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A 60-year-old Japanese man with obstructive hypertrophic cardiomyopathy was found to have a mutation in the cardiac myosin binding protein C gene: a single base deletion of a thymidine residue at nucleotide 11645 (codon 593) in exon 18. He was diagnosed at the age of 43 and has been followed for 17 years. During this follow-up period, echocardiograms and mechanocardiograms revealed progressive hypertrophy until the age of 54, then gradual dilation of the left ventricle associated with a decrease in the obstruction. Paroxysmal atrial fibrillation occurred at the age of 52 and progressed to chronic atrial fibrillation at the age of 53. He had congestive heart failure at the age of 58.

An 18-year-old male patient with biventricular hypertrophic obstructive cardiomyopathy (HOCM) had successful reduction of the pressure gradients by cibenzoline. At 11 months after birth, he was first diagnosed with cardiac murmurs and by the age of 5 years, he was diagnosed with subpulmonic infundibular stenosis with a pressure gradient of 10 mmHg by cardiac catheterization. At the age of 14, re-catherterization revealed hypertrophic cardiomyopathy with isolated obstruction of the right ventricular outflow tract, with a pressure gradient of 70 mmHg, but no obstruction in the left ventricle. He began daily treatment with 30 mg propranolol. At the age of 18, he was admitted for cardiac evaluation. An echocardiogram revealed left mid-ventricular and subpulmonic obstructions associated with pressure gradients of 88 mmHg and 65 mmHg, respectively. A single oral dose of 200 mg of cibenzoline decreased the pressure gradients in the left and right ventricles (38 mmHg and 36 mmHg, respectively). He was then given 300 mg daily of cibenzoline, and both pressure gradients remained low without any complications 8 months later at the time of discharge.

Insulin-like growth factor-1 (IGF-1) is important in the hypertrophic response of the myocardium, so the present study was designed to elucidate whether the circulating levels of IGF-1 and its binding proteins (IGFBPs) are related to the disease condition of patients with hypertrophic cardiomyopathy (HCM), in particular the occurrence of congestive heart failure (CHF). The study group comprised 124 patients with HCM and 15 healthy control subjects. The HCM patients were subdivided into 3 groups: 39 with hypertrophic obstructive cardiomyopathy (HOCM), 67 with hypertrophic non-obstructive cardiomyopathy (HNCM), and 18 with HCM and a history of CHF (HF-HCM, n=18). Serum levels of IGF-1 and IGFBPs (IGFBP-1 and -3) were compared between groups. IGF-1 levels were significantly higher in patients with HOCM and HNCM, and lower in patients with HF-HCM than in control subjects (p<0.0001, p<0.005, and p<0.05, respectively). IGFBP-1 levels were significantly higher in patients with HF-HCM than in the other 3 groups (p<0.0001 for all). The findings suggest that circulating levels of IGF-1 and IGFBP-1 are related to the extent of myocardial injury in patients with HCM.

Atrial fibrillation (AF) occurs in about 20% of patients with hypertrophic cardiomyopathy (HCM). HCM patients with AF have an increased risk for clinical decline and thromboembolism. In addition, AF is known to be associated with the atrial renin-angiotensin system (RAS). However, the relation between AF and the RAS in HCM has not been investigated. We genotyped the insertion/ deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene in 138 HCM patients (26 with AF, 112 with sinus rhythm). Distribution of the ACE genotypes (DD, ID, and II) among the total HCM patients was 15%, 46%, and 38%. AF was documented in 3 patients with the DD genotype, 7 with the ID genotype, and 16 with the II genotype (P < 0.03 vs. sinus rhythm group). The odds of AF were 3.2-fold greater in patients with the II genotype than in those with the other genotypes (P = 0.009, 95% confidence interval = 1.3-7.8). Kaplan-Meier curves examining the time to the first documented AF event showed a significant difference between genotypes during the follow-up period (mean 116 months, P < 0.05). These findings suggest that the II genotype of the ACE gene is a significant risk factor for AF in patients with HCM.

