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Abnormal blood-pressure response to exercise and oxygen consumption in patients with hypertrophic cardiomyopathy
Abnormal blood-pressure response to exercise and oxygen consumption in patients with hypertrophic cardiomyopathy Quirino Ciampi, MD, PhD,a,b Sandro Betocchi, MD,a Maria Angela Losi, MD,a Adele Ferro, MD,c Alberto Cuocolo, MD,c Raffaella Lombardi, MD,a Bruno Villari, MD, PhD,b and Massimo Chiariello, MDa Background. Abnormal blood-pressure response during exercise occurs in about one third of patients with hypertrophic cardiomyopathy (HCM), and it has been associated with a high risk of sudden cardiac death. We assessed the hemodynamics of exercise in HCM patients with abnormal blood-pressure response by using ambulatory radionuclide monitoring (VEST) of left-ventricular (LV) function, and exercise tolerance by oxygen consumption. Methods. Twenty-two HCM patients uderwent treadmill exercise during VEST monitoring. A cardiopulmonary exercise test was performed a few days after. The VEST data were averaged for 1 minute. Stroke volume, cardiac output, and systemic vascular resistance were expressed as percent of baseline. Exercise tolerance was assessed as maximal oxygen consumption. Results. In eight HCM patients (36%) with an abnormal blood-pressure response, endsystolic volume increased more (52% ⴞ 21% vs 31% ⴞ 28%, P ⴝ .012), and the ejection fraction (ⴚ31% ⴞ 17% vs ⴚ14% ⴞ 22%, P ⴝ .029) and stroke volume (ⴚ21% ⴞ 21% vs 3% ⴞ 28%, P ⴝ .026) fell more, than in patients with normal response. Cardiac output increased less in the former patients (49% ⴞ 44% vs 94% ⴞ 44%, P ⴝ .012). Systemic vascular resistance decreased similarly, irrespective of blood-pressure response (ⴚ28% ⴞ 26% vs ⴚ34% ⴞ 26%, P ⴝ N.S.). Percent of maximal predicted oxygen consumption was lower in HCM patients with an abnormal blood-pressure response (63% ⴞ 11% vs 78% ⴞ 15%, P ⴝ .025). Conclusions. In HCM patients, abnormal blood-pressure response was associated with exercise-induced LV systolic dysfunction and impairment in oxygen consumption. This may cause hemodynamic instability, associated with a high risk of sudden cardiac death. (J Nucl Cardiol 2007;14:869-75.) Key Words: Cardiomyopathy • exercise • hemodynamics • hypertrophy Sudden cardiac death is an ominous complication in hypertrophic cardiomyopathy (HCM), especially in adolescents and young adults, and it may be the first clinical manifestation in previously asymptomatic patients.1,2 An abnormal blood-pressure response during exercise occurs in about one third of patients with HCM, and it has From the Department of Clinical Medicine and Cardiovascular and Immunological Sciences,a Federico II University School of Medicine, Naples, Italy; Division of Cardiology,b Fatebenefratelli Hospital, Benevento, Italy; and Department of Morphological and Functional Sciences,c “Federico II” University School of Medicine, Naples, Italy. Received for publication May 29, 2007; final revision accepted August 1, 2007. Reprint requests: Sandro Betocchi, MD, FESC, Department of Clinical Medicine and Cardiovascular and Immunological Sciences, Federico II University School of Medicine, Via S. Pansini 5, I-80131 Naples, Italy; [email protected]. 1071-3581/$32.00 Copyright © 2007 by the American Society of Nuclear Cardiology. doi:10.1016/j.nuclcard.2007.08.003
been associated with a high risk of sudden cardiac death, because it may lead to hemodynamic instability, which may trigger life-threatening arrhythmias.1,3-6 The mechanism responsible for exercise-induced abnormal blood pressure in patients with HCM is still debated. Previously,7 our group demonstrated that exerciseinduced abnormal blood pressure was associated with exercise-induced left-ventricular (LV) systolic dysfunction. We thus hypothesize a “central” mechanism responsible for the abnormal blood pressure in response to exercise. Our hypothesis is supported by studies showing that an abnormal blood pressure response during exercise was associated with the development of subendocardial ischemia in HCM patients during thallium scintigraphy8 and with lower oxygen consumption.9 Conversely, Counihan et al.3 and Frenneaux et al.4 reported that an abnormal blood-pressure response to exercise was associated with an excessive fall in systemic vascular resistance during exercise because of peripheral vasodilatation. 869
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Myocardial ischemia without significant coronary artery stenosis was demonstrated in patients with HCM, exhibiting fixed or reversible defects with the use of thallium scintigraphy,10 cavity dilatation during exercise,8 myocardial lactate production during atrial pacing,11 and positron emission tomography.12 Moreover, ischemia-related LV systolic dysfunction during exercise was observed in about one half of HCM patients during exercise.13,14 The aim of our study was to assess the effects of exercise on hemodynamics in HCM patients with and without an abnormal blood-pressure response to exercise, by means of ambulatory radionuclide monitoring (VEST) of LV function, and exercise tolerance by oxygen consumption. METHODS
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each of the four ventricular segments (anterior and posterior septum, and posterior and lateral walls).20,21 Color Doppler flow imaging was used for identifying and semiquantitatively estimating mitral regurgitation.22 The LV outflow tract gradient was recorded, both at rest and during provocation by amyl nitrite inhalation, using a 1.9-MHz nonimaging transducer and a simplified Bernoulli equation (P ⫽ 4V2, where P is pressure and V is flow velocity). Care was taken to distinguish ejection velocity from the mitral regurgitation jet.23
Radionuclide Angiography Red blood cells were labeled in vivo with 15 to 20 mCi of Technetium. Each subject underwent equilibrium radionuclide angiography in the supine position, under control conditions, to determine the basal LV ejection fraction. The ejection fraction was computed on the raw time-activity curve. The accuracy and reproducibility of measurements in our laboratory were previously reported.24
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Patient Population Twenty-two consecutive patients with HCM (17 men and 5 women; mean age ⫾ SD was 37 ⫾ 14 years; range, 16 to 64 years) were enrolled from our cardiomyopathy outpatient clinic at the Federico II University School of Medicine. The diagnosis of HCM was based on echocardiographic evidence of hypertrophied, nondilated left ventricles without apparent cause, such as systemic hypertension or aortic stenosis.15,16 All patients were in normal sinus rhythm. All cardioactive medications were withdrawn for at least five half-lives before the study of HCM patients. In 8 men older than 40 years of age and 1 woman older than 50 years of age, care was taken to rule out abnormal blood pressure response to exercise consequence to exercise-induced ischemia in the presence of epicardial coronary artery disease. None of them had any conventional risk factors for atherosclerosis, and nine had angina pectoris, but coronary artery disease was excluded in all subjects by myocardial scintigraphy, which indicated normal perfusion or spotty, and not discrete, reversible hypoperfusion.17
Echocardiography Each subject underwent M-mode and two-dimensional echocardiography, followed by color-flow imaging and pulsed and continuous-wave Doppler ultrasound study. The M-mode echocardiograms were obtained from two-dimensional images under direct anatomic visualization. Left atrial, LV end-diastolic, and LV end-systolic diameters were measured according to the guidelines of the American Society of Echocardiography,18 and were normalized to body surface area. Left-ventricular hypertrophy was evaluated from the short-axis view by dividing the LV wall into four segments at the level of the mitral valve and papillary muscle.19 An index of the extent of LV hypertrophy was calculated by adding the maximal wall thickness measured (at the level of either the mitral valve or papillary muscle) in
VEST Immediately after radionuclide angiography, the VEST detector (Capintec, Inc., Ramsey, NJ) was placed over the subject’s chest and tightened to ensure stable contact. Because the VEST detector is a nonimaging device, it was positioned, under gamma camera control, over the left ventricle.25 At the end of the protocol, a 30-second static image was obtained to confirm that the radionuclide detector had not moved during recording. At the end of monitoring, data were reviewed for technical adequacy. Briefly, the average count rate (decaycorrected) of the entire recording was displayed. If the curve had an abrupt deviation ⬎10% from a straight line, the VEST study was considered inadequate. Sudden shifts in the slope of the line indicate detector movement or instrument malfunction.25,26 Radionuclide and electrocardiogram data were averaged for 60-second intervals, and analyzed at baseline, at 3 minutes, and at peak exercise. The ejection fraction was computed as stroke counts divided by the background-corrected end-diastolic counts. The background was determined by matching the initial resting VEST ejection fraction value to that obtained by gamma camera. Systemic vascular resistance was calculated according to the following formula: 80 ⫻ (mean arterial pressure/LV cardiac output). The LV end-diastolic volume, end-systolic volume, stroke volume, cardiac output, and systemic vascular resistance were considered to be 100% at the beginning of the study, and were subsequently expressed relative to this value.
