Cardiomyopathy Characterized by Abnormal Accumulation of Desmin-type Intermediate Filaments in Cardiac Muscle Fibers: A Case Report and Review of the Literature

A 42 year old Japanese male, who had been suffering from congestive heart failure and electrocardiographic abnormalities (A V block, intraventricular conduction disturbance, ventricular tachycardia), died after a clinical course of 2 years and 1 month. Macroscopic investigation revealed dilation of the left ventricle and thickening of the right ventricular wall. The unique finding in this case was a circumferential fibrous scar in the median circular layer and outer oblique layer of the left ventricular wall. Biopsy and autopsy materials revealed diffuse loss of myofibrils in the central zone of cardiac muscle fibers, and replacement with aniline blue positive homogeneous material (17–35% of the area of one muscle fiber). Electron microscopy revealed abnormal accumulation of fine filamentous material (7.5–25 nm in diameter), which was immunohisto-chemically proved to be desmin type intermediate filament. Moreover, sarcoplasmic reticulum like material was detected in the degenerated area. At autopsy, degeneration was detected all over the heart. The ventricular muscle fibers were more severely affected than the atrial muscle fibers. The conduction system was also affected, in some parts more severely than the surrounding ordinary muscle fibers. The pathogenesis of this disorder remains to be clarified. Acta Pathol Jpn 39: 266–273, 1989.     

Congestive heart failure due to mitochondrial cardiomyopathy in kearns-sayre syndrome

Summary Despite extensive analysis of the ultrastructural changes in skeletal muscle fibers in chronic progressive external ophthalmoplegia (CPEO), similar changes in the heart muscle fibers of patients with cardiac involvement in CPEO, called Kearns-Sayre syndrome, have not been described in detail. We report the clinical long-term course in a patient with Kearns-Sayre syndrome in whom mitochondrial cardiomyopathy was suspected in vivo and was confirmed at autopsy as the underlying cause of severe dilative cardiomyopathy. Enlarged, abnormally structured, excessively augmented mitochondria and loss of myofibrils could be shown both in skeletal and heart muscle cells.Abbreviations CPEO chronic progressive external ophthalmoplegia - EMG electromyogram - ENT department ear, nose, and throat department - LAH left anterior hemiblock - LVEDP left ventricular end-diastolic pressure - LVEDVI left ventricular end-diastolic volume index - LVEF left ventricular ejection fraction - LVESVI left ventricular end-systolic volume index - PAP pulmonary artery pressure - RAP right arterial pressure Supported by the Dr. Sepp and Hanne-Sturm-Stiftung     

牦牛心室蒲肯野纤维的立体分布和结构特点

目的 探讨牦牛心室普肯耶纤维的分布和结构特点,为高原哺乳动物心室传导系统的研究积累形态学资料。 方法 采用墨汁灌注、ABS树脂灌注铸型,石蜡切片HE染色、Masson染色和免疫组织化学染色技术,观察60只成年牦牛的心室普肯耶纤维分布及结构特征。结果 牦牛心室普肯耶纤维束周围包绕有结缔组织鞘。左束支在室间隔内膜下层有2条或3条分支;右束支经隔缘肉柱在右前乳头肌根部心肌层中有3条或4条分支。心室普肯耶纤维在心内膜下层呈多边形网状分布,并在心肌层中发出大量分支,左、右心室乳头肌顶端内膜下层未观察到普肯耶纤维分布。普肯耶纤维呈卷轴状、蜂窝状、漏斗状或脊状构型。Cx43在普肯耶纤维呈膜阳性。结论ABS树脂灌注铸型技术能用于心室普肯耶纤维分布的研究。牦牛心脏左束支和右束支呈不对称分布,左束支较发达。     

Cardiac expression of polysialylated NCAM in the chicken embryo: correlation with the ventricular conduction system.

