Although a subsequent reanalysis of the ENRICHD study revealed that antidepressant use was associated with improved clinical outcomes,⁶⁶ because patients were not randomized to pharmacologic treatment it could not be concluded that SSRI use was responsible for the improved outcomes.

In a randomized trial of patients with acute coronary syndrome (the Sertraline Antidepressant Heart Attack Randomized Trial, or SADHART),⁶⁷ almost 400 patients were treated with the SSRI sertraline or with placebo. Reductions in depressive symptoms were similar for patients receiving sertraline compared with placebo in the full sample, although a subgroup analysis revealed that patients with more severe depression (ie, those patients who reported two or more previous episodes) benefited more from sertraline compared with placebo. Interestingly, patients receiving sertraline tended to have more favorable cardiac outcomes, including a composite measure of both “hard” and “soft” clinical events, compared with placebo controls. These results suggested that antidepressant medication may improve underlying physiologic processes, such as platelet function, independent of changes in depression.⁶⁸ However, because SADHART was not powered to detect differences in clinical events, there remain unanswered questions about the clinical value of treating depression in cardiac patients with antidepressant medication.

In a second sertraline trial, SADHART-HF,⁶⁹ 469 men and women with MDD and chronic systolic HF were randomized to receive either sertraline or placebo for 12 weeks. Participants were followed for a minimum of 6 months. Results showed that while sertraline was safe, its use did not result in greater reductions in depressive symptoms compared with placebo (−7.1 ± 0.5 vs −6.8 ± 0.5) and there were no differences in clinical event rates between patients receiving sertraline compared with those receiving placebo.

In an observational study of patients with HF,⁴⁴ use of antidepressant medication was associated with increased risk of mortality or hospitalization. Although the potential harmful effects of antidepressant medication could not be ruled out, a more likely interpretation is that antidepressant medication use was a marker for individuals with more severe depression, and that the underlying depression may have contributed to their higher risk. Further, patients who are depressed, despite receiving treatment, may represent a subset of treatment-resistant patients who may be especially vulnerable to further cardiac events. Indeed, worsening depression is associated with worse outcomes in HF patients⁴⁶; this is consistent with data from the ENRICHD trial, which showed that patients receiving CBT (and, in some cases, antidepressant medication) who failed to improve with treatment had higher mortality rates compared with patients who exhibited a positive response to treatment.⁷⁰

A fourth randomized trial of CHD patients, the Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy (CREATE) trial,⁷¹ used a modified “2 by 2” design; 284 CHD patients with MDD and HAM-D rating scores of 20 or greater were randomized to receive 12 weeks of (a) interpersonal therapy (IPT) plus clinical management (CM) or (b) CM only and citalopram or matching placebo. Because the same interventionists delivered the CM and IPT, patients assigned to IPT received IPT plus CM within the same (extended) session. Patients receiving citalopram had greater reductions in depressive symptoms compared with placebo, with a small to medium effect size of 0.33, and better remission rates (35.9%) compared with placebo (22.5%). Unexpectedly, patients who received just CM tended to have greater improvements in depressive symptoms compared with patients who received IPT plus CM (P < .07); no clinical CHD end points were assessed, however.

Alternative approaches needed

Taken together, these data illustrate that antidepressant medications may reduce depressive symptoms for some patients; for other patients, however, medication fails to adequately relieve depressive symptoms and may perform no better than placebo. Adverse effects also may affect a subgroup of patients and may be relatively more common or more problematic in older persons with CHD.⁷² Thus, a need remains to identify alternative approaches for treating depression in cardiac patients. We believe that aerobic exercise, the cornerstone of traditional CR, may be one such approach. Exercise is safe for most cardiac patients,^73,74 including patients with HF,⁷⁵ and, if proven effective as a treatment for depression, exercise would hold several potential advantages over traditional medical therapies: it is relatively inexpensive, improves cardiovascular functioning, and avoids the side effects sometimes associated with medication use.

Some studies of exercise treatment for CHD patients have tracked depressive symptoms and thus have provided information regarding the potential efficacy of exercise as a treatment for depression in this population.^{76 –81} Although most previous studies have reported significant improvements in depression after completion of an exercise program, many studies had important methodologic limitations, including the absence of a control group.

In one of the few controlled studies in this field, Stern et al⁸² randomized 106 male patients who had a recent history of AMI along with elevated depression and anxiety or low fitness to 12 weeks of exercise training, group therapy, or a usual-care control group. At 1-year followup, both the exercise and counseling groups showed improvements in depression relative to controls.

Cross-sectional studies of non-CHD samples have reported that active individuals obtain significantly lower depression scores on self-report measures than sedentary persons.⁸³ Studies also have shown that aerobic exercise may reduce self-reported depressive symptoms in nonclinical populations and in patients diagnosed with MDD.⁸³ In 2001, a meta-analysis evaluating 11 randomized controlled trials of non-CHD patients with MDD⁸⁴ noted that studies were limited because of self-selection bias, absence of control groups or nonrandom controls, and inadequate assessment of exercise training effects; the authors concluded that “the effectiveness of exercise in reducing symptoms of depression cannot be determined because of a lack of good quality research on clinical populations with adequate followup.”

Randomized controlled trials needed

A subsequent meta-analysis⁸⁵ included 25 studies; for 23 trials (907 participants) that compared exercise with no treatment or a control intervention, the pooled standardized mean difference (SMD) was −0.82 (95% CI, −1.12, −0.51), indicating a large effect size. However, when only the three trials (216 participants) with adequate allocation concealment, intention to treat analysis, and blinded outcome assessment were included, the pooled SMD was −0.43 (95% CI, −0.88, 0.03), with a point estimate that was half the size of that with all trials. As a result, the authors concluded that “exercise seems to improve depressive symptoms in people with a diagnosis of depression, but when only the methodologically robust trials are included, the effect size is only moderate.”

