- Email: [email protected]
Beta-Blockers and Exercise
1284
Correspondence
JACC Vol. 48, No. 6, 2006 September 19, 2006:1283–8
REPLY We thank Drs. Bahl and Chongtham for their interest in our study on the effects of atorvastatin on systolic function and markers of inflammation in patients with nonischemic heart failure (HF) (1). We agree with them that nonischemic HF represents a heterogeneous condition with various etiologies. The authors correctly point out that duration of illness is an important determinant in response to therapy in patients with nonischemic HF. Patients with newly diagnosed nonischemic HF, for example, may have myocarditis with transient left ventricular (LV) systolic function followed by a spontaneous improvement in ventricular function, regardless of medical therapy. We disagree, however, that patients in this trial should have been randomized according to duration of illness. The inclusion criteria for this study required that patients on stable HF medications for at least three months before study entry, effectively excluding patients with more transient forms of nonischemic HF that may be likely to resolve spontaneously. Moreover, we believe that other factors play a much more important role in determining response to therapy and long-term prognosis in these patients. For example, Felker et al. (2) followed 1,230 patients with nonischemic HF for an average of 4.4 years and found that older age, male gender, and etiology of HF were associated with increased mortality. Other teams have demonstrated that prognosis in this group of patients is primarily determined by age, LV ejection fraction, and symptomatic HF (3,4). In conclusion, our study demonstrated that therapy with atorvastatin improved LV systolic function and markers of inflammation in patients with chronic forms of nonischemic HF—results that we believe were relatively unbiased by duration of illness. Srikanth Sola, MD *Bobby V. Khan, MD, PhD *Emory University School of Medicine Cardiology 69 Jesse Hill Drive SE C233 Atlanta, Georgia 30303 E-mail: [email protected] doi:10.1016/j.jacc.2006.06.030
REFERENCES 1. Sola S, Mir MQS, Lerakis S, Tandon N, Khan BV. Atorvastatin improves left ventricular systolic function and serum markers of inflammation in non-ischemic heart failure. J Am Coll Cardiol 2006;47: 332–7. 2. Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000;342:1077– 84. 3. Bard BA, Shaw LK, McCants CB, et al. Clinical determinants of mortality in patients with angiographically diagnosed ischemic or nonischemic cardiomyopathy. J Am Coll Cardiol 1997;30:1002– 8. 4. Felker GM, Jaeger CJ, Klodas E. Myocarditis and long-term survival in peripartum cardiomyopathy. Am Heart J 2000;140:785–91.
Beta-Blockers and Exercise In a recent issue of JACC, Kokkinos et al. (1), after evaluating the role of beta-blockers at mitigating exercise-induced blood pres-
sure (BP) rise in hypertensive men, concluded that “for patients engaging in vigorous activities such as snow-shoveling, basketball, tennis, racquetball, and so on, beta-blockade– based therapy can protect against excessive and repetitive elevations in BP which may occur during such activities.” Earlier studies have shown that beta-blockers bring about a clear reduction in exercise endurance in young healthy subjects (2,3) and trained sportsmen (4,5). Similarly, in patients with hypertension who are on beta-blockers, the reduction in exercise tolerance in part could be attributable to be secondary to these drugs (6). In the study by Kokkinos et al. (1), both the exercise duration and the total metabolic equivalents achieved were significantly lower in the group on beta-blockers compared to other medications. In the ASCOT–BPLA (Anglo-Scandinavian Cardiac Outcome Trial– Blood Pressure Lowering Arm) study of 19,257 patients with hypertension and at least three other coronary risk factors but no coronary artery disease, atenolol-based treatment resulted in a 14% higher risk of coronary events and a 23% increase in stroke rate compared to amlodipine-based regimen (7). In a recent metaanalysis of 134,000 patients on antihypertensive therapy, betablocker treatment was associated with a 16% higher incidence of stroke compared to other antihypertensive treatments (8). Of note, beta-blockers have recently been shown to differ in their effect on central aortic BP compared to peripheral brachial pressure. The Conduit Artery Functional Endpoint (CAFÉ trial) and other studies have documented that beta-blockers have a lesser effect on central systolic pressure than do angiotensin-converting enzyme (ACE) inhibitors, diuretics, and calcium antagonists (9 –11). In fact, results of the CAFÉ (12) study show that a calcium antagonist– based treatment is much more effective at reducing central aortic BP than is a conventional atenolol-based (betablocker) regimen. Importantly, the study also suggests that the central aortic BP may be more predictive of cardiovascular events, such as stroke and myocardial infarction, than traditional peripheral (brachial) BP measurements (12). We believe, therefore, that a conclusion, such as the above, based on peripheral BP measurements may be inappropriate. For hypertensive patients engaging in “vigorous activities,” we do need a medication that curtails their (central) BP rise but not one that curtails their activity. Sripal Bangalore, MD, MHA *Franz H. Messerli, MD *Hypertension Program Division of Cardiology Columbia University College of Physicians and Surgeons St. Luke’s–Roosevelt Hospital Center 1000 Tenth Avenue, Suite 3B-30 New York, New York 10025 E-mail: [email protected] doi:10.1016/j.jacc.2006.06.038
REFERENCES 1. Kokkinos P, Chrysohoou C, Panagiotakos D, Narayan P, Greenberg M, Singh S. Beta-blockade mitigates exercise blood pressure in hypertensive male patients. J Am Coll Cardiol 2006;47:794 – 8. 2. Folgering H, van Bussel M. Maximal exercise power after a single dose of metoprolol and of slow-release metoprolol. Eur J Clin Pharmacol 1980;18:225–9.
