Quantitation of fibrosis of the heart in chronic obstructive pulmonary disease with and without cor pulmonale

This study examined the hearts of 55 patients dying of chronic obstructive pulmonary disease, with and without cor pulmonale, quantitated histologically the degree of myocardial fibrosis in the left and right ventricle, and determined the relationship to associated disease states. Comparison has been made to a control group of 17 patients free of cardiopulmonary disease. Patients with associated and advanced ischemic heart disease, as proved by marked atherosclerosis and myocardial infarction, have significantly increased myocardial fibrosis throughout all layers of the left ventricular wall in comparison to control patients or patients with chronic obstructive pulmonary disease free of associated cardiac disease. Right ventricular fibrosis was not significantly increased; however, one case showed a marked degree of fibrosis related to myocardial infarction. Subdivision of patients with chronic obstructive pulmonary disease into groups with definite anatomic right ventricular hypertrophy, a clinical diagnosis of cor pulmonale, or with chronic hypoxemia failed to show any difference in the percentage of myocardial fibrosis of the ventricles among these groups. Increased fibrosis of the right or left ventricle in patients with chronic obstructive pulmonary disease, therefore, is not related to the degree of myocardial hypertrophy pathologically, the hypoxemic state, or clinical heart failure, but to ischemic heart disease with myocardial infarction.     

Myocardial necrosis, fibrosis, and DNA synthesis in experimental cardiac hypertrophy induced by sudden pressure overload.

The development of myocardial fibrosis as a result of cardiac hypertrophy was studied in 11 cats in which the pulmonary artery was banded, six rabbits in which the ascending aorta was banded, and eight cats with various congenital cardiac anomalies. Histological examination of the myocardium revealed multifocal areas of degeneration and necrosis with healing by fibrosis in the right ventricle of cats in which the pulmonary artery was banded and in the left ventricle of rabbits in which the aorta was banded. In five of eight cats with congenital anomalies, myocardial necrosis and fibrosis were not present in spite of heart weight to body weight ratios 2-4 times greater than in the experimental models. In the other three cats, fibrosis was subendocardial or diffuse rather than multifocal as in the banded animals. This suggests that the increased connective tissue found in animals with cardiac hypertrophy induced by banding the aorta or pulmonary artery is an artifact of the preparation. Autoradiographic studies of the myocardium of pulmonary artery-banded cats indicated that all newly synthesized DNA in this model is restricted to interstitial cell and endothelial cell proliferation.     

Relation between coronary stenosis and myocardial lesions determined by a semiquantitative approach to myocardial fibrosis and hypertrophy due to ischemia

To clarify the cause of myocardial hypertrophy in ischemic heart disease, the relation between the extent of fibrosis and myocyte diameter was examined in patients with cardiac hypertrophy of unknown etiology except for coronary sclerosis. In 79 unselected cases, the heart weight tended to be higher in patients with severe coronary stenosis and fibrosis. In a morphometric study of 33 additional hearts of patients without a clinical history of hypertension, valvular disease or diabetes mellitus, 15 of which had anterior infarction, a positive correlation (r = 0.63) was observed between myocyte diameter and the percent area of fibrosis in the anterior wall of the left ventricle. In the heart of patients with severe coronary stenosis (more than 75% luminal narrowing), the regression coefficient was 0.83. The hearts of 8 patients with nontransmural infarction showed a strong correlation between myocyte diameter and fibrosis, compared with the hearts of 7 patients with transmural infarction. In most cases, the main mechanism of hypertrophy in ischemic heart disease was considered to be compensatory hypertrophy for existence of myocardial fibrosis.     

Clinico-morphological and echocardiographic parallels in myocardial hypertrophy in patients with ischemic heart disease]

Left ventricular myocardial hypertrophy was found in patients with repeated myocardial infarctions, the greatest weight of the left ventricle being noted in those with congestive heart failure. A high correlation (r = 0.78) was established between the mass of the left ventricular myocardium calculated with the aid of echocardiography and the actual weight of the left ventricle. The important compensatory role of the ventricular septum is emphasized for the cases of myocardial infarction occurring in the free wall of the left ventricle. Left ventricular hypertrophy was detected by ECG in only 25% of those ischaemic heart disease cases in whom signs of myocardial hypertrophy were revealed by echocardiography.     

