Small arteries show change in women with preeclampsia history

ORLANDO – Women with a history of severe preeclampsia show signs of small artery dysfunction as early as 2 years after delivery, an indication of cardiovascular disease later in life if not addressed by ob.gyns. and cardiologists early on, according to a small, unpublished study.

Researchers led by Dr. Karolina Kublickiene found that in women with a history of preeclampsia, endothelium-dependent dilation to flow was reduced, a change that could be due to nitric oxide contribution deficiency. The small arteries seen in the study group also exhibited increased myogenic tone, with enhanced sensitivity to the vasoconstrictor norepinephrine.

Dr. Louise Kenny, who moderated the session at the annual meeting of the Society for Gynecologic Investigation, said the study was "exquisitely executed."

"This is very basic science, but has massive clinical implications," said Dr. Kenny, a professor of obstetrics at the University College Cork, Ireland.

Several studies have shown that a history of preeclampsia is a risk factor for developing cardiovascular disease (Circulation 2012;125:1367-80). However, many women with preeclampsia go back to the community without proper follow-up with a cardiologist.

"I’m a high-risk maternal medicine obstetrician, and I’m very well aware that the long-term follow-up for women with preeclampsia is quite patchy," said Dr. Kenny. "We have a complete disconnect at several levels, and it is time to act."

Researchers hypothesized that functional and structural abnormalities in peripheral arteries are present as early as 2 years after delivery in mothers who had a pregnancy complicated by early-onset and severe preeclampsia.

They selected 15 women with a history of severe preeclampsia who had delivered between 2007 and 2011 at Karolinska University Hospital in Stockholm. They selected 15 closely matched controls who had normal pregnancies and gave birth during the same period. The women were on average 35 years old.

The investigators defined severe preeclampsia as systolic blood pressure of more than 160 mm Hg and/or diastolic blood pressure of more than 110 mm Hg on two occasions, at least 6 hours apart, and/or proteinuria of more than 5 g in a 24-hour period and/or organ damage.

The preeclampsia group and the control group were closely matched with regard to several biochemical characteristics, including the low-density lipoprotein to high-density lipoprotein (LDL/HDL) ratio (1.9 and 1.6, respectively). However, women in the preeclampsia group had higher blood pressure, insulin levels, and hemostatic model assessment index than did controls: The average diastolic blood pressure in the preeclampsia group was 74 mm Hg, versus 66 mm Hg in the control group. The average fasting insulin level in the preeclampsia group was almost twice as high as that of the control group (83 pmol/L vs. 44 pmol/L). Neither group showed evidence of early renal damage.

Researchers took subcutaneous fat biopsies from the women. They used pressure myography to compare the structure and function of the isolated small subcutaneous resistance arteries. They used immunostaining to compare endothelial nitric oxide synthase (eNOS) and lectin-like oxidized LDL receptor-1 (LOX-1) expression.

The arteries in both groups had similar diameters, wall thickness, wall-lumen ratio, and cross-sectional area.

Results showed that eNOS expression was similar in both groups, but LOX-1 expression was significantly enhanced in the study group. Inhibition of NOS had no effect on either group.

Myogenic tone was enhanced in the arteries of women with a history of preeclampsia, and was positively correlated with the LDL/HDL ratio, a change characterizing small artery dysfunction.

Basal tone in the study group also was positively correlated with the LDL/HDL ratio, triglycerides, glycated hemoglobin, and high-sensitivity C-reactive protein, and was negatively correlated with HDL. Basal tone at 60 mm Hg was 8 in the preeclampsia group, compared with 5 in the control group (P = .07).

Meanwhile, the study group had higher sensitivity to norepinephrine and angiotensin II, and showed reduced distensibility. Distensibility was negatively correlated with homocysteine level, which has been associated with cardiovascular disease, in the study group only.

"The changes in passive properties of vascular wall are characterized by reduced distensibility that will affect stiffness of the arteries in women with a history of preeclampsia," said Dr. Kublickiene, an associate professor of obstetrics and gynecology and senior researcher at the Karolinska Institute Hospital-Huddinge in Stockholm. She also leads the Center for Gender Medicine at the institute.

