Endurance exercise tied to more coronary atherosclerosis

The suggestion that long-term endurance exercise may lead to a paradoxical increase in coronary atherosclerosis has been raised again by a new study.

In the Master@Heart study, lifelong endurance athletes had more coronary plaques, including more noncalcified plaques, than fit and healthy individuals with a similarly low cardiovascular risk profile.

The study was presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. It was also simultaneously published online in the European Heart Journal.

“We consistently see higher plaque burden in lifelong endurance athletes. This is regardless of the plaque type, whether it is calcified, mixed, noncalcified, in the proximal segment or causing more than 50% stenosis,” concluded Ruben De Bosscher, MD, Catholic University of Leuven (Belgium), during his presentation.

The researchers suggested that all the information to date suggests there may be a “reverse J-shaped” dose-response relationship between exercise and coronary atherosclerosis.

Dr. De Bosscher added that “the worst thing you can do is nothing at all. As soon as you do a little bit of exercise – just brisk walking or jogging up to 3 hours a week – it seems that’s where you get the most benefit. And after that, we tend to see an increase in coronary plaque burden.”

The discussant of the study at the ACC session, Michael Emery, MD, codirector of the Sports Cardiology Center at the Cleveland Clinic, asked how this information should be translated into advice for the general public, given that it is known that endurance athletes show much improved mortality.

“That is a very good question,” Dr. De Bosscher replied. “Yes, we do see less events and adverse outcomes in endurance athletes, but that is compared to the whole population, including those that are unhealthy and do not exercise.

“If we only look at healthy individuals who do exercise but at varying levels, the question is, do we then see the same relationship?” he asked. “There is increasing evidence that there may be a point of diminished returns – and at a certain point, an increased cardiovascular risk is seen in endurance athletes.”

On advice to the public, Dr. De Bosscher added, “one of the main findings here is that, despite having a very healthy lifestyle style and exercising a lot, no one is granted immunity to coronary atherosclerosis. It would seem that the most benefit occurs in individuals doing a moderate amount of exercise – up to about 3 hours a week.”

In a comment, Dr. Emery noted: “This continues to be a ‘hot topic,’ although I continue to be underwhelmed, given a lack of hard outcomes, and I worry about the wrong take-home message being sent, that too much exercise will do more harm than good.”

He added that fitness still matters regardless of calcium score, and he would not advise people to stop exercising, because “the better your fitness, the better the outcome.”

However, he acknowledged that “the study does nicely illustrate that exercise does not make you immune from heart disease (which is a message a lot of athletes need to hear, honestly).”

Also commenting, Paul D. Thompson, MD, Hartford (Conn.) Hospital, who has studied the cardiac implications of exercise for many years, said: “The problem we have in the U.S. and in most developed countries is not too much exercise but rather that most people don’t exercise very much at all.”

He noted that the Master@Heart study as an “important contribution” to the field.

“We have seen in previous trials that lifelong endurance athletes appear to have more deposition of cholesterol in their coronary arteries than you would expect,” he said. “But, while prior studies suggested that most of the deposits in endurance athletes were the safer type of highly calcified plaques, this study shows that the plaques in endurance athletes are not quite as benign as we had previously thought.”

It’s not clear what this means though, he added, because “despite these findings, it’s pretty clear that endurance athletes live longer than most people. But do they live longer because of the amount of exercise they do or because they are just hardier than the rest of us?”

He does not believe the study should be interpreted to mean that endurance exercise is dangerous. “We don’t have great evidence for that. This is a finding in a coronary artery. We don’t have outcome data.”

However, he added, “it doesn’t seem like you have to do a lot of extreme sport to get the cardiovascular benefits of exercise. All the studies show that the greatest benefits happen in people who go from doing very little to doing a moderate amount of exercise. Then it seems to plateau.”

Dr. Thompson pointed out that the most recent physical activity guidelines in the United States recommend between 150 and 300 minutes of moderate exercise, such as brisk walking, or 75-150 minutes a week of vigorous activity, such as running.

But he does not believe this study should put people off participating in endurance exercise, noting that many individuals engage in high levels of vigorous exercise for other reasons, not necessarily for their cardiovascular health.