MRI in chronic myocarditis

In most cases inflammatory changes of the myocardium are asymptomatic. If inflammatory changes of the myocardium manifest with clinical symptoms, the condition is termed myocarditis. Myocarditis is regarded as a major cause for sudden death of young adults and accounts for up to 20% of the cases. In Europe viral infections represent the most important cause of myocarditis. In chronic myocarditis, viremia is often absent and myocardial fibrosis and dilated cardiomyopathy (DCM) resulting in heart failure can occur. The role of cardiac MRI in chronic myocarditis is not yet well understood. MRI is a sensitive tool detecting myocardial fibrosis on late images after application of paramagnetic contrast agents. The region of contrast accumulation is defined as "late enhancement" (LE). Data are available now suggesting that differentiating fibrosis due to myocardial infarction from inflammatory causes is facilitated using MRI late images. Fibrosis after ischemic infarction includes the subendocardial layer of the myocardium. If the subendocardial layer of the myocardium is not involved in the fibrosis, infarction is unlikely and can be reliably excluded as an important differential diagnosis in the vast majority of affected patients.     

Morphometric analysis of collagen network and plasma perfused capillary bed in the myocardium of rats during evolution of cardiac hypertrophy

Summary In order to investigate the consequences of different types of cardiac hypertrophy on myocardial capillary and fibrosis density in rats we describe here, in the same hearts, the pattern of capillary bed density visualized by fluoresceine isothiocyanate dextran (FITC-dextran) and the pattern of fibrosis density as determined by automated image analysis. Pressure overload was induced by clipping one renal artery in rats (one-clip, two-kidney Goldblatt hypertension, RHV). Volume overload was induced by creation of an arteriovenous shunt between the abdominal aorta and the vena cava (aorto-caval fistula model ACF). Animals were sacrified at 1, 3 and 6 months following surgical procedure. Immediately prior to sacrifice, FITC-dextran (MW 150,000) was injected with the animal under ether anesthesia. Five minutes later, cardiac diastolic arrest was induced by the i.v. injection of potassium chloride. The heart was rapidly excised and placed in a formaldehyde solution. The degree of cardiac hypertrophy was calculated after measurement of cardiac weight. Left ventricular wall thickness and cavity area were measured by microscopic methods.Capillary density and geometry were determined by morphometric methods, under ultraviolet light microscopy, using a graphic tablet connected to a microcomputer. The degree of myocardial fibrosis, visualized with Sirius Red, was estimated by the use of automated image analysis using light microscopy.In renovascular hypertension, cardiac hypertrophy was maximum at one month (36%) and persisted through the six months of the study. This increase in cardiac mass was concentric, due to a significant increase in ventricular wall thickness and was associated with a marked increase in fibrosis and a significant decrease in subendocardial capillary density. These effects existed already one month and did not change with time.In the aorto-caval fistula model, cardiac hypertrophy was also maximum at one month (+56%), but this eccentric increase in cardiac mass was associated with no significant change in left ventricular wall thickness, but rather with a significant increase in the surface area of the left ventricular cavity. This volume overload hypertrophy was associated with a decrease in subendocardial capillary density which was negatively correlated with time. In contrast to concentric hypertrophy there was no increase in the fibrosis density compared to the sham-operated groups.Despite the identical degrees of hypertrophy, pressure and volume cardiac overload differed in a significant manner in both left ventricular wall thickness and cavity surface area. The observed changes in capillary bed and fibrosis density seem to be influenced predominantly by this change in geometry of the left ventricle.     

Diastolic function in valvular heart disease.