To date, no randomized clinical trials (RCTs) have examined the effects of exercise on clinical outcomes in depressed cardiac patients. However, data from the ENRICHD trial suggest that exercise may reduce the rates of mortality and nonfatal reinfarction in patients with depression or in post-MI patients who are socially isolated.⁸⁶ Self-report data were used to categorize participants as exercising regularly or not exercising regularly. After controlling for medical and demographic variables, the magnitude of reduction in risk associated with regular exercise was nearly 40% for nonfatal reinfarction and 50% for mortality. The evidence that exercise mitigates depression, reduces CHD risk factors, and improves CHD outcomes suggests that exercise may be a particularly promising intervention for depressed CHD patients.

COMPARATIVE EFFECTIVENESS OF EXERCISE AND ANTIDEPRESSANT MEDICATION

In 2008, an Institute of Medicine (IOM) report called for a national initiative of research that would provide a basis for better decision-making about how to best treat various medical conditions, including depression. In 2009, the American Reinvestment Recovery Act provided a major boost in funding for comparative effectiveness research (CER). The act allotted $1.1 billion to support this form of research. CER refers to the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition, or to improve the delivery of care. The purpose of CER is to assist consumers, clinicians, purchasers, and policy makers in reaching informed decisions that will improve health care at both the individual and population levels.⁸⁷

Two research categories inform decision-making

Two broad categories of research have been used to inform decision-making:

• Epidemiologic studies provide evidence linking various treatments with patient outcomes. These sources of data are limited because they seldom specify the basis for medical decisions and they fail to consider patient characteristics that affect both clinical decisions and clinical outcomes. Indeed, it has been suggested that “overcoming the limitations of observational research is the most important frontier of research on study methods.”⁸⁸
• RCTs address these limitations by randomly assigning patients to different treatment conditions. While this design may eliminate some of the uncertainty and potential confounders that characterize purely observational studies, most RCTs are efficacy studies; patients are carefully selected and a treatment is usually compared with a placebo or usual care.

The RCT design addresses the question of whether a given treatment is effective, but it does not necessarily address questions that many physicians want answers to: namely, is this treatment better than that treatment? Further, physicians want to know if one treatment is more effective than another for a given patient. For example, Hlatky et al⁸⁹ showed that mortality associated with percutaneous coronary interventions (PCIs) and CABG surgery was comparable; however, mortality with CABG surgery was significantly lower for patients older than 65 years while PCI was superior for patients younger than 55 years. Thus, examination of individual differences may also help to inform clinicians about the optimal therapy for their particular patients.

 

 

Treatment of depression not necessarily a research priority

The IOM committee sought advice from a broad range of stakeholders and prioritized areas for research. The top-ranked topic was comparison of treatment strategies for atrial fibrillation, including surgery, catheter ablation, and pharmacologic treatment. Coming in at #98 was comparison of the effectiveness of different treatment strategies (eg, psychotherapy, antidepressants, combination treatment with case management) for depression after MI and their impact on medication adherence, cardiovascular events, hospitalization, and death.

Reprinted, with permission, from Archives of Internal Medicine (Blumenthal JA, et al. Arch Intern Med 1999 Oct 25; 159:2349–2356), Copyright © 1999 American Medical Association. All rights reserved.

In a second Duke study that compared exercise and antidepressant medication,⁹² 202 adults (153 women; 49 men) diagnosed with MDD were randomly assigned to one of four groups: supervised exercise in a group setting, home-based exercise, antidepressant medication (sertraline, 50 to 200 mg daily), or placebo pill for 16 weeks. Once again, patients underwent the Structured Clinical Interview for Depression and completed the HAM-D. After 4 months of treatment, 41% of participants achieved remission, defined as no longer meeting criteria for MDD and a HAM-D score of less than 8 points. Patients receiving active treatments tended to have higher remission rates than placebo controls: supervised exercise, 45%; home-based exercise, 40%; medication, 47%; placebo, 31% (P = .057). All treatment groups had lower HAM-D scores after treatment; scores for the active treatment groups were not significantly different from the placebo group (P = .23). However, when immediate responders (ie, those patients who reported more than 50% reduction in depressive symptoms after only 1 week of treatment) were excluded from the analysis, patients receiving active treatments (ie, either sertraline or exercise) had greater reductions in depressive symptoms compared with placebo controls (P = .048). There was no difference between the exercise and antidepressant groups. We concluded that the efficacy of exercise appears generally comparable with antidepressant medication and both tend to be better than placebo in patients with MDD. Placebo response rates were high, suggesting that a considerable portion of the therapeutic response could be determined by patient expectations, ongoing symptom monitoring, attention, and other nonspecific factors. Similar to our previous trial, participants who continued to exercise following the completion of the program were less likely to be depressed.⁹³

Another RCT⁹⁴ also demonstrated that exercise was associated with reduced depression, independent of group support. Participants exercised alone in a secluded setting, and the study included a no-treatment control group. Only 53 of 80 patients actually completed the 12-week trial, however, including only five of 13 no-treatment controls. Moreover, there was no active treatment comparison group, so that an estimate of comparative effectiveness could not be determined.

While these results are preliminary and should be interpreted with caution, it appears that exercise may be comparable with conventional antidepressant medication in reducing depressive symptoms, at least for patients who are willing to try it, and maintenance of exercise reduces the risk of relapse.

SUMMARY

Three decades ago, we recognized that CR was a new frontier for behavioral medicine. We now know that successful rehabilitation of patients with CHD involves modification of lifestyle behaviors, including smoking cessation, dietary modification, and exercise. Exercise is no longer considered unsafe for most cardiac patients, and exercise is currently the key component of CR services. Research also has provided strong evidence that depression is an important risk factor for CHD, although there is no consensus regarding the optimal way to treat depression in CHD patients.⁹⁵ Research on comparative effectiveness of established and alternative treatments for depressed cardiac patients is a new frontier for future pioneers in heart-brain medicine.

The associations among depression, cardiovascular disease, and cognitive impairment are well known. Inflammation is increasingly recognized as playing an important role as well. However, the nature of their relationships and which may actually cause the other is not well understood. This article reviews studies over the past year that link depression with dementia and vascular disease. Desirable directions for future work are also explored.

