Systolic heart failure induced by butylparaben in zebrafish is caused through oxidative stress and immunosuppression.

Due to Butylparaben (BuP) widespread application in cosmetics, food, pharmaceuticals, and its presence as an environmental residue, human and animal exposure to BuP is common, potentially posing hazards to both human and animal health. Congenital heart disease is already a serious problem. However, the effects of BuP on the developing heart and its underlying mechanisms remain unclear. Here, zebrafish embryos were exposed to environmentally and human-relevant concentrations of BuP (0.6 mg/L, 1.2 mg/L, and 1.8 mg/L, calculated but not measured) at 6 h post-fertilization (hpf) and were treated until 72 hpf. Exposure to BuP led to cardiac morphological defects and cardiac dysfunction in zebrafish embryos, manifesting symptoms similar to systolic heart failure. The etiology of BuP-induced systolic heart failure in zebrafish embryos is multifactorial, including cardiomyocyte apoptosis, endocardial and atrioventricular valve damage, insufficient myocardial energy, impaired Ca2+ homeostasis, depletion of cardiac-resident macrophages, cardiac immune non-responsiveness, and cardiac oxidative stress. However, excessive accumulation of reactive oxygen species (ROS) in the cardiac region and cardiac immunosuppression (depletion of cardiac-resident macrophages and cardiac immune non-responsiveness) may be the predominant factors. In conclusion, this study indicates that BuP is a potential hazardous substance that can cause adverse effects on the developing heart and provides evidence and insights into the pathological mechanisms by which BuP leads to cardiac dysfunction. It may help to prevent the BuP-based congenital heart disease heart failure in human through ameliorating strategies and BuP discharge policies, while raising awareness to prevent the misuse of preservatives.

Systolic Dysfunction of the Heart in Type 1 Diabetes Mellitus.

Impaired insulin synthesis is accompanied by hyperglycemia and the development of diabetic cardiomyopathy. Echocardiography and left-ventricular catheterization were employed for studying the contractile function of the left ventricle in 2 weeks after administration of streptozotocin (60 mg/kg). The results obtained by both methods were similar and indicated the development of systolic dysfunction with a 27% decrease in cardiac output. The invasive study showed that the maximum rate of left-ventricular pressure development, the contractility index, and systolic left-ventricular pressure were within the normal range, but the peak ejection rate was reduced by 28%. BP was normal, but the vascular stiffness index was increased by about 1.5 times and inversely correlated with the peak ejection rate (r=-0.69). The results showed that systolic dysfunction in type 1 diabetes model was due to reduced ejection from the left ventricle at normal rate of left-ventricular pressure development.

Adaptations in Protein Expression and Regulated Activity of Pyruvate Dehydrogenase Multienzyme Complex in Human Systolic Heart Failure.

Pyruvate dehydrogenase (PDH) complex, a multienzyme complex at the nexus of glycolytic and Krebs cycles, provides acetyl-CoA to the Krebs cycle and NADH to complex I thus supporting a critical role in mitochondrial energy production and cellular survival. PDH activity is regulated by pyruvate dehydrogenase phosphatases (PDP1, PDP2), pyruvate dehydrogenase kinases (PDK 1-4), and mitochondrial pyruvate carriers (MPC1, MPC2). As NADH-dependent oxidative phosphorylation is diminished in systolic heart failure, we tested whether the left ventricular myocardium (LV) from end-stage systolic adult heart failure patients (n = 26) exhibits altered expression of PDH complex subunits, PDK, MPC, PDP, and PDH complex activity, compared to LV from nonfailing donor hearts (n = 21). Compared to nonfailing LV, PDH activity and relative expression levels of E2, E3bp, E1α, and E1ß subunits were greater in LV failure. PDK4, MPC1, and MPC2 expressions were decreased in failing LV, whereas PDP1, PDP2, PDK1, and PDK2 expressions did not differ between nonfailing and failing LV. In order to examine PDK4 further, donor human LV cardiomyocytes were induced in culture to hypertrophy with 0.1 µM angiotensin II and treated with PDK inhibitors (0.2 mM dichloroacetate, or 5 mM pyruvate) or activators (0.6 mM NADH plus 50 µM acetyl CoA). In isolated hypertrophic cardiomyocytes in vitro, PDK activators and inhibitors increased and decreased PDK4, respectively. In conclusion, in end-stage failing hearts, greater expression of PDH proteins and decreased expression of PDK4, MPC1, and MPC2 were evident with higher rates of PDH activity. These adaptations support sustained capacity for PDH to facilitate glucose metabolism in the face of other failing bioenergetic pathways.

