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A 69-year-old woman presented with a harsh systolic murmur and severe anemia. Echocardiography demonstrated hypertrophic obstructive cardiomyopathy with a peak pressure gradient of 154 mmHg. Endoscopic examinations disclosed an angiodysplasia and multiple diverticula in the colon, but no active bleeding was noted in these lesions. A selective defect of large multimers of von Willebrand factor was detected by electrophoresis. After collection of anemia and Ca antagonist therapy, left ventricular obstruction was relieved and cessation of the occult gastrointestinal bleeding was obtained. This is the first report whereby acquired type 2A von Willebrand syndrome was caused by hypertrophic obstructive cardiomyopathy.

It has been demonstrated previously that clinical phenotypes of HCM (hypertrophic cardiomyopathy) caused by mutations in the cardiac MyBP-C (myosin-binding protein C) gene show late onset, low penetrance and favourable clinical course. However, we have encountered severe phenotypes in several carriers of the MyBP-C gene mutations. The aim of the present study was to screen novel MyBP-C gene mutations in patients with HCM and to investigate the genetic differences in affected subjects with severe phenotypes. The MyBP-C gene was screened in 292 Japanese probands with HCM, and a novel c.2067+1G-->A mutation was present in 15 subjects in five families. Clinical phenotypes of carriers of the c.2067+1G-->A mutation were compared with those of a previously identified Arg820Gln (Arg820-->Gln) mutation in the MyBP-C gene. The disease penetrance in subjects aged > or =30 years was 90% in carriers of the c.2067+1G-->A mutation and 61% in carriers of the Arg820Gln mutation. Sudden death occurred in four subjects from three families with the c.2067+1G-->A mutation and in two subjects from one family with the Arg820Gln mutation. Two carriers of the c.2067+1G-->A mutation had substantial hypertrophy (maximal wall thickness > or =30 mm). In contrast, two carriers of the Arg820Gln mutation had end-stage HCM. In conclusion, the c.2067+1G-->A mutation is associated with HCM with substantial hypertrophy and moderate incidence of sudden death, whereas the Arg820Gln mutation is associated with end-stage HCM. These observations may provide important prognostic information regarding the clinical practice of HCM.

The diagnostic value of various classic electrocardiographic (ECG) voltage criteria for hypertrophic cardiomyopathy (HC) has not been established in a genotyped population. This study aimed to determine the most accurate diagnostic definition of classic ECG voltage criteria for detecting carriers of HC. ECG and echocardiographic findings were analyzed in 161 genotyped subjects (97 genetically affected, 64 unaffected) from 20 families with disease-causing mutations in 4 genes. The diagnostic value of 4 voltage criteria (Cornell, Sokolow-Lyon, Romhilt-Estes, and 12-lead QRS voltage) for detecting carriers of HC was investigated. In all subjects, the Romhilt-Estes (point score > or =4) criterion and 12-lead QRS voltage (> or =240 mm) were most sensitive (37% and 36%, respectively), with high specificity (95% each), resulting in the greatest accuracy (60% and 59%, respectively). Using these criteria, in subjects without echocardiographic evidence of left ventricular hypertrophy, voltage abnormalities were found in 22.6% of carriers and 4.7% of noncarriers (p <0.01). In conclusion, these findings suggest that the Romhilt-Estes and the 12-lead QRS voltage criteria may be the most accurate diagnostic definitions for HC on the basis of molecular genetic diagnoses. Furthermore, this study demonstrated that voltage abnormalities may be found in prehypertrophic carriers. Even when genetic testing becomes widely available, it will be difficult to make genetic diagnoses in all patients with HC because of its genetic heterogeneity. Therefore, understanding the diagnostic value of classic ECG voltage criteria may be important in detecting carriers, including those without left ventricular hypertrophy.

Background: Early detection in patients with hypertrophic cardiomyopathy (HCM) is very important. Integrated backscatter (IB) provides a useful noninvasive measure of the acoustic properties of the myocardium, and may detect early myocardial changes., Methods: Thirty-four carriers who had gene mutations causing HCM were studied. The patients were divided into three groups as follows: (1) 21 patients with wall hypertrophy (Group A), (2) 7 patients with ECG abnormalities but without wall hypertrophy (Group B), and (3) 6 carriers with neither ECG abnormalities nor wall hypertrophy (Group C). All subjects underwent ECG, conventional echocardiography and acoustic densitometry. In addition, we studied subjects < or =20 years old from Groups B and C (Group B-2 and Group C-2, respectively), and compared them with control subjects with no cardiac disorders who were < or =20 years old., Results: In Group A, cyclic variations of integrated backscatter (CV-IB) in the interventricular septum and left ventricular posterior wall were significantly smaller than in Group C. The amplitude of IB in the interventricular septum and left ventricular posterior wall in Group A was significantly higher than those in Group C. Even in Group B, CV-IB in the interventricular septum was significantly smaller than those in Group C. Among patients < or =20 years old, CV-IB in the interventricular septum was significantly smaller in Group B-2 than in control subjects, while that in Group C-2 did not differ from that in control subjects., Conclusions: Changes in tissue characterization were found in the hearts of HCM gene carriers even in the absence of wall hypertrophy. These results suggest that tissue changes detectable by the acoustic densitometry methods may occur in the hearts of HCM gene carriers without wall hypertrophy, and that they may be detectable at the time of appearance of ECG abnormalities.

Background: Some patients with hypertrophic cardiomyopathy (HCM) develop left ventricular (LV) wall thinning associated with LV dilatation and systolic dysfunction. Recently, matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) were reported to be involved in ventricular remodeling, however, little is known about MMPs and TIMPs in patients with HCM., Methods and Results: Enzyme-linked immunoassays were used to measure the plasma concentrations of MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 in 11 patients with HCM accompanied by systolic dysfunction (fractional shortening (FS) <25%, group A), 17 patients with HCM who had preserved systolic function (FS> or =25%, group B), and 50 age-matched clinically healthy control subjects (mean age: 57 years). The concentration of MMP-2 in group A was significantly higher than in group B and the control subjects (1,124 +/- 84, 792 +/- 49, 809 +/- 26 ng/ml, respectively), whereas there was no significant difference between group B and the control subjects. MMP-2 concentrations significantly increased as the New York Heart Association functional class increased in patients with HCM. TIMP-2 was also significantly higher in group A patients than in group B and the control subjects (45.3 +/- 4.7, 34.6 +/- 2.2, 33.7 +/- 1.8 ng/ml, respectively), but there was no difference between group B and control subjects. TIMP-1 was significantly higher in HCM patients than in control subjects. MMP-3 and MMP-9 concentrations did not differ among the 3 groups. Both MMP-2 and TIMP-2 correlated significantly with FS and LV dimension, negatively and positively, respectively., Conclusions: These results suggest that changes in the release and activity of MMP-2 and TIMP-2 may be associated with the mechanisms responsible for cardiac remodeling in patients with HCM.

Aims: There are currently no established diagnostic criteria for the identification of abnormal Q waves in patients with hypertrophic cardiomyopathy (HCM), resulting in various definitions being applied in each previous study. The aim of this study was to determine the most accurate diagnostic definition of abnormal Q waves for HCM based on a molecular genetic diagnosis, and also to apply abnormal Q waves to the identification of preclinical carriers., Methods and Results: We applied three different criteria used in previous reports for abnormal Q waves in 148 genotyped subjects. Of the three criteria, Criterion 3 (Q wave >3mm in depth and/or >0.04s in duration in at least two leads except aVR) showed the highest sensitivity (50% in the young, 29% in adults) while retaining a high specificity (90% in the young, 97% in adults), resulting in the highest accuracy (69% in the young, 52% in adults). Using Criterion 3, abnormal Q waves were present 27.6% of preclinical carriers, and in 5.4% of non-carriers (P<0.01)., Conclusions: These findings suggest that Criterion 3 may be the most accurate diagnostic definition for HCM. Understanding the diagnostic value of abnormal Q waves may be useful in screening preclinical carriers of HCM.

