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PubMed1995

Aldosterone and heart failure.

In untreated congestive heart failure, aldosterone plasma concentrations are elevated in proportion to the severity of the disease and are further increased by the use of diuretic treatment. Angiotensin II, plasma potassium concentration, and corticotropin are the major stimulators of aldosterone synthesis. During angiotensin converting enzyme (ACE) inhibition, the role of alternative major or minor regulatory mechanisms may become significant. This may explain why during continuous ACE inhibition, after an initial reduction, plasma aldosterone measurements may subsequently increase to pretherapeutic levels. In addition to causing sodium and water retention, aldosterone contributes to hypokalaemia and hypomagnesaemia, which may induce electrical instability and death of cardiac myocytes. Aldosterone is also one factor involved in cardiac hypertrophy and fibrosis, which, together with myocardial cell death, may underlie progressive adverse myocardial remodelling. Evidence for a direct vascular effect of aldosterone suggests that this hormone may contribute to generalized vasoconstriction. Elevated plasma aldosterone levels can also contribute to depression of baroreflex sensitivity, and they are associated with increased mortality in patients with severe heart failure. Experimental and clinical research should be further expanded to investigate the potential benefits of opposing the effects of aldosterone by use of specific antagonists or other potentially more potent pharmacological agents with favourable side-effect profiles.

Aldosterone↗
PubMed1990

An autopsy case of cardiomyopathy with restrictive physiology in a child.

An autopsy case of cardiomyopathy with restrictive physiology associated with subendocardial myocardial necrosis and fibrosis in a seven-year-old child is described. Cardiac catheterization showed high left ventricular end-diastolic pressure with a dip-and-plateau pattern. Macroscopically, marked dilatation with fibroelastosis in both atria and mild dilatation in both ventricles were observed. Histologic examination revealed extensive subendocardial necrosis with marked disorganization of myocardial cells and moderate arteriolosclerosis. We speculate that these extensive myocardial lesions, which contributed to the restrictive hemodynamic changes, could have been induced by anoxia or a Ca2+ transport abnormality of unknown cause.

Cardiomyopathy, Restrictive↗
PubMed1999

L-NAME-induced protein remodeling and fibrosis in the rat heart.

The aim of the present study was to determine whether NO deficiency itself or rather the elevation of systolic blood pressure is responsible for the protein and structural remodeling of the heart during hypertension induced by long-term treatment by nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Three groups of rats were investigated. The first group served as control. In the second group L-NAME was given in the dose of 20 mg/kg/day in the drinking water and in the third group L-NAME was given in the dose of 40 mg/kg/day during 4 weeks. While L-NAME treatment in both doses caused essentially the same increase in systolic blood pressure (SBP), NO synthase activity and cGMP concentration in the left ventricle decreased by 17% and 13%, respectively in the 20 mg/kg/day L-NAME group and by 69% and 27%, respectively in the 40 mg/kg/day L-NAME group. The protein profile of the left ventricle in both L-NAME groups was characterized by an increased concentration of metabolic proteins. Nevertheless, a significant increase in the concentration of pepsin-soluble collagenous proteins and the concentration of hydroxyproline in pepsin-insoluble collagenous proteins was found only in the group receiving 40 mg/kg/day L-NAME. The morphometric evaluation revealed a significant increase in myocardial fibrosis in both L-NAME groups. However, this was more pronounced in the 40 mg/kg/day L-NAME group. It is concluded that NO deficiency resulted in significant enhancement of fibrotic tissue growth in proportion to the administered L-NAME dose, while SBP was increased similarly in both L-NAME groups. Thus, NO deficiency rather than hemodynamic changes appears to be crucially involved in collagenous protein and fibrotic tissue changes of the left ventricle in hypertension induced by L-NAME.

Animals↗
PubMed2006

Treatment of combined aortic regurgitation and systemic hypertension: Insights from an animal model study.