Correspondence
JACC Vol. 48, No. 6, 2006 September 19, 2006:1283–8 3. Wilmore JH, Freund BJ, Joyner MJ, et al. Acute response to submaximal and maximal exercise consequent to beta-adrenergic blockade: implications for the prescription of exercise. Am J Cardiol 1985;55:135D– 41D. 4. Anderson RL, Wilmore JH, Joyner MJ, et al. Effects of cardioselective and nonselective beta-adrenergic blockade on the performance of highly trained runners. Am J Cardiol 1985;55:149D–54D. 5. Vanhees L, Fagard R, Lijnen P, Amery A. Effect of antihypertensive medication on endurance exercise capacity in hypertensive sportsmen. J Hypertens 1991;9:1063– 8. 6. Lim PO, MacFadyen RJ, Clarkson PB, MacDonald TM. Impaired exercise tolerance in hypertensive patients. Ann Intern Med 1996; 124(1 Pt 1):41–55. 7. Dahlof B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895–906. 8. Lindholm LH, Carlberg B, Samuelsson O. Should beta-blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005;366:1545–53. 9. London GM, Marchais SJ, Guerin AP, Pannier B. Arterial stiffness: pathophysiology and clinical impact. Clin Exp Hypertens 2004;26: 689 –99. 10. Morgan T, Lauri J, Bertram D, Anderson A. Effect of different antihypertensive drug classes on central aortic pressure. Am J Hypertens 2004;17:118 –23. 11. Hirata K, Vlachopoulos C, Adji A, O’Rourke MF. Benefits from angiotensin-converting enzyme inhibitor ‘beyond blood pressure lowering’: beyond blood pressure or beyond the brachial artery? J Hypertens 2005;23:551– 6. 12. Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes. Principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 2006;113:1213–25.
REPLY We appreciate Drs. Bangalore and Messerli’s interest in our study (1). In their letter to the editor they argue that our statement—“for patients engaging in vigorous activities . . . -blockade-based therapy can protect against excessive and repetitive elevations in blood pressure (BP) which may occur during such activities”—may be inappropriate because it is based on peripheral BP measurements. They present evidence for greater risk of cardiovascular events or lower-risk reduction with beta-blockers versus other antihypertensive agents (2– 4) and they suggest that this lower risk is due to lower central BP achieved by antihypertensive agents other than beta-blockers, as supported by the 4.3-mm Hg lower central BP reported in the CAFÉ trial (4). Finally, they suggest that for hypertensive patients “we do need a medication that curtails their (central) BP rise but not one that curtails their activity.” We agree that beta-blockers are not as effective in reducing stroke rates when compared to other antihypertensive agents. However, it is important to point out that there are no data on therapies and outcomes in hypertensive patients with an exaggerated BP response to exercise. Our statement is based on observations that the exercise BP on those treated with beta-blockers was 14 –19 mm Hg lower at different workloads and for different antihypertensive agents. Most will agree that the relationship between central and peripheral BP is direct, and a change in one (central or peripheral) will result in a proportional change in the same direction on the other. Therefore, it is reasonable to assume that a peripheral exercise BP that is 14 –19 mm Hg lower than the BP of those treated with antihy-
1285
pertensive agents other than beta-blockers is more likely to reflect a proportionally lower than higher central BP. We also agree that beta-blockers reduce exercise time. The peak exercise time in our patients on beta-blocker-based therapy was lower by 19 s compared to the other agents. However, we are confident that most health care providers and patients will gladly trade 19-s reduction in peak exercise time for 19-mm Hg lower systolic BP during physical activities. *Peter F. Kokkinos, PhD Steven Singh, MD Puneet Narayan, MD *Veterans Affairs Medical Center/Cardiology 50 Irving Street NW Washington, DC 20422 E-mail: [email protected] doi:10.1016/j.jacc.2006.06.037
REFERENCES 1. Kokkinos P, Chrysohoou C, Panagiotakos D, Narayan P, Greenberg M, Singh S. Beta-blockade mitigates exercise blood pressure in hypertensive male patients. J Am Coll Cardiol 2006;47:794 – 8. 2. Dahlof B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT–BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895–906. 3. Lindholm LH, Carlberg B, Samuelsson O. Should beta-blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005;366:1545–53. 4. Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes. Principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 2006;113:1213–25.