Cardiovascular diseases and systolic function of left ventricle in clean up workers of Chernobyl accident (based on 30 years follow up). / SERTsEVO SUDYNNI ZAKhVORIuVANNIa TA STAN SYSTOLIChNOÏ FUNKTsIÏ LIVOGO ShLUNOChKA V UChASNYKIV LIKVIDATsIÏ NASLIDKIV ChORNOBYL'S'KOÏ AVARIÏ (ZA DANYMY 30 RIChNOGO SPOSTEREZhENNIa).

OBJECTIVE: To study the dynamics of circulatory system diseases during the 30 year period after irradiation, changes in the status of systolic function of heart left ventricle (LV) and the features of its remodeling in clean up workers (CW) of the accident at the Chernobyl nuclear power plant (ChNPP). MATERIAL AND METHODS: It was examined 144 CW at ChNPP, including 52 patients, who survived acute radiation sick ness (ARS) grade of severity 1-3, and 105 non irradiated persons (control group - CG). CW have been divided into two subgroups: without signs of ARS (ARS0) and those who suffered from ARS. CW and CG patients were male who had no signs of cardiovascular, nervous, pulmonary or endocrine pathology prior to the Chernobyl accident. Their average age at the beginning of the accident was 33.9-37.7 years. The study program included clinical examina tion, echocardiography, retrospective and statistical analysis. RESULTS: Hypertensive heart disease (HHD) has developed in the CW, including the ARS convalescents, by 12 years, and ischemic heart disease (CHD) at 9-11 years is believed to be earlier than in comparable non irradiated patients. In the post accident period, there was an increased mean value of LV posterior wall (PW) thickness, interventricular septum (IVS), myocardium mass and myocardium mass normalized by body surface area. These indices grew with the increase of HHD duration. Over the 30 year follow up period, between CW and CG from 14.3 to 28.6 % of patients with LV increased volumes it was found a decreased ejection fraction (EF), what indicated the development of sys tolic LV dysfunction with the phenomena of left ventricular heart failure (HF). Reduction of EF correlated with increase of end systolic volume (ESV) having the highest statistical strength. In CW and persons of CG there was from 77.3 to 84.8 % of patients had clinical signs of HF with preserved EF. From this number, 56-63.6 % of patients had concentric and 18.8-26.7 % had eccentric LV hypertrophy (LVH), and in 6.1 to 15.6% of patients, normal LV geom etry or its concentric remodeling was observed. CONCLUSIONS: The CW and non irradiated persons differed significantly by the onset of HHD and CHD, which previ ously developed in the CW, including the ARS survivors. Changes in the structural and functional state of myocardi um during long term follow up did not have any probable differences between CW and non irradiated persons and consisted of BW and IVS thickening, which predetermined the development of LVH. In CW and CG concentric LVH was dominant. The LV systolic dysfunction with decreased EF and increased ESV was characterized by clinical symptoms of left ventricular HF. More than half of patients with clinical symptoms of HF and preserved EF had signs of concen tric hypertrophy.

Hippo pathway deficiency reverses systolic heart failure after infarction.

