Valdecir Blefari

Coronary Microvascular Disease in Chronic Chagas Cardiomyopathy Including an Overview on History, Pathology, and Other Proposed Pathogenic Mechanisms

This review focuses on the short and bewildered history of Brazilian scientist Carlos Chagass discovery and subsequent developments, the anatomopathological features of chronic Chagas cardiomyopathy (CCC), an overview on the controversies surrounding theories concerning its pathogenesis, and studies that support the microvascular hypothesis to further explain the pathological features and clinical course of CCC. It is our belief that knowledge of this particular and remarkable cardiomyopathy will shed light not only on the microvascular involvement of its pathogenesis, but also on the pathogenetic processes of other cardiomyopathies, which will hopefully provide a better understanding of the various changes that may lead to an end-stage heart disease with similar features. This review is written to celebrate the 100th anniversary of the discovery of Chagas disease.

Reduced expression of adherens and gap junction proteins can have a fundamental role in the development of heart failure following cardiac hypertrophy in rats.

Hypertension causes cardiac hypertrophy, cardiac dysfunction and heart failure (HF). The mechanisms implicated in the transition from compensated to decompensated cardiac hypertrophy are not fully understood. This study was aimed to investigate whether alterations in the expression of intercalated disk proteins could contribute to the transition of compensated cardiac hypertrophy to dilated heart development that culminates in HF. Male rats were submitted to abdominal aortic constriction and at 90 days post surgery (dps), three groups were observed: sham-operated animals (controls), animals with hypertrophic hearts (HH) and animals with hypertrophic + dilated hearts (HD). Blood pressure was evaluated. The hearts were collected and Western blot and immunofluorescence were performed to desmoglein-2, desmocollin-2, N-cadherin, plakoglobin, Bcatenin, and connexin-43. Cardiac systolic function was evaluated using the Vevo 2100 ultrasound system. Data were considered significant when p b 0.05. Seventy percent of the animals presented with HH and 30% were HD at 90 dps. The blood pressure increased in both groups. The amount of desmoglein-2 and desmocollin-2 expression was increased in both groups and no difference was observed in either group. The expression of N-cadherin, plakoglobin and B-catenin increased in the HHgroup and decreased in the HDgroup; and connexin-43 decreased only in theHDgroup. Therewas no difference between the ejection fraction and fractional shortening at 30 and 60 dps; however, they were decreased in the HD group at 90 dps. We found that while some proteins have increased expression accompanied by the increase in the cell volume associated with preserved systolic cardiac function in theHHgroup, these same proteins had decreased expression evenwithout significant reduction in the cell volume associated with decreased systolic cardiac function in HD group. The increased expression of desmoglein-2 and desmocollin-2 in both the HH and HD groups could work as a protective compensatory mechanism, helping tomaintain the dilated heart.We can hypothesize that inappropriate intercellular mechanical and electrical coupling associated with necrosis and/or apoptosis are important factors contributing to the transition to HF.

Early dystrophin loss is coincident with the transition of compensated cardiac hypertrophy to heart failure

Hypertension causes cardiac hypertrophy, one of the most important risk factors for heart failure (HF). Despite the importance of cardiac hypertrophy as a risk factor for the development of HF, not all hypertrophied hearts will ultimately fail. Alterations of cytoskeletal and sarcolemma-associated proteins are considered markers cardiac remodeling during HF. Dystrophin provides mechanical stability to the plasma membrane through its interactions with the actin cytoskeleton and, indirectly, to extracellular matrix proteins. This study was undertaken to evaluate dystrophin and calpain-1 in the transition from compensated cardiac hypertrophy to HF. Wistar rats were subjected to abdominal aorta constriction and killed at 30, 60 and 90 days post surgery (dps). Cardiac function and blood pressure were evaluated. The hearts were collected and Western blotting and immunofluorescence performed for dystrophin, calpain-1, alpha-fodrin and calpastatin. Statistical analyses were performed and considered significant when p<0.05. After 90 dps, 70% of the animals showed hypertrophic hearts (HH) and 30% hypertrophic+dilated hearts (HD). Systolic and diastolic functions were preserved at 30 and 60 dps, however, decreased in the HD group. Blood pressure, cardiomyocyte diameter and collagen content were increased at all time points. Dystrophin expression was lightly increased at 30 and 60 dps and HH group. HD group showed decreased expression of dystrophin and calpastatin and increased expression of calpain-1 and alpha-fodrin fragments. The first signals of dystrophin reduction were observed as early as 60 dps. In conclusion, some hearts present a distinct molecular pattern at an early stage of the disease; this pattern could provide an opportunity to identify these failure-prone hearts during the development of the cardiac disease. We showed that decreased expression of dystrophin and increased expression of calpains are coincident and could work as possible therapeutic targets to prevent heart failure as a consequence of cardiac hypertrophy.