Exercise Test During VEST All patients and control subjects underwent maximal symptom-limited treadmill exercise testing, using a protocol modified from that of Bruce and McDonough.27 The test duration was measured in seconds. Blood pressure was measured using a cuff sphygmomanometer at rest, at 1-minute intervals during exercise, and at 1-minute intervals for 5
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Table 1. Characteristics of HCM patients with normal blood-pressure response, and HCM patients with exercise-induced abnormal blood-pressure response
Age (y) Male gender (%) NYHA functional class ⱖ2 (%) Left atrial diameter (mm) Maximal wall thickness (mm) Hypertrophy score (mm) LV outflow tract gradient (mm Hg) Ejection fraction at baseline (%) Exercise duration during VEST monitoring (seconds) Exercise duration during cardiopulmonary test (seconds) VO2 peak (mL/kg/min) Anaerobic threshold
Normal BP response (n ⴝ 14)
Abnormal BP response (n ⴝ 8)
P
42 ⫾ 14 11 (78) 8 (38) 44 ⫾ 7 22 ⫾ 5 60 ⫾ 14 22 ⫾ 24 73 ⫾ 9 514 ⫾ 130 495 ⫾ 84 26 ⫾ 8 16 ⫾ 8
31 ⫾ 12 6 (75) 5 (43) 44 ⫾ 5 21 ⫾ 4 59 ⫾ 7 31 ⫾ 30 72 ⫾ 6 474 ⫾ 147 488 ⫾ 114 23 ⫾ 5 17 ⫾ 4
.01 NS NS NS NS NS NS NS NS NS NS NS
LV, left ventricle; BP, blood pressure; HCM, hypertrophic cardiomyopathy; VEST, ambulatory radionuclide monitoring device; NS, not significant; NYHA, New York Heart Association; VO2, oxygen consumption.
minutes during the recovery period after exercise. A normal blood-pressure response was defined as a gradual increase of at least 20 mm Hg in systolic blood pressure during exercise. An abnormal blood-pressure response is considered, according to most studies, (1) an increase or decrease in systolic blood pressure during exercise ⬍20 mm Hg compared with baseline; (2) an initial increase in systolic blood pressure with a subsequent fall ⬎20 mm Hg compared with peak blood-pressure value; and (3) a continuous decrease in systolic blood pressure throughout the exercise test ⬎20 mm Hg compared with baseline.3-6 These last two conditions are termed “hypotensive blood pressure response,” while the first condition represents a flat response. A three-lead electrocardiographic monitor allowed for continuous evaluation of heart rate, rhythm, T-waves, and ST segment. Cardiopulmonary exercise test. All patients underwent a cardiopulmonary exercise test on a treadmill according to a protocol modified from that of Bruce and McDonough,27 with expired gas measurement. This test was performed within a few days of the VEST exercise test. Oxygen uptake, carbon dioxide production, and minute ventilation were measured using a breath-by-breath gas analysis. A 12-lead electrocardiogram was continuously registered, and blood pressure was recorded every minute by means of a cuff sphygmomanometer. Peak oxygen uptake was determined to be the highest value in the terminal phase of exercise. Oxygen uptake at the anaerobic threshold was determined by the V-slope method. The anaerobic threshold was determined by V-slope analysis on oxygen consumption vs carbon dioxide production, and was defined as a respiratory ratio of ⱖ1.05.28 The predicted value of peak oxygen uptake was calculated using the equation of Wasserman et al., which normalizes peak oxygen uptake for age, sex, and height.29 The percent of predicted peak oxygen uptake was calculated for each patient. The exclusion criteria were exercise-limiting diseases other
than cardiac, e.g., peripheral vascular disease or degenerative joint disease, and any relevant primary pulmonary disease.
Statistics Data were expressed as means ⫾ 1 standard deviation. The chi-square test with Yates’ correction for continuity was used to analyze categorical variables. Normal distribution of all continuous variables, including percent differences from peak to baseline, was tested using the one-sample KolmogorovSmirnov test. All variables were normally distributed, and therefore parametric tests were used. An unpaired Student t test was performed to determine differences between mean values for continuous variables when appropriate. A probability value of ⬍.05 was considered statistically significant. All statistical calculations were performed by SPSS for Windows, release 12.0 (Chicago, Ill).
RESULTS Patient Characteristics The clinical, echocardiographic, and radionuclide baseline characteristics of the two HCM patient groups with normal and abnormal and abnormal blood-pressure responses to exercise are shown in Table 1. The HCM patients with an abnormal blood-pressure response were significantly younger. Hemodynamics During Exercise The achieved level of exercise was maximal in five patients (23%). The test was interrupted for fatigue in
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Figure 1. Mean value ⫾ 1 standard deviation of percent difference between peak exercise and baseline of end-systolic volume (%) in the two study groups: patients with hypertrophic cardiomyopathy and normal systolic blood-pressure response to exercise (Normal BP response), and patients with hypertrophic cardiomyopathy and abnormal systolic blood-pressure response to exercise (Abnormal BP response).
nine patients (41%), and for shortness of breath or angina in eight patients (36%). The mean exercise duration was similar between the two groups and the two exercises during VEST monitoring and the cardiopulmonary test (Table 1). Eight HCM patients (36%) showed an abnormal blood-pressure response to exercise. In three HCM patients, systolic blood pressure fell from the start of exercise by ⬎20 mm Hg from the resting value. In three patients there was an appropriate initial increase in systolic blood pressure, with a subsequent fall by at least 20 mm Hg from peak blood pressure. The remaining two patients had a flat blood-pressure response to exercise. The blood-pressure response was consistent during the two exercise tests. Hemodynamic Adaptation of HCM Patients With Exercise-Induced Abnormal Systolic Blood Pressure During exercise, the heart rate rose significantly and similarly in HCM patients with a normal systolic bloodpressure response and with exercise-induced abnormal blood pressure (94% ⫾ 44% and 88% ⫾ 25%, respectively, over baseline; P ⫽ NS). There were significant differences in end-systolic volume changes during exercise between the two HCM patient groups. End-systolic volume increased significantly more in HCM patients with abnormal bloodpressure response to exercise than in HCM patients with normal response (52% ⫾ 21% vs 31% ⫾ 28%, respectively; Figure 1). The ejection fraction decreased in the whole group. The magnitude of the decrease, however, was greater in
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Figure 2. Mean value ⫾ 1 standard deviation of percent difference between peak exercise and baseline of stroke volume (%) in the two study groups: patients with hypertrophic cardiomyopathy and normal systolic blood-pressure response to exercise (Normal BP response), and patients with hypertrophic cardiomyopathy and abnormal systolic blood-pressure response to exercise (Abnormal BP response).
