Baicalin Attenuates Cardiac Dysfunction and Myocardial Remodeling in a Chronic Pressure-Overload Mice Model.

BACKGROUND/AIMS: Baicalin has been shown to be effective for various animal models of cardiovascular diseases, such as pulmonary hypertension, atherosclerosis and myocardial ischaemic injury. However, whether baicalin plays a role in cardiac hypertrophy remains unknown. Here we investigated the protective effects of baicalin on cardiac hypertrophy induced by pressure overload and explored the potential mechanisms involved. METHODS: C57BL/6J-mice were treated with baicalin or vehicle following transverse aortic constriction or Sham surgery for up to 8 weeks, and at different time points, cardiac function and heart size measurement and histological and biochemical examination were performed. RESULTS: Mice under pressure overload exhibited cardiac dysfunction, high mortality, myocardial hypertrophy, increased apoptosis and fibrosis markers, and suppressed cardiac expression of PPARα and PPARß/δ. However, oral administration of baicalin improved cardiac dysfunction, decreased mortality, and attenuated histological and biochemical changes described above. These protective effects of baicalin were associated with reduced heart and cardiomyocyte size, lower fetal genes expression, attenuated cardiac fibrosis, lower expression of profibrotic markers, and decreased apoptosis signals in heart tissue. Moreover, we found that baicalin induced PPARα and PPARß/δ expression in vivo and in vitro. Subsequent experiments demonstrated that long-term baicalin treatment presented no obvious cardiac lipotoxicity. CONCLUSIONS: The present results demonstrated that baicalin attenuates pressure overload induced cardiac dysfunction and ventricular remodeling, which would be due to suppressed cardiac hypertrophy, fibrosis, apoptosis and metabolic abnormality.

Prognostic impact of myocardial interstitial fibrosis in non-ischemic heart failure. -Comparison between preserved and reduced ejection fraction heart failure.-.

BACKGROUND: Although myocardial fibrosis plays an important role in the progression of heart failure (HF), its prognostic impact still remains to be clarified. METHODS AND RESULTS: A total of 172 consecutive patients with chronic HF, who underwent cardiac catheterization and endomyocardial biopsy between January 2001 and September 2008, were examined. They were divided into 2 groups: HF with preserved ejection fraction (HFPEF; left ventricular ejection fraction [LVEF] ≥ 50%, n=81); and HF with reduced LVEF (HFREF; LVEF < 50%, n=91). The collagen volume fraction (CVF) in biopsy samples was calculated and its prognostic impact examined. Mean follow-up in the HFPEF and the HFREF groups was 41 ± 33 months and 41 ± 26 months, respectively. Although CVF was similar between the 2 groups (1.83 ± 1.54% vs. 2.07 ± 2.35%), CVF was significantly correlated with LV end-diastolic pressure in the HFREF group but not in the HFPEF group. When HF stage was adjusted, the long-term prognosis was comparable between the 2 groups. When the patients were divided into 2 groups according to median CVF, however, severe fibrosis was a significant predictor for all-cause death (P=0.014) and cardiac events (P=0.02) in the HFREF, but not in the HFPEF group. CONCLUSIONS: Myocardial fibrosis evaluated on biopsy samples is a useful indicator for long-term survival, suggesting that it may be an important therapeutic target as well.

Fibrosis endomiocárdica tropical e hipertensión pulmonar secundaria a esquistosomiasis / Schistosomiasis and tropical endomyocardial fibrosis with pulmonary hypertension

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Prognostic value of galectin-3, a novel marker of fibrosis, in patients with chronic heart failure: data from the DEAL-HF study.