“If people want to do more – for competitive reasons or if it makes them feel good – I say go ahead and do it,” Dr. Thompson added. “You should enjoy your life. But if you’re doing high levels of endurance exercise for your health and you’re miserable doing it, you may be wasting your time, as it doesn’t look as these more extreme levels of exercise do you any good. Does it do you any harm? We don’t have evidence yet to conclude that.”

In his presentation, Dr. De Bosscher noted that previous studies have reported higher calcium scores in athletes as well as more coronary plaques, compared with control persons. But the atherosclerotic lesions observed in the athletes were predominantly calcified plaques that were considered more stable and less prone to rupture, whereas nonathletes had predominantly mixed plaques that were considered less stable and more prone to rupture.

He pointed out, however, that these studies had limitations in that they included some individuals with other cardiovascular risk factors, such as smoking and intake of statins or antihypertensive drugs; they did not always assess the association between exercise and coronary atherosclerosis in a dose-response relationship; and while they reported the relative difference in plaque types, they didn’t report the absolute prevalence in calcified, noncalcified, and mixed plaques.

The Master@Heart study aimed to look at this question in a more comprehensive way.

The observational cohort study evaluated coronary atherosclerosis in 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after age 30 years), and 176 healthy nonathletes who engaged in no more than 3 hours a week of exercise. All participants were male and had a low cardiovascular risk profile. The median age was 55 in the three groups.

Maximal oxygen uptake (VO_2max) was used to quantify fitness. Lifelong and late-onset athletes had higher percentage predicted VO_2max than nonathletes (159 vs. 155 vs. 122).

There was no significant difference between the three groups with regard to age, weight, blood pressure cholesterol levels, or hemoglobin A1c levels. While the control group had a healthy body mass index and body fat percentage (19%), both groups of athletes were significantly leaner (body fat percentage, 14%-15%).

The exercise performed by the lifelong and late-onset endurance athletes was similar – mainly cycling and running. The endurance athletes reported an average of 10-11 hours of exercise per week, compared with 1 hour per week for the control persons. Only 22% of the control group reported engaging in no exercise at all; the others reported jogging, cycling, or engaging in nonendurance exercise, such as tennis.

Results showed that the overall coronary plaque burden assessed by segment stenosis score and segment-involvement score was higher among lifelong athletes than control persons (between-group difference, 0.86 and 0.65, respectively).

In comparison to control persons, lifelong endurance sport participation was associated with having one or more of each of the following, compared with a healthy nonathletic lifestyle:

• More than one coronary plaque (odds ratio, 1.86; 95% confidence interval, 1.17-2.94)
• More than one proximal plaque (OR, 1.96; 95% CI, 1.24-3.11)
• More than one calcified plaque (OR, 1.58; 95% CI, 1.01-2.49)
• More than one calcified proximal plaque (OR, 2.07; 95% CI, 1.28-3.35)
• More than one noncalcified plaque (OR, 1.95; 95% CI, 1.12-3.40)
• More than one noncalcified proximal plaque (OR, 2.80; 95% CI, 1.39-5.65)
• More than one mixed plaque (OR, 1.78; 95% CI, 1.06-2.99)

In comparison with late-onset athletes, at least 50% stenosis in any coronary segment (OR, 2.79; 95% CI, 1.20-6.50) and at least 50% stenosis in a proximal segment (OR, 5.92; 95% CI, 1.22 – 28.80) were more prevalent among lifelong athletes.

Vulnerable plaques, as defined by the presence of at least two high-risk features, were uncommon in all groups, but a lifelong athletic lifestyle was associated with a lower prevalence (OR, 0.11; 95% CI, 0.01-0.98).

In their article in the European Heart Journal, the researchers noted that the Master@Heart study is the largest and most comprehensive study to assess the dose-response relationship between intensive endurance exercise and coronary atherosclerosis.

“The findings do not support the hypothesis that highly trained endurance athletes have a more benign plaque composition to explain their lower risk of cardiovascular events compared to nonathletes,” they wrote.

“As studies on the impact of physical activity in the upper range are lacking, our data open the question on whether coronary events are indeed less prevalent in this high-end exercise cohort, and if that is the case, on what explains the paradox,” they concluded. “More and longitudinal research at the higher end of the endurance exercise spectrum is definitely needed.”