Figure 3. Mean value ⫾ 1 standard deviation of percent difference between peak exercise and baseline of cardiac output (%) in the two study groups: patients with hypertrophic cardiomyopathy and normal systolic blood-pressure response to exercise (Normal BP response), and patients with hypertrophic cardiomyopathy and abnormal systolic blood-pressure response to exercise (Abnormal BP response).
patients with an abnormal rather than normal bloodpressure response (⫺31% ⫾ 17% and ⫺14% ⫾ 22%, respectively; P ⫽ .029). Likewise, changes in stroke volume during exercise were significantly different (Figure 2) between HCM patients with normal and abnormal systolic blood-pressure responses to exercise. In fact, stroke volume increased in HCM patients with a normal blood-pressure response to exercise, whereas it fell in HCM patients with an abnormal blood-pressure response (3% ⫾ 28% and ⫺21% ⫾ 21%, respectively; Figure 2). As a consequence, the increase in cardiac output was significantly different between HCM patients with normal and abnormal blood pressure responses to exercise (94% ⫾ 44% and 49% ⫾ 44% respectively; Figure 3). Systemic vascular resistance decreased similarly in
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HCM patients without and with abnormal blood pressure responses to exercise (⫺34% ⫾ 26% and ⫺28% ⫾ 26%, respectively, over baseline; P ⫽ NS). The percent of maximal predicted oxygen consumption was lower in HCM patients with an abnormal blood pressure response than in HCM patients with a normal response (63% ⫾ 11% vs 78% ⫾ 15%, respectively; Figure 4). DISCUSSION Hemodynamic Adaptation to Exercise In this study, we demonstrated that HCM patients with an abnormal blood-pressure response to exercise exhibited an abnormal hemodynamic adaptation to exercise caused by an impairment in systolic function: an increase in end-systolic volume (Figure 1), a more pronounced fall in ejection fraction and stroke volume (Figure 2), a lower increase in cardiac output (Figure 3), and poorer aerobic exercise tolerance (Figure 4). An abnormal blood-pressure response to exercise has been regarded as evidence for hemodynamic instability, and was proposed as a marker of increased risk for sudden cardiac death in patients with HCM,1,3-4 especially in young patients,5,6 Patients with HCM and an abnormal blood-pressure response to exercise were younger compared with HCM patients with a normal systolic blood-pressure response, in our study and in previous studies.5,6 They further exhibited poor hemodynamic adaptation to exercise and impairment in systolic function, as indicated by a more pronounced fall in ejection fraction and stroke volume (Figure 2), and a lower increase in cardiac output (Figure 3). Hence, as we demonstrated previously,7 the mechanisms for exercise-induced abnormal blood pressure could be a cascade from marked LV systolic dysfunction, to a decrease in cardiac output, and finally to hypotension. We thus hypothesize a “central” mechanism responsible for the abnormal blood-pressure response to exercise. An impaired systolic response to exercise in HCM patients with an exercise-induced abnormal blood-pressure response was due to a significant increase in LV endsystolic volume. This suggests that a potential mechanism for such an abnormal response to exercise in HCM patients may be myocardial ischemia. Myocardial ischemia was clearly demonstrated in HCM patients,8,10-12 and it is a major risk factor for sudden cardiac death.30 It could be induced by an increased myocardial oxygen demand,31 as occurs during exercise. Our findings are consistent with previous studies that demonstrated exerciseinduced myocardial ischemia during VEST in patients with coronary artery disease,32 in whom exercise-related myocardial ischemia caused a fall in ejection fraction
Figure 4. Mean value ⫾ 1 standard deviation of percent difference between peak exercise and baseline of percent of maximal predicted oxygen consumption (%) in the two study groups: patients with hypertrophic cardiomyopathy and normal systolic blood-pressure response to exercise (Normal BP response), and patients with hypertrophic cardiomyopathy and abnormal systolic blood-pressure response to exercise (Abnormal BP response).
and an increase in end-systolic and end-diastolic volume. Similarly, Taki et al.13 demonstrated that LV dysfunction during exercise, assessed by VEST, is a common phenomenon in patients with HCM, and postulated that it was due to myocardial ischemia. Okeie et al.14 showed that myocardial ischemia was the primary reason for the decrease in ejection fraction in HCM during exercise, assessed by VEST; this was associated with the development of dobutamine-induced, new wall-motion abnormalities. Also, there was a significant correlation between changes in ejection fraction and the number of dysfunctional LV segments.14 In patients with coronary artery disease, exercise-induced hypotension is strictly associated with severe coronary disease, and is related to global and regional LV systolic dysfunction.33,34 Our results complement with those by Yoshida et al.,8 who demonstrated in HCM patients that an exerciseinduced hypotensive response was related to subendocardial ischemia, as assessed by thallium scintigraphy, with a higher prevalence of LV cavity dilatation compared with those with a normal blood-pressure response. Our findings shed a light on the mechanism by which subendocardial ischemia is related to an abnormal bloodpressure response. Another (not necessarily alternative) mechanism may be exercise-induced outflow-tract obstruction. Although the hemodynamic adaptation to exercise was similar irrespective of resting outflow-tract gradient, an increase or development of obstruction during exercise cannot be predicted, and could explain both the systolic impairment and fall in blood pressure. In fact, the afterload increase associated with obstruction might explain the systolic impairment, according to the law of
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Hill. An exercise-induced blood-pressure fall was abolished in HCM patients with LV outflow tract obstruction by means of alcohol ablation of the septum.35 This is in accordance with the previous hypothesis. It should be pointed out, however, that this hypothesis is in conflict with the observed enlargement in LV end-systolic volume (Figure 1). In this setting, the LV outflow tract gradient should decrease. To support the nuclear data, we showed that HCM patients with an exercise-induced abnormal blood-pressure response exhibited poorer aerobic exercise tolerance, with a lower percent of maximal predicted oxygen consumption (Figure 4). Sharma et al.9 found that patients with an abnormal blood-pressure response had a lower peak oxygen consumption than those with a normal response. These data are in agreement with ours, and are consistent with our finding of a blunted cardiacoutput increase in HCM patients with exercise-induced hypotension. Previous studies3,4 suggest that in HCM patients, exercise-induced hypotension was due to an exaggerated decrease in systemic vascular resistance. Those authors assessed systemic vascular resistance using forearm blood flow, and they thought that an activation of ventricular mechanoreceptors may relate to exercise hypotension or an increased sensitivity of arterial baroreflex, and hence a “peripheral” mechanism. In our study, we assessed global systemic vascular resistance indirectly, as the ratio of mean blood pressure and cardiac output, and we showed a similar decrease in systemic vascular resistance during exercise in HCM patients with exercise-induced hypotension and in patients with a normal blood-pressure response to exercise. The difference in systemic vascular resistance responses during exercise between these previous studies and ours may be explained by the difference in methods: systemic vascular resistance changes differently in different regions. Global systemic vascular resistance is the sum of different adaptation processes to exercise: the local effect of exercise metabolites, cortical influences, reflex activation of metabolic receptors in skeletal muscle, and increased ventricular baroreceptor activity.36 Therefore, it is reasonable that local changes in resistance do not reflect modifications in global systemic vascular resistance. In this study, we demonstrated that systemic vascular resistance decreased similarly in HCM patients without and with an abnormal blood-pressure response to exercise. In terms of an alternative mechanism, an abnormal decrease in systemic vascular resistance may cause or aggravate ongoing myocardial ischemia during exercise. Nevertheless, this hypothesis is unlikely, because, in our study, systemic vascular resistance showed a similar
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decrease during exercise in HCM patients with and without exercise induced-hypotension. Study Limitations The VEST is a functional tool that assesses the LV relative volume curve. We hypothesize that the mechanism responsible for exercise-induced abnormal blood pressure could be myocardial ischemia or outflow-tract obstruction. Nevertheless, we only have evidence of exercise-induced systolic dysfunction, with a fall in stroke volume, ejection fraction, and hence cardiac output. Left-ventricular outflow-tract obstruction may play a role in hemodynamics during exercise in HCM patients. However, the simultaneous echocardiographic monitoring of changes in LV outflow-tract obstruction during handgrip was prevented by the presence of the VEST placed over the subject’s chest.
