Journal of Cardiology 63 (2014) 89–94
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Review
Subendocardial ischemia in hypertrophic cardiomyopathy Tatsuya Kawasaki (MD, PhD) ∗ , Hiroki Sugihara (MD, PhD) Department of Cardiology, Matsushita Memorial Hospital, Osaka, Japan
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Article history: Received 9 June 2013 Received in revised form 5 September 2013 Accepted 4 October 2013 Available online 20 November 2013 Keywords: Cardiomyopathies Hypertrophic Ischemia Subendocardium
a b s t r a c t Hypertrophic cardiomyopathy (HCM) patients often develop subendocardial ischemia in the left ventricle without atherosclerotic coronary stenosis. Myocardial ischemia plays an important role in the pathophysiology of HCM, but diagnostic techniques for the detection of subendocardial ischemia have not been widely available. We developed specific techniques to quantify subendocardial ischemia on stress scintigraphy, and have compared the results with various clinical features in patients with HCM. This article reviews our understanding of subendocardial ischemia in HCM based on more than 20 years of experience. © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Contents Case presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electrocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Autonomic function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Echocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Scintigraphy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Positron emission tomography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Magnetic resonance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Case presentation A 61-year-old man presents with chest pain on exertion. On examination, physical signs are normal without heart murmur. An electrocardiogram shows marked left ventricular (LV) hypertrophy in the absence of a history of hypertension. Imaging modalities show asymmetric septal hypertrophy on magnetic resonance imaging, no provokable LV outflow tract obstruction on echocardiography, no atherosclerotic stenosis on coronary computed
∗ Corresponding author at: Department of Cardiology, Matsushita Memorial Hospital, Sotojima 5-55, Moriguchi, Osaka 570-8540, Japan. Tel.: +81 66992 1231; fax: +81 66992 4845. E-mail address: [email protected] (T. Kawasaki).
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tomography angiography, and unique findings on myocardial perfusion scintigraphy (Fig. 1). How should this case be managed?
Background HCM is an entity first described clinically in 1957 by Brock [1], followed pathologically the next year by Teare [2]. In the mid1970s, the assessment of myocardial perfusion with thallium-201 was introduced to patients with HCM, showing regional myocardial hypoperfusion in the absence of epicardial coronary artery disease [3,4]. In 1987, O’Gara et al. [5] demonstrated transient LV cavity dilation on thallium-201 obtained immediately after cessation of maximal treadmill exercise in HCM patients with normal coronary arteries. This scintigraphic abnormality was reported by Udelson
0914-5087/$ – see front matter © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jjcc.2013.10.005
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Fig. 1. Representative case of subendocardial ischemia in hypertrophic cardiomyopathy. Cardiac magnetic resonance shows asymmetric septal hypertrophy (Panel A, shortaxis; Panel B, long-axis) in a 61-year-old man with chest pain on exertion. Coronary computed tomography angiography shows no atherosclerotic stenosis in the left descending coronary artery (Panel C), the left circumflex coronary artery (Panel D), and the right coronary artery (Panel E). Notably, exercise-induced transient cavity dilation is apparent on short-axis slices of thallium-201 scintigraphy after exercise (Panel F), compared with at rest (Panel G), features consistent with left ventricular subendocardial ischemia.
et al. in 1989 to occur without any significant changes in the LV cavity volume before and after exercise [6]. Moreover, in 1991, Cannon et al. [7] showed the association of the unique scintigraphic findings with myocardial lactate abnormalities. Thus, transient LV cavity dilation on stress scintigraphy in HCM patients without coronary stenosis, for example, as shown in Fig. 1, has been considered to reflect subendocardial ischemia in the LV. Myocardial ischemia plays an important role in the pathophysiology of HCM [8,9], but quantitative diagnostic techniques for the detection of subendocardial ischemia have not been fully understood in clinical practice. In 1990, we developed specific software to quantify transient LV cavity dilation or subendocardial ischemia based on stress scintigraphy in patients with HCM [10]. Briefly, in a thallium-201 short-axis slice of the mid-LV, 36 radii were generated at 10-degree intervals from the center of the image. An area surrounded by 36 points, each displaying the maximum count on each radius, was calculated automatically in the stress and rest images, and subendocardial ischemia was assessed on the basis of the ratio of the surface area during stress to that at rest. The ratio that we calculated was not based on a genuine LV cavity during stress to that at rest, but the ratio could be an index of subendocardial ischemia because subendocardial ischemia causes the maximum count on the radius to move outward. This speculation is supported by our findings that LV end-diastolic volume did not change 10 min after exercise and at rest as assessed by radionuclide ventriculography [10]. We had applied this technique to HCM patients in the clinical setting for almost 10 years [11]. In 2000, we modified our method for a more accurate analysis; the LV was divided into 15 short-axis slices and 100 radii were generated at 3.6-degree intervals from the center of each image, as shown in Fig. 2. An area surrounded by 100 points each displaying the maximum count on each radius was calculated automatically in the stress and rest images. Subendocardial ischemia was considered present if the stress to rest ratio in the sum of the 15 surface areas was greater than the mean plus 2 standard deviations in normal subjects (i.e. 1.07) [12]. These programs that we previously developed and appropriately modified have enabled us to compare subendocardial ischemia with various clinical features in patients with HCM. This article reviews our
