Probiotic administration attenuates myocardial hypertrophy and heart failure following myocardial infarction in the rat

Background—Probiotics are extensively used to promote gastrointestinal health and emerging evidence suggests that their beneficial properties can extend beyond the local environment of the gut. Here, we determined whether oral probiotic administration can alter the progression of post-infarction heart failure. Methods and Results—Rats were subjected to six weeks of sustained coronary artery occlusion and administered the probiotic Lactobacillus rhamnosus GR-1 or placebo in the drinking water ad libitum. Culture and 16s rRNA sequencing showed no evidence of GR-1 colonization or a significant shift in the composition of the cecal microbiome. However, animals administered GR-1 exhibited a significant attenuation of left ventricular hypertrophy based on tissue weight assessment as well as gene expression of atrial natriuretic peptide. Moreover, these animals demonstrated improved hemodynamic parameters reflecting both improved systolic and diastolic left ventricular function. Serial echocardiography revealed significantly improved left ventricular parameters throughout the six week follow-up period including a marked preservation of left ventricular ejection fraction as well as fractional shortening. Beneficial effects of GR-1 were still evident in those animals in which GR-1 was withdrawn at four weeks suggesting persistence of the GR-1 effects following cessation of therapy. Investigation of mechanisms showed a significant increase in the leptin to adiponectin plasma concentration ratio in rats subjected to coronary ligation which was abrogated by GR-1. Metabonomic analysis showed differences between sham control and coronary artery ligated hearts particularly with respect to preservation of myocardial taurine levels. Conclusions—The study suggests that probiotics offer promise as a potential therapy for the attenuation of heart failure.

Targeting myocardial remodelling to develop novel therapies for heart failure: a position paper from the Working Group on Myocardial Function of the European Society of Cardiology

The failing heart is characterized by complex tissue remodelling involving increased cardiomyocyte death, and impairment of sarcomere function, metabolic activity, endothelial and vascular function, together with increased inflammation and interstitial fibrosis. For years, therapeutic approaches for heart failure (HF) relied on vasodilators and diuretics which relieve cardiac workload and HF symptoms. The introduction in the clinic of drugs interfering with beta-adrenergic and angiotensin signalling have ameliorated survival by interfering with the intimate mechanism of cardiac compensation. Current therapy, though, still has a limited capacity to restore muscle function fully, and the development of novel therapeutic targets is still an important medical need. Recent progress in understanding the molecular basis of myocardial dysfunction in HF is paving the way for development of new treatments capable of restoring muscle function and targeting specific pathological subsets of LV dysfunction. These include potentiating cardiomyocyte contractility, increasing cardiomyocyte survival and adaptive hypertrophy, increasing oxygen and nutrition supply by sustaining vessel formation, and reducing ventricular stiffness by favourable extracellular matrix remodelling. Here, we consider drugs such as omecamtiv mecarbil, nitroxyl donors, cyclosporin A, SERCA2a (sarcoplasmic/endoplasmic Ca(2 +) ATPase 2a), neuregulin, and bromocriptine, all of which are currently in clinical trials as potential HF therapies, and discuss novel molecular targets with potential therapeutic impact that are in the pre-clinical phases of investigation. Finally, we consider conceptual changes in basic science approaches to improve their translation into successful clinical applications.

The Antiapoptotic Effect of Granulocyte Colony-stimulating Factor Reduces Infarct Size and Prevents Heart Failure Development in Rats