Background: Hypertrophic cardiomyopathy (HCM) is caused by mutations in the genes that encode sarcomeric proteins. Although some patients with HCM have shown dilated cardiomyopathy (DCM)-like features, the relationship between genotype and histologic findings is not well known., Hypothesis: Family members with the same gene mutation may show the same histopathologic changes and clinical manifestations., Methods: Siblings with HCM caused by an Arg92Trp mutation in the cardiac troponin T gene, showing DCM-like features, were examined., Results: The patients were a 69-year-old woman and her 57-year-old brother who both died from congestive heart failure. Their autopsies revealed the same histopathologic findings in the heart. The anterior walls and interventricular septa of their hearts were replaced with extensive fibrosis and showed thinning. Myocyte hypertrophy, disarray, and thickened medial walls of the intramural coronary arteries were found. On electron microscopy, the number of mitochondria was seen to be increased and they formed many clusters., Conclusions: Patients with HCM caused by an Arg92Trp mutation in the cardiac troponin T gene may have the same histopathologic findings, which may result in DCM-like features.

Echocardiography was used to evaluate the incidence, flow dynamics and morphological characteristics of right ventricular obstruction in 91 patients with hypertrophic cardiomyopathy. Color flow mapping was used to define the sites of obstruction in the left and right ventricles. Ventricular obstruction was considered to be present if the flow velocity was less than 2.0 m/s as measured by continuous wave Doppler. The thickness of both the right ventricular free wall and anterior ventricular septum was measured to assess the magnitude and extent of hypertrophy. Right ventricular obstruction was present in 14 patients of whom 6 (43%) had left ventricular obstruction also. The right ventricular obstructions were found in the outflow tract (9 patients), mid-base septal bulge (2 patients) and apical trabecular region (3 patients). Doppler waveform was confined to systole in all patients with obstruction in the outflow tract and in one of the patients with mid-base septal bulge. Moreover, the flow wave persisted into early diastole in 4 patients, including 2 with apical trabecular obstruction. The thickness of both the right ventricular free wall and anterior ventricular septum suggested that these hypertrophied regions were the sites of right ventricular obstruction. Thus, echocardiography was useful in evaluating right ventricular obstruction in hypertrophic cardiomyopathy.

Unlabelled: Left ventricular (LV) systolic function in hypertrophic cardiomyopathy (HCM) is usually normal. Late in the disease, however, LV systolic dysfunction and dilatation are recognized. Although abnormalities in cardiac sympathetic nerve activity in patients with HCM have been demonstrated using (123)I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy, the changes of cardiac sympathetic nerve activity throughout the clinical course from typical to end-stage HCM are unclear. The objective of this study was to evaluate the relationship between abnormalities on (123)I-MIBG myocardial scintigraphy and pathophysiologic changes in patients with HCM., Methods: We performed (123)I-MIBG scintigraphy on 46 patients with HCM and 18 age-matched control subjects. The patients were categorized into 3 groups: 28 patients with normal LV systolic function (group A), 9 patients with LV systolic dysfunction (group B), and 9 patients with LV systolic dysfunction and dilatation (group C). With planar (123)I-MIBG imaging, the heart-to-mediastinum ratio for early and delayed acquisitions and the washout rate were calculated. With SPECT, polar maps of the LV myocardium were divided into 20 segments. The regional uptake and washout rate were calculated from semiquantitative 20-segment bull's-eye analysis., Results: The early uptake was significantly lower in group C than in the control group (P < 0.01). The washout rate was progressively higher in group A, group B, and group C (P < 0.01). Reduced regional early uptake was found in 2.9 +/- 3.4 (group A), 4.1 +/- 4.7 (group B), and 7.4 +/- 4.3 (group C) segments, respectively. In group C, regional early uptake was significantly reduced, predominantly in the interventricular septal wall, and regional washout rate was increased in the apex and lateral wall., Conclusion: These results suggest that cardiac sympathetic nerve abnormalities in patients with HCM may advance with development of LV systolic dysfunction and dilatation and that (123)I-MIBG myocardial scintigraphy may be a useful tool for the evaluation of pathophysiologic changes in HCM.

Objective: To evaluate the relation between QT variables and disproportion of left ventricular wall hypertrophy in patients with hypertrophic cardiomyopathy., Design: Retrospective analysis of the results of echocardiography and electrocardiography., Setting: University hospital (tertiary referral centre)., Patients: 70 patients with hypertrophic cardiomyopathy were divided into four groups according to the distribution of left ventricular wall hypertrophy on cross sectional echocardiography: group A--hypertrophy confined to the interventricular septum; group B--hypertrophy confined to the interventricular septum and left ventricular anterior wall; group C--hypertrophy confined to the interventricular septum, left ventricular anterior wall, and lateral free wall; group D--hypertrophy involving all portions of the left ventricle., Main Outcome Measures: QT intervals and QT dispersion in precordial six lead ECGs., Results: There were no significant differences in the maximum left ventricular wall thickness among the four groups, and maximum and minimum QTc intervals also did not differ. QTc dispersion was increased significantly in groups A and B compared with groups C and D. Dispersions of the interval from the J point to the end of the T wave (JTc dispersions) in groups A and B were also increased significantly compared with groups C and D. By linear regression analysis, QTc and JTc dispersions correlated with the ratio of the interventricular septal thickness to left ventricular posterior wall thickness (p = 0.0152 and p = 0.0075, respectively)., Conclusions: QT dispersion may be affected by not only electrical inhomogeneity but also by morphological inhomogeneity of the left ventricle in patients with hypertrophic cardiomyopathy.

Background: Malignant ventricular tachyarrhythmia (VT) and sudden death are serious events in hypertrophic cardiomyopathy (HCM). However, the pathophysiology of this condition is not well understood. The objective of this study was to evaluate the relationship between cardiac sympathetic nerve activity and the occurrence of VT in HCM patients. Methods and results We studied iodine 123 metaiodobenzylguanidine scintigraphy and 24-hour ambulatory electrocardiographic monitoring in 44 HCM patients, 15 with VT (group A) and 29 without VT (group B). With planar I-123 metaiodobenzylguanidine imaging, the heart-to-mediastinum ratio for early and delayed acquisition and washout rate were calculated. Polar maps of left ventricular myocardium were divided into 20 segments, and the SD of uptake and washout rate in 20 segments were calculated as indices of regional variation. The global washout rate was significantly higher in group A than in group B (26.8 +/- 6.4% vs 17.4 +/- 5.7%, P <.0001), although other parameters including heterogeneity indices did not differ. The logistic multiple regression analysis also determined that washout rate was the most powerful predictor of VT in patients with HCM., Conclusions: The occurrence of malignant VT in HCM may be associated with global cardiac sympathetic nerve activity rather than with the heterogeneity of this activity.

Objectives: We studied the clinical features of hypertrophic cardiomyopathy (HCM) caused by a novel mutation in the myosin binding protein-C (MyBP-C) gene in patients and family members of Japanese descent., Background: Previous reports have demonstrated that the clinical features of HCM associated with mutations in the MyBP-C gene include late onset and a favorable clinical course. Recently, some mutations in genes encoding sarcomeric proteins have been reported to be a cause of dilated cardiomyopathy (DCM), as well as HCM. However, mutations of the MyBP-C gene have not been reported as a cause of DCM up to now., Methods: We analyzed MyBP-C gene mutations in 250 unrelated probands with HCM and in 90 with DCM. We used electrocardiography (ECG) and echocardiography to determine clinical phenotypes., Results: We identified 17 individuals in 8 families (7 HCM, 1 DCM) with an Arg820Gln mutation in the MyBP-C gene. Overall, 2 (40%) of 5 carriers age >70 years displayed "burnt-out" phase HCM, and one of them had been diagnosed as having DCM before genetic identification. The disease penetrance in subjects age >50 years was 70% by echocardiography and 100% by ECG, and that in those age <50 years was 40% and 50%, respectively., Conclusions: Elderly patients with Arg820Gln mutation may show "burnt-out" phase HCM, and patients with this mutation may be included among those diagnosed as having DCM. Screening of patients with DCM, as well as HCM, for this mutation is of significant importance because patients with this mutation may be diagnosed clinically as having DCM.

Background: An abnormal blood pressure response (BPR) during exercise has been proposed as a risk factor for sudden cardiac death in patients with hypertrophic cardiomyopathy (HCM). Some patients with HCM show systolic dysfunction during exercise., Hypothesis: The aim of this study was to clarify the hemodynamic response during exercise and prognosis in patients with HCM and abnormal BPR., Methods: Sixty-five patients with HCM underwent radionuclide monitoring of left ventricular function and measurement of blood pressure during supine ergometer exercise. Thereafter, cardiac events were recorded for an average period of 76 months., Results: Seven of 65 patients had abnormal BPR, while the others had normal BPR. Changes of heart rate and systemic vascular resistance during exercise did not differ between the two groups. Stroke volume did not increase in the abnormal BPR group but did in the normal BPR group. During a mean follow-up period of 76 months, three of the seven patients (43%) with abnormal but only one patient (2%) with normal BPR suffered a malignant arrhythmia., Conclusions: Abnormal BPR occurred in about 11% of patients with nonobstructive HCM and was associated with a high prevalence of cardiac events. The predictor of abnormal BPR during exercise may not be an abnormal response of systemic vascular resistance and heart rate, but the lack of an appropriate increase in stroke volume.

