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PubMed1990

Comparative study of dilated cardiomyopathy and specific heart muscle diseases from pathophysiological aspects--echocardiographic observation.

To investigate the causative factors of dilated cardiomyopathy (DCM), 29 DCM patients were echocardiographically and histopathologically compared with 17 patients with specific heart muscle diseases mimicking DCM. These consisted of 6 cases of myocarditis and 11 of alcoholic heart muscle disease. Myocarditis patients had less dilation of the left ventricle, more marked segmental wall motion abnormality on admission and more extensive myocardial fibrosis than patients with alcoholic heart muscle disease and DCM. Four myocarditis patients died of congestive heart failure before showing a marked dilatation of the left ventricle. The alcoholic heart muscle disease patients revealed diffuse wall motion abnormality on admission. Out of these 8 patients who had abstained showed amelioration. However, in 3 who had not abstained, both wall motion abnormality and dilatation of the left ventricle markedly progressed and 2 died of congestive heart failure. Although the DCM patients as a group showed deterioration throughout the follow-up period, individual patients revealed a variety of echocardiographic and pathological findings, which led to the regrouping of 29 patients with DCM into 2 subgroups. One group had characteristic features similar to these of patients with myocarditis, and the other had characteristics similar to these of patients with alcoholic heart muscle disease. These findings suggested that different causative factors might coexist in DCM.

Adolescent↗
PubMed1995

The ageing spontaneously hypertensive rat as a model of the transition from stable compensated hypertrophy to heart failure.

Spontaneously hypertensive rats (SHR) of advanced age exhibit depressed myocardial contractile function and ventricular fibrosis, as stable compensated hypertrophy progresses to heart failure. Transition to heart failure in SHR aged 18-24 months was characterized by impaired left ventricular (LV) function, ventricular dilatation, and reduced ejection fraction without an increase in LV mass. Studies of papillary muscles from SHR with failing hearts (SHR-F), SHR without failure (SHR-NF), and age-matched Wistar Kyoto (WKY) rats allowed examination of changes in the mechanical properties of myocardium during the transition to heart failure. Papillary muscles of SHR-F exhibited increased fibrosis, impaired contraction, and decreased myocyte fractional area. These findings in papillary muscles were correlated with a higher concentration of hydroxyproline and increased histological evidence of fibrosis in the LV free wall. While a depression in active tension accompanied these structural alterations in papillary muscles, it was not evident when active tension was normalized to myocyte fractional area. Together, these data suggest that individual myocyte function may be preserved but that myocyte loss and replacement by extracellular matrix contribute substantially to the decrement in active tension. An absent or negative inotropic response to isoproterenol is observed in SHR-F and SHR-NF papillary muscles and may result in part from age-related alterations in beta-adrenergic receptor dynamics and a shift from alpha- to beta-myosin heavy chain (MHC) protein. During the transition to failure, ventricles of SHR exhibit a marked increase in collagen and fibronectin mRNA levels, suggesting that an increase in the expression of specific extracellular matrix genes may contribute to fibrosis, tissue stiffness, and impaired function. Transforming growth factor-beta 1 (TGF-beta 1) mRNA levels also increase in SHR-F, consistent with the concept that TGF-beta 1 plays a key regulatory role in remodelling of the extracellular matrix gene during the transition to failure. The renin-angiotensin-aldosterone system is also implicated in the transition to failure: SHR treated with the angiotensin converting enzyme inhibitor captopril starting at 12 months of age did not develop heart failure during the 18-24 month observation period. Captopril treatment that was initiated after rats were identified with evidence of failure led to a reappearance of alpha-MHC mRNA but did not improve papillary muscle function. Research opportunities include investigation of apoptosis as a mechanism of cell loss, delineation of the regulatory roles of TGF-beta 1 and the renin-angiotensin-aldosterone system in matrix accumulation, and studies of proteinase cascades that regulate matrix remodelling.

