Genetic screening and double mutation in Japanese patients with hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder with an autosomal-dominant pattern of inheritance mainly caused by single heterozygous mutations in sarcomere genes. Although multiple gene mutations have recently been reported in Western countries, clinical implications of multiple mutations in Japanese subjects are not clear. METHODS AND RESULTS: A comprehensive genetic analysis of 5 sarcomere genes (cardiac ß-myosin heavy chain gene [MYH7], cardiac myosin-binding protein C gene [MYBPC3], cardiac troponin T gene [TNNT2], α-tropomyosin gene [TPM1] and cardiac troponin I gene [TNNI3]) was performed in 93 unrelated patients and 14 mutations were identified in 28 patients. Twenty-six patients had single heterozygosity (20 in MYBPC3, 4 in MYH7, 1 in TNNT2, 1 in TNNI3), whereas 2 proband patients with familial HCM had double heterozygosity: 1 with P106fs in MYBPC3 and R869C in MYH7 and 1 with R945fs in MYBPC3 and E1049D in MYH7. From the results of the family survey and the previous literature on HCM mutations, P106fs, R945fs and R869C seemed to be pathological mutations and E1049D might be a rare polymorphism. The proband patient with P106fs and R869C double mutation was diagnosed as having HCM at an earlier age (28 years of age) than her relatives with single mutation, and had greater wall thickness with left ventricular outflow obstruction. CONCLUSIONS: One double mutation was identified in a Japanese cohort of HCM patients. Further studies are needed to clarify the clinical significance of multiple mutations including phenotypic severity.

Combined measurements of cardiac troponin I and brain natriuretic peptide are useful for predicting adverse outcomes in hypertrophic cardiomyopathy.

BACKGROUND: Although serum cardiac troponin I (cTnI) and plasma brain natriuretic peptide (BNP) have become clinically important tools as diagnostic and prognostic markers for ischemic heart disease and heart failure, the usefulness of these biomarkers for risk stratification of hypertrophic cardiomyopathy (HCM) is not clear. METHODS AND RESULTS: We studied 167 patients with HCM, and cTnI and BNP were measured. During follow-up (38.5 months), 20 patients suffered from cardiovascular events: HCM-related deaths in 6, hospitalization for heart failure in 8, embolic stroke in 5 and 1 patient with spontaneous sustained ventricular tachycardia. Patients with high cTnI values (≥0.04 ng/ml) had more frequent cardiovascular events than did those with low cTnI values (P=0.008). Similarly, there were more frequent adverse events in the high BNP group (≥200 pg/ml) than in the low BNP group (P=0.002). When groups were allocated according to both cTnI and BNP measurements, serum cTnI used in conjunction with BNP further improved the prognostic value; patients with both high cTnI and BNP values had an 11.7-fold increased risk of cardiovascular events compared with those with both low cTnI and BNP values. CONCLUSIONS: CTnI and BNP are useful parameters for identifying patients at risk for clinical deteriorations, and combined measurements of these biomarkers further improves the prognostic value of increased cardiovascular events in HCM.

Turbulent left-to-right shunt flow through the interatrial septum suggesting high left atrial pressure in patients with heart failure with preserved ejection fraction.

Lutembacher's syndrome is a combination of interatrial septal (IAS) defect or patent foramen ovale (PFO), associated with mitral stenosis. High left atrial (LA) pressure in mitral stenosis exaggerates left-to-right shunt in patients with interatrial communication. We present a case of heart failure with preserved ejection fraction. Echocardiography revealed normal left ventricular systolic function without mitral stenosis and turbulent left-to-right shunt through the IAS. The peak velocity of the shunt flow was 2.3 m/s and the estimated pressure gradient was 22 mmHg, indicating high LA pressure. The presence of turbulent left-to-right shunt through the IAS is helpful for detecting high LA pressure.

Abdominal visceral fat thickness measured by ultrasonography predicts the presence and severity of coronary artery disease.

Abdominal visceral fat plays a critical role in the pathogenesis of metabolic syndrome, which is a risk factor for coronary artery disease (CAD). Ultrasonography (US) distinctively quantifies visceral fat and subcutaneous fat. We measured the maximum preperitoneal visceral fat thickness (Vmax) and the minimum subcutaneous fat thickness (Smin) by US in 185 patients who underwent coronary angiography. Although the 144 patients with CAD had larger Vmax (8.8 ± 3.6 vs. 6.4 ± 2.8 mm; p < 0.001) than those without, there was no difference in Smin. Vmax of 6.9 mm or higher was an independent predictor of CAD (odds ratio, 3.710, p = 0.008) by multiple logistic regression analysis. Vmax significantly correlated with the number of diseased vessels. Assessment of abdominal visceral fat by US gives us incremental information beyond conventional risk factors for predicting CAD in routine clinical practice.

