© 2014, Wiley Periodicals, Inc. DOI: 10.1111/echo.12537
Echocardiography
ORIGINAL INVESTIGATION
Factors Predicting Long-Term Mortality in Patients with Hypertrophic Cardiomyopathy Cem Bostan, M.D., Umit Yasar Sinan, M.D., Polat Canbolat, M.D., Okay Abaci, M.D., Sezer Karcier Munipoglu, M.D., and Serdar Kucukoglu, M.D. Department of Cardiology, Institute of Cardiology, Istanbul University, Haseki, Istanbul/Turkey
Objectives: In this study, we aimed to elucidate the factors affecting long-term all-cause mortality in patients with hypertrophic cardiomyopathy (HCM). Method: We retrospectively examined 31 patients (22 males and 9 females) diagnosed with HCM from 1999 to 2013. All subjects had sinus rhythm at the time of evaluation. Four patients had history of paroxysmal atrial fibrillation (PAF). In addition to echocardiographic examination plasma angiotensin-converting enzyme (ACE) activity and gene polymorphism were determined. The variables that were found to be significant in mortality were then included in multivariate analysis. Results: At the final follow-up examination, 12 patients had died, including 2 due to congestive heart failure and 10 due to sudden cardiac death. Patients with PAF had significantly higher mortality (P = 0.008). Moreover, left ventricular (LV) end-diastolic diameter (P = 0.04), LV systolic diameter (P = 0.001), LV mass index (P = 0.01), and left atrium diameter (P = 0.003) were found to be significantly correlated with mortality. However, no significant correlation was noted between mortality and age, type of HCM (familial/nonfamilial and obstructive/nonobstructive), ACE gene polymorphism, and plasma ACE level. In the multivariate analysis, left atrial (LA) diameter was still significantly associated with mortality. The LA diameter with a cutoff value of 4.1 cm predicted 13-year mortality with a sensitivity of 82% and specificity of 78%. Conclusion: Instead of the ACE genotype and activity, echocardiographic evaluation findings such as LV systolic and diastolic diameters, LV mass index, and particularly LA dimension may predict long-term mortality in patients with HCM. PAF has also significant importance in the long-term mortality in patients with HCM. (Echocardiography 2014;00:1–6)
Hypertrophic cardiomyopathy (HCM) is a complex primary and hereditary cardiac disease with a diverse clinical course that include a stable clinical course, progressive congestive symptoms requiring therapeutic intervention, or sudden cardiac death.1 Autocrine, paracrine, and endocrine factors with tropic and mitogenic effects on myocytes have been considered to affect the phenotypic expression and prognosis of HCM. In particular, the renin–angiotensin system plays an important role in the cardiovascular system, and partly regulates the expression of cardiac hypertrophy.2 Thus, although HCM is a monogenic disease, additional genetic factors such as angiotensinconverting enzyme genotypes may partially account for the interfamilial and intrafamilial variability in the phenotypic expression of the disease. Furthermore, the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene, due to the presence or Address for correspondence and reprint requests: Cem Bostan, M.D., Department of Cardiology, Institute of Cardiology, Istanbul University, Haseki, Fatih 34350 Istanbul/Turkey. Fax: 90(216)469-3796; E-mail: [email protected]
absence of a 287 bp Alu repeat in intron 16 of the ACE gene, has been previously described. This polymorphism yields 3 genotypes; DD, ID, and II. The ACE genotype DD is characterized by the presence of plasma ACE levels that are 2 times that noted in ACE genotype II.3 Angiotensin-converting enzyme activity and polymorphisms are known to significantly contribute to the prognosis of patients with cardiomyopathy. The presence of ACE genotype DD, which results in increased ACE levels in plasma and possibly the heart, is associated with an increased incidence of sudden cardiac death in HCM.4 In this study, we aimed to determine the effects of ACE activity and the type of ACE polymorphism on long-term mortality in patients with familial and nonfamilial HCM, and to assess the relationships between these factors and echocardiographic measurements. In addition, we aimed to determine the echocardiographic parameters that predict long-term all-cause mortality in HCM. Material and Methods: Patients with known HCM aged >18 years were enrolled in this study. HCM was diagnosed in 1
Bostan, et al.