Age Factors↗
PubMed2004

Development of test systems for the discovery of selective human aldosterone synthase (CYP11B2) and 11beta-hydroxylase (CYP11B1) inhibitors. Discovery of a new lead compound for the therapy of congestive heart failure, myocardial fibrosis and hypertension.

Two key players in adrenal steroid hormone biosynthesis are the human mitochondrial cytochrome P450 enzymes CYP11B1 and CYP11B2 that catalyze the final steps in the biosynthesis of cortisol and aldosterone, respectively. Overproduction of both hormones contributes to a number of severe diseases, as illustrated by the association of elevated aldosterone levels with hypertension and higher mortality in congestive heart failure, and by Cushing's syndrome as the clinical correlate of chronic hypercortisolism. Thus, CYP11B1 and CYP11B2 comprise new targets for drug treatment and selective inhibitors of both enzymes are of high pharmacological interest. To facilitate the search for such compounds, we have established novel test procedures using recombinant fission yeast strains that stably express these enzymes. The aim of this study was to compare the inhibition profiles displayed by these enzymes in established mammalian cell culture test systems to those obtained with the new fission yeast assays, and to evaluate the usefulness of the Schizosaccharomyces pombe strains as screening systems for the identification of novel lead compounds. Using these test systems, we were able to identify a new and very selective CYP11B2 inhibitor (SIAS-1) that displayed no detectable interference with CYP11B1 activity.

Cushing Syndrome↗
PubMed1995

Response of hypertensive left ventricular hypertrophy and coronary microvascular disease to calcium antagonists.

Hypertensive left ventricular hypertrophy comprises not only myocyte hypertrophy, but is often associated with interstitial fibrosis and structural alterations of the coronary microcirculation. The consequences are early diastolic dysfunction and often later systolic dysfunction of the left ventricle, resulting in congestive heart failure. Involvement of the coronary resistance vessels leads to an impairment of coronary flow reserve despite normal epicardial arteries. Therefore, antihypertensive treatment should aim at reversing myocyte hypertrophy, restoring myocardial structure, and improvement in coronary flow reserve apart from blood pressure lowering. Many clinical studies have shown that calcium antagonists are effective in lowering blood pressure and can induce regression of left ventricular hypertrophy. Moreover, experimental studies have shown a restoration of myocardial structure. Recent clinical studies have demonstrated a marked improvement of the impaired coronary vasodilator reserve in hypertensive patients after long-term treatment with calcium antagonists. In summary, calcium antagonists can be regarded as an antihypertensive treatment modality that is able to restore myocardial structure and to repair coronary microcirculation and therefore can be considered as causative treatment of hypertensive cardiac remodeling.

Antihypertensive Agents↗
PubMed1989

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.

Adult↗
PubMed2003

Comparative effects of perindopril with enalapril in rats with dilated cardiomyopathy.

