- Email: [email protected]
Comparison of prevalence of apical hypertrophic cardiomyopathy in Japan and the United States
Comparison of Prevalence of Apical Hypertrophic Cardiomyopathy in Japan and the United States Hiroaki Kitaoka,
MD,
Yoshinori Doi, MD, Susan A. Casey, RN, Nobuhiko Hitomi, Takashi Furuno, MD, and Barry J. Maron, MD
MD,
The morphologic apical form of hypertrophic cardiomyopathy (HC), in which left ventricular (LV) wall thickening is confined to the most distal region at the apex, has been regarded as a phenotypic expression of nonobstructive HC largely unique to Japanese patients. To investigate this question further, we directly compared unselected and regional hospital-based cohorts of adult patients with HC ( >18 years of age) from Japan (Kochi; n ⴝ 100) and from the United States (US) (Minneapolis; n ⴝ 361). Japanese and American patients with HC had similar clinical features and did not differ significantly with regard to the severity of symptoms and frequency of outflow obstruction. Although Japanese and American patients also showed similar maximum LV thickness, they differed significantly with respect to the distribution of LV hypertrophy. In particular, the segmental form of HC, with hypertrophy confined to the LV apex, was more
frequent in Japanese patients (i.e., apical HC, 15% in Japan vs 3% in US, p <0.0001). Giant negative T waves were also more common in Japanese patients with HC (26% vs 2%, p <0.001), including those with the apical form (64% vs. 30%, p <0.05). Each patient with apical HC had either no or only mild symptoms, and all survived. The morphologic form of nonobstructive HC with hypertrophy limited to the LV apex (apical form of HC) was 5 times more common in an unselected Japanese population. These findings document variability in the phenotypic expression of HC between countries and races, which may be due to differences in environmental factors or genetic background. Patients with the apical form of HC had a benign clinical course. 䊚2003 by Excerpta Medica, Inc. (Am J Cardiol 2003;92:1183–1186)
ypertrophic cardiomyopathy (HC) is a genetic cardiac disease in which a hypertrophied nondiH lated left ventricle, which is characterized by a wide
tertiary referred Japanese and American populations, particularly with respect to the relative prevalence of apical HC.
variety of patterns of asymmetric wall thickening, is the morphologic hallmark.1–3 Distribution of hypertrophy is often diffuse, but may also be mild and localized.4,5 In particular, the apical form of HC, in which wall thickening is confined to the most distal portion of the left ventricular (LV) wall, was first reported in Japan by Sakamoto and colleagues in 19766 and subsequently by Yamaguchi et al in 1979.7 Apical HC was described as a striking electrocardiographic pattern of giant negative T waves and an angiographic feature of end-diastolic LV cavity configuration resembling an “ace-of-spades.”6,7 This apical morphologic form is regarded as a subgroup of nonobstructive HC that occurs largely in Japanese patients.8 –11 Although there have been several reports of apical HC from centers outside of Japan,12–19 the true prevalence in Western countries (in relation to Japan) remains unknown. Therefore, the aim of this echocardiographic study was to directly compare the clinical and morphologic expression of HC in regional and nonFrom the Department of Medicine and Geriatrics, Kochi Medical School, Kochi, Japan; and the Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, Minnesota. Manuscript received February 20, 2003; revised manuscript received and accepted July 15, 2003. Address for reprints: Yoshinori Doi, MD, Department of Medicine and Geriatrics, Kochi Medical School, Oko-cho, Nankoku-shi, Kochi 783-8505, Japan. E-mail: [email protected]. ©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 92 November 15, 2003
METHODS
Patient selection: Consecutively enrolled patients with HC from 2 regional community-based centers were combined for a cohort of 461 patients, including (1) 100 patients from the Kochi prefecture in southwestern Japan evaluated at the Kochi Medical School, and (2) 361 patients from the Minneapolis Heart Institute, a population consisting primarily of Minnesota residents and those from the adjacent states of Wisconsin, Iowa, and North and South Dakota, who were selected as previously reported.20 The United States (US) population was predominantly white: 357 patients (99%) were Caucasian, 4 patients (1%) were black, and there were no Asians. Follow-up from initial HC diagnosis to August 2000 was 9.3 ⫾ 7.7 years. Echocardiography: Echocardiographic studies were performed with commercially available Phillips (Andover, Massachusetts) and Toshiba (Tokyo, Japan) instruments. Magnitude and distribution of LV hypertrophy were assessed prospectively with 2-dimensional echocardiography, according to previously published criteria.4 The greatest wall thickness measured at any site in the LV wall was regarded as the maximal thickness, independent of correction for body surface area, gender, or age. Wall thickness was assessed directly from the television monitor with a calibration scale produced by the instrument. Location of endocardial and epicardial 0002-9149/03/$–see front matter doi:10.1016/j.amjcard.2003.07.027
1183
Statistical analysis: Data are expressed as mean ⫾ SD. Differences between means were analyzed using unpaired Student’s t test, and comparison of nominal variables, expressed as proportions, was performed using the chi-square test. A p value ⬍0.05 was considered statistically significant. All calculations were performed using Statview, version 5.0 (SAS Institute Inc., Cary, North Carolina).