Diastolic dysfunction in patients with valvular heart disease is characterized by an impaired isovolumic relaxation, a normal or even enhanced early diastolic filling rate and an increased myocardial stiffness. These abnormalities do not depend on coexisting systolic dysfunction but are often combined. Several mechanisms are responsible for the occurrence of diastolic dysfunction, such as increased wall stress, altered myocardial structure, subendocardial hypoperfusion and/or diastolic calcium overload. Postoperative regression of myocardial hypertrophy is beneficial in regard to wall stress, subendocardial hypoperfusion and calcium overload but diastolic dysfunction might become worse after valve replacement due to a relative increase in interstitial fibrosis consequent to the decrease in myocyte mass (= myocardial remodeling). Persisting diastolic dysfunction with a substantial rise in left ventricular filling pressure can be observed during dynamic exercise in postoperative patients with preoperative severe pressure overload hypertrophy. Thus, diastolic dysfunction can be present as a primary derangement of cardiac function and can be unmasked as an abnormal response of diastolic filling pressure during exercise.     

Left ventricular contractility related to the state of the coronary bed

The authors studied total and segmental contractility of the left ventricular (LV) myocardium in patients with acute myocardial infarction with single and multiple coronary artery (CA) disease. The group included 75 patients with acute transmural myocardial infarction; coronary arteriography was performed in 56 of them. All patients underwent echocardiography (sector scanning), on the basis of which total (ejection fraction) and segmental parameters (segmental ejection fraction, fraction of segmental wall shortening, velocity of change of segmental area, velocity of change in segmental wall thickness) of LV contractility were calculated. Patients with single CA affection display only a moderate decrease in total ejection fraction, and an insignificant number of complications of myocardial infarction. Segmental contractility data showed severe hyperkinesis of the intact segments of the left ventricle. Multiple CA disease is associated with a marked decrease in both total and segmental contractility of the LV myocardium, and there is no hyperkinesis of the intact segments of the heart.     

Effects of left ventricular hypertrophy on the coronary circulation

Many laboratories have provided evidence to support the concept that LV hypertrophy is associated with many significant coronary perfusion abnormalities. The decreased coronary flow reserve in the presence of LV hypertrophy is implicated as the mechanism of angina in patients with aortic stenosis and normal coronary arteries. The abnormal subendocardial autoregulation found in dogs may have important implications for the abrupt treatment of hypertension in patients with LV hypertrophy. The marked increase in mortality and the wavefront of infarction in dogs with hypertension and LV hypertrophy may have striking clinical implications for the salvage of myocardium in patients with chronic hypertension and LV hypertrophy during acute myocardial infarction.     

Cellular basis of ventricular remodeling after myocardial infarction.

To determine whether acute left ventricular failure associated with myocardial infarction leads to architectural changes in the spared nonischemic portion of the ventricular wall, large infarcts were produced in rats, and the animals were sacrificed 2 days after surgery. Left ventricular end-diastolic pressure was increased, whereas left ventricular dP/dt and systolic pressure were decreased, indicating the presence of severe ventricular dysfunction. Absolute infarct size, determined by measuring the fraction of myocyte nuclei lost from the left ventricular free wall, averaged 63%. Transverse midchamber diameter increased by 20%, and wall thickness diminished by 33%. The number of mural myocytes in this spared region of the left ventricular free wall decreased by 36% and the capillary profiles by 40%. Thus, side-to-side slippage of myocytes in the myocardium occurs acutely in association with ventricular dilation after a large myocardial infarction. In order to analyze the chronic consequences of myocardial infarction on ventricular remodeling, a second group of experiments was performed in which the left coronary artery was ligated and the functional and structural properties of the heart were examined 1 month later. In infarcts affecting an average 38% of the free wall of the left ventricle (small infarcts), reactive hypertrophy in the spared myocardium resulted in a complete reconstitution of functioning tissue. However, left ventricular end-diastolic pressure was increased, left ventricular dP/dt was decreased, and diastolic wall stress was increased 2.4-fold. After infarctions resulting in a 60% loss of mass (large infarcts), a 10% deficit was present in the recovery of viable myocardium. Functionally, ventricular performance was markedly depressed, and diastolic wall stress was increased 9-fold. The alterations in loading of the spared myocardium were due to an increase in chamber volume and a decrease in the myocardial mass/chamber volume ratio that affected both infarct groups. Thus, decompensated eccentric ventricular hypertrophy develops chronically after infarction and growth processes in myocytes are inadequate for normalization of wall stress when myocyte loss involves nearly 40% or more of the cells of the left ventricular free wall. The persistence of elevated myocardial and cellular loads may sustain the progression of the disease state toward end-stage congestive heart failure.     