Angiotensin-converting enzyme inhibitors have been shown to reduce morbidity and mortality in patients with heart failure. The angiotensin type-1 blocking and cardioprotective properties of perindopril and enalapril were studied in a rat model of dilated cardiomyopathy after autoimmune myocarditis. Enalapril at 20 mg/kg showed the same angiotensin type-1 blocking action as perindopril at 2 mg/kg in rats with heart failure. Twenty-eight days after immunization, surviving Lewis rats (90/120 = 75%) were divided into six groups and administered perindopril at 0.02, 0.2 and 2 mg/kg per day (Groups P0.02, P0.2 and P2), enalapril at 2 and 20 mg/kg per day (Groups E2 and E20) or vehicle alone (Group V, all groups n = 15). After oral administration for 1 month, four of 15 (27%) rats in Group V, and two (13%) in Groups P0.02 and E2 died. None of the animals in Groups P0.2, P2 and E20, or normal rats (Group N) died. Although both angiotensin-converting enzyme inhibitors improved ventricular function in a dose-dependent manner, the left ventricular end-diastolic pressure and area of myocardial fibrosis were lower, and +/- dP/dt was higher in Group P2 (4.9 +/- 0.6 mmHg, 7.5 +/- 1.4% and +2651 +/- 254/-2622 +/- 189 mmHg/s, respectively) than in Group V (16.7 +/- 1.3, 36 +/- 2.6 and +2659 +/- 176/-2516 +/- 205, respectively) and Group E20 (7.5 +/- 2.5, 15.6 +/- 2.0 and +2018 +/- 110/-2097 +/- 102, respectively). Although the expression levels of transforming growth factor-beta1 and collagen-III mRNA in Group V (36.3 +/- 5.7 and 157.6 +/- 12.7%) were significantly higher than those in Group N (19.6 +/- 3.0 and 65.2 +/- 1.5%, both p < 0.01), they were reduced in Group P2 (21.4 +/- 5.9 and 75.2 +/- 9.3%, both p < 0.01). These results suggest that although enalapril can block increases in blood pressure caused by circulating angiotensin type-1, perindopril at 2 mg/kg may confer greater protection than enalapril at 20 mg/kg against injury from the renin-angiotensin system in heart failure.

Administration, Oral↗
PubMed2006

Poly(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy.

Poly(ADP-ribose) polymerase-1 (PARP), a chromatin-bound enzyme, is activated by cell oxidative stress. Because oxidative stress is also considered a main component of angiotensin II-mediated cell signaling, it was postulated that PARP could be a downstream target of angiotensin II-induced signaling leading to cardiac hypertrophy. To determine a role of PARP in angiotensin II-induced hypertrophy, we infused angiotensin II into wild-type (PARP(+/+)) and PARP-deficient mice. Angiotensin II infusion significantly increased heart weight-to-tibia length ratio, myocyte cross-sectional area, and interstitial fibrosis in PARP(+/+) but not in PARP(-/-) mice. To confirm these results, we analyzed the effect of angiotensin II in primary cultures of cardiomyocytes. When compared with PARP(-/-) cardiomyocytes, angiotensin II (1 microM) treatment significantly increased protein synthesis in PARP(+/+) myocytes, as measured by (3)H-leucine incorporation into total cell protein. Angiotensin II-mediated hypertrophy of myocytes was accompanied with increased poly-ADP-ribosylation of nuclear proteins and depletion of cellular NAD content. When cells were treated with cell death-inducing doses of angiotensin II (10-20 microM), robust myocyte cell death was observed in PARP(+/+) but not in PARP(-/-) myocytes. This type of cell death was blocked by repletion of cellular NAD levels as well as by activation of the longevity factor Sir2alpha deacetylase, indicating that PARP induction and subsequent depletion of NAD levels are the sequence of events causing angiotensin II-mediated cardiomyocyte cell death. In conclusion, these results demonstrate that PARP is a nuclear integrator of angiotensin II-mediated cell signaling contributing to cardiac hypertrophy and suggest that this could be a novel therapeutic target for the management of heart failure.

Angiotensin II↗
PubMed1988

Spontaneously occurring hypertrophic cardiomyopathy in the rat. II. Distribution of, and correlations between, various cardiac abnormalities in the WKY/NCrj and its related strains.