Endothelium-dependent dilation to bradykinin (BK) and NO donor compounds were similar between the two groups. But endothelium-dependent response to flow was significantly attenuated in the study group, which could mean possible impairment of flow detection and signaling, according to Dr. Kublickiene.

"Preserved relaxation and the contribution of NO to BK-induced responses to NO donor and eNOS expression between the groups further support the specific importance of NO deficiency in flow-mediated dilation," she said.

"The observed changes will contribute to an increased peripheral resistance and blood pressure, which are of critical importance for long-term women’s cardiovascular health," she said. Counseling following a preeclamptic pregnancy and preterm delivery should include a discussion about reproduction and cardiovascular risks, she said.

And, she emphasized, "Let’s work with cardiologists."

A 2012 study that focused on a different group of women showed that collaboration between cardiologists and ob.gyns. is indeed possible.

Dr. Kublickiene said that several questions remain: What are the appropriate preventive strategies? What screening schedules should be recommended? What are the clinical targets? And, what are the treatment regimens?

"I think now clinical trials of statins and other early interventions in these women are warranted," said Dr. Kenny.

Dr. Kublickiene and Dr. Kenny said they had no disclosures. The study was funded by the Center for Gender Medicine at the Karolinska Institute, by the Karolinska Institute, and by the ALF fund of the Stockholm County Council.

nmiller@frontlinemedcom.com

On Twitter @NaseemSMiller

ORLANDO – Women with a history of severe preeclampsia show signs of small artery dysfunction as early as 2 years after delivery, an indication of cardiovascular disease later in life if not addressed by ob.gyns. and cardiologists early on, according to a small, unpublished study.

Researchers led by Dr. Karolina Kublickiene found that in women with a history of preeclampsia, endothelium-dependent dilation to flow was reduced, a change that could be due to nitric oxide contribution deficiency. The small arteries seen in the study group also exhibited increased myogenic tone, with enhanced sensitivity to the vasoconstrictor norepinephrine.

Dr. Louise Kenny, who moderated the session at the annual meeting of the Society for Gynecologic Investigation, said the study was "exquisitely executed."

"This is very basic science, but has massive clinical implications," said Dr. Kenny, a professor of obstetrics at the University College Cork, Ireland.

Several studies have shown that a history of preeclampsia is a risk factor for developing cardiovascular disease (Circulation 2012;125:1367-80). However, many women with preeclampsia go back to the community without proper follow-up with a cardiologist.

"I’m a high-risk maternal medicine obstetrician, and I’m very well aware that the long-term follow-up for women with preeclampsia is quite patchy," said Dr. Kenny. "We have a complete disconnect at several levels, and it is time to act."

Researchers hypothesized that functional and structural abnormalities in peripheral arteries are present as early as 2 years after delivery in mothers who had a pregnancy complicated by early-onset and severe preeclampsia.

They selected 15 women with a history of severe preeclampsia who had delivered between 2007 and 2011 at Karolinska University Hospital in Stockholm. They selected 15 closely matched controls who had normal pregnancies and gave birth during the same period. The women were on average 35 years old.

The investigators defined severe preeclampsia as systolic blood pressure of more than 160 mm Hg and/or diastolic blood pressure of more than 110 mm Hg on two occasions, at least 6 hours apart, and/or proteinuria of more than 5 g in a 24-hour period and/or organ damage.

The preeclampsia group and the control group were closely matched with regard to several biochemical characteristics, including the low-density lipoprotein to high-density lipoprotein (LDL/HDL) ratio (1.9 and 1.6, respectively). However, women in the preeclampsia group had higher blood pressure, insulin levels, and hemostatic model assessment index than did controls: The average diastolic blood pressure in the preeclampsia group was 74 mm Hg, versus 66 mm Hg in the control group. The average fasting insulin level in the preeclampsia group was almost twice as high as that of the control group (83 pmol/L vs. 44 pmol/L). Neither group showed evidence of early renal damage.

Researchers took subcutaneous fat biopsies from the women. They used pressure myography to compare the structure and function of the isolated small subcutaneous resistance arteries. They used immunostaining to compare endothelial nitric oxide synthase (eNOS) and lectin-like oxidized LDL receptor-1 (LOX-1) expression.