RESULTS
Patient characteristics: Clinical and morphologic findings in the 2 HC cohorts are compared in Table 1. FIGURE 1. Representative echocardiographic and electrocardiographic features in a Although Japanese patients were 41-year-old asymptomatic Japanese patient with apical HC. Left panel, striking elecmore often men and less frequently trocardiographic pattern of deep T-wave inversion (“ giant negative T waves”) in the left precordial leads; less marked T-wave inversion is also present in leads I, II, III, had outflow obstruction, Japanese and AVF. Right panel, LV wall thickening confined to the most distal region of the and American patients were similar apex, below the papillary muscle level, is shown in a modified apical view. with regard to age, symptom severity, and maximum LV thickness. Morphologic findings: Fifteen of TABLE 1 Demographic, Clinical, and Echocardiographic Data in Hypertrophic the 100 patients (15%) in the Japanese Cardiomyopathy Cohorts from Japan and the United States (US) cohort and 10 of the 361 patients (3%) Japan (Kochi) US (Minnesota) in the American cohort had apical hypertrophy (Table 1 and Figure 1). (n ⫽ 100) (n ⫽ 361) p Value Therefore, the prevalence of apical HC Age at diagnosis in Japanese patients was 5 times higher Mean ⫾ SD (yrs) 51 ⫾ 13 49 ⫾ 18 NS than that in the American patients (TaMen 70 (69%) 206 (57%) 0.02 Severe symptoms (NYHA 8 (8%) 22 (6%) NS ble 2 and Figure 2). Wall thickness at functional class III/IV) the apex was greater in the American Maximum LV wall thickness 20.8 ⫾ 4.3 21.5 ⫾ 5 NS patients than in the Japanese patients (mean ⫾ SD) (mm) (23 ⫾ 4 vs 18 ⫾ 2 mm, respectively) ⱕ20 61 (60%) 198 (55%) NS (Table 2). ⱖ30 6 (6%) 32 (9%) NS Outflow obstruction (ⱖ30 mm Hg) 16 (16%) 91 (25%) 0.03 Hypertrophy localized to 1 segGiant negative T wave 26 (26%) 7 (2%) ⬍0.001 ment of the LV wall other than the apex (usually the anterior septum) NYHA ⫽ New York Heart Association. was more common in American patients than in Japanese patients (37% vs 8%, respectively, p ⬍0.001); borders was identified by viewing the pertinent portions more diffuse hypertrophy involving ⱖ2 LV segments of videotape in slow motion and real-time modes. Peak was present with similar frequency in Japanese and instantaneous LV outflow gradient was estimated with American patients (75% vs 60%; p ⫽ NS). Clinical characteristics of apical hypertrophic continuous-wave Doppler under basal conditions.21 Definitions: The diagnosis of HC was based on the cardiomyopathy: Clinical characteristics of the 25 pa2-dimensional echocardiographic demonstration of a tients with apical HC are shown in Table 2. None of hypertrophied LV wall (wall thickness ⱖ15 mm) and these patients had severe symptoms (New York Heart a nondilated LV cavity in the absence of another Association functional class III to IV) and 12 (48%) cardiac or systemic disease capable of producing that were completely asymptomatic (6 Americans and 6 magnitude of hypertrophy (e.g., systemic hyperten- Japanese). Also, none of the 25 patients had LV outsion or aortic stenosis). Uniform morphologic criteria flow obstruction under basal conditions. Of all the for apical HC were agreed upon prospectively and patients with HC, giant negative T waves on the applied at both centers. Apical HC was defined as LV electrocardiogram (defined as a depth of ⱖ10 mm) wall thickening confined to the most distal region at were significantly more common in Japanese patients the apex below the papillary muscle level; hypertro- than in Americans (26% vs 2%, p ⬍0.0001; Table 1). phy in this region of the left ventricle was not detect- In addition, of the 25 patients with apical HC, giant able in parasternal echocardiographic cross-sectional negative T waves were again more common in Japaplanes and was evident only on apical views. Repre- nese patients than in Americans (64% vs 30%, p sentative echocardiographic and electrocardiographic ⬍0.05; Table 2 and Figure. 1). Maximum wall thickfeatures of apical HC are shown in Figure 1. ness (in the LV apex) was significantly more marked 1184 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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although the overall demographic and clinical expression of HC was generally similar in our communityKochi Minneapolis p Value based regional Japanese and American cohorts, which were not subject Patients n ⫽ 15 n ⫽ 10 ⬍0.0001 Age at diagnosis (yrs) 56 ⫾ 14 45 ⫾ 14 0.06 to tertiary center referral bias. In Range (30–70) (26–64) clinical terms, our patients with apiMen 15 (83%) 6 (60%) NS cal HC represented a distinctive subSevere symptoms* 0 (0%) 0 (0%) NS set in which male gender predomiNo or mild symptoms† 15 (100%) 10 (100%) Outflow obstruction 0 (0%) 0 (0%) NS nated, all patients had either no or Maximal apical LV wall thickness (mm) 18 ⫾ 2 23 ⫾ 4 0.003 mild cardiovascular symptoms, progHC-related death 0 (0%) 0 (0%) NS nosis was generally benign, and outGiant negative T wave 12 (64%) 3 (30%) 0.02 flow obstruction was absent. These *New York Heart Association functional class III to IV. findings are generally consistent with † New York Heart Association functional class I to II. previous observations in Japanese and other patients with apical HC,8,9,11,16 –19,23 although a minority of non-Asian patients with similar morphologic forms of HC has experienced adverse outcomes.12 The 15% prevalence of apical HC in our Japanese cohort is less than that previously reported in Japan (i.e., up to 25%).7–9,11 This finding may be partially due to our study design, which was based on the strict echocardiographic demonstration of hypertrophy confined to the most distal region of the left ventricle below the papillary muscle level. Therefore, patients were not included in this definition of apical HC if they had hypertrophy in other regions of the left ventricle beyond the apex. In contrast, earlier studies from Japan were based predominantly on the angiographic demFIGURE 2. Prevalence of apical and other morphologic forms of onstration of apical hypertrophy (by virtue of