5807
J Physiol 591.23 (2013) pp 5807–5808
JOURNAL CLUB
Coronary artery disease and age: beyond atherosclerosis Mit Shah and Markus B. Sikkel NHLI Imperial College London, Hammersmith Hospital, Ducane Road, London, W12 0NN, UK
The Journal of Physiology
Email: [email protected] Coronary artery disease is a major cause of morbidity and mortality in the UK, resulting in 80,000 deaths per year, of which more than 50% occur in patients aged 75 years or more (Townsend et al. 2012). The final common pathway causing death and other manifestations of coronary artery disease (including angina and myocardial infarction) is a reduction in blood flow to the myocardium. Typically, the age-related increase in disease severity has been ascribed to an increasing prevalence of physical obstruction of the coronary arteries caused by atherosclerosis. However, there is increasing evidence that age-related functional impairment of the mechanisms that regulate flow in the coronary arteries may also contribute. Novel insights into this age-related impairment have been possible using a combination of cold-induced stress responses and non-invasive imaging of the coronary arteries. This combination was first exemplified in a study that assessed coronary flow in young and old subjects under conditions of acute whole body cold stress (Gao et al. 2012). Cold stress was used to elevate myocardial oxygen demand and the subsequent coronary haemodynamic response was measured. Appropriate coronary vasodilatation was found to occur only in young subjects and was absent in old subjects, despite their greater myocardial oxygen demand. In a recent issue of the journal, the same group published a study elucidating some of the mechanisms involved (Monahan et al. 2013). The authors assessed how the coronary artery responds to a sympathetoexcitatory stressor, the cold pressor test (CPT), in old healthy men and young healthy controls. They used transthoracic echocardiography to assess coronary vascular resistance (CVR) via a calculation based on measured coronary blood velocity (CBV) in the distal
left anterior descending artery. This non-invasive approach made it ethically acceptable to recruit healthy individuals in their study, in contrast to previous studies using coronary catheterization in which the study populations were limited to individuals in whom the procedure would otherwise be indicated. This allows for the drawing of conclusions on the effects of age on coronary physiology that are not confounded by the effects of coronary disease. One challenge associated with this non-invasive approach is the technical acquisition of precise measures of coronary flow because measurements of coronary diameter are difficult to obtain but are required to calculate flow from velocity measurements. Therefore coronary blood velocity measurements were used as a surrogate for flow. The study builds on the authors’ previous work and tests the hypotheses that there would be greater coronary vasodilatation in young healthy subjects than in old subjects in response to the CPT and that these differences could be abolished by systemic α- and β-adrenergic blockade. Old and young males were well matched at baseline with similar body habitus and were non-smokers, not endurance trained and not taking medication. However, resting systolic and diastolic blood pressures were significantly higher in old subjects (means of 128/76 mmHg vs. 118/62 mmHg). CBV was found to increase in both young and old subjects, but the increase was greater in the younger group. Following adrenergic blockade, there was a reduced increase of CBV in response to CPT in both groups and the difference between the responses of young and old subjects was abrogated. CVR was reduced by CPT in the younger group (CVR −33 ± 6%), but not in the old subjects (CVR −3 ± 4%). Following adrenergic blockade, young subjects retained a slight reduction in CVR in response to CPT, whereas old subjects showed a small, but significant, increase in CVR. The differences between findings in young and old subjects persisted when CVR was corrected to rate pressure product (RPP), a measure of myocardial oxygen demand, suggesting that impaired coronary vasodilatation in old subjects is not merely a result of reduced stimulus for vasodilatation.