these patients based on typical clinical, electrocardiographic (Hewlett Packard Pagewriter XLe Philips, Boeblingen Germany), and echocardiographic (Acuson Sequoia, Mountain View, CA, USA) features, along with the occurrence of ventricular hypertrophy (end-diastolic wall thickness, ≥15 mm) in the absence of any other cardiac or systemic disease that could have been responsible for the hypertrophy.5 Patients with valvulopathy was not included in the study. The degree of myocardial hypertrophy was assessed by Mmode and two-dimensional transthoracic echocardiography, using standard techniques. According to the methods established by the American Society of Echocardiography, we measured the left atrial (LA) diameter, inter ventricular septum thickness, left ventricle posterior wall thickness, left ventricular (LV) end-systolic and end-diastolic dimensions, ejection fraction (EF) peak mitral flow velocity of the early rapid filling wave (E), peak velocity of the late filling wave due to atrial contraction (A), the E/A ratio, deceleration time of the early mitral filling wave, and left ventricle mass (LVM).6 The LV mass index (LVMI) was estimated by dividing the LVM by the body surface area. All echocardiographic measurements were performed by the same cardiologist at a single center to minimize the interobserver variation. Venous blood was collected into tubes containing ethylenediaminetetraacetic acid (a disodium salt) for isolating peripheral blood leukocytes. Thereafter, genomic DNA was extracted from these cells by using a standard method and amplified by the polymerase chain reaction (PCR). The PCR products were separated by electrophoresis using a 2% agarose gel. The results were assessed using the gel analysis software. The serum ACE levels were measured using the Sigma diagnostic kit (Sigma Diagnostics, St. Louis, MO, USA) with the Technicon RA-1000 auto analyzer (Miles Inc., Tarrytown, NY, USA). The plasma ACE activity was expressed in U/L. Follow-up Examinations: The included patients underwent follow-up examinations between 1999 and 2013. In cases of deceased patients, death certificates were procured and the relatives were interviewed to determine the cause of death. Death due to congestive heart failure was defined as death occurring in the context of long-standing cardiac decompensation, and involving the progression of the disease over the preceding year with the development of pulmonary edema or cardiogenic shock. Moreover, sudden cardiac death was defined as instantaneous and unexpected death, with or without documented ventricular fibrillation, within 1 hour after a witnessed col2
lapse in patients who previously were in a stable clinical condition, or nocturnal death with no antecedent history of worsening symptoms. The endpoint events were recorded through telephone communication with the patients’ relatives or by systematic review of death certificates, hospital notes, and discharge forms. Statistical Analysis: Categorical variables were compared using the chi-square test. Moreover, continuous variables are expressed as mean and standard deviation, and were compared using Student’s t-test. A Pvalue of 7 years, Kawasaki et al.7 indicated that 24% of nonobstructive HCM patients died or required hospitalization because of heart failure. TABLE III Cox Regression Analysis for Predictors of Total Mortality Multivariate Variable
HR (95% CI)
Rhythm LA LVMI LVDd LVDs PWd
0.58 (0.09–3.69) 9.70 (1.62–58.0) 0.99 (0.98–1.01) 0.78 (0.15–4.14) 4.52 (0.60–34.23) 0.89 (0.003–313.40)
P-Value 0.587 0.013 0.242 0.769 0.144 0.969
HR = hazard ratio; LA = left atrial; LVMI = LV mass index.
4
1,0
Sensitivity
0,8
Area::82% p= 0.004 Sensitivity: 82% Spesificity: 78%
0,6
0,4
0,2
0,0 0,0
0,2
0,4
0,6
0,8
1.0
1 - Specificity
Figure 2. Receiver-operating characteristic curve analysis, illustrating the diagnostic accuracy of left atrial diameter in predicting all-cause mortality in patients with hypertrophic cardiomyopathy (HCM).
1,0
Left Atrial diameter < 4.1 cm > 4.1 cm
0,8
Cum Survival
group had history of paroxysmal atrial fibrillation (PAF). Patients with PAF had significantly higher mortality (P = 0.008). Among the main clinical and echocardiographic data (Table I), LVMI (P = 0.01), LA diameter (P = 0.003), LV end-diastolic diameter (P = 0.04), LV end-systolic diameter (P = 0.001), and LV posterior wall thickness (P = 0.017) significantly differed between the survivor and nonsurvivors. All patients had normal EF and no difference was found between two groups. However, no difference in the Doppler parameters was noted between these groups (Table I). Table III presents Cox regression analysis for predictors of all-cause mortality, which were statistically significant in Table I. LA diameter (hazard ratio (HR) 9.70, 95% CI of HR: (1.62–58.0), P < 0.05) was independent predictor of cardiovascular survival. Receiver-operating characteristics curve analysis indicated that a maximum LA diameter of 4.1 cm could identify patients with a risk of mortality, with a sensitivity of 82% and a specificity of 78% (area under the ROC curve, 0.821) (Fig. 2). Figure 3 shows the Kaplan–Meier survival curves illustrating the predictive role of LA diameter. The mean initial ACE activity among the survivors and nonsurvivors with HCM was 31.5 17.8 U/L and 42.62 21.6 U/L, respectively (P = 0.136). Moreover, ACE activity was found to be correlated with only the LA diameter (P < 0.05; r = 0.4).
0,6
0,4
Log Rank: 8.86 p=0.003
0,2
0,0 8
10
12
14
Time (Yrs)
Figure 3. Kaplan–Meier survival curves predictive role of left atrial diameter.