CONCLUSIONS In HCM patients, an exercise-induced abnormal bloodpressure response was associated with exercise-induced LV systolic dysfunction and impairment in oxygen consumption. This may cause hemodynamic instability, associated with a high risk of sudden cardiac death. References 1. Spirito P, Seidman CE, McKenna WJ, Maron BJ. The management of hypertrophic cardiomyopathy. N Engl J Med 1997;11:775-85. 2. Maki S, Ikeda H, Muro A, Yoshida N, Shibata A, Koga Y, et al. Predictors of sudden cardiac death in hypertrophic cardiomyopathy. Am J Cardiol 1998;82:774-8. 3. Counihan PJ, Frenneaux MP, Webb DJ, McKenna WJ. Abnormal vascular response to supine exercise in hypertrophic cardiomyopathy. Circulation 1991;84:686-96. 4. Frenneaux MP, Counihan PJ, Caforio ALP, Chikamori T, McKenna WJ. Abnormal blood pressure response during exercise in hypertrophic cardiomyopathy. Circulation 1990;82:1995-2002. 5. Olivotto I, Maron BJ, Montereggi A, Mazzuoli F, Dolara A, Cecchi F. Prognostic value of systemic blood pressure response during exercise in a community-based patient population with hypertrophic cardiomyopathy. J Am Coll Cardiol 1999;33: 2044-51. 6. Sadoul N, Prasad K, Elliott PM, Bannerjee S, Frenneaux MP, McKenna WJ. Prospective assessment of blood pressure response during exercise in patients with hypertrophic cardiomyopathy. Circulation 1997;96:2987-91. 7. Ciampi Q, Betocchi S, Lombardi R, Losi MA, Manganelli F, Storto G, et al. Hemodynamic determinants of exercise-induced abnormal blood pressure response in hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;40:278-84. 8. Yoshida N, Ikeda H, Wada T, Matsumoto A, Maki S, Muro A, et al. Exercise-induced abnormal blood pressure response are related to subendocardial ischemia in hypertrophic cardiomyopathy. J Am Coll Cardiol 1998;32:1938-42.
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9. Sharma S, Elliott P, Whyte G, Jones S, Mahon N, Whipp B, et al. Utility of cardiopulmonary exercise in the assessment of clinical determinants of functional capacity in hypertrophic cardiomyopathy. Am J Cardiol 2000;86:162-8. 10. Yamada M, Elliott PM, Kaski JC, Prasad K, Gane JN, Lowe CM, et al. Dipyridamole stress thallium-201 perfusion abnormalities in patients with hypertrophic cardiomyopathy. Eur Heart J 1998;19: 500-7. 11. Cannon RO III, Schenke WH, Maron BJ, Tracy CM, Leon MB, Brush JE, et al. Differences in coronary flow and myocardial metabolism at rest and during pacing between patients with obstructive and patients with nonobstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 1987;10:53-62. 12. Camici P, Chiriatti G, Lorenzoni R, Bellina RC, Gistri R, Italiani G, et al. Coronary vasodilation is impaired in both hypertrophied and nonhypertrophied myocardium of patients with hypertrophic cardiomyopathy: a study with nitrogen-13 ammonia and positron emission tomography. J Am Coll Cardiol 1991;5:879-86. 13. Taki J, Nakajima K, Shimizu M, Tonami N, Hisada K. Left ventricular functional reserve in nonobstructive hypertrophic cardiomyopathy: evaluation by continuous left ventricular function monitoring. J Nucl Med 1994;35:1937-43. 14. Okeie K, Shimizu M, Yoshio H, Ino H, Yamaguchi M, Matsuyama T, et al. Left ventricular systolic dysfunction during exercise and dobutamine stress in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2000;36:856-63. 15. Wigle ED, Sasson Z, Henderson MA, Ruddy TD, Fulop J, Rakowski H, et al. Hypertrophic cardiomyopathy: the importance of the site and the extent of hypertrophy: a review. Prog Cardiovasc Dis 1985;28:1-83. 16. Maron BJ, Epstein SE. Hypertrophic cardiomyopathy: a discussion of nomenclature. Am J Cardiol 1979;43:1242-4. 17. O’Gara PT, Bonow RO, Maron BJ, Damske BA, Van Lingen A, Bacharach SL, et al. Myocardial perfusion abnormalities in patients with hypertrophic cardiomyopathy: assessment with thallium-201 emission computed tomography. Circulation 1987;76: 1214-23. 18. Sahn DJ, DeMaria A, Kisslo J, Weiman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58: 1072-83. 19. Spirito P, Maron BJ, Chiarella F, Bellotti P, Tramarin R, Pozzoli M, et al. Diastolic abnormalities in patients with hypertrophic cardiomyopathy: relation to magnitude of left ventricular hypertrophy. Circulation 1985;72:310-6. 20. Spirito P, Maron BJ, Bonow RO, Epstein SE. Occurrence and significance of progressive left ventricular wall thinning and relative cavity dilatation in hypertrophic cardiomyopathy. Am J Cardiol 1987;59:123-9. 21. Spirito P, Chiarella M, Carratino L, Zoni Berisso M, Bellotti P, Vecchio C. Clinical course and prognosis of hypertrophic cardiomyopathy in an outpatient population. N Engl J Med 1989; 320:749-55.