Gender-specific differences in the clinical features of hypertrophic cardiomyopathy in a community-based Japanese population: results from Kochi RYOMA study.

OBJECTIVES: Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder with a broad spectrum of clinical features. Although gender may be one of the important modifying factors in HCM, there has been little information on gender differences. METHODS: We investigated gender-specific differences in the clinical features of HCM in a community-based Japanese population. We established cardiomyopathy registration in Kochi Prefecture named Kochi RYOMA study consisting of 9 hospitals as an unselected regional Japanese population. RESULTS: 261 patients with diagnosis of HCM were registered. At registration, 88 patients (34%) were women. Female patients were more frequently diagnosed as having HCM at ≥65 years (41% versus 27%) and had a higher ratio of familial HCM (35% versus 19%). More female patients had diagnosis of HCM due to cardiac symptoms (64% versus 40%) and were symptomatic both at diagnosis and at registration. Although the prevalence of atrial fibrillation was not different between males and females, embolic events occurred less frequently in female patients at registration than in male patients (2% versus 10%). In female patients, there were more obstructive HCM patients and fewer patients with apical HCM. Left ventricular and left atrial diameters were smaller and fractional shortening was higher in females than in males. CONCLUSIONS: The manifestations of HCM in unselected Japanese patients differed in men and women, which suggest that hormonal, social, and genetic factors may influence the clinical presentation of HCM.

Clinical features of the dilated phase of hypertrophic cardiomyopathy in comparison with those of dilated cardiomyopathy.

BACKGROUND: Although the dilated phase of hypertrophic cardiomyopathy (D-HCM) characterized by left ventricular (LV) systolic dysfunction and cavity dilatation has been reported to be a poor prognosis, this is now in contrast to the improved prognosis of dilated cardiomyopathy (DCM) in the era of advancements in heart failure management. There has been no investigation of the clinical features of D-HCM compared with those of DCM from the point of management of systolic dysfunction. HYPOTHESIS: The aim of this study was to investigate the clinical features of D-HCM in comparison with those of DCM in a single institute. METHODS: We studied 20 consecutive patients with D-HCM (global ejection fraction < 50%) and 115 consecutive patients with DCM. RESULTS: At diagnosis of D-HCM, 8 (40%) of the D-HCM patients already experienced dyspnea (New York Heart Association [NYHA] class >or= III). Left atrial diameter was larger and prevalence of atrial fibrillation was higher in the D-HCM group, although LV size was larger and LV ejection fraction was lower in the DCM group. During the follow-up period (4.0 years), 11 (55%) of the patients with D-HCM died. The 5-year survival rate from all-cause mortality including cardiac transplantation was 45.6% in patients with D-HCM vs 81.6% in patients with DCM (log-rank P = .0001). CONCLUSIONS: Patients with D-HCM were more symptomatic at diagnosis, although LV dilatation and impaired fractional shortening seemed more severe in patients with DCM. The prognosis for D-HCM patients was worse than that for patients with DCM despite similar or even more intensive treatment for heart failure.

A frameshift deletion mutation in the cardiac myosin-binding protein C gene associated with dilated phase of hypertrophic cardiomyopathy and dilated cardiomyopathy.

OBJECTIVES: A few studies reported that some mutations in the cardiac myosin-binding protein C (MyBPC) gene were associated with dilated phase of hypertrophic cardiomyopathy (D-HCM) resembling dilated cardiomyopathy (DCM). We studied 5 unrelated cardiomyopathy probands caused by an identical mutation in the MyBPC gene. The results of clinical and genetic investigations in these patients are presented in this paper. METHODS: We analyzed MyBPC gene in DCM patients as well as patients with HCM. RESULTS: An R945fs/105 mutation, 2-base deletion at nucleotides 18,535 and 18,536, was identified in 4 of the 176 HCM probands and in 1 of the 54 DCM probands. Genetic analysis in relatives of those probands revealed another one member with this mutation. A total of 6 subjects had R945fs/105 mutation. The mean age of these six patients at diagnosis was 61 years. At initial evaluation, three of them were diagnosed as having HCM with normal left ventricular (LV) systolic function. The other two patients already had D-HCM. The remaining one patient was diagnosed as having DCM because of reduced LV systolic function (ejection fraction=31%) without increased LV wall thickness. During follow-up (7.6 years), all three patients with impaired LV systolic function were admitted for treatment of heart failure and/or sustained ventricular tachycardia. Finally, one patient with the diagnosis of D-HCM died of heart failure. CONCLUSIONS: The patients with this mutation may develop LV systolic dysfunction and suffer from cardiovascular events through mid-life and beyond.