The effect of cibenzoline on left ventricular diastolic function was investigated in patients with hypertrophic cardiomyopathy (HCM). Before and 2 h after an oral administration of 200 mg of cibenzoline, echocardiographic, apexcardiographic and gated radionuclide angiographic studies were performed in 12 patients with hypertrophic obstructive cardiomyopathy (HOCM) and 7 with hypertrophic nonobstructive cardiomyopathy (HNCM). After administration of cibenzoline, the left ventricular pressure gradient decreased from 96+/-33 mmHg to 29+/-22 mmHg (<0.0001). Fractional shortening decreased from 53.3+/-7.5 to 45.4+/-6.2% (p=0.0008) in patients with HOCM and from 49.9+/-8.7 to 40.9+/-7.5% (p=0.0039) in patients with HNCM. On the other hand, E-wave velocity increased and A-wave velocity decreased in both groups. The time between the second heart sound and O point was shortened from 253+/-53 to 176+/-21 ms (p<0.0001) in patients with HOCM and from 245+/-54 to 185+/-44 ms (p=0.0050) in patients with HNCM. The time to peak filling rate was shortened from 248+/-79 to 190+/-40 ms (p=0.0072) in patients with HOCM and from 218+/-33 to 163+/-26 ms (p=0.0052) in patients with HNCM. These results indicate that in patients with HCM, cibenzoline suppresses left ventricular systolic function, but can markedly improve left ventricular diastolic dysfunction through its direct action.

Background: There has been no report of ECG changes during anginal attacks in patients with coexistent hypertrophic cardiomyopathy (HCM) and vasospastic angina., Study Objectives: To elucidate the change in ST-segment during anginal attacks in patients with coexistent HCM and vasospastic angina (the HCM group) in comparison with that of patients with vasospastic angina and no left ventricular hypertrophy (the non-HCM group)., Design: Retrospective study., Patients: Twelve patients in the HCM group, and 28 patients in the non-HCM group., Measurements: The direction of ST segment shift, either ST-segment elevation or depression, on the ECGs recorded during vasospastic anginal attacks with severe vasoconstriction in the epicardial coronary artery after intracoronary injection of acetylcholine., Results: Age, male gender, and distribution of coronary arteries in which the vasospasm occurred were similar between the two groups. Collateral circulation to the affected arteries was absent in all the study patients. The prevalence of anginal attacks associated with ST-segment elevation was 2.7 times higher in the non-HCM group than in the HCM group (51. 5% [17 of 33 attacks] vs 18.8% [3 of 16 attacks], respectively; p = 0.03)., Conclusions: In the HCM group, myocardial ischemia associated with a transmural injury pattern seen on the ECG, which is represented as ST-segment elevation, seldom develops during vasospastic anginal attacks because of marked left ventricular hypertrophy.

A 58-year-old male patient had apical hypertrophic cardiomyopathy (HCM) associated with a life-threatening tachycardia due to atrial flutter. Following palpitation and dyspnea for 2-3 h, he became unconscious because of circulatory catastrophe, but was fully resuscitated. An electrocardiogram recorded just before the loss of consciousness revealed atrial flutter at a rate of 260 beats/min with a 2:1 ventricular response. He was diagnosed as having apical HCM based on the echocardiographic and left ventriculographic findings. Atrial stimulation at a rate of 150 pacings/min for 1 min caused a marked drop in systemic systolic blood pressure from 170 to 120 mmHg. The patient was treated with 150 mg of cibenzoline per day to prevent supraventricular tachyarrhythmias and to improve left ventricular diastolic function. At the time of the recent follow-up at 2 and a half years, he felt quite well.

A 54-year-old woman had been treated for hypertrophic cardiomyopathy and paroxysmal atrial fibrillation since 1992. She was admitted with paroxysmal atrial fibrillation which was resolved by medical treatment. However, on the next day, left lateral chest pain appeared. Computed tomography disclosed a low density area in the spleen. She received anticoagulant therapy under a diagnosis of splenic infarction, and the pain disappeared. Echocardiography showed hypertrophic cardiomyopathy with mid-ventricular obstruction. She was treated with cibenzoline to prevent paroxysmal atrial fibrillation attack and attenuate the hemodynamic load. After treatment, the pressure gradient decreased from 41 to 7 mmHg. This patient with hypertrophic cardiomyopathy suffered a rare isolated splenic infarction associated with paroxysmal atrial fibrillation.

There are only a few reports concerning coexistent hypertrophic cardiomyopathy (HCM) and vasospastic angina. Clinical characteristics in patients with both diseases have not been clarified yet. This study was designed to elucidate the relationship between chest pain and coronary vasospasm in HCM patients and to delineate clinical characteristics in patients with both HCM and coronary vasospasm. First, 36 patients with HCM underwent acetylcholine provocation test for coronary vasospasm and were divided into two groups on the basis of presence or absence of coronary vasospasm. Next, the following risk factors for coronary artery disease were compared between the two groups: hypertension, smoking, hyperlipidemia, diabetes mellitus, and hyperuricemia. Coronary vasospasm was induced in 10 (28%) of 36 patients with HCM. There were no significant differences in age and male gender between the two groups. Smoking was more prominent in HCM patients with than without coronary vasospasm (80% vs 35%, p<0.05), but there were no differences in the prevalence of other risk factors between the two groups. In conclusion, coronary vasospasm appears to play a significant role in the etiology of myocardial ischemia in Japanese patients with HCM, and smoking might be a major risk factor for coexistence of HCM and coronary vasospasm.

