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Cumulative exercise-induced left ventricular systolic and diastolic dysfunction in hypertrophic cardiomyopathy
International Journal of Cardiology 122 (2007) 76 – 78 www.elsevier.com/locate/ijcard
Letter to the Editor
Cumulative exercise-induced left ventricular systolic and diastolic dysfunction in hypertrophic cardiomyopathy☆ Francesco Pelliccia a,b,⁎, Cinzia Cianfrocca a , Christian Pristipino a , Vincenzo Pasceri a , Antonio Auriti a , Giuseppe Richichi a , Enrico Mangieri b , Carlo Gaudio b a
Department of Cardiovascular Diseases, San Filippo Neri Hospital, Rome, Italy b Department “Attilio Reale”, University “La Sapienza”, Rome, Italy Received 12 August 2006; accepted 2 November 2006 Available online 29 December 2006
Abstract The phenomenon of cumulative exercise-induced left ventricular function impairment was studied in 40 patients with non-obstructive hypertrophic cardiomyopathy with resting normal left ventricular function and no increase in ejection fraction on exercise. All patients underwent two symptom-limited exercise tests one-hour apart. Cumulative myocardial dysfunction was seen in 13 patients (group I) but not in the remaining 27 patients (group II). During follow-up, group I showed more commonly than group II a deterioration in symptoms (67% vs 22%, P = 0.025) and left ventricular function (50% vs 9%, P = 0.019). In conclusion, cumulative exercise-induced myocardial dysfunction can occur in hypertrophic cardiomyopathy and may be associated with clinical deterioration and worse outcome. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Echocardiography; Exercise stress test; Hypertrophic cardiomyopathy; Left ventricular function; Myocardial dysfunction
In hypertrophic cardiomyopathy, left ventricular contraction is usually normal or even supernormal [1], and asymptomatic patients are not generally adviced about daily physical activities [2] with the exception of athletes who are precluded from competitive sports to reduce the risk of sudden cardiac death [3]. Similarly to what has been observed in ischemic heart disease [4], however, it is possible that the occurrence of repetitive episodes of myocardial dysfunction is common also in hypertrophic cardiomyopathy and that it might be associated with evolution of the disease. To address this issue, we prospectively evaluated 87 patients with non-obstructive hypertrophic cardiomyopathy. For the purpose of the study, only patients who had normal ☆
This paper was presented in part at the Annual Scientific Session of the American College of Cardiology, 6–9 March, 2004, New Orleans, Louisiana. ⁎ Corresponding author. Viale Liegi 49, 00198 Rome, Italy. Tel.: +39 348 339 2006; fax: +39 06 330 6251. E-mail address: [email protected] (F. Pelliccia). 0167-5273/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.11.030
left ventricular systolic function at rest (i.e. baseline left ventricular ejection fraction N 50%) but showed no increase in ejection fraction with exercise were considered. Other inclusion criteria were a New York Heart Association functional class I, no left bundle branch block on 12-lead electrocardiogram, normal exercise capacity, no stress-induced rhythm disturbances or hypotension, no evidence of moderate to severe mitral regurgitation, and no indication to surgery. Accordingly, 40 patients (26 men, age: 55 ± 16 years) could be included in the study. A control group of 10 agematched normal volunteers (6 men, age: 54 ± 11 years) was also evaluated. Both patients and controls underwent offdrugs two consecutive symptom-limited bicycle exercise tests, one-hour apart, and cumulative myocardial dysfunction was diagnosed if a more prolonged and greater deterioration in left ventricular systolic function after the repeat exercise stress test was found [5,6]. Doppler echocardiography was performed at baseline, at peak exercise, and at 30 and 60 min after each test. Cardiac dimensions were measured according to the recommendations of the American Society of Echocardiography. Left ventricular fractional shortening
F. Pelliccia et al. / International Journal of Cardiology 122 (2007) 76–78
77
Table 1 Echocardiographic and Doppler findings before and after the two exercise stress tests Baseline
EF (%)
Group I Group II Controls FS (%) Group I Group II Controls Peak E Group I (cm/s) Group II Controls Peak A Group I (cm/s) Group II Controls E/A Group I ratio Group II Controls DT (ms) Group I Group II Controls