The arteries in both groups had similar diameters, wall thickness, wall-lumen ratio, and cross-sectional area.

Results showed that eNOS expression was similar in both groups, but LOX-1 expression was significantly enhanced in the study group. Inhibition of NOS had no effect on either group.

Myogenic tone was enhanced in the arteries of women with a history of preeclampsia, and was positively correlated with the LDL/HDL ratio, a change characterizing small artery dysfunction.

Basal tone in the study group also was positively correlated with the LDL/HDL ratio, triglycerides, glycated hemoglobin, and high-sensitivity C-reactive protein, and was negatively correlated with HDL. Basal tone at 60 mm Hg was 8 in the preeclampsia group, compared with 5 in the control group (P = .07).

Meanwhile, the study group had higher sensitivity to norepinephrine and angiotensin II, and showed reduced distensibility. Distensibility was negatively correlated with homocysteine level, which has been associated with cardiovascular disease, in the study group only.

"The changes in passive properties of vascular wall are characterized by reduced distensibility that will affect stiffness of the arteries in women with a history of preeclampsia," said Dr. Kublickiene, an associate professor of obstetrics and gynecology and senior researcher at the Karolinska Institute Hospital-Huddinge in Stockholm. She also leads the Center for Gender Medicine at the institute.

Endothelium-dependent dilation to bradykinin (BK) and NO donor compounds were similar between the two groups. But endothelium-dependent response to flow was significantly attenuated in the study group, which could mean possible impairment of flow detection and signaling, according to Dr. Kublickiene.

"Preserved relaxation and the contribution of NO to BK-induced responses to NO donor and eNOS expression between the groups further support the specific importance of NO deficiency in flow-mediated dilation," she said.

"The observed changes will contribute to an increased peripheral resistance and blood pressure, which are of critical importance for long-term women’s cardiovascular health," she said. Counseling following a preeclamptic pregnancy and preterm delivery should include a discussion about reproduction and cardiovascular risks, she said.

And, she emphasized, "Let’s work with cardiologists."

A 2012 study that focused on a different group of women showed that collaboration between cardiologists and ob.gyns. is indeed possible.

Dr. Kublickiene said that several questions remain: What are the appropriate preventive strategies? What screening schedules should be recommended? What are the clinical targets? And, what are the treatment regimens?

"I think now clinical trials of statins and other early interventions in these women are warranted," said Dr. Kenny.

Dr. Kublickiene and Dr. Kenny said they had no disclosures. The study was funded by the Center for Gender Medicine at the Karolinska Institute, by the Karolinska Institute, and by the ALF fund of the Stockholm County Council.

nmiller@frontlinemedcom.com

On Twitter @NaseemSMiller

ORLANDO – Women with a history of severe preeclampsia show signs of small artery dysfunction as early as 2 years after delivery, an indication of cardiovascular disease later in life if not addressed by ob.gyns. and cardiologists early on, according to a small, unpublished study.

Researchers led by Dr. Karolina Kublickiene found that in women with a history of preeclampsia, endothelium-dependent dilation to flow was reduced, a change that could be due to nitric oxide contribution deficiency. The small arteries seen in the study group also exhibited increased myogenic tone, with enhanced sensitivity to the vasoconstrictor norepinephrine.

Dr. Louise Kenny, who moderated the session at the annual meeting of the Society for Gynecologic Investigation, said the study was "exquisitely executed."

"This is very basic science, but has massive clinical implications," said Dr. Kenny, a professor of obstetrics at the University College Cork, Ireland.

Several studies have shown that a history of preeclampsia is a risk factor for developing cardiovascular disease (Circulation 2012;125:1367-80). However, many women with preeclampsia go back to the community without proper follow-up with a cardiologist.

"I’m a high-risk maternal medicine obstetrician, and I’m very well aware that the long-term follow-up for women with preeclampsia is quite patchy," said Dr. Kenny. "We have a complete disconnect at several levels, and it is time to act."

Researchers hypothesized that functional and structural abnormalities in peripheral arteries are present as early as 2 years after delivery in mothers who had a pregnancy complicated by early-onset and severe preeclampsia.

