Muscle fiber disarray in patients without hypertrophic cardiomyopathy

Muscle fiber disarray (MFD) has been described as the histologic feature of hypertrophic cardiomyopathy (HC), but it was also found in normal and other abnormal conditions. Its distribution related to the topography of the myocardium has not been described. In this paper, the incidence of MFD in hearts free from HC, the frequency of the histologic disorganization and the affected muscles involved were studied at autopsy. 29 hearts with acute myocardial infarction and 1 with suppurated myocarditis were employed. Macroslides containing the point of maximum septal enlargement were selected for histological examination. The areas of MFD were measured by a polar planimeter and correlated with the involved wall, the total slice area, parietal widths and involved muscles. 27 patients (90%) presented with MFD; hypertrophic ventricular walls were observed in 10, 8 of which had MFD. The remaining 20 patients with nonhypertrophic ventricular walls had MFD in 19 instances. There was septal posterior involvement in 26 cases (p less than 0.0005). 12 patients (44.4%) had only one wall involved. Only 1 patient presented more than 5% of MFD in regard to the total area. The septal wall was the most affected (p less than 0.0005). The most commonly affected muscle was the deep-sinospiral, either alone or combined with other muscles (p less than 0.01). Greater MFD was found (23/30) in patients with septum/posterior wall ratio less than 1.3 cm. It is concluded that MFD may affect up to 10% of the septum in patients free from HC, and that secondary hypertrophy is not a prerequisite for MFD.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relation between ventricular and myocyte function with tachycardia-induced cardiomyopathy.

Chronic supraventricular tachycardia (SVT) causes left ventricular (LV) dilatation and dysfunction. Changes in myocyte function and structure may be important factors in the development of SVT cardiomyopathy. Accordingly, LV function and isolated myocyte structure and function were examined in six pigs with pacing-induced SVT cardiomyopathy (3 weeks at 240 beats per minute) and six control pigs. LV function was examined by simultaneous echocardiography and catheterization, and isolated myocyte function was studied using computer-assisted video microscopy. Indexes of isolated myocyte contractile performance were examined in the unloaded, unattached state (31 control and 24 SVT cells) and after attachment to a basement membrane substrate (65 control and 45 SVT cells). LV fractional shortening and peak +dP/dt significantly decreased in SVT cells compared with control cells (12 +/- 2% versus 28 +/- 2%, and 842 +/- 61 versus 1,216 +/- 119 mm Hg/sec, respectively; p less than 0.05). Isolated myocyte percent shortening and normalized peak velocity of shortening of SVT myocytes adherent to a basement membrane were significantly lower than attached control myocytes (1.2 +/- 0.2% versus 4.3 +/- 0.3%, and 15 +/- 2 versus 37 +/- 5% resting cell length/sec, respectively; p less than 0.05). Similarly, in the unattached state, the extent and velocity of shortening of SVT myocytes were reduced by over 50% from control values. Contractile properties of attached and unattached cardiocytes were also examined in the presence of 2-8 mM extracellular Ca2+. For both attached and unattached SVT myocytes, responsiveness to increases in extracellular Ca2+ were significantly blunted from control values. Ultrastructural examination of SVT myocytes revealed that the percent volume of myofibrils within isolated myocytes was reduced from control values (46 +/- 7% versus 65 +/- 2%, p less than 0.05). In summary, SVT cardiomyopathy is probably due to a primary defect in isolated myocyte contractile performance. The reduced contractile function of SVT cardiomyopathic myocytes was associated with abnormalities in cytoarchitecture and Ca2+ responsiveness.     

Relation between echocardiographic image and the electrocardiogram in hypertrophic cardiomyopathy

Authors analyzed the correlation between anatomic changes estimated by echocardiographic examination and electrocardiographic recordings in group of 104 patients with hypertrophic cardiomyopathy. It was stated that morphological type III by Maron (8) is characterized, in comparison with other types, by significantly lower percentage of right ventricular hypertrophy and higher percentage of QTc interval prolongation, whereas percentage of patients with mitral or left ventricular hypertrophy was insignificantly higher. P Mitrale was significantly more often observed in patients with left ventricular diastolic dimension less than 35 mm. Generally ecg recordings had no distinct markers of the extent and localization of hypertrophic changes. Authors conclude that the unmistakable recognition of the anatomical type of hypertrophy basing on electrocardiogram is possible.     