60 ± 11 64 ± 10 66 ± 5 36 ± 9 38 ± 10 45 ± 10 50 ± 15 52 ± 16 71 ± 14 61 ± 16 64 ± 18 43 ± 11 0.82 ± 0.21 0.81 ± 0.27 1.65 ± 0.61 156 ± 38 151 ± 32 192 ± 31
Exercise test 1
P†
Exercise test 2
Peak exercise
Post exercise 30 min
Post exercise 60 min
Peak exercise
Post exercise 30 min
Post exercise 60 min
48 ± 12⁎ 62 ± 9 73 ± 9 27 ± 11 33 ± 9 53 ± 9 42 ± 19 45 ± 18 85 ± 18 95 ± 17⁎ 73 ± 15 73 ± 15 0.44 ± 0.25⁎ 0.61 ± 0.21 1.16 ± 0.44 121 ± 32 127 ± 35 211 ± 24
51 ± 10⁎ 60 ± 11 70 ± 7 30 ± 9 35 ± 10 50 ± 10 48 ± 15 43 ± 14 80 ± 17 87 ± 19⁎ 68 ± 18 50 ± 15 0.55 ± 0.28 0.63 ± 0.32 1.60 ± 0.39 143 ± 37 148 ± 36 194 ± 36
59 ± 9 65 ± 11 67 ± 6 38 ± 10 36 ± 11 51 ± 11 51 ± 18 49 ± 19 70 ± 15 70 ± 17 69 ± 19 45 ± 13 0.70 ± 0.30 0.71 ± 0.38 1.55 ± 0.41 150 ± 32 157 ± 33 191 ± 28
44 ± 11⁎ 61 ± 10 71 ± 8 23 ± 11⁎ 34 ± 10 50 ± 10 38 ± 19 45 ± 15 84 ± 19 100 ± 21⁎ 70 ± 20 77 ± 16 0.38 ± 0.27⁎ 0.64 ± 0.31 1.09 ± 0.50 118 ± 34 128 ± 38 222 ± 29
45 ± 9⁎ 63 ± 10 74 ± 9 26 ± 9⁎ 34 ± 9 52 ± 10 43 ± 16 47 ± 18 77 ± 18 98 ± 18⁎ 66 ± 16 49 ± 16 0.44 ± 0.31⁎ 0.71 ± 0.32 1.57 ± 0.47 123 ± 31⁎ 150 ± 32 195 ± 29
46 ± 10⁎ 64 ± 12 68 ± 6 25 ± 10⁎ 37 ± 12 48 ± 12 45 ± 13 48 ± 17 76 ± 15 88 ± 19⁎ 65 ± 18 40 ± 13 0.51 ± 0.29⁎ 0.74 ± 0.30 1.82 ± 0.51 129 ± 39⁎ 159 ± 38 190 ± 35
b0.001 NS NS b0.001 NS NS NS NS NS b0.001 NS b0.001 b0.001 NS b0.05 b0.05 b0.05 NS
DT: deceleration time; EF: ejection fraction; FS: fractional shortening; †P refers to comparisons within group; ⁎P b 0.05 versus Group II.
and ejection fraction (area-length single-plan method) were assessed from all examinations. Doppler parameters of left ventricular diastolic function were derived from the mitral inflow profile. All patients were seen at 1-year intervals during follow-up. Patients were precluded from any competitive sport [3], but no specific advice on work activities was given. Most patients were treated with beta-blockers or verapamil, and none underwent myotomy–myectomy during the period of analysis. Cumulative exercise-induced left ventricular dysfunction was diagnosed in a total of 13 patients (8 men, age 52 ± 13 years, group I) who had a significantly lower left ventricular ejection fraction 60 min after the second exercise test than 60 min after the first test (46 ± 10% vs 59 ± 9%, P = 0.005). The remaining 27 patients (18 men, age 57 ± 16 years, group II) had similar values of left ventricular ejection fraction 1 h after both the first and the second exercise tests (64 ± 12% vs 65 ± 11%, NS). Echocardiographic and Doppler findings before and after the two exercise stress tests in controls and in the two groups of patients are shown in Table 1. Differences in ejection fraction between groups were paralleled by similar difference in fractional shortening. Also, left ventricular diastolic function worsened to a greater extent in group I than in group II after the second exercise test than after the first one. All presenting features were similar in the two groups, with only maximal left ventricular wall thickness being significantly greater in group I than group II (23 ± 6 vs 18 ± 5 mm, P b 0.005). During a follow-up of 6 ± 4 years, 2 patients died suddenly (1 of group I and 1 of group II) and 3 patients (1 of group I and 2 of group II) did not undergo serial ultrasound evaluations. In the remaining 35 patients (12 of group I and 23 of group II), symptoms worsened more
commonly in group I than in group II (8/12 patients versus 5/ 23 patients, P = 0.025). Serial echocardiographic evaluations showed that left ventricular ejection fraction decreased significantly in group I (from 60 ± 11 to 49 ± 10%, P = 0.018) but slightly in group II (from 64 ± 10 to 61 ± 11%, NS). Noteworthy, a significant decrease in left ventricular ejection fraction occurred even in group I patients with high baseline values (Fig. 1). Overall, progressive myocardial dysfunction occurred in 6 patients of group I and in only 2 patients of group II (50% vs 9%, P = 0.019). Specifically, a left ventricular ejection fraction b 50% developed in 3 patients of group I and in 2 patients of group II, and an increase in left ventricular end-diastolic diameter N 5 mm was seen only in 3 patients of group I. The present data document that repeated episodes of exercise-induced left ventricular dysfunction have a
Fig. 1. Individual data for left ventricular ejection fraction at baseline and at last follow-up evaluation in patients of group I and group II.