understanding of subendocardial ischemia in HCM based on more than 20 years of experience. Epidemiology Approximately one-third to one-half of patients with HCM developed subendocardial ischemia during stress testing without atherosclerotic coronary stenosis in our cohorts [10–12] and other populations [5,7]. In our different groups of patients with HCM, chest symptoms were more frequently observed in HCM patients with subendocardial ischemia than in patients without subendocardial ischemia (67% versus 31%, p = 0.01 [10] and 65% versus 25%, p = 0.01 [13]), but subendocardial ischemia was not associated with age, gender, body mass index, a previous history of syncope, or family history of HCM, or of unexpected sudden death [12]. Electrocardiography We examined the details of electrocardiographic findings during exercise testing with scintigraphy in 48 HCM patients, and found that resting ST-segment depression, defined as >0.1 mV in depth except for aVR, as shown in Fig. 3A, was an independent predictor for the presence of subendocardial ischemia [12]. In brief, the incidence of resting ST-segment depression was 11 patients of 17 with subendocardial ischemia and 9 of 31 patients without subendocardial ischemia (p = 0.02). The diagnostic performance of the total number of leads with resting ST-segment depression ≥3 was a sensitivity of 65%, a specificity of 90%, an accuracy of 81%, a positive predictive value of 79%, and a negative predictive value of 82%. On the other hand, ST-segment depression during exercise was not a reliable marker of subendocardial ischemia, findings consistent with previous reports [5,7]. Repetitive ischemia in the subendocardium is a possible cause of resting ST-segment depression in HCM patients with subendocardial ischemia, as in patients with chronic ischemic heart disease [14]. Moreover, in 29 HCM patients with asymmetric septal hypertrophy, we found that 5 of 15 patients with diffuse subendocardial ischemia had small q waves in leads V5 and V6 (i.e. septal q waves)
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Fig. 2. Quantitative assessment for subendocardial ischemia in hypertrophic cardiomyopathy. The left ventricle on technetium-99m tetrofosmin myocardial scintigraphy is divided into 15 short-axis slices (Panel A). Panel B shows the close-up view of the last short-axis slice (surrounded by a white line on Panel A) under analysis; white radii are drawn at 3.6-degree intervals from the center of the left ventricle; a white circle is composed of black points located on the maximum count of each radius.
at rest, all the 5 showing a decrease in amplitude during exercise, as shown in Fig. 3B. Of 14 HCM patients with no subendocardial ischemia, 7 had a septal q wave at rest, 4 of them showing a decrease in amplitude during exercise. Decreased amplitude of the sum of septal q waves in leads V5 and V6 during exercise yielded a sensitivity of 100%, a specificity of 43%, an accuracy of 67%, a positive predictive value of 56%, and a negative predictive value of 100% for the detection of subendocardial ischemia [15]. Septal q waves are considered to reflect the rightward-directed depolarization through the ventricular septum [16]. The response of septal q waves to exercise has been reported to be a reliable marker of septal ischemia in patients with ischemic heart disease [17]. Other electrocardiographic findings at rest and the responses to exercise, for example, abnormal Q wave, ST-segment elevation, T-wave inversion, and R-wave amplitude were not associated with subendocardial ischemia in our HCM patients [12,18].
Autonomic function Patients with HCM often fail to increase blood pressure during exercise [19,20], known as abnormal blood pressure response, which has been reported to be associated with subendocardial ischemia [21]. Vagal nerves mediate inhibitory responses in the cardiovascular system. Thus, we examined vagal response to subendocardial ischemia in relation to abnormal blood pressure response; vagal modulation was assessed by means of the percentage change in the high-frequency component of heart rate variability from 5 min before to after exercise using commercially available software (MemCalc/Tarawa, GMS Co. Ltd., Tokyo, Japan) [22]. We found that vagal enhancement after exercise was higher in HCM patients with subendocardial ischemia than in those without it. Furthermore, HCM patients with abnormal blood pressure response, defined as a failure to exhibit an increase ≥25 mmHg during exercise, were characterized by higher vagal enhancement after exercise. These findings suggest that subendocardial ischemia provoked vagal enhancement in patients with HCM, leading to the development of an abnormal blood pressure response to exercise. The fact that vagal nerves are predominantly distributed in the LV subendocardium [23–25] may explain the