BACKGROUND: Hypertension (HT) and aortic valve regurgitation (AR) often coexist but the specific impacts of AR + HT on the left ventricle (LV) are still unknown. The best treatment strategy for this combination of diseases is also unclear. The objectives of this study were 1) to evaluate LV function, remodeling and 2) to assess the effects of the angiotensin-converting enzyme (ACE) inhibitor captopril (C) in rats with AR +/- HT in spontaneously hypertensive rats (SHR). METHODS: Animals were grouped as follows: normotensive (NT) Wistar-Kyoto, NT + AR, hypertensive SHR (HT), and HT + AR receiving or not captopril (150 mg/kg/d). Hearts were evaluated in vivo by echocardiography and harvested for tissue analysis after 6 months of evolution. RESULTS: The HT + AR rats had the worst LV hypertrophy (LVH), subendocardial fibrosis, and lowest ejection fraction. Captopril normalized BP in HT and HT + AR, but could not prevent LVH in HT + AR as well as it did in isolated HT. The LV ejection fraction remained below normal in HT + AR + captopril compared to HT alone + captopril. Cardiomyocyte hypertrophy remained in HT + AR + captopril but was normalized in HT + captopril. Subendocardial fibrosis was reduced by captopril in HT + AR. CONCLUSIONS: The AR + HT rats had the most severe myocardial abnormalities. High dose captopril was effective to slow LVH and preserve normal LV ejection fraction in isolated HT or AR, but was less effective when both pathologies were combined. Prohypertrophic stimuli clearly remain active in HT + AR despite ACE inhibition. These results suggest that a very aggressive medical treatment strategy may be required to optimize LV protection when AR and HT co-exist.

Animals↗
PubMedDate not supplied

[Extensive myocardial fibrosis in an 8-month old infant following an inflammatory condition of probable viral origin].

The authors found lesions of inflammatory-fibrotic character in the myocardium of an 8-month-old infant in whom during the first 7.5 months of life no signs of disease were observed. At the end of the 8th month of life the signs of upper respiratory tract infection appeared. In view of rapidly deteriorating health condition, the infant was admitted to hospital, where severe heart failure was revealed, which became the cause of death after three weeks of treatment. The authors supposed that viral myocardial infection initiated the inflammatory process which--after activation of autoimmune mechanisms--led to vast destruction of myocardial fibres and development of fibrous connective tissue.

Autoimmune Diseases↗
PubMed2004

Global remodeling of the ventricular interstitium in idiopathic myocardial fibrosis and sudden cardiac death.

OBJECTIVE: Characterization of a distinct, and as yet unexplained phenotype of sudden cardiac death (SCD). BACKGROUND: In a subgroup of patients with SCD, postmortem findings are limited to isolated idiopathic myocardial fibrosis (IMF). The absence of confounding factors may facilitate evaluation of the relationship between myocardial fibrosis and ventricular arrhythmogenesis. METHODS: Six patients with IMF were identified from a postmortem, consecutive 13-year series of 270 subjects presenting with SCD. Ventricular interstitial remodeling was assessed quantitatively and qualitatively and comparisons made with 6 age- and sex-matched control subjects who suffered noncardiac death. Myocardial collagen volume fraction and perivascular fibrosis ratio were determined and evidence for inflammatory response and apoptotic cell death was sought. The potential role of transforming growth factor beta 1 (TGF-beta(1)) in the pathogenesis of IMF was evaluated. RESULTS: Overall myocardial collagen volume fraction was 1.6-fold higher in IMF (mean age 34 +/- 4 yrs) vs. controls (mean age 34 +/- 4 yrs, .022 +/- .001 vs .013 +/- .001; P < .001). Collagen volume fraction increase was diffuse but disproportionately so in the LV inferior wall (3.4-fold increase; .035 +/- .005 vs .012 +/- .018; P < .001). Perivascular fibrosis ratio was also increased (.770 +/- .014 vs .723 +/- .010; P = .007). There was no evidence of either myocardial inflammatory response or myocyte apoptosis in cases or controls. Expression of TGF-beta(1) was significantly increased in IMF vs controls. CONCLUSION: IMF involves diffuse and heterogeneous remodeling of the ventricular interstitium, with a predilection for the LV inferior wall. TGF-beta(1) is a potential mediator of interstitial remodeling in IMF and SCD.

Adult↗
PubMed2006

[Heart involvement in systemic sclerosis].