Mammalian organs vary widely in regenerative capacity. Poorly regenerative organs, such as the heart are particularly vulnerable to organ failure. Once established, heart failure commonly results in mortality. The Hippo pathway, a kinase cascade that prevents adult cardiomyocyte proliferation and regeneration, is upregulated in human heart failure. Here we show that deletion of the Hippo pathway component Salvador (Salv) in mouse hearts with established ischaemic heart failure after myocardial infarction induces a reparative genetic program with increased scar border vascularity, reduced fibrosis, and recovery of pumping function compared with controls. Using translating ribosomal affinity purification, we isolate cardiomyocyte-specific translating messenger RNA. Hippo-deficient cardiomyocytes have increased expression of proliferative genes and stress response genes, such as the mitochondrial quality control gene, Park2. Genetic studies indicate that Park2 is essential for heart repair, suggesting a requirement for mitochondrial quality control in regenerating myocardium. Gene therapy with a virus encoding Salv short hairpin RNA improves heart function when delivered at the time of infarct or after ischaemic heart failure following myocardial infarction was established. Our findings indicate that the failing heart has a previously unrecognized reparative capacity involving more than cardiomyocyte renewal.

Cardiac Myosin Activators in Systolic Heart Failure: More Friend than Foe?

Despite the rising prevalence of HF, new evidence-based novel therapies for patients with worsening HF remain lacking, e.g., safe inotropic therapies. Traditional inotropes increase contractility by altering intracellular calcium flux, a pathway that may be responsible for the multitude of adverse effects associated with current options. Omecamtiv mecarbil, a direct myosin activator, increases contractility through a distinct pathway by increasing the proportion of myosin heads that are bound to actin in a high-affinity state. Phase II clinical trials in patients with chronic HF with this agent seem promising. A phase III trial investigating this therapy has not yet been pursued to date.

Melanoma cell adhesion molecule as an emerging biomarker with prognostic significance in systolic heart failure.

BACKGROUND: Melanoma cell adhesion molecule (MCAM) is a marker of endothelial damage. MCAM diagnostic and prognostic value was assessed in chronic heart failure (CHF). MATERIALS & METHODS: 130 CHF patients and 32 controls were included in the study. Telephone follow-up lasted one year. End points were: death from all causes, and hospitalization with CHF exacerbation. RESULTS: MCAM was higher in patients than in controls (p = 0.01). Receiver operator curve analysis revealed that MCAM may serve as a predictor of death (area under the curve: 0.8404; p < 0.002). Patients with MCAM above 500 ng/ml had worse prognosis (p = 0.03). NT-proBNP and age were independent predictors of death in multivariate analysis. CONCLUSION: The increased MCAM indicates endothelial damage in CHF and may serve as a marker of worse prognosis in these patients.

Clinical Benefits of Stem Cells for Chronic Symptomatic Systolic Heart Failure: A Systematic Review of the Existing Data and Ongoing Trials.

The benefits of stem cell therapy for patients with chronic symptomatic systolic heart failure due to ischemic and nonischemic cardiomyopathy (ICM and NICM, respectively) are unclear. We performed a systematic review of major published and ongoing trials of stem cell therapy for systolic heart failure and compared measured clinical outcomes for both types of cardiomyopathy. The majority of the 29 published studies demonstrated clinical benefits of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs). Left ventricular ejection fraction (LVEF) was improved in the majority of trials after therapy. Cell delivery combined with coronary artery bypass grafting was associated with the greatest improvement in LVEF. Left ventricular end-systolic volume (or diameter), New York Heart Association functional classification, quality of life, and exercise capacity were also improved in most studies after cell therapy. Most ICM trials demonstrated a significant improvement in perfusion defects, infarct size, and myocardial viability. Several larger clinical trials that are in progress employ alternative delivery modes, cell types, and longer follow-up periods. Stem cells are a promising therapeutic modality for patients with heart failure due to ICM or NICM. More data are required from larger blinded trials to determine which combination of cell type and delivery mode will yield the most benefit with avoidance of harm in these patient populations.

Heart failure: when form fails to follow function.