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22. Helmcke F, Nanda NC, Hsiung MC, Soto B, Adey CK, Goyal RG, et al. Color Doppler assessment of mitral regurgitation with orthogonal planes. Circulation 1987;75:175-83. 23. Panza JA, Petrone RK, Fananapazir L, Maron BJ. Utility of continuous wave Doppler echocardiography in the noninvasive assessment of left ventricular outflow tract pressure gradient in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 1991;19:91-9. 24. Betocchi S, Piscione F, Villari B, Pace L, Ciarmiello A, PerroneFilardi P, et al. Effects of induced asynchrony on left ventricular diastolic function in patients with coronary artery disease. J Am Coll Cardiol 1993;21:1124-31. 25. Wilson RA, Sullivan PJ, Moore RH, Zielonka JS, Alpert NM, Boucher CA, et al. An ambulatory ventricular function monitor: validation and preliminary results. Am J Cardiol 1983;52:601-6. 26. Pace L, Cuocolo A, Nappi A, Nicolai E, Trimarco B, Salvatore M. Accuracy and repeatability of left ventricle systolic and diastolic function measurements using an ambulatory radionuclide monitor. Eur J Nucl Med 1992;19:800-6. 27. Bruce RA, McDonough JR. Stress testing for cardiovascular disease. Bull NY Acad Med 1969;45:1288-94. 28. Jones NL. Clinical exercise testing. Philadelphia: W.B. Saunders, 1988:208 –12. 29. Wassermann K, Hansen JE, Sue DY. Principles of exercise testing and interpretation. Philadephia: Lea & Febiger, 1986:73. 30. Dilsizian V, Bonow RO, Epstein SE, Fananapazir L. Myocardial ischemia detected by thallium scintigraphy is frequently related to cardiac arrest and syncope in young patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 1993;22:796-804. 31. Cannon RO III, Rosing DR, Maron BJ, Leon MB, Bonow RO, Watson RM, et al. Myocardial ischemia in patients with hypertrophic cardiomyopathy: contribution of inadequate vasodilator reserve and elevated left ventricular filling pressure. Circulation 1985;71:234-43. 32. Tamaki N, Yashuda T, Moore RH, Gill JB, Boucher CA, Hutter AM, et al. Continuous monitoring of left ventricular function by an ambulatory radionuclide detector in patients with coronary artery disease. J Am Coll Cardiol 1988;12:669-79. 33. Dubach P, Froelicher VF, Klein J, Oakes D, Grover-McKay, Friis R. Exercise-induced hypotension in a male population. Criteria, causes and prognosis. Circulation 1988;78:1380-7. 34. Gibbons RJ, Hu DC, Clements IP, Mankin HT, Zinsmeister AR, Brown ML. Anatomic and functional significance of hypotensive response during supine exercise radionuclide ventriculography. Am J Cardiol 1987;60:1-4. 35. Kim JJ, Lee CW, Park SW, Hong MK, Lim HY, Song JK, et al. Improvement in exercise capacity and exercise blood pressure response after transcoronary alcohol ablation therapy of septal hypertrophy in hypertrophic cardiomyopathy. Am J Cardiol 1999; 83:1120-3. 36. Flamm SD, Taki J, Moore R, Lewis SF, Keech F, Maltais F, et al. Redistribution of regional and organ blood volume and effect on cardiac function in elation to upright exercise intensity in healthy human subjects. Circulation 1990;81:1550-9.
been associated with a high risk of sudden cardiac death, because it may lead to hemodynamic instability, which may trigger life-threatening arrhythmias.1,3-6 The mechanism responsible for exercise-induced abnormal blood pressure in patients with HCM is still debated. Previously,7 our group demonstrated that exerciseinduced abnormal blood pressure was associated with exercise-induced left-ventricular (LV) systolic dysfunction. We thus hypothesize a “central” mechanism responsible for the abnormal blood pressure in response to exercise. Our hypothesis is supported by studies showing that an abnormal blood pressure response during exercise was associated with the development of subendocardial ischemia in HCM patients during thallium scintigraphy8 and with lower oxygen consumption.9 Conversely, Counihan et al.3 and Frenneaux et al.4 reported that an abnormal blood-pressure response to exercise was associated with an excessive fall in systemic vascular resistance during exercise because of peripheral vasodilatation. 869
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Myocardial ischemia without significant coronary artery stenosis was demonstrated in patients with HCM, exhibiting fixed or reversible defects with the use of thallium scintigraphy,10 cavity dilatation during exercise,8 myocardial lactate production during atrial pacing,11 and positron emission tomography.12 Moreover, ischemia-related LV systolic dysfunction during exercise was observed in about one half of HCM patients during exercise.13,14 The aim of our study was to assess the effects of exercise on hemodynamics in HCM patients with and without an abnormal blood-pressure response to exercise, by means of ambulatory radionuclide monitoring (VEST) of LV function, and exercise tolerance by oxygen consumption. METHODS
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each of the four ventricular segments (anterior and posterior septum, and posterior and lateral walls).20,21 Color Doppler flow imaging was used for identifying and semiquantitatively estimating mitral regurgitation.22 The LV outflow tract gradient was recorded, both at rest and during provocation by amyl nitrite inhalation, using a 1.9-MHz nonimaging transducer and a simplified Bernoulli equation (P ⫽ 4V2, where P is pressure and V is flow velocity). Care was taken to distinguish ejection velocity from the mitral regurgitation jet.23
Radionuclide Angiography Red blood cells were labeled in vivo with 15 to 20 mCi of Technetium. Each subject underwent equilibrium radionuclide angiography in the supine position, under control conditions, to determine the basal LV ejection fraction. The ejection fraction was computed on the raw time-activity curve. The accuracy and reproducibility of measurements in our laboratory were previously reported.24
99m
Patient Population Twenty-two consecutive patients with HCM (17 men and 5 women; mean age ⫾ SD was 37 ⫾ 14 years; range, 16 to 64 years) were enrolled from our cardiomyopathy outpatient clinic at the Federico II University School of Medicine. The diagnosis of HCM was based on echocardiographic evidence of hypertrophied, nondilated left ventricles without apparent cause, such as systemic hypertension or aortic stenosis.15,16 All patients were in normal sinus rhythm. All cardioactive medications were withdrawn for at least five half-lives before the study of HCM patients. In 8 men older than 40 years of age and 1 woman older than 50 years of age, care was taken to rule out abnormal blood pressure response to exercise consequence to exercise-induced ischemia in the presence of epicardial coronary artery disease. None of them had any conventional risk factors for atherosclerosis, and nine had angina pectoris, but coronary artery disease was excluded in all subjects by myocardial scintigraphy, which indicated normal perfusion or spotty, and not discrete, reversible hypoperfusion.17
Echocardiography Each subject underwent M-mode and two-dimensional echocardiography, followed by color-flow imaging and pulsed and continuous-wave Doppler ultrasound study. The M-mode echocardiograms were obtained from two-dimensional images under direct anatomic visualization. Left atrial, LV end-diastolic, and LV end-systolic diameters were measured according to the guidelines of the American Society of Echocardiography,18 and were normalized to body surface area. Left-ventricular hypertrophy was evaluated from the short-axis view by dividing the LV wall into four segments at the level of the mitral valve and papillary muscle.19 An index of the extent of LV hypertrophy was calculated by adding the maximal wall thickness measured (at the level of either the mitral valve or papillary muscle) in
VEST Immediately after radionuclide angiography, the VEST detector (Capintec, Inc., Ramsey, NJ) was placed over the subject’s chest and tightened to ensure stable contact. Because the VEST detector is a nonimaging device, it was positioned, under gamma camera control, over the left ventricle.25 At the end of the protocol, a 30-second static image was obtained to confirm that the radionuclide detector had not moved during recording. At the end of monitoring, data were reviewed for technical adequacy. Briefly, the average count rate (decaycorrected) of the entire recording was displayed. If the curve had an abrupt deviation ⬎10% from a straight line, the VEST study was considered inadequate. Sudden shifts in the slope of the line indicate detector movement or instrument malfunction.25,26 Radionuclide and electrocardiogram data were averaged for 60-second intervals, and analyzed at baseline, at 3 minutes, and at peak exercise. The ejection fraction was computed as stroke counts divided by the background-corrected end-diastolic counts. The background was determined by matching the initial resting VEST ejection fraction value to that obtained by gamma camera. Systemic vascular resistance was calculated according to the following formula: 80 ⫻ (mean arterial pressure/LV cardiac output). The LV end-diastolic volume, end-systolic volume, stroke volume, cardiac output, and systemic vascular resistance were considered to be 100% at the beginning of the study, and were subsequently expressed relative to this value.