A version of this article first appeared on Medscape.com.

The suggestion that long-term endurance exercise may lead to a paradoxical increase in coronary atherosclerosis has been raised again by a new study.

In the Master@Heart study, lifelong endurance athletes had more coronary plaques, including more noncalcified plaques, than fit and healthy individuals with a similarly low cardiovascular risk profile.

The study was presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. It was also simultaneously published online in the European Heart Journal.

“We consistently see higher plaque burden in lifelong endurance athletes. This is regardless of the plaque type, whether it is calcified, mixed, noncalcified, in the proximal segment or causing more than 50% stenosis,” concluded Ruben De Bosscher, MD, Catholic University of Leuven (Belgium), during his presentation.

The researchers suggested that all the information to date suggests there may be a “reverse J-shaped” dose-response relationship between exercise and coronary atherosclerosis.

Dr. De Bosscher added that “the worst thing you can do is nothing at all. As soon as you do a little bit of exercise – just brisk walking or jogging up to 3 hours a week – it seems that’s where you get the most benefit. And after that, we tend to see an increase in coronary plaque burden.”

The discussant of the study at the ACC session, Michael Emery, MD, codirector of the Sports Cardiology Center at the Cleveland Clinic, asked how this information should be translated into advice for the general public, given that it is known that endurance athletes show much improved mortality.

“That is a very good question,” Dr. De Bosscher replied. “Yes, we do see less events and adverse outcomes in endurance athletes, but that is compared to the whole population, including those that are unhealthy and do not exercise.

“If we only look at healthy individuals who do exercise but at varying levels, the question is, do we then see the same relationship?” he asked. “There is increasing evidence that there may be a point of diminished returns – and at a certain point, an increased cardiovascular risk is seen in endurance athletes.”

On advice to the public, Dr. De Bosscher added, “one of the main findings here is that, despite having a very healthy lifestyle style and exercising a lot, no one is granted immunity to coronary atherosclerosis. It would seem that the most benefit occurs in individuals doing a moderate amount of exercise – up to about 3 hours a week.”

In a comment, Dr. Emery noted: “This continues to be a ‘hot topic,’ although I continue to be underwhelmed, given a lack of hard outcomes, and I worry about the wrong take-home message being sent, that too much exercise will do more harm than good.”

He added that fitness still matters regardless of calcium score, and he would not advise people to stop exercising, because “the better your fitness, the better the outcome.”

However, he acknowledged that “the study does nicely illustrate that exercise does not make you immune from heart disease (which is a message a lot of athletes need to hear, honestly).”

Also commenting, Paul D. Thompson, MD, Hartford (Conn.) Hospital, who has studied the cardiac implications of exercise for many years, said: “The problem we have in the U.S. and in most developed countries is not too much exercise but rather that most people don’t exercise very much at all.”

He noted that the Master@Heart study as an “important contribution” to the field.

“We have seen in previous trials that lifelong endurance athletes appear to have more deposition of cholesterol in their coronary arteries than you would expect,” he said. “But, while prior studies suggested that most of the deposits in endurance athletes were the safer type of highly calcified plaques, this study shows that the plaques in endurance athletes are not quite as benign as we had previously thought.”

It’s not clear what this means though, he added, because “despite these findings, it’s pretty clear that endurance athletes live longer than most people. But do they live longer because of the amount of exercise they do or because they are just hardier than the rest of us?”

He does not believe the study should be interpreted to mean that endurance exercise is dangerous. “We don’t have great evidence for that. This is a finding in a coronary artery. We don’t have outcome data.”

However, he added, “it doesn’t seem like you have to do a lot of extreme sport to get the cardiovascular benefits of exercise. All the studies show that the greatest benefits happen in people who go from doing very little to doing a moderate amount of exercise. Then it seems to plateau.”

Dr. Thompson pointed out that the most recent physical activity guidelines in the United States recommend between 150 and 300 minutes of moderate exercise, such as brisk walking, or 75-150 minutes a week of vigorous activity, such as running.

But he does not believe this study should put people off participating in endurance exercise, noting that many individuals engage in high levels of vigorous exercise for other reasons, not necessarily for their cardiovascular health.