Impact of metalloproteinases on left ventricular remodeling and heart failure events in patients with hypertrophic cardiomyopathy.

BACKGROUND: The impact of matrix metalloproteinase (MMP) on left ventricular (LV) remodeling and heart failure events is unresolved in patients with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: Plasma levels of MMP-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and clinical findings and heart failure events were evaluated in 41 HCM patients, including 8 with LV systolic impairment. Plasma B-type natriuretic peptide (BNP) levels were also measured. MMP-2 levels in patients with severe symptoms were higher than that in those with no or mild symptoms. The levels of MMP-2 and TIMP-1 were positively related to LV end-systolic and left atrial dimensions, and inversely related to LV ejection fraction. MMP-2 levels were positively related to BNP levels (r=0.52, P=0.0009). However, MMP-9 levels were not related to echocardiographic parameters and plasma BNP levels. Six patients had complicated heart failure events during the follow-up period of 3.2+/-0.7 years. Patients with high plasma MMP-2 levels (>1,170 ng/ml) revealed a poorer prognosis than those with low MMP-2 levels. CONCLUSIONS: Elevated levels of MMP-2 were related to LV remodeling and poor prognosis in patients with HCM. These results suggest that regulation of the extracellular collagen matrix might be one of the therapeutic targets in patients with HCM.

A novel cardiac myosin-binding protein C S297X mutation in hypertrophic cardiomyopathy.

BACKGROUND: Mutations in the cardiac myosin-binding protein C gene (MYBPC3) have been reported to be associated with delayed expression of hypertrophic cardiomyopathy (HCM) and a relatively good prognosis. PURPOSE: The aim of this study was to evaluate clinical manifestations in patients with familial HCM caused by a novel nonsense mutation, S297X, in MYBPC3. METHODS: We analyzed the sarcomere protein genes in 93 probands with HCM. RESULTS: The nonsense mutation S297X in MYBPC3 was present in nine subjects from two unrelated families. Eight of those nine subjects with this mutation were found to be phenotype-positive and the remaining individual was not affected phenotypically. The age range at diagnosis was 9-75 years. There was no family history of sudden death in either family. At presentation, there were various left ventricular hypertrophy (LVH) patterns, including Maron type III hypertrophy from the LV base to apex, hypertrophy confined to the anterolateral wall at the basal LV wall. Two patients showed a significant LV outflow tract gradient and one patient showed intra-right-ventricular obstruction. During follow-up, one patient was repeatedly hospitalized for the treatment of heart failure after development of paroxysmal atrial fibrillation at the age of 86 years and the remaining eight subjects were in relatively stable condition and did not require hospitalization for the treatment of HCM-related events. CONCLUSION: The novel mutation S297X in MYBPC3 causes HCM in a broad range of ages and heterogeneous clinical manifestations, though the clinical course in patients with this mutation seems to be benign.

Serum cardiac troponin I is related to increased left ventricular wall thickness, left ventricular dysfunction, and male gender in hypertrophic cardiomyopathy.

BACKGROUND: Serum cardiac troponin I (cTnI) is a sensitive and specific marker of myocardial injury. However, a systematic evaluation of cTnI in hypertrophic cardiomyopathy (HCM) patients has not been performed. HYPOTHESIS: The purpose of this study is to evaluate cTnI and determine its relationship to clinical features in HCM. METHODS: We studied serum cTnI in 162 consecutive HCM patients. RESULTS: Serum cTnI ranged from 0.01 to 0.83 ng/mL (mean, 0.068 +/- 0.100 ng/mL) and was higher in male patients (P < .001), those with atrial fibrillation (P = .033), and left ventricular (LV) systolic dysfunction (P = .046). Serum cTnI values were also correlated with maximum LV wall thickness (r = 0.30, P < .001), LV end-systolic diameter (r = 0.20, P = .012), and E/Ea (peak early transmitral filling velocity/early diastolic mitral annulus velocity; r = 0.24, P = .004). Serum cTnI levels were not significantly different among New York Heart Association (NYHA) functional class and there was no difference between patients with or without LV outflow tract obstruction; although B-type natriuretic peptide (BNP) levels showed significant difference in those variables. Serum cTnI had very weak correlation with BNP values (r = 0.18, P = .023). Multivariate analysis revealed an independent relationship between cTnI and maximum LV wall thickness, E/Ea, and male gender. CONCLUSIONS: In patients with HCM, serum cTnI was associated with important clinical indices such as maximum LV wall thickness, LV dysfunction, and male gender. Serum cTnI seemed to have clinical significance different from that of BNP and may not be reflecting cardiac load but the LV remodeling process in HCM.