Primary myocardial involvement is common in systemic sclerosis. Increasing evidence strongly suggests that this involvement is related to repeated focal ischemic injury causing irreversible myocardial fibrosis. The underlying mechanism appears to be microcirculatory impairment with abnormal vasoreactivity, with or without structural vascular abnormalities. Clinically evident cardiac involvement is recognized to be a poor prognostic factor. Pericardial involvement is frequent but usually asymptomatic. Conduction system abnormalities appear common but not serious, while arrhythmias may be life-threatening. No significant valvular involvement appears to be associated with systemic sclerosis. Treatment for myocardial involvement includes long-term systematic administration of calcium channel blockers and possibly angiotensin-converting enzyme inhibitors, frequently given at high dosage.

Angiography↗
PubMed1992

Regulatory mechanisms of myocardial hypertrophy and fibrosis: results of in vivo studies.

Left ventricular hypertrophy is a major risk factor associated with the appearance of adverse cardiovascular events. A distortion in myocardial structure, mediated by an abnormal accumulation of fibrillar collagen within the adventitia of intramyocardial coronary arteries and neighbouring interstitial spaces, alters the electrical and mechanical behaviour of the myocardium. The mechanisms responsible for the regulation of cardiac myocyte growth and collagen accumulation are therefore of considerable interest. Herein we review results of in vivo studies conducted in the authors' laboratory that addressed these issues in various experimental models. The findings indicate that in arterial hypertension myocardial hypertrophy is related to ventricular systolic pressure work. Myocardial fibrosis, on the other hand, is not related to haemodynamic workload, but rather the presence of mineralocorticoid excess relative to sodium intake and excretion. Accordingly, fibrosis can appear in both the hypertensive left and non-hypertensive right ventricles. Pharmacological probes, administered in variable doses, were used to further test and support this hypothesis. In both primary and secondary hyperaldosteronism, it was possible to prevent the pathological structural remodelling of the myocardium with an aldosterone receptor antagonist, while in unilateral renal ischaemia ACE inhibition was similarly cardioprotective. Other studies demonstrated that it was feasible to regress the fibrous tissue response and normalise diastolic stiffness. This concept of cardioreparation suggests that heart failure due to this type of structural remodelling may be reversible.

Animals↗
PubMed1988

[Prognosis of hypertrophic cardiomyopathy: echocardiographic and postmortem histopathologic study of 30 patients].

To clarify the influence of cardiac function of myocardial histologic lesions on the prognosis of hypertrophic cardiomyopathy (HCM), most recent echocardiographic findings of 30 deceased patients were reviewed. In 12 patients, histological sections from the left ventricular transverse plane made at necropsy were examined. According to the main causes of death, patients were categorized into four groups as sudden death (17 cases), heart failure death (four cases), embolic death (four cases), and non-cardiac death (five cases). 1. Clinically, atrial fibrillation and heart failure (NYHA III, IV) were frequently observed in heart failure and embolic groups. 2. Echocardiographically, left ventricular wall thickness did not differ among the four groups, but percent fractional shortening was significantly smaller in heart failure group than in non-cardiac group, and left ventricular end-diastolic dimension (LVDd) and left atrial dimension were significantly greater in heart failure group than in non-cardiac group. The normalized rapid filling rate was less in heart failure, embolic, sudden death and non-cardiac groups in that order. 3. Histopathologically, the mean myocyte diameter (MD) and percent area of disarray (%D) did not differ among the four groups, but % area of massive fibrosis (MF) greater than 2 mm2 was larger in heart failure, embolic, sudden death and non-cardiac groups in that order, especially in heart failure group. 4. Comparison of echocardiographic and histopathological findings: Though MD and %D did not correlate with any echocardiographic indices, %MF correlated significantly with LVDd (r = 0.83, p less than 0.005), and correlated inversely with the normalized rapid filling rate (r = -0.80, p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1985

Endomyocardial biopsy detection of acute rejection in cardiac allograft recipients.