“If people want to do more – for competitive reasons or if it makes them feel good – I say go ahead and do it,” Dr. Thompson added. “You should enjoy your life. But if you’re doing high levels of endurance exercise for your health and you’re miserable doing it, you may be wasting your time, as it doesn’t look as these more extreme levels of exercise do you any good. Does it do you any harm? We don’t have evidence yet to conclude that.”

In his presentation, Dr. De Bosscher noted that previous studies have reported higher calcium scores in athletes as well as more coronary plaques, compared with control persons. But the atherosclerotic lesions observed in the athletes were predominantly calcified plaques that were considered more stable and less prone to rupture, whereas nonathletes had predominantly mixed plaques that were considered less stable and more prone to rupture.

He pointed out, however, that these studies had limitations in that they included some individuals with other cardiovascular risk factors, such as smoking and intake of statins or antihypertensive drugs; they did not always assess the association between exercise and coronary atherosclerosis in a dose-response relationship; and while they reported the relative difference in plaque types, they didn’t report the absolute prevalence in calcified, noncalcified, and mixed plaques.

The Master@Heart study aimed to look at this question in a more comprehensive way.

The observational cohort study evaluated coronary atherosclerosis in 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after age 30 years), and 176 healthy nonathletes who engaged in no more than 3 hours a week of exercise. All participants were male and had a low cardiovascular risk profile. The median age was 55 in the three groups.

Maximal oxygen uptake (VO_2max) was used to quantify fitness. Lifelong and late-onset athletes had higher percentage predicted VO_2max than nonathletes (159 vs. 155 vs. 122).

There was no significant difference between the three groups with regard to age, weight, blood pressure cholesterol levels, or hemoglobin A1c levels. While the control group had a healthy body mass index and body fat percentage (19%), both groups of athletes were significantly leaner (body fat percentage, 14%-15%).

The exercise performed by the lifelong and late-onset endurance athletes was similar – mainly cycling and running. The endurance athletes reported an average of 10-11 hours of exercise per week, compared with 1 hour per week for the control persons. Only 22% of the control group reported engaging in no exercise at all; the others reported jogging, cycling, or engaging in nonendurance exercise, such as tennis.

Results showed that the overall coronary plaque burden assessed by segment stenosis score and segment-involvement score was higher among lifelong athletes than control persons (between-group difference, 0.86 and 0.65, respectively).

In comparison to control persons, lifelong endurance sport participation was associated with having one or more of each of the following, compared with a healthy nonathletic lifestyle:

• More than one coronary plaque (odds ratio, 1.86; 95% confidence interval, 1.17-2.94)
• More than one proximal plaque (OR, 1.96; 95% CI, 1.24-3.11)
• More than one calcified plaque (OR, 1.58; 95% CI, 1.01-2.49)
• More than one calcified proximal plaque (OR, 2.07; 95% CI, 1.28-3.35)
• More than one noncalcified plaque (OR, 1.95; 95% CI, 1.12-3.40)
• More than one noncalcified proximal plaque (OR, 2.80; 95% CI, 1.39-5.65)
• More than one mixed plaque (OR, 1.78; 95% CI, 1.06-2.99)

In comparison with late-onset athletes, at least 50% stenosis in any coronary segment (OR, 2.79; 95% CI, 1.20-6.50) and at least 50% stenosis in a proximal segment (OR, 5.92; 95% CI, 1.22 – 28.80) were more prevalent among lifelong athletes.

Vulnerable plaques, as defined by the presence of at least two high-risk features, were uncommon in all groups, but a lifelong athletic lifestyle was associated with a lower prevalence (OR, 0.11; 95% CI, 0.01-0.98).

In their article in the European Heart Journal, the researchers noted that the Master@Heart study is the largest and most comprehensive study to assess the dose-response relationship between intensive endurance exercise and coronary atherosclerosis.

“The findings do not support the hypothesis that highly trained endurance athletes have a more benign plaque composition to explain their lower risk of cardiovascular events compared to nonathletes,” they wrote.

“As studies on the impact of physical activity in the upper range are lacking, our data open the question on whether coronary events are indeed less prevalent in this high-end exercise cohort, and if that is the case, on what explains the paradox,” they concluded. “More and longitudinal research at the higher end of the endurance exercise spectrum is definitely needed.”

A version of this article first appeared on Medscape.com.