Clinical profiles of hypertrophic cardiomyopathy with apical phenotype--comparison of pure-apical form and distal-dominant form.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) with an apical phenotype, in which hypertrophy of the myocardium predominantly involves the apex of the left ventricle, is not uncommon in Japan, but its morphologic variations are not well recognized. The aim of this study was to investigate if these variations have different clinical characteristics although they are still confused to be the same. METHODS AND RESULTS: Patients with the apical phenotype were divided into 2 groups, the "pure-apical" form and the "distal-dominant" form, and their clinical profiles were compared. From the study cohort of 264 patients with HCM, 80 (30%) were classified as having the apical phenotype: 51 with the pure-apical form and 29 with the distal-dominant form. The age at diagnosis was approximately 60 years, and in both groups the majority were male. The distal-dominant group had a significantly larger left atrial diameter (43 vs 39 mm) and higher ratio of proven familial HCM (28 vs 6%), and were more symptomatic (New York Heart Association >or=3) at presentation (17 vs 0%). The event-free rate of cardiovascular events in patients with the distal-dominant form was significantly worse (log-rank P=0.012) than that in patients with the pure-apical form (follow-up period: asymptotically approximately 5 years). CONCLUSIONS: The 2 phenotypes of apical HCM should be recognized and distinguished clinically.

[Severe pulmonary hypertension and congestive heart failure in an elderly patient with Basedow's disease].

An 83-year-old woman was admitted to our hospital with dyspnea. A chest X-ray showed cardiomegaly and pulmonary congestion. An echocardiogram revealed severe tricuspid regurgitation and markedly elevated transtricuspid pressure gradient of 103 mmHg. There was no left ventricular systolic or diastolic dysfunction. Laboratory evaluation revealed elevated free T4 and suppressed TSH levels. Serum level of anti-TSH receptor antibody was significantly elevated. A thyroid echogram demonstrated increased internal flow pattern in the thyroid gland. As a result of these findings, she was given a diagnosis of Basedow's disease associated with severe pulmonary hypertension and congestive heart failure. After treatment for hyperthyroidism with thiamazole, propranolol, furosemide, and warfarin, she made good recovery with gradual resolution of pulmonary hypertension. The severity of pulmonary hypertension in this case was significantly higher than that in previous reports, possibly because of concomitant minor pulmonary embolism, thiamine deficiency and anemia. In summary, we report a rare case of Basedow's disease with severe and reversible pulmonary hypertension that appeared in very old age.

Clinical impact of atrial fibrillation in patients with hypertrophic cardiomyopathy. Results from Kochi RYOMA Study.

BACKGROUND: There have been few studies of the clinical features of hypertrophic cardiomyopathy (HCM) in a community-based patient cohort in Japan. METHODS AND RESULTS: Cardiomyopathy registration was established in Kochi Prefecture and named the Kochi RYOMA (registry of myocardial diseases) study, consisting of 9 hospitals that registered 261 patients with a diagnosis of HCM. At registration, 74 patients (28%) had documented paroxysmal or chronic atrial fibrillation (AF). Although most patients (93%) were in New York Heart Association (NYHA) class I or II, 17 of the 18 patients in NYHA III had AF; 37 of the 74 patients with AF suffered from morbid events (embolism and/or heart failure (HF) admission), and 15 of 19 patients with embolic events had AF prior to or at the time of embolism. Of the 29 patients who had a history of HF admission, 8 had left ventricular systolic dysfunction, and the other 21 patients were hospitalized because of diastolic HF. AF occurred prior to HF in 20 of those 21 patients. Furthermore, 19 of those 20 patients with AF and diastolic HF were hospitalized within 1 year after detection of AF. CONCLUSIONS: In an unselected regional registry, AF was the major determinant of clinical deteriorations in patients with HCM.

Utility of tissue Doppler imaging to predict exercise capacity in hypertrophic cardiomyopathy: comparison with B-type natriuretic peptide.