78
F. Pelliccia et al. / International Journal of Cardiology 122 (2007) 76–78
cumulative effect in cardiomyopathic patients, which makes impairment of cardiac contractility more pronounced and longer lasting well after cessation of exercise. Along with cumulative systolic dysfunction, we have found that also diastolic abnormalities can accumulate in hypertrophic cardiomyopathy. Indeed, diastolic function paralleled changes in left ventricular contractility and remained more transiently impaired as a result of repeat exercise in a subset of our patients. These novel findings indicate that strenuous exercise may consistently affect all aspects of cardiac function in cardiomyopathy, similarly to what occurs in coronary artery disease [7]. In ischemic heart disease, serial episodes of exerciseinduced dysfunction can lead to progressive left ventricular remodeling and worsening of the contractile function [4]. Similarly, our findings suggest a possible link between repetitive left ventricular dysfunction and clinical deterioration in hypertrophic cardiomyopathy, as changes over time in left ventricular morphology and/or function occurred mainly in those patients who had evidence of cumulative myocardial dysfunction. In conclusion, cumulative exercise-induced myocardial dysfunction can occur in a subset of patients with hypertrophic cardiomyopathy and may be associated with clinical deterioration and worse outcome. The possibility that repetitive episodes of left ventricular impairment during daily life play an important pathophysiologic role in hypertrophic cardiomyopathy has relevant clinical implications. Our findings suggest that some cardiomyopathic patients, apart from being precluded from competitive sports [3], should be adviced to avoid repetitive, heavy activities during daily life
even if asymptomatic and with a normal systolic function. To this end, the use of two consecutive symptom-limited exercise tests one-hour apart appears to constitute a simple and reliable tool for identifying the subgroup of patients with cumulative myocardial dysfunction at higher risk of clinical deterioration. References [1] Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA 2002;287:1308–20. [2] Wald DS, Law M, Morris JK. Mortality from hypertrophic cardiomyopathy in England and Wales: clinical and screening implications. Int J Cardiol 2004;97:479–84. [3] Pelliccia A, Fagard R, Bjornstad HH. Recommendations for competitive sports participation in athletes with cardiovascular disease: a consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J 2005;26:1422–45. [4] Camici PG, Dukta DP. Repetitive stunning, hibernation, and heart failure: contribution of PET to establishing a link. Am J Physiol Heart Circ Physiol 2001;280:H929–36. [5] Homans DC, Laxson DD, Sublett F, et al. Cumulative deterioration of myocardial function after repeated episodes of exercise induced ischemia. Am J Physiol 1989;256:H1462–71. [6] Rinaldi CA, Masani ND, Linka AZ, Hall RJ. Effect of repetitive episodes of exercise induced myocardial ischaemia on left ventricular function in patients with chronic stable angina: evidence for cumulative stunning or ischaemic preconditioning? Heart 1999;81:404–11. [7] Stoddard MF, Johnstone J, Dillon S, Kupersmith J. The effect of exercise-induced myocardial ischemia on postischemic left ventricular diastolic filling. Clin Cardiol 1992;15:265–73.