We performed gross-anatomic and histologic examinations quantitatively on 18 male and 30 female WKY/NCrj rats, and their 299 first generation off spring. The results were analyzed in comparison with those obtained from 3 other strains of rats. The offspring of the WKY rats showed various cardiac abnormalities quite similar to those in their parents. The cardiac abnormalities in the offspring of the WKY rats were: increased heart weight (in about 10%), left or right atrial hypertrophy (50%), disproportionate septal thickening (50%), small left ventricular cavity (40%), right ventricular hypertrophy (40%), abnormal fiber arrangement greater than 5% in either of the 3 ventricular walls (90%), myocardial fibrosis (70%), and abnormal location of arteries in the ventricular septum (30%). ECG findings of the WHY-F rats such as high QRS complexes and high T waves and axis deviation showed a high sensitivity and specificity in the diagnosis of marked cardiac hypertrophy. Another conspicuous histologic finding observed in the WKY hearts was that the continuity of the latitudinal fiber bundle of the ventricular septum with that of the left ventricular free wall, an important functioning unit for pressure generation in the left ventricle, was markedly disturbed in the area of junction between the 2 walls; the smaller the continuity, the greater the cardiac hypertrophy; the disadvantage of the discontinuity for the pressure generation may be related to the development of cardiac hypertrophy. Also examined were two strains of Wistar rats with the same origin as the WKY/NCrj. These rats also had gross-anatomic and histologic abnormalities of the heart quite similar to those in the 2 generations of WKY/NCrj rats, suggesting that a common factor related to the development of the abnormalities, probably a genetic predisposition, has been transmitted in these 3 strains.

Animals↗
PubMed1999

Cardiac fibrosis and inflammation: interaction with hemodynamic and hormonal factors.

It is generally admitted that the pathogenesis of perivascular and interstitial cardiac fibrosis involves the response to two types of stimuli: a hormonal one, mainly involving the renin-angiotensin-aldosterone system and the more recently described endothelin system, and a hemodynamic stimulus, particularly high blood pressure. We propose in the present review a third step which, although not exclusive, interacts with the hormonal and hemodynamic ones, and involves inflammatory mechanisms. Indeed, hypertension is invariably associated with inflammatory cell infiltration either in the intimal part of large vessels or in the adventitial region of arterioles. This has led us to hypothesize that arterial wall cells may trigger the initial communications attracting inflammatory cells to the perivascular region. In this paper, we review the proinflammatory intercellular communications as well as the intracellular signaling which confer an inflammatory phenotype to arteries. In this context, the profibrogenic and proinflammatory effects of hemodynamic overload and peptidergic systems such as angiotensin II and endothelin are considered. The study of the inflammatory process is not without interest, especially in view of the strong modulating effect of the inflammatory mediators both on the inflammatory process itself and on the fibrotic process. The principal and the most potent mediators are reviewed. Finally, the hypothesis that the inflammatory process could be in reality an immune specific process is suggested.

Angiotensin II↗
PubMed2005

Enhanced expression of fibrillin-1, a constituent of the myocardial extracellular matrix in fibrosis.

Fibrillin-1 localization in the myocardium and the modulation of its expression in cardiac fibrosis were examined. In normal rat hearts, fibrillin-1 was abundant throughout the myocardium as thin fibers that crossed over the perimysium and around arteries. After cardiac fibrosis was induced in rats by either 14-day ANG II infusion or 21-day DOCA-salt treatment [a high endothelin-1 (ET-1) model], fibrillin-1 immunostaining was stronger in the interstitium (2.8-fold and 4.4-fold increases, respectively, in each model), extended between myocytes, and accumulated in microscopic scars and in the perivascular area of both ventricles. mRNA analysis confirmed its enhanced ventricular expression in both groups of rats (2.5-fold and 6.6-fold increments, respectively, in each model). In 1B normotensive and 2C hypertensive transgenic mice, two lines expressing an ANG II fusion protein in cardiac myocytes, strong fibrillin-1 immunoreactivity was observed in the interstitium and around arteries (3.7-fold and 7-fold increases, respectively). ANG II and transforming growth factor-beta1 enhanced fibrillin-1 synthesis by cardiac fibroblasts. Some fibrillin-1 fragments interacted with RGD-dependent integrins, including alpha(8)beta(1)-integrin, of cardiac fibroblasts but not necessarily through the RGD motif. Our findings illustrate that fibrillin-1 is an important constituent of the myocardium. In vitro and in vivo evidence suggests that ANG II can directly induce fibrillin-1 expression in cardiac fibroblasts. This protein can thus contribute to reactive and reparative processes.