LV HC in Japanese and United States cohorts. configuration) but without direct echocardiographic demonstration of isolated apical hypertrophy7; these studies may have overestimated the prevalence of in American patients than that in Japanese patients. apical HC. In Japan, apical HC has been regarded as repreNone of the 25 patients with apical HC developed complications (e.g., apical infarction, apical thrombi, senting a significant proportion of the overall HC and secondary ventricular tachycardia beleived origi- patient population,7–9,11 but this syndrome is reported nated from apical scarring) during a 9-year follow-up. less commonly in Western patients.1,13,17,18,23,24 For There were also no HC-related deaths in either group example, in observations on 600 patients with HC from 2 referral centers, Klues and colleagues24 rewith apical HC. ported the apical form of HC in only 1% of their patients. However, the patients of Klues et al24 repreDISCUSSION Japanese investigators first reported apical HC as a sented a highly selected hospital-based referral popumorphologic variant of HC characterized by a striking lation and may not have included a representative electrocardiographic pattern of particularly deep T- proportion of asymptomatic patients with segmental wave inversion in the precordial leads (“ giant nega- hypertrophy. Moreover, a recent report by Eriksson et tive T waves”) and the distinctive angiographic spade- al23 indicated a 7% prevalence of apical HC in their shaped appearance of the left ventricle at end-diastole. cohort of patients from a tertiary referral center. Subsequently, apical HC has been reported with echoIn the present study, we directly compared regional cardiography from several centers outside of Japan, cohorts of adult patients with HC from Japan and the although the characteristic electrocardiographic pat- US, applying uniform morphologic criteria for the tern is seen inconsistently in Western patients.12–19 apical form of HC. A total of 100 Japanese patients However, the prevalence of apical HC in Western from Kochi in the southwestern part of Japan and 361 countries, in relation to Japan, has remained unre- American patients from Minnesota and the Upper solved. Also, there are limited data available suggest- Midwest were studied. We found a significantly ing variability in the HC phenotype between cultures, higher prevalence (fivefold) of apical HC in Japanese countries, and racial groups.22 patients compared with Americans. Although the reaIn the present study, using uniform echocardio- sons for these differences are not completely undergraphic criteria, we have shown that the prevalence of stood, several possibilities should be considered. First, the morphologic apical form of HC is significantly it is possible that patient selection factors play a role, higher in Japanese patients than in American patients, namely, the different healthcare systems operational TABLE 2 Clinical Comparison of Japanese and United States Patients With Apical Hypertrophic Cardiomyopathy
CARDIOMYOPATHY/APICAL HC IN JAPANESE AND AMERICANS
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in these 2 countries. For example, in Japan, electrocardiograms are routinely required of all workers after the age of 40 years, even in the absence of recognized medical problems. If the electrocardiogram is abnormal, the employee is referred for further cardiovascular evaluation. Because the level of awareness regarding apical HC is high in Japan, cardiologists carefully search for apical hypertrophy with echocardiography, particularly in the presence of T-wave inversion on electrocardiogram. Therefore, we cannot exclude the possibility that differences between the selection of patients in Japanese and the US account for some of the discordance in the prevalence of apical HC in the 2 populations. We believe the previously cited lack of difference in occurrence of apical HC between Japanese and Caucasian patients may be due to the use of less restrictive mophologic definitions.19 Second, it is possible that differences in the genetic substrate and the nature and frequency of HC-causing mutant genes could explain these discrepancies in prevalence between the US and Japan. However, comparative molecular data are not available at present in our study populations. There was a period of a temporary suspension of genetic testing in the year 2000, while the guidelines dictated by the Japanese government for genetic research were reevaluated. This had the effect of suppressing mutational analysis for Japanese patients, including those in this study with apical HC. Based on findings of early Japanese studies, giant negative T waves on electrocardiograms have been regarded as a hallmark of apical HC.25 However, reports from centers outside Japan have shown that this pattern of deep T-wave inversion is absent in most non-Japanese patients with apical HC.17,26 In the present study, giant negative T waves were more than twice as common in Japanese patients with apical HC than in American patients with the same LV morphology. Although the origin of such differences between populations is unresolved, it is possible that the precise distribution of hypertrophy at the LV apex may, in part, be responsible for the development of giant negative T waves. Suzuki and colleagues10 showed, using nuclear magnetic resonance imaging, that apical hypertrophy in HC without giant negative T waves was confined to the most distal region of the septum or the anterolateral apical wall, but when giant negative T waves were seen, there was more diffuse involvement of the apex. Moreover, Koga et al9 reported that giant negative T waves in patients with apical HC were labile and may have disappeared during followup, which is possibly related to disease evolution. 1. Wigle ED, Sasson Z, Henderson MA, Ruddy TD, Fulop J, Rakowski H, Williams WG. Hypertrophic cardiomyopathy: the importance of the site and extent of hypertrophy. A review. Prog Cardiovasc Dis 1985;28:1–83. 2. Maron BJ. Hypertonic cardiomyopathy. Lancet 1997;350:127–133.