Involvement of the microvasculature in the pathogenesis of terlipressin-related myocardial infarction

We report an autopsy case of a 24-year-old man with diagnoses of advanced alcoholic liver cirrhosis, portal hypertension, and esophageal variceal bleeding that presented extensive myocardial infarction after treatment with terlipressin. On postmortem examination the cut surface of the heart presented myocardial infarction implicating the left ventricle free wall, apex of the heart and ventricular septum. Light microscopic examination revealed that the extensive area of cardiac infarction was the result of the sum of diffuse foci of microinfarction of various ages interspersed with small clusters of preserved myocytes. Moreover, the epicardial vessels were patent while the small intramyocardial vessels presented thickened wall, apparent reduction in lumen diameter and disruption of endothelial cells indicative of spasm. The observations in this case allow clear insight into the involvement of the microcirculation in the pathogenesis of myocardial infarction with the use of terlipressin.

248 IS DYSTROPHIN ABSENCE IMPLICATED IN THE TRANSITION FROM PHYSIOLOGICAL TO PATHOLOGICAL CARDIAC HYPERTROPHY

Hypertension causes cardiac hypertrophy, cardiac dysfunction, and heart failure (HF). The mechanisms implicated in the transition from physiological to pathological hypertrophy are still unknown. Growing evidence points out to the role of inappropriate mechanical coupling in the pathogenesis of HF and the cytoskeletal proteins as the most obvious candidates for intracellular remodeling. We investigated dystrophin and its potential role in the pathogenesis of HF in rats submitted to chronic abdominal aorta stenosis. Wistar rats were submitted to abdominal aorta stenosis and killed at 30, 60 and 90 days post surgery. The hearts were collected and Western blot (WB) and immunofluorescence (IF) were performed for dystrophin. Blood pressure was evaluated and cardiac function evaluate by echocardiography. Data were considered significant when p<0.05. At 90d 70% presented hypertrophied hearts (HH) and 30% hypertrophied and dilated hearts (DH), as evaluated by echocardiography. Blood pressure increased 53, 42% 30d, 50, 8% 60d and 64, 36% at 60d post surgery. Dystrophin expression reduced 15% 30d, 22% 60d and 26% at 90d post surgery in HH and 31% in DH. The ejection fraction was the same as control at 30d and 60d post surgery, however it was reduced 35% at 90d in HH and 48% in DH. Dystrophin absence may be partly responsible for the development of heart failure in rats submitted to chronic abdominal aorta stenosis. Thus, it is essential to define the mechanistic aspects of the pathophysiological processes involved in deterioration of cardiac function and design develop strategies to inhibit and/or reverse evolution of heart hypertrophy from compensated to decompensated phase. Grants from FAPESP 09/17787–8; 09/54010–1; 10/19216–5.

Disruption of sarcolemmal dystrophin and β-dystroglycan may be a potential mechanism for myocardial dysfunction in severe sepsis

Evidence from our laboratory has shown alterations in myocardial structure in severe sepsis/septic shock. The morphological alterations are heralded by sarcolemmal damage, characterized by increased plasma membrane permeability caused by oxidative damage to lipids and proteins. The critical importance of the dystrophin-glycoprotein complex (DGC) in maintaining sarcolemmal stability led us to hypothesize that loss of dystrophin and associated glycoproteins could be involved in early increased sarcolemmal permeability in experimentally induced septic cardiomyopathy.