Letter to the Editor
Cumulative exercise-induced left ventricular systolic and diastolic dysfunction in hypertrophic cardiomyopathy☆ Francesco Pelliccia a,b,⁎, Cinzia Cianfrocca a , Christian Pristipino a , Vincenzo Pasceri a , Antonio Auriti a , Giuseppe Richichi a , Enrico Mangieri b , Carlo Gaudio b a
Department of Cardiovascular Diseases, San Filippo Neri Hospital, Rome, Italy b Department “Attilio Reale”, University “La Sapienza”, Rome, Italy Received 12 August 2006; accepted 2 November 2006 Available online 29 December 2006
Abstract The phenomenon of cumulative exercise-induced left ventricular function impairment was studied in 40 patients with non-obstructive hypertrophic cardiomyopathy with resting normal left ventricular function and no increase in ejection fraction on exercise. All patients underwent two symptom-limited exercise tests one-hour apart. Cumulative myocardial dysfunction was seen in 13 patients (group I) but not in the remaining 27 patients (group II). During follow-up, group I showed more commonly than group II a deterioration in symptoms (67% vs 22%, P = 0.025) and left ventricular function (50% vs 9%, P = 0.019). In conclusion, cumulative exercise-induced myocardial dysfunction can occur in hypertrophic cardiomyopathy and may be associated with clinical deterioration and worse outcome. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Echocardiography; Exercise stress test; Hypertrophic cardiomyopathy; Left ventricular function; Myocardial dysfunction
In hypertrophic cardiomyopathy, left ventricular contraction is usually normal or even supernormal [1], and asymptomatic patients are not generally adviced about daily physical activities [2] with the exception of athletes who are precluded from competitive sports to reduce the risk of sudden cardiac death [3]. Similarly to what has been observed in ischemic heart disease [4], however, it is possible that the occurrence of repetitive episodes of myocardial dysfunction is common also in hypertrophic cardiomyopathy and that it might be associated with evolution of the disease. To address this issue, we prospectively evaluated 87 patients with non-obstructive hypertrophic cardiomyopathy. For the purpose of the study, only patients who had normal ☆
This paper was presented in part at the Annual Scientific Session of the American College of Cardiology, 6–9 March, 2004, New Orleans, Louisiana. ⁎ Corresponding author. Viale Liegi 49, 00198 Rome, Italy. Tel.: +39 348 339 2006; fax: +39 06 330 6251. E-mail address: [email protected] (F. Pelliccia). 0167-5273/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2006.11.030
left ventricular systolic function at rest (i.e. baseline left ventricular ejection fraction N 50%) but showed no increase in ejection fraction with exercise were considered. Other inclusion criteria were a New York Heart Association functional class I, no left bundle branch block on 12-lead electrocardiogram, normal exercise capacity, no stress-induced rhythm disturbances or hypotension, no evidence of moderate to severe mitral regurgitation, and no indication to surgery. Accordingly, 40 patients (26 men, age: 55 ± 16 years) could be included in the study. A control group of 10 agematched normal volunteers (6 men, age: 54 ± 11 years) was also evaluated. Both patients and controls underwent offdrugs two consecutive symptom-limited bicycle exercise tests, one-hour apart, and cumulative myocardial dysfunction was diagnosed if a more prolonged and greater deterioration in left ventricular systolic function after the repeat exercise stress test was found [5,6]. Doppler echocardiography was performed at baseline, at peak exercise, and at 30 and 60 min after each test. Cardiac dimensions were measured according to the recommendations of the American Society of Echocardiography. Left ventricular fractional shortening
F. Pelliccia et al. / International Journal of Cardiology 122 (2007) 76–78
77
Table 1 Echocardiographic and Doppler findings before and after the two exercise stress tests Baseline
EF (%)
Group I Group II Controls FS (%) Group I Group II Controls Peak E Group I (cm/s) Group II Controls Peak A Group I (cm/s) Group II Controls E/A Group I ratio Group II Controls DT (ms) Group I Group II Controls
60 ± 11 64 ± 10 66 ± 5 36 ± 9 38 ± 10 45 ± 10 50 ± 15 52 ± 16 71 ± 14 61 ± 16 64 ± 18 43 ± 11 0.82 ± 0.21 0.81 ± 0.27 1.65 ± 0.61 156 ± 38 151 ± 32 192 ± 31