Exercise Test During VEST All patients and control subjects underwent maximal symptom-limited treadmill exercise testing, using a protocol modified from that of Bruce and McDonough.27 The test duration was measured in seconds. Blood pressure was measured using a cuff sphygmomanometer at rest, at 1-minute intervals during exercise, and at 1-minute intervals for 5
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Table 1. Characteristics of HCM patients with normal blood-pressure response, and HCM patients with exercise-induced abnormal blood-pressure response
Age (y) Male gender (%) NYHA functional class ⱖ2 (%) Left atrial diameter (mm) Maximal wall thickness (mm) Hypertrophy score (mm) LV outflow tract gradient (mm Hg) Ejection fraction at baseline (%) Exercise duration during VEST monitoring (seconds) Exercise duration during cardiopulmonary test (seconds) VO2 peak (mL/kg/min) Anaerobic threshold
Normal BP response (n ⴝ 14)
Abnormal BP response (n ⴝ 8)
P
42 ⫾ 14 11 (78) 8 (38) 44 ⫾ 7 22 ⫾ 5 60 ⫾ 14 22 ⫾ 24 73 ⫾ 9 514 ⫾ 130 495 ⫾ 84 26 ⫾ 8 16 ⫾ 8
31 ⫾ 12 6 (75) 5 (43) 44 ⫾ 5 21 ⫾ 4 59 ⫾ 7 31 ⫾ 30 72 ⫾ 6 474 ⫾ 147 488 ⫾ 114 23 ⫾ 5 17 ⫾ 4
.01 NS NS NS NS NS NS NS NS NS NS NS
LV, left ventricle; BP, blood pressure; HCM, hypertrophic cardiomyopathy; VEST, ambulatory radionuclide monitoring device; NS, not significant; NYHA, New York Heart Association; VO2, oxygen consumption.
minutes during the recovery period after exercise. A normal blood-pressure response was defined as a gradual increase of at least 20 mm Hg in systolic blood pressure during exercise. An abnormal blood-pressure response is considered, according to most studies, (1) an increase or decrease in systolic blood pressure during exercise ⬍20 mm Hg compared with baseline; (2) an initial increase in systolic blood pressure with a subsequent fall ⬎20 mm Hg compared with peak blood-pressure value; and (3) a continuous decrease in systolic blood pressure throughout the exercise test ⬎20 mm Hg compared with baseline.3-6 These last two conditions are termed “hypotensive blood pressure response,” while the first condition represents a flat response. A three-lead electrocardiographic monitor allowed for continuous evaluation of heart rate, rhythm, T-waves, and ST segment. Cardiopulmonary exercise test. All patients underwent a cardiopulmonary exercise test on a treadmill according to a protocol modified from that of Bruce and McDonough,27 with expired gas measurement. This test was performed within a few days of the VEST exercise test. Oxygen uptake, carbon dioxide production, and minute ventilation were measured using a breath-by-breath gas analysis. A 12-lead electrocardiogram was continuously registered, and blood pressure was recorded every minute by means of a cuff sphygmomanometer. Peak oxygen uptake was determined to be the highest value in the terminal phase of exercise. Oxygen uptake at the anaerobic threshold was determined by the V-slope method. The anaerobic threshold was determined by V-slope analysis on oxygen consumption vs carbon dioxide production, and was defined as a respiratory ratio of ⱖ1.05.28 The predicted value of peak oxygen uptake was calculated using the equation of Wasserman et al., which normalizes peak oxygen uptake for age, sex, and height.29 The percent of predicted peak oxygen uptake was calculated for each patient. The exclusion criteria were exercise-limiting diseases other
than cardiac, e.g., peripheral vascular disease or degenerative joint disease, and any relevant primary pulmonary disease.
Statistics Data were expressed as means ⫾ 1 standard deviation. The chi-square test with Yates’ correction for continuity was used to analyze categorical variables. Normal distribution of all continuous variables, including percent differences from peak to baseline, was tested using the one-sample KolmogorovSmirnov test. All variables were normally distributed, and therefore parametric tests were used. An unpaired Student t test was performed to determine differences between mean values for continuous variables when appropriate. A probability value of ⬍.05 was considered statistically significant. All statistical calculations were performed by SPSS for Windows, release 12.0 (Chicago, Ill).
RESULTS Patient Characteristics The clinical, echocardiographic, and radionuclide baseline characteristics of the two HCM patient groups with normal and abnormal and abnormal blood-pressure responses to exercise are shown in Table 1. The HCM patients with an abnormal blood-pressure response were significantly younger. Hemodynamics During Exercise The achieved level of exercise was maximal in five patients (23%). The test was interrupted for fatigue in
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Figure 1. Mean value ⫾ 1 standard deviation of percent difference between peak exercise and baseline of end-systolic volume (%) in the two study groups: patients with hypertrophic cardiomyopathy and normal systolic blood-pressure response to exercise (Normal BP response), and patients with hypertrophic cardiomyopathy and abnormal systolic blood-pressure response to exercise (Abnormal BP response).
nine patients (41%), and for shortness of breath or angina in eight patients (36%). The mean exercise duration was similar between the two groups and the two exercises during VEST monitoring and the cardiopulmonary test (Table 1). Eight HCM patients (36%) showed an abnormal blood-pressure response to exercise. In three HCM patients, systolic blood pressure fell from the start of exercise by ⬎20 mm Hg from the resting value. In three patients there was an appropriate initial increase in systolic blood pressure, with a subsequent fall by at least 20 mm Hg from peak blood pressure. The remaining two patients had a flat blood-pressure response to exercise. The blood-pressure response was consistent during the two exercise tests. Hemodynamic Adaptation of HCM Patients With Exercise-Induced Abnormal Systolic Blood Pressure During exercise, the heart rate rose significantly and similarly in HCM patients with a normal systolic bloodpressure response and with exercise-induced abnormal blood pressure (94% ⫾ 44% and 88% ⫾ 25%, respectively, over baseline; P ⫽ NS). There were significant differences in end-systolic volume changes during exercise between the two HCM patient groups. End-systolic volume increased significantly more in HCM patients with abnormal bloodpressure response to exercise than in HCM patients with normal response (52% ⫾ 21% vs 31% ⫾ 28%, respectively; Figure 1). The ejection fraction decreased in the whole group. The magnitude of the decrease, however, was greater in
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Figure 2. Mean value ⫾ 1 standard deviation of percent difference between peak exercise and baseline of stroke volume (%) in the two study groups: patients with hypertrophic cardiomyopathy and normal systolic blood-pressure response to exercise (Normal BP response), and patients with hypertrophic cardiomyopathy and abnormal systolic blood-pressure response to exercise (Abnormal BP response).
Figure 3. Mean value ⫾ 1 standard deviation of percent difference between peak exercise and baseline of cardiac output (%) in the two study groups: patients with hypertrophic cardiomyopathy and normal systolic blood-pressure response to exercise (Normal BP response), and patients with hypertrophic cardiomyopathy and abnormal systolic blood-pressure response to exercise (Abnormal BP response).