illustrating
the
Moreover, Cecchi et al.8 reported that 16 of 51 (31%) patients with HCM died or exhibited a severe deterioration in their condition during an average follow-up period of >8 years. In this study, the overall crude probability of 10-year survival (71%) and the annual mortality (2.9%) were consistent with those reported in the literature.7,8 Although the identification of HCM patients at increased risk is clinically important, risk stratification remains challenging in such patients due to the marked heterogeneity in clinical expression, natural history, and prognosis. In this study, the probability of survival did not significantly differ between women and men. Furthermore, although the mortality rate was higher in the
Factors Predicting Mortality in Hypertrophic Cardiomyopathy
sporadic HCM group, this difference did not reach statistical significance. Yashiro et al.9 have recently reported that each type of AF had a different clinical impact, with paroxysmal AF being a significant independent determinant of an adverse outcome, including sudden death. We found that patients with PAF had significantly higher mortality in HCM. The relationship between the LV wall thickness and mortality remains controversial. No direct relationship between the LV wall thickness and the risk of death was noted in this study. This finding is consistent with those of studies that indicated that LV wall thickness should not be considered as an isolated risk factor for mortality due to cardiovascular disease in patients with HCM.10–12 However, a direct relationship between LV wall thickness and the risk of sudden death or heart failure-related death has been reported in certain studies.13–15 Olivotto et al.12 proposed that LV wall thickness may be a potential risk factor for sudden death only in patients who are diagnosed with HCM at a very young age. The prognostic significance of LVOT obstruction in cases of HCM has also been debated. In this study, the resting LVOT gradient was not associated with an increased risk of death. Certain studies have indicated that LVOT obstruction is associated with poorer survival.16–19 However, Losi et al.20 indicated that no significant differences in outcome were noted between patients with and without LVOT obstruction. Several studies have reported that echocardiographically determined LVMI is a significant prognostic indicator and that increased LVMI is a risk factor for mortality and sudden cardiac death in HCM patients.14,15 In this study, we identified a significant relationship between echocardiographically determined LVMI and mortality in HCM patients. Furthermore, the prognostic value of the LA diameter in HCM remains controversial. Mild LA enlargement is commonly observed in HCM cases, and may be a result of impaired diastolic function associated with the thickened and noncompliant left ventricle.21 Assessment of LA enlargement reportedly provides important information on patient outcome. Tani et al.22 indicated that the echocardiographically determined LA volume, rather than the LA diameter, was associated with the risk of cardiovascular events. However, Maron et al.13 reported that LA diameter was not an independent predictor of cardiovascular mortality in HCM patients. Nistri et al.23 reported that each 5-mm increase in LA size was associated with a hazard ratio (HR) of 1.2 for all-cause mortality, whereas an LA dimension of >48 mm was associated with
a HR of 1.9 for all-cause mortality in HCM patients. Finocchiaro et al.24 indicated that the LA diameter at diagnosis possessed incremental prognostic power in HCM cases. In addition, Kitaoka et al.25 noted that patients who experienced cardiovascular events had a larger LV size and LA volume compared with those who did not experience any cardiovascular events. This study indicated that the LA diameter was most powerful predictive factor among parameters used in this study for mortality in HCM, and an LA diameter cutoff value of 4.1 cm could predict 13-year mortality with a sensitivity of 82% and specificity of 78%. The ACE genotypes may influence the development of hypertrophy through their association with plasma and possibly tissue ACE levels. Thus, the difference in ACE genotypes can account for approximately half of the variability in the plasma ACE level in such cases the genotype DD is associated with plasma ACE levels that are 2 times that associated with genotype II.3 However, in another study, as in the present study, the ACE activity did not differ between subjects with the II genotype and those with the ID genotype, as well as between those with familial and nonfamilial forms of HCM.26 Buck et al.27 indicated the presence of a positive association between serum ACE activity and LVMI. The ACE activity was found to be twice as high in patients with familial HCM compared to those with the nonfamilial form. However, no correlation was noted between ACE polymorphisms and the degree of myocardial hypertrophy. Moreover, in another study, ACE activity rather than ACE polymorphisms was associated with the degree of myocardial hypertrophy in patients with HCM.27 In this study, the ACE levels were higher in patients with the DD genotype, but no correlation between LVMI and mortality was observed. The association between the ACE genotype and LV mass in HCM cases is controversial. Although the ACE D alleles have been reported to be associated with increased LV hypertrophy in HCM cases,28 certain other studies did not indicate any relationship between the ACE D alleles and left ventricular hypertrophy.27,29 The results of this study did not indicate a significant influence of the ACE genotype on the LVM and long-term mortality in HCM patients. Conclusion: This study indicated that, rather than the ACE genotype and activity, the echocardiographic evaluation parameters such as LV systolic and diastolic diameter, LVMI, and particularly LA
5
Bostan, et al.
dimension may predict the long-term mortality in patients with HCM. PAF has also significant importance in the long-term mortality in patients with HCM.
13. 14.
Limitations: Although the sample of the study group was relatively small, the follow-up duration was sufficiently long, thus accounting for a comparable number of patient-years for the subgroups of baseline prognostic factors. Another limitation of this study is that we could not differentiate HCMrelated deaths, including sudden deaths and deaths caused by end-stage cardiac failure, from other causes of mortality, and instead only reported all-cause mortality as the main outcome.
15.
16.
17.
18.