Exercise test 1
P†
Exercise test 2
Peak exercise
Post exercise 30 min
Post exercise 60 min
Peak exercise
Post exercise 30 min
Post exercise 60 min
48 ± 12⁎ 62 ± 9 73 ± 9 27 ± 11 33 ± 9 53 ± 9 42 ± 19 45 ± 18 85 ± 18 95 ± 17⁎ 73 ± 15 73 ± 15 0.44 ± 0.25⁎ 0.61 ± 0.21 1.16 ± 0.44 121 ± 32 127 ± 35 211 ± 24
51 ± 10⁎ 60 ± 11 70 ± 7 30 ± 9 35 ± 10 50 ± 10 48 ± 15 43 ± 14 80 ± 17 87 ± 19⁎ 68 ± 18 50 ± 15 0.55 ± 0.28 0.63 ± 0.32 1.60 ± 0.39 143 ± 37 148 ± 36 194 ± 36
59 ± 9 65 ± 11 67 ± 6 38 ± 10 36 ± 11 51 ± 11 51 ± 18 49 ± 19 70 ± 15 70 ± 17 69 ± 19 45 ± 13 0.70 ± 0.30 0.71 ± 0.38 1.55 ± 0.41 150 ± 32 157 ± 33 191 ± 28
44 ± 11⁎ 61 ± 10 71 ± 8 23 ± 11⁎ 34 ± 10 50 ± 10 38 ± 19 45 ± 15 84 ± 19 100 ± 21⁎ 70 ± 20 77 ± 16 0.38 ± 0.27⁎ 0.64 ± 0.31 1.09 ± 0.50 118 ± 34 128 ± 38 222 ± 29
45 ± 9⁎ 63 ± 10 74 ± 9 26 ± 9⁎ 34 ± 9 52 ± 10 43 ± 16 47 ± 18 77 ± 18 98 ± 18⁎ 66 ± 16 49 ± 16 0.44 ± 0.31⁎ 0.71 ± 0.32 1.57 ± 0.47 123 ± 31⁎ 150 ± 32 195 ± 29
46 ± 10⁎ 64 ± 12 68 ± 6 25 ± 10⁎ 37 ± 12 48 ± 12 45 ± 13 48 ± 17 76 ± 15 88 ± 19⁎ 65 ± 18 40 ± 13 0.51 ± 0.29⁎ 0.74 ± 0.30 1.82 ± 0.51 129 ± 39⁎ 159 ± 38 190 ± 35
b0.001 NS NS b0.001 NS NS NS NS NS b0.001 NS b0.001 b0.001 NS b0.05 b0.05 b0.05 NS
DT: deceleration time; EF: ejection fraction; FS: fractional shortening; †P refers to comparisons within group; ⁎P b 0.05 versus Group II.
and ejection fraction (area-length single-plan method) were assessed from all examinations. Doppler parameters of left ventricular diastolic function were derived from the mitral inflow profile. All patients were seen at 1-year intervals during follow-up. Patients were precluded from any competitive sport [3], but no specific advice on work activities was given. Most patients were treated with beta-blockers or verapamil, and none underwent myotomy–myectomy during the period of analysis. Cumulative exercise-induced left ventricular dysfunction was diagnosed in a total of 13 patients (8 men, age 52 ± 13 years, group I) who had a significantly lower left ventricular ejection fraction 60 min after the second exercise test than 60 min after the first test (46 ± 10% vs 59 ± 9%, P = 0.005). The remaining 27 patients (18 men, age 57 ± 16 years, group II) had similar values of left ventricular ejection fraction 1 h after both the first and the second exercise tests (64 ± 12% vs 65 ± 11%, NS). Echocardiographic and Doppler findings before and after the two exercise stress tests in controls and in the two groups of patients are shown in Table 1. Differences in ejection fraction between groups were paralleled by similar difference in fractional shortening. Also, left ventricular diastolic function worsened to a greater extent in group I than in group II after the second exercise test than after the first one. All presenting features were similar in the two groups, with only maximal left ventricular wall thickness being significantly greater in group I than group II (23 ± 6 vs 18 ± 5 mm, P b 0.005). During a follow-up of 6 ± 4 years, 2 patients died suddenly (1 of group I and 1 of group II) and 3 patients (1 of group I and 2 of group II) did not undergo serial ultrasound evaluations. In the remaining 35 patients (12 of group I and 23 of group II), symptoms worsened more
commonly in group I than in group II (8/12 patients versus 5/ 23 patients, P = 0.025). Serial echocardiographic evaluations showed that left ventricular ejection fraction decreased significantly in group I (from 60 ± 11 to 49 ± 10%, P = 0.018) but slightly in group II (from 64 ± 10 to 61 ± 11%, NS). Noteworthy, a significant decrease in left ventricular ejection fraction occurred even in group I patients with high baseline values (Fig. 1). Overall, progressive myocardial dysfunction occurred in 6 patients of group I and in only 2 patients of group II (50% vs 9%, P = 0.019). Specifically, a left ventricular ejection fraction b 50% developed in 3 patients of group I and in 2 patients of group II, and an increase in left ventricular end-diastolic diameter N 5 mm was seen only in 3 patients of group I. The present data document that repeated episodes of exercise-induced left ventricular dysfunction have a
Fig. 1. Individual data for left ventricular ejection fraction at baseline and at last follow-up evaluation in patients of group I and group II.