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3. Maron BJ. Hypertrophic cardiomyopathy: systematic review. JAMA 2002;287: 1308 –1320. 4. Maron BJ, Gottdiener JS, Epstein SE. Patterns and significance of distribution of left ventricular hypertrophy in hypertrophic cardiomyopathy: a wide-angle, two- dimensional echocardiographic study of 125 patients. Am J Cardiol 1981; 48:418 –428. 5. Shapiro LM, McKenna WJ. Distribution of left ventricular hypertrophy in hypertrophic cardiomyopathy: a two-dimensional echocardiographic study. J Am Coll Cardiol 1983;2:437–444. 6. Sakamoto T, Tei C, Murayama M, Ichiyasu H, Hada Y. Giant T wave inversion as a manifestation of asymmetrical apical hypertrophy (AAH) of the left ventricle: echocardiographic and ultrasono-cardiotomographic study. Jpn Heart J 1976; 17:611–629. 7. Yamaguchi H, Ishimura T, Nishiyama S, Nagasaki F, Nakanishi S, Takatsu F, Nishijo T, Umeda T, Machii K. Hypertrophic nonobstructive cardiomyopathy with giant negative T waves (apical hypertrophy): ventriculographic and echocardiographic features in 30 patients. Am J Cardiol 1979;44:401–412. 8. Sakamoto T. Apical hypertrophic cardiomyopathy (apical hypertrophy): an overview. J Cardiol 2001;37(suppl I):161–178. 9. Koga Y, Katoh A, Matsuyama K, Ikeda H, Hiyamuta K, Toshima H. Disappearance of giant negative T waves in patients with the Japanese form of apical hypertrophy. J Am Coll Cardiol 1995;26:1672–1678. 10. Suzuki J, Watanabe F, Takenaka K, Amano K, Amano W, Igarashi T, Aoki T, Serizawa T, Sakamoto T, Sugimoto T, Nishikawa J. New subtype of apical hypertrophic cardiomyopathy identified with nuclear magnetic imaging as an underlying cause of markedly inverted T waves. J Am Coll Cardiol 1993;22: 1175–1181. 11. Koga Y, Nohara M, Miyazaki Y, Toshima H. Two forms of apical hypertrophic cardiomyopathy: Japanese and Western forms. In: Toshima H. Maron BJ, eds. Cardiomyopathy Update 2: Hypertrophic Cardiomyopathy. Tokyo, Japan: University of Tokyo Press, 1988:293–308. 12. Maron BJ, Bonow RO, Seshagiri TNR, Roberts WC, Epstein SE. Hypertrophic cardiomyopathy with ventricular septal hypertrophy localized to the apical region of the left ventricle (apical hypertrophic cardiomyopathy). Am J Cardiol 1982;49:1838 –1848. 13. Vacek JL, Davis WR, Bellinger RL, McKiernan TL. Apical hypertrophic cardiomyopathy in American patients. Am Heart J 1984;108:1501–1506. 14. Abinader EG, Rauchfleisch S, Naschits J. Hypertrophic apical cardiomyopathy: a subtype of hypertrophic cardiomyopathy. Israel J Med Sci 1982;18:1005– 1009. 15. Bertrand ME, Tilmant PY, Lablanche JM, Thieuleux FA. Apical hypertrophic cardiomyopathy: clinical and metabolic studies. Eur Heart J 1983;4(suppl F): 127–133. 16. Keren G, Belhassen B, Sherez J, Miller HI, Megidish R, Berenfeld D, Laniado S. Apical hypertrophic cardiomyopathy: evaluation by noninvasive and invasive technique in 23 patients. Circulation 1985;71:45–56. 17. Louie ER, Maron BJ. Apical hypertrophic cardiomyopathy: clinical and two-dimensional echocardiographic assessment. Ann Intern Med 1987;106:663– 670. 18. Webb JG, Sasson Z, Rakowski H, Liu P, Wigle ED. Apical hypertrophic cardiomyopathy: clinical follow-up and diagnostic correlates. J Am Coll Cardiol 1990;15:83–90. 19. Chikamori T, Doi YL, Akizawa M, Yonezawa Y, Ozawa T, McKenna WJ. Comparison of clinical, morphological, and prognostic features in hypertrophic cardiomyopathy between Japanese and Western patients. Clin Cardiol 1992;15: 833–837. 20. Maron BJ, Casey SA, Poliac LC, Gohman TE, Almquist AK, Aeppli DM. Clinical course of hypertrophic cardiomyopathy in a regional United States cohort. JAMA 1999;281:650 –655. 21. 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 1992;19:91–99. 22. Maron BJ, Schiffer A, Klues HG. Comparison of phenotypic expression of hypertrophic cardiomyopathy in patients from the United States and Germany. Am J Cardiol 1999;83:626 –627. 23. Eriksson MJ, Sonnenberg B, Woo A, Rakowski P, Thomas GP, Eigle D. Long-term outcome in patients with apical hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;39:638 –645. 24. Klues HG, Schiffers A, Maron BJ. Phenotypic spectrum and patterns of left ventricular hypertrophy in hypertrophic cardiomyopathy: morphologic observations and significance as assessed by two-dimensional echocardiography in 600 patients. J Am Coll Cardiol 1995;26:1699 –1708. 25. Maron BJ. Apical hypertrophic cardiomyopathy: the continuing saga (editorial). J Am Coll Cardiol 1990;15:91–93. 26. Maron BJ. The giant negative T wave revisited in hypertrophic cardiomyopathy (editorial). J Am Coll Cardiol 1990;15:972–973.