Relation of electrocardiographic patterns to phenotypic expression and clinical outcome in hypertrophic cardiomyopathy

Twelve-lead electrocardiography, a traditional component in evaluations of patients with hypertrophic cardiomyopathy (HC), is often regarded as a marker for the magnitude of left ventricular (LV) hypertrophy, which in turn has been linked to sudden death risk. To determine whether electrocardiographic (ECG) patterns have clinical utility by accurately reflecting phenotypic expression or predicting clinical outcome, voltages and patterns were compared with LV wall thicknesses assessed by echocardiography and with clinical outcomes in 448 consecutive patients with HC. Significant but relatively weak correlations were evident between maximum LV wall thickness and ECG voltage: r = 0.295 (p <0.01) for the sum of R- and S-wave voltages in all 12 leads, r = 0.254 (p <0.01) for the maximum R or S wave in any lead, and r = 0.210 (p <0.01) for the sum of SV(1) (or SV(2)) and RV(5) (or RV(6)). Of 55 patients with extreme LV hypertrophy (LV wall thickness > or =30 mm), only 24 (44%) showed greatly increased ECG voltage > or =30 mm in any lead. Of 102 patients with outflow gradients > or =30 mm Hg at rest, only 43 (42%) had ECG voltage > or =30 mm in any lead. Normal ECG results were uncommonly associated with HC-related death (1 of 40 patients, 2.5%) but had similar prevalence in surviving patients (17 of 376 patients, 4.5%; p = NS). In conclusion, in HC, 12-lead ECG voltages are not a reliable clinical marker for the magnitude of LV hypertrophy or outflow obstruction. Diverse ECG patterns, consistent with heterogeneous expression of this disease, did not predict HC-related death. Scalar electrocardiography has selective but limited power in routine clinical assessments of patients with HC.     

An improved method for detecting and quantifying cardiac muscle disarray in hypertrophic cardiomyopathy

The presence of muscle disarray in hypertrophic cardiomyopathy (HC), although well established, has only been semiquantitatively assessed. A quantitative method that uses polarized light microscopy is described. Hematoxylin and eosin-stained sections of ventricular septa from six HC patients and six normal hearts were examined. Cell orientations were measured in five regions from each section using a polarizing microscope with a rotating stage. Histograms of cell orientation angles were plotted and the mean and angular deviation of each sample were calculated. In normal hearts, cells were predominantly aligned parallel to each other. Orientation distributions were sharply peaked, with angular deviations ranging from 4 to 13 degrees. For HC, the sharp peak was lacking and angular deviations varied from 7 to 37 degrees; some distributions were bimodal. Areas in HC septa that appeared normal by gross inspection had abnormal orientation distributions. Polarized light microscopy provides an improved method of detecting and quantifying cellular disorganization in HC.     

Regional myocyte hypertrophy and increased interstitial myocardial fibrosis in hypertrophic cardiomyopathy

The purpose of this study was to determine if the thickened cardiac walls of patients with hypertrophic cardiomyopathy (HC) are due to increased size or number of myocytes or increased amounts of fibrous tissue. Eight patients, aged 18 to 42 years, who died from complications of HC and 8 age-matched control subjects without heart disease were studied. A 1.5-cm3 block of tissue was removed from the left ventricular free wall, right ventricular free wall and ventricular septum (VS). Each region of each wall was evaluated for fibrous tissue by point counting; cell diameter was measured using an ocular micrometer disc. Cell layers were counted across the walls. The results revealed that increased cell size, cell layers and fibrous tissue are characteristic of HC, but only in the VS are all 3 significantly increased. The fibrous tissue was most extensive in the VS (19 +/- 9%), but it was more extensive than in the control subjects in all 3 walls. Cell diameters were largest in the layers closest to the left ventricular cavity.     

Relation between extent of left ventricular hypertrophy and age in hypertrophic cardiomyopathy

This investigation was undertaken to determine whether a relation could be identified between left ventricular wall thickness and age in a large population of symptomatic patients with hypertrophic cardiomyopathy. Extent of left ventricular hypertrophy was assessed with two-dimensional echocardiography in 173 patients with hypertrophic cardiomyopathy who ranged in age from 21 to 74 years (mean 45) and had mild to severe cardiac symptoms. The overall study group was classified into five age subgroups (each corresponding to a decade); maximal left ventricular wall thickness and wall thickness index (a quantitative expression of the overall extent of hypertrophy) were assessed in each group. These two indexes were significantly higher in patients 21 to 30 years of age than in patients in each of the other four older age groups. The two indexes of left ventricular hypertrophy were also significantly higher in patients 31 to 40 years of age than in patients who were 61 to 74 years old. Multivariate regression analysis showed that the relation between wall thickness and age was not influenced by other clinical variables such as severity of symptoms, presence of subaortic obstruction, left ventricular cavity dimension and gender. In conclusion, the findings indicate that, in a population of symptomatic adult patients with hypertrophic cardiomyopathy, left ventricular hypertrophy is considerably more severe in younger than in older patients and that there is an inverse relation between left ventricular wall thickness and age.     