DEPRESSION AND ALZHEIMER DISEASE

Several studies have shown significant correlations between depression and the risk of developing Alzheimer disease; the frequency of depressive episodes appears to be an important factor. Despite the risk relationship, however, depression and Alzheimer disease may not share a common pathology.

No shared pathology

Wilson and colleagues¹ analyzed data from the Chicago Health and Aging Project, a longitudinal cohort study of risk factors for Alzheimer disease that involved two groups of people aged 65 years and older; one group was composed of people who developed dementia during the study, while the other group had already developed dementia or had some degree of cognitive impairment. The investigators reasoned that if pathologic changes are common to depression and dementia, then there would be evidence of change in depressive symptoms along with the progression of dementia. They found only a barely perceptible increase in depressive symptoms among people who developed Alzheimer disease and concluded that there is no shared pathology between depression and Alzheimer disease.

Degree of depression signals risk

Depression has been associated with nearly double the risk of developing dementia and Alzheimer disease. Saczynski et al² evaluated 949 people in the Framingham study, mean age 79 years, using the 60-point Center for Epidemiologic Studies Depression Scale (depression defined as > 16 points). Individuals who had depression at baseline were 1.7 times more likely to develop dementia over the 17-year evaluation period. Results were similar when adjusted for major vascular risk factors (smoking, diabetes, hypertension, and cardiovascular disease). The correlation was slightly lower but still significant when subjects taking antidepressant medications were included in the depressed group.

The study also found a continuous relationship between the level of depression and the likelihood of developing dementia and Alzheimer disease: for every 10-point increase on the depression scale, the risk of developing dementia increased by nearly 50%. This study supports depression as a risk factor for dementia. One could also argue that depression as a simple prodrome to dementia seems unlikely because of the long followup between baseline assessment and the development of dementia.

Multiple episodes of depression increase risk

Dotson et al³ analyzed data from 1,239 older adults from the Baltimore Longitudinal Study of Aging who did not have depression, dementia, or mild cognitive impairment at baseline. Every 1 to 2 years for about 25 years, cognitive status and mood of the subjects were evaluated. About 10% of the participants developed dementia during the course of the study. Of those who developed dementia, 35% had at least one episode of depression; among those who did not develop dementia, only 23% had a depressive episode. Findings were similar when investigators controlled for vascular risks and vascular dementia.

One episode of depression was associated with an 87% increase in risk of dementia; at least two episodes of depression more than doubled the risk (108%). Overall, each episode of depression conferred an additional 14% risk of developing dementia. Among subjects who had had two or more episodes of depression, the median age of developing dementia was 85 years versus 95 years for those without an episode of depression.

This study had the advantages of being prospective for both depression and dementia and of having a long followup period. A dose-effect relationship was observed, with the “dose” being the number of depressive episodes (rather than severity of depression). Because the definition of a depressive episode included subsyndromal depression (not likely to meet the criteria of clinical depression, but still clinically significant), the findings suggest that even minor depression increases the risk of dementia.

 

 

Baseline depression predicts cognitive impairment

Rosenberg et al⁴ found depression to be associated with cognitive impairment in their evaluation of 436 women in their 70s; the women, who were participants in the Women’s Health and Aging Study, were evaluated for up to 9 years. To be included in the evaluation, subjects needed a Mini-Mental State Examination score of at least 24 points (out of 30 possible) and could not be impaired in more than one basic functional capacity: mobility and exercise tolerance, upper extremity, higher functioning (eg, shopping), and basic self-care). Baseline depressive symptoms were measured using the Geriatric Depression Scale.

Cognitive testing included Hopkins Verbal Learning Tests (for immediate and delayed word recall) and Trail Making Tests (for psychomotor speed and executive functioning). Those who were not impaired (ie, having a cognitive test score below the 10th percentile for age-adjusted norms) were followed with up to six examinations over the next 9 years.

Baseline depression was found to be highly associated with incident impairment in all cognitive areas, especially in executive functioning. For every point increase in the depression scale, a 6% to 7% increase was found in the annual risk of impairment in each cognitive domain.

DEPRESSION AND VASCULAR DISEASE LINKED

It is somewhat easier to assess the relationship between depression and vascular disease than between depression and cognitive impairment because of the availability of objective measures of cardiovascular function.

The International Stroke Study (INTERSTROKE),⁵ a case-control study in 22 countries with 3,000 cases of stroke and 3,000 age-, gender-, and ethnicity-matched controls, found nine risk factors that were correlated with 90% of ischemic stroke cases. Depression, with an odds ratio of 1.86, was found to be a more significant risk factor than physical activity, diet, or heavy drinking.

Paranthaman et al⁶ evaluated a number of measures of arterial anatomy and function in 25 subjects with depressive disorder and in 21 nondepressed controls (mean age, 72 years). They found that depressed subjects had significantly higher mean carotid intima media thickness, reduced dilation in response to acetyl choline in preconstricted small arteries, and more dilated Virchow-Robin spaces in the basal ganglia observed on magnetic resonance imaging. This study provides evidence that arterial structure and function may mediate the relationship between depression and vascular disease.

FUTURE DIRECTIONS

Future studies into depression as a risk factor should use very well-characterized cohorts that are controlled for blood pressure and other vascular risk factors. Finding biomarkers for depression would be useful, permitting its detection earlier and with more certainty than is now possible. Prospective studies to evaluate the relationship of depression to cognitive impairment and dementia are needed that start earlier than in middle or old age. The key question that needs study is whether treatment of depression can actually change the onset of cognitive impairment, Alzheimer disease, and vascular disease.

The associations among depression, cardiovascular disease, and cognitive impairment are well known. Inflammation is increasingly recognized as playing an important role as well. However, the nature of their relationships and which may actually cause the other is not well understood. This article reviews studies over the past year that link depression with dementia and vascular disease. Desirable directions for future work are also explored.

DEPRESSION AND ALZHEIMER DISEASE

Several studies have shown significant correlations between depression and the risk of developing Alzheimer disease; the frequency of depressive episodes appears to be an important factor. Despite the risk relationship, however, depression and Alzheimer disease may not share a common pathology.