C 2013 The Authors. The Journal of Physiology C 2013 The Physiological Society
The novel findings of this study support several conclusions on the role of ageing in the impairment of normal coronary artery physiology. Firstly, transthoracic echocardiography can be used to answer clinically relevant questions regarding coronary physiology and pathophysiology non-invasively. Secondly, the reduction in coronary vasodilatation in response to a sympathetic stimulus in old subjects is confirmed in the context of the use of CPT to induce this stimulus. Thirdly, the age-related difference is eliminated by combined α- and β-adrenergic blockade, which confirms that the difference is attributable to an adrenergic mechanism. Finally, the age-related difference is most likely to reflect a difference in response to the adrenergic stimulus rather than the magnitude of the stimulus itself as RPP is increased to a similar extent in young and old subjects. One potential problem with the measurements used in this study is that changes in CBV are effectively equated to blood flow in order to calculate coronary resistance. This assumes that there is no systematic difference between young and old individuals in the baseline coronary artery cross-sectional area, which may not be the case. In addition, velocity may be influenced by other factors, including differences in lusitropy in the presence of increased sympathetic drive between the groups. However, the authors also include a ‘stimulus–response ratio’ in which CVR is corrected to RPP, which enhances the ability to compare measures between young and old subjects. The authors acknowledge that these findings of age-related differences in responses to CPT do not necessarily localize the physiological differences between young and old individuals purely to the adrenergic system as the control of the coronary vasomotor system is integrative. For example, endothelial dysfunction may play a role as it is known to become more markedly disturbed with age and itself may lead to impaired vasodilatation through reduced nitric oxide bioavailability in response to the increase in shear stress induced by CPT (Seals et al. 2011). A potentially interesting finding that may warrant further exploration is the observation that older men have a more marked drop in blood pressure with combined
DOI: 10.1113/jphysiol.2013.263400
5808 α- and β-adrenergic blockade prior to the application of CPT. This suggests greater tonic adrenergic agonism in old subjects, which may contribute to the reduction in response to CPT as chronically activated adrenoceptors tend to desensitize, in part via a process of receptor internalization. It is unclear whether the findings of this study can be generalized to females or patients with atherosclerosis because other factors may begin to take on greater importance in these groups. Furthermore, although the study groups were appropriately matched for certain confounders (see above), this did not account for other factors, such as serum lipid concentration, which is known to alter endothelial function (Seals et al. 2011), and other risk factors for coronary artery disease, including a positive family history, long-term salt intake and abnormal glucose homeostasis. Clinical application
The work has several potential clinical applications. The vasomotor system in disease has received much attention. For example, Schachinger et al. (2000) demonstrated the prognostic implications of impaired coronary vasodilatation in a prospective study. They assessed coronary vasoreactivity using various tests, including CPT, and used cardiovascular events (cardiovascular death, unstable angina, myocardial infarction, ischaemic stroke, and coronary vessel and peripheral artery intervention) as outcome variables. They found patients who had significantly
Journal Club increased vasoconstriction and blunted vasodilatation to the vasoreactivity tests were more likely to suffer cardiovascular events. Blunted nitroglycerin-induced vasodilatation was also a significant risk factor, which further suggested the critical importance of endothelium-dependent and endothelium-independent vasodilator capacity in predicting atherosclerotic disease progression. The study by Monahan et al. complements these findings and suggests a mechanism that may explain these results. The screening of individuals for CPT-induced changes in coronary artery velocity measured by transthoracic echocardiography may have a role as a measure of risk for cardiac events. The primary prevention of coronary events could then be targeted towards individuals at most risk. Hypertensive patients and those with diabetes (Seals et al. 2011) also show marked vasomotor disturbances and a subsequently increased risk for such events and it may potentially be useful to focus screening on such at-risk populations. These questions can be answered only with larger prospective studies. To conclude, the study by Monahan et al. further elucidates the mechanism of age-related impairment of coronary vasodilatation in older men. The deterioration in the sympathetic control of the coronary vasculature plays a part in the poorer blood supply of myocardium in the elderly male, particularly in response to stress and exertion. As coronary vascular response to CPT is an integrative physiological process, future work to explore the alternative pathways and their contributions
J Physiol 591.23
is warranted. In particular, it would be of interest, and potentially therapeutically relevant, to demonstrate the differential role of changes in α1-, α2- and β2-adrenergic receptor sensitivity, as well as changes in endothelial function in age-related coronary vasomotor dysfunction. The clinical application of the techniques in this study to the screening of populations at risk for vasomotor dysfunction may also be an exciting future direction.