We studied twelve patients with hypertensive left ventricular hypertrophy (LVH), 10 patients with hypertrophic cardiomyopathy (HCM) and 10 control subjects to examine the differences in coronary blood flow (CBF) dynamics between patients with hypertensive LVH and those with HCM. All subjects had normal coronary arteriograms. Measurements of CBF using Doppler Flo-Wire were performed at rest, and after infusions of acetylcholine and papaverine. The baseline CBF was significantly increased in both hypertensive LVH patients and HCM patients compared to that noted in control subjects (64.1+/-36.9, 80.0+/-38.1, 32.3+/-8.0 ml/min, respectively, p<0.01). Coronary flow reserve and endothelium-dependent vasodilatation were significantly lower in hypertensive LVH patients and HCM patients than in control subjects, but there was no significant difference between the hypertensive LVH and HCM patients themselves. In contrast, the diastolic/systolic velocity ratio at baseline was significantly lower in hypertensive LVH patients than in HCM patients (1.53+/-0.40, 6.31+/-7.50, p<0.05). Although CBF and coronary flow reserve correlated positively and negatively, respectively, with left ventricular mass index (r=0.51, -0.59, respectively), the diastolic/systolic velocity ratio at baseline did not show a significant correlation to left ventricular mass index. In conclusion, the diastolic/systolic velocity ratio differed between hypertensive LVH and HCM patients, independent of left ventricular mass. These results suggest that the difference of phasic pattern of CBF may be essential for coronary circulation in patients with hypertensive LVH and in those with HCM.

Background: Patients with hypertrophic cardiomyopathy (HCM) associated with a deletion of lysine 183 (K183del) in the cardiac troponin I (cTnI) gene suffer sudden cardiac death at all ages. However, the correlation between QT variables and sudden cardiac death in these patients remains uncertain., Hypothesis: We evaluated the correlation between QT variables and sudden cardiac death and/or ventricular tachyarrhythmia (SCD/VT) in patients with HCM associated with the cTnI mutation., Methods: We analyzed 10 probands with HCM associated with the cTnI gene K183del and their family members. The subjects were divided into three groups: Group A (n = 7), mutation carriers with SCD/VT; Group B (n = 16), mutation carriers without SCD/VT; Group C (n = 24), no mutation carriers. QT intervals were corrected using Bazett's formula., Results: Maximum QTc and corrected QT dispersion were significantly longer in Groups A and B than in Group C. However, there were no differences in either parameter between Groups A and B. On the contrary, the peak-to-end interval of T wave/QT interval in V5 (Tpe) in Group A was significantly longer than that in Groups B and C. Logistic regression analysis revealed that Tpe was a good clinical predictor for SCD/VT in patients with HCM in this study., Conclusions: These results suggest that Tpe rather than QT dispersion may be one of the best predictors for SCD/VT in patients with HCM associated with the K183del mutation in the cTnI gene.

Background: Lysine 183 deletion in the cardiac troponin I gene is 1 of the mutations that causes hypertrophic cardiomyopathy (HCM). However, the clinical course and determinants of poor prognosis in patients with this mutation have not been well established., Methods and Results: We analyzed 10 probands with HCM caused by this mutation and their family members. Forty-six of these 79 subjects were found to be carriers, and 33 were non-carriers. All non-carriers had a percent fractional shortening (%FS) of >25% at all ages. By contrast, 7 of 24 carriers >40 years of age had a %FS of <25%, and no carriers <40 years of age had a %FS of <25%. The change in interventricular septal thickness and the change in %FS were significantly correlated (R = 0.758; P =.0017)., Conclusion: These results suggest that about 30% of patients with HCM caused by a lysine 183 deletion mutation in the cardiac troponin I gene have systolic dysfunction develop after 40 years of age, and that patients with this mutation whose interventricular septal thickness shows a serial decrease should be followed-up closely for development of systolic dysfunction.

Background: Deletion of lysine 183 (K183del) in the cardiac troponin I (cTnI) gene is one of the mutations that causes hypertrophic cardiomyopathy (HCM). However, the phenotypic expression of this mutation has not been well established., Methods and Results: We analyzed 10 probands with HCM associated with a K183del in the cTnI gene, as well as their family members. Forty-seven of these 80 subjects were found to be carriers and 33 were noncarriers. In the carrier subjects, electrocardiogram (ECG) abnormalities were initially noted during the early teenage years preceding echocardiographic abnormalities. Abnormal Q waves were found first and most frequently compared with other ECG abnormalities. Abnormal Q waves were frequently observed in leads II, III, aVF, V5, and V6 in teenage patients, whereas they were observed in many leads in patients >20 years old. The youngest of the 11 patients who had sudden cardiac death among studied pedigrees was a 14-year-old boy., Conclusions: These results suggest that the first phenotypic manifestation in patients with HCM associated with a K183del mutation in the cTnI gene is abnormal Q waves in leads II, III, aVF, V5, and V6 during the early teenage years. To prevent sudden death in family members of patients with this mutation, it may be necessary to genetically diagnose it before age 10 years and to pay careful attention to any development of abnormal Q waves.

Unlabelled: Cardiac sympathetic nerve activity is changed in patients with hypertrophic cardiomyopathy (HCM). However, the relationship between heterogeneity of this activity and systolic left ventricular dysfunction in patients with HCM is not well established. This study was performed to evaluate the sympathetic nerve activity in various cardiac regions and to investigate the relationship between cardiac dysfunction and heterogeneity of the cardiac sympathetic nerve activity in patients with HCM., Methods: Cardiac sympathetic nerve activity was evaluated in 25 patients with HCM and 10 control subjects using planar imaging and SPECT by 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. With planar 123I-MIBG imaging, the heart-to-mediastinum activity ratios (H/M), at early (20 min) and delayed (3 h) acquisition, and the washout rate were calculated. Polar maps of the left ventricular myocardium were divided into 20 segments, and the dispersion (maximal to minimal values) and SD of uptake and the washout rate in 20 segments were calculated., Results: The early H/M did not differ between the 2 groups. The delayed H/M was significantly lower and the washout rate of the whole heart was significantly higher in the HCM group than those in the control group. In patients with HCM, the delayed H/M, early uptake dispersion, and SD of early uptake showed good correlation with the left ventricular end-diastolic and end-systolic dimensions and the percentage of fractional shortening. A stepwise regression analysis revealed that the SD of early uptake was a powerful determinant for the percentage of fractional shortening in patients with HCM., Conclusion: These results suggest that the heterogeneity of regional cardiac sympathetic nerve activity may be correlated with cardiac dysfunction in patients with HCM.

Background: QT dispersion (QTD) reflects regional variation of ventricular repolarization. However, the relationship between QTD and the regional variation of cardiac sympathetic nerve activity in hypertrophic cardiomyopathy (HCM) is not yet elucidated., Methods: Cardiac sympathetic nerve activity was evaluated in 25 patients with HCM by iodine 123 metaiodobenzylguanidine (MIBG) myocardial scintigraphy. With planar MIBG imaging, heart and mediastinum ratios (H/M) at early (20 minutes) and delayed (3 hours) acquisition and the washout rate (WR) were calculated. Polar maps of left ventricular myocardium were divided into 20 segments. The SD of early uptake (EU-SD), delayed uptake (DU-SD), and WR (WR-SD) in 20 segments as indices of regional variation were calculated. QT intervals were corrected by use of the Bazett formula., Results: Maximum QTc correlated positively with H/M early, WR, and left ventricular wall thickness (LVWT). Minimum QTc correlated positively with WR and LVWT. Corrected QTD (QTDc) correlated negatively with EU-SD, DU-SD, and WR-SD and positively with the interventricular septal thickness/posterior wall thickness ratio. Stepwise regression analysis revealed that the most powerful determinants for maximum QTc, minimum QTc, and QTDc were WR, LVWT, and EU-SD, respectively., Conclusions: QTD correlated negatively rather than positively with the regional variability index of cardiac sympathetic nerve activity. These results suggest that increased QTD in patients with HCM may not reflect increased heterogeneity of cardiac sympathetic nerve activity.