mechanism linking subendocardial ischemia to vagal enhancement [26]. Echocardiography In our HCM cohort, patients with and without subendocardial ischemia did not differ significantly with respect to conventional echocardiographic findings including LV fractional shortening, ventricular septum thickness, E/A, or deceleration time of E, but left atrial end-systolic diameter was larger in patients with subendocardial ischemia than in patients without subendocardial ischemia (43 ± 5 mm versus 40 ± 3 mm, p = 0.04 [13] or 42 ± 5 mm versus 38 ± 3 mm, p = 0.03 [27]). Enlarged left atrial diameter associated with subendocardial ischemia may be supported by elevated LV filling pressure in HCM patients with subendocardial ischemia [6,7]. However, the diagnostic value of left atrial diameter does not seem to be of clinical use because of the considerable overlap in the values between HCM patients with and without subendocardial ischemia. In our study using ultrasonic tissue characterization in HCM patients with asymmetric septal hypertrophy, as shown in Fig. 3C, the ratio of cyclic variation of integrated backscatter in the right halves to the left halves was significantly higher in patients with subendocardial ischemia than in those without it [13]. In receiver operator characteristic curve analysis, a ratio of cyclic variation of integrated backscatter in the right halves to the left halves >1.0 had good predictive value in detecting subendocardial ischemia: a sensitivity of 80%, a specificity of 71%, an accuracy of 76%, a positive predictive value of 80%, and a negative predictive value of 71%. We may safely consider that repetitive subendocardial ischemia causes reduction in cyclic variation of integrated backscatter in the left halves of the ventricular septum in HCM, as in patients with chronic stable ischemic heart disease [28]. Scintigraphy We examined the hypothesis that volumetric variables obtained by technetium-99m tetrofosmin gated single-photon emission computed tomography using commercially available software (QGS Software, Cedars-Sinai Medical Center, Los Angeles, CA, USA)
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Fig. 3. Diagnostic techniques for subendocardial ischemia in hypertrophic cardiomyopathy. The keys to detecting subendocardial ischemia in hypertrophic cardiomyopathy are ST-segment depression on resting electrocardiography (Panel A), a decreased septal q wave during exercise electrocardiography (Panel B, arrow), decreased cyclic variation of integrated backscatter in the left half of the ventricular septum on ultrasonic tissue characterization (Panel C), a superficially increased left ventricular volume after exercise on gated single-photon emission computed tomography (Panel D), and possibly 18F-fluorodeoxyglucose accumulation predominantly distributed in the left half of the ventricular septum on positron emission tomography after exercise (Panel E).
are useful in detecting subendocardial ischemia in HCM patients with asymmetric septal hypertrophy and a maximum wall thickness of ≤20 mm [27]. This patient selection was based on the results of a study of cardiac phantom modifying HCM with asymmetric septal hypertrophy [29], which showed that the difference between the LV volume obtained by QGS software and the actual LV volume was within 3% when the maximum wall thickness was ≤20 mm, but otherwise the difference was ≥8%. In our selected population [27], LV end-systolic and end-diastolic volumes after exercise, compared with at rest, were higher in HCM patients with subendocardial ischemia than in those without it, as shown in Fig. 3D. Considering no significant changes in true LV cavity volumes assessed by radionuclide ventriculography before and after exercise [6,10], we speculate that the superficial increase in LV volumes on QGS software in HCM patients with subendocardial ischemia was a result of decreased tracer accumulation in the LV subendocardium after exercise. The receiver operator characteristic curve analysis of exercise-induced percentage changes in LV end-systolic volume for the detection of subendocardial ischemia showed that the optimal cut-off was 17%, with a sensitivity of 89%, a specificity of 82%, an accuracy of 82%, a positive predictive value of 73%, and a negative predictive value of 93%. The indexes for regional myocardial ischemia (i.e. summed stress score and summed difference score) were significantly higher in patients with subendocardial ischemia than in those without it [12,27]. These findings indicate that our method for the
detection of subendocardial ischemia is not completely independent of regional myocardial ischemia. This limitation is, however, inevitable because subendocardial ischemia often occurs accompanied by regional myocardial ischemia in most patients with HCM [5–7].
Positron emission tomography A technique that combines exercise testing and positron emission tomography with 18F-fluorodeoxyglucose has been reported to provide direct imaging of myocardial ischemia in patients with ischemic heart disease [30]. Similarly, we showed that the technique was available in detecting subendocardial ischemia in a patient with HCM, as shown in Fig. 3E [31]. Briefly, 18Ffluorodeoxyglucose was injected intravenously 3 min after peak exercise, and positron emission tomography/computed tomography of the LV was acquired 50 min after the injection, showing tracer accumulation predominantly in the left half of the ventricular septum in a patient with nonobstructive HCM with asymmetric septal hypertrophy. We applied this technique to 6 nonobstructive HCM patients with asymmetric septal hypertrophy, and found that 3 of 6 showed apparent uptake of 18F-fluorodeoxyglucose predominantly in the left halves of the ventricular septum, whereas 2 of the 3 were diagnosed with subendocardial ischemia on the basis of exercise testing with thallium-201.
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Magnetic resonance Late gadolinium enhancement on cardiac magnetic resonance was examined in relationship to subendocardial ischemia in our HCM patients with asymmetric septal hypertrophy [13], showing that late gadolinium enhancement as assessed separately in the right halves and the left halves of the ventricular septum failed to provide useful information for detecting subendocardial ischemia. Late gadolinium enhancement has been established as the most reliable noninvasive imaging method for assessing myocardial fibrosis [32,33]. Thus, repetitive subendocardial ischemia is unlikely to cause myocardial fibrosis in patients with HCM. More recently, cardiac magnetic resonance stress testing, for example, adenosine stress perfusion imaging or dobutamine stress wall motion analysis, has been reported to demonstrate high diagnostic accuracy for the detection of significant coronary artery disease [34]. Further studies are needed to clarify whether stress cardiac magnetic resonance detects subendocardial ischemia in patients with HCM.