References Gao Z, Wilson TE, Drew RC, Ettinger J & Monahan KD (2012). Altered coronary vascular control during cold stress in healthy older adults. Am J Physiol Heart Circ Physiol 302, H312–H318. Monahan KD, Feehan RP, Sinoway LI & Gao Z (2013). Contribution of sympathetic activation to coronary vasodilatation during the cold pressor test in healthy men: effect of ageing. J Physiol 591, 2937–2947. Schachinger V, Britten MB & Zeiher AM (2000). Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 101, 1899–1906. Seals DR, Jablonski KL & Donato AJ (2011). Aging and vascular endothelial function in humans. Clin Sci (Lond) 120, 357–375. Townsend N, Wickramasinghe K, Bhatnagar P, Smolina K, Nichols M, Leal J, Luengo-Fernandez R & Rayner M (2012). Coronary Heart Disease Statistics, 2012 edition. British Heart Foundation, London. Acknowledgements
Markus B. Sikkel is supported by the Wellcome Trust WT092852
C 2013 The Authors. The Journal of Physiology C 2013 The Physiological Society
J Physiol 591.23 (2013) pp 5807–5808
JOURNAL CLUB
Coronary artery disease and age: beyond atherosclerosis Mit Shah and Markus B. Sikkel NHLI Imperial College London, Hammersmith Hospital, Ducane Road, London, W12 0NN, UK
The Journal of Physiology
Email: [email protected] Coronary artery disease is a major cause of morbidity and mortality in the UK, resulting in 80,000 deaths per year, of which more than 50% occur in patients aged 75 years or more (Townsend et al. 2012). The final common pathway causing death and other manifestations of coronary artery disease (including angina and myocardial infarction) is a reduction in blood flow to the myocardium. Typically, the age-related increase in disease severity has been ascribed to an increasing prevalence of physical obstruction of the coronary arteries caused by atherosclerosis. However, there is increasing evidence that age-related functional impairment of the mechanisms that regulate flow in the coronary arteries may also contribute. Novel insights into this age-related impairment have been possible using a combination of cold-induced stress responses and non-invasive imaging of the coronary arteries. This combination was first exemplified in a study that assessed coronary flow in young and old subjects under conditions of acute whole body cold stress (Gao et al. 2012). Cold stress was used to elevate myocardial oxygen demand and the subsequent coronary haemodynamic response was measured. Appropriate coronary vasodilatation was found to occur only in young subjects and was absent in old subjects, despite their greater myocardial oxygen demand. In a recent issue of the journal, the same group published a study elucidating some of the mechanisms involved (Monahan et al. 2013). The authors assessed how the coronary artery responds to a sympathetoexcitatory stressor, the cold pressor test (CPT), in old healthy men and young healthy controls. They used transthoracic echocardiography to assess coronary vascular resistance (CVR) via a calculation based on measured coronary blood velocity (CBV) in the distal
left anterior descending artery. This non-invasive approach made it ethically acceptable to recruit healthy individuals in their study, in contrast to previous studies using coronary catheterization in which the study populations were limited to individuals in whom the procedure would otherwise be indicated. This allows for the drawing of conclusions on the effects of age on coronary physiology that are not confounded by the effects of coronary disease. One challenge associated with this non-invasive approach is the technical acquisition of precise measures of coronary flow because measurements of coronary diameter are difficult to obtain but are required to calculate flow from velocity measurements. Therefore coronary blood velocity measurements were used as a surrogate for flow. The study builds on the authors’ previous work and tests the hypotheses that there would be greater coronary vasodilatation in young healthy subjects than in old subjects in response to the CPT and that these differences could be abolished by systemic α- and β-adrenergic blockade. Old and young males were well matched at baseline with similar body habitus and were non-smokers, not endurance trained and not taking medication. However, resting systolic and diastolic blood pressures were significantly higher in old subjects (means of 128/76 mmHg vs. 118/62 mmHg). CBV was found to increase in both young and old subjects, but the increase was greater in the younger group. Following adrenergic blockade, there was a reduced increase of CBV in response to CPT in both groups and the difference between the responses of young and old subjects was abrogated. CVR was reduced by CPT in the younger group (CVR −33 ± 6%), but not in the old subjects (CVR −3 ± 4%). Following adrenergic blockade, young subjects retained a slight reduction in CVR in response to CPT, whereas old subjects showed a small, but significant, increase in CVR. The differences between findings in young and old subjects persisted when CVR was corrected to rate pressure product (RPP), a measure of myocardial oxygen demand, suggesting that impaired coronary vasodilatation in old subjects is not merely a result of reduced stimulus for vasodilatation.