NOVEMBER 15, 2003
MD,
Yoshinori Doi, MD, Susan A. Casey, RN, Nobuhiko Hitomi, Takashi Furuno, MD, and Barry J. Maron, MD
MD,
The morphologic apical form of hypertrophic cardiomyopathy (HC), in which left ventricular (LV) wall thickening is confined to the most distal region at the apex, has been regarded as a phenotypic expression of nonobstructive HC largely unique to Japanese patients. To investigate this question further, we directly compared unselected and regional hospital-based cohorts of adult patients with HC ( >18 years of age) from Japan (Kochi; n ⴝ 100) and from the United States (US) (Minneapolis; n ⴝ 361). Japanese and American patients with HC had similar clinical features and did not differ significantly with regard to the severity of symptoms and frequency of outflow obstruction. Although Japanese and American patients also showed similar maximum LV thickness, they differed significantly with respect to the distribution of LV hypertrophy. In particular, the segmental form of HC, with hypertrophy confined to the LV apex, was more
frequent in Japanese patients (i.e., apical HC, 15% in Japan vs 3% in US, p <0.0001). Giant negative T waves were also more common in Japanese patients with HC (26% vs 2%, p <0.001), including those with the apical form (64% vs. 30%, p <0.05). Each patient with apical HC had either no or only mild symptoms, and all survived. The morphologic form of nonobstructive HC with hypertrophy limited to the LV apex (apical form of HC) was 5 times more common in an unselected Japanese population. These findings document variability in the phenotypic expression of HC between countries and races, which may be due to differences in environmental factors or genetic background. Patients with the apical form of HC had a benign clinical course. 䊚2003 by Excerpta Medica, Inc. (Am J Cardiol 2003;92:1183–1186)
ypertrophic cardiomyopathy (HC) is a genetic cardiac disease in which a hypertrophied nondiH lated left ventricle, which is characterized by a wide
tertiary referred Japanese and American populations, particularly with respect to the relative prevalence of apical HC.
variety of patterns of asymmetric wall thickening, is the morphologic hallmark.1–3 Distribution of hypertrophy is often diffuse, but may also be mild and localized.4,5 In particular, the apical form of HC, in which wall thickening is confined to the most distal portion of the left ventricular (LV) wall, was first reported in Japan by Sakamoto and colleagues in 19766 and subsequently by Yamaguchi et al in 1979.7 Apical HC was described as a striking electrocardiographic pattern of giant negative T waves and an angiographic feature of end-diastolic LV cavity configuration resembling an “ace-of-spades.”6,7 This apical morphologic form is regarded as a subgroup of nonobstructive HC that occurs largely in Japanese patients.8 –11 Although there have been several reports of apical HC from centers outside of Japan,12–19 the true prevalence in Western countries (in relation to Japan) remains unknown. Therefore, the aim of this echocardiographic study was to directly compare the clinical and morphologic expression of HC in regional and nonFrom the Department of Medicine and Geriatrics, Kochi Medical School, Kochi, Japan; and the Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis, Minnesota. Manuscript received February 20, 2003; revised manuscript received and accepted July 15, 2003. Address for reprints: Yoshinori Doi, MD, Department of Medicine and Geriatrics, Kochi Medical School, Oko-cho, Nankoku-shi, Kochi 783-8505, Japan. E-mail: [email protected]. ©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 92 November 15, 2003
METHODS
Patient selection: Consecutively enrolled patients with HC from 2 regional community-based centers were combined for a cohort of 461 patients, including (1) 100 patients from the Kochi prefecture in southwestern Japan evaluated at the Kochi Medical School, and (2) 361 patients from the Minneapolis Heart Institute, a population consisting primarily of Minnesota residents and those from the adjacent states of Wisconsin, Iowa, and North and South Dakota, who were selected as previously reported.20 The United States (US) population was predominantly white: 357 patients (99%) were Caucasian, 4 patients (1%) were black, and there were no Asians. Follow-up from initial HC diagnosis to August 2000 was 9.3 ⫾ 7.7 years. Echocardiography: Echocardiographic studies were performed with commercially available Phillips (Andover, Massachusetts) and Toshiba (Tokyo, Japan) instruments. Magnitude and distribution of LV hypertrophy were assessed prospectively with 2-dimensional echocardiography, according to previously published criteria.4 The greatest wall thickness measured at any site in the LV wall was regarded as the maximal thickness, independent of correction for body surface area, gender, or age. Wall thickness was assessed directly from the television monitor with a calibration scale produced by the instrument. Location of endocardial and epicardial 0002-9149/03/$–see front matter doi:10.1016/j.amjcard.2003.07.027
1183
Statistical analysis: Data are expressed as mean ⫾ SD. Differences between means were analyzed using unpaired Student’s t test, and comparison of nominal variables, expressed as proportions, was performed using the chi-square test. A p value ⬍0.05 was considered statistically significant. All calculations were performed using Statview, version 5.0 (SAS Institute Inc., Cary, North Carolina).