The suggestion that long-term endurance exercise may lead to a paradoxical increase in coronary atherosclerosis has been raised again by a new study.

In the Master@Heart study, lifelong endurance athletes had more coronary plaques, including more noncalcified plaques, than fit and healthy individuals with a similarly low cardiovascular risk profile.

The study was presented at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. It was also simultaneously published online in the European Heart Journal.

“We consistently see higher plaque burden in lifelong endurance athletes. This is regardless of the plaque type, whether it is calcified, mixed, noncalcified, in the proximal segment or causing more than 50% stenosis,” concluded Ruben De Bosscher, MD, Catholic University of Leuven (Belgium), during his presentation.

The researchers suggested that all the information to date suggests there may be a “reverse J-shaped” dose-response relationship between exercise and coronary atherosclerosis.

Dr. De Bosscher added that “the worst thing you can do is nothing at all. As soon as you do a little bit of exercise – just brisk walking or jogging up to 3 hours a week – it seems that’s where you get the most benefit. And after that, we tend to see an increase in coronary plaque burden.”

The discussant of the study at the ACC session, Michael Emery, MD, codirector of the Sports Cardiology Center at the Cleveland Clinic, asked how this information should be translated into advice for the general public, given that it is known that endurance athletes show much improved mortality.

“That is a very good question,” Dr. De Bosscher replied. “Yes, we do see less events and adverse outcomes in endurance athletes, but that is compared to the whole population, including those that are unhealthy and do not exercise.

“If we only look at healthy individuals who do exercise but at varying levels, the question is, do we then see the same relationship?” he asked. “There is increasing evidence that there may be a point of diminished returns – and at a certain point, an increased cardiovascular risk is seen in endurance athletes.”

On advice to the public, Dr. De Bosscher added, “one of the main findings here is that, despite having a very healthy lifestyle style and exercising a lot, no one is granted immunity to coronary atherosclerosis. It would seem that the most benefit occurs in individuals doing a moderate amount of exercise – up to about 3 hours a week.”

In a comment, Dr. Emery noted: “This continues to be a ‘hot topic,’ although I continue to be underwhelmed, given a lack of hard outcomes, and I worry about the wrong take-home message being sent, that too much exercise will do more harm than good.”

He added that fitness still matters regardless of calcium score, and he would not advise people to stop exercising, because “the better your fitness, the better the outcome.”

However, he acknowledged that “the study does nicely illustrate that exercise does not make you immune from heart disease (which is a message a lot of athletes need to hear, honestly).”

Also commenting, Paul D. Thompson, MD, Hartford (Conn.) Hospital, who has studied the cardiac implications of exercise for many years, said: “The problem we have in the U.S. and in most developed countries is not too much exercise but rather that most people don’t exercise very much at all.”

He noted that the Master@Heart study as an “important contribution” to the field.

“We have seen in previous trials that lifelong endurance athletes appear to have more deposition of cholesterol in their coronary arteries than you would expect,” he said. “But, while prior studies suggested that most of the deposits in endurance athletes were the safer type of highly calcified plaques, this study shows that the plaques in endurance athletes are not quite as benign as we had previously thought.”

It’s not clear what this means though, he added, because “despite these findings, it’s pretty clear that endurance athletes live longer than most people. But do they live longer because of the amount of exercise they do or because they are just hardier than the rest of us?”

He does not believe the study should be interpreted to mean that endurance exercise is dangerous. “We don’t have great evidence for that. This is a finding in a coronary artery. We don’t have outcome data.”

However, he added, “it doesn’t seem like you have to do a lot of extreme sport to get the cardiovascular benefits of exercise. All the studies show that the greatest benefits happen in people who go from doing very little to doing a moderate amount of exercise. Then it seems to plateau.”

Dr. Thompson pointed out that the most recent physical activity guidelines in the United States recommend between 150 and 300 minutes of moderate exercise, such as brisk walking, or 75-150 minutes a week of vigorous activity, such as running.

But he does not believe this study should put people off participating in endurance exercise, noting that many individuals engage in high levels of vigorous exercise for other reasons, not necessarily for their cardiovascular health.