References 1. Williams LK, Frenneaux MP, Steeds RP: Echocardiography in hypertrophic cardiomyopathy diagnosis, prognosis, and role in management. Eur J Echocardiogr 2009;10:iii9– iii14. 2. Griendling KK, Murphy TJ, Alexander RW: Molecular biology of the renin-angiotensin system. Circulation 1993;87:1816–1828. 3. Rigat B, Hubert C, Alhenc-Gelas F, et al: An insertion/ deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half of the variance of serum enzyme levels. J Clin Invest 1990;86:1343– 1346. 4. Marian AJ, Yu Q-T, Workman R, et al: Angiotensin-converting enzyme polymorphism in hypertrophic cardiomyopathy and sudden cardiac death. Lancet 1993;342:1085–1086. 5. Richardson P, McKenna W, Bristow M, et al: Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation 1996;93:841–842. 6. Henry WL, DeMaria A, Gramiak R, et al: Report of the American Society of Echocardiography Committee on Nomenclature and Standards in Two-dimensional Echocardiography. Circulation 1980;62:212–217. 7. Kawasaki T, Yamano M, Kuribayashi T, et al: Three-layer ultrasonic tissue characterization of the ventricular septum is predictive of prognosis in patients with nonobstructive hypertrophic cardiomyopathy. Eur J Echocardiogr 2011;12:90–97. 8. Cecchi F, Olivotto I, Gistri R, et al: Coronary micro vascular dysfunction and prognosis in hypertrophic cardiomyopathy. N Engl J Med 2003;349:1027–1035. 9. Yashiro B, Minami Y, Terajima Y, et al: Prognostic difference between paroxysmal and non-paroxysmal atrial fibrillation in patients with hypertrophic cardiomyopathy. J Cardiol 2013 Nov 23 [Epub ahead of print]. 10. Nasermoaddeli A, Miura K, Matsumori A, et al: Prognosis and prognostic factors in patients with hypertrophic cardiomyopathy in Japan: Results from a nationwide study. Heart 2007;93:711–715. 11. Elliott PM, Gimeno-Blanes JR, Mahon NG, et al: Relation between severity of left ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy. Lancet 2001;357:420–427. 12. Olivotto I, Gistri R, Petrone P, et al: Maximum left ventricular thickness and risk of sudden death in patients
6
19.
20.
21. 22.
23.
24.
25.
26.
27.
28.
29.
with hypertrophic cardiomyopathy. J Am Coll Cardiol 2003;41:315–321. Maron BJ, Casey SA, Poliac LC, et al: Clinical course of hypertrophic cardiomyopathy in a regional United States cohort. JAMA 1999 Feb 17;281:650–655. Spirito P, Maron BJ: Relation between extent of left ventricular hypertrophy and occurrence of sudden cardiac death in hypertrophic cardiomyopathy. J Am Coll Cardiol 1990;15:1521–1526. Spirito P, Bellone P, Harris KM, et al: Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy. N Engl J Med 2000;342:1778–1785. Maron MS, Olivotto I, Betocchi S, et al: Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med 2003;348:295–303. Elliott PM, Gimeno JR, Tome MT, et al: Left ventricular outflow tract obstruction and sudden death risk in patients with hypertrophic cardiomyopathy. Eur Heart J 2006;27:1933–1941. Autore C, Bernabo P, Barilla CS, et al: The prognostic importance of left ventricular outflow obstruction in hypertrophic cardiomyopathy varies in relation to the severity of symptoms. J Am Coll Cardiol 2005;45:1076– 1080. Sorajja P, Nishimura RA, Gersh BJ, et al: Outcome of mildly symptomatic or asymptomatic obstructive hypertrophic cardiomyopathy: A long-term follow-up study. J Am Coll Cardiol 2009;54:234–241. Losi MA, Betocchi S, Barbati G, et al: Prognostic significance of left atrial volume dilatation in patients with hypertrophic cardiomyopathy. J Am Soc Echocardiogr 2009;22:76–81. Losi MA, Betocchi S, Grimaldi M, et al: Heterogeneity of left ventricular filling dynamics in hypertrophic cardiomyopathy. Am J Cardiol 1994;73:987–990. Tani T, Yagi T, Kitai T, et al: Left atrial volume predicts adverse cardiac and cerebrovascular events in patients with hypertrophic cardiomyopathy. Cardiovasc Ultrasound 2011;18:34. Nistri S, Olivotto I, Betocchi S, et al: Prognostic significance of left atrial size in patients with hypertrophic cardiomyopathy (from the Italian Registry for Hypertrophic Cardiomyopathy). Am J Cardiol 2006;98:960– 965. Finocchiaro G, Pinamonti B, Merlo M, et al: Prognostic role of clinical presentation in symptomatic patients with hypertrophic cardiomyopathy. J Cardiovasc Med (Hagerstown) 2012;13:810–818. Kitaoka H, Kubo T, Hayashi K, et al: Tissue Doppler imaging and prognosis in asymptomatic or mildly symptomatic patients with hypertrophic cardiomyopathy. Eur Heart J Cardiovasc Imaging 2013;14:544–549. Danser AH, Schalekamp MA, Bax WA, et al: Angiotensinconverting enzyme in the human heart. Effect of the deletion/insertion polymorphism. Circulation 1995;92:1387–1388. Buck PC, Fernandes F, Arteaga E, et al: Association of angiotensin-converting enzyme activity and polymorphism with echocardiographic measures in familial and nonfamilial hypertrophic cardiomyopathy. Braz J Med Biol Res 2009;42:717–721. Doolan G, Nguyen L, Chung J, et al: Progression of left ventricular hypertrophy and the angiotensin-converting enzyme gene polymorphism in hypertrophic cardiomyopathy. Int J Cardiol 2004;96:157–163. Lindpaintner K, Lee M, Larson MG, et al: Absence of association or genetic linkage between the angiotensinconverting- enzyme gene and left ventricular mass. N Engl J Med 1996;334:1023–1028.