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of patients and disappeared in 67% after the administration of verapamil (240 mg daily) [42], findings consistent with a previous study [6]. We also showed that diltiazem (120 mg daily) improved both subendocardial ischemia and chest symptoms in more than 60% of HCM patients without negatively affecting exercise tolerance [43]. Conclusions Our experience suggests that subendocardial ischemia is associated with various clinical features in patients with HCM. A diagnosis of subendocardial ischemia may be helpful in selecting HCM patients who will benefit from medications to relieve chest symptoms. The patient described in the introduction of this article is likely to suffer from subendocardial ischemia associated with HCM, which could be treated with appropriate medications. Conflict of interest None declared.
Prognosis We prospectively followed 55 patients with nonobstructive HCM for the occurrence of cardiovascular events after the assessment of subendocardial ischemia on exercise scintigraphy [35]. Cardiovascular events were defined as sudden death, cardiovascular death, and hospitalization due to heart failure or stroke associated with atrial fibrillation because these 3 modes of death were prevalent in patients with HCM [36]. Cardiovascular events occurred in 10 of 55 patients during an average follow-up period of 5.7 years (range, 0.4–7.3 years): 2 patients died suddenly and 1 died of stroke; 5 were hospitalized for heart failure and 2 for stroke. The frequency of subendocardial ischemia did not differ significantly between patients with and without cardiovascular death (10% versus 3%, p = 0.32) and cardiovascular events (50% versus 36%, p = 0.40). Kaplan–Meier event-free rates showed that cardiovascular events were not related to subendocardial ischemia (Chi-square = 0.56, Log-rank test p = 0.46). Lack of prognostic value of subendocardial ischemia in our HCM cohort is consistent with our other finding that subendocardial ischemia was not associated with the presence of gadolinium enhancement on magnetic resonance imaging [13]; prospective studies on HCM demonstrated that the presence of late gadolinium enhancement is a predictor of adverse events [37,38]. On the other hand, subendocardial ischemia has been reported to be associated with elevated LV filling pressure [6,7] and abnormal blood pressure response to exercise [21,22], possibly leading to poor prognosis. Multicenter studies with longer follow-up are needed to confirm the effect of subendocardial ischemia on prognosis in patients with HCM. It should be also noted that a subset of patients with HCM is known to have different clinical courses, compared with our cohort [39]. Treatment A major cause of chest symptoms in HCM patients is thought to be myocardial ischemia [8,40], which results from failure of the coronary microcirculation due to reduced arteriolar density, increased oxygen demand of the hypertrophied myocardium, abnormalities of the small vessels, fibrosis, disarray, or elevated LV end-diastolic pressure, among others [8,9,41]. In our HCM cohort, the frequency of chest symptoms was significantly higher in patients with subendocardial ischemia than in patients without it [10,13]. Furthermore, in our study consisting of mostly nonobstructive HCM patients, subendocardial ischemia improved in 89%
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[18] Kawasaki T, Akakabe Y, Yamano M, Miki S, Kamitani T, Kuribayashi T, Sugihara H. R-wave amplitude response to myocardial ischemia in hypertrophic cardiomyopathy. J Electrocardiol 2008;41:68–71. [19] Olivotto I, Maron BJ, Montereggi A, Mazzuoli F, Dolara A, Cecchi F. Prognostic value of systemic blood pressure response during exercise in a communitybased patient population with hypertrophic cardiomyopathy. J Am Coll Cardiol 1999;33:2044–51. [20] Spirito P, Seidman CE, McKenna WJ, Maron BJ. The management of hypertrophic cardiomyopathy. N Engl J Med 1997;336:775–85. [21] Yoshida N, Ikeda H, Wada T, Matsumoto A, Maki S, Muro A, Shibata A, Imaizumi T. Exercise-induced abnormal blood pressure responses are related to subendocardial ischemia in hypertrophic cardiomyopathy. J Am Coll Cardiol 1998;32:1938–42. [22] Kawasaki T, Azuma A, Kuribayashi T, Akakabe Y, Yamano M, Miki S, Sawada T, Kamitani T, Matsubara H, Sugihara H. Vagal enhancement due to subendocardial ischemia as a cause of abnormal blood pressure response in hypertrophic cardiomyopathy. Int J Cardiol 2008;129:59–64. [23] Barber MJ, Mueller TM, Davies BG, Zipes DP. Phenol topically applied to canine left ventricular epicardium interrupts sympathetic but not vagal afferents. Circ Res 1984;55:532–44. [24] Zipes DP. Influence of myocardial ischemia and infarction on autonomic innervation of heart. Circulation 1990;82:1095–105. [25] Kawano H, Okada R, Yano K. Histological study on the distribution of autonomic nerves in the human heart. Heart Vessels 2003;18:32–9. [26] Thorén P. Role of cardiac vagal C-fibers in cardiovascular control. Rev Physiol Biochem Pharmacol 1979;86:1–94. [27] Kawasaki T, Akakabe Y, Yamano M, Miki S, Kamitani