Standard Deviation of Sequential FiveMinute R-R Interval Means (SDANN) Is a Prognostic Marker, but Not Necessarily an Autonomic Marker The recent study by Fantoni et al. (1) provides strong data that standard deviation of sequential 5-minute R-R interval means (SDANN, a long-term measure of heart rate variability [HRV]) is an important clinical tool. The researchers have convincingly shown that 1) successful cardiac resynchronization therapy (CRT) improved SDANN and 2) that an early improvement in SDANN predicted a favorable long-term outcome. The investigators interpret this increase in SDANN as reflecting changes in autonomic tone, specifically modifications of the sympathetic nervous system and parasympathetic nervous system interactions in the heart. Although we agree that short-term measures of HRV such as high-frequency (0.15 to 0.4 Hz) and low-frequency (0.04 to 0.15 Hz) variability have been shown to be modulated by the autonomic nervous system, there are no data showing that SDANN is a reflection of the autonomic nervous system. In contrast, we have shown that SDANN is heavily influenced by physical activity. In an earlier study, the largest contributions to the SDANN came around the transitions going into and waking from sleep (2). We have also shown in both patients with heart failure and in healthy subjects that SDANN significantly increased by changing
Correspondence
JACC Vol. 48, No. 6, 2006 September 19, 2006:1283–8
REPLY We thank Drs. Bahl and Chongtham for their interest in our study on the effects of atorvastatin on systolic function and markers of inflammation in patients with nonischemic heart failure (HF) (1). We agree with them that nonischemic HF represents a heterogeneous condition with various etiologies. The authors correctly point out that duration of illness is an important determinant in response to therapy in patients with nonischemic HF. Patients with newly diagnosed nonischemic HF, for example, may have myocarditis with transient left ventricular (LV) systolic function followed by a spontaneous improvement in ventricular function, regardless of medical therapy. We disagree, however, that patients in this trial should have been randomized according to duration of illness. The inclusion criteria for this study required that patients on stable HF medications for at least three months before study entry, effectively excluding patients with more transient forms of nonischemic HF that may be likely to resolve spontaneously. Moreover, we believe that other factors play a much more important role in determining response to therapy and long-term prognosis in these patients. For example, Felker et al. (2) followed 1,230 patients with nonischemic HF for an average of 4.4 years and found that older age, male gender, and etiology of HF were associated with increased mortality. Other teams have demonstrated that prognosis in this group of patients is primarily determined by age, LV ejection fraction, and symptomatic HF (3,4). In conclusion, our study demonstrated that therapy with atorvastatin improved LV systolic function and markers of inflammation in patients with chronic forms of nonischemic HF—results that we believe were relatively unbiased by duration of illness. Srikanth Sola, MD *Bobby V. Khan, MD, PhD *Emory University School of Medicine Cardiology 69 Jesse Hill Drive SE C233 Atlanta, Georgia 30303 E-mail: [email protected] doi:10.1016/j.jacc.2006.06.030
REFERENCES 1. Sola S, Mir MQS, Lerakis S, Tandon N, Khan BV. Atorvastatin improves left ventricular systolic function and serum markers of inflammation in non-ischemic heart failure. J Am Coll Cardiol 2006;47: 332–7. 2. Felker GM, Thompson RE, Hare JM, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 2000;342:1077– 84. 3. Bard BA, Shaw LK, McCants CB, et al. Clinical determinants of mortality in patients with angiographically diagnosed ischemic or nonischemic cardiomyopathy. J Am Coll Cardiol 1997;30:1002– 8. 4. Felker GM, Jaeger CJ, Klodas E. Myocarditis and long-term survival in peripartum cardiomyopathy. Am Heart J 2000;140:785–91.