Mechanisms of cardiac fibrosis in hypertension

Changes in the composition of cardiac tissue develop in hypertensive patients with left ventricular hypertrophy (ie, hypertensive heart disease) and lead to structural remodeling of the myocardium. One of these changes is related to the disruption of the equilibrium between the synthesis and degradation of collagen types I and III molecules, which results in an excessive accumulation of collagen types I and III fibers within the myocardium. Myocardial fibrosis is the consequence of a number of pathologic processes mediated by mechanical, neurohormonal, and cytokine routes. The clinical relevance of fibrosis is that it may contribute to heart failure and other cardiac complications in patients with hypertensive heart disease. This brief review focuses on the mechanisms of hypertensive myocardial fibrosis.     

Impending myocardial infarction in a patient with marked left ventricular hypertrophy and normal coronary arteriogram--a case report

A middle-aged woman with long-term uncontrolled arterial hypertension developed a clinical picture of impending myocardial infarction. A normal coronary arteriogram was obtained. However, left heart catheterization showed a marked increase in left ventricular end-diastolic pressure, while left angiocardiography revealed marked left ventricular hypertrophy. She was successfully treated with a beta-blocking and calcium-antagonist agent. The present case shows that an impending myocardial infarction may occur in patients having normal coronary arteriogram but with left ventricular hypertrophy secondary to arterial hypertension.     

Structural changes in the myocardium during diabetes-induced cardiomyopathy

Diabetes mellitus (DM) is a major metabolic disorder currently affecting over 250 million people globally. It costs the worldwide health services almost £800 billion annually to diagnose, treat and care for patients with diabetes. DM is predicted to rise to 350 million by 2030. If left unmanaged, DM can lead to numerous long-term complications including micro- and macro-angiopathy and heart failure (HF). Most diabetics usually die as a result of HF resulting from diabetes-induced coronary artery disease and cardiomyopathy. Coronary artery disease and cardiomyopathy are normally preceded by hyperglycaemia (HG). This review examines the structural changes, which occur within the myocardium and cardiomyocytes during exposure of the heart to diabetes-induced HG and HG-induced oxidative stress. HG and the resulting oxidative stress are associated with marked myocardial hypertrophy and fibrosis compared to control heart. At the ultrastructural level, cardiomyocytes subjected to chronic HG and subsequent oxidative stress display swollen mitochondria, reduced mitochondrial number and defective myofibrils and intercalated discs. Evidence from many studies shows that both type 1 and type 2 diabetes-induced HG can cause myocardial fibrosis, mitochondriopathy, myocyte hypertrophy and deranged myofibrils. All of these structural changes may eventually result in HF if left untreated.     

Prevention of myocardial ischemia during coronary angioplasty: a simple new method for distal antegrade arterial blood perfusion

The nature and cause of the striking regional dilatation of the microvasculature of the subendocardial myocardium seen in some patients with ischemic heart disease are unknown. To examine this question, we reviewed nine patients in whom regions of the left ventricular free wall had marked prominence of subendocardial vasculature on postmortem arteriography. All hearts had severe diffuse atherosclerosis of major epicardial coronary arteries. Histologic findings, including serial transmural sections, showed extreme dilatation of arterioles, capillaries, and venules of the subendocardial third of the myocardium. In this same region myocytes showed atrophy, vacuolization (a marker of chronic ischemia), and small foci of necrosis and fibrosis. The generalized small-vessel dilatation with adjacent ischemic myocytes makes it improbable that the vascular changes are caused by collateral flow. Previous anatomic studies have shown artery-vein arrangements in the myocardium providing for countercurrent regulation of regional blood flow. This mechanism, which produces vascular enlargement on the basis of metabolic need, may explain the regional variceal transformation of the subendocardial microvasculature seen with chronic ischemia.     