A 57-year-old woman was admitted for examination because of chest discomfort. Transthoracic echocardiography was performed and she was diagnosed as having hypertrophic cardiomyopathy. An echocardiogram also revealed that she had midventricular obstruction with a pressure gradient of 125 mmHg determined by Doppler echocardiography. A phonocardiogram showed an early systolic sound and the beginning of the sound coincided with the time of septal-posterior wall contact. In addition, the timing also corresponded to the sudden obstruction of blood flow in the region of the midventricular narrowing. Furthermore, this sound markedly decreased with the reduction in pressure gradient caused by cibenzoline treatment. Thus, it was concluded that the early systolic sound was associated with midventricular obstruction and produced by a rapid deceleration of the interventricular flow caused by midventricular obstruction.

1. The aim of this study was to elucidate the pathophysiological role of adrenomedullin and the relation between adrenomedullin and other hormones in patients with hypertrophic cardiomyopathy. 2. Fourteen patients with hypertrophic obstructive cardiomyopathy (HOCM), 26 patients with hypertrophic non-obstructive cardiomyopathy (HNCM) and 14 normal control subjects participated in this study. Radioimmunoassay for plasma adrenomedullin concentration was performed with adrenomedullin-M antibody. Plasma levels of endothelin-1, atrial and brain natriuretic peptides and noradrenaline were also measured. 3. Plasma levels of adrenomedullin were higher in patients with hypertrophic cardiomyopathy (8.43 +/- 3.73 pmol/l) than in normal controls (5.24 +/- 0.44 pmol/l, P < 0.005). There was no significant difference between HOCM and HNCM patients. There was a weak correlation between plasma levels of adrenomedullin and total 12-lead QRS voltage in patients with hypertrophic cardiomyopathy (r = 0.323, P < 0.05). 4. Plasma levels of endothelin-1, atrial and brain natriuretic peptides were higher in hypertrophic cardiomyopathy than in normal controls. Endothelin-1 showed no significant difference between HOCM and HNCM patients, but atrial and brain natriuretic peptides were higher in HOCM than in HNCM patients. There was a positive correlation between plasma levels of adrenomedullin and endothelin-1 (r = 0.575, P < 0.0001), but no correlation between plasma levels of adrenomedullin and atrial natriuretic peptide, brain natriuretic peptide and noradrenaline. 5. Our results indicate that adrenomedullin may play an important role to maintain haemodynamics in patients with hypertrophic cardiomyopathy, and its action may be related to endothelin-1 but independent of atrial natriuretic peptide, brain natriuretic peptide and noradrenaline.

Background: The class Ia antiarrhythmic drug disopyramide relieves the outflow tract obstruction of hypertrophic obstructive cardiomyopathy (HOCM). Disopyramide, however, has several adverse effects, such as dysuria and thirst, resulting from its anticholinergic activity. A new class Ia antiarrhythmic drug, cibenzoline, has little anticholinergic activity. The aim of this study is to elucidate whether cibenzoline attenuates left ventricular pressure gradient (LVPG) in patients with HOCM., Methods and Results: Ten patients with HOCM (mean age, 59+/-12 years) participated in this study. LVPG and left ventricular functions were measured before and 2 hours after administration of a single oral dose of 150 or 200 mg cibenzoline. LVPG decreased from 123+/-60 to 39+/-33 mm Hg (P=.0026). The E/A ratio in transmitral Doppler flow increased from 1.20+/-0.84 to 2.00+/-1.72 (P=.029). Isovolumic relaxation time increased from 73+/-16 to 101+/-23 ms (P=.0026). Left ventricular diastolic dimension remained unchanged, but left ventricular systolic dimension enlarged significantly, from 21.6+/-2.4 to 26.2+/-3.3 mm (P=.0004). Fractional shortening decreased from 47.6+/-6.1% to 34.6+/-8.8% (P=.0007). Left ventricular ejection time index decreased significantly, and preejection period index increased in all the patients. Decreased LVPG remained maintained even in the long-term treatment with cibenzoline. Conclusions These results indicate that cibenzoline can markedly attenuate LVPG in patients with HOCM. A decrease in myocardial contractility seems to be closely related to a marked decrease in LVPG.