The neural cell adhesion molecule (NCAM) and its polysialic acid moeity (PSA) affect cellular interactions during the development of the nervous system and skeletal muscle. NCAM has also been identified in the embryonic heart of various species including humans. However, knowledge regarding the role of NCAM and its function-modulating PSA in cardiogenesis is limited. The distribution of NCAM and its PSA in the ventricular myocardium of chicken embryos was determined by indirect immunofluorescence staining. The NCAM polypeptide was found throughout the cardiac myocardium. In contrast PSA was located in discrete regions in stage 20 to 44 embryos (during and after septation). Myocardium at the subendocardial regions of the atrioventricular canal and ventricular trabeculae were PSA positive by stage 20. At later stages, transverse sections of the postseptation heart just below the level of the atrioventricular interface revealed a PSA-positive bundle of myocardium in the septum. This bundle was continuous with two branches at a more apical level which in turn were continuous with the PSA-positive subendocardial myocardium lining the left and right ventricles. This pattern of PSA in the myocardium was similar to that of the ventricular conduction system configuration defined in the adult heart. Electron micrographs of the subendocardium of the ventricular septum revealed PSA positivity on myofibril-containing cells with the ultrastructural location of Purkinje fibers. At later stages (35-44) a subset of cells within PSA-positive regions was stained by an antibody against an isoform of the myosin heavy chain found in adult Purkinje fibers. These cells and surrounding tissue lacked PSA in the adult heart. Thus polysialylated NCAM may be modulating cell-cell interactions during the development of the ventricular conduction system.     

The comparative pathology of primary endocardial fibroelastosis in burmese cats

Summary A recently discovered, naturally occurring, familial, cardiac disorder of purebred Burmese cats resembling primary endocardial fibroelastosis (EFE) was compared to EFE in man. Study of 22 kittens and 20 human infants with EFE (with appropriate controls), revealed striking clinical, gross anatomic, histopathological and ultrastructural similarities between the human and feline conditions. Clinically, the disease was manifested in both species by signs of congestive heart failure.At autopsy, anatomic heart or great vessel defects other than EFE were not detected. Cardiac lesions were not observed in kittens less than 2 days old. In kittens 5 to 19 days old, lesions were generally limited to endocardial edema with subendothelial proliferation of fibroblasts, which caused no grossly recognizable endocardial thickening. Left ventricular dilation and endocardial thickening were observed in essentially all affected kittens which survived 20 or more days after birth, and in all human infant hearts. Dilated lymphatic capillaries were observed at the endomyocardial junction in many of the feline and human hearts. Rapidly maturing collagen fibrils, and later elastic fibers, were formed by fibroblasts near the endothelial surface. Collagen and elastic fibers in the deeper endocardium became 3 to 5 times thicker than those in age-matched controls. Purkinje fibers of the left bundle branch became incorporated into the fibroelastic endocardial thickening in many human and feline cases. Most of these conduction fibers underwent degeneration and atrophy.The similarity of findings in feline and human EFE indicate that affected Burmese cats may be a valuable model of human EFE. The concurrence of early endocardial edema and dilated lymphatics suggests that lymphatic obstruction may be important in the pathogenesis. The observation that early cases of EFE may appear grossly normal suggests that the disease may occur more frequently than is commonly diagnosed. Isolation and degeneration of Purkinje fibers may be responsible for serious conduction disturbances. Finally, the heredity nature of primary EFE in Burmese cats should promote further investigation into this cause of the human counterpart.This work was supported in part by Grant NIH-5-SO1-RR5359-16, Division of Research Resources. National Institutes of Health, Department of Health, Education and Welfare.     

Right ventricular false tendons, a cadaveric approach

Left ventricular false tendons (LFTs) have been extensively described and recognized by gross anatomic studies. However, there is very little information available regarding right ventricular false tendons (RFTs). The aim of our study, therefore, was to explore and delineate the morphology, topography and morphometry of the RFTs, and provide a comprehensive picture of their anatomy across a broad range of specimens. We identified 35/100 heart specimens containing right ventricular RFTs and classified them into five types. In Type I (21, 47.7%) the RFTs, was located between the ventricular septum and the anterior papillary muscle; in Type II (11, 22.9%) between ventricular septum and the posterior papillary muscle; in Type III (7, 14.5%) between the anterior leaflet of the tricuspid valve and the right ventricular free wall; in Type IV (5, 10.4%) between the posterior papillary muscle and the ventricular free wall; and lastly, in Type V (4, 8.3%) between the anterior papillary muscle and ventricular free wall. The mean length of the RFTs was 18 ± 7 mm with a mean diameter of 1.4 ± 05 mm. Histologic examination with Masson trichrome and PAS revealed that 20 (41.6%) of the 48 RFTs carried conduction tissue fibers. The presence of conduction tissue fibers within the RFTs was limited to Types I, III, and IV. In Types II and V the RFTs resembled fibrous structures in contrast with Type I, II and IV, which were composed more of muscular fibers, including conduction tissue fibers. RFTs containing conduction tissue fibers were identified, which may implicate them in the appearance of arrhythmias.     