Echocardiography
ORIGINAL INVESTIGATION
Factors Predicting Long-Term Mortality in Patients with Hypertrophic Cardiomyopathy Cem Bostan, M.D., Umit Yasar Sinan, M.D., Polat Canbolat, M.D., Okay Abaci, M.D., Sezer Karcier Munipoglu, M.D., and Serdar Kucukoglu, M.D. Department of Cardiology, Institute of Cardiology, Istanbul University, Haseki, Istanbul/Turkey
Objectives: In this study, we aimed to elucidate the factors affecting long-term all-cause mortality in patients with hypertrophic cardiomyopathy (HCM). Method: We retrospectively examined 31 patients (22 males and 9 females) diagnosed with HCM from 1999 to 2013. All subjects had sinus rhythm at the time of evaluation. Four patients had history of paroxysmal atrial fibrillation (PAF). In addition to echocardiographic examination plasma angiotensin-converting enzyme (ACE) activity and gene polymorphism were determined. The variables that were found to be significant in mortality were then included in multivariate analysis. Results: At the final follow-up examination, 12 patients had died, including 2 due to congestive heart failure and 10 due to sudden cardiac death. Patients with PAF had significantly higher mortality (P = 0.008). Moreover, left ventricular (LV) end-diastolic diameter (P = 0.04), LV systolic diameter (P = 0.001), LV mass index (P = 0.01), and left atrium diameter (P = 0.003) were found to be significantly correlated with mortality. However, no significant correlation was noted between mortality and age, type of HCM (familial/nonfamilial and obstructive/nonobstructive), ACE gene polymorphism, and plasma ACE level. In the multivariate analysis, left atrial (LA) diameter was still significantly associated with mortality. The LA diameter with a cutoff value of 4.1 cm predicted 13-year mortality with a sensitivity of 82% and specificity of 78%. Conclusion: Instead of the ACE genotype and activity, echocardiographic evaluation findings such as LV systolic and diastolic diameters, LV mass index, and particularly LA dimension may predict long-term mortality in patients with HCM. PAF has also significant importance in the long-term mortality in patients with HCM. (Echocardiography 2014;00:1–6)
Hypertrophic cardiomyopathy (HCM) is a complex primary and hereditary cardiac disease with a diverse clinical course that include a stable clinical course, progressive congestive symptoms requiring therapeutic intervention, or sudden cardiac death.1 Autocrine, paracrine, and endocrine factors with tropic and mitogenic effects on myocytes have been considered to affect the phenotypic expression and prognosis of HCM. In particular, the renin–angiotensin system plays an important role in the cardiovascular system, and partly regulates the expression of cardiac hypertrophy.2 Thus, although HCM is a monogenic disease, additional genetic factors such as angiotensinconverting enzyme genotypes may partially account for the interfamilial and intrafamilial variability in the phenotypic expression of the disease. Furthermore, the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene, due to the presence or Address for correspondence and reprint requests: Cem Bostan, M.D., Department of Cardiology, Institute of Cardiology, Istanbul University, Haseki, Fatih 34350 Istanbul/Turkey. Fax: 90(216)469-3796; E-mail: [email protected]
absence of a 287 bp Alu repeat in intron 16 of the ACE gene, has been previously described. This polymorphism yields 3 genotypes; DD, ID, and II. The ACE genotype DD is characterized by the presence of plasma ACE levels that are 2 times that noted in ACE genotype II.3 Angiotensin-converting enzyme activity and polymorphisms are known to significantly contribute to the prognosis of patients with cardiomyopathy. The presence of ACE genotype DD, which results in increased ACE levels in plasma and possibly the heart, is associated with an increased incidence of sudden cardiac death in HCM.4 In this study, we aimed to determine the effects of ACE activity and the type of ACE polymorphism on long-term mortality in patients with familial and nonfamilial HCM, and to assess the relationships between these factors and echocardiographic measurements. In addition, we aimed to determine the echocardiographic parameters that predict long-term all-cause mortality in HCM. Material and Methods: Patients with known HCM aged >18 years were enrolled in this study. HCM was diagnosed in 1
Bostan, et al.