Extensive myocardial fiber disarray in aortic and pulmonary atresia. Relevance to hypertrophic cardiomyopathy

Myocardial fiber disarray is a distinctive histopathologic finding seen in asymmetric hypertrophic cardiomyopathy. We studied 14 hearts with aortic atresia and intact interventricular septum, six hearts with pulmonic atresia and intact interventricular septum, eight normal infant hearts matched for age of the study hearts, and one nonadult heart with hypertrophic cardiomyopathy and asymmetric hypertrophy and quantitatively analyzed tissue sections through both ventricles and the septum. Normal hearts had an average overall fiber disarray of 8.7% (range 3.8-17%) of the left ventricle including septum. Hearts with pulmonary atresia had an overall disarray of 70.4% (range 13-97%) of the entire right ventricle, and those with aortic atresia 62.1% (range 26-97%) of the left ventricle. The one infant heart with hypertrophic cardiomyopathy showed 15.5% disorder of the left ventricular free wall, 75% disorder of the septum and 47% overall myocardial fiber disarray. Thus, while quantitative criterion distinguished normal from abnormal hearts, they did not distinguish among the various pathologic states. Although extensive myocardial fiber disarray is not exclusive to, or pathognomonic of, hypertrophic cardiomyopathy, it is a useful finding taken in the context of the overall disease. The sensitivity and specificity of this isolated morphologic observation as an indication of hypertrophic cardiomyopathy may be misleading.     

Relation between serum nifedipine concentration and hemodynamic effects in nonobstructive hypertrophic cardiomyopathy

The relation between nifedipine concentration and hemodynamic effects after sublingual administration of 10 or 20 mg was examined in 13 patients with nonobstructive hypertrophic cardiomyopathy (HC). Serum nifedipine concentrations were determined by gas chromatography and were not related to dose. Peripheral vascular resistance decreased as a function of nifedipine concentration (r = -0.63, p less than 0.001); this was associated with a concentration-related increase in heart rate (r = 0.56, p less than 0.001) and in cardiac index (r = 0.50, p less than 0.001). However, evidence for a pure vasodilator effect of nifedipine was inconsistent, in that the change in stroke volume index with nifedipine was not significant. Although stroke volume index increased at nifedipine concentrations between 60 and 120 ng/ml (38 +/- 6 to 42 +/- 4 ml/m2, p less than 0.01), it decreased at concentrations greater than 120 ng/ml (40 +/- 3 to 38 +/- 4 ml/m2, p less than 0.01). Moreover, pulmonary artery wedge pressure increased at nifedipine concentrations greater than 120 ng/ml (11 +/- 2 to 16 +/- 4 mm Hg, p less than 0.001), suggesting either depressed left ventricular (LV) systolic function or reduced LV filling. To investigate these possible mechanisms, LV systolic and diastolic function was studied during catheterization with a nonimaging scintillation probe in 6 of the 13 patients. In these subjects, heart rate was held constant by atrial pacing.(ABSTRACT TRUNCATED AT 250 WORDS)     

A computer model of myocardial disarray in simulating ECG features of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) was simulated with a computer heart model having a realistic shape and rotating fiber orientation in order to elucidate possible mechanisms for abnormal ECG findings. The disarray of myocardial muscle in HCM was simulated by assigning random fiber direction and isotropic electrophysiologic properties to abnormal hypertrophic regions, in contrast to the anisotropic modeling for normal myocardium. With these models, main ECG features including abnormal Q wave and QS pattern were reproduced and were comparable with clinical findings. This study suggests that the change in anisotropy in the hypertrophic myocardium is likely to be the main factor responsible to the ECG features of HCM.     

Histopathological specificity of hypertrophic obstructive cardiomyopathy. Myocardial fibre disarray and myocardial fibrosis.

The topography and specificity of fibre disarray and fibrosis in hypertrophic obstructive cardiomyopathy were determined in a histological study comprising 40 necropsy hearts--10 with hypertrophic cardiomyopathy, 10 with congestive cardiomyopathy, 10 with aortic valve stenosis, and 10 normal hearts. Seven standard regional sections were sampled from each heart and graded "double-blind" (tissue location and disease entity) for severity and extent of fibre dissarray and four distinct types of myocardial fibrosis. Statistical comparison of the severity and distribution of indices of fibre disarray and fibrosis within each group and between the normal and the disease groups showed that fibre disarray and fibrosis were qualitatively non-specific for hypertrophic cardiomyopathy. However, when fibre disarray was quantified (1) it was significantly increased in hypertrophic cardiomyopathy and allowed separation of hearts with hypertrophic cardiomyopathy from normal hearts and from those with congestive cardiomyopathy and aortic stenosis, (2) it did not vary significantly among sections of the left ventricle (that is, between the septum and the free wall) in hypertrophic cardiomyopathy, (3) it was closely associated with plexiform fibrosis, and (4) it varied independently of wall and septal thickness. Though the histogenesis of fibre disarray is unknown, it probably represents an exaggeration of a non-specific common pathway for many diverse pathophysiological processes.     