T, Kuribayashi T, Sugihara H. Gated single-photon emission computed tomography detects subendocardial ischemia in hypertrophic cardiomyopathy. Circ J 2007;71:256–60. [28] Lin LC, Kao HL, Wu CC, Ho YL, Lee YT. Alterations of myocardial ultrasonic tissue characterization by coronary angioplasty in patients with chronic stable coronary artery disease. Ultrasound Med Biol 2001;27:1191–8. [29] Nishimura Y, Katafuchi T, Hirase Y, Sagoh M, Oka H, Mori H, Murase K. Measurement of left ventricular chamber and myocardial volume in hypertrophic cardiomyopathy patients by ECG-gated myocardial perfusion SPECT: application of a newly developed edge-detection algorithm. Nihon Hoshasen Gijutsu Gakkai Zasshi 2002;58:1586–91 [in Japanese]. [30] He ZX, Shi RF, Wu YJ, Tian YQ, Liu XJ, Wang SW, Shen R, Qin XW, Gao RL, Narula J, Jain D. Direct imaging of exercise-induced myocardial ischemia with fluorine18-labeled deoxyglucose and Tc-99m-sestamibi in coronary artery disease. Circulation 2003;108:1208–13. [31] Yamano M, Kawasaki T, Sugihara H. Direct imaging of myocardial ischaemia with [18F]fluorodeoxyglucose on exercise PET in hypertrophic cardiomyopathy. Heart 2009;95:1051.
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Review
Subendocardial ischemia in hypertrophic cardiomyopathy Tatsuya Kawasaki (MD, PhD) ∗ , Hiroki Sugihara (MD, PhD) Department of Cardiology, Matsushita Memorial Hospital, Osaka, Japan
a r t i c l e
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Article history: Received 9 June 2013 Received in revised form 5 September 2013 Accepted 4 October 2013 Available online 20 November 2013 Keywords: Cardiomyopathies Hypertrophic Ischemia Subendocardium
a b s t r a c t Hypertrophic cardiomyopathy (HCM) patients often develop subendocardial ischemia in the left ventricle without atherosclerotic coronary stenosis. Myocardial ischemia plays an important role in the pathophysiology of HCM, but diagnostic techniques for the detection of subendocardial ischemia have not been widely available. We developed specific techniques to quantify subendocardial ischemia on stress scintigraphy, and have compared the results with various clinical features in patients with HCM. This article reviews our understanding of subendocardial ischemia in HCM based on more than 20 years of experience. © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Contents Case presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electrocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Autonomic function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Echocardiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Scintigraphy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Positron emission tomography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Magnetic resonance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Case presentation A 61-year-old man presents with chest pain on exertion. On examination, physical signs are normal without heart murmur. An electrocardiogram shows marked left ventricular (LV) hypertrophy in the absence of a history of hypertension. Imaging modalities show asymmetric septal hypertrophy on magnetic resonance imaging, no provokable LV outflow tract obstruction on echocardiography, no atherosclerotic stenosis on coronary computed
∗ Corresponding author at: Department of Cardiology, Matsushita Memorial Hospital, Sotojima 5-55, Moriguchi, Osaka 570-8540, Japan. Tel.: +81 66992 1231; fax: +81 66992 4845. E-mail address: [email protected] (T. Kawasaki).
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tomography angiography, and unique findings on myocardial perfusion scintigraphy (Fig. 1). How should this case be managed?
Background HCM is an entity first described clinically in 1957 by Brock [1], followed pathologically the next year by Teare [2]. In the mid1970s, the assessment of myocardial perfusion with thallium-201 was introduced to patients with HCM, showing regional myocardial hypoperfusion in the absence of epicardial coronary artery disease [3,4]. In 1987, O’Gara et al. [5] demonstrated transient LV cavity dilation on thallium-201 obtained immediately after cessation of maximal treadmill exercise in HCM patients with normal coronary arteries. This scintigraphic abnormality was reported by Udelson
0914-5087/$ – see front matter © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jjcc.2013.10.005
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Fig. 1. Representative case of subendocardial ischemia in hypertrophic cardiomyopathy. Cardiac magnetic resonance shows asymmetric septal hypertrophy (Panel A, shortaxis; Panel B, long-axis) in a 61-year-old man with chest pain on exertion. Coronary computed tomography angiography shows no atherosclerotic stenosis in the left descending coronary artery (Panel C), the left circumflex coronary artery (Panel D), and the right coronary artery (Panel E). Notably, exercise-induced transient cavity dilation is apparent on short-axis slices of thallium-201 scintigraphy after exercise (Panel F), compared with at rest (Panel G), features consistent with left ventricular subendocardial ischemia.