Background/Aim. Granulocyte colony-stimulating factor (G-CSF) reduces myocardial injury and improves cardiac function after myocardial infarction (MI). We investigated the early alterations provided by G-CSF and the chronic repercussions in infarcted rats. Methods. Male Wistar rats (200-250g) received vehicle (MI) or G-CSF (MI-GCSF) (50 mu g/kg, sc) at 7, 3 and 1 days before MI surgery. Afterwards MI was produced and infarct size was measured 1 and 15 days after surgery. Expression of anti-and proapoptotic proteins was evaluated immediately before surgery. 24 hours after surgery, apoptotic nuclei were evaluated. Two weeks after MI, left ventricular (LV) function was evaluated, followed by in situ LV diastolic pressure-volume evaluation. Results. Infarct size was decreased by 1 day pretreatment before occlusion (36 +/- 2.8 vs. 44 +/- 2.1% in MI; P<0.05) and remained reduced at 15 days after infarction (28 +/- 2.2 vs. 36 +/- 1.4% in MI; P<0.05). G-CSF pretreatment increased Bcl-2 and Bcl-xL protein expression, but did not alter Bax in LV. Apoptotic nuclei were reduced by treatment (Sham: 0.46 +/- 0.42, MI: 15.5 +/- 2.43, MI-GCSF: 5.34 +/- 3.34%; P<0.05). Fifteen days after MI, cardiac function remained preserved in G-CSF pretreated rats. The LV dilation was reduced in MI-G-CSF group as compared to MI rats, being closely associated with infarct size. Conclusion. The early beneficial effects of G-CSF were essentials to preserve cardiac function at a chronic stage of myocardial infarction. Copyright (C) 2011 S. Karger AG, Basel

The renin-angiotensin system is modulated by swimming training depending on the age of spontaneously hypertensive rats

Aim: To investigate the effects of swimming training on the renin-angiotensin system (RAS) during the development of hypertensive disease. Main methods: Male spontaneously hypertensive rats (SHR) were randomized into: sedentary young (SY), trained young (TV), sedentary adult (SA), and trained adult (TA) groups. Swimming was performed 5 times/wk/8wks. Key findings: Trained young and adult rats showed both decreased systolic and mean blood pressure, and bradycardia after the training protocol. The left ventricular hypertrophy (LVH) was observed only in the TA group (12.7%), but there was no increase on the collagen volume fraction. Regarding the components of the RAS, TV showed lower activity and gene expression of angiotensinogen (AGT) compared to SY. The TA group showed lower activity of circulatory RAS components, such as decreased serum ACE activity and plasma renin activity compared to SA. However, depending on the age, although there were marked differences in the modulation of the RAS by training, both trained groups showed a reduction in circulating angiotensin II levels which may explain the lower blood pressure in both groups after swimming training. Significance: Swimming training regulates the RAS differently in adult and young SHR rats. Decreased local cardiac RAS may have prevented the LVH exercise-induced in the TV group. Both groups decreased serum angiotensin II content, which may, at least in part, contribute to the lowering blood pressure effect of exercise training. (C) 2011 Elsevier Inc. All rights reserved.

History of hypertension and eplerenone in patients with acute myocardial infarction complicated by heart failure

In the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study ( n = 6632), eplerenone- associated reduction in all- cause mortality was significantly greater in those with a history of hypertension ( Hx- HTN). There were 4007 patients with Hx- HTN ( eplerenone: n = 1983) and 2625 patients without Hx- HTN ( eplerenone: n = 1336). Propensity scores for eplerenone use, separately calculated for patients with and without Hx- HTN, were used to assemble matched cohorts of 1838 and 1176 pairs of patients. In patients with Hx- HTN, all- cause mortality occurred in 18% of patients treated with placebo ( rate, 1430/ 10 000 person- years) and 14% of patients treated with eplerenone ( rate, 1058/ 10 000 person- years) during 2350 and 2457 years of follow- up, respectively ( hazard ratio [ HR]: 0.71; 95% CI: 0.59 to 0.85; P < 0.0001). Composite end point of cardiovascular hospitalization or cardiovascular mortality occurred in 33% of placebo-treated patients ( 3029/ 10 000 person- years) and 28% of eplerenone- treated patients (2438/10 000 person- years) with Hx- HTN ( HR: 0.82; 95% CI: 0.72 to 0.94; P = 0.003). In patients without Hx- HTN, eplerenone reduced heart failure hospitalization ( HR: 73; 95% CI: 0.55 to 0.97; P = 0.028) but had no effect on mortality ( HR: 0.91; 95% CI: 0.72 to 1.15; P = 0.435) or on the composite end point ( HR: 0.91; 95% CI: 0.76 to 1.10; P = 0.331). Eplerenone should, therefore, be prescribed to all of the post - acute myocardial infarction patients with reduced left ventricular ejection fraction and heart failure regardless of Hx- HTN.