RESULTS
Patient characteristics: Clinical and morphologic findings in the 2 HC cohorts are compared in Table 1. FIGURE 1. Representative echocardiographic and electrocardiographic features in a Although Japanese patients were 41-year-old asymptomatic Japanese patient with apical HC. Left panel, striking elecmore often men and less frequently trocardiographic pattern of deep T-wave inversion (“ giant negative T waves”) in the left precordial leads; less marked T-wave inversion is also present in leads I, II, III, had outflow obstruction, Japanese and AVF. Right panel, LV wall thickening confined to the most distal region of the and American patients were similar apex, below the papillary muscle level, is shown in a modified apical view. with regard to age, symptom severity, and maximum LV thickness. Morphologic findings: Fifteen of TABLE 1 Demographic, Clinical, and Echocardiographic Data in Hypertrophic the 100 patients (15%) in the Japanese Cardiomyopathy Cohorts from Japan and the United States (US) cohort and 10 of the 361 patients (3%) Japan (Kochi) US (Minnesota) in the American cohort had apical hypertrophy (Table 1 and Figure 1). (n ⫽ 100) (n ⫽ 361) p Value Therefore, the prevalence of apical HC Age at diagnosis in Japanese patients was 5 times higher Mean ⫾ SD (yrs) 51 ⫾ 13 49 ⫾ 18 NS than that in the American patients (TaMen 70 (69%) 206 (57%) 0.02 Severe symptoms (NYHA 8 (8%) 22 (6%) NS ble 2 and Figure 2). Wall thickness at functional class III/IV) the apex was greater in the American Maximum LV wall thickness 20.8 ⫾ 4.3 21.5 ⫾ 5 NS patients than in the Japanese patients (mean ⫾ SD) (mm) (23 ⫾ 4 vs 18 ⫾ 2 mm, respectively) ⱕ20 61 (60%) 198 (55%) NS (Table 2). ⱖ30 6 (6%) 32 (9%) NS Outflow obstruction (ⱖ30 mm Hg) 16 (16%) 91 (25%) 0.03 Hypertrophy localized to 1 segGiant negative T wave 26 (26%) 7 (2%) ⬍0.001 ment of the LV wall other than the apex (usually the anterior septum) NYHA ⫽ New York Heart Association. was more common in American patients than in Japanese patients (37% vs 8%, respectively, p ⬍0.001); borders was identified by viewing the pertinent portions more diffuse hypertrophy involving ⱖ2 LV segments of videotape in slow motion and real-time modes. Peak was present with similar frequency in Japanese and instantaneous LV outflow gradient was estimated with American patients (75% vs 60%; p ⫽ NS). Clinical characteristics of apical hypertrophic continuous-wave Doppler under basal conditions.21 Definitions: The diagnosis of HC was based on the cardiomyopathy: Clinical characteristics of the 25 pa2-dimensional echocardiographic demonstration of a tients with apical HC are shown in Table 2. None of hypertrophied LV wall (wall thickness ⱖ15 mm) and these patients had severe symptoms (New York Heart a nondilated LV cavity in the absence of another Association functional class III to IV) and 12 (48%) cardiac or systemic disease capable of producing that were completely asymptomatic (6 Americans and 6 magnitude of hypertrophy (e.g., systemic hyperten- Japanese). Also, none of the 25 patients had LV outsion or aortic stenosis). Uniform morphologic criteria flow obstruction under basal conditions. Of all the for apical HC were agreed upon prospectively and patients with HC, giant negative T waves on the applied at both centers. Apical HC was defined as LV electrocardiogram (defined as a depth of ⱖ10 mm) wall thickening confined to the most distal region at were significantly more common in Japanese patients the apex below the papillary muscle level; hypertro- than in Americans (26% vs 2%, p ⬍0.0001; Table 1). phy in this region of the left ventricle was not detect- In addition, of the 25 patients with apical HC, giant able in parasternal echocardiographic cross-sectional negative T waves were again more common in Japaplanes and was evident only on apical views. Repre- nese patients than in Americans (64% vs 30%, p sentative echocardiographic and electrocardiographic ⬍0.05; Table 2 and Figure. 1). Maximum wall thickfeatures of apical HC are shown in Figure 1. ness (in the LV apex) was significantly more marked 1184 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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although the overall demographic and clinical expression of HC was generally similar in our communityKochi Minneapolis p Value based regional Japanese and American cohorts, which were not subject Patients n ⫽ 15 n ⫽ 10 ⬍0.0001 Age at diagnosis (yrs) 56 ⫾ 14 45 ⫾ 14 0.06 to tertiary center referral bias. In Range (30–70) (26–64) clinical terms, our patients with apiMen 15 (83%) 6 (60%) NS cal HC represented a distinctive subSevere symptoms* 0 (0%) 0 (0%) NS set in which male gender predomiNo or mild symptoms† 15 (100%) 10 (100%) Outflow obstruction 0 (0%) 0 (0%) NS nated, all patients had either no or Maximal apical LV wall thickness (mm) 18 ⫾ 2 23 ⫾ 4 0.003 mild cardiovascular symptoms, progHC-related death 0 (0%) 0 (0%) NS nosis was generally benign, and outGiant negative T wave 12 (64%) 3 (30%) 0.02 flow obstruction was absent. These *New York Heart Association functional class III to IV. findings are generally consistent with † New York Heart Association functional class I to II. previous observations in Japanese and other patients with apical HC,8,9,11,16 –19,23 although a minority of non-Asian patients with similar morphologic forms of HC has experienced adverse outcomes.12 The 15% prevalence of apical HC in our Japanese cohort is less than that previously reported in Japan (i.e., up to 25%).7–9,11 This finding may be partially due to our study design, which was based on the strict echocardiographic demonstration of hypertrophy confined to the most distal region of the left ventricle below the papillary muscle level. Therefore, patients were not included in this definition of apical HC if they had hypertrophy in other regions of the left ventricle beyond the apex. In contrast, earlier studies from Japan were based predominantly on the angiographic demFIGURE 2. Prevalence of apical and other morphologic forms of onstration of apical