Background: Mutations in the cardiac troponin T gene causing familial hypertrophic cardiomyopathy (HCM) are associated with a very poor prognosis but only mild hypertrophy. To date, the serial morphologic changes in patients with HCM linked to cardiac troponin T gene mutations have not been reported., Hypothesis: The aim of this study was to determine the long-term course of patients with familial HCM caused by the cardiac troponin T gene mutation, Arg92Trp., Methods: In all, 140 probands with familial HCM were screened for mutations in the cardiac troponin T gene., Results: The Arg92Trp missense mutation was present in 10 individuals from two unrelated pedigrees. They exhibited different cardiac morphologies: three had dilated cardiomyopathy-like features, five had asymmetric septal hypertrophy with normal left ventricular systolic function, one had electrocardiographic abnormalities without hypertrophy, and one had the disease-causing mutation but did not fulfill the clinical criteria for the disease. The mean maximum wall thickness was 14.1 +/- 6.0 mm. The three patients with dilated cardiomyopathy-like features had progressive left ventricular dilation. Three individuals underwent right ventricular endomyocardial biopsy. There was a modest degree of myocardial hypertrophy (myocyte diameter: 18.9 +/- 5.2 microm), and minimal myocardial disarray and mild fibrosis were noted., Conclusion: The Arg92Trp substitution in the cardiac troponin T gene shows a high degree of penetrance, moderate hypertrophy, and early progression to dilated cardiomyopathy in Japanese patients. Early identification of individuals with this mutation may provide the opportunity to evaluate the efficacy of early therapeutic interventions.

Background: The relationship between the extent of myocardial interstitial fibrosis, the percentage of each type of collagen, and cardiac function in patients with hypertrophic cardiomyopathy (HC) has not been established., Hypothesis: The study aimed to establish that increases in some types of collagen may correlate with cardiac dysfunction., Methods: Mallory-Azan staining and immunohistochemical staining by the avidin-biotin-complex (ABC) method using anticollagen antibodies were performed on the myocardial biopsy specimens in 35 patients with HC, and the percentage and type of collagen present was determined. Left ventricular (LV) function was evaluated by cardiac catheterization and ventriculography., Results: The percentage of myocardial interstitial fibrosis correlated highly with indices of LV diastolic and systolic function. The amount of type III collagen correlated significantly with the peak negative dp/dt, the rapid filling volume/stroke volume, and the ejection fraction (EF). Significant correlations also were noted between the amount of type VI collagen and peak negative dp/dt, peak positive dp/dt, and EF. Type I collagen did not correlate with any of the LV function indices, and type IV collagen correlated only with peak ejection rate. Type V collagen did not accumulate substantially in the myocardial interstitium., Conclusions: The progression of myocardial interstitial fibrosis in the HC heart adversely impacts both the diastolic and systolic function of the LV. Increases in the percentage of type III and VI collagen correlate with cardiac dysfunction.

Objectives: We sought to characterize stress-induced left ventricular systolic dysfunction in patients with hypertrophic cardiomyopathy (HCM)., Background: Myocardial ischemia and diastolic dysfunction occur in patients with HCM. We hypothesized that, in the setting of transient myocardial ischemia, left ventricular systolic dysfunction occurs during exercise and dobutamine stress., Methods: We studied 39 patients with HCM but without obstructive symptoms at rest or coronary artery disease. A continuous ventricular function monitor equipped with cadmium telluride detectors (VEST) was used to evaluate left ventricular function during supine bicycle ergometer exercise. Dobutamine stress echocardiography (DSE) was also performed. The left ventricular ejection fraction (LVEF) and regional wall motion were determined from echocardiographic images., Results: Changes in the LVEF correlated between exercise and dobutamine stress (r = 0.643, p < 0.0001). The LVEF decreased more than 5% at peak exercise in 17 of patients (group II), while the other patients had normal responses (group I). New regional wall motion abnormalities during dobutamine infusion were detected in 18 of 110 (16.4%) segments in group I and 42 of 85 (49.4%) segments in group II. Decreased or unchanged regional wall motion occurred more frequently in hypertrophied segments than in nonhypertrophied segments (p < 0.0001). There were significant inverse correlations between the LVEF responses during both stresses and the number of abnormal segments noted during dobutamine stress in all patients (VEST: p < 0.005; DSE: p < 0.0005). Signs of left ventricular obstruction were observed in 11 of 39 patients during DSE. However, there was no significant correlation between the LVEF response and the dobutamine-induced left ventricular pressure gradient., Conclusions: Exercise-induced systolic dysfunction occurred in 50% of patients with HCM. In these patients, regional wall motion abnormalities were present in hypertrophied segments.

Background: Mutations that cause hypertrophic cardiomyopathy (HCM) have been identified in 9 genes that code proteins in the sarcomere. Previous reports have demonstrated that cardiac troponin I (cTnI) gene mutations may account for familial HCM; however, the clinical characteristics and prognosis of patients with HCM caused by cTnI gene mutations are not known., Methods and Results: We analyzed cTnI gene mutations in 130 unrelated probands with HCM and their families to clarify the genotype-phenotype correlations. We identified 25 individuals in 7 families with a Lys183 deletion (Lys183 del) mutation in exon 7 of the cTnI gene. The disease penetrance in subjects aged >20 years was 88% by echocardiography and 96% by ECG. Sudden death occurred in 7 individuals of 4 families at any age. Overall, 7 (43.8%) of 16 individuals aged >40 years had left ventricular systolic dysfunction, and 3 (18.8%) displayed dilated cardiomyopathy-like features. Of affected individuals, 4 of 5 individuals aged >40 years followed by echocardiography showed septal thinning and decreased fractional shortening during >5 years of follow-up., Conclusions: The Lys183 del mutation in the cTnI gene in patients with HCM is associated with variable clinical features and outcomes. HCM caused by the Lys183 del mutation has a significant disease penetrance. This mutation is associated with sudden death at any age and dilated cardiomyopathy-like features in those aged >40 years. However, it remains unclear whether screening of families with HCM for this mutation will be useful in patient management and counseling.

Background: ST-segment depression is common in patients with hypertrophic cardiomyopathy (HCM). However, it is not clear whether exercise-induced ST-segment depression in patients with HCM and patent coronary arteries is associated with changes in left ventricular function., Methods: Left ventricular function was continuously evaluated in 53 patients with nonobstructive HCM during supine ergometer exercise with a radionuclide ventricular function monitor equipped with a cadmium telluride detector. On the basis of the ST-segment changes during exercise, the patients were divided into 2 groups: group N had no ST-segment depression, and group D had >/=0.1 mV ST-segment depression., Results: Exercise duration, blood pressure, heart rate, and rate-pressure product during exercise did not differ between the 2 groups. End-diastolic volume at rest and at peak exercise did not differ between groups D and N. In contrast, the end-systolic volume in group N decreased during exercise, whereas in group D it increased. As a result, the left ventricular ejection fraction in group D decreased from 70% +/- 7% to 59% +/- 15% (P <.0001), whereas ejection fraction in group N increased from 65% +/- 8% to 71% +/- 11% (P =.0002). There was a strong correlation between exercise-induced ST-segment depression and changes in ejection fraction from rest to peak exercise (P <.0001)., Conclusions: These results suggest that the exercise-induced ST-segment depression seen in patients with nonobstructive HCM is associated with systolic dysfunction during exercise.

Background: In patients with essential hypertension (HT), proportional (symmetric) left ventricular hypertrophy (LVH) is common. In contrast, hypertrophic cardiomyopathy (HCM) is characterized by disproportional LVH and, in particular, asymmetric septal hypertrophy (ASH); however, some hypertensive patients also develop ASH. It has not been determined whether such cases represent a distinct type of hypertensive LVH or HCM combined with hypertension., Hypothesis: The study was undertaken to evaluate sympathetic activity in the interventricular septum in patients with HT and ASH or in patients with HCM., Methods: The patients were evaluated by I-123 meta-iodobenzylguanidine (MIBG) and thallium-201 (201Tl) single-photon emission computed tomography (SPECT), respectively. They were divided into three groups: patients with essential HT and symmetric septal hypertrophy (Group A), patients with HT and ASH (Group B), and patients with HCM and ASH (Group C)., Results: Compared with the lateral wall, early uptake of MIBG in the septum was significantly higher in Group B than in Group A, but not significantly different between Groups A and C. Compared with the lateral wall, early uptake of 201Tl in the septum did not differ among the three groups. No significant difference in the MIBG clearance in the lateral wall was seen among the three groups. By contrast, MIBG clearances in the septum and apex were significantly greater in Group C than in Groups A and B. There was an inverse correlation between systolic thickening and MIBG clearance in the septum., Conclusion: These findings suggest that sympathetic activity in the septum differs between patients with HT and ASH and patients with HCM.