They selected 15 women with a history of severe preeclampsia who had delivered between 2007 and 2011 at Karolinska University Hospital in Stockholm. They selected 15 closely matched controls who had normal pregnancies and gave birth during the same period. The women were on average 35 years old.

The investigators defined severe preeclampsia as systolic blood pressure of more than 160 mm Hg and/or diastolic blood pressure of more than 110 mm Hg on two occasions, at least 6 hours apart, and/or proteinuria of more than 5 g in a 24-hour period and/or organ damage.

The preeclampsia group and the control group were closely matched with regard to several biochemical characteristics, including the low-density lipoprotein to high-density lipoprotein (LDL/HDL) ratio (1.9 and 1.6, respectively). However, women in the preeclampsia group had higher blood pressure, insulin levels, and hemostatic model assessment index than did controls: The average diastolic blood pressure in the preeclampsia group was 74 mm Hg, versus 66 mm Hg in the control group. The average fasting insulin level in the preeclampsia group was almost twice as high as that of the control group (83 pmol/L vs. 44 pmol/L). Neither group showed evidence of early renal damage.

Researchers took subcutaneous fat biopsies from the women. They used pressure myography to compare the structure and function of the isolated small subcutaneous resistance arteries. They used immunostaining to compare endothelial nitric oxide synthase (eNOS) and lectin-like oxidized LDL receptor-1 (LOX-1) expression.

The arteries in both groups had similar diameters, wall thickness, wall-lumen ratio, and cross-sectional area.

Results showed that eNOS expression was similar in both groups, but LOX-1 expression was significantly enhanced in the study group. Inhibition of NOS had no effect on either group.

Myogenic tone was enhanced in the arteries of women with a history of preeclampsia, and was positively correlated with the LDL/HDL ratio, a change characterizing small artery dysfunction.

Basal tone in the study group also was positively correlated with the LDL/HDL ratio, triglycerides, glycated hemoglobin, and high-sensitivity C-reactive protein, and was negatively correlated with HDL. Basal tone at 60 mm Hg was 8 in the preeclampsia group, compared with 5 in the control group (P = .07).

Meanwhile, the study group had higher sensitivity to norepinephrine and angiotensin II, and showed reduced distensibility. Distensibility was negatively correlated with homocysteine level, which has been associated with cardiovascular disease, in the study group only.

"The changes in passive properties of vascular wall are characterized by reduced distensibility that will affect stiffness of the arteries in women with a history of preeclampsia," said Dr. Kublickiene, an associate professor of obstetrics and gynecology and senior researcher at the Karolinska Institute Hospital-Huddinge in Stockholm. She also leads the Center for Gender Medicine at the institute.

Endothelium-dependent dilation to bradykinin (BK) and NO donor compounds were similar between the two groups. But endothelium-dependent response to flow was significantly attenuated in the study group, which could mean possible impairment of flow detection and signaling, according to Dr. Kublickiene.

"Preserved relaxation and the contribution of NO to BK-induced responses to NO donor and eNOS expression between the groups further support the specific importance of NO deficiency in flow-mediated dilation," she said.

"The observed changes will contribute to an increased peripheral resistance and blood pressure, which are of critical importance for long-term women’s cardiovascular health," she said. Counseling following a preeclamptic pregnancy and preterm delivery should include a discussion about reproduction and cardiovascular risks, she said.

And, she emphasized, "Let’s work with cardiologists."

A 2012 study that focused on a different group of women showed that collaboration between cardiologists and ob.gyns. is indeed possible.

Dr. Kublickiene said that several questions remain: What are the appropriate preventive strategies? What screening schedules should be recommended? What are the clinical targets? And, what are the treatment regimens?

"I think now clinical trials of statins and other early interventions in these women are warranted," said Dr. Kenny.

Dr. Kublickiene and Dr. Kenny said they had no disclosures. The study was funded by the Center for Gender Medicine at the Karolinska Institute, by the Karolinska Institute, and by the ALF fund of the Stockholm County Council.

nmiller@frontlinemedcom.com

On Twitter @NaseemSMiller