Endomyocardial biopsy provides a safe, reliable, morphologic index of acute rejection and has an important role to play in the management of patients in whom acute rejection occurs. Repeated endomyocardial biopsies are well tolerated, permitting monitoring of acute rejection in cardiac recipients. Some patients have undergone over 30 serial biopsies. Adequate sampling requires at least four pieces of tissue. The biopsies are graded in the following manner: Mild acute rejection is characterized by a perivascular and mild interstitial infiltrate of pyroninophilic lymphoblasts without myocyte necrosis. Moderate acute rejection has an increased infiltrate extending into the interstitium and causing focal myocyte necrosis. This requires augmentation of immunosuppression. Severe acute rejection, which is more difficult to reverse, includes a more prolific infiltrate with the addition of neutrophils, hemorrhage, and increased myocyte necrosis. Ongoing acute rejection implies that the degree of acute rejection is the same, or worse, than the previous biopsy. Resolving or resolved acute rejection shows reparative changes with diminishing or absent inflammatory infiltrate following treatment. Recipients treated with Cyclosporin-A develop rejection and respond to treatment more slowly than with conventional treatment. This group also develops endocardial infiltrates and a dose-related fine perimyocytic cardiac fibrosis. The endomyocardial biopsy is also useful in identifying infectious agents, for example, toxoplasmosis in cardiac recipients.

Acute Disease↗
PubMedDate not supplied

Morphological aspects of the myocarditis and myositis in Calomys callosus experimentally infected with Trypanosoma cruzi: fibrogenesis and spontaneous regression of fibrosis.

Calomys callosus a wild rodent, is a natural host of Trypanosoma cruzi. Twelve C. callosus were infected with 10(5) trypomastigotes of the F strain (a myotropic strain) of T. cruzi. Parasitemia decreased on the 21st day becoming negative around the 40th day of infection. All animals survived but had positive parasitological tests, until the end of the experiment. The infected animals developed severe inflammation in the myocardium and skeletal muscle. This process was pronounced from the 26th to the 30th day and gradually subsided from the 50th day becoming absent or residual on the 64th day after infection. Collagen was identified by the picro Sirius red method. Fibrogenesis developed early, but regression of fibrosis occurred between the 50th and 64th day. Ultrastructural study disclosed a predominance of macrophages and fibroblasts in the inflammatory infiltrates, with small numbers of lymphocytes. Macrophages had active phagocytosis and showed points of contact with altered muscle cells. Different degrees of matrix expansion were present, with granular and fibrillar deposits and collagen bundles. These alterations subsided by the 64th days. Macrophages seem to be the main immune effector cell in the C. callosus model of infection with T. cruzi. The mechanisms involved in the rapid fibrogenesis and its regression deserve further investigation.

Animals↗
PubMed1989

[Ultrastructural study of left ventricular myocardium in mitral regurgitation--correlations with postoperative cardiac functions].

Light and electron microscopic examination was carried out in tissue samples which were obtained from the left ventricular free wall in 21 patients with mitral regurgitation during open-heart surgery. Their correlations with postoperative cardiac functions were also studied. The area of the interstitial fibrosis (%fib) was calculated from the light microscopic examination of the tissue samples, and changes of intracellular structures were expressed in scores by means of electron microscopy (EM-SCORE). Postoperative hemodynamics were studied with echocardiography before and after exercise. The hemodynamic parameters consisted of SVI, CI, EF, FS, mVcf and percent changes of these parameters before and after exercise. 1. EM-scores correlated with EF, FS and mVcf at rest with correlation coefficient of -0.653, -0.629 and -0.712 respectively and their significant levels were all less than 0.005. They also correlated with EF, FS and mVcf after exercise with correlation coefficient of -0.665 and -0.708 respectively and their significant levels were all less than 0.005. They also correlated with %delta EF, %delta FS and %delta Vcf with correlation coefficient of -0.79, -0.76 and -0.811 respectively and their significant levels were all less than 0.005. 2. Percent fibrosis did not correlated with the hemodynamics at rest. But they correlated with EF, FS after exercise with correlation coefficient of -0.577 and -0.599 respectively and their significant level reached less than 0.01. They also correlated with %delta EF, %delta FS and %delta mVcf with correlation coefficient of -0.584, -0.599 and -0.571 respectively and their significant levels were all less than 0.01. 3. There were no correlations between EM-score and %fib. 4. There were significant correlations between left ventricular function and myocardial morphology, in patients with mitral regurgitation. The patients with EM-score over 7 and %fib. over 14% showed poor left ventricular function and poor cardiac reserve postoperatively.