“If people want to do more – for competitive reasons or if it makes them feel good – I say go ahead and do it,” Dr. Thompson added. “You should enjoy your life. But if you’re doing high levels of endurance exercise for your health and you’re miserable doing it, you may be wasting your time, as it doesn’t look as these more extreme levels of exercise do you any good. Does it do you any harm? We don’t have evidence yet to conclude that.”

In his presentation, Dr. De Bosscher noted that previous studies have reported higher calcium scores in athletes as well as more coronary plaques, compared with control persons. But the atherosclerotic lesions observed in the athletes were predominantly calcified plaques that were considered more stable and less prone to rupture, whereas nonathletes had predominantly mixed plaques that were considered less stable and more prone to rupture.

He pointed out, however, that these studies had limitations in that they included some individuals with other cardiovascular risk factors, such as smoking and intake of statins or antihypertensive drugs; they did not always assess the association between exercise and coronary atherosclerosis in a dose-response relationship; and while they reported the relative difference in plaque types, they didn’t report the absolute prevalence in calcified, noncalcified, and mixed plaques.

The Master@Heart study aimed to look at this question in a more comprehensive way.

The observational cohort study evaluated coronary atherosclerosis in 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports initiation after age 30 years), and 176 healthy nonathletes who engaged in no more than 3 hours a week of exercise. All participants were male and had a low cardiovascular risk profile. The median age was 55 in the three groups.

Maximal oxygen uptake (VO_2max) was used to quantify fitness. Lifelong and late-onset athletes had higher percentage predicted VO_2max than nonathletes (159 vs. 155 vs. 122).

There was no significant difference between the three groups with regard to age, weight, blood pressure cholesterol levels, or hemoglobin A1c levels. While the control group had a healthy body mass index and body fat percentage (19%), both groups of athletes were significantly leaner (body fat percentage, 14%-15%).

The exercise performed by the lifelong and late-onset endurance athletes was similar – mainly cycling and running. The endurance athletes reported an average of 10-11 hours of exercise per week, compared with 1 hour per week for the control persons. Only 22% of the control group reported engaging in no exercise at all; the others reported jogging, cycling, or engaging in nonendurance exercise, such as tennis.

Results showed that the overall coronary plaque burden assessed by segment stenosis score and segment-involvement score was higher among lifelong athletes than control persons (between-group difference, 0.86 and 0.65, respectively).

In comparison to control persons, lifelong endurance sport participation was associated with having one or more of each of the following, compared with a healthy nonathletic lifestyle:

• More than one coronary plaque (odds ratio, 1.86; 95% confidence interval, 1.17-2.94)
• More than one proximal plaque (OR, 1.96; 95% CI, 1.24-3.11)
• More than one calcified plaque (OR, 1.58; 95% CI, 1.01-2.49)
• More than one calcified proximal plaque (OR, 2.07; 95% CI, 1.28-3.35)
• More than one noncalcified plaque (OR, 1.95; 95% CI, 1.12-3.40)
• More than one noncalcified proximal plaque (OR, 2.80; 95% CI, 1.39-5.65)
• More than one mixed plaque (OR, 1.78; 95% CI, 1.06-2.99)

In comparison with late-onset athletes, at least 50% stenosis in any coronary segment (OR, 2.79; 95% CI, 1.20-6.50) and at least 50% stenosis in a proximal segment (OR, 5.92; 95% CI, 1.22 – 28.80) were more prevalent among lifelong athletes.

Vulnerable plaques, as defined by the presence of at least two high-risk features, were uncommon in all groups, but a lifelong athletic lifestyle was associated with a lower prevalence (OR, 0.11; 95% CI, 0.01-0.98).

In their article in the European Heart Journal, the researchers noted that the Master@Heart study is the largest and most comprehensive study to assess the dose-response relationship between intensive endurance exercise and coronary atherosclerosis.

“The findings do not support the hypothesis that highly trained endurance athletes have a more benign plaque composition to explain their lower risk of cardiovascular events compared to nonathletes,” they wrote.

“As studies on the impact of physical activity in the upper range are lacking, our data open the question on whether coronary events are indeed less prevalent in this high-end exercise cohort, and if that is the case, on what explains the paradox,” they concluded. “More and longitudinal research at the higher end of the endurance exercise spectrum is definitely needed.”

A version of this article first appeared on Medscape.com.