Relation between regional contractile dynamics and myocardial lesions in patients with hypertrophic cardiomyopathy

To investigate the influence of wall hypertrophy and myocardial lesions on the regional contractile dynamics of the left ventricle (LV) in patients of hypertrophic cardiomyopathy (HCM), we obtained the thicknesses of the ventricular septum (VS) and posterior wall at end-diastole and systole (E.Td, E.Ts) from echocardiograms made before death for 11 patients of HCM and 6 patients of secondary concentric hypertrophic heart disease (SHH), and the percent regional systolic wall thickening normalized by that of 15 normal controls (%NRWT). We then compared the %NRWT with the pathological wall thickness (P.T.), myocyte diameter (MD), and percent areas of fibrosis (%F) and disarray (%D) in specimens of the corresponding portion from each autopsied heart. The %NRWT in the VS of HCM patients was significantly less than that in SHH patients. All of the MD, %F and %D in the LV wall of HCM patients were significantly greater than those in SHH patients. The %NRWT in the LV wall of HCM patients and SHH patients correlated inversely with the E.Td (r = -0.53, p less than 0.02 and r = -0.70, p less than 0.02, respectively), but not with the E.Ts or P.T. The %NRWT in the LV wall of HCM patients had an inverse correlation with the %F (r V -0.59, p less than 0.005). Furthermore, that in the VS had an inverse relationship with the %D (r = -0.63, p less than 0.05). Thus, it is suggested that not only LV hypertrophy, but also LV myocardial lesions affect the abnormality of the regional LV contractile dynamics in HCM patients. In addition, observation of the regional contractile dynamics by echocardiography may be useful for speculating on myocardial lesions associated with this disease.     

肥厚性心肌病患者左心室形态学改变与QT间期离散度的关系

目的探讨体表心电图上QT间期离散度（QTd）与肥厚性心肌病（HCM）左心室形态学改变的关系。方法43例HCM患者,均经二维超声心动图确诊。根据心室肥厚的部位不同,将患者分为4组:A组（室间隔肥厚）16例、B组（室间隔肥厚及左室前壁肥厚）10例、C组（室间隔肥厚、左室前壁肥厚及左室侧壁肥厚）10例、D组（室间隔肥厚及广泛左室壁肥厚）7例。在安静状态下记录同步12导联心电图（ECG）,人工测量各导联的QT间期、QRS波时间,并计算QT及QRS离散度（QTd及QRSd）。结果超声心动图检查D组的左室后壁厚度（PWT）明显大于A、B、C组,D组的室间隔厚度（IVST）/PWT明显小于A、B、C组。A、B组的QTd明显大于C、D组,差异有显著性意义。结论QTd不仅反应了左心室复极的不均一性,也反应了左心室肥厚的形态学改变的不均性。     

Relation between ventricular and myocyte remodeling with the development and regression of supraventricular tachycardia-induced cardiomyopathy