Heart Failure After Myocardial Infarction: Clinical Implications and Treatment

Heart failure is a frequent complication of myocardial infarction. Several factors, such as recurrent myocardial ischemia, infarct size, ventricular remodeling, stunned myocardium, mechanical complications, and hibernating myocardium influence the appearance of left ventricular systolic dysfunction after myocardial infarction. Importantly, its presence increases the risk of death by at least 3- to 4-fold. The knowledge of the mechanisms and clinical features are essential for the diagnosis and treatment of left ventricular dysfunction and heart failure after myocardial infarction. Therefore, this review will focus on the clinical implications and treatment of heart failure after myocardial infarction.

Chronic heart failure-induced skeletal muscle atrophy, necrosis, and changes in myogenic regulatiory factors

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Echocardiographic detection of congestive heart failure in postinfarction rats

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Growth hormone attenuates skeletal muscle changes in experimental chronic heart failure

Objective: This study evaluated the effects of growth hormone (GH) on morphology and myogenic regulatory factors (MRF) gene expression in skeletal muscle of rats with ascending aortic stenosis (AAS) induced chronic heart failure.Design: Male 90-100 g Wistar rats were subjected to thoracotomy. AAS was created by placing a stainless-steel clip on the ascending aorta. Twenty five weeks after surgery, rats were treated with daily subcutaneous injections of recombinant human GH (2 mg/kg/day; AAS-GH group) or saline (AAS group) for 14 days. Sham-operated animals served as controls. Left ventricular (LV) function was assessed before and after treatment. IGF-1 serum levels were measured by ELISA. After anesthesia, soleus muscle was frozen in liquid nitrogen. Histological sections were stained with HE and picrosirius red to calculate muscle fiber cross-sectional area and collagen fractional area, respectively. MRF myogenin and MyoD expression was analyzed by reverse transcription PCR.Results: Body weight was similar between groups. AAS and AAS-GH groups presented dilated left atrium, left ventricular (LV) hypertrophy (LV mass index: Control 1.90 +/- 0.15; AAS 3.11 +/- 0.44; AAS-GH 2.94 +/- 0.47 g/kg; p < 0.05 AAS and AAS-GH vs. Control), and reduced LV posterior wall shortening velocity. Soleus muscle fiber area was significantly lower in AAS than in Control and AAS-GH groups; there was no difference between AAS-GH and Control groups. Collagen fractional area was significantly higher in MS than Control; AAS-GH did not differ from both Control and AAS groups. Serum IGF-1 levels decreased in AAS compared to Control. MyoD mRNA was significantly higher in AAS-GH than AAS; there was no difference between AAS-GH and Control groups. Myogenin mRNA levels were similar between groups.Conclusion: In rats with aortic stenosis-induced heart failure, growth hormone administration increases MyoD gene expression above non-treated animal levels, preserves muscular trophism and attenuates interstitial fibrosis. These results suggest that growth hormone may have a potential role as an adjuvant therapy for chronic heart failure. (C) 2009 Elsevier Ltd. All rights reserved.

Myostatin and follistatin expression in skeletal muscles of rats with chronic heart failure

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Assessment of inotropic and vasodilating effects of milrinone lactate in patients with dilated cardiomyopathy and severe heart failure

OBJECTIVE: To assess the hemodynamic and vasodilating effects of milrinone lactate (ML) in patients with dilated cardiomyopathy (DCM) and New York Heart Association (NYHA) class III and IV heart failure. METHODS: Twenty patients with DCM and NYHA class III and IV heart failure were studied. The hemodynamic and vasodilating effects of ML, administered intravenously, were evaluated. The following variables were compared before and during drug infusion: cardiac output (CO) and cardiac index (CI); pulmonary capillary wedge pressure (PCWP); mean aortic pressure (MAP); mean pulmonary artery pressure (MPAP); mean right atrial pressure (MRAP); left ventricular systolic and end-diastolic pressures (LVSP and LVEDP, respectively); peak rate of left ventricular pressure rise (dP/dt); systemic vascular resistance (SVR); pulmonary vascular resistance (PVR); and heart rate (HR). RESULTS: All patients showed a significant improvement of the analysed parameters of cardiac performance with an increase of CO and CI; a significant improvement in myocardial contractility (dP/dt) and reduction of the LVEDP; PCWP; PAP; MAP; MRAP; SVR; PVR. Were observed no significant increase in HR occurred. CONCLUSION: Milrinone lactate is an inotropic dilating drug that, when administered intravenously, has beneficial effects on cardiac performance and myocardial contractility. It also promotes reduction of SVR and PVR in patients with DCM and NYHA class III and IV of heart failure.