To evaluate the relationship between myocardial scintigraphic abnormalities based on (123)I-radioiodinated 15-(p-iodophenyl)-3(R, S)-methylpentadecanoic acid (BMIPP) uptake and cardiac function and the relationship between these abnormalities and long-term prognosis in patients with hypertrophic cardiomyopathy (HCM), 27 patients with nonobstructive HCM underwent BMIPP myocardial scintigraphic study, echocardiography, and exercise radionuclide study. Based on the extent of BMIPP scintigraphic defects, the patients were divided into two groups: Group A (n = 19) patients had no or small defects, and group B (n = 8) patients had moderate to large defects. Cardiac events were recorded over an average period of 64 months. The left ventricular end-diastolic and end-systolic dimensions were significantly greater in group B than in group A. The fractional shortening in group B was less than in group A (p = 0.0002). The BMIPP score and fractional shortening at rest correlated significantly (p < 0.05). The BMIPP score and the change in ejection fraction between rest and peak exercise correlated significantly (p < 0.05). While only 1 cardiac event occurred in the 19 patients in group A during a mean follow-up period of 64 months, 6 cardiac events occurred in the 8 patients in group B. The 84-month event-free survival rate was 94.4% in group A and 14.6% in group B (p < 0.01). These results suggest that patients with HCM and moderate to large defects as assessed by BMIPP myocardial scintigraphy have decreased cardiac function and a poor prognosis., (Copyright 2000 S. Karger AG, Basel)

We investigated the reliability and reproducibility of an image-analyzing system run on a personal computer for measurement of myocardial interstitial fibrosis. Measurements of myocardial interstitial fibrosis in right ventricular endomyocardial biopsies obtained from patients with hypertrophic cardiomyopathy determined by this image-analyzing system were compared with measurements determined by the point-counting method. We also investigated the correlation between measurements of interstitial fibrosis obtained by image analysis and biochemical measurements of myocardial levels of hydroxyproline in normal and cardiomyopathic hamsters. The intra- and interobserver variability were significantly lower for measurements obtained by the image-analyzing system than for measurements obtained by the point-counting system. Reproducibility was superior with the image-analyzing method. The rate of myocardial interstitial fibrosis determined by the computer image-analyzing method was positively correlated with the hydroxyproline measurement (r = 0.89). Our results suggest that an image-analyzing system using a personal computer provides reproducible results with a high level of reliability.

Autonomic nervous dysfunction has recently been considered to be an etiological factor in syncope and sudden death in cases of hypertrophic cardiomyopathy. However, the precise mechanism is still unknown. A 73-year-old woman with obstructive hypertrophic cardiomyopathy was hospitalized with complaints of impaired consciousness; faintness 3 to 4 h after meals, lightheadedness while walking, and syncope during and after defecation and micturition. Faintness was induced by alimentary hypoglycemia related to gastrectomy performed 5 years previously. Lightheadedness and syncope were accounted for by autonomic nervous failure combined with an impairment of alpha 1-adrenoceptor in vasoconstriction and the carotid sinus hypersensitivity which accompanied preceding events such as abdominal pain, defecation and micturition, which could enhance the vagally-mediated baroreceptor reflex.

123I 15-(p-iodophenyl)-3(R,S)-methylpentadecanoic acid (BMIPP) myocardial scintigraphy and exercise stress thallium (TI)-201 myocardial scintigraphy were performed in 17 patients with hypertrophic cardiomyopathy (HCM) to evaluate the existence of abnormal fatty acid metabolism in the myocardium and the relationship between this abnormality and myocardial ischemia. On the BMIPP scintigraphy, abnormalities were found in 12 of 17 patients (71%). Five patients showing no abnormalities on the BMIPP scintigraphy had well preserved exercise tolerance and had longer exercise duration than the others showing BMIPP scintigraphic abnormalities (P < 0.001). On the evaluation of the segmental abnormalities, TI scintigraphic abnormalities were found in 15 (50%) of 30 segments showing decreased accumulation of BMIPP. On the other hand, BMIPP scintigraphic abnormalities were found in all segments showing decreased accumulation of TI. The sites of decreased accumulation of BMIPP and TI were in good agreement with the sites of wall hypertrophy. Four patients showing BMIPP scintigraphic abnormalities and no T1 scintigraphic abnormalities were in higher New York Heart Association functional classes, had shorter exercise duration (P < 0.05) than the 5 patients showing no abnormalities on either scintigraphy. It is concluded that abnormalities of fatty acid metabolism in the heart are detected at a high rate in patients with HCM, and may be due in part to factors other than myocardial perfusion disturbance.

The flow dynamics of midventricular obstruction in hypertrophic cardiomyopathy were evaluated with intravenous injection of sonicated albumin in 14 patients with vague velocity profiles on conventional continuous wave Doppler echocardiography. Nine patients (64%) demonstrated a clear envelope after the injection. The following three patterns of continuous Doppler profiles were obtained : 1) a monophasic flow profile with a brief and sharp increase in peak velocity in late systole, 2) a late-peaking systolic flow and a diastolic flow during isovolumic relaxation time emerging after sonicated albumin injection (biphasic flow profile), 3) a biphasic flow profile with systolic and diastolic flow waves having a notch around the second heart sound. The calculated peak pressure gradients from the modified Bernoulli equation did not differ significantly with the presence of diastolic wave or the site of obstruction. Therefore, these are independent parameters for estimating the severity of midventricular obstruction. Therefore, these are independent parameters for estimating the severity of midventricular obstruction. The sonicated albumin method was useful in delineating the flow profile, and thus evaluating the hemodynamics of midventricular obstruction in hypertrophic cardiomyopathy.

Unlabelled: The cardiac functional response to exercise in patients with nonobstructive hypertrophic cardiomyopathy (HCM) was evaluated using a continuous ventricular function monitor with a cadmium telluride detector (CdTe-VEST)., Methods: Supine ergometric exercise was performed under CdTe-VEST monitoring in 41 patients with nonobstructive HCM (34 men and 7 women, age 18-72 yr, mean 51 yr) and 15 patients without cardiac disease (9 men and 6 women, age 36-56 yr, mean 49 yr)., Results: Although 20 of 41 patients with HCM maintained a LVEF above baseline at peak exercise (Group A), 21 did not show an EF increase at peak exercise (Group B). Exercise duration and work load in Group A were longer and higher, respectively, than in Group B. Resting EF in Group B (72 +/- 7.7%) was significantly higher than that in Group A (65 +/- 8.2%) and the control group (62 +/- 5.9%). The EF increase from baseline to EF overshoot during recovery and the time to EF overshoot were lower and longer, respectively, in Group B than in Group A and the control group. Septal wall thickness and the septum-to-posterior-wall-thickness ratio between Groups A and B were not different. ST-segment depression was observed in all 21 Group B patients and in 8 of the Group A patients., Conclusion: In patients with nonobstructive HCM, left ventricular dysfunction during exercise and during recovery was frequently observed but was not related to the degree of septal wall hypertrophy. The CdTe-VEST is a useful means to evaluate left ventricular functional reserve to exercise in patients with HCM.

Basement membrane of myocytes from patients with hypertrophic cardiomyopathy who died suddenly, seemed to be discontinuous by immunohistochemical methods. With the use of the sandwich immunoassay technique, we determined the frequency of type IV collagen and its influence on functional abnormality in 31 patients with hypertrophic cardiomyopathy and controls. Hypertrophic cardiomyopathy exhibited significantly increased serum type IV collagen compared with controls. A significant correlation was observed between serum type IV collagen and fractional shortening (r = -0.42 p < 0.05), and end-diastolic volume (r = 0.40 p < 0.05), DT (r = -0.50 p < 0.05). These data suggest that serum type IV collagen enhances clusters of cell-surface type IV collagen, including an alteration of the cytoskeleton, which may account for functional abnormalities in hypertrophic cardiomyopathy. Considering the fact that microscopic examination is unable to resolve the structure of the myocardial basement membrane, measurement of serum type IV collagen is thought to be useful in the diagnosis of myocardial basement membrane injury and the progression of hypertrophic cardiomyopathy.