Angiotensin II↗
PubMed1999

Repetitive coxsackievirus infection induces cardiac dilatation in post-myocarditic mice.

The relation between mycarditis and dilated cardiomyopathy (DCM) is controversial. To clarify the pathogenic mechanism of these diseases, the present study examined the effect of repetitive inoculation with coxsackievirus B3 (CVB3) in post-myocarditic mice. Inbred 3-week-old A/J mice were inoculated intraperitoneally with CVB3 (Nancy strain; 2x10(4) plaque-forming units) and reinfected in the same manner with CVB3 at 40 weeks (3W+/40W+). All mice were killed at 42 weeks old. The weight of the hearts of the 3W+/40W+ group were significantly increased compared with those of the 3W-/40W+ group, and both the heart weight/body weight and lung weight/body weight ratios of the 3W+/40W+ group were also significantly increased over those of the 3W-/40W- group, although the levels of serum neutralizing antibody titers were significantly increased in the 3W+/40W+ group over the level of the other groups. No increase in inflammatory cell infiltration or fibrosis progression was observed in the 3W+/40W+ group relative to the 3W+/40W- group, but the second inoculation resulted in a significant left ventricular dilatation and in left and right ventricular free wall thinning (3.31+/-0.20 mm vs 2.61+/-0.19 mm, p<0.05; 0.54+/-0.09 mm vs 0.72+/-0.16 mm, p<0.05, respectively). The sarcomere length was also significantly increased in the 3W+/40W+ group compared with that of the other groups, as determined by electron microscopy. Degenerative or necrotic areas in the infected hearts were not stained with anti-mouse IgG antibody, but were stained, only in 3W+/40W+ mice, with anti-mouse IgM antibody. The concentrations of TNF-alpha in the hearts of the 3W+/40W+ group were increased significantly over those of the 3W+/40W- group. Repetitive CVB3 infection produced cardiac dilatation without inflammatory cell infiltration in post- myocarditic mice. Autoimmunity mediated by the circulation of certain antibodies (eg, antibodies against the CVB3 genome or a CVB3-related protein) may be part of the pathogenic mechanism for this phenomenon. Thus, repetitive virus infection might contribute to the pathogenesis of cardiac dilatation.

Animals↗
PubMed2006

Histopathology of the right ventricular outflow tract and its relationship to clinical outcomes and arrhythmias in patients with tetralogy of Fallot.

OBJECTIVES: The purposes of this study were to evaluate the myocardial histopathology and ultrastructure in patients with tetralogy of Fallot and to identify the histopathologic characteristics that may predispose patients to postoperative myocardial dysfunction and arrhythmias. PATIENTS AND METHODS: Operatively resected crista supraventricularis muscle from 183 patients undergoing intracardiac repair of tetralogy of Fallot aged 12 months to 42 years (mean, 106.84 +/- 79.35 months) were studied by light and electron microscopy. Biventricular function and cardiac rhythm were assessed by 2-dimensional echocardiography and electrocardiography. RESULTS: The incidence of moderate or severe cellular hypertrophy, endocardial thickening, and interstitial fibrosis was 36%, 68.3%, and 65%, respectively. Logistic regression analysis demonstrated age greater than 4 years, systemic arterial desaturation, higher hematocrit values, and elevated ventricular end-diastolic pressures as the major predisposing risk factors for pathologic changes. Twenty-seven (81.8%) patients more than 15 years of age and 29 (29.3%) patients between 4 and 15 years of age had predominant right ventricular dysfunction and low cardiac output (chi(2) [1 degree of freedom (df)] = 27.95; P < .001; odds ratio [OR] = 10.86 [3.75-33.10]). Ventricular arrhythmia was detected in 11 patients in whom repair was performed between 4 and 15 years of age and in 13 patients whose age at operation was 15 years or older. According to an additive logistic model, the effect of age at repair on the influence of ventricular arrhythmia was significant (chi(2) [1 df] = 24.4; P < .001; OR = 8.21 (2.96-23.11]). CONCLUSIONS: The great majority of myocardial tissues in cyanotic tetralogy of Fallot indicates pre-existing ultrastructural hypertrophic and degenerative changes. The changes are more pronounced in older patients subjected to long-standing cyanosis and pressure overload and may account for or may coexist with the higher incidence of myocardial dysfunction and ventricular arrhythmia.