et al. in 1989 to occur without any significant changes in the LV cavity volume before and after exercise [6]. Moreover, in 1991, Cannon et al. [7] showed the association of the unique scintigraphic findings with myocardial lactate abnormalities. Thus, transient LV cavity dilation on stress scintigraphy in HCM patients without coronary stenosis, for example, as shown in Fig. 1, has been considered to reflect subendocardial ischemia in the LV. Myocardial ischemia plays an important role in the pathophysiology of HCM [8,9], but quantitative diagnostic techniques for the detection of subendocardial ischemia have not been fully understood in clinical practice. In 1990, we developed specific software to quantify transient LV cavity dilation or subendocardial ischemia based on stress scintigraphy in patients with HCM [10]. Briefly, in a thallium-201 short-axis slice of the mid-LV, 36 radii were generated at 10-degree intervals from the center of the image. An area surrounded by 36 points, each displaying the maximum count on each radius, was calculated automatically in the stress and rest images, and subendocardial ischemia was assessed on the basis of the ratio of the surface area during stress to that at rest. The ratio that we calculated was not based on a genuine LV cavity during stress to that at rest, but the ratio could be an index of subendocardial ischemia because subendocardial ischemia causes the maximum count on the radius to move outward. This speculation is supported by our findings that LV end-diastolic volume did not change 10 min after exercise and at rest as assessed by radionuclide ventriculography [10]. We had applied this technique to HCM patients in the clinical setting for almost 10 years [11]. In 2000, we modified our method for a more accurate analysis; the LV was divided into 15 short-axis slices and 100 radii were generated at 3.6-degree intervals from the center of each image, as shown in Fig. 2. An area surrounded by 100 points each displaying the maximum count on each radius was calculated automatically in the stress and rest images. Subendocardial ischemia was considered present if the stress to rest ratio in the sum of the 15 surface areas was greater than the mean plus 2 standard deviations in normal subjects (i.e. 1.07) [12]. These programs that we previously developed and appropriately modified have enabled us to compare subendocardial ischemia with various clinical features in patients with HCM. This article reviews our
understanding of subendocardial ischemia in HCM based on more than 20 years of experience. Epidemiology Approximately one-third to one-half of patients with HCM developed subendocardial ischemia during stress testing without atherosclerotic coronary stenosis in our cohorts [10–12] and other populations [5,7]. In our different groups of patients with HCM, chest symptoms were more frequently observed in HCM patients with subendocardial ischemia than in patients without subendocardial ischemia (67% versus 31%, p = 0.01 [10] and 65% versus 25%, p = 0.01 [13]), but subendocardial ischemia was not associated with age, gender, body mass index, a previous history of syncope, or family history of HCM, or of unexpected sudden death [12]. Electrocardiography We examined the details of electrocardiographic findings during exercise testing with scintigraphy in 48 HCM patients, and found that resting ST-segment depression, defined as >0.1 mV in depth except for aVR, as shown in Fig. 3A, was an independent predictor for the presence of subendocardial ischemia [12]. In brief, the incidence of resting ST-segment depression was 11 patients of 17 with subendocardial ischemia and 9 of 31 patients without subendocardial ischemia (p = 0.02). The diagnostic performance of the total number of leads with resting ST-segment depression ≥3 was a sensitivity of 65%, a specificity of 90%, an accuracy of 81%, a positive predictive value of 79%, and a negative predictive value of 82%. On the other hand, ST-segment depression during exercise was not a reliable marker of subendocardial ischemia, findings consistent with previous reports [5,7]. Repetitive ischemia in the subendocardium is a possible cause of resting ST-segment depression in HCM patients with subendocardial ischemia, as in patients with chronic ischemic heart disease [14]. Moreover, in 29 HCM patients with asymmetric septal hypertrophy, we found that 5 of 15 patients with diffuse subendocardial ischemia had small q waves in leads V5 and V6 (i.e. septal q waves)
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Fig. 2. Quantitative assessment for subendocardial ischemia in hypertrophic cardiomyopathy. The left ventricle on technetium-99m tetrofosmin myocardial scintigraphy is divided into 15 short-axis slices (Panel A). Panel B shows the close-up view of the last short-axis slice (surrounded by a white line on Panel A) under analysis; white radii are drawn at 3.6-degree intervals from the center of the left ventricle; a white circle is composed of black points located on the maximum count of each radius.
at rest, all the 5 showing a decrease in amplitude during exercise, as shown in Fig. 3B. Of 14 HCM patients with no subendocardial ischemia, 7 had a septal q wave at rest, 4 of them showing a decrease in amplitude during exercise. Decreased amplitude of the sum of septal q waves in leads V5 and V6 during exercise yielded a sensitivity of 100%, a specificity of 43%, an accuracy of 67%, a positive predictive value of 56%, and a negative predictive value of 100% for the detection of subendocardial ischemia [15]. Septal q waves are considered to reflect the rightward-directed depolarization through the ventricular septum [16]. The response of septal q waves to exercise has been reported to be a reliable marker of septal ischemia in patients with ischemic heart disease [17]. Other electrocardiographic findings at rest and the responses to exercise, for example, abnormal Q wave, ST-segment elevation, T-wave inversion, and R-wave amplitude were not associated with subendocardial ischemia in our HCM patients [12,18].