patients with an abnormal rather than normal bloodpressure response (⫺31% ⫾ 17% and ⫺14% ⫾ 22%, respectively; P ⫽ .029). Likewise, changes in stroke volume during exercise were significantly different (Figure 2) between HCM patients with normal and abnormal systolic blood-pressure responses to exercise. In fact, stroke volume increased in HCM patients with a normal blood-pressure response to exercise, whereas it fell in HCM patients with an abnormal blood-pressure response (3% ⫾ 28% and ⫺21% ⫾ 21%, respectively; Figure 2). As a consequence, the increase in cardiac output was significantly different between HCM patients with normal and abnormal blood pressure responses to exercise (94% ⫾ 44% and 49% ⫾ 44% respectively; Figure 3). Systemic vascular resistance decreased similarly in
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HCM patients without and with abnormal blood pressure responses to exercise (⫺34% ⫾ 26% and ⫺28% ⫾ 26%, respectively, over baseline; P ⫽ NS). The percent of maximal predicted oxygen consumption was lower in HCM patients with an abnormal blood pressure response than in HCM patients with a normal response (63% ⫾ 11% vs 78% ⫾ 15%, respectively; Figure 4). DISCUSSION Hemodynamic Adaptation to Exercise In this study, we demonstrated that HCM patients with an abnormal blood-pressure response to exercise exhibited an abnormal hemodynamic adaptation to exercise caused by an impairment in systolic function: an increase in end-systolic volume (Figure 1), a more pronounced fall in ejection fraction and stroke volume (Figure 2), a lower increase in cardiac output (Figure 3), and poorer aerobic exercise tolerance (Figure 4). An abnormal blood-pressure response to exercise has been regarded as evidence for hemodynamic instability, and was proposed as a marker of increased risk for sudden cardiac death in patients with HCM,1,3-4 especially in young patients,5,6 Patients with HCM and an abnormal blood-pressure response to exercise were younger compared with HCM patients with a normal systolic blood-pressure response, in our study and in previous studies.5,6 They further exhibited poor hemodynamic adaptation to exercise and impairment in systolic function, as indicated by a more pronounced fall in ejection fraction and stroke volume (Figure 2), and a lower increase in cardiac output (Figure 3). Hence, as we demonstrated previously,7 the mechanisms for exercise-induced abnormal blood pressure could be a cascade from marked LV systolic dysfunction, to a decrease in cardiac output, and finally to hypotension. We thus hypothesize a “central” mechanism responsible for the abnormal blood-pressure response to exercise. An impaired systolic response to exercise in HCM patients with an exercise-induced abnormal blood-pressure response was due to a significant increase in LV endsystolic volume. This suggests that a potential mechanism for such an abnormal response to exercise in HCM patients may be myocardial ischemia. Myocardial ischemia was clearly demonstrated in HCM patients,8,10-12 and it is a major risk factor for sudden cardiac death.30 It could be induced by an increased myocardial oxygen demand,31 as occurs during exercise. Our findings are consistent with previous studies that demonstrated exerciseinduced myocardial ischemia during VEST in patients with coronary artery disease,32 in whom exercise-related myocardial ischemia caused a fall in ejection fraction
Figure 4. Mean value ⫾ 1 standard deviation of percent difference between peak exercise and baseline of percent of maximal predicted oxygen consumption (%) in the two study groups: patients with hypertrophic cardiomyopathy and normal systolic blood-pressure response to exercise (Normal BP response), and patients with hypertrophic cardiomyopathy and abnormal systolic blood-pressure response to exercise (Abnormal BP response).
and an increase in end-systolic and end-diastolic volume. Similarly, Taki et al.13 demonstrated that LV dysfunction during exercise, assessed by VEST, is a common phenomenon in patients with HCM, and postulated that it was due to myocardial ischemia. Okeie et al.14 showed that myocardial ischemia was the primary reason for the decrease in ejection fraction in HCM during exercise, assessed by VEST; this was associated with the development of dobutamine-induced, new wall-motion abnormalities. Also, there was a significant correlation between changes in ejection fraction and the number of dysfunctional LV segments.14 In patients with coronary artery disease, exercise-induced hypotension is strictly associated with severe coronary disease, and is related to global and regional LV systolic dysfunction.33,34 Our results complement with those by Yoshida et al.,8 who demonstrated in HCM patients that an exerciseinduced hypotensive response was related to subendocardial ischemia, as assessed by thallium scintigraphy, with a higher prevalence of LV cavity dilatation compared with those with a normal blood-pressure response. Our findings shed a light on the mechanism by which subendocardial ischemia is related to an abnormal bloodpressure response. Another (not necessarily alternative) mechanism may be exercise-induced outflow-tract obstruction. Although the hemodynamic adaptation to exercise was similar irrespective of resting outflow-tract gradient, an increase or development of obstruction during exercise cannot be predicted, and could explain both the systolic impairment and fall in blood pressure. In fact, the afterload increase associated with obstruction might explain the systolic impairment, according to the law of
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Hill. An exercise-induced blood-pressure fall was abolished in HCM patients with LV outflow tract obstruction by means of alcohol ablation of the septum.35 This is in accordance with the previous hypothesis. It should be pointed out, however, that this hypothesis is in conflict with the observed enlargement in LV end-systolic volume (Figure 1). In this setting, the LV outflow tract gradient should decrease. To support the nuclear data, we showed that HCM patients with an exercise-induced abnormal blood-pressure response exhibited poorer aerobic exercise tolerance, with a lower percent of maximal predicted oxygen consumption (Figure 4). Sharma et al.9 found that patients with an abnormal blood-pressure response had a lower peak oxygen consumption than those with a normal response. These data are in agreement with ours, and are consistent with our finding of a blunted cardiacoutput increase in HCM patients with exercise-induced hypotension. Previous studies3,4 suggest that in HCM patients, exercise-induced hypotension was due to an exaggerated decrease in systemic vascular resistance. Those authors assessed systemic vascular resistance using forearm blood flow, and they thought that an activation of ventricular mechanoreceptors may relate to exercise hypotension or an increased sensitivity of arterial baroreflex, and hence a “peripheral” mechanism. In our study, we assessed global systemic vascular resistance indirectly, as the ratio of mean blood pressure and cardiac output, and we showed a similar decrease in systemic vascular resistance during exercise in HCM patients with exercise-induced hypotension and in patients with a normal blood-pressure response to exercise. The difference in systemic vascular resistance responses during exercise between these previous studies and ours may be explained by the difference in methods: systemic vascular resistance changes differently in different regions. Global systemic vascular resistance is the sum of different adaptation processes to exercise: the local effect of exercise metabolites, cortical influences, reflex activation of metabolic receptors in skeletal muscle, and increased ventricular baroreceptor activity.36 Therefore, it is reasonable that local changes in resistance do not reflect modifications in global systemic vascular resistance. In this study, we demonstrated that systemic vascular resistance decreased similarly in HCM patients without and with an abnormal blood-pressure response to exercise. In terms of an alternative mechanism, an abnormal decrease in systemic vascular resistance may cause or aggravate ongoing myocardial ischemia during exercise. Nevertheless, this hypothesis is unlikely, because, in our study, systemic vascular resistance showed a similar
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decrease during exercise in HCM patients with and without exercise induced-hypotension. Study Limitations The VEST is a functional tool that assesses the LV relative volume curve. We hypothesize that the mechanism responsible for exercise-induced abnormal blood pressure could be myocardial ischemia or outflow-tract obstruction. Nevertheless, we only have evidence of exercise-induced systolic dysfunction, with a fall in stroke volume, ejection fraction, and hence cardiac output. Left-ventricular outflow-tract obstruction may play a role in hemodynamics during exercise in HCM patients. However, the simultaneous echocardiographic monitoring of changes in LV outflow-tract obstruction during handgrip was prevented by the presence of the VEST placed over the subject’s chest.