Adolescent↗
PubMedDate not supplied

Aldosterone and aldosterone antagonism in cardiovascular disease: focus on eplerenone (Inspra).

Aldosterone has long been known to mediate water and electrolyte balance by acting on mineralocorticoid receptors in the kidneys. However, recent studies have demonstrated the presence of these receptors in nonclassical locations, including the brain, blood vessels, and the heart. This finding suggests that aldosterone may play a larger role than once appreciated in normal physiologic function and cardiovascular disease. Some of the adverse cardiovascular effects that have been described include cardiac and vascular fibrosis, left ventricular hypertrophy, congestive heart failure, hypertension, endothelial dysfunction, reduced fibrinolysis, and cardiac arrhythmias. In light of these findings, aldosterone receptor blockers have become increasingly more important. This is especially true considering the fact that traditional therapies, such as angiotensin-converting enzyme inhibitors and angiotensin II-receptor blockers, may not be effective in maintaining long-term suppression of aldosterone. Therefore, a great deal of focus has been placed on spironolactone, which has proven to be an effective, albeit nonselective, aldosterone receptor blocker. The Randomized Aldactone Evaluation Study has shown that spironolactone results in a 30% reduction in mortality among patients with severe congestive heart failure. Other studies have shown spironolactone to lower high blood pressure, improve endothelial dysfunction, reduce left ventricular hypertrophy, and lower the incidence of fatal arrhythmias. However, spironolactone, because of its interaction with other steroid receptors, is not without its limitations, which include gynecomastia, breast tenderness, menstrual irregularities, and impotence. As a result, eplerenone (INSPRA), a selective aldosterone blocker, is currently being investigated for its efficacy and side-effect profile compared with spironolactone. Eplerenone has already been approved for the treatment of systemic hypertension, and several clinical trials are currently underway to identify other therapeutic uses for this agent in cardiovascular disease management.

Aldosterone↗
PubMed1993

Identification of functional angiotensin II receptors on rat cardiac fibroblasts.

BACKGROUND: Cardiac hypertrophy results in an increased deposition of the extracellular matrix (ECM) proteins fibronectin and collagen. Recent evidence indicates that angiotensin II (Ang II) might have an important role in the development of myocardial fibrosis accompanying cardiac hypertrophy. We sought to determine whether fibroblasts of cardiac origin (isolated from neonatal and adult animals) express receptors for Ang II and to examine the ability of this peptide to regulate fibronectin and collagen gene expression in a cultured adult cardiac fibroblast cell preparation. METHODS AND RESULTS: Binding of 125I-Ang II to both neonatal and adult cardiac fibroblasts in culture was specific, reversible, and saturable, with the receptor evenly distributed over the cell population. Competition binding experiments with receptor-specific antagonists indicate that Ang II receptors found on both fibroblast types were of the AT1 subtype. Analysis of mRNA levels for the AT1 receptor indicates that adult cardiac fibroblasts express higher levels of the message than neonatal fibroblasts or cardiac myocytes. Addition of 10(-9) mol/L Ang II to adult cardiac fibroblasts resulted in an induction of ECM proteins above control levels, as determined through Northern blots and total collagen assays. CONCLUSIONS: Results from this study indicate that neonatal and adult rat cardiac fibroblasts in culture express AT1 receptors for Ang II. Ang II stimulation of AT1 receptors results in an increased gene expression for ECM proteins. These data suggest that Ang II might have important regulatory roles over cardiac fibroblast function under normal and pathological conditions.