123I-labelled 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) myocardial single photon emission computed tomography (SPECT) was performed in 17 patients with hypertrophic cardiomyopathy, and was compared with 201Tl exercise stress myocardial perfusion SPECT images. Fourteen patients showed asymmetrical hypertrophy, and three demonstrated apical hypertrophy. SPECT was performed 20 min and 3 h after injection of 111 MBq 123I-BMIPP at rest. Exercise stress 201Tl SPECT was performed at 10 min and 3 h after injection and was compared with BMIPP imaging. In 13 patients BMIPP accumulation in the hypertrophied area in the 20 min image was lower than that of 3 h 201Tl uptake. Interestingly, six patients demonstrated 201Tl redistribution in the region where the uncoupling of BMIPP uptake at 20 min and 201Tl accumulation at 3 h after exercise was observed. These findings suggest that impaired fatty acid metabolism or utilization in hypertrophic myocardium and ischaemia or impaired coronary flow reserve may be one of the causes of the abnormality of fatty acid accumulation.

In our previous study, we reported that the left atrial contribution to left ventricular filling was decreased to a greater extent in patients with hypertrophic cardiomyopathy than in those with myocardial infarction or normal subjects during lower body negative pressure (LBNP)-induced preload reduction. To clarify the factors responsible for this difference in response, we examined changes in left atrial hemodynamic and M-mode echocardiographic indices during LBNP in patients with hypertrophic cardiomyopathy and myocardial infarction. The same degree of decrease in left atrial preload and afterload was found in both groups. Moreover, we detected no change in the left atrial fractional shortening during left atrial systole (%LAFS) in patients with hypertrophic cardiomyopathy, in contrast to a significant increase found in patients with myocardial infarction. These results showed that the greater decrease in the left atrial contribution in hypertrophic cardiomyopathy during LBNP could not result from differences in changes in left atrial preload or afterload, suggesting that it may be closely related to limitations in the compensatory augmentation of left atrial contractility.

To determine whether asymmetrical septal hypertrophy (ASH) in patients with essential hypertension (HT) is a type of hypertensive left ventricular (LV) hypertrophy or hypertrophic cardiomyopathy (HCM) combined with HT, we investigated a group of 7 hypertensive patients with ASH compared with 12 HCM patients and 10 healthy controls using radionuclide angiography and right ventricular endomyocardial biopsy. The LV time-volume curve and its first and second derivative curves were constructed from cardiac output and time-activity curves constructed by combined forward and reverse-gating from the R wave. The LV wall thickness and ejection fraction were significantly greater in both the HT and HCM groups than in the control group, whereas there were no differences in these indices between the HT and HCM groups. Rapid filling volume index and rapid filling fraction showed significantly lower values in the HCM group than in the control group (p < 0.005). In contrast to the HCM group, these indices in the HT group did not differ from those in the control group. The time to peak filling rate was prolonged in the control, hypertension, and HCM groups in increasing order. Histopathological study revealed a higher incidence of myocardial cell disarray in the HCM than in the HT group. The above results suggest that ASH in hypertensive patients is a type of hypertensive LV hypertrophy.

Objective: To investigate left atrial chamber stiffness and its influence on left atrial and left ventricular functions in hypertrophic cardiomyopathy., Design: Prospective study., Setting: Department of internal medicine in a university teaching hospital., Patients: Five control subjects, six patients with essential hypertension, and 11 patients with hypertrophic cardiomyopathy., Interventions: Measurement of left atrial pressure by a tip micromanometer and of real-time left atrial volume from left atrial cineangiograms., Main Outcome Measure: Left atrial stiffness constant determined by fitting the ascending limb of the v loop of the left atrial pressure-volume relation to an exponential curve., Results: The mean (SD) left atrial chamber stiffness constant was significantly larger in patients with hypertrophic cardiomyopathy than in controls (0.063 (0.018) v 0.041 (0.006), p < 0.05) and was correlated with left ventricular wall thickness (r = 0.560, p < 0.01). Left atrial reservoir volume (left atrial emptying volume before atrial contraction) was significantly smaller in patients with hypertrophic cardiomyopathy than in the controls (7.3 (2.1) v 12.5 (4.4) ml/m2, p < 0.01) and was inversely correlated with the left atrial chamber stiffness constant (r = -0.598, p < 0.01). The cardiac index was inversely correlated with the left atrial chamber stiffness constant (r = -0.542, p < 0.01)., Conclusions: Left atrial chamber stiffness was increased in patients with hypertrophic cardiomyopathy and this affected the left atrial reservoir function. This may in turn have affected cardiac output.

Objective: To investigate the relation between regional myocardial sympathetic nerve activity and the electrocardiographic and cardiac functional changes in hypertrophic cardiomyopathy., Design: A retrospective study to compare the findings of myocardial scintigraphy with iodine-123 metaiodobenzylguanidine (MIBG) and the serial electrocardiographic changes., Setting: Myocardial scintigraphy was performed with iodine-123 MIBG and thallium-201 and single photon emission computed tomography (SPECT) in the division of nuclear medicine of Kanazawa University Hospital. Both SPECT studies were performed within a week., Patients: 22 patients with hypertrophic cardiomyopathy classified according to their serial electrocardiographic changes--namely, 15 patients with an increase in or the appearance of a negative T wave (group A) and seven patients with a conduction disturbance or a decrease in or disappearance of the negative T wave (group B). The mean follow up period was 45 (range 12-143) months., Results: Group B showed a high rate of decreased activity or defects in MIBG uptake compared with group A (p less than 0.005). The areas of decreased activity or defects corresponded with the hypertrophied portion of the left ventricular wall. Although the early myocardial uptake (MIBG: thallium ratio) was similar in both groups, the mean (SD) MIBG clearance rate was significantly higher (p less than 0.05) in group B (0.25 (0.17)) than in group A (0.10 (0.15))., Conclusion: Abnormalities of regional myocardial sympathetic nerve activity may be important in patients with hypertrophic cardiomyopathy and suspected progression of myocardial damage.

In patients with hypertrophic cardiomyopathy (HCM) and essential hypertension (HT), left ventricular dysfunction in early diastole which is associated with left atrial contraction plays an important role in left ventricular filling. To evaluate left atrial booster pump function, we analyzed left atrial preload (left atrial pressure at the end of diastasis; LAPd, left atrial volume index at the end of diastasis; LAVd), left atrial afterload (left ventricular end-diastolic pressure; LVEDP, left ventricular chamber stiffness constant; K), and left atrial ejection indices (left atrial ejection fraction during atrial contraction; LAEF, left atrial ejection volume index during atrial contraction; ACVI). The study subjects consisted of control subjects (n = 5), HT patients (n = 6), and HCM patients (n = 11). The left ventricular wall was significantly thicker in the HT and HCM groups. The left ventricular rapid filling volume index was less in the HT group, and significantly less in the HCM than in the control group. LAPd and LAVd were greater in the HT group than in the control group, and greater in the HCM group than in the HT group. LVEDP and K were greater in the HT group than in the control group, and significantly greater in the HCM group than in the other 2 groups. ACVI was greater in the HT group than in the control group, but in the HCM group, ACVI was significantly less than in the HT group and did not differ significantly from that in the control group. LAEF was significantly less in the HCM group than in the other 2 groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The characteristic of myocardial damage in hypertrophic cardiomyopathy (HCM) was evaluated as to whether the damage is limited to the hypertrophied wall or extends throughout the entire wall. The myocardial damage was detected by exercise thallium-201 (Tl-201) scintigraphy and was evaluated using circumferential profile analysis, calculation of initial uptake and washout rate. Eleven patients with asymmetrical hypertrophy (ASH), whose septal and posterior wall thickness ratio exceeded 1.3 on left ventriculography and biventriculography, and 13 age-matched control subjects without heart disease were studied. The mean values of initial uptake in both groups did not differ significantly, but the washout rate for the entire heart was significantly decreased only in the HCM group (p < 0.05). All of the regional washout rates (antero-septal, apical and postero-lateral) were significantly decreased in the HCM group (p < 0.05), without any difference between the hypertrophied wall and the non-thickened free wall being noted. These results demonstrated that the analysis of myocardial damage by exercise Tl-201 scintigraphy using calculation of the washout rate is a very sensitive means of detecting myocardial damage in HCM, and that such myocardial damage is not restricted to the hypertrophied wall, but rather extends to the entire wall, including the free wall which is not thickened.