CONCLUSIONS In HCM patients, an exercise-induced abnormal bloodpressure response was associated with exercise-induced LV systolic dysfunction and impairment in oxygen consumption. This may cause hemodynamic instability, associated with a high risk of sudden cardiac death. References 1. Spirito P, Seidman CE, McKenna WJ, Maron BJ. The management of hypertrophic cardiomyopathy. N Engl J Med 1997;11:775-85. 2. Maki S, Ikeda H, Muro A, Yoshida N, Shibata A, Koga Y, et al. Predictors of sudden cardiac death in hypertrophic cardiomyopathy. Am J Cardiol 1998;82:774-8. 3. Counihan PJ, Frenneaux MP, Webb DJ, McKenna WJ. Abnormal vascular response to supine exercise in hypertrophic cardiomyopathy. Circulation 1991;84:686-96. 4. Frenneaux MP, Counihan PJ, Caforio ALP, Chikamori T, McKenna WJ. Abnormal blood pressure response during exercise in hypertrophic cardiomyopathy. Circulation 1990;82:1995-2002. 5. Olivotto I, Maron BJ, Montereggi A, Mazzuoli F, Dolara A, Cecchi F. Prognostic value of systemic blood pressure response during exercise in a community-based patient population with hypertrophic cardiomyopathy. J Am Coll Cardiol 1999;33: 2044-51. 6. Sadoul N, Prasad K, Elliott PM, Bannerjee S, Frenneaux MP, McKenna WJ. Prospective assessment of blood pressure response during exercise in patients with hypertrophic cardiomyopathy. Circulation 1997;96:2987-91. 7. Ciampi Q, Betocchi S, Lombardi R, Losi MA, Manganelli F, Storto G, et al. Hemodynamic determinants of exercise-induced abnormal blood pressure response in hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;40:278-84. 8. Yoshida N, Ikeda H, Wada T, Matsumoto A, Maki S, Muro A, et al. Exercise-induced abnormal blood pressure response are related to subendocardial ischemia in hypertrophic cardiomyopathy. J Am Coll Cardiol 1998;32:1938-42.
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9. Sharma S, Elliott P, Whyte G, Jones S, Mahon N, Whipp B, et al. Utility of cardiopulmonary exercise in the assessment of clinical determinants of functional capacity in hypertrophic cardiomyopathy. Am J Cardiol 2000;86:162-8. 10. Yamada M, Elliott PM, Kaski JC, Prasad K, Gane JN, Lowe CM, et al. Dipyridamole stress thallium-201 perfusion abnormalities in patients with hypertrophic cardiomyopathy. Eur Heart J 1998;19: 500-7. 11. Cannon RO III, Schenke WH, Maron BJ, Tracy CM, Leon MB, Brush JE, et al. Differences in coronary flow and myocardial metabolism at rest and during pacing between patients with obstructive and patients with nonobstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 1987;10:53-62. 12. Camici P, Chiriatti G, Lorenzoni R, Bellina RC, Gistri R, Italiani G, et al. Coronary vasodilation is impaired in both hypertrophied and nonhypertrophied myocardium of patients with hypertrophic cardiomyopathy: a study with nitrogen-13 ammonia and positron emission tomography. J Am Coll Cardiol 1991;5:879-86. 13. Taki J, Nakajima K, Shimizu M, Tonami N, Hisada K. Left ventricular functional reserve in nonobstructive hypertrophic cardiomyopathy: evaluation by continuous left ventricular function monitoring. J Nucl Med 1994;35:1937-43. 14. Okeie K, Shimizu M, Yoshio H, Ino H, Yamaguchi M, Matsuyama T, et al. Left ventricular systolic dysfunction during exercise and dobutamine stress in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2000;36:856-63. 15. Wigle ED, Sasson Z, Henderson MA, Ruddy TD, Fulop J, Rakowski H, et al. Hypertrophic cardiomyopathy: the importance of the site and the extent of hypertrophy: a review. Prog Cardiovasc Dis 1985;28:1-83. 16. Maron BJ, Epstein SE. Hypertrophic cardiomyopathy: a discussion of nomenclature. Am J Cardiol 1979;43:1242-4. 17. O’Gara PT, Bonow RO, Maron BJ, Damske BA, Van Lingen A, Bacharach SL, et al. Myocardial perfusion abnormalities in patients with hypertrophic cardiomyopathy: assessment with thallium-201 emission computed tomography. Circulation 1987;76: 1214-23. 18. Sahn DJ, DeMaria A, Kisslo J, Weiman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58: 1072-83. 19. Spirito P, Maron BJ, Chiarella F, Bellotti P, Tramarin R, Pozzoli M, et al. Diastolic abnormalities in patients with hypertrophic cardiomyopathy: relation to magnitude of left ventricular hypertrophy. Circulation 1985;72:310-6. 20. Spirito P, Maron BJ, Bonow RO, Epstein SE. Occurrence and significance of progressive left ventricular wall thinning and relative cavity dilatation in hypertrophic cardiomyopathy. Am J Cardiol 1987;59:123-9. 21. Spirito P, Chiarella M, Carratino L, Zoni Berisso M, Bellotti P, Vecchio C. Clinical course and prognosis of hypertrophic cardiomyopathy in an outpatient population. N Engl J Med 1989; 320:749-55.
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22. Helmcke F, Nanda NC, Hsiung MC, Soto B, Adey CK, Goyal RG, et al. Color Doppler assessment of mitral regurgitation with orthogonal planes. Circulation 1987;75:175-83. 23. Panza JA, Petrone RK, Fananapazir L, Maron BJ. Utility of continuous wave Doppler echocardiography in the noninvasive assessment of left ventricular outflow tract pressure gradient in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 1991;19:91-9. 24. Betocchi S, Piscione F, Villari B, Pace L, Ciarmiello A, PerroneFilardi P, et al. Effects of induced asynchrony on left ventricular diastolic function in patients with coronary artery disease. J Am Coll Cardiol 1993;21:1124-31. 25. Wilson RA, Sullivan PJ, Moore RH, Zielonka JS, Alpert NM, Boucher CA, et al. An ambulatory ventricular function monitor: validation and preliminary results. Am J Cardiol 1983;52:601-6. 26. Pace L, Cuocolo A, Nappi A, Nicolai E, Trimarco B, Salvatore M. Accuracy and repeatability of left ventricle systolic and diastolic function measurements using an ambulatory radionuclide monitor. Eur J Nucl Med 1992;19:800-6. 27. Bruce RA, McDonough JR. Stress testing for cardiovascular disease. Bull NY Acad Med 1969;45:1288-94. 28. Jones NL. Clinical exercise testing. Philadelphia: W.B. Saunders, 1988:208 –12. 29. Wassermann K, Hansen JE, Sue DY. Principles of exercise testing and interpretation. Philadephia: Lea & Febiger, 1986:73. 30. Dilsizian V, Bonow RO, Epstein SE, Fananapazir L. Myocardial ischemia detected by thallium scintigraphy is frequently related to cardiac arrest and syncope in young patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 1993;22:796-804. 31. Cannon RO III, Rosing DR, Maron BJ, Leon MB, Bonow RO, Watson RM, et al. Myocardial ischemia in patients with hypertrophic cardiomyopathy: contribution of inadequate vasodilator reserve and elevated left ventricular filling pressure. Circulation 1985;71:234-43. 32. Tamaki N, Yashuda T, Moore RH, Gill JB, Boucher CA, Hutter AM, et al. Continuous monitoring of left ventricular function by an ambulatory radionuclide detector in patients with coronary artery disease. J Am Coll Cardiol 1988;12:669-79. 33. Dubach P, Froelicher VF, Klein J, Oakes D, Grover-McKay, Friis R. Exercise-induced hypotension in a male population. Criteria, causes and prognosis. Circulation 1988;78:1380-7. 34. Gibbons RJ, Hu DC, Clements IP, Mankin HT, Zinsmeister AR, Brown ML. Anatomic and functional significance of hypotensive response during supine exercise radionuclide ventriculography. Am J Cardiol 1987;60:1-4. 35. Kim JJ, Lee CW, Park SW, Hong MK, Lim HY, Song JK, et al. Improvement in exercise capacity and exercise blood pressure response after transcoronary alcohol ablation therapy of septal hypertrophy in hypertrophic cardiomyopathy. Am J Cardiol 1999; 83:1120-3. 36. Flamm SD, Taki J, Moore R, Lewis SF, Keech F, Maltais F, et al. Redistribution of regional and organ blood volume and effect on cardiac function in elation to upright exercise intensity in healthy human subjects. Circulation 1990;81:1550-9.