No shared pathology

Wilson and colleagues¹ analyzed data from the Chicago Health and Aging Project, a longitudinal cohort study of risk factors for Alzheimer disease that involved two groups of people aged 65 years and older; one group was composed of people who developed dementia during the study, while the other group had already developed dementia or had some degree of cognitive impairment. The investigators reasoned that if pathologic changes are common to depression and dementia, then there would be evidence of change in depressive symptoms along with the progression of dementia. They found only a barely perceptible increase in depressive symptoms among people who developed Alzheimer disease and concluded that there is no shared pathology between depression and Alzheimer disease.

Degree of depression signals risk

Depression has been associated with nearly double the risk of developing dementia and Alzheimer disease. Saczynski et al² evaluated 949 people in the Framingham study, mean age 79 years, using the 60-point Center for Epidemiologic Studies Depression Scale (depression defined as > 16 points). Individuals who had depression at baseline were 1.7 times more likely to develop dementia over the 17-year evaluation period. Results were similar when adjusted for major vascular risk factors (smoking, diabetes, hypertension, and cardiovascular disease). The correlation was slightly lower but still significant when subjects taking antidepressant medications were included in the depressed group.

The study also found a continuous relationship between the level of depression and the likelihood of developing dementia and Alzheimer disease: for every 10-point increase on the depression scale, the risk of developing dementia increased by nearly 50%. This study supports depression as a risk factor for dementia. One could also argue that depression as a simple prodrome to dementia seems unlikely because of the long followup between baseline assessment and the development of dementia.

Multiple episodes of depression increase risk

Dotson et al³ analyzed data from 1,239 older adults from the Baltimore Longitudinal Study of Aging who did not have depression, dementia, or mild cognitive impairment at baseline. Every 1 to 2 years for about 25 years, cognitive status and mood of the subjects were evaluated. About 10% of the participants developed dementia during the course of the study. Of those who developed dementia, 35% had at least one episode of depression; among those who did not develop dementia, only 23% had a depressive episode. Findings were similar when investigators controlled for vascular risks and vascular dementia.

One episode of depression was associated with an 87% increase in risk of dementia; at least two episodes of depression more than doubled the risk (108%). Overall, each episode of depression conferred an additional 14% risk of developing dementia. Among subjects who had had two or more episodes of depression, the median age of developing dementia was 85 years versus 95 years for those without an episode of depression.

This study had the advantages of being prospective for both depression and dementia and of having a long followup period. A dose-effect relationship was observed, with the “dose” being the number of depressive episodes (rather than severity of depression). Because the definition of a depressive episode included subsyndromal depression (not likely to meet the criteria of clinical depression, but still clinically significant), the findings suggest that even minor depression increases the risk of dementia.

 

 

Baseline depression predicts cognitive impairment

Rosenberg et al⁴ found depression to be associated with cognitive impairment in their evaluation of 436 women in their 70s; the women, who were participants in the Women’s Health and Aging Study, were evaluated for up to 9 years. To be included in the evaluation, subjects needed a Mini-Mental State Examination score of at least 24 points (out of 30 possible) and could not be impaired in more than one basic functional capacity: mobility and exercise tolerance, upper extremity, higher functioning (eg, shopping), and basic self-care). Baseline depressive symptoms were measured using the Geriatric Depression Scale.

Cognitive testing included Hopkins Verbal Learning Tests (for immediate and delayed word recall) and Trail Making Tests (for psychomotor speed and executive functioning). Those who were not impaired (ie, having a cognitive test score below the 10th percentile for age-adjusted norms) were followed with up to six examinations over the next 9 years.

Baseline depression was found to be highly associated with incident impairment in all cognitive areas, especially in executive functioning. For every point increase in the depression scale, a 6% to 7% increase was found in the annual risk of impairment in each cognitive domain.

DEPRESSION AND VASCULAR DISEASE LINKED

It is somewhat easier to assess the relationship between depression and vascular disease than between depression and cognitive impairment because of the availability of objective measures of cardiovascular function.

The International Stroke Study (INTERSTROKE),⁵ a case-control study in 22 countries with 3,000 cases of stroke and 3,000 age-, gender-, and ethnicity-matched controls, found nine risk factors that were correlated with 90% of ischemic stroke cases. Depression, with an odds ratio of 1.86, was found to be a more significant risk factor than physical activity, diet, or heavy drinking.

Paranthaman et al⁶ evaluated a number of measures of arterial anatomy and function in 25 subjects with depressive disorder and in 21 nondepressed controls (mean age, 72 years). They found that depressed subjects had significantly higher mean carotid intima media thickness, reduced dilation in response to acetyl choline in preconstricted small arteries, and more dilated Virchow-Robin spaces in the basal ganglia observed on magnetic resonance imaging. This study provides evidence that arterial structure and function may mediate the relationship between depression and vascular disease.

FUTURE DIRECTIONS

Future studies into depression as a risk factor should use very well-characterized cohorts that are controlled for blood pressure and other vascular risk factors. Finding biomarkers for depression would be useful, permitting its detection earlier and with more certainty than is now possible. Prospective studies to evaluate the relationship of depression to cognitive impairment and dementia are needed that start earlier than in middle or old age. The key question that needs study is whether treatment of depression can actually change the onset of cognitive impairment, Alzheimer disease, and vascular disease.

The associations among depression, cardiovascular disease, and cognitive impairment are well known. Inflammation is increasingly recognized as playing an important role as well. However, the nature of their relationships and which may actually cause the other is not well understood. This article reviews studies over the past year that link depression with dementia and vascular disease. Desirable directions for future work are also explored.

DEPRESSION AND ALZHEIMER DISEASE

Several studies have shown significant correlations between depression and the risk of developing Alzheimer disease; the frequency of depressive episodes appears to be an important factor. Despite the risk relationship, however, depression and Alzheimer disease may not share a common pathology.

No shared pathology

Wilson and colleagues¹ analyzed data from the Chicago Health and Aging Project, a longitudinal cohort study of risk factors for Alzheimer disease that involved two groups of people aged 65 years and older; one group was composed of people who developed dementia during the study, while the other group had already developed dementia or had some degree of cognitive impairment. The investigators reasoned that if pathologic changes are common to depression and dementia, then there would be evidence of change in depressive symptoms along with the progression of dementia. They found only a barely perceptible increase in depressive symptoms among people who developed Alzheimer disease and concluded that there is no shared pathology between depression and Alzheimer disease.