Slowly progressive heart failure due to subepicardial myocardial fibrosis in a patient with chronic pericardial effusion

A 65-year-old woman was admitted to hospital because of orthopnea. She had been followed-up for chronic pericardial effusion detected by echocardiography 10 years previously. Initial echocardiography showed that the left ventricular diastolic diameter (LVDd) was 39 mm and percent fractional shortening (%FS) was 33.3%. Neither fluid samples nor a pericardial biopsy specimen identified the etiology. Cardiac tamponade was not evident, and C-reactive protein and creatine-kinase values were within normal limits. During follow-up, the %FS decreased gradually, but the LVDd remained unchanged. On admission, echocardiography showed that the %FS was 12.5% and LVDd was 40 mm. She developed intractable hyponatremic heart failure with bilateral pleural effusion. Autopsy findings revealed that infiltration of small lymphocytes in the epicardium had penetrated into the subepicardial myocardium. The subepicardial myocardium and the interventricular septal myocardium were diffusely replaced by fibrosis, which could have induced restrictive diastolic heart failure and reduced left ventricular contractility. The fibrosis was not detected in the epicardium itself nor the subendocardial myocardium. This is the first report describing diffuse subepicardial myocardial fibrosis in a patient with chronic pericardial effusion and progressive heart failure.     

Constituents of the human ventricular myocardium: connective tissue hyperplasia accompanying muscular hypertrophy

Left-sided congestive heart failure may be secondary to decreased left ventricular myocardial compliance in some patients. To investigate the anatomic basis for altered wall stiffness, morphometric determinations of muscle cell nuclear density and percent of myocardium consisting of muscle cells were made for right and left ventricular free wall and septum in 127 hearts with normal coronary arteries. The hearts were normal (33 patients), had left ventricular hypertrophy (28 patients), right ventricular hypertrophy (25 patients), or chronic dilatation (41 patients). With cardiac enlargement, the average percent of myocardium consisting of muscle did not change from the approximately 75% value characteristic of normal hearts. In contrast, muscle cell nuclear density decreased proportionate to cardiac enlargement, demonstrating that muscle cell hypertrophy, not hyperplasia, is the basis for weight increase. Some hearts with marked longstanding dilatation also had perivascular and interstitital "striae" of connective tissue differing from replacement fibrosis. An increase in epicardial coronary artery caliber commensurate with increased heart weight suggests that ischemia is not the basis of connective tissue increase. The results show that cardiac muscle cell hypertrophy is accompanied by commensurate increase in interstitial connective tissues. This pattern of myocardial growth with cardiac enlargement may produce increased myocardial stiffness simply as a result of increased wall thickness, and may lead to left-sided congestive heart failure.     

Changes in regional myocardial blood flow and variable development of hypertrophy after aortic banding in puppies

Supravalvar aortic banding was performed in 6 to 12 week puppies. Sixteen animals were studied 7.3 (3.5 to 10) months later, closed-chested under morphine-chloralose, catheters being positioned in the great vessels and heart, including the left atrium for microsphere injection. Compared with 11 controls, eight dogs developed biventricular hypertrophy, four isolated left ventricular hypertrophy and four had no hypertrophy. The left ventricular systolic pressure was similar (P greater than 0.05) in these 3 banded groups (mean, 30 +/- 2 [SEM] kPa, [222 +/- 16 mmHg], n = 16). The left ventricle was divided into three coronal slices with approximately 59 samples being taken from subendocardial, midwall, and subepicardial layers and additional samples from the atria and right ventricle for regional myocardial flow measurement. As left ventricular hypertrophy increased, the subendocardial/subepicardial flow ratio decreased (r = -0.8). Heterogeneity of left ventricular regional myocardial flow, including a base-to-apex decrease in flow, present in controls, was markedly reduced in the banded dogs. Analysis of variance was found to be the most sensitive test for detecting left ventricular perfusion abnormalities since in banded dogs without hypertrophy, total and regional subendocardial/subepicardial flow ratios were not significantly different from control values, whereas the subendocardial circumferential flow pattern determined by analysis of variance was significantly different from control in these dogs (P less than 0.05).     