C 2013 The Authors. The Journal of Physiology C 2013 The Physiological Society
The novel findings of this study support several conclusions on the role of ageing in the impairment of normal coronary artery physiology. Firstly, transthoracic echocardiography can be used to answer clinically relevant questions regarding coronary physiology and pathophysiology non-invasively. Secondly, the reduction in coronary vasodilatation in response to a sympathetic stimulus in old subjects is confirmed in the context of the use of CPT to induce this stimulus. Thirdly, the age-related difference is eliminated by combined α- and β-adrenergic blockade, which confirms that the difference is attributable to an adrenergic mechanism. Finally, the age-related difference is most likely to reflect a difference in response to the adrenergic stimulus rather than the magnitude of the stimulus itself as RPP is increased to a similar extent in young and old subjects. One potential problem with the measurements used in this study is that changes in CBV are effectively equated to blood flow in order to calculate coronary resistance. This assumes that there is no systematic difference between young and old individuals in the baseline coronary artery cross-sectional area, which may not be the case. In addition, velocity may be influenced by other factors, including differences in lusitropy in the presence of increased sympathetic drive between the groups. However, the authors also include a ‘stimulus–response ratio’ in which CVR is corrected to RPP, which enhances the ability to compare measures between young and old subjects. The authors acknowledge that these findings of age-related differences in responses to CPT do not necessarily localize the physiological differences between young and old individuals purely to the adrenergic system as the control of the coronary vasomotor system is integrative. For example, endothelial dysfunction may play a role as it is known to become more markedly disturbed with age and itself may lead to impaired vasodilatation through reduced nitric oxide bioavailability in response to the increase in shear stress induced by CPT (Seals et al. 2011). A potentially interesting finding that may warrant further exploration is the observation that older men have a more marked drop in blood pressure with combined
DOI: 10.1113/jphysiol.2013.263400
5808 α- and β-adrenergic blockade prior to the application of CPT. This suggests greater tonic adrenergic agonism in old subjects, which may contribute to the reduction in response to CPT as chronically activated adrenoceptors tend to desensitize, in part via a process of receptor internalization. It is unclear whether the findings of this study can be generalized to females or patients with atherosclerosis because other factors may begin to take on greater importance in these groups. Furthermore, although the study groups were appropriately matched for certain confounders (see above), this did not account for other factors, such as serum lipid concentration, which is known to alter endothelial function (Seals et al. 2011), and other risk factors for coronary artery disease, including a positive family history, long-term salt intake and abnormal glucose homeostasis. Clinical application
The work has several potential clinical applications. The vasomotor system in disease has received much attention. For example, Schachinger et al. (2000) demonstrated the prognostic implications of impaired coronary vasodilatation in a prospective study. They assessed coronary vasoreactivity using various tests, including CPT, and used cardiovascular events (cardiovascular death, unstable angina, myocardial infarction, ischaemic stroke, and coronary vessel and peripheral artery intervention) as outcome variables. They found patients who had significantly
Journal Club increased vasoconstriction and blunted vasodilatation to the vasoreactivity tests were more likely to suffer cardiovascular events. Blunted nitroglycerin-induced vasodilatation was also a significant risk factor, which further suggested the critical importance of endothelium-dependent and endothelium-independent vasodilator capacity in predicting atherosclerotic disease progression. The study by Monahan et al. complements these findings and suggests a mechanism that may explain these results. The screening of individuals for CPT-induced changes in coronary artery velocity measured by transthoracic echocardiography may have a role as a measure of risk for cardiac events. The primary prevention of coronary events could then be targeted towards individuals at most risk. Hypertensive patients and those with diabetes (Seals et al. 2011) also show marked vasomotor disturbances and a subsequently increased risk for such events and it may potentially be useful to focus screening on such at-risk populations. These questions can be answered only with larger prospective studies. To conclude, the study by Monahan et al. further elucidates the mechanism of age-related impairment of coronary vasodilatation in older men. The deterioration in the sympathetic control of the coronary vasculature plays a part in the poorer blood supply of myocardium in the elderly male, particularly in response to stress and exertion. As coronary vascular response to CPT is an integrative physiological process, future work to explore the alternative pathways and their contributions
J Physiol 591.23
is warranted. In particular, it would be of interest, and potentially therapeutically relevant, to demonstrate the differential role of changes in α1-, α2- and β2-adrenergic receptor sensitivity, as well as changes in endothelial function in age-related coronary vasomotor dysfunction. The clinical application of the techniques in this study to the screening of populations at risk for vasomotor dysfunction may also be an exciting future direction.
References Gao Z, Wilson TE, Drew RC, Ettinger J & Monahan KD (2012). Altered coronary vascular control during cold stress in healthy older adults. Am J Physiol Heart Circ Physiol 302, H312–H318. Monahan KD, Feehan RP, Sinoway LI & Gao Z (2013). Contribution of sympathetic activation to coronary vasodilatation during the cold pressor test in healthy men: effect of ageing. J Physiol 591, 2937–2947. Schachinger V, Britten MB & Zeiher AM (2000). Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 101, 1899–1906. Seals DR, Jablonski KL & Donato AJ (2011). Aging and vascular endothelial function in humans. Clin Sci (Lond) 120, 357–375. Townsend N, Wickramasinghe K, Bhatnagar P, Smolina K, Nichols M, Leal J, Luengo-Fernandez R & Rayner M (2012). Coronary Heart Disease Statistics, 2012 edition. British Heart Foundation, London. Acknowledgements
Markus B. Sikkel is supported by the Wellcome Trust WT092852
C 2013 The Authors. The Journal of Physiology C 2013 The Physiological Society