Degree of depression signals risk

Depression has been associated with nearly double the risk of developing dementia and Alzheimer disease. Saczynski et al² evaluated 949 people in the Framingham study, mean age 79 years, using the 60-point Center for Epidemiologic Studies Depression Scale (depression defined as > 16 points). Individuals who had depression at baseline were 1.7 times more likely to develop dementia over the 17-year evaluation period. Results were similar when adjusted for major vascular risk factors (smoking, diabetes, hypertension, and cardiovascular disease). The correlation was slightly lower but still significant when subjects taking antidepressant medications were included in the depressed group.

The study also found a continuous relationship between the level of depression and the likelihood of developing dementia and Alzheimer disease: for every 10-point increase on the depression scale, the risk of developing dementia increased by nearly 50%. This study supports depression as a risk factor for dementia. One could also argue that depression as a simple prodrome to dementia seems unlikely because of the long followup between baseline assessment and the development of dementia.

Multiple episodes of depression increase risk

Dotson et al³ analyzed data from 1,239 older adults from the Baltimore Longitudinal Study of Aging who did not have depression, dementia, or mild cognitive impairment at baseline. Every 1 to 2 years for about 25 years, cognitive status and mood of the subjects were evaluated. About 10% of the participants developed dementia during the course of the study. Of those who developed dementia, 35% had at least one episode of depression; among those who did not develop dementia, only 23% had a depressive episode. Findings were similar when investigators controlled for vascular risks and vascular dementia.

One episode of depression was associated with an 87% increase in risk of dementia; at least two episodes of depression more than doubled the risk (108%). Overall, each episode of depression conferred an additional 14% risk of developing dementia. Among subjects who had had two or more episodes of depression, the median age of developing dementia was 85 years versus 95 years for those without an episode of depression.

This study had the advantages of being prospective for both depression and dementia and of having a long followup period. A dose-effect relationship was observed, with the “dose” being the number of depressive episodes (rather than severity of depression). Because the definition of a depressive episode included subsyndromal depression (not likely to meet the criteria of clinical depression, but still clinically significant), the findings suggest that even minor depression increases the risk of dementia.

 

 

Baseline depression predicts cognitive impairment

Rosenberg et al⁴ found depression to be associated with cognitive impairment in their evaluation of 436 women in their 70s; the women, who were participants in the Women’s Health and Aging Study, were evaluated for up to 9 years. To be included in the evaluation, subjects needed a Mini-Mental State Examination score of at least 24 points (out of 30 possible) and could not be impaired in more than one basic functional capacity: mobility and exercise tolerance, upper extremity, higher functioning (eg, shopping), and basic self-care). Baseline depressive symptoms were measured using the Geriatric Depression Scale.

Cognitive testing included Hopkins Verbal Learning Tests (for immediate and delayed word recall) and Trail Making Tests (for psychomotor speed and executive functioning). Those who were not impaired (ie, having a cognitive test score below the 10th percentile for age-adjusted norms) were followed with up to six examinations over the next 9 years.

Baseline depression was found to be highly associated with incident impairment in all cognitive areas, especially in executive functioning. For every point increase in the depression scale, a 6% to 7% increase was found in the annual risk of impairment in each cognitive domain.

DEPRESSION AND VASCULAR DISEASE LINKED

It is somewhat easier to assess the relationship between depression and vascular disease than between depression and cognitive impairment because of the availability of objective measures of cardiovascular function.

The International Stroke Study (INTERSTROKE),⁵ a case-control study in 22 countries with 3,000 cases of stroke and 3,000 age-, gender-, and ethnicity-matched controls, found nine risk factors that were correlated with 90% of ischemic stroke cases. Depression, with an odds ratio of 1.86, was found to be a more significant risk factor than physical activity, diet, or heavy drinking.

Paranthaman et al⁶ evaluated a number of measures of arterial anatomy and function in 25 subjects with depressive disorder and in 21 nondepressed controls (mean age, 72 years). They found that depressed subjects had significantly higher mean carotid intima media thickness, reduced dilation in response to acetyl choline in preconstricted small arteries, and more dilated Virchow-Robin spaces in the basal ganglia observed on magnetic resonance imaging. This study provides evidence that arterial structure and function may mediate the relationship between depression and vascular disease.

FUTURE DIRECTIONS

Future studies into depression as a risk factor should use very well-characterized cohorts that are controlled for blood pressure and other vascular risk factors. Finding biomarkers for depression would be useful, permitting its detection earlier and with more certainty than is now possible. Prospective studies to evaluate the relationship of depression to cognitive impairment and dementia are needed that start earlier than in middle or old age. The key question that needs study is whether treatment of depression can actually change the onset of cognitive impairment, Alzheimer disease, and vascular disease.

The relationships among inflammation, Alzheimer disease, and depression have been the subject of recent research at several centers. Alzheimer disease and depression appear to be linked by several genetic and inflammatory processes, although the exact nature of the relationship is not clearly understood. The two disorders also share risk factors for vascular disease. This article reviews the current state of knowledge about inflammation and its implications for Alzheimer disease and depression, and it presents recent findings from the Texas Alzheimer’s Research Consortium, which assessed an array of inflammatory markers in a cohort of patients with Alzheimer disease.

INFLAMMATION MAY MEDIATE DEPRESSION, COGNITIVE DECLINE, AND DEMENTIA

Alzheimer disease and depression share several vascular disease risk factors and appear to be linked through complex and integrated processes. The link may be mediated by long-term inflammatory processes. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction, chronic inflammation, and a deficit in neurotrophin signaling all may play roles in the pathogenesis of depression and Alzheimer disease.¹ Excessive release of glucocorticoids subsequent to HPA-axis dysfunction in chronic depression appears to damage the hippocampus: hippocampal atrophy is a feature in both depression and dementia, and recurrent depression is associated with greater atrophy. The direction of influence—whether depression leads to the factors that increase the risk of Alzheimer disease or the other way around—remains a controversial topic.