Spontaneously occurring hypertrophic cardiomyopathy in the rat. I. Pathologic features

The gross anatomic and microscopic appearance of the hearts of young and adult WKY/NCrj rats was examined in comparison with that of normotensive Wistar and SHR/NCrj rats. In a substantial number of the WKY rats, the heart weight and thickness of ventricular septum were much greater than those of the Wistar and SHR rats. The ventricular septum to left ventricular free wall thickness ratio was greater than 1.3 in about one sixth of the WKY rats. In most of the hypertrophied WKY hearts, the transverse area of the left ventricular cavity was smaller in relation to the wall area than in the Wistar and SHR rat hearts, although in a few it was greater. Abnormal fiber arrangement, myocyte hypertrophy, and myocardial fibrosis were far more prominent in the hypertrophied myocardium of the WKY rats compared with the Wistar or SHR rats. Intramural arteries with marked wall thickening existed frequently in the hypertrophied and dilated hearts. Electron microscopic examination revealed marked disarrangement of bundles of myofilaments and widened Z-bands in the hypertrophied myocardium. Blood pressure was not elevated in the rats with cardiac hypertrophy. These findings show that a disease of the myocardium with the pathologic features similar to those of hypertrophic cardiomyopathy in man occurs spontaneously in rats.     

Clinical aspects of hypertensive myocardial fibrosis.

Myocardial fibrosis is one of the histologic constituents of myocardial remodeling present in hypertensive patients with hypertensive heart disease. In fact, an exaggerated interstitial and perivascular accumulation of fibrillar collagens type I and type III has been found in the myocardium of patients with arterial hypertension and left ventricular hypertrophy. Hypertensive myocardial fibrosis has been shown to facilitate abnormalities of cardiac function, coronary reserve, and electrical activity that adversely affect the clinical outcome of hypertensive patients. Therefore, development of noninvasive tools for the monitoring of myocardial fibrosis and pharmacological strategies aimed to promote the regression of fibrosis could be of particular relevance in the clinical treatment of patients with hypertensive heart disease.     

Post-ischemic myocardial fibrosis occurs independent of hemodynamic changes

OBJECTIVES: Myocardial fibrosis is a major component of ventricular remodeling after large myocardial infarction (MI). The present study tests the hypothesis that post-ischemic myocardial fibrosis can occur independent of hemodynamic changes. METHODS: A mouse model of distal left coronary artery ligation was established to induce a small infarct (less than 15% of the left ventricle) in order to avoid significant mechanical overload after permanent myocardial ischemia. Left heart catheterization was performed to evaluate the post-infarct hemodynamics. Tissues from both ischemic and non-ischemic myocardium were examined for mRNA and protein expression at 24, 72 h and 7 days after ligation. RESULTS: Heart/body weight ratio after ligation was increased by approximately 10% over sham control although there is no statistically significant difference in hemodynamic parameters between the two groups. Non-ischemic myocardium distant from the infarct site showed molecular evidence of myocardial fibrosis 72 h and 7 days after ligation. There was marked up-regulation of mRNAs for extracellular matrix (ECM) proteins and their cross-linking enzyme, such as collagens type I, III and VI, and lysyl oxidase. Immunohistochemical study confirmed that the expression of these ECM proteins was significantly increased in the non-ischemic myocardium after 7 days. TGF-beta1 was up-regulated after 72 h in both ischemic and non-ischemic myocardium. CONCLUSIONS: Molecular and histopathological findings demonstrate that abnormal myocardial fibrosis can be induced by a small infarct independent of secondary hemodynamic changes.