Angiotensin II↗
PubMed2002

Low doses of 2,3,7,8-tetrachlorodibenzo- p-dioxin increase transforming growth factor beta and cause myocardial fibrosis in marmosets ( Callithrix jacchus).

Epidemiological studies have suggested an association between exposure to dioxins and cardiovascular morbidity and mortality. However, cardiotoxic effects of low doses of 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) in animals have not been reported so far. We studied the hearts of male marmosets ( Callithrix jacchus)after treatment with single subcutaneous doses of 1, 10 or 100 ng TCDD/kg body weight or vehicle (toluene/DMSO 1+2 v/v, 100 microl/kg body weight). The animals were killed 2 or 4 weeks after treatment. Tissue samples of left ventricular myocardium were stained with picrosirius red and examined histologically along with quantitative image analysis. Extracellular matrix proteins were additionally analysed by western blotting. Monkeys showed no overt signs of toxicity nor did their relative heart weights differ significantly depending on treatment. Histology revealed an increase of picrosirius red-positive area above control values in 2 of 4 (1 ng TCDD/kg body weight), 6 of 12 (10 ng/kg) and 6 of 10 (100 ng/kg) marmosets. Western blotting confirmed these histological findings showing an increase of collagen, fibronectin and laminin in the hearts of TCDD-treated animals. Western blotting additionally showed an increased concentration of transforming growth factor beta1 (TGF-beta1) as well as TGF-beta receptor type I which could be a functional link to the effects on extracellular matrix. Our findings might explain the association of TCDD exposure with increased cardiovascular mortality observed in epidemiological studies and should stimulate further research on the role of changes in the extracellular matrix in the toxic effects of dioxins and related substances on other organs.

Animals↗
PubMed1998

Coxsackievirus B3-induced myocarditis: perforin exacerbates disease, but plays no detectable role in virus clearance.

Viral myocarditis is remarkably common, being detected in approximately 1% of unselected asymptomatic individuals. Many cases are attributable to enteroviral infection, and in particular to coxsackievirus B3. The underlying pathogenesis is controversial, but most studies admit the important immunopathological role of infiltrating CD8+ (cytotoxic) T lymphocytes (CTLs). We have previously shown that CTLs play conflicting roles in coxsackievirus B (CVB) myocarditis; they assist in controlling virus replication, but also are instrumental in causing the extensive inflammatory disease, which often results in severe myocardial scarring. A role for perforin, the major CTL cytolytic protein, in CVB myocarditis has been suggested, but never proven. In the present study we use perforin knockout (PKO) mice to show that perforin plays a major role in CVB infection; in broad terms, perforin is important in immunopathology, but not in CVB clearance. For example, PKO mice are better able to withstand a normally lethal dose of CVB (100% survival of PKO mice compared with 90% death in +/+ littermates). In addition, PKO mice given a nonlethal dose of CVB develop only a mild myocarditis, whereas their perforin+ littermates have extensive myocardial lesions. The myocarditis in PKO mice resolves more quickly, and these mice show minimal histological sequelae; in contrast, late in disease the perforin+ mice develop severe myocardial fibrosis. PKO mice, despite lacking this major CTL effector function, can control the infection and eradicate the virus; growth kinetics and peak CVB titers are indistinguishable in PKO and perforin+ mice. Therefore, the immunopathological and antiviral effects of CTLs can be uncoupled by ablation of perforin; this offers a promising target for therapy of myocarditis. Furthermore, we evaluate the possible roles of apoptosis, and of chemokine expression, in CVB infection. In perforin+ mice, apoptotic cells are detected within the inflammatory infiltrate, whereas in their PKO counterparts, apoptotic myocyte nuclei are seen. Chemokine expression in both PKO and perforin+ mice precedes and parallels the course of myocarditis. Several chemokines are detectable earlier in PKO mice than in perforin+ mice, but PKO mice show reduced peak levels, and chemokine expression decays sooner. In particular, MIP-1alpha expression is barely detectable at any time point in PKO mice, but it is readily identified in perforin+ animals, peaking just before the time of maximal myocarditis; this is particularly interesting, given that MIP-1alpha knockout mice are resistant to CVB myocarditis, but remain able to control viral infection. Thus, the chemokine pathway offers a second route of intervention to diminish myocarditis and its sequelae, while permitting the host to eradicate the virus.