Familial nonobstructive hypertrophic cardiomyopathy in 78-year-old woman was diagnosed in 1988. Since then she has been treated with a beta-blocking drug and a calcium antagonist. Her clinical condition was NYHA I or II for several years. Echocardiography revealed asymmetric septal hypertrophy in 1988 (interventricular septal thickness = 21 mm, posterior wall thickness = 10 mm). Systolic anterior motion of the mitral valve was first observed at the end of 1992. The left ventricular pressure gradient also gradually increased; it was about 138 mmHg in 1993 (age 82 yrs). The left ventricular ejection time index increased from 376 msec in May, 1992 to 459 msec in May, 1994. In September, 1994, the patient's condition gradually deteriorated (NYHA IV), and she was admitted to our hospital. To attenuate the left ventricular pressure gradient, 150 mg of disopyramide was administered. Her condition markedly improved: the left ventricular pressure gradient decreased from 180 mmHg to 76 mmHg, and the left ventricular ejection time index decreased from 485 msec to 419 msec. These results indicate that a left ventricular pressure gradient can be generated rapidly even in a very old patient, and that disopyramide may be useful to attenuate the left ventricular pressure gradient.

To elucidate the morphologic characteristics of the left ventricle in patients with hypertrophic cardiomyopathy who developed atrial fibrillation, we studied left ventricular geometry by two-dimensional echocardiography in 92 patients with hypertrophic cardiomyopathy. These patients were divided into two groups; 24 patients with transient or persistent atrial fibrillation (group I) and 68 patients with sinus rhythm (group II). Left ventricular chamber size in group I was significantly smaller than that in group II. Left ventricular chamber size was correlated positively with stroke volume, and was correlated negatively with left ventricular end-diastolic pressure. The incidence of systemic thromboembolism in group I was 7.1% per patient year. In hypertrophic cardiomyopathy, the size of the left ventricle appears to have major pathophysiologic significance in the development of atrial fibrillation. In addition, since patients with hypertrophic cardiomyopathy who develop atrial fibrillation have a potential risk of systemic thromboembolism, prophylactic anticoagulant therapy should be performed in these patients.

To determine the common morphological characteristics of hypertrophic cardiomyopathy (HCM) by ventriculography from a right anterior oblique projection, diaphragmatic and free wall configurations were analyzed in 15 patients with obstructive HCM (HOCM), 32 patients with nonobstructive HCM (HNCM) and 17 controls. There was a convexity extending into the left ventricle in the right anterior oblique projection due to hypertrophy of the interventricular septum (IVS) in all patients with HCM. The peak convexity, where septal thickness was maximal (M point), was closer to the base in HOCM than in HNCM. Due to this convexity, the left ventricle showed a catenoid-shaped distortion at the M point. The distortion was severer in HOCM than in HNCM. Left ventricular free wall (LVFW) thickness was measured at the base and near the apex. LVFW thickness in HOCM decreased toward the apex, similar to that in controls, but in 17 of 32 HNCM (53%) LVFW thickness increased toward the apex. Cardiac index and stroke index in HCM were significantly smaller than those in controls. There was a significant correlation between the position of the M point and stroke index in HCM. These results indicate that a common morphological characteristic of HCM on the diaphragmatic side is the existence of a convexity extending into the left ventricle, and that cardiac performance in HCM is greatly influenced by the nature of the convexity. Myocardial abnormality seems to exist primarily at the base of the IVS in HOCM, and primarily in the lower part of the IVS and LVFW in HNCM.

We retrospectively analyzed coronary arteriograms in 66 patients with hypertrophic cardiomyopathy (HCM) who underwent coronary arteriography. Four of these patients showed a large conus artery supplying the interventricular septum, and the characteristics of their echocardiograms revealed a marked interventricular septal hypertrophy. It is suggested that in some patients with HCM, the conus artery may develop in compensation for the relatively reduced coronary blood flow which is due to the hypertrophied myocardium.