Beta-Blockers and Exercise In a recent issue of JACC, Kokkinos et al. (1), after evaluating the role of beta-blockers at mitigating exercise-induced blood pres-
sure (BP) rise in hypertensive men, concluded that “for patients engaging in vigorous activities such as snow-shoveling, basketball, tennis, racquetball, and so on, beta-blockade– based therapy can protect against excessive and repetitive elevations in BP which may occur during such activities.” Earlier studies have shown that beta-blockers bring about a clear reduction in exercise endurance in young healthy subjects (2,3) and trained sportsmen (4,5). Similarly, in patients with hypertension who are on beta-blockers, the reduction in exercise tolerance in part could be attributable to be secondary to these drugs (6). In the study by Kokkinos et al. (1), both the exercise duration and the total metabolic equivalents achieved were significantly lower in the group on beta-blockers compared to other medications. In the ASCOT–BPLA (Anglo-Scandinavian Cardiac Outcome Trial– Blood Pressure Lowering Arm) study of 19,257 patients with hypertension and at least three other coronary risk factors but no coronary artery disease, atenolol-based treatment resulted in a 14% higher risk of coronary events and a 23% increase in stroke rate compared to amlodipine-based regimen (7). In a recent metaanalysis of 134,000 patients on antihypertensive therapy, betablocker treatment was associated with a 16% higher incidence of stroke compared to other antihypertensive treatments (8). Of note, beta-blockers have recently been shown to differ in their effect on central aortic BP compared to peripheral brachial pressure. The Conduit Artery Functional Endpoint (CAFÉ trial) and other studies have documented that beta-blockers have a lesser effect on central systolic pressure than do angiotensin-converting enzyme (ACE) inhibitors, diuretics, and calcium antagonists (9 –11). In fact, results of the CAFÉ (12) study show that a calcium antagonist– based treatment is much more effective at reducing central aortic BP than is a conventional atenolol-based (betablocker) regimen. Importantly, the study also suggests that the central aortic BP may be more predictive of cardiovascular events, such as stroke and myocardial infarction, than traditional peripheral (brachial) BP measurements (12). We believe, therefore, that a conclusion, such as the above, based on peripheral BP measurements may be inappropriate. For hypertensive patients engaging in “vigorous activities,” we do need a medication that curtails their (central) BP rise but not one that curtails their activity. Sripal Bangalore, MD, MHA *Franz H. Messerli, MD *Hypertension Program Division of Cardiology Columbia University College of Physicians and Surgeons St. Luke’s–Roosevelt Hospital Center 1000 Tenth Avenue, Suite 3B-30 New York, New York 10025 E-mail: [email protected] doi:10.1016/j.jacc.2006.06.038
REFERENCES 1. Kokkinos P, Chrysohoou C, Panagiotakos D, Narayan P, Greenberg M, Singh S. Beta-blockade mitigates exercise blood pressure in hypertensive male patients. J Am Coll Cardiol 2006;47:794 – 8. 2. Folgering H, van Bussel M. Maximal exercise power after a single dose of metoprolol and of slow-release metoprolol. Eur J Clin Pharmacol 1980;18:225–9.
Correspondence
JACC Vol. 48, No. 6, 2006 September 19, 2006:1283–8 3. Wilmore JH, Freund BJ, Joyner MJ, et al. Acute response to submaximal and maximal exercise consequent to beta-adrenergic blockade: implications for the prescription of exercise. Am J Cardiol 1985;55:135D– 41D. 4. Anderson RL, Wilmore JH, Joyner MJ, et al. Effects of cardioselective and nonselective beta-adrenergic blockade on the performance of highly trained runners. Am J Cardiol 1985;55:149D–54D. 5. Vanhees L, Fagard R, Lijnen P, Amery A. Effect of antihypertensive medication on endurance exercise capacity in hypertensive sportsmen. J Hypertens 1991;9:1063– 8. 6. Lim PO, MacFadyen RJ, Clarkson PB, MacDonald TM. Impaired exercise tolerance in hypertensive patients. Ann Intern Med 1996; 124(1 Pt 1):41–55. 7. Dahlof B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895–906. 8. Lindholm LH, Carlberg B, Samuelsson O. Should beta-blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005;366:1545–53. 9. London GM, Marchais SJ, Guerin AP, Pannier B. Arterial stiffness: pathophysiology and clinical impact. Clin Exp Hypertens 2004;26: 689 –99. 10. Morgan T, Lauri J, Bertram D, Anderson A. Effect of different antihypertensive drug classes on central aortic pressure. Am J Hypertens 2004;17:118 –23. 11. Hirata K, Vlachopoulos C, Adji A, O’Rourke MF. Benefits from angiotensin-converting enzyme inhibitor ‘beyond blood pressure lowering’: beyond blood pressure or beyond the brachial artery? J Hypertens 2005;23:551– 6. 12. Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes. Principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 2006;113:1213–25.