BACKGROUND: Recent reports suggest that left ventricular diastolic function assessed by tissue Doppler imaging (TDI) and plasma B-type natriuretic peptide (BNP) levels can relate to functional status in patients with hypertrophic cardiomyopathy (HCM). However, it is unclear which is more useful to predict the exercise capacity in HCM patients without systolic impairment and/or atrial fibrillation, TDI or BNP levels. PURPOSE: The present study directly compared the clinical relevance of assessing diastolic function using TDI and measuring the plasma BNP level in patients with HCM. METHODS AND SUBJECTS: We evaluated diastolic function using TDI as well as plasma BNP levels in 31 patients (52.2+/-16.9 years of age; 20 males) with HCM and examined the relationship of these values to exercise capacity (peak O(2) consumption (VO(2))) measured by cardiopulmonary exercise tests. RESULTS: Average peak VO(2) was 18.5+/-4.7 ml/(kg min). Although the E/A ratio by transmitral flow was not correlated with peak VO(2), the lateral E/E(a) ratio assessed by TDI was significantly correlated with peak VO(2) (r=-0.52, p=0.003). On the other hand, plasma BNP level was not significantly related to peak VO(2) but NYHA class. CONCLUSIONS: Assessment of diastolic function using TDI, not plasma BNP levels, is more useful for predicting objective exercise capacity in HCM patients without systolic impairment and/or atrial fibrillation.

Improvement in prognosis of dilated cardiomyopathy in the elderly over the past 20 years.

BACKGROUND AND PURPOSE: Although dilated cardiomyopathy (DCM) had a poor prognosis in the past, recent studies have shown better survival. However, little is known about the improvement of prognosis in the elderly. This study sought to clarify the changes in prognosis in elderly patients with DCM over the past 20 years. METHODS AND SUBJECTS: We studied 54 consecutive patients with DCM (38 men and 16 women, aged 65-83 years) who were diagnosed at over 65 years of age. The patients were divided into two groups (group A: 12 patients diagnosed before 1990; group B: 42 patients diagnosed after 1990) because after 1990, based on growing evidence from large-scale, randomized clinical studies, we intentionally increased the use of angiotensin-converting enzyme inhibitors (ACEI) and then beta-blockers at our hospital. RESULTS: There were no significant differences in age, gender, NYHA functional class, and the prevalence of atrial fibrillation and ventricular tachycardia between the two groups. Left ventricular (LV) size assessed by echocardiography was larger (LV end-diastolic diameter, 67+/-5.9 versus 62+/-6.6 mm; p=0.039) and LV ejection fraction measured by left ventriculography was lower (ejection fraction, 24+/-9 versus 35+/-10%; p=0.004) in group A. ACEI/angiotensin II type 1 receptor blockers (ARB) (0% versus 88%) or beta-blockers (0% versus 52%) were more frequently used in group B. Antiarrhythmics (class Ia or Ib) (75% versus 14%) were less often used in group B. The 5- and 10-year event-free survival rates for cardiac death were 75.4% and 22.0% in group A versus 81.2% and 71.3% in group B (log-rank test, p=0.014). CONCLUSIONS: The prognosis of DCM patients in the elderly has significantly improved over the past 20 years. The advances in the pharmacologic treatment and earlier diagnosis may have contributed to the better survival.

Hypertrophic cardiomyopathy with mild left ventricular remodeling: echocardiographic assessment using left ventricular wall motion score.

OBJECTIVES: The present study sought to investigate the echocardiographic features of hypertrophic cardiomyopathy (HCM) with mild left ventricular (LV) remodeling, particularly in relation to wall motion abnormalities. METHODS: Among the 137 consecutive patients with HCM, 13 patients (mean age 52 +/- 13 years) who progressed to mild LV systolic dysfunction (LV ejection fraction (LVEF) of 35-50%) were studied. By reviewing the echocardiograms of these patients, wall motion score index (WMSI) was scored using 16 segments model. RESULTS: HCM patients with mild LV systolic dysfunction exhibited mild LV dilatation, mild left atrial dilatation, septal hypertrophy, and LV wall motion impairment localized in the septal and apical regions (septal WMSI 1.94 +/- 0.33 vs. total WMSI 1.51 +/- 0.25 and posterior WMSI 1.02 +/- 0.07; p < 0.001). During follow-up, further deterioration of LV systolic function (LVEF< 35%) was noted in five patients, who had less severe hypertrophy at the initial echocardiograms. These patients developed progressive LV cavity enlargement and more severe and extensive wall motion abnormalities, accompanied by septal akinesis and wall thinning, although posterolateral wall motion impairment was relatively mild (posterior WMSI 1.80 +/- 0.27 vs. septal WMSI 2.95 +/- 0.11; p < 0.001). CONCLUSIONS: Septal and apical wall motions are reduced in HCM with mild LV remodeling. As LV dysfunction progresses, septal akinesis and wall thinning develop and LV cavity enlargement becomes more prominent, though posterolateral wall motion impairment is relatively mild.