AIMS: Biomarkers are increasingly being used in the management of patients with chronic heart failure (HF). Galectin-3 is a recently developed biomarker associated with fibrosis and inflammation, and it may play a role in cardiac remodeling in HF. We determined its prognostic value in patients with chronic HF. METHODS AND RESULTS: Patients with chronic HF (New York Heart Association functional class III or IV) who participated in the Deventer-Alkmaar heart failure study were studied. Galectin-3 levels were determined at baseline using a novel optimized enzyme-linked immunosorbent assay. Univariate and multivariate analyses were used to determine the prognostic value of this biomarker. We studied 232 patients; their mean age was 71 +/- 10 years, 72% were male, and 96% were in NYHA class III. During a follow-up period of 6.5 years, 98 patients died. Galectin-3 was a significant predictor of mortality risk after adjustment for age and sex, and severity of HF and renal dysfunction, as assessed by NT-proBNP and estimated glomerular filtration rate, respectively (hazard ratio per standard deviation 1.24, 95% CI 1.03-1.50, P = 0.026). CONCLUSION: Plasma galectin-3 is a novel prognostic marker in patients with chronic HF. Its prognostic value is independent of severity of HF, as assessed by NT-proBNP levels, and it may potentially be used in the management of such patients.

Utility of virtual crossmatch in sensitized patients awaiting heart transplantation.

BACKGROUND: Organ transplant candidates with serum antibodies directed against human leukocyte antigens (HLA) face longer waiting times and higher mortality while awaiting transplantation. This study examined the accuracy of virtual crossmatch, in which recipient HLA-specific antibodies, identified by solid-phase assays, are compared to the prospective donor HLA-type in heart transplantation. METHODS: We examined the accuracy of virtual crossmatch in predicting immune compatibility of donors and recipients in heart transplantation and clinical outcomes in immunologically sensitized heart transplant recipients in whom virtual crossmatch was used in allograft allocation. RESULTS: Based on analysis of 257 T-cell antihuman immunoglobulin complement-dependent cytotoxic (AHG-CDC) crossmatch tests, the positive predictive value of virtual crossmatch (the likelihood of an incompatible virtual crossmatch resulting in an incompatible T-cell CDC-AHG crossmatch) was 79%, and the negative predictive value of virtual crossmatch (the likelihood of a compatible virtual crossmatch resulting in a compatible T-cell CDC-AHG crossmatch) was 92%. When used in a cohort of 28 sensitized patients awaiting heart transplantation, 14 received allografts based on a compatible virtual crossmatch alone from donors in geographically distant locations. Compared with the other 14 sensitized patients who underwent transplant after a compatible prospective serologic crossmatch, the rejection rates and survival were similar. CONCLUSION: Our findings are evidence of the accuracy of virtual crossmatch and its utility in augmenting the opportunities for transplantation of sensitized patients.

Echocardiographic predictors of functional capacity in endomyocardial fibrosis patients.

AIMS: Endomyocardial fibrosis (EMF) is a restrictive cardiomyopathy manifested mainly by diastolic heart failure. It is recognized that diastole is an important determinant of exercise capacity. The purpose of this study was to determine whether resting echocardiographic parameters might predict oxygen consumption (VO(2p)) by ergoespirometry and the prognostic role of functional capacity in EMF patients. METHODS AND RESULTS: A total of 32 patients with biventricular EMF (29 women, 55.3 +/- 11.4 years) were studied by echocardiography and ergoespirometry. The relationship between the echocardiographic indexes and the percentage of predicted VO(2p) (%VO(2p)) was investigated by the 'stepwise' linear regression analysis. The median VO(2p) was 11 +/- 3 mL/kg/min and the %VO(2p) was 53 +/- 9%. There was a correlation of %VO(2p) with an average of A' at four sites of the mitral annulus (A' peak, r = 0.471, P = 0.023), E'/A' of the inferior mitral annulus (r = -0.433, P = 0.044), and myocardial performance index (r = -0.352, P = 0.048). On multiple regression analysis, only A' peak was an independent predictor of %VO(2p) (%VO(2p)= 26.34 + 332.44 x A' peak). EMF patients with %VO(2p)< 53% had an increased mortality rate with a relative risk of 8.47. CONCLUSION: In EMF patients, diastolic function plays an important role in determining the limitations to exercise and %VO(2p) has a prognostic value.

Cardiac-related findings at autopsy in people with severe mental illness treated with clozapine or risperidone.