Gastrointestinal changes associated to heart failure

Over the last decade, several studies were conducted on the gastrointestinal changes associated to chronic heart failure. This article presents a literature review on the physiopathology and clinical consequences of pathological digestive changes of heart failure patients. Structural and functional abnormalities of the gastrointestinal tract, such as edema of absorptive mucosa and intestinal bacterial overgrowth, have been leading to serious clinical consequences. Some of these consequences are cardiac cachexia, systemic inflammatory activation and anemia. These conditions, alone or in combination, may lead to worsening of the pre-existing ventricular dysfunction. Although currently there is no therapy specifically earmarked for gastrointestinal changes associated to heart failure, the understanding of digestive abnormalities is germane for the prevention and management of systemic consequences.

Heart failure-induced skeletal myopathy in spontaneously hypertensive rats

Background: Although skeletal muscle atrophy and changes in myosin heavy chain (MyHC) isoforms have often been observed during heart failure, their pathophysiological mechanisms are not completely defined. In this study we tested the hypothesis that skeletal muscle phenotype changes are related to myogenic regulatory factors and myostatin/follistatin expression in spontaneously hypertensive rats (SHR) with heart failure. Methods: After developing tachypnea, SHR were subjected to transthoracic echocardiogram. Pathological evidence of heart failure was assessed during euthanasia. Age-matched Wistar-Kyoto (WKY) rats were used as controls. Soleus muscle morphometry was analyzed in histological sections, and MyHC isoforms evaluated by electrophoresis. Protein levels were assessed by Western blotting. Statistical analysis: Student's t test and Pearson correlation. Results: All SHR presented right ventricular hypertrophy and seven had pleuropericardial effusion. Echocardiographic evaluation showed dilation in the left chambers and left ventricular hypertrophy with systolic and diastolic dysfunction in SHR. Soleus weight and fiber cross sectional areas were lower (WKY 3615±412; SHR 2035±224 μm2; P < 0.001), and collagen fractional volume was higher in SHR. The relative amount of type I MyHC isoform was increased in SHR. Myogenin, myostatin, and follistatin expression was lower and MRF4 levels higher in SHR. Myogenin and follistatin expression positively correlated with fiber cross sectional areas and MRF4 levels positively correlated with I MyHC isoform. Conclusion: Reduced myogenin and follistatin expression seems to participate in muscle atrophy while increased MRF4 protein levels can modulate myosin heavy chain isoform shift in skeletal muscle of spontaneously hypertensive rats with heart failure. © 2012 Elsevier B.V.

Diastolic function is associated with quality of life and exercise capacity in stable heart failure patients with reduced ejection fraction

Exercise capacity and quality of life (QOL) are important outcome predictors in patients with systolic heart failure (HF), independent of left ventricular (LV) ejection fraction (LVEF). LV diastolic function has been shown to be a better predictor of aerobic exercise capacity in patients with systolic dysfunction and a New York Heart Association (NYHA) classification >II. We hypothesized that the currently used index of diastolic function E/e' is associated with exercise capacity and QOL, even in optimally treated HF patients with reduced LVEF. This prospective study included 44 consecutive patients aged 55±11 years (27 men and 17 women), with LVEF,0.50 and NYHA functional class I-III, receiving optimal pharmacological treatment and in a stable clinical condition, as shown by the absence of dyspnea exacerbation for at least 3 months. All patients had conventional transthoracic echocardiography and answered the Minnesota Living with HF Questionnaire, followed by the 6-min walk test (6MWT). In a multivariable model with 6MWT as the dependent variable, age and E/e' explained 27% of the walked distance in 6MWT (P=0.002; multivariate regression analysis). No association was found between walk distance and LVEF or mitral annulus systolic velocity. Only normalized left atrium volume, a sensitive index of diastolic function, was associated with decreased QOL. Despite the small number of patients included, this study offers evidence that diastolic function is associated with physical capacity and QOL and should be considered along with ejection fraction in patients with compensated systolic HF.

Diastolic function and functional capacity after a single session of continuous positive airway pressure in patients with compensated heart failure

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)