To investigate left atrial (LA) booster pump function in hypertrophic cardiomyopathy (HC), LA and left ventricular pressure-volume loops were estimated in 5 control subjects, 6 patients with essential hypertension and 11 patients with HC. Investigation of LA preload revealed that LA pressure and volume immediately before LA contraction were both increased in patients with hypertension (10 +/- 5 mm Hg, 71 +/- 19 ml/m2) compared with control subjects (7 +/- 1 mm Hg, 59 +/- 6 ml/m2), and even more increased in patients with HC (16 +/- 7 mm Hg, 81 +/- 25 ml/m2). Investigation of LA afterload revealed that the left ventricular chamber stiffness constant was higher in patients with hypertension (0.035 +/- 0.015) than in control subjects (0.028 +/- 0.009), and even more increased in patients with HC (0.056 +/- 0.017). LA stroke work index was higher in patients with hypertension (116 +/- 34 mm Hg.ml) and HC (115 +/- 19 mm Hg.ml) than in control subjects (87 +/- 23 mm Hg.ml). Investigation of LA ejection revealed that LA stroke index was higher in patients with hypertension (24 +/- 5 ml/m2) than in control subjects (18 +/- 4 ml/m2) and patients with HC (18 +/- 2 ml/m2), and LA ejection fraction was lower in patients with HC (23 +/- 6%) than in control subjects (32 +/- 7%) and patients with hypertension (34 +/- 8%). In patients with HC, LA function curve showed a shift to the lower right, and LA stroke index was inversely correlated (r = -0.76) with LA afterload. This study suggests that LA booster pump failure due to LA afterload mismatch exists in HC.

An autopsy case of hypertrophic obstructive cardiomyopathy (HOCM), in which the clinical features of dilated cardiomyopathy (DCM) developed after 10 years is described. Three serial left ventriculograms (LVG) and bi-ventriculograms (BVG) were performed during the 10-year follow-up. At the time of the first observation, the ECG revealed a giant negative T wave (GNT) in V5 (-1.5mV) and high voltage (SV1 + RV5 = 8.1mV). The LVG and BVG showed concentric left ventricular wall hypertrophy and a pressure gradient in the left ventricular out-flow tract. However, follow-up studies disclosed resolution of the GNT with decreased high voltage. All wall thicknesses and the ejection fraction were significantly decreased and the wall motion was reduced serially. These findings were consistent with the clinical profile of DCM. At autopsy, the heart weighed 610 g and showed dilated change of the left ventricular cavity. Significant myocardial fibrosis, bizarre myocardial hypertrophy with disorganization (BMHD) and severe narrowing of the intramural small arteries due to intimal thickening were found in the left ventricular wall, especially in the anterior and interventricular septal wall. This autopsy case suggests that some cases of HCM, with serial disappearance of the deep negative T wave and high voltage, deteriorate to the clinical profile of DCM.

Myocardial scintigraphy with 123I-meta-iodobenzylguanidine (MIBG) and thallium-201 (201Tl) was performed in 29 patients with hypertrophic cardiomyopathy (HCM) using whole-body scintigraphy and single-photon emission computed tomography (SPECT). Nonhypertensive patients were classified into three groups according to the septal thickness determined by ultrasonography; group 1 (wall thickness less than 16 mm, n = 5), group 2 (from 16 to 20 mm, n = 12) and group 3 (greater than 20 mm, n = 4). The regional myocardial uptakes of both 201Tl and 123I-MIBG (percent of injected dose/cm3 myocardium) were higher in the more hypertrophic septa. However, when regional MIBG uptake at 3 hours was divided by the 201Tl uptake to calculate the MIBG uptake per unit of blood flow, the hypertrophic septa showed lower mean values--0.39 +/- 0.23 and 0.50 +/- 0.10 in groups 3 and 2, respectively (p less than 0.1 compared with 0.69 +/- 0.20 in group 1). The regional MIBG clearance rate in the septum was significantly higher in group 3 compared with group 1 (13.4 +/- 8.0%/hr versus 1.5 +/- 6.2%/hr, p less than 0.05). The uptake and 123I-MIBG clearance rate in the lateral wall showed a similar tendency. Myocardial uptake determined by whole-body scintigraphy was slightly increased in group 2 (3.5 +/- 0.6%, p less than 0.05) compared with group 1 (2.7 +/- 0.8%); however, it was lower in group 3 (2.7 +/- 0.4%). Myocardial 123I-MIBG distribution demonstrated various patterns in comparison with 201Tl distribution, suggesting that flow-independent changes in sympathetic innervation or activity may exist in patients with HCM.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study was performed to clinically clarify the pathogenesis of hypertensive cardiac hypertrophy (HT) and hypertrophic cardiomyopathy (HCM). Exercise thallium-201 (Tl-201) myocardial scintigraphy using a bicycle ergometer was performed for controls, HT and HCM. The scintigrams were evaluated by the circumferential profile analysis. Furthermore, the changes in Tl-201 dynamics in exercise Tl-201 scintigraphy with verapamil injections were examined in these three groups. Analysis of exercise Tl-201 scintigraphy without verapamil injections showed that the initial uptake did not differ among the three groups, but the washout rate three hours after the Tl-201 injections (WR3) did differ among the three groups. Although the WR3 of HT did not differ from that of the controls, the WR3 of HCM was lower than that of the controls. The WR3 with and without verapamil were compared. Although the WR with verapamil injections equalled that without verapamil injections in the controls and HT, the WR3 with verapamil injections decreased more than did that without verapamil injections in HCM. As an index of great and rapid changes in circulation, the washout rate one hour after the Tl-201 injection (WR1) was calculated. The WR1 without verapamil did not differ among the three groups and did not differ from that with verapamil injections in each group. These results suggest that Tl-201 dynamics of HT differ from those of HCM and lowering of the WR3 in HCM may not be caused by disturbance in the microcirculation, but rather by disturbance of Tl-clearance through the cell membrane and its cytoplasm.

Single-photon emission computed tomography was performed in 29 patients with hypertrophic cardiomyopathy (HCM) using 123I-metaiodobenzylguanidine (MIBG). Segmental myocardial uptake of MIBG and 201T1 was calculated in 21 patients with primary HCM without history of hypertension. Septal thickness was measured by echocardiography and the relationship to septal MIBG uptake was studied. Initial MIBG uptake and 201T1 uptake showed positive correlation with the septal thickness (R = 0.581, p = 0.0058 and R = 0.677, p = 0.0007). When the septal MIBG uptake was divided by the corresponding 201T1 uptake (MIBG/T1), both the early and delayed MIBG/T1 showed negative correlation with the septal thickness (R = -0.485, p = 0.0255 and R = -0.535, p = 0.0125). Significant positive correlation was observed between septal MIBG clearance and the thickness (R = 0.510, p = 0.0182). In patients with severe septal hypertrophy (greater than 20 mm), the MIBG clearance was significantly higher compared with less hypertrophic (less than or equal to 20 mm) group (13.4 +/- 8.0%/hr vs. 3.2 +/- 4.7%/hr, p = 0.0028). Thus, MIBG was useful for the evaluation of sympathetic innervation and activity in HCM. The MIBG clearance and uptake in conjunction with 201T1 study seemed to reflect the severity of hypertrophy in HCM.