Clozapine is a superior agent for treatment-refractory patients with schizophrenia, but is underutilized in the US, likely due to the risk of side effects. This study examined all available autopsy data on cardiac disease and risk factors in people with schizophrenia in a sample of deceased persons with severe mental illness who had received clozapine (N=62) or risperidone (N=42). The mean body mass index (BMI) at the time of death was 31.4+/-8.8 kg/m2 and 27.1+/-8.2 kg/m2 in the clozapine and risperidone groups respectively (t=1.98, df=60, p=0.052). Cardiac related measures examined included: abdominal wall thickness, heart weight, left ventricle thickness, right ventricle thickness, presence of notable cardiac involvement (atherosclerosis, fibrosis and hypertrophy) and number of cardiac arteries occluded. No significant differences in any of the cardiac findings were noted between patients in the clozapine and risperidone groups. Independent of treatment, cardiomyopathy deaths were associated with a higher abdominal wall thickness (p=0.042) and a tendency towards higher BMI (p=0.051) as compared to the other causes of death. The results of this study suggest that while clozapine is associated with weight gain and metabolic abnormalities, there does not appear to be an increased occurrence of cardiac abnormalities in deceased persons who were treated with clozapine as compared to risperidone.

[Kidney insufficiency and cardiovascular disease]. / Niereninsuffizienz und kardiovaskuläre Erkrankungen.

Cardiovascular disease (CVD) is the leading cause of mortality and morbidity in patients with chronic renal disease. Severe cardiac and arterial disorders such as left ventricular hypertrophy, coronary artery disease, and arteriosclerosis of the large vessels are already evident in early renal disease, even in young patients. Despite major advances in dialysis therapy and treatment options for acute coronary syndromes, mortality remains high--up to 10-30 times higher than in the general population. The increased risk for cardiovascular disorders results from the additive effect of traditional risk factors, volume overload, and endocrine and metabolic abnormalities in uremia. During the course of the renal disease, the progression of CVD disease manifestations significantly influences outcome. Thus, preventive measures and optimal treatment are mandatory and should be among the main targets of early management of patients with chronic renal disease.

[Cardiac alterations caused by renal failure]. / Veränderungen am Herzen durch Niereninsuffizienz.

Cardiac disease is the most common cause of death in patients with endstage renal disease. It was assumed that the high rate of cardiovascular mortality was based on accelerated atherosclerosis. Recently published articles, however, demonstrated that only 30-50% of all cardiac deaths in patients with uremia was due to myocardial infarction. On the other hand 30-40% of all patients with renal insufficiency, angina pectoris and documented ischemia have normal coronary arteries. Therefore, it is suggested that in patients with chronic uremia apart from accelerated atherosclerosis further abnormalities of the heart lead to myocardial ischemia. Recently published papers report functional and structural changes, which affect myocardial perfusion reserve. These structural changes include left ventricular hypertrophy, interstitial myocardial fibrosis, and microvascular disease.

Pitfalls in diagnosis and clinical, echocardiographic, and hemodynamic findings in endomyocardial fibrosis: a 25-year experience.

Endomyocardial fibrosis (EMF) is a fascinating disease entity of unknown etiology. It is prevalent in the tropical zone. Its essential features are the formation of fibrous tissue on the endocardium and to a lesser extent in the myocardium of the inflow tract and apex of one or both ventricles. It results in endocardial rigidity, atrioventricular valve incompetence secondary to papillary muscle involvement, and progressive reduction of the cavity of the involved ventricle leading to restriction in filling and atrial enlargement. This article will present 21 patients with EMF who were initially referred to our hospital from 1979 to 2004 with different diagnoses: rheumatic heart disease with mitral and or tricuspid regurgitation (n = 9), constrictive pericarditis (n = 6), restrictive cardiomyopathy (n = 1), hypertrophic cardiomyopathy apical type (n = 2), dilated cardiomyopathy (n = 2), and Ebstein malfunction of the tricuspid valve (n = 1). The clinical, echocardiographic, hemodynamic, and angiographic findings in these 21 patients are presented; echocardiographic findings lead to the right diagnosis. The presence of a small ventricle with obliteration of the apex and large atrium shown on two-dimensional echocardiography is highly suggestive of EMF.

T-wave alternans in patients with right ventricular tachycardia.