Cardiac performance is normally determined by architectural, cellular, and molecular structures that determine the heart's form, and by physiological and biochemical mechanisms that regulate the function of these structures. Impaired adaptation of form to function in failing hearts contributes to two syndromes initially called systolic heart failure (SHF) and diastolic heart failure (DHF). In SHF, characterized by high end-diastolic volume (EDV), the left ventricle (LV) cannot eject a normal stroke volume (SV); in DHF, with normal or low EDV, the LV cannot accept a normal venous return. These syndromes are now generally defined in terms of ejection fraction (EF): SHF became 'heart failure with reduced ejection fraction' (HFrEF) while DHF became 'heart failure with normal or preserved ejection fraction' (HFnEF or HFpEF). However, EF is a chimeric index because it is the ratio between SV--which measures function, and EDV--which measures form. In SHF the LV dilates when sarcomere addition in series increases cardiac myocyte length, whereas sarcomere addition in parallel can cause concentric hypertrophy in DHF by increasing myocyte thickness. Although dilatation in SHF allows the LV to accept a greater venous return, it increases the energy cost of ejection and initiates a vicious cycle that contributes to progressive dilatation. In contrast, concentric hypertrophy in DHF facilitates ejection but impairs filling and can cause heart muscle to deteriorate. Differences in the molecular signals that initiate dilatation and concentric hypertrophy can explain why many drugs that improve prognosis in SHF have little if any benefit in DHF.

Modeling Pathologies of Diastolic and Systolic Heart Failure.

Chronic heart failure is a medical condition that involves structural and functional changes of the heart and a progressive reduction in cardiac output. Heart failure is classified into two categories: diastolic heart failure, a thickening of the ventricular wall associated with impaired filling; and systolic heart failure, a dilation of the ventricles associated with reduced pump function. In theory, the pathophysiology of heart failure is well understood. In practice, however, heart failure is highly sensitive to cardiac microstructure, geometry, and loading. This makes it virtually impossible to predict the time line of heart failure for a diseased individual. Here we show that computational modeling allows us to integrate knowledge from different scales to create an individualized model for cardiac growth and remodeling during chronic heart failure. Our model naturally connects molecular events of parallel and serial sarcomere deposition with cellular phenomena of myofibrillogenesis and sarcomerogenesis to whole organ function. Our simulations predict chronic alterations in wall thickness, chamber size, and cardiac geometry, which agree favorably with the clinical observations in patients with diastolic and systolic heart failure. In contrast to existing single- or bi-ventricular models, our new four-chamber model can also predict characteristic secondary effects including papillary muscle dislocation, annular dilation, regurgitant flow, and outflow obstruction. Our prototype study suggests that computational modeling provides a patient-specific window into the progression of heart failure with a view towards personalized treatment planning.

Effects of Statin Therapy on Clinical Outcomes of Survivors of Acute Myocardial Infarction with Severe Systolic Heart Failure.

OBJECTIVE: Large randomized trials have failed to show a beneficial effect of statin treatment in chronic HF. The investigators tried to evaluate the long-term effects of statin therapy in patients with new onset heart failure (HF) following acute myocardial infarction (AMI). METHODS: Between January 2008 and December 2011, a total of 13,616 AMI patients were enrolled in the Korea Acute Myocardial Infarction Registry (KAMIR) which was a prospective, multi-center, nationwide, web-based database of AMI in Korea. From this database, we studied 1,055 patients with AMI who had newly developed severe acute HF [left ventricular ejection fraction ≤ 40%] and were discharged alive. The patients were divided into two groups, a statin group (n = 756) and a no-statin group (n = 299). We investigated the one-year major adverse cardiovascular events (MACEs), including all-cause mortality, MI, and any revascularization of each group. We then performed a propensity-score matched analysis. RESULTS: In the original cohort, one-year MACEs were similar between the two groups (16.5% vs. 14.7% in the statin or no-statin groups; p = 0.47). Propensity-score matching yielded 256 pairs, and in that population we observed comparable results in terms of MACEs (18.0% vs. 12.5% in the statin or no-statin groups, p = 0.11) and mortality (5.1% vs. 3.5% in the statin or no-statin groups, p = 0.51). Cox-regression analysis revealed that statin therapy was not an independent predictor for occurrence of a MACE [Hazard ratio (HR) 1.11, 95% CI 0.79-1.57, p = 0.54] or all-cause mortality (HR 1.42, 95% CI 0.75-2.70, p = 0.28). CONCLUSION: Statin therapy was not associated with a reduction in the long-term occurrence of MACEs or mortality in survivors of AMI with severe acute HF in this retrospective cohort study.

Experimental heart failure modelled by the cardiomyocyte-specific loss of an epigenome modifier, DNMT3B.