these patients based on typical clinical, electrocardiographic (Hewlett Packard Pagewriter XLe Philips, Boeblingen Germany), and echocardiographic (Acuson Sequoia, Mountain View, CA, USA) features, along with the occurrence of ventricular hypertrophy (end-diastolic wall thickness, ≥15 mm) in the absence of any other cardiac or systemic disease that could have been responsible for the hypertrophy.5 Patients with valvulopathy was not included in the study. The degree of myocardial hypertrophy was assessed by Mmode and two-dimensional transthoracic echocardiography, using standard techniques. According to the methods established by the American Society of Echocardiography, we measured the left atrial (LA) diameter, inter ventricular septum thickness, left ventricle posterior wall thickness, left ventricular (LV) end-systolic and end-diastolic dimensions, ejection fraction (EF) peak mitral flow velocity of the early rapid filling wave (E), peak velocity of the late filling wave due to atrial contraction (A), the E/A ratio, deceleration time of the early mitral filling wave, and left ventricle mass (LVM).6 The LV mass index (LVMI) was estimated by dividing the LVM by the body surface area. All echocardiographic measurements were performed by the same cardiologist at a single center to minimize the interobserver variation. Venous blood was collected into tubes containing ethylenediaminetetraacetic acid (a disodium salt) for isolating peripheral blood leukocytes. Thereafter, genomic DNA was extracted from these cells by using a standard method and amplified by the polymerase chain reaction (PCR). The PCR products were separated by electrophoresis using a 2% agarose gel. The results were assessed using the gel analysis software. The serum ACE levels were measured using the Sigma diagnostic kit (Sigma Diagnostics, St. Louis, MO, USA) with the Technicon RA-1000 auto analyzer (Miles Inc., Tarrytown, NY, USA). The plasma ACE activity was expressed in U/L. Follow-up Examinations: The included patients underwent follow-up examinations between 1999 and 2013. In cases of deceased patients, death certificates were procured and the relatives were interviewed to determine the cause of death. Death due to congestive heart failure was defined as death occurring in the context of long-standing cardiac decompensation, and involving the progression of the disease over the preceding year with the development of pulmonary edema or cardiogenic shock. Moreover, sudden cardiac death was defined as instantaneous and unexpected death, with or without documented ventricular fibrillation, within 1 hour after a witnessed col2
lapse in patients who previously were in a stable clinical condition, or nocturnal death with no antecedent history of worsening symptoms. The endpoint events were recorded through telephone communication with the patients’ relatives or by systematic review of death certificates, hospital notes, and discharge forms. Statistical Analysis: Categorical variables were compared using the chi-square test. Moreover, continuous variables are expressed as mean and standard deviation, and were compared using Student’s t-test. A Pvalue of 7 years, Kawasaki et al.7 indicated that 24% of nonobstructive HCM patients died or required hospitalization because of heart failure. TABLE III Cox Regression Analysis for Predictors of Total Mortality Multivariate Variable
HR (95% CI)
Rhythm LA LVMI LVDd LVDs PWd
0.58 (0.09–3.69) 9.70 (1.62–58.0) 0.99 (0.98–1.01) 0.78 (0.15–4.14) 4.52 (0.60–34.23) 0.89 (0.003–313.40)
P-Value 0.587 0.013 0.242 0.769 0.144 0.969
HR = hazard ratio; LA = left atrial; LVMI = LV mass index.
4
1,0
Sensitivity
0,8
Area::82% p= 0.004 Sensitivity: 82% Spesificity: 78%
0,6
0,4
0,2
0,0 0,0
0,2
0,4
0,6
0,8
1.0
1 - Specificity
Figure 2. Receiver-operating characteristic curve analysis, illustrating the diagnostic accuracy of left atrial diameter in predicting all-cause mortality in patients with hypertrophic cardiomyopathy (HCM).
1,0
Left Atrial diameter < 4.1 cm > 4.1 cm
0,8
Cum Survival
group had history of paroxysmal atrial fibrillation (PAF). Patients with PAF had significantly higher mortality (P = 0.008). Among the main clinical and echocardiographic data (Table I), LVMI (P = 0.01), LA diameter (P = 0.003), LV end-diastolic diameter (P = 0.04), LV end-systolic diameter (P = 0.001), and LV posterior wall thickness (P = 0.017) significantly differed between the survivor and nonsurvivors. All patients had normal EF and no difference was found between two groups. However, no difference in the Doppler parameters was noted between these groups (Table I). Table III presents Cox regression analysis for predictors of all-cause mortality, which were statistically significant in Table I. LA diameter (hazard ratio (HR) 9.70, 95% CI of HR: (1.62–58.0), P < 0.05) was independent predictor of cardiovascular survival. Receiver-operating characteristics curve analysis indicated that a maximum LA diameter of 4.1 cm could identify patients with a risk of mortality, with a sensitivity of 82% and a specificity of 78% (area under the ROC curve, 0.821) (Fig. 2). Figure 3 shows the Kaplan–Meier survival curves illustrating the predictive role of LA diameter. The mean initial ACE activity among the survivors and nonsurvivors with HCM was 31.5 17.8 U/L and 42.62 21.6 U/L, respectively (P = 0.136). Moreover, ACE activity was found to be correlated with only the LA diameter (P < 0.05; r = 0.4).
0,6
0,4
Log Rank: 8.86 p=0.003
0,2
0,0 8
10
12
14
Time (Yrs)
Figure 3. Kaplan–Meier survival curves predictive role of left atrial diameter.