Microvolt T-wave alternans has been proposed as a new risk marker for ventricular arrhythmias. However, the clinical significance of T-wave alternans in patients with ventricular tachycardia (VT) originating from the right ventricle has been unknown. The study population consisted of 20 patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) or idiopathic VT. T-wave alternans was measured during bicycle exercise testing using the CH 2000 system. Of the 7 patients with ARVC, 6 (86%) were positive for T-wave alternans. On the other hand, only 1 (8%) of 13 patients with idiopathic VT originating from the right-ventricular outflow tract was positive for T-wave alternans.

Your bleeding heart: lessons from low tissue factor expression in mice.

Tissue factor (TF) is the cellular receptor and cofactor for blood coagulation factor VII (FVII). Exposure of flowing blood to cells that express TF leads to the initiation of blood coagulation. A recent study of mice expressing low levels of TF has demonstrated the importance of TF and FVII in maintaining adequate haemostasis within the heart. In addition, the study indicates that the heart is subject to a succession of minor bleeds most probably as a result of repetitive minor mechanical injury to the blood vessels.

Myocardial ischemic-fibrotic injury after human heart transplantation is associated with increased progression of vasculopathy, decreased cellular rejection and poor long-term outcome.

OBJECTIVES: We sought to assess the influence of peritransplant ischemia and fibrosis on the development of allograft vasculopathy, acute cellular rejection and long-term outcome. BACKGROUND: Allograft vasculopathy is a common long-term complication of cardiac transplantation. One of the potential risk factors is peritransplant allograft ischemia. METHODS: One hundred forty heart transplant recipients had baseline and one-year intravascular ultrasound analysis done to assess the progression of allograft vasculopathy. Serial endomyocardial biopsies were evaluated for cellular rejection, vascular rejection, ischemia and fibrosis. Based on histology, patients were classified into one of the following groups: nonischemic (n = 32), ischemia (n = 24), fibrosis (n = 62) or vascular rejection (n = 22). Three-color flow cytometry crossmatching (FCXM) was used to assess donor-specific human lymphocyte antigens (HLA) sensitization. Long-term outcome of patients in each group was assessed by estimating incidence of graft failure or deaths over a seven-year follow up. RESULTS: Patients in the fibrosis group had the lowest incidence of donor-specific HLA sensitization (40%, p = 0.008) and lowest average episodes of cellular rejection (1.7 +/- 1.4, p = 0.04), but they had increased coronary vasculopathy progression (change in coronary intimal thickness = 0.59 +/- 0.28 mm, p < 0.0001) and poor seven-year event-free survival (49%, p = 0.01). CONCLUSIONS: The development of fibrosis after cardiac transplantation is associated with advanced coronary vasculopathy, although a low incidence of acute cellular rejection is noted, suggesting the presence of nonimmune mechanisms in mediating the pathogenesis of allograft vasculopathy.

Endomyocardial fibrosis in children.

We describe 10 children with endomyocardial fibrosis who underwent surgical treatment between 1978 and 1999. Seven were male and 3 female, with an age range from 4 to 15 years, having a mean age of 11 years. All were in the final stage of heart failure. Three had biventricular disease, 6 had involvement of the right ventricle alone, and one had endomyocardial fibrosis confined to the left ventricle. There were 3 deaths (30%) in the postoperative period due to low cardiac output. The 7 survivors were followed up for a period ranging from 12 to 168 months, with a mean of 72 months. Two late deaths have occurred resulting from heart failure and infectious endocarditis. Five (50%) children are still alive. Two required 3 reoperations for dysfunction of the inserted valvar prosthesis. One patient is in functional Class IV, and 4 are in Class II to III, despite intensive medical treatment. It is concluded that surgery for endomyocardial fibrosis is an essentially palliative procedure and, especially in children, the results of surgical treatment leave much to be desired.

Histologic compaison of allograft myocardium between short- and long-term survivors of human cardiac transplantation.

Myocardial histology of cardiac allografts differed between short-term (<5 years) and long-term (>5 years) survivors after transplantation. These differences may partially be attributable to a higher prevalence of systemic hypertension and allograft rejection in the short-term survivors, affecting hemodynamics and allograft function.

Surgery for endomyocardial fibrosis revisited.