Symptoms of depression tend to appear early in Alzheimer disease and increase as dementia progresses to moderate severity. In advanced dementia, depression symptoms tend to decline, although this may reflect the difficulty in assessing depression at advanced stages of dementia.²

Numerous reports have linked inflammation to cognitive dysfunction or decline, as well as to the development of Alzheimer disease.^3–5 Evidence suggests that inflammation is a key mediator between cardiovascular risk factors and Alzheimer disease, although this is also still controversial.

FINDINGS FROM THE TEXAS ALZHEIMER’S RESEARCH CONSORTIUM

The Texas Alzheimer’s Research Consortium, composed of five medical centers, is pursuing a longitudinal, multi-institutional study of Alzheimer disease. The group recently published the results of a study assessing whether inflammatory markers were over- or underexpressed in patients with Alzheimer disease, and whether biomarkers could predict Alzheimer disease status and the age at onset of the disease.⁴ The analysis included 197 patients with Alzheimer disease and 203 control subjects. The evaluation consisted of cognitive assessment, DNA analysis for human genome-wide association studies, and protein microarray analysis from blood. Cardiovascular risk factors were also measured, including serum lipids and blood factors for diabetes risk. The goal was to better understand the pathophysiology of cognitive decline and predict conversion of mild cognitive impairment to Alzheimer disease.

Significant differences were found in the study groups. For example, the median age in the Alzheimer group was significantly higher than in controls (79 vs 70 years, P < .0001), an issue that is being addressed as subjects are replaced due to attrition. The median educational level was higher in the control group (14 vs 16 years, P < .0001) than in the Alzheimer group. Subjects in the Alzheimer group were significantly more likely (P < .001) to carry at least one copy of the APOE ε4 allele.

 

 

Inflammation is associated with Alzheimer disease

Degree of inflammation also correlated with Mini-Mental State Examination (MMSE) scores. Subjects with a high inflammatory score had a more accelerated decline in MMSE scores over a 3-year period than those with a low inflammatory score. The association was significant, although not as dramatic as the association between inflammation and age at onset of Alzheimer disease.

The investigators concluded that their findings, while considered preliminary, suggest the existence of an inflammatory endophenotype associated with Alzheimer disease. The findings need to be validated in other populations, including ethnic groups other than Caucasian. The Consortium also will evaluate whether inflammatory biomarkers are associated with progression of mild cognitive impairment to Alzheimer disease.

Inflammation has a mixed association with depression

In a study whose results are not yet published, the Texas Consortium also examined the association between inflammatory markers and depression. Four subscales of depression were used, derived from the Geriatric Depression Scale (GDS) 30: dysphoria (consisting of 11 items), meaninglessness (seven items), apathy and withdrawal (six items), and cognitive impairment (six items).⁵

The GDS30 results as a whole suggested a trend toward an association between depression and inflammatory biomarkers, but the association was not significant. When the results were examined by subscale, however, striking differences were found between Alzheimer patients and the control group. For example, apathy was significantly associated with the C-reactive protein level, and the assocation was much stronger in patients with Alzheimer disease than in controls. Further, the association of apathy with C-reactive protein level was more significant in women than in men.

Other associations were found between several of the inflammatory and antiinflammatory cytokines and the various subscales; the relationship between inflammatory factors and depression appears to be complex and often gender-specific.

Inflammation-depression link is suggestive, not linear

Despite the relationships suggested by the data, no simple linear relationship was identified to indicate that more inflammation leads to more depression in Alzheimer disease. The relationship between inflammation and depression in Alzheimer disease appears to involve a complex interplay between many physiologic processes.

The effect of inflammation also varies with gender and with cognitive impairment. The mechanism that underlies these relationships remains to be determined and will be the focus of further studies with the Texas Alzheimer’s Research Consortium.

The relationships among inflammation, Alzheimer disease, and depression have been the subject of recent research at several centers. Alzheimer disease and depression appear to be linked by several genetic and inflammatory processes, although the exact nature of the relationship is not clearly understood. The two disorders also share risk factors for vascular disease. This article reviews the current state of knowledge about inflammation and its implications for Alzheimer disease and depression, and it presents recent findings from the Texas Alzheimer’s Research Consortium, which assessed an array of inflammatory markers in a cohort of patients with Alzheimer disease.

INFLAMMATION MAY MEDIATE DEPRESSION, COGNITIVE DECLINE, AND DEMENTIA

Alzheimer disease and depression share several vascular disease risk factors and appear to be linked through complex and integrated processes. The link may be mediated by long-term inflammatory processes. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction, chronic inflammation, and a deficit in neurotrophin signaling all may play roles in the pathogenesis of depression and Alzheimer disease.¹ Excessive release of glucocorticoids subsequent to HPA-axis dysfunction in chronic depression appears to damage the hippocampus: hippocampal atrophy is a feature in both depression and dementia, and recurrent depression is associated with greater atrophy. The direction of influence—whether depression leads to the factors that increase the risk of Alzheimer disease or the other way around—remains a controversial topic.

Symptoms of depression tend to appear early in Alzheimer disease and increase as dementia progresses to moderate severity. In advanced dementia, depression symptoms tend to decline, although this may reflect the difficulty in assessing depression at advanced stages of dementia.²

Numerous reports have linked inflammation to cognitive dysfunction or decline, as well as to the development of Alzheimer disease.^3–5 Evidence suggests that inflammation is a key mediator between cardiovascular risk factors and Alzheimer disease, although this is also still controversial.

FINDINGS FROM THE TEXAS ALZHEIMER’S RESEARCH CONSORTIUM

The Texas Alzheimer’s Research Consortium, composed of five medical centers, is pursuing a longitudinal, multi-institutional study of Alzheimer disease. The group recently published the results of a study assessing whether inflammatory markers were over- or underexpressed in patients with Alzheimer disease, and whether biomarkers could predict Alzheimer disease status and the age at onset of the disease.⁴ The analysis included 197 patients with Alzheimer disease and 203 control subjects. The evaluation consisted of cognitive assessment, DNA analysis for human genome-wide association studies, and protein microarray analysis from blood. Cardiovascular risk factors were also measured, including serum lipids and blood factors for diabetes risk. The goal was to better understand the pathophysiology of cognitive decline and predict conversion of mild cognitive impairment to Alzheimer disease.