Autonomic function Patients with HCM often fail to increase blood pressure during exercise [19,20], known as abnormal blood pressure response, which has been reported to be associated with subendocardial ischemia [21]. Vagal nerves mediate inhibitory responses in the cardiovascular system. Thus, we examined vagal response to subendocardial ischemia in relation to abnormal blood pressure response; vagal modulation was assessed by means of the percentage change in the high-frequency component of heart rate variability from 5 min before to after exercise using commercially available software (MemCalc/Tarawa, GMS Co. Ltd., Tokyo, Japan) [22]. We found that vagal enhancement after exercise was higher in HCM patients with subendocardial ischemia than in those without it. Furthermore, HCM patients with abnormal blood pressure response, defined as a failure to exhibit an increase ≥25 mmHg during exercise, were characterized by higher vagal enhancement after exercise. These findings suggest that subendocardial ischemia provoked vagal enhancement in patients with HCM, leading to the development of an abnormal blood pressure response to exercise. The fact that vagal nerves are predominantly distributed in the LV subendocardium [23–25] may explain the
mechanism linking subendocardial ischemia to vagal enhancement [26]. Echocardiography In our HCM cohort, patients with and without subendocardial ischemia did not differ significantly with respect to conventional echocardiographic findings including LV fractional shortening, ventricular septum thickness, E/A, or deceleration time of E, but left atrial end-systolic diameter was larger in patients with subendocardial ischemia than in patients without subendocardial ischemia (43 ± 5 mm versus 40 ± 3 mm, p = 0.04 [13] or 42 ± 5 mm versus 38 ± 3 mm, p = 0.03 [27]). Enlarged left atrial diameter associated with subendocardial ischemia may be supported by elevated LV filling pressure in HCM patients with subendocardial ischemia [6,7]. However, the diagnostic value of left atrial diameter does not seem to be of clinical use because of the considerable overlap in the values between HCM patients with and without subendocardial ischemia. In our study using ultrasonic tissue characterization in HCM patients with asymmetric septal hypertrophy, as shown in Fig. 3C, the ratio of cyclic variation of integrated backscatter in the right halves to the left halves was significantly higher in patients with subendocardial ischemia than in those without it [13]. In receiver operator characteristic curve analysis, a ratio of cyclic variation of integrated backscatter in the right halves to the left halves >1.0 had good predictive value in detecting subendocardial ischemia: a sensitivity of 80%, a specificity of 71%, an accuracy of 76%, a positive predictive value of 80%, and a negative predictive value of 71%. We may safely consider that repetitive subendocardial ischemia causes reduction in cyclic variation of integrated backscatter in the left halves of the ventricular septum in HCM, as in patients with chronic stable ischemic heart disease [28]. Scintigraphy We examined the hypothesis that volumetric variables obtained by technetium-99m tetrofosmin gated single-photon emission computed tomography using commercially available software (QGS Software, Cedars-Sinai Medical Center, Los Angeles, CA, USA)
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Fig. 3. Diagnostic techniques for subendocardial ischemia in hypertrophic cardiomyopathy. The keys to detecting subendocardial ischemia in hypertrophic cardiomyopathy are ST-segment depression on resting electrocardiography (Panel A), a decreased septal q wave during exercise electrocardiography (Panel B, arrow), decreased cyclic variation of integrated backscatter in the left half of the ventricular septum on ultrasonic tissue characterization (Panel C), a superficially increased left ventricular volume after exercise on gated single-photon emission computed tomography (Panel D), and possibly 18F-fluorodeoxyglucose accumulation predominantly distributed in the left half of the ventricular septum on positron emission tomography after exercise (Panel E).
are useful in detecting subendocardial ischemia in HCM patients with asymmetric septal hypertrophy and a maximum wall thickness of ≤20 mm [27]. This patient selection was based on the results of a study of cardiac phantom modifying HCM with asymmetric septal hypertrophy [29], which showed that the difference between the LV volume obtained by QGS software and the actual LV volume was within 3% when the maximum wall thickness was ≤20 mm, but otherwise the difference was ≥8%. In our selected population [27], LV end-systolic and end-diastolic volumes after exercise, compared with at rest, were higher in HCM patients with subendocardial ischemia than in those without it, as shown in Fig. 3D. Considering no significant changes in true LV cavity volumes assessed by radionuclide ventriculography before and after exercise [6,10], we speculate that the superficial increase in LV volumes on QGS software in HCM patients with subendocardial ischemia was a result of decreased tracer accumulation in the LV subendocardium after exercise. The receiver operator characteristic curve analysis of exercise-induced percentage changes in LV end-systolic volume for the detection of subendocardial ischemia showed that the optimal cut-off was 17%, with a sensitivity of 89%, a specificity of 82%, an accuracy of 82%, a positive predictive value of 73%, and a negative predictive value of 93%. The indexes for regional myocardial ischemia (i.e. summed stress score and summed difference score) were significantly higher in patients with subendocardial ischemia than in those without it [12,27]. These findings indicate that our method for the
detection of subendocardial ischemia is not completely independent of regional myocardial ischemia. This limitation is, however, inevitable because subendocardial ischemia often occurs accompanied by regional myocardial ischemia in most patients with HCM [5–7].