In this study, we investigated correlations of left ventricular hypertrophy and its histopathology with diastolic dysfunction in patients with hypertrophic cardiomyopathy. Nine control subjects and 14 hypertrophic cardiomyopathy (HCM) patients with asymmetrical septal hypertrophy were evaluated. M-mode echocardiography was used to assess fractional shortening (FS), isovolumic relaxation time (IRT), and the left ventricular filling volume index during rapid and slow filling periods and atrial contraction period (RFVI, SFVI and ACVI). End-diastolic thickness of the interventricular septum and posterior wall was determined using biventriculography. Right ventricular endomyocardial biopsies were performed to calculate the diameters of myocytes, the percentage of fibrosis and the eccentricity e which indicates the degree of myocardial disarrangement including disorganization. The FS was normal in the two groups. The IRT of the HCM group was significantly greater and the RFVI significantly less than those of the controls. The left ventricular wall thickness, the diameters of myocytes and the percentage of fibrosis in the HCM group were significantly greater; and the eccentricity e was significantly less, suggesting that myocardial disarrangement was significantly more severe than that in the controls. Significant positive correlations were observed between the IRT and the wall thickness (r = 0.647), between the diameter of myocytes (r = 0.681) and the percentage of fibrosis (r = 0.628), and there was a significantly negative correlation between the IRT and the eccentricity e (r = -0.759). There was a significantly negative correlation between the RFVI and the wall thickness (r = -0.663); and a significantly positive correlation between the RFVI and the eccentricity e (r = 0.579). Multiple regression analyses showed that the diameter of myocytes, the percentage of fibrosis and the eccentricity e all correlated significantly with the IRT (R = 0.821) and the RFVI (R =0.604). The standard regression coefficients of the diameter of myocytes, the percentage of fibrosis and the eccentricity e were 0.253, 0.278 and -0.431 in respect to IRT, and those of the percentage of fibrosis and the eccentricity e were -0.204 and 0.469 in respect to RFVI, respectively. These results indicated that diastolic dysfunction in hypertrophic cardiomyopathy is related not only to the degree of left ventricular hypertrophy, but also to the degree of myocardial hypertrophy, increased interstitial fibrosis, and especially to myocardial disarrangement including disorganization.

The characteristics of ECG findings as they relate to myocardial changes during long-term course of hypertrophic cardiomyopathy (HCM) were studied. Serial changes in ECG were compared with changes left ventriculogram and bi-ventriculogram in 15 patients with HCM without intraventricular conduction disturbance. Serial changes in ECG findings, with special reference to the negative T wave, were categorized in three groups; 1) 5 patients with increase or appearance of the negative T wave (A-1 group). 2) 4 patients with decrease or disappearance of the negative T wave (A-2 group). 3) 6 patients without significant changes in the T wave (B-group). A-1 group presented a marked increase in SV1 + RV5, and of the thickness of anterior and apical wall, and a decrease of the peak dV/dt/EDV (end diastolic volume-normalized peak filling rate), serially. End diastolic volume (EDV) and ejection fraction (EF) did not change significantly. The configuration of left ventriculogram changed from a round form to a spade-like form. A-2 group presented a marked decrease in SV1 + RV5, the thickness of anterior and apical wall, peak dV/dt/EDV and peak dV/dt/V (left ventricular volume of the time of peak filling-normalized peak filling rote). EF decreased serially, 2 cases of A-2 group presented the clinical picture of dilated cardiomyopathy in the end stage. In B group, SV1 + RV5, the wall thickness and left ventricular function did not change, serially. In conclusion, serial observations of ECG are useful for assessing alterations in wall thickness, LV-form and LV-function.

Electrocardiographic follow-up was conducted for 17 patients with hypertrophic cardiomyopathy including six cases who received left ventriculographic follow-up. 1. Serial ECG changes were as follows: 1) In seven patients negativity of the T wave appeared or increased concomitantly with increased voltage of SV1 + RV5 (A-1 group). 2) In four patients, negativity of the T wave decreased or disappeared with the decreased voltage of SV1 + RV5 (A-2 group). 3) In six patients, there were insignificant changes of both T wave and SV1 + RV5 (B group). 2. Results of serial left ventriculography and biventriculography were as follows: 1) Two patients (A-1 group) showed an increased voltage of SV1 + RV5 (25 mm----48 mm, 42 mm----54 mm), and increased thickness of the apical wall (10 mm----12 mm, 8 mm----11 mm) and the anterior wall (13 mm----16 mm, 10 mm----16 mm). However, the thickness of the posterior and interventricular septal walls did not change. The configuration of the end-diastolic left ventriculogram (RAO 30 degrees) changed from a round configuration to the so-called "beak" configuration. 2) Two patients (A-2 group) showed a decreased voltage of SV1 + RV5 (81 mm----26 mm, 73 mm----53 mm), decreased thickness of the apical wall (18 mm----10 mm, 21 mm----15 mm) and the anterior wall (12 mm----9 mm, 17 mm----12 mm). The end-diastolic left ventriculogram changed from a spade-like configuration to a round configuration. In the analysis of diastolic function measured by digitized cineangiograms using a picture-analyzer, diastolic dysfunction was already present at the initial observation. The diastolic and systolic dysfunction progressed during serial observations. These patients showed the clinical pictures of dilated cardiomyopathy at the final observation. 3) Two patients with no remarkable changes of the T wave (B group) showed insignificant changes in configuration of the left ventriculogram and wall thickness. In conclusion, serial changes in configuration of the left ventricle and wall thickness, especially of the anterior and apical walls, are compatible with the serial changes of the ECG in hypertrophic cardiomyopathy. The patients whose negative T waves decreased or disappeared had diastolic dysfunction at the initial observation, and deterioration of both diastolic and systolic dysfunctions during serial observations.

Myocardial interstitial fibrosis is an important microscopic feature of hypertrophic cardiomyopathy. To determine whether interstitial fibrosis of the myocardium in hypertrophic cardiomyopathy and essential hypertension differ in quality or quantity, and to determine whether fibrosis affects cardiac function directly, we measured the percentage of fibrosis in patients of both categories and compared the severity of fibrosis with several cardiac functions. Left and right ventricular endomyocardial biopsies were performed in 25 patients with essential hypertension and in 19 patients with hypertrophic cardiomyopathy. Interstitial fibrosis was classified into four different microscopic types, and the percentage of total and of each type was calculated using the point-counting method. Although the percentage of total fibrosis was similar between the two groups, the type of fibrosis was different. There was no correlation between the percentage of total fibrosis and the mean size of myocytes in either group. Although there was a significant correlation between the percentage of total fibrosis and the thickness of the interventricular septum in hypertrophic cardiomyopathy, such correlation was lacking in hypertension. There was no correlation between the percentage of total fibrosis and the ejection fraction, cardiac index, or left ventricular end-diastolic pressure in either group. We concluded that the amount of myocardial interstitial fibrosis in hypertrophic cardiomyopathy is no greater than that in essential hypertension, but the type of fibrosis is different. Furthermore, in subjects in whom the ejection fraction is normal or only slightly decreased, fibrosis does not influence global cardiac functions.

The present study clarified the pathogenesis of disproportional hypertrophy in terms of disturbed coronary microcirculation. Twenty-eight patients with hypertrophic cardiomyopathy (HCM) who had normal coronary angiograms were categorized in four groups according to distributions of disproportional hypertrophy on left ventriculography and biventriculography: (1) Interventricular septal hypertrophy, (2) septal and apico-anterior wall hypertrophy, (3) apico-anterior hypertrophy, and (4) nonspecific hypertrophy of the entire wall. All 28 HCM patients and 10 normal volunteers were tested using exercise myocardial scintigraphy, and the circumferential profiles were processed by computer to relate the washout rate and disproportional hypertrophy. Comparison of the mean curves and mean segmental values of the circumferential profiles of the HCM groups with those of the control group showed that the mean initial uptake values of the HCM groups were to be relatively low in the apical segment and in the lower portion of the anteroseptal segment representing disproportional hypertrophy of these segments. The mean values were significantly elevated in the upper portion of the anteroseptal segment which was projected as the largest amount of the myocardium three-dimensionally. The mean washout rates in the HCM groups were significantly decreased in all segments, especially in those segments which reflected disproportional hypertrophy. This trend was also observed in the segments with increased initial uptakes. On comparing the segmental values of all groups, the segments with initial uptakes and/or washout rates with having the mean value minus 2SD of the control group were observed in the profiles of 12 of the 28 HCM patients. These all had decreased washout rates. In 25 of the total segments of the HCM patients, the initial uptakes and/or washout rates were below the normal limit; 21 of these segments had only decreased washout rates, and 16 of these 21 segments belonged to disproportionally hypertrophic wall. These results indicate that the decreased washout rate in the disproportionally hypertrophic wall is characteristic of HCM. It is suggested that the decreased washout rate with the decreased initial uptake is caused by disturbance of the coronary microcirculation. In addition, the decreased washout rate without a decreased initial uptake is caused not only by disturbance of coronary microcirculation, but by a metabolic disturbance of the myocardial cells as well. Furthermore, both disturbances are closely related to the pathogenesis of disproportional hypertrophy.