hypertrophy (by virtue of LV HC in Japanese and United States cohorts. configuration) but without direct echocardiographic demonstration of isolated apical hypertrophy7; these studies may have overestimated the prevalence of in American patients than that in Japanese patients. apical HC. In Japan, apical HC has been regarded as repreNone of the 25 patients with apical HC developed complications (e.g., apical infarction, apical thrombi, senting a significant proportion of the overall HC and secondary ventricular tachycardia beleived origi- patient population,7–9,11 but this syndrome is reported nated from apical scarring) during a 9-year follow-up. less commonly in Western patients.1,13,17,18,23,24 For There were also no HC-related deaths in either group example, in observations on 600 patients with HC from 2 referral centers, Klues and colleagues24 rewith apical HC. ported the apical form of HC in only 1% of their patients. However, the patients of Klues et al24 repreDISCUSSION Japanese investigators first reported apical HC as a sented a highly selected hospital-based referral popumorphologic variant of HC characterized by a striking lation and may not have included a representative electrocardiographic pattern of particularly deep T- proportion of asymptomatic patients with segmental wave inversion in the precordial leads (“ giant nega- hypertrophy. Moreover, a recent report by Eriksson et tive T waves”) and the distinctive angiographic spade- al23 indicated a 7% prevalence of apical HC in their shaped appearance of the left ventricle at end-diastole. cohort of patients from a tertiary referral center. Subsequently, apical HC has been reported with echoIn the present study, we directly compared regional cardiography from several centers outside of Japan, cohorts of adult patients with HC from Japan and the although the characteristic electrocardiographic pat- US, applying uniform morphologic criteria for the tern is seen inconsistently in Western patients.12–19 apical form of HC. A total of 100 Japanese patients However, the prevalence of apical HC in Western from Kochi in the southwestern part of Japan and 361 countries, in relation to Japan, has remained unre- American patients from Minnesota and the Upper solved. Also, there are limited data available suggest- Midwest were studied. We found a significantly ing variability in the HC phenotype between cultures, higher prevalence (fivefold) of apical HC in Japanese countries, and racial groups.22 patients compared with Americans. Although the reaIn the present study, using uniform echocardio- sons for these differences are not completely undergraphic criteria, we have shown that the prevalence of stood, several possibilities should be considered. First, the morphologic apical form of HC is significantly it is possible that patient selection factors play a role, higher in Japanese patients than in American patients, namely, the different healthcare systems operational TABLE 2 Clinical Comparison of Japanese and United States Patients With Apical Hypertrophic Cardiomyopathy
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in these 2 countries. For example, in Japan, electrocardiograms are routinely required of all workers after the age of 40 years, even in the absence of recognized medical problems. If the electrocardiogram is abnormal, the employee is referred for further cardiovascular evaluation. Because the level of awareness regarding apical HC is high in Japan, cardiologists carefully search for apical hypertrophy with echocardiography, particularly in the presence of T-wave inversion on electrocardiogram. Therefore, we cannot exclude the possibility that differences between the selection of patients in Japanese and the US account for some of the discordance in the prevalence of apical HC in the 2 populations. We believe the previously cited lack of difference in occurrence of apical HC between Japanese and Caucasian patients may be due to the use of less restrictive mophologic definitions.19 Second, it is possible that differences in the genetic substrate and the nature and frequency of HC-causing mutant genes could explain these discrepancies in prevalence between the US and Japan. However, comparative molecular data are not available at present in our study populations. There was a period of a temporary suspension of genetic testing in the year 2000, while the guidelines dictated by the Japanese government for genetic research were reevaluated. This had the effect of suppressing mutational analysis for Japanese patients, including those in this study with apical HC. Based on findings of early Japanese studies, giant negative T waves on electrocardiograms have been regarded as a hallmark of apical HC.25 However, reports from centers outside Japan have shown that this pattern of deep T-wave inversion is absent in most non-Japanese patients with apical HC.17,26 In the present study, giant negative T waves were more than twice as common in Japanese patients with apical HC than in American patients with the same LV morphology. Although the origin of such differences between populations is unresolved, it is possible that the precise distribution of hypertrophy at the LV apex may, in part, be responsible for the development of giant negative T waves. Suzuki and colleagues10 showed, using nuclear magnetic resonance imaging, that apical hypertrophy in HC without giant negative T waves was confined to the most distal region of the septum or the anterolateral apical wall, but when giant negative T waves were seen, there was more diffuse involvement of the apex. Moreover, Koga et al9 reported that giant negative T waves in patients with apical HC were labile and may have disappeared during followup, which is possibly related to disease evolution. 1. Wigle ED, Sasson Z, Henderson MA, Ruddy TD, Fulop J, Rakowski H, Williams WG. Hypertrophic cardiomyopathy: the importance of the site and extent of hypertrophy. A review. Prog Cardiovasc Dis 1985;28:1–83. 2. Maron BJ. Hypertonic cardiomyopathy. Lancet 1997;350:127–133.