Significant differences were found in the study groups. For example, the median age in the Alzheimer group was significantly higher than in controls (79 vs 70 years, P < .0001), an issue that is being addressed as subjects are replaced due to attrition. The median educational level was higher in the control group (14 vs 16 years, P < .0001) than in the Alzheimer group. Subjects in the Alzheimer group were significantly more likely (P < .001) to carry at least one copy of the APOE ε4 allele.

 

 

Inflammation is associated with Alzheimer disease

Degree of inflammation also correlated with Mini-Mental State Examination (MMSE) scores. Subjects with a high inflammatory score had a more accelerated decline in MMSE scores over a 3-year period than those with a low inflammatory score. The association was significant, although not as dramatic as the association between inflammation and age at onset of Alzheimer disease.

The investigators concluded that their findings, while considered preliminary, suggest the existence of an inflammatory endophenotype associated with Alzheimer disease. The findings need to be validated in other populations, including ethnic groups other than Caucasian. The Consortium also will evaluate whether inflammatory biomarkers are associated with progression of mild cognitive impairment to Alzheimer disease.

Inflammation has a mixed association with depression

In a study whose results are not yet published, the Texas Consortium also examined the association between inflammatory markers and depression. Four subscales of depression were used, derived from the Geriatric Depression Scale (GDS) 30: dysphoria (consisting of 11 items), meaninglessness (seven items), apathy and withdrawal (six items), and cognitive impairment (six items).⁵

The GDS30 results as a whole suggested a trend toward an association between depression and inflammatory biomarkers, but the association was not significant. When the results were examined by subscale, however, striking differences were found between Alzheimer patients and the control group. For example, apathy was significantly associated with the C-reactive protein level, and the assocation was much stronger in patients with Alzheimer disease than in controls. Further, the association of apathy with C-reactive protein level was more significant in women than in men.

Other associations were found between several of the inflammatory and antiinflammatory cytokines and the various subscales; the relationship between inflammatory factors and depression appears to be complex and often gender-specific.

Inflammation-depression link is suggestive, not linear

Despite the relationships suggested by the data, no simple linear relationship was identified to indicate that more inflammation leads to more depression in Alzheimer disease. The relationship between inflammation and depression in Alzheimer disease appears to involve a complex interplay between many physiologic processes.

The effect of inflammation also varies with gender and with cognitive impairment. The mechanism that underlies these relationships remains to be determined and will be the focus of further studies with the Texas Alzheimer’s Research Consortium.

The relationships among inflammation, Alzheimer disease, and depression have been the subject of recent research at several centers. Alzheimer disease and depression appear to be linked by several genetic and inflammatory processes, although the exact nature of the relationship is not clearly understood. The two disorders also share risk factors for vascular disease. This article reviews the current state of knowledge about inflammation and its implications for Alzheimer disease and depression, and it presents recent findings from the Texas Alzheimer’s Research Consortium, which assessed an array of inflammatory markers in a cohort of patients with Alzheimer disease.

INFLAMMATION MAY MEDIATE DEPRESSION, COGNITIVE DECLINE, AND DEMENTIA

Alzheimer disease and depression share several vascular disease risk factors and appear to be linked through complex and integrated processes. The link may be mediated by long-term inflammatory processes. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction, chronic inflammation, and a deficit in neurotrophin signaling all may play roles in the pathogenesis of depression and Alzheimer disease.¹ Excessive release of glucocorticoids subsequent to HPA-axis dysfunction in chronic depression appears to damage the hippocampus: hippocampal atrophy is a feature in both depression and dementia, and recurrent depression is associated with greater atrophy. The direction of influence—whether depression leads to the factors that increase the risk of Alzheimer disease or the other way around—remains a controversial topic.

Symptoms of depression tend to appear early in Alzheimer disease and increase as dementia progresses to moderate severity. In advanced dementia, depression symptoms tend to decline, although this may reflect the difficulty in assessing depression at advanced stages of dementia.²

Numerous reports have linked inflammation to cognitive dysfunction or decline, as well as to the development of Alzheimer disease.^3–5 Evidence suggests that inflammation is a key mediator between cardiovascular risk factors and Alzheimer disease, although this is also still controversial.

FINDINGS FROM THE TEXAS ALZHEIMER’S RESEARCH CONSORTIUM

The Texas Alzheimer’s Research Consortium, composed of five medical centers, is pursuing a longitudinal, multi-institutional study of Alzheimer disease. The group recently published the results of a study assessing whether inflammatory markers were over- or underexpressed in patients with Alzheimer disease, and whether biomarkers could predict Alzheimer disease status and the age at onset of the disease.⁴ The analysis included 197 patients with Alzheimer disease and 203 control subjects. The evaluation consisted of cognitive assessment, DNA analysis for human genome-wide association studies, and protein microarray analysis from blood. Cardiovascular risk factors were also measured, including serum lipids and blood factors for diabetes risk. The goal was to better understand the pathophysiology of cognitive decline and predict conversion of mild cognitive impairment to Alzheimer disease.

Significant differences were found in the study groups. For example, the median age in the Alzheimer group was significantly higher than in controls (79 vs 70 years, P < .0001), an issue that is being addressed as subjects are replaced due to attrition. The median educational level was higher in the control group (14 vs 16 years, P < .0001) than in the Alzheimer group. Subjects in the Alzheimer group were significantly more likely (P < .001) to carry at least one copy of the APOE ε4 allele.

 

 

Inflammation is associated with Alzheimer disease

Degree of inflammation also correlated with Mini-Mental State Examination (MMSE) scores. Subjects with a high inflammatory score had a more accelerated decline in MMSE scores over a 3-year period than those with a low inflammatory score. The association was significant, although not as dramatic as the association between inflammation and age at onset of Alzheimer disease.