Chronic supraventricular tachycardia (SVT) causes left ventricular (LV) dilatation and dysfunction. Termination of SVT appears to reduce LV size and improve function. However, changes in myocyte structure and morphology that accompany the development and regression of SVT-induced cardiomyopathy have not been studied. Accordingly, we measured LV function using echocardiography and catheterization in three groups of six pigs each: 3 weeks of atrial pacing (SVT; 240 beats/min), 4-week recovery from SVT (PST), and sham-operated controls. At each of these three end points, isolated myocyte dimensions and nuclear number were measured using fluorescence, and the volume percent of myocytes and myofibrils was computed from tissue sections using stereological techniques. SVT resulted in reduced LV fractional shortening (15 +/- 3% versus 31 +/- 2%, p less than 0.05), increased end-diastolic dimension (5.6 +/- 0.8 versus 3.8 +/- 0.2 cm, p less than 0.05), and no change in mass (2.6 +/- 0.1 versus 2.6 +/- 0.2 g/kg, p = NS) compared with controls. Myocyte length significantly increased with SVT (171 +/- 9 versus 109 +/- 11 microns, p less than 0.05), without significant changes in cell width (28 +/- 2 versus 26 +/- 2 microns). Nuclear number did not change with SVT; however, nuclear area/myocyte area significantly increased compared with controls (9.5 +/- 0.8 versus 8.7 +/- 0.8 x 10(-2), p less than 0.05). The volume percent of myocytes within the ventricular wall and the volume percent of myofibrils within myocytes decreased with SVT compared with controls (72 +/- 3% versus 80 +/- 3% and 45 +/- 5% versus 63 +/- 4%, respectively, p less than 0.05), with no change in total myocyte volume (54.2 +/- 2.7 versus 54.3 +/- 1.8 microns3 x 10(12)). In the PST group, LV fractional shortening returned to control values; however, there was persistent dilatation (end-diastolic dimension: 4.2 +/- 0.1 cm, p less than 0.05), and LV hypertrophy developed (3.3 +/- 0.3 g/kg, p less than 0.05). Increased myocyte length (158 +/- 5 microns, p less than 0.05) and width (33 +/- 2 microns, p less than 0.05) were observed in the PST group. The volume percent of myocytes and myofibrils returned to control values, with total myocyte volume significantly increased in the PST group compared with the control and SVT groups (74.5 +/- 2.6 microns3 x 10(12), p less than 0.05). In addition, the number of nuclei per myocyte in the PST group significantly increased from control values (5.1 +/- 0.1 versus 4.0 +/- 0.1, p less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)     

Relation between extent of left ventricular hypertrophy and diastolic filling abnormalities in hypertrophic cardiomyopathy

In hypertrophic cardiomyopathy, the relation between left ventricular diastolic impairment and magnitude of left ventricular hypertrophy has not been clearly defined. In the present study, Doppler echocardiographic indexes of left ventricular diastolic filling were compared in 78 patients with hypertrophic cardiomyopathy and in 72 normal control subjects of similar age, and the relation between abnormalities of diastolic filling and magnitude of left ventricular hypertrophy was assessed. In patients with hypertrophic cardiomyopathy, isovolumic relaxation was prolonged (94 +/- 25 ms); peak early diastolic flow velocity (53 +/- 18 cm/s), deceleration of flow velocity in early diastole (341 +/- 142 cm/s2) and the ratio between early and late peaks of flow velocity (1.6 +/- 0.9) were reduced; and peak late diastolic flow velocity was increased (38 +/- 15 cm/s) compared with values in control subjects (76 +/- 12 ms, 65 +/- 12 cm/s, 512 +/- 131 cm/s2, 2.3 +/- 0.8 and 30 +/- 7 cm/s, respectively; p less than 0.001). Individual patient analysis showed that diastolic filling was abnormal in 52 (67%) of the 78 patients with hypertrophic cardiomyopathy. However, within the patient group, none of the Doppler diastolic indexes showed a significant correlation with maximal left ventricular wall thickness or the wall thickness index (correlation coefficients ranged from -0.15 to 0.10).(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term outcome in patients with apical hypertrophic cardiomyopathy

OBJECTIVES: The aim of this study was to describe long-term outcome in patients with apical hypertrophic cardiomyopathy (ApHCM) followed in a tertiary referral center. BACKGROUND: Apical hypertrophic cardiomyopathy is a relatively rare form of hypertrophic cardiomyopathy (HCM), first described in Japan. Initial reports, based on a limited number of patients, emphasized the benign nature of this condition. METHODS: A retrospective study of 105 patients with ApHCM diagnosed at the Toronto General Hospital from 1975 to 2000 was performed. Symptoms, clinical findings, mortality and cardiovascular morbidity were analyzed. RESULTS: The mean age at presentation was 41.4 +/- 14.5 years. During a mean follow-up of 13.6 +/- 8.3 years from presentation, cardiovascular mortality was 1.9% (2/105) and annual cardiovascular mortality was 0.1%. Overall survival was 95% at 15 years. Thirty-two patients (30%) had one or more major morbid events, the most frequent being atrial fibrillation (12%) and myocardial infarction (10%). Probability of survival without morbid events was 74% at 15 years. Three predictors of cardiovascular morbidity were identified: age at presentation <41 years, left atrial enlargement, and New York Heart Association (NYHA) class > or = II at baseline. Forty-four percent of the patients were asymptomatic at the time of last follow-up. CONCLUSIONS: Apical hypertrophic cardiomyopathy in North American patients is not associated with sudden cardiac death and has a benign prognosis in terms of cardiovascular mortality. Nevertheless, one third of these patients experience serious cardiovascular complications, such as myocardial infarction and arrhythmias. These data are likely to influence the counseling and management of patients with ApHCM.