Differential DNA methylation exists in the epigenome of end-stage failing human hearts but whether it contributes to disease progression is presently unknown. Here, we report that cardiac specific deletion of Dnmt3b, the predominant DNA methyltransferase in adult mouse hearts, leads to an accelerated progression to severe systolic insufficiency and myocardial thinning without a preceding hypertrophic response. This was accompanied by widespread myocardial interstitial fibrosis and myo-sarcomeric disarray. By targeted candidate gene quantitative RT-PCR, we discovered an over-activity of cryptic splice sites in the sarcomeric gene Myh7, resulting in a transcript with 8 exons missing. Moreover, a region of differential methylation overlies the splice site locus in the hearts of the cardiac-specific conditional knockout (CKO) mice. Although abundant and complex forms of alternative splice variants have been reported in diseased hearts and the contribution of each remains to be understood in further detail, our results demonstrate for the first time that a link may exist between alternative splicing and the cardiac epigenome. In particular, this gives the novel evidence whereby the loss of an epigenome modifier promotes the development and progression of heart disease.

Clinical implications of chronic heart failure phenotypes defined by cluster analysis.

BACKGROUND: Classification of chronic heart failure (HF) is on the basis of criteria that may not adequately capture disease heterogeneity. Improved phenotyping may help inform research and therapeutic strategies. OBJECTIVES: This study used cluster analysis to explore clinical phenotypes in chronic HF patients. METHODS: A cluster analysis was performed on 45 baseline clinical variables from 1,619 participants in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) study, which evaluated exercise training versus usual care in chronic systolic HF. An association between identified clusters and clinical outcomes was assessed using Cox proportional hazards modeling. Differential associations between clinical outcomes and exercise testing were examined using interaction testing. RESULTS: Four clusters were identified (ranging from 248 to 773 patients in each), in which patients varied considerably among measures of age, sex, race, symptoms, comorbidities, HF etiology, socioeconomic status, quality of life, cardiopulmonary exercise testing parameters, and biomarker levels. Differential associations were observed for hospitalization and mortality risks between and within clusters. Compared with cluster 1, risk of all-cause mortality and/or all-cause hospitalization ranged from 0.65 (95% confidence interval [95% CI]: 0.54 to 0.78) for cluster 4 to 1.02 (95% CI: 0.87 to 1.19) for cluster 3. However, for all-cause mortality, cluster 3 had a disproportionately lower risk of 0.61 (95% CI: 0.44 to 0.86). Evidence suggested differential effects of exercise treatment on changes in peak oxygen consumption and clinical outcomes between clusters (p for interaction <0.04). CONCLUSIONS: Cluster analysis of clinical variables identified 4 distinct phenotypes of chronic HF. Our findings underscore the high degree of disease heterogeneity that exists within chronic HF patients and the need for improved phenotyping of the syndrome. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437).

CMR-verified diffuse myocardial fibrosis is associated with diastolic dysfunction in HFpEF.

OBJECTIVES: The purpose of this study was to investigate diffuse myocardial fibrosis in patients with systolic heart failure (SHF) and in patients with heart failure with preserved ejection fraction (HFpEF) and the association with diastolic dysfunction of the left ventricle (LV). BACKGROUND: Increased diffuse myocardial fibrosis may impair LV diastolic function. However, no study has verified the association between the degree of diffuse myocardial fibrosis and the severity of impaired diastolic function in SHF and HFpEF. METHODS: Forty patients with SHF, 62 patients with HFpEF, and 22 patients without HF underwent cardiac magnetic resonance (CMR), including T1 mapping and cine CMR on a 3-T system. Extracellular volume fraction (ECV), a measure of diffuse myocardial fibrosis, was quantified from T1 mapping. Systolic and diastolic functions of the LV were assessed by cine CMR. The ECV values and LV functional indexes were compared among the 3 groups. Associations between ECV and LV diastolic function were also investigated. RESULTS: Compared with patients without HF, significantly higher ECV was found in patients with SHF (31.2% [interquartile range (IQR): 29.0% to 34.1%] vs. 27.9% [IQR: 26.2% to 29.4%], p < 0.001) and HFpEF (28.9% [IQR: 27.8% to 31.3%] vs. 27.9% [IQR: 26.2% to 29.4%], p = 0.006). Peak filling rate, a diastolic functional index assessed by cine CMR, was significantly decreased in patients with SHF (1.00 s(-1) [IQR: 0.79 to 1.49 s(-1)] vs. 3.86 s(-1) [IQR: 3.34 to 4.48 s(-1)], p < 0.001) and HFpEF (2.89 s(-1) [IQR: 2.13 to 3.50 s(-1)] vs. 3.86 s(-1) [IQR: 3.34 to 4.48 s(-1)], p < 0.001). Myocardial ECV was significantly correlated with peak filling rate in the HFpEF group (r = -0.385, p = 0.002), but no correlation was found in the SHF and non-HF groups (r = 0.030, p = 0.856 and r = -0.238, p = 0.285, respectively). CONCLUSIONS: In patients with HF, only those with HFpEF show a significant correlation between increased diffuse myocardial fibrosis and impaired diastolic function. Diffuse myocardial fibrosis plays a unique role in the pathogenesis of HFpEF.