The investigators concluded that their findings, while considered preliminary, suggest the existence of an inflammatory endophenotype associated with Alzheimer disease. The findings need to be validated in other populations, including ethnic groups other than Caucasian. The Consortium also will evaluate whether inflammatory biomarkers are associated with progression of mild cognitive impairment to Alzheimer disease.

Inflammation has a mixed association with depression

In a study whose results are not yet published, the Texas Consortium also examined the association between inflammatory markers and depression. Four subscales of depression were used, derived from the Geriatric Depression Scale (GDS) 30: dysphoria (consisting of 11 items), meaninglessness (seven items), apathy and withdrawal (six items), and cognitive impairment (six items).⁵

The GDS30 results as a whole suggested a trend toward an association between depression and inflammatory biomarkers, but the association was not significant. When the results were examined by subscale, however, striking differences were found between Alzheimer patients and the control group. For example, apathy was significantly associated with the C-reactive protein level, and the assocation was much stronger in patients with Alzheimer disease than in controls. Further, the association of apathy with C-reactive protein level was more significant in women than in men.

Other associations were found between several of the inflammatory and antiinflammatory cytokines and the various subscales; the relationship between inflammatory factors and depression appears to be complex and often gender-specific.

Inflammation-depression link is suggestive, not linear

Despite the relationships suggested by the data, no simple linear relationship was identified to indicate that more inflammation leads to more depression in Alzheimer disease. The relationship between inflammation and depression in Alzheimer disease appears to involve a complex interplay between many physiologic processes.

The effect of inflammation also varies with gender and with cognitive impairment. The mechanism that underlies these relationships remains to be determined and will be the focus of further studies with the Texas Alzheimer’s Research Consortium.

Alzheimer disease (AD) is a progressive, irreversible, neurodegenerative disease that affects more than 5.3 million people in the United States.¹ This number is significantly higher than the previous estimate of 4.5 million and is projected to increase sharply to nearly 8 million by 2030.¹ At present, the few agents that are approved by the US Food and Drug Administration for treatment of AD have demonstrated only modest effects in modifying clinical symptoms for relatively short periods; none has shown a clear effect on disease progression. New therapeutic approaches are desperately needed.

VASCULAR DISEASE AND ALZHEIMER DISEASE

Although AD is classified as a neurodegenerative dementia, there is epidemiologic and pathologic evidence of an association with vascular risk factors and vascular disease.^2–6 Vascular disease appears to lower the threshold for the clinical presentation of dementia at a given level of AD-related pathology.⁷ The possible association of AD with vascular disease suggests that there are important pathogenic mechanisms common to both AD and vascular disease. For example, there is increasing evidence that perturbations in cerebral vascular structure and function occur in AD.⁸

It has been suggested that cerebral hypoperfusion/hypoxia triggers hypometabolic, cognitive, and degenerative changes in the brain and contributes to the pathologic processes of AD.⁹ A study by Roher and colleagues reveals an association between severe circle of Willis atherosclerosis and sporadic AD.¹⁰ These observations suggest that atherosclerosis-induced brain hypoperfusion contributes to the clinical and pathologic manifestations of AD.

Hypoxia is also known to stimulate angiogenesis, especially via upregulation of hypoxia-inducible genes such as vascular endothelial growth factor (VEGF).^11,12 VEGF, a critical mediator of angiogenesis, is present in the AD brain in the walls of intra-parenchymal vessels, in diffuse perivascular deposits, and in clusters of reactive astrocytes.¹³ In addition, intrathecal levels of VEGF in AD are related to clinical severity and intrathecal levels of amyloid-beta (Aβ).¹⁴ Emerging data support the idea that factors and processes characteristic of angiogenesis are found in the AD brain.^15,16

ENDOTHELIAL ACTIVATION AND ANGIOGENESIS

The angiogenic process is complex and involves several discrete steps, such as endothelial activation, extracellular matrix degradation, proliferation and migration of endothelial cells, and morphologic differentiation of endothelial cells to form tubes. Stimuli known to initiate angiogenesis, including hypoxia, inflammation, and mechanical factors such as shear stress and stretch,²³ either directly or indirectly activate endothelial cells. Activated endothelial cells elaborate adhesion molecules, cytokines and chemokines, growth factors, vasoactive molecules, major histocompatibility complex molecules, procoagulant and anticoagulant moieties, and a variety of other gene products with biologic activity.²⁴ The activated endothelium exerts direct local effects by producing at least 20 paracrine factors that act on adjacent cells.²⁵

ANGIOGENIC SIGNALING MECHANISMS IN BRAIN MICROVESSELS

Signaling mechanisms that have been identified as important to endothelial cell viability and angiogenesis include PI3K/Akt, p38 kinase, ERK, and JNK. In this regard, intracellular Aβ accumulation is toxic to endothelial cells and decreases PI3K/Akt.²⁶ Extracellular Aβ peptides decrease phosphorylation and thus activation of ERK and p38 kinase.²⁶ VEGF promotes endothelial survival, proliferation, and migration through numerous pathways, including activation of ERK, p38 kinase, JNK, and Rho GTPase family members.²³

VASCULAR ACTIVATION IN ALZHEIMER DISEASE

Despite increases in several proangiogenic factors in the AD brain, evidence for increased vascularity in AD is lacking. On the contrary, it has been suggested that the angiogenic process is delayed or impaired in aged tissues, with several studies showing decreased microvascular density in the AD brain.^30–33 Paris et al showed that wild-type Aβ peptides have antiangiogenic effects in vitro and in vivo.³⁴

How can the data showing antiangiogenic effects of Aβ be reconciled with the presence or expression of a large number of proangiogenic proteins by brain microvessels in AD? These conflicting observations suggest an imbalance between proangiogenic and antiangiogeneic processes in the AD brain.

Preliminary experiments in our laboratory show that pharmacologic blockade of vascular activation improves cognitive function in an animal model of AD. Thus, “vascular activation” could be a novel, unexplored therapeutic target in AD.

Acknowledgment

The authors gratefully acknowledge the secretarial assistance of Terri Stahl.