Animals↗
PubMed1996

Influence of nicotine on myocardial stiffness and fibrosis during chronic ethanol use.

Cardiomyopathy related to ethanol abuse is often accompanied by cigarette use. To examine if the major cardioactive component may intensify the abnormal function and composition induced by chronic ethanol, nicotine was administered orally, 2.5 mg bid, to a canine model receiving 36% of calories as ethanol for 6 months (group III). These animals were compared with group II receiving ethanol alone, group IV on nicotine alone, and controls (group I). In the intact, ventilated, anesthetized dog, left ventricular pressures and volumes were measured before and after dextran infusion and related to left ventricular collagen alterations. Basal heart rate, aortic pressure, and ejection fraction were comparable with controls. End-diastolic pressure and diastolic chamber stiffness (KPV) were significantly higher in the basal state and during dextran infusion in the three experimental groups, compared with group I. The increment was largest in the ethanol-nicotine group. Analysis of left ventricular myocardium revealed a rise of collagen concentrations in all three experimental groups, with an interstitial distribution on histochemical examination. Moreover, determination of advanced glycosylation endproducts, as a measure of alterations in collagen cross-links, revealed higher concentrations versus controls. The greater increase of diastolic stiffness in the nicotine-ethanol group occurred despite a similar concentration of fluorescent products as group II. Because the former had a larger increase of collage concentration, total cross-linked collagen content was presumably greater after the combined use of nicotine-ethanol. Thus, nicotine in relatively high dose when combined with ethanol, elicited a modest further increase in the left ventricular chamber stiffness and collagen concentration.

Administration, Oral↗
PubMed1976

The cardiac conduction system in progressive systemic sclerosis. Clinical and pathologic features of 35 patients.

Progressive systemic sclerosis may be associated with focal myocardial fibrosis. Electrocardiographic abnormalities including conduction block are common in progressive systemic sclerosis but whether they are due to direct destruction of the specialized conduction tissue of the heart is uncertain. The conduction systems of 35 patients with progressive systemic sclerosis were studied. Of these 35 patients, 17 (50 per cent) had myocardial fibrosis of the type seen in progressive systemic sclerosis. In 10 of the 17, it was severe. Sinus node fibrosis was present in 13 patients and was nearly as frequent in those with as in those without the progressive systemic sclerosis myocardial lesion. Overlying pericarditis may have contributed to the fibrotic changes within the sinoatrial nodes in seven of the 13 patients. The atrioventricular node and main His bundles were normal. However, fibrotic changes were found in the proximal bundle systems in six patients. In three of the six, severe myocardial progressive systemic sclerosis was present, two had focal fibrous atrophy of the left bundle, and one had complete interruption of the right bundle. In only the latter patient was this reflected in the electrocardiogram which showed a right bundle branch block. Three patients without progressive systemic sclerosis myocardial lesions also had fibrous atrophy of a portion of the proximal left bundle branch, and in one the electrocardiogram showed an isolated left anterior hemiblock. Thus, morphologic abnormalities within the conduction system in our patients are difficult to attribute to progressive systemic sclerosis per se. Furthermore, although conduction abnormalities were more frequent in patients with myocardial disease, specific conduction system disease was not the cause in most patients. As has been noted in ischemic heart disease, the conduction system appears to be relatively spared from the myocardial changes of progressive systemic sclerosis, and the high incidence of conduction disturbances in this condition may be a consequence, rather, of damage to working myocardium.

Adolescent↗