The vortex cordis is never reversely directed, even in situs inversus and L-loop anomaly

In 1926, Taussig reported on two instances of complete situs inversus of the heart and stated that "the main anatomical structure and the deep muscle bundles of the ventricles presented the mirror image of the normal, while the direction of the superficial muscle bundles remained unchanged". In an attempt to analyze whether her statement always held true, we examined the myocardial architecture of five specimens of situs inversus totalis. They were all from patients over sixty years of age and were diagnosed by postmortem examination. Every part of the heart and great vessels presented exact mirror images of the normal. However, the external muscle fibers of the ventricles ran clockwise from base to apex toward the center of the vortex, which had a striking resemblance to the normal rather than the mirror image pattern. Peeling off of the external layer revealed that the direction of fibers was first inverted and then changed into an approximate mirror image of the normal architecture within the deeper muscle layers, as illustrated by Taussig. The exception to this tendency was found at the posterior region of the morphologically left ventricle, in which there was no mirror imaging but a normal pattern throughout the depth of the wall. For the purpose of comparison, two hearts of corrected transposition (L-TGA) were examined. Their chambers were inverted but the external fibers followed the same clockwise course seen in the normal heart. Further dissection revealed that there was no mirror imaging of the architecture at any depth of the morphologically left ventricular wall. Thus there were regional differences and similarities in muscular architecture between these two kinds of ventricular inversion. It was concluded that the vortex layer was never reversely directed, even in situs inversus and L-loop anomaly, and that the deep layers within the sinus region of the left ventricle did not present a mirror image to the normal.     

Spectrum of pathological changes in both ventricles of patients dying suddenly with arrhythmogenic right ventricular dysplasia. Relation of changes to age

AIMS: To quantify the variation in fibrosis, fat and muscle within the walls of both ventricles and within the different regions of the heart from six patients dying suddenly of arrhythmogenic right ventricular dysplasia (ARVD) aged 20-60 years. METHODS: Seven heart regions were examined both macroscopically and histologically using the Picro-Sirius red stain. Quantification of fibrosis, fat and muscle was performed in each region and transmural layer using grid counting. RESULTS: There were macroscopic changes in all examined hearts. A higher percentage of fat with less fibrosis and muscle was observed within the right ventricle of the older patients. The left ventricle had more pathology in the older age group. Statistical differences in pathology in the heart were found. Fat predominated in the epicardial layer in the right and left ventricles of all patients, while the interventricular septum was the least affected. CONCLUSIONS: In ARVD, the pathology varies with age in both ventricles, fibrosis being the earliest hallmark of disease, with fatty infiltration evolving later. It should be labelled arrhythmogenic ventricular dysplasia because of biventricular involvement. Histopathologists should therefore sample from whole slices of the heart, so that all the changes can be observed.     

Visualization of left ventricular Purkinje fiber distribution using widefield optical coherence microscopy

Background: The distribution and connection of ventricular Purkinje fibers are known to be associated with idiopathic left ventricular arrhythmias. Unusual anatomy is one of the important factors associated with catheter ablation success rate. With the widefield high-speed, swept-source optical coherence microscopy (OCM) and light microscope, we visualized the left ventricular Purkinje fiber distribution. Methods: Left ventricular walls of five adult ovine hearts were incised from the mitral annulus to the apex. Using the widefield OCM technique and light microscopy, we observed the distribution, direction, depth, and dividing patterns of the Purkinje network with multiple tangential angles and without tissue destruction. Results: Widefield OCM was used to characterize the ovine heart Purkinje network system in a 4 × 4 mm² field. Left ventricular Purkinje fibers traveled in the sub-endocardial area near the left-sided peri-membranous septal area and ran like a wide hair bundle. The distal branching fibers penetrated to the endocardium and connected to the contractile muscle. In this distal area, Purkinje fibers were connected to each other, forming multiple layers. Some Purkinje fibers were directly connected within the false tendon between the papillary muscles or between the trabeculations. Some free-running Purkinje fibers were directly connected to the papillary muscle from the left bundle. Conclusion: Using widefield OCM, we were able to observe the left bundle and its branching patterns in ovine left ventricle without tissue destruction. This might be applied to future cardiac ablation procedures.     