REPLY We appreciate Drs. Bangalore and Messerli’s interest in our study (1). In their letter to the editor they argue that our statement—“for patients engaging in vigorous activities . . . -blockade-based therapy can protect against excessive and repetitive elevations in blood pressure (BP) which may occur during such activities”—may be inappropriate because it is based on peripheral BP measurements. They present evidence for greater risk of cardiovascular events or lower-risk reduction with beta-blockers versus other antihypertensive agents (2– 4) and they suggest that this lower risk is due to lower central BP achieved by antihypertensive agents other than beta-blockers, as supported by the 4.3-mm Hg lower central BP reported in the CAFÉ trial (4). Finally, they suggest that for hypertensive patients “we do need a medication that curtails their (central) BP rise but not one that curtails their activity.” We agree that beta-blockers are not as effective in reducing stroke rates when compared to other antihypertensive agents. However, it is important to point out that there are no data on therapies and outcomes in hypertensive patients with an exaggerated BP response to exercise. Our statement is based on observations that the exercise BP on those treated with beta-blockers was 14 –19 mm Hg lower at different workloads and for different antihypertensive agents. Most will agree that the relationship between central and peripheral BP is direct, and a change in one (central or peripheral) will result in a proportional change in the same direction on the other. Therefore, it is reasonable to assume that a peripheral exercise BP that is 14 –19 mm Hg lower than the BP of those treated with antihy-
1285
pertensive agents other than beta-blockers is more likely to reflect a proportionally lower than higher central BP. We also agree that beta-blockers reduce exercise time. The peak exercise time in our patients on beta-blocker-based therapy was lower by 19 s compared to the other agents. However, we are confident that most health care providers and patients will gladly trade 19-s reduction in peak exercise time for 19-mm Hg lower systolic BP during physical activities. *Peter F. Kokkinos, PhD Steven Singh, MD Puneet Narayan, MD *Veterans Affairs Medical Center/Cardiology 50 Irving Street NW Washington, DC 20422 E-mail: [email protected] doi:10.1016/j.jacc.2006.06.037
REFERENCES 1. Kokkinos P, Chrysohoou C, Panagiotakos D, Narayan P, Greenberg M, Singh S. Beta-blockade mitigates exercise blood pressure in hypertensive male patients. J Am Coll Cardiol 2006;47:794 – 8. 2. Dahlof B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT–BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895–906. 3. Lindholm LH, Carlberg B, Samuelsson O. Should beta-blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005;366:1545–53. 4. Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes. Principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 2006;113:1213–25.
Standard Deviation of Sequential FiveMinute R-R Interval Means (SDANN) Is a Prognostic Marker, but Not Necessarily an Autonomic Marker The recent study by Fantoni et al. (1) provides strong data that standard deviation of sequential 5-minute R-R interval means (SDANN, a long-term measure of heart rate variability [HRV]) is an important clinical tool. The researchers have convincingly shown that 1) successful cardiac resynchronization therapy (CRT) improved SDANN and 2) that an early improvement in SDANN predicted a favorable long-term outcome. The investigators interpret this increase in SDANN as reflecting changes in autonomic tone, specifically modifications of the sympathetic nervous system and parasympathetic nervous system interactions in the heart. Although we agree that short-term measures of HRV such as high-frequency (0.15 to 0.4 Hz) and low-frequency (0.04 to 0.15 Hz) variability have been shown to be modulated by the autonomic nervous system, there are no data showing that SDANN is a reflection of the autonomic nervous system. In contrast, we have shown that SDANN is heavily influenced by physical activity. In an earlier study, the largest contributions to the SDANN came around the transitions going into and waking from sleep (2). We have also shown in both patients with heart failure and in healthy subjects that SDANN significantly increased by changing