Adult↗
PubMed1986

[Scintigraphy of the myocardium in postinfarct cardiac fibrosis].

The authors conducted a scintigraphic study of 50 patients with a 2-7 year history of myocardial infarction and clinical findings of postinfarction myocardiofibrosis. 201Tl-chloride with the activity of 74 MBq and the Picker 500 magna-scanner (USA) were employed. Four projections were used in the study. It was stressed that in anterior myocardial infarction the best positions were the front and front-left-oblique ones (30 and 45 degrees) and in posterior myocardial infarction the front-left-oblique one (75 degrees). A conclusion has been made as to a high sensitivity of the method to confirm postinfarction myocardiofibrosis represented in the form of a zone with disturbed perfusion. The authors underlined a high value of the method in cases accompanied by conductive disorders as the information value of a scintigram exceeded that of ECG.

Adult↗
PubMed2000

Calcineurin inhibitor attenuates the development and induces the regression of cardiac hypertrophy in rats with salt-sensitive hypertension.

BACKGROUND: It remains unclear how hemodynamic overload induces cardiac hypertrophy. Recently, activation of calcium-dependent phosphatase, calcineurin, has been elucidated to induce cardiac hypertrophy. In the present study, we examined the role of calcineurin in load-induced cardiac hypertrophy by using Dahl salt-sensitive (DS) rats, which develop both pressure and volume overload when fed a high salt diet. METHODS AND RESULTS: In the DS rat heart, the activity of calcineurin was increased and cardiac hypertrophy was induced by high salt diet. Treatment of DS rats with the calcineurin inhibitor FK506 (0.1 or 0.01 mg/kg twice daily) from the age of 6 weeks to 12 weeks inhibited the activation of calcineurin in the heart in a dose-dependent manner and attenuated the development of load-induced cardiac hypertrophy and fibrosis without change of hemodynamic parameters. Additionally, treatment with 0.1 mg/kg twice daily but not with 0.01 mg/kg twice daily of FK506 from the age of 12 weeks to 16 weeks induced regression of cardiac hypertrophy in DS rats. Load-induced reprogramming of gene expression was also suppressed by the FK506 treatment. CONCLUSIONS: These results suggest that calcineurin is involved in the development of cardiac hypertrophy in rats with salt-sensitive hypertension and that inhibition of calcineurin could induce regression of cardiac hypertrophy.

Animals↗
PubMed1998

[Morphological studies of myocardial fibrosis in different types of Keshan disease].

OBJECTIVE: To clarify the localization, distribution, content and type of collagen in the myocardium of patients with Keshan disease (KD). METHODS: Picrosirium red staining, polarization microscopy and image analysis were used to study autopsy specimens from 335 KD patients. RESULTS: A loose network of collagen and a higher ratio of type III collagen were found in the myocardial scar tissues of acute KD patients. In the myocardial scar tissues from chronic KD patients, the collagen fibers were dense, the ratio of type I collagen was higher, the ratio of type I to type III is increased in chronic KD and decreased in acute KD. The amount of collagen in non-necrotic regions was significantly higher than that of the controls. CONCLUSION: The degeneration and necrosis of myocytes in KD is associated with disorders of collagen metabolism and with structural modelling of collagen.

Cardiomyopathies↗
PubMed1986

Myocardial mechanics in allylamine-induced myocardial fibrosis.