Localization of neurotensin immunoreactive nerve fibers in the guinea-pig heart: evidence derived by immunohistochemistry, radioimmunoassay and chromatography

By the use of the peroxidase-antiperoxidase technique guinea-pig hearts were investigated for the occurrence of neurotensin immunoreactivity. Neurotensin immunoreactive nerve fibers were found in distinct localisations in all hearts studied. In addition, neurotensin immunoreactive fibers were present in the adventitia of the ascending aorta, the aortic arch and the pulmonary trunk. All segments of the coronary vasculature exhibited a dense network of neurotensin immunoreactive fibers. This innervation pattern was most pronounced in the arterial portions. Neurotensin immunoreactive fibers occurred also in close contact with atrial and ventricular muscle cells. A particularly dense innervation by neurotensin immunoreactive fibers was present in the sinu-atrial node and in the atrio-ventricular node. The fibers were associated intimately with blood vessels as well as with nodal cells. In addition, neurotensin immunoreactive fibers were found in intracardiac ganglia. The presence of neurotensin-like immunoreactive material in the guinea-pig heart was demonstrated also by radioimmunoassay. The results of immunohistochemistry and radioimmunoassay were correlated. High performance liquid chromatographic analysis indicated that 20-30% of the total immunoreactivity co-chromatographed with guinea-pig or synthetic neurotensin. Evaluation of consecutive sections revealed different innervation patterns of neurotensin and substance P immunoreactive fibers. The findings suggest a neurotransmitter and/or neuromodulator function of neurotensin in the regulation of coronary circulation, of cardiac impulse generation and conduction, of heart muscle contractility and of cardiac reflex mechanisms. It is speculated that neurotensin might represent the efferent and substance P the afferent part of a cardiac regulatory system.     

Emerging patterns of cardiac conduction in the chick embryo: waveform analysis with photodiode array-based optical imaging.

Major difficulties investigating the developing cardiac conduction system stem from that the embryonic heart is extremely small (< 2 mm) and cardiac activation is relatively rapid (< 8 msec). The objective of this study was to investigate the electrophysiology of the embryonic chick cardiac conduction system at periseptation stages with a photodiode array-based detection method of optical mapping capable of high spatial and temporal resolution. Previous work indicated that, in chicken embryos, a switch occurs in ventricular activation pattern from immature base-to-apex to mature apex-to-base pattern at the time of ventricular septation. It was our aim to map activation in more detail to identify the active pathway or pathways of atrioventricular conduction at these particular stages. Analysis of preseptated hearts (n = 10) showed that the latest atrial activation took place just above the site of the earliest ventricular activation at the ventral left ventricular base. Analysis of postseptated hearts (n = 11) showed apex-to-base conduction consistent with activation through the maturing His-Purkinje system. Evaluation of hearts during septation revealed a gradual transition of ventricular activation patterns rather than an abrupt "switch." External pacing of preseptated hearts revealed significant slowing of interventricular conduction compared with spontaneous beats (spontaneous, 61.7 cm/sec +/- 9 cm/sec vs. paced, 36.5 cm/sec +/- 10 cm/sec). The more detailed mapping revealed that, before septation, the pattern of activation of the ventricular myocardium is consistent with direct atrial-ventricular myocardial connections at the left lateral atrioventricular junction; however, functional evidence for a preferential conduction pathway within the ventricles was present before septation.     

Structural basis of ventricular arrhythmias in human myocardial infarction: A hypothesis

The present study was undertaken using light and electron microscopic techniques to determine whether Purkinje fibers survive in the subendocardial region of anteroseptal infarcts in humans. Tissue was obtained for this purpose from 11 patients with 12 documented infarctions at the time of autopsy; six patients died within 72 hours of the infarction and five had healed infarcts. Seven of the 11 patients had ventricular arrhythmias.Light microscopic study indicated that intact cells with a normal appearance remained on the subendocardial surface, although the underlying ventricular muscle either was necrotic or was replaced by fibrous tissue. Electron microscopy demonstrated that these intact surviving cells over the surface of the infarct had few randomly oriented myofibrils, abundant glycogen, and other characteristics of Purkinje fibers. These cells could be readily distinguished from normal or infarcted ventricular muscle cells. Purkinje fibers, the most peripheral part of the conduction system, survive in extensive anteroseptal infarcts and may be the site of origin of ventricular arrhythmias.     