1. To determine whether a persistent release of creatine kinase from the myocardium occurs in patients with hypertrophic cardiomyopathy, the activities of serum creatine kinase MM isoforms were measured in 22 patients with hypertrophic cardiomyopathy and in 14 normal control subjects. 2. Serum creatine kinase MB activity was significantly higher in patients with hypertrophic cardiomyopathy (7.8 +/- 3.8 i.u./l) than in normal control subjects (0.4 +/- 0.8 i.u./l; P less than 0.01). 3. Serum MMa, MMb and MMc activities in patients with hypertrophic cardiomyopathy were 19.4 +/- 4.1%, 26.7 +/- 2.5% and 33.5 +/- 7.0% of the total creatine kinase MM activity, respectively. These values for each isoform were significantly different from those in normal control subjects (11.3 +/- 3.0%, 21.5 +/- 4.4% and 40.7 +/- 7.0%, respectively). The MMa/MMc activity ratio was significantly higher in patients with hypertrophic cardiomyopathy (0.61 +/- 0.25) than in normal control subjects (0.30 +/- 0.10; P less than 0.01). 4. Our results indicate that a small amount of the myocardial tissue isoform of creatine kinase MM (MMa) is constantly released in many patients with hypertrophic cardiomyopathy.

The present study clarified the effect of disopyramide on left-ventricular function in patients with hypertrophic cardiomyopathy (5 obstructive type: HOCM, 21 non-obstructive type: HNCM). The systolic and early diastolic time intervals were assessed 3 hours after a single oral administration of 100-mg disopyramide. The following parameters were evaluated at rest and after administration of disopyramide: 1) left-ventricular ejection time index (LVETI), 2) pre-ejection period index (PEPI), 3) the interval from aortic component of the second heart sound to mitral valve opening (IIA-MVO), and 4) the interval from MVO to O point of apexcardiogram (MVO-O). LVETI in HNCM did not change after disopyramide but that in HOCM was significantly shortened (P less than .05). PEPI in both HOCM and HNCM was significantly prolonged after administration of disopyramide. IIA-MVO time in both HOCM and HNCM was not influenced by disopyramide. MVO-O time in both HOCM and HNCM was significantly shortened after disopyramide. These results suggest that 1) shortening of LVETI in HOCM after disopyramide seemed to be due to the decrease in pressure gradient, 2) PEPI prolongation after disopyramide reflected the decrease in myocardial contractility, and 3) shortening of MVO-O time after disopyramide indicated the improvement of left-ventricular filling. The authors conclude that disopyramide may be an important new therapeutic agent in the treatment of patients with hypertrophic cardiomyopathy.

To assess the regional cardiac adrenergic innervation in patients with essential hypertension (EHT), simultaneous iodine-123 metaiodobenzylguanidine ([123I]MIBG) and thallium-201 (201Tl) myocardial imagings were performed in five patients with EHT, seven patients with hypertrophic cardiomyopathy (HCM), and seven normal subjects. Short axial images at rest were divided into five segments: anterior, septal, posterior, lateral, and apical segments. Percent regional uptake (%RU) of 201Tl except the septal segment in patients with EHT showed no significant difference. However, the %RU of [123I]MIBG at posterior, lateral, and apical segments was significantly lower than that at anterior and septal segments in EHT. This intraimage heterogeneity of [123I]MIBG was also observed in HCM. These results suggest that there is a difference in regional adrenergic innervation of the left ventricle with myocardial hypertrophy.

A 17-year-old female patient with hypertrophic cardiomyopathy whose serum cardiac enzymes (creatine phosphokinase = CPK, lactic dehydrogenase = LDH) showed persistent elevation was presented. Percent of CPK-MB and LDH1 in 6-year-follow-up period ranged from 3.2% to 8.5%, and 58.0% to 63.2%, respectively. This finding strongly suggests the existence of a small amount of continuous myocardial necrosis for a long time. The influence of cardiac enzyme release on the heart was assessed by serial checks of electrocardiogram, echocardiogram and 201-thallium myocardial scintigram. In serial checks of electrocardiograms, markedly decreased R wave amplitude ranging between 31% and 47% was observed in II, III, aVF and V3-6. On echocardiograms, asymmetric septal hypertrophy and a narrow left ventricular cavity were observed in all echocardiograms through the follow-up period. But, in most recent apical two-dimensional echocardiograms, hourglass appearance of the left ventricle due to a distinct cavity-formation at the apex was observed. In 201-thallium single photon emission computed tomogram, hypoperfusion area markedly extended in anterior and lateral parts. These changes in electrocardiograms, echocardiograms and 201-thallium myocardial scintigrams seemed to reflect myocardial necrosis. Our case points to a mechanism for hypertrophic cardiomyopathy to change, over time, to dilated cardiomyopathy-like features.