illustrating
the
Moreover, Cecchi et al.8 reported that 16 of 51 (31%) patients with HCM died or exhibited a severe deterioration in their condition during an average follow-up period of >8 years. In this study, the overall crude probability of 10-year survival (71%) and the annual mortality (2.9%) were consistent with those reported in the literature.7,8 Although the identification of HCM patients at increased risk is clinically important, risk stratification remains challenging in such patients due to the marked heterogeneity in clinical expression, natural history, and prognosis. In this study, the probability of survival did not significantly differ between women and men. Furthermore, although the mortality rate was higher in the
Factors Predicting Mortality in Hypertrophic Cardiomyopathy
sporadic HCM group, this difference did not reach statistical significance. Yashiro et al.9 have recently reported that each type of AF had a different clinical impact, with paroxysmal AF being a significant independent determinant of an adverse outcome, including sudden death. We found that patients with PAF had significantly higher mortality in HCM. The relationship between the LV wall thickness and mortality remains controversial. No direct relationship between the LV wall thickness and the risk of death was noted in this study. This finding is consistent with those of studies that indicated that LV wall thickness should not be considered as an isolated risk factor for mortality due to cardiovascular disease in patients with HCM.10–12 However, a direct relationship between LV wall thickness and the risk of sudden death or heart failure-related death has been reported in certain studies.13–15 Olivotto et al.12 proposed that LV wall thickness may be a potential risk factor for sudden death only in patients who are diagnosed with HCM at a very young age. The prognostic significance of LVOT obstruction in cases of HCM has also been debated. In this study, the resting LVOT gradient was not associated with an increased risk of death. Certain studies have indicated that LVOT obstruction is associated with poorer survival.16–19 However, Losi et al.20 indicated that no significant differences in outcome were noted between patients with and without LVOT obstruction. Several studies have reported that echocardiographically determined LVMI is a significant prognostic indicator and that increased LVMI is a risk factor for mortality and sudden cardiac death in HCM patients.14,15 In this study, we identified a significant relationship between echocardiographically determined LVMI and mortality in HCM patients. Furthermore, the prognostic value of the LA diameter in HCM remains controversial. Mild LA enlargement is commonly observed in HCM cases, and may be a result of impaired diastolic function associated with the thickened and noncompliant left ventricle.21 Assessment of LA enlargement reportedly provides important information on patient outcome. Tani et al.22 indicated that the echocardiographically determined LA volume, rather than the LA diameter, was associated with the risk of cardiovascular events. However, Maron et al.13 reported that LA diameter was not an independent predictor of cardiovascular mortality in HCM patients. Nistri et al.23 reported that each 5-mm increase in LA size was associated with a hazard ratio (HR) of 1.2 for all-cause mortality, whereas an LA dimension of >48 mm was associated with
a HR of 1.9 for all-cause mortality in HCM patients. Finocchiaro et al.24 indicated that the LA diameter at diagnosis possessed incremental prognostic power in HCM cases. In addition, Kitaoka et al.25 noted that patients who experienced cardiovascular events had a larger LV size and LA volume compared with those who did not experience any cardiovascular events. This study indicated that the LA diameter was most powerful predictive factor among parameters used in this study for mortality in HCM, and an LA diameter cutoff value of 4.1 cm could predict 13-year mortality with a sensitivity of 82% and specificity of 78%. The ACE genotypes may influence the development of hypertrophy through their association with plasma and possibly tissue ACE levels. Thus, the difference in ACE genotypes can account for approximately half of the variability in the plasma ACE level in such cases the genotype DD is associated with plasma ACE levels that are 2 times that associated with genotype II.3 However, in another study, as in the present study, the ACE activity did not differ between subjects with the II genotype and those with the ID genotype, as well as between those with familial and nonfamilial forms of HCM.26 Buck et al.27 indicated the presence of a positive association between serum ACE activity and LVMI. The ACE activity was found to be twice as high in patients with familial HCM compared to those with the nonfamilial form. However, no correlation was noted between ACE polymorphisms and the degree of myocardial hypertrophy. Moreover, in another study, ACE activity rather than ACE polymorphisms was associated with the degree of myocardial hypertrophy in patients with HCM.27 In this study, the ACE levels were higher in patients with the DD genotype, but no correlation between LVMI and mortality was observed. The association between the ACE genotype and LV mass in HCM cases is controversial. Although the ACE D alleles have been reported to be associated with increased LV hypertrophy in HCM cases,28 certain other studies did not indicate any relationship between the ACE D alleles and left ventricular hypertrophy.27,29 The results of this study did not indicate a significant influence of the ACE genotype on the LVM and long-term mortality in HCM patients. Conclusion: This study indicated that, rather than the ACE genotype and activity, the echocardiographic evaluation parameters such as LV systolic and diastolic diameter, LVMI, and particularly LA
5
Bostan, et al.
dimension may predict the long-term mortality in patients with HCM. PAF has also significant importance in the long-term mortality in patients with HCM.
13. 14.
Limitations: Although the sample of the study group was relatively small, the follow-up duration was sufficiently long, thus accounting for a comparable number of patient-years for the subgroups of baseline prognostic factors. Another limitation of this study is that we could not differentiate HCMrelated deaths, including sudden deaths and deaths caused by end-stage cardiac failure, from other causes of mortality, and instead only reported all-cause mortality as the main outcome.
15.
16.
17.
18.