Cardiac sarcoidosis and sudden death. The heart may look normal or mimic other cardiomyopathies

Cardiac sarcoidosis has been known to give rise to heart failure, arrhythmias and sudden cardiac death. We have a large database of sudden cardiac death cases at the CRY Centre for Cardiac Pathology at Imperial College, London, UK in which we found 17 of 1,720 cases with a diagnosis of cardiac sarcoid. Macroscopic examination showed a variety of findings including left ventricular hypertrophy, a dilated thin-walled left ventricle ,areas of fibrosis, changes resembling arrhythmogenic right ventricular cardiomyopathy and in some cases, no gross abnormalities. Histological examination revealed large areas of fibrosis and focal lymphocytic inflammation mimicking infarction/myocarditis. Careful search had to be made for non-necrotizing granulomata, since the lymphocytic foci, fibrosis and granulation tissue often predominated throughout the heart. The conduction tissue is often not sampled at autopsy despite the history of heart block. The heterogeneous nature of the macroscopic appearance and histological findings means that widespread sampling of the heart and the conduction system is essential in cases of sudden death in order that a diagnosis of myocardial sarcoidosis is not missed.     

A histochemical study of the esterases of the rat heart

The histochemistry of esterases was studied in the rat heart, using various methods of tissue preparation and a large number of substrates, inhibitors and activators. Non-specific esterase and cholinesterase was demonstrated in the fibers of the atrioventricular conduction system, in atrial and ventricular muscle fibers, in cardiac neurons and in some of the nerve fibers of the heart. The highest concentration of both types of enzymes was found in the conduction system and in the neural elements. Pericytes and macrophages showed only non-specific esterase activity. Two broad types of non-specific esterase activity, cytoplasmic and lysosomal, were distinguished in the pericytes, macrophages and cardiac muscle fibers by the use of selective inhibitors and activators. The cytoplasmic activity is due to the presence of B and C esterases and was better demonstrated with esters of a-naphthol than with naphthol AS derivatives or indigogenic esters. The esterase activity of lysosomes appears to be due to a group of fluoride- and organophosphate-resistant enzymes, some of which are probably cathepsins.     

Fine Structure of A: Autonomic Nerve Fibers and Terminals in Human Myocardium; and B: Myocardial Changes in Congenital Heart Disease

In a histological and fine structural study of right atrial biopsy specimens from 31 patients with rheumatic heart disease (RHD), aged 7 to 46 years, and 11 patients with congenital heart disease (CHD), aged 3 to 36 years, nerve fibers or endings were seen by electron microscopy in 11 specimens. There was concurrence of ordinary axons along with terminals bearing pale cholinergic or dark adrenergic synaptic vesicles. Smaller and denser cholinergic vesicles suggested proliferation followed by exhaustion of such nerve endings. The closest proximity of nerve terminal to muscle fiber was about 100 nm. In one RHD specimen a “specific terminal cell” was present between a nerve ending and muscle fiber; in another a possible neuromuscular contact was developing at the surface of a regenerating small muscle fiber with a few myofilaments. Unmyelinated axons amidst increased subendocardial and subepicardial collagen, with prominent fibroblasts and depleted muscle fibers, were seen more frequently in specimens of CHD. Loss of myofibrils and accumulation of mitochondria, with infrequent formation of lipofuscin bodies, characterized degenerating muscle fibers in CHD also, although to a lesser degree than in RHD (reported earlier, 1985). The myocardial blood vessels in CHD tended to have pale swollen endothelial cells and narrowed lumen. The most severely affected cases of CHD were those with (1) a very wide atrial septal defect (ASD), (2) ventricular septal defect (VSD) with vegetations near the defect, (3) 1 infundibular pulmonary stenosis, and (4) Fallot's tetralogy.     

Succinate dehydrogenase activities of fibers in the rat extensor digitorum longus, soleus, and cardiac muscles

Succinate dehydrogenase (SDH) activities and cross-sectional areas (CSAs) of different types of fibers in the superficial (EDLs) and deep (EDLd) regions of the extensor digitorum longus and soleus (SOL) muscles and the left ventricular muscle of the heart (HEART) of 10-week-old male rats were determined using quantitative histochemistry and a computer-assisted image processing system. The fibers were classified as type I, type IIA, type IIB, or type IIC according to their histochemically assessed adenosine triphosphatase activities. The mean SDH activity was higher and the mean CSA was smaller in type IIA fibers than in type IIB fibers in both the EDLs and EDLd. The mean SDH activity of type IIA fibers in the SOL was higher than that of type I fibers. Fibers in the HEART showed the highest mean SDH activity and the smallest mean CSA among all fiber types in the muscles examined. There was an inverse correlation between CSA and SDH activity for the different fiber types in different muscles. These data suggest that the SDH activity of fibers in muscle is fiber type- and size-specific, and that the highest SDH activity of fibers in the left ventricular muscle of the heart contributes to their functional properties, i.e., high fatigue resistance.     