78
F. Pelliccia et al. / International Journal of Cardiology 122 (2007) 76–78
cumulative effect in cardiomyopathic patients, which makes impairment of cardiac contractility more pronounced and longer lasting well after cessation of exercise. Along with cumulative systolic dysfunction, we have found that also diastolic abnormalities can accumulate in hypertrophic cardiomyopathy. Indeed, diastolic function paralleled changes in left ventricular contractility and remained more transiently impaired as a result of repeat exercise in a subset of our patients. These novel findings indicate that strenuous exercise may consistently affect all aspects of cardiac function in cardiomyopathy, similarly to what occurs in coronary artery disease [7]. In ischemic heart disease, serial episodes of exerciseinduced dysfunction can lead to progressive left ventricular remodeling and worsening of the contractile function [4]. Similarly, our findings suggest a possible link between repetitive left ventricular dysfunction and clinical deterioration in hypertrophic cardiomyopathy, as changes over time in left ventricular morphology and/or function occurred mainly in those patients who had evidence of cumulative myocardial dysfunction. In conclusion, cumulative exercise-induced myocardial dysfunction can occur in a subset of patients with hypertrophic cardiomyopathy and may be associated with clinical deterioration and worse outcome. The possibility that repetitive episodes of left ventricular impairment during daily life play an important pathophysiologic role in hypertrophic cardiomyopathy has relevant clinical implications. Our findings suggest that some cardiomyopathic patients, apart from being precluded from competitive sports [3], should be adviced to avoid repetitive, heavy activities during daily life
even if asymptomatic and with a normal systolic function. To this end, the use of two consecutive symptom-limited exercise tests one-hour apart appears to constitute a simple and reliable tool for identifying the subgroup of patients with cumulative myocardial dysfunction at higher risk of clinical deterioration. References [1] Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA 2002;287:1308–20. [2] Wald DS, Law M, Morris JK. Mortality from hypertrophic cardiomyopathy in England and Wales: clinical and screening implications. Int J Cardiol 2004;97:479–84. [3] Pelliccia A, Fagard R, Bjornstad HH. Recommendations for competitive sports participation in athletes with cardiovascular disease: a consensus document from the Study Group of Sports Cardiology of the Working Group of Cardiac Rehabilitation and Exercise Physiology and the Working Group of Myocardial and Pericardial Diseases of the European Society of Cardiology. Eur Heart J 2005;26:1422–45. [4] Camici PG, Dukta DP. Repetitive stunning, hibernation, and heart failure: contribution of PET to establishing a link. Am J Physiol Heart Circ Physiol 2001;280:H929–36. [5] Homans DC, Laxson DD, Sublett F, et al. Cumulative deterioration of myocardial function after repeated episodes of exercise induced ischemia. Am J Physiol 1989;256:H1462–71. [6] Rinaldi CA, Masani ND, Linka AZ, Hall RJ. Effect of repetitive episodes of exercise induced myocardial ischaemia on left ventricular function in patients with chronic stable angina: evidence for cumulative stunning or ischaemic preconditioning? Heart 1999;81:404–11. [7] Stoddard MF, Johnstone J, Dillon S, Kupersmith J. The effect of exercise-induced myocardial ischemia on postischemic left ventricular diastolic filling. Clin Cardiol 1992;15:265–73.