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3. Maron BJ. Hypertrophic cardiomyopathy: systematic review. JAMA 2002;287: 1308 –1320. 4. Maron BJ, Gottdiener JS, Epstein SE. Patterns and significance of distribution of left ventricular hypertrophy in hypertrophic cardiomyopathy: a wide-angle, two- dimensional echocardiographic study of 125 patients. Am J Cardiol 1981; 48:418 –428. 5. Shapiro LM, McKenna WJ. Distribution of left ventricular hypertrophy in hypertrophic cardiomyopathy: a two-dimensional echocardiographic study. J Am Coll Cardiol 1983;2:437–444. 6. Sakamoto T, Tei C, Murayama M, Ichiyasu H, Hada Y. Giant T wave inversion as a manifestation of asymmetrical apical hypertrophy (AAH) of the left ventricle: echocardiographic and ultrasono-cardiotomographic study. Jpn Heart J 1976; 17:611–629. 7. Yamaguchi H, Ishimura T, Nishiyama S, Nagasaki F, Nakanishi S, Takatsu F, Nishijo T, Umeda T, Machii K. Hypertrophic nonobstructive cardiomyopathy with giant negative T waves (apical hypertrophy): ventriculographic and echocardiographic features in 30 patients. Am J Cardiol 1979;44:401–412. 8. Sakamoto T. Apical hypertrophic cardiomyopathy (apical hypertrophy): an overview. J Cardiol 2001;37(suppl I):161–178. 9. Koga Y, Katoh A, Matsuyama K, Ikeda H, Hiyamuta K, Toshima H. Disappearance of giant negative T waves in patients with the Japanese form of apical hypertrophy. J Am Coll Cardiol 1995;26:1672–1678. 10. Suzuki J, Watanabe F, Takenaka K, Amano K, Amano W, Igarashi T, Aoki T, Serizawa T, Sakamoto T, Sugimoto T, Nishikawa J. New subtype of apical hypertrophic cardiomyopathy identified with nuclear magnetic imaging as an underlying cause of markedly inverted T waves. J Am Coll Cardiol 1993;22: 1175–1181. 11. Koga Y, Nohara M, Miyazaki Y, Toshima H. Two forms of apical hypertrophic cardiomyopathy: Japanese and Western forms. In: Toshima H. Maron BJ, eds. Cardiomyopathy Update 2: Hypertrophic Cardiomyopathy. Tokyo, Japan: University of Tokyo Press, 1988:293–308. 12. Maron BJ, Bonow RO, Seshagiri TNR, Roberts WC, Epstein SE. Hypertrophic cardiomyopathy with ventricular septal hypertrophy localized to the apical region of the left ventricle (apical hypertrophic cardiomyopathy). Am J Cardiol 1982;49:1838 –1848. 13. Vacek JL, Davis WR, Bellinger RL, McKiernan TL. Apical hypertrophic cardiomyopathy in American patients. Am Heart J 1984;108:1501–1506. 14. Abinader EG, Rauchfleisch S, Naschits J. Hypertrophic apical cardiomyopathy: a subtype of hypertrophic cardiomyopathy. Israel J Med Sci 1982;18:1005– 1009. 15. Bertrand ME, Tilmant PY, Lablanche JM, Thieuleux FA. Apical hypertrophic cardiomyopathy: clinical and metabolic studies. Eur Heart J 1983;4(suppl F): 127–133. 16. Keren G, Belhassen B, Sherez J, Miller HI, Megidish R, Berenfeld D, Laniado S. Apical hypertrophic cardiomyopathy: evaluation by noninvasive and invasive technique in 23 patients. Circulation 1985;71:45–56. 17. Louie ER, Maron BJ. Apical hypertrophic cardiomyopathy: clinical and two-dimensional echocardiographic assessment. Ann Intern Med 1987;106:663– 670. 18. Webb JG, Sasson Z, Rakowski H, Liu P, Wigle ED. Apical hypertrophic cardiomyopathy: clinical follow-up and diagnostic correlates. J Am Coll Cardiol 1990;15:83–90. 19. Chikamori T, Doi YL, Akizawa M, Yonezawa Y, Ozawa T, McKenna WJ. Comparison of clinical, morphological, and prognostic features in hypertrophic cardiomyopathy between Japanese and Western patients. Clin Cardiol 1992;15: 833–837. 20. Maron BJ, Casey SA, Poliac LC, Gohman TE, Almquist AK, Aeppli DM. Clinical course of hypertrophic cardiomyopathy in a regional United States cohort. JAMA 1999;281:650 –655. 21. 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 1992;19:91–99. 22. Maron BJ, Schiffer A, Klues HG. Comparison of phenotypic expression of hypertrophic cardiomyopathy in patients from the United States and Germany. Am J Cardiol 1999;83:626 –627. 23. Eriksson MJ, Sonnenberg B, Woo A, Rakowski P, Thomas GP, Eigle D. Long-term outcome in patients with apical hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;39:638 –645. 24. Klues HG, Schiffers A, Maron BJ. Phenotypic spectrum and patterns of left ventricular hypertrophy in hypertrophic cardiomyopathy: morphologic observations and significance as assessed by two-dimensional echocardiography in 600 patients. J Am Coll Cardiol 1995;26:1699 –1708. 25. Maron BJ. Apical hypertrophic cardiomyopathy: the continuing saga (editorial). J Am Coll Cardiol 1990;15:91–93. 26. Maron BJ. The giant negative T wave revisited in hypertrophic cardiomyopathy (editorial). J Am Coll Cardiol 1990;15:972–973.
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