Positron emission tomography A technique that combines exercise testing and positron emission tomography with 18F-fluorodeoxyglucose has been reported to provide direct imaging of myocardial ischemia in patients with ischemic heart disease [30]. Similarly, we showed that the technique was available in detecting subendocardial ischemia in a patient with HCM, as shown in Fig. 3E [31]. Briefly, 18Ffluorodeoxyglucose was injected intravenously 3 min after peak exercise, and positron emission tomography/computed tomography of the LV was acquired 50 min after the injection, showing tracer accumulation predominantly in the left half of the ventricular septum in a patient with nonobstructive HCM with asymmetric septal hypertrophy. We applied this technique to 6 nonobstructive HCM patients with asymmetric septal hypertrophy, and found that 3 of 6 showed apparent uptake of 18F-fluorodeoxyglucose predominantly in the left halves of the ventricular septum, whereas 2 of the 3 were diagnosed with subendocardial ischemia on the basis of exercise testing with thallium-201.
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Magnetic resonance Late gadolinium enhancement on cardiac magnetic resonance was examined in relationship to subendocardial ischemia in our HCM patients with asymmetric septal hypertrophy [13], showing that late gadolinium enhancement as assessed separately in the right halves and the left halves of the ventricular septum failed to provide useful information for detecting subendocardial ischemia. Late gadolinium enhancement has been established as the most reliable noninvasive imaging method for assessing myocardial fibrosis [32,33]. Thus, repetitive subendocardial ischemia is unlikely to cause myocardial fibrosis in patients with HCM. More recently, cardiac magnetic resonance stress testing, for example, adenosine stress perfusion imaging or dobutamine stress wall motion analysis, has been reported to demonstrate high diagnostic accuracy for the detection of significant coronary artery disease [34]. Further studies are needed to clarify whether stress cardiac magnetic resonance detects subendocardial ischemia in patients with HCM.
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of patients and disappeared in 67% after the administration of verapamil (240 mg daily) [42], findings consistent with a previous study [6]. We also showed that diltiazem (120 mg daily) improved both subendocardial ischemia and chest symptoms in more than 60% of HCM patients without negatively affecting exercise tolerance [43]. Conclusions Our experience suggests that subendocardial ischemia is associated with various clinical features in patients with HCM. A diagnosis of subendocardial ischemia may be helpful in selecting HCM patients who will benefit from medications to relieve chest symptoms. The patient described in the introduction of this article is likely to suffer from subendocardial ischemia associated with HCM, which could be treated with appropriate medications. Conflict of interest None declared.
Prognosis We prospectively followed 55 patients with nonobstructive HCM for the occurrence of cardiovascular events after the assessment of subendocardial ischemia on exercise scintigraphy [35]. Cardiovascular events were defined as sudden death, cardiovascular death, and hospitalization due to heart failure or stroke associated with atrial fibrillation because these 3 modes of death were prevalent in patients with HCM [36]. Cardiovascular events occurred in 10 of 55 patients during an average follow-up period of 5.7 years (range, 0.4–7.3 years): 2 patients died suddenly and 1 died of stroke; 5 were hospitalized for heart failure and 2 for stroke. The frequency of subendocardial ischemia did not differ significantly between patients with and without cardiovascular death (10% versus 3%, p = 0.32) and cardiovascular events (50% versus 36%, p = 0.40). Kaplan–Meier event-free rates showed that cardiovascular events were not related to subendocardial ischemia (Chi-square = 0.56, Log-rank test p = 0.46). Lack of prognostic value of subendocardial ischemia in our HCM cohort is consistent with our other finding that subendocardial ischemia was not associated with the presence of gadolinium enhancement on magnetic resonance imaging [13]; prospective studies on HCM demonstrated that the presence of late gadolinium enhancement is a predictor of adverse events [37,38]. On the other hand, subendocardial ischemia has been reported to be associated with elevated LV filling pressure [6,7] and abnormal blood pressure response to exercise [21,22], possibly leading to poor prognosis. Multicenter studies with longer follow-up are needed to confirm the effect of subendocardial ischemia on prognosis in patients with HCM. It should be also noted that a subset of patients with HCM is known to have different clinical courses, compared with our cohort [39]. Treatment A major cause of chest symptoms in HCM patients is thought to be myocardial ischemia [8,40], which results from failure of the coronary microcirculation due to reduced arteriolar density, increased oxygen demand of the hypertrophied myocardium, abnormalities of the small vessels, fibrosis, disarray, or elevated LV end-diastolic pressure, among others [8,9,41]. In our HCM cohort, the frequency of chest symptoms was significantly higher in patients with subendocardial ischemia than in patients without it [10,13]. Furthermore, in our study consisting of mostly nonobstructive HCM patients, subendocardial ischemia improved in 89%
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