OBJECTIVE: To identify life expectancy after surgery for endomyocardial fibrosis (EMF) and the events that influence it. METHODS: Eighty-three patients with EMF underwent endocardial decortication and atrioventricular valve replacement or repair, between December 1977 and December 1997. There were 66 (79.6%) female and 17 (20.4%) male patients, ranging in age from 4 to 59 years (mean, 31). Thirty-seven (44.5%) had biventricular disease, 34 (41.0%) had disease of the right ventricle alone and 12 (14.5%) had EMF confined to the left ventricle. All were in functional class III or IV (New York Heart Association classification). RESULTS: Sixty-eight (81.9%) patients survived the operation and were followed up for periods ranging from 2 months to 17 years. The total follow-up time was 6290 patient/months (mean, 92 months). There were 15 late deaths, but in six, the cause was not related to the underlying disease. Four (5.8%) patients presented recurrence of the fibrosis and were reoperated on and in six (8.8%), EMF appeared in the other ventricle. Five (7.3%) patients were reoperated on to replace either a valve prosthesis or a native valve which had been preserved during the first procedure. Only 24 (45%) of the 53 surviving patients are in functional class I or II. The actuarial probability of survival at 17 years, including operative mortality, was 55%. CONCLUSION: Surgical treatment of EMF should be considered a palliative procedure because surgery does not alter the progressive nature of the disease. However, surgical therapy is recommended for patients with EMF and heart failure as it is their only hope of survival.

Pattern of cardiac fibrosis in rabbits periodically fed a magnesium-restricted diet and administered rare earth chloride through drinking water.

It has been postulated that causation of the tropical cardiomyopathy endomyocardial fibrosis (EMF) is linked to magnesium (Mg) deficiency and cardiac toxicity of the rare earth element cerium (Ce). The aim of the present study was to define the myocardial lesions in rabbits that were fed on Mg-restricted diet (70-80 ppm) periodically and were provided drinking water contaminated with rare earth chloride (1 g/L). Forty New Zealand white rabbits were divided into four groups following a 2 x 2 factorial design. Two groups were periodically fed on Mg-restricted diet with one of them receiving water contaminated with rare earth chloride. The other two groups were continuously fed on Mg-sufficient diet (350-400 ppm) with one of them receiving water contaminated with rare earth chloride. All animals were sacrificed at the end of 6 mo. Cardiac tissues were subjected to histology, elemental analysis (calcium [Ca], Mg, and Ce) and estimation of collagen content and collagen phenotypes. Histological lesions were compared with those of EMF in humans and those of acute Mg deficiency in animals. The results suggest that in rabbits, recurrent episodes of Mg deficiency lead to myocardial fibrosis similar to the pattern observed in human EMF.

Heart transplant rejection with hemodynamic compromise: a multiinstitutional study of the role of endomyocardial cellular infiltrate. Cardiac Transplant Research Database.

BACKGROUND: The natural history of patients experiencing hemodynamic compromise with rejection has been incompletely characterized. This multiinstitutional study examined the outcome of such episodes, particularly with regard to the extent of cellular infiltrate on the index endomyocardial biopsy. METHODS: From January 1, 1990, through June 30, 1994, 3367 patients in the Cardiac Transplant Research Database experienced 4137 episodes of rejection. Severe hemodynamic compromise occurred in approximately 5% of the rejection episodes, and this proportion remained relatively constant over time. RESULTS: Recipient risk factors for rejection with severe hemodynamic compromise included black race, female recipient sex, and diabetes. The 3-month actuarial survival rate was 60% after rejection with severe hemodynamic compromise versus 95% after rejection with no or mild compromise. Low initial biopsy score conferred a higher early survival, but a lower survival at 2 years after rejection with severe hemodynamic compromise. Among patients who survive an initial rejection episode with severe hemodynamic compromise, survival at 2 years after an episode was 46% among those who had a low initial biopsy score versus 84% with a high biopsy score. CONCLUSIONS: Rejection with hemodynamic compromise, although rare, represents a major complication of heart transplantation with a poor long-term outcome. Survivors of hemodynamically compromising rejection episodes associated with low biopsy scores in the International Society for Heart and Lung Transplantation grading system have a significantly worse long-term outcome than survivors of episodes associated with high scores. These findings suggest that immunologic mechanisms other than lymphocytic infiltration of the cardiac allograft are important and distinct causes of allograft dysfunction.