References 1. Williams LK, Frenneaux MP, Steeds RP: Echocardiography in hypertrophic cardiomyopathy diagnosis, prognosis, and role in management. Eur J Echocardiogr 2009;10:iii9– iii14. 2. Griendling KK, Murphy TJ, Alexander RW: Molecular biology of the renin-angiotensin system. Circulation 1993;87:1816–1828. 3. Rigat B, Hubert C, Alhenc-Gelas F, et al: An insertion/ deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half of the variance of serum enzyme levels. J Clin Invest 1990;86:1343– 1346. 4. Marian AJ, Yu Q-T, Workman R, et al: Angiotensin-converting enzyme polymorphism in hypertrophic cardiomyopathy and sudden cardiac death. Lancet 1993;342:1085–1086. 5. Richardson P, McKenna W, Bristow M, et al: Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of cardiomyopathies. Circulation 1996;93:841–842. 6. Henry WL, DeMaria A, Gramiak R, et al: Report of the American Society of Echocardiography Committee on Nomenclature and Standards in Two-dimensional Echocardiography. Circulation 1980;62:212–217. 7. Kawasaki T, Yamano M, Kuribayashi T, et al: Three-layer ultrasonic tissue characterization of the ventricular septum is predictive of prognosis in patients with nonobstructive hypertrophic cardiomyopathy. Eur J Echocardiogr 2011;12:90–97. 8. Cecchi F, Olivotto I, Gistri R, et al: Coronary micro vascular dysfunction and prognosis in hypertrophic cardiomyopathy. N Engl J Med 2003;349:1027–1035. 9. Yashiro B, Minami Y, Terajima Y, et al: Prognostic difference between paroxysmal and non-paroxysmal atrial fibrillation in patients with hypertrophic cardiomyopathy. J Cardiol 2013 Nov 23 [Epub ahead of print]. 10. Nasermoaddeli A, Miura K, Matsumori A, et al: Prognosis and prognostic factors in patients with hypertrophic cardiomyopathy in Japan: Results from a nationwide study. Heart 2007;93:711–715. 11. Elliott PM, Gimeno-Blanes JR, Mahon NG, et al: Relation between severity of left ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy. Lancet 2001;357:420–427. 12. Olivotto I, Gistri R, Petrone P, et al: Maximum left ventricular thickness and risk of sudden death in patients
6
19.
20.
21. 22.
23.
24.
25.
26.
27.
28.
29.
with hypertrophic cardiomyopathy. J Am Coll Cardiol 2003;41:315–321. Maron BJ, Casey SA, Poliac LC, et al: Clinical course of hypertrophic cardiomyopathy in a regional United States cohort. JAMA 1999 Feb 17;281:650–655. Spirito P, Maron BJ: Relation between extent of left ventricular hypertrophy and occurrence of sudden cardiac death in hypertrophic cardiomyopathy. J Am Coll Cardiol 1990;15:1521–1526. Spirito P, Bellone P, Harris KM, et al: Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy. N Engl J Med 2000;342:1778–1785. Maron MS, Olivotto I, Betocchi S, et al: Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med 2003;348:295–303. Elliott PM, Gimeno JR, Tome MT, et al: Left ventricular outflow tract obstruction and sudden death risk in patients with hypertrophic cardiomyopathy. Eur Heart J 2006;27:1933–1941. Autore C, Bernabo P, Barilla CS, et al: The prognostic importance of left ventricular outflow obstruction in hypertrophic cardiomyopathy varies in relation to the severity of symptoms. J Am Coll Cardiol 2005;45:1076– 1080. Sorajja P, Nishimura RA, Gersh BJ, et al: Outcome of mildly symptomatic or asymptomatic obstructive hypertrophic cardiomyopathy: A long-term follow-up study. J Am Coll Cardiol 2009;54:234–241. Losi MA, Betocchi S, Barbati G, et al: Prognostic significance of left atrial volume dilatation in patients with hypertrophic cardiomyopathy. J Am Soc Echocardiogr 2009;22:76–81. Losi MA, Betocchi S, Grimaldi M, et al: Heterogeneity of left ventricular filling dynamics in hypertrophic cardiomyopathy. Am J Cardiol 1994;73:987–990. Tani T, Yagi T, Kitai T, et al: Left atrial volume predicts adverse cardiac and cerebrovascular events in patients with hypertrophic cardiomyopathy. Cardiovasc Ultrasound 2011;18:34. Nistri S, Olivotto I, Betocchi S, et al: Prognostic significance of left atrial size in patients with hypertrophic cardiomyopathy (from the Italian Registry for Hypertrophic Cardiomyopathy). Am J Cardiol 2006;98:960– 965. Finocchiaro G, Pinamonti B, Merlo M, et al: Prognostic role of clinical presentation in symptomatic patients with hypertrophic cardiomyopathy. J Cardiovasc Med (Hagerstown) 2012;13:810–818. Kitaoka H, Kubo T, Hayashi K, et al: Tissue Doppler imaging and prognosis in asymptomatic or mildly symptomatic patients with hypertrophic cardiomyopathy. Eur Heart J Cardiovasc Imaging 2013;14:544–549. Danser AH, Schalekamp MA, Bax WA, et al: Angiotensinconverting enzyme in the human heart. Effect of the deletion/insertion polymorphism. Circulation 1995;92:1387–1388. Buck PC, Fernandes F, Arteaga E, et al: Association of angiotensin-converting enzyme activity and polymorphism with echocardiographic measures in familial and nonfamilial hypertrophic cardiomyopathy. Braz J Med Biol Res 2009;42:717–721. Doolan G, Nguyen L, Chung J, et al: Progression of left ventricular hypertrophy and the angiotensin-converting enzyme gene polymorphism in hypertrophic cardiomyopathy. Int J Cardiol 2004;96:157–163. Lindpaintner K, Lee M, Larson MG, et al: Absence of association or genetic linkage between the angiotensinconverting- enzyme gene and left ventricular mass. N Engl J Med 1996;334:1023–1028.