To examine the effect of fibrosis on myocardial mechanics, we studied isolated left ventricular papillary muscles from 18 rats given 0.1% allylamine, an agent known to cause myocardial fibrosis, in drinking water for 4-8 wk. Six control rats were given tap water. Left ventricular hydroxyproline concentration was higher in the allylamine-treated group [3.47 +/- 2.12 vs. 2.10 +/- 0.66 (SD) micrograms/mg dry wt; P less than 0.01]. Because of variable and heterogeneous involvement of the ventricle by fibrosis, preparations from allylamine-fed rats were divided into two subgroups; data from four papillary muscles with more than 25% fibrosis by point counting (AL-B group) were compared with eight control muscles from nonallylamine-treated rats. A third subgroup of nine muscles from allylamine-treated rats but with normal left ventricular hydroxyproline concentration and fibrosis as determined by point counting served as another control group (AL-A) for the evaluation of effects of allylamine not due to fibrosis. Myocardial fiber diameters of AL-B preparations were significantly larger than other groups (controls, 12.1 +/- 1.7 microns; AL-A group, 12.7 +/- 1.7 microns; AL-B group, 18.0 +/- 1.2 microns; P less than 0.01). Passive and active stiffness constants in AL-B muscles were significantly increased compared with control and AL-A preparations (P less than 0.05). Electromechanical delay plus time to peak tension and the time for tension to fall from its peak to one-half of that value at the peak of the length-tension curve were significantly prolonged in AL-B muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

Allylamine↗
PubMed1987

[Relationships between distribution of disorganized cardiac muscle cells and disease state in hypertrophic cardiomyopathy].

Congestive heart failure is rare in hypertrophic cardiomyopathy (HCM). Therefore, disorganization of the cardiac muscle cells, a histological hallmark of HCM, has not been associated with reduced ventricular contraction. We performed a clinicopathological study of 18 patients with HCM to determine whether disorganization contributes to dilatation and impaired contraction of the ventricles, resulting in affecting the disease condition. The subjects were classified into Group A (11 patients) without dilatation of the ventricular cavities after formalin fixation at autopsy (left 11.9 ml and right 19.1 ml), Group B (two patients) with dilatation of the left but without of the right ventricular cavity (left 31.9 ml and right 25.6 ml), and Group C (five patients) with biventricular dilatation (left 38.6 ml and right 36.8 ml). Various parameters were compared among the three groups. The mean age of the patients was 44.0 years for Group A, 18.5 for Group B and 10.2 section for Group C. The mean cardiothoracic ratio was 51.8% (n = 7) for Group A, 53% (n = 1) or Group B, and 74.0% section for Group C. Obstruction of the left ventricular outflow tract was observed in 100% (n = 8) of the Group A patients, in 0% section of the Group B patients, and in 20.0% section of the Group C patients. The mean left ventricular ejection fraction was 81.0% (n = 5) in Group A, 65.5% in Group B and 39.0% section (n = 2) in Group C. None of the Group A patients had chronic congestive heart failure, whereas all Group C patients died of this condition. Using transverse and longitudinal tissue sections from the ventricles, and a quantitative method employing light microscopy, we determined the area of the myocardium characterized by disorganization and interstitial fibrosis. Septal disorganization was observed in 67.4%, 83.4% and 91.1% section of the transverse sections in Groups A, B and C, respectively, and in 17.0%, 24.9% and 63.5% section of the longitudinal sections in the respective groups. As for the left ventricular free wall, disorganization involved 21.2%, 69.4% section and 90.8% section of the transverse sections and 15.9%, 34.9% section and 38.1% section of the longitudinal sections in Groups A, B and C, respectively. In the right ventricular free wall, there was disorganization in 17.7%, 20.4% and 84.3% section of the transverse sections in 12.4%, 11.5% and 57.0% section of the longitudinal sections in the respective groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1995

Aldosterone: intracellular receptors in human heart.

It has been suggested that aldosterone exerts direct effects on heart functioning, in particular by inducing cardiac fibrosis. We examined human heart tissue for the expression of aldosterone receptors (mineralocorticoid receptors, MRs) and of the MR-protecting enzyme, 11 beta hydroxysteroid dehydrogenase (11 beta HSD). In situ hybridization using cRNA probes specific for human MRs revealed the presence of mRNA encoding for MRs in cardiomyocytes. Immunohistochemistry with specific antibodies against the MR exhibited the expression of MR protein in cardiomyocytes. In contrast, intramyocardial small blood vessels showed no evidence of immunolabelling. A distinct 11 beta HSD activity, which was nicotinamide-adenine dinucleotide dependent, was also demonstrated in human cardiac tissue. These results illustrate that all the components required for a specific aldosterone effect are present in the human heart.

11-beta-Hydroxysteroid Dehydrogenases↗