Fine Structure of A: Autonomic Nerve Fibers and Terminals in Human Myocardium; and B: Myocardial Changes in Congenital Heart Disease

In a histological and fine structural study of right atrial biopsy specimens from 31 patients with rheumatic heart disease (RHD), aged 7 to 46 years, and 11 patients with congenital heart disease (CHD), aged 3 to 36 years, nerve fibers or endings were seen by electron microscopy in 11 specimens. There was concurrence of ordinary axons along with terminals bearing pale cholinergic or dark adrenergic synaptic vesicles. Smaller and denser cholinergic vesicles suggested proliferation followed by exhaustion of such nerve endings. The closest proximity of nerve terminal to muscle fiber was about 100 nm. In one RHD specimen a “specific terminal cell” was present between a nerve ending and muscle fiber; in another a possible neuromuscular contact was developing at the surface of a regenerating small muscle fiber with a few myofilaments. Unmyelinated axons amidst increased subendocardial and subepicardial collagen, with prominent fibroblasts and depleted muscle fibers, were seen more frequently in specimens of CHD. Loss of myofibrils and accumulation of mitochondria, with infrequent formation of lipofuscin bodies, characterized degenerating muscle fibers in CHD also, although to a lesser degree than in RHD (reported earlier, 1985). The myocardial blood vessels in CHD tended to have pale swollen endothelial cells and narrowed lumen. The most severely affected cases of CHD were those with (1) a very wide atrial septal defect (ASD), (2) ventricular septal defect (VSD) with vegetations near the defect, (3) 1 infundibular pulmonary stenosis, and (4) Fallot's tetralogy.     

SYSTEMIC AMYLOIDOSIS TERMINATING IN CARDIAC INSUFFICIENCY

An autopsy case of systemic amyloidosis is presented. The patient, a 57-year-old male, died of congestive heart failure. Autopsy revealed systemic amyloidosis which involved the heart, liver, spleen, kidneys, lymph nodes, tongue, prostate, rectum, and small blood vessels of various organs. In the heart, amyloid deposited diffusely in the myocardium, subendocardial tissue, and blood vessel walls. A lot of vacuolated cardiac muscle fibers were noted. Electron microscopic examination of the myocardium revealed that amyloid fibrils surrounded most of the cardiac muscle fibers in the very close vicinity of their basement membranes. Fashion of the amyloid deposition throughout various organs and the mechanism of heart failure are discussed. ACTA PATHOL. JPN. 36:1593-1604, 1986.     

Muscle fiber orientation and connective tissue content in the hypertrophied human heart

To elucidate the structural correlates of cardiac failure in myocardial tissue, muscle fiber alignment and connective tissue volume fraction were measured at multiple sites in the left ventricular free wall and in the interventricular septum of 14 human hearts. Group 1 (five hearts; 280 +/- 20 gm.) had no evidence of cardiac disease, group 2 (five hearts; 380 +/- 30 gm.) had a history of systemic hypertension without clinical heart failure, and group 3 (four hearts;; 590 +/- 40 gm.) had both left ventricular overload and congestive failure. Fiber orientations were determined by measuring fiber angle relative to the circumferential direction (helix angle). The fraction of the myocardial volume occupied by connective tissue was determined by point counting. Our results indicate a smooth transition of helix angle from epi- to endocardial surface in the normal left ventricular free wall with nearly 55 per cent of the wall occupied by circumferentially oriented fibers near the cardiac equator (latitude of largest ventricular diameter); morphologically, the interventricular septum was nearly identical with the free wall. Fiber alignment was maintained in all three groups as was the fraction of wall occupied by circumferential fibers. Connective tissue volume fraction was, however, significantly increased (p less than 0.02) in hypertrophied hearts (groups 2 and 3) as compared with normal hearts, and at two of six sites in clinically failed hearts as compared with hypertrophied but functionally compensated hearts. Thus, muscle fiber orientation is not altered in the hypertrophied pressure-overloaded left ventricle, whereas connective tissue content is increased with the increase being greatest in the failing heart.