Comparison the prognostic value of galectin-3 and serum markers of cardiac extracellular matrix turnover in patients with chronic systolic heart failure.

BACKGROUND: Galectin-3 (Gal-3) shows the ability of survival prediction in heart failure (HF) patients. However, Gal-3 is strongly associated with serum markers of cardiac extracellular matrix (ECM) turnover. The aim of this study is to compare the impact of Gal-3 and serum markers of cardiac ECM turnover on prognostic prediction of chronic systolic HF patients. METHODS: Serum Gal-3, brain natriuretic peptide (BNP), extracellular matrix including type I and III aminoterminal propeptide of procollagen (PINP and PIIINP), matrix metalloproteinase-2, 9 (MMP-2, 9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were analyzed. Cox regression analysis was used for survival analysis. RESULTS: A total of 105 (81 male) patients were enrolled. During 980±346 days follow-up, 17 patients died and 36 episodes of HF admission happened. Mortality of these patients was significantly associated with the log PIIINP (ß= 15.380; P=0.042), log TIMP-1(ß= 44.530; P=0.003), log MMP-2 (ß= 554.336; P<0.001), log BNP (ß= 28.273; P=0.034). Log Gal-3 (ß= 7.484; P=0.066) is borderline associated with mortality. Mortality or first HF admission of these patients was significantly associated with the log TIMP-1(ß= 16.496; P=0.006), log MMP-2 (ß= 221.864; P<0.001), log BNP (ß= 5.999; P=0.034). Log Gal-3 (ß= 4.486; P=0.095) only showed borderline significance. In several models adjusting clinical parameters, log MMP-2 was significantly associated with clinical outcome. In contrast, log Gal-3 was not. CONCLUSION: The prognostic strength of MMP-2 to clinical outcome prediction in HF patients is stronger than Gal-3.

Left atrial function in heart failure with impaired and preserved ejection fraction.

PURPOSE OF REVIEW: Left atrial structural and functional changes in heart failure are relatively ignored parts of cardiac assessment. This review illustrates the pathophysiological and functional changes in left atrium in heart failure as well as their prognostic value. RECENT FINDINGS: Heart failure can be divided into those with systolic dysfunction and heart failure with preserved ejection fraction (HFPEF). Left atrial enlargement and dysfunction commonly occur in systolic heart failure, in particular, in idiopathic dilated cardiomyopathy. Atrial enlargement and dysfunction also carry important prognostic value in systolic heart failure, independently of known parameters such as left ventricular ejection fraction. In HFPEF, there is evidence of left atrial enlargement, impaired atrial compliance, and reduction of atrial pump function. This occurs not only at rest but also during exercise, indicating significant impairment of atrial contractile reserve. Furthermore, atrial dyssynchrony is common in HFPEF. These factors further contribute to the development of new onset or progression of atrial arrhythmias, in particular, atrial fibrillation. SUMMARY: Left atrial function is an integral part of cardiac function and its structural and functional changes in heart failure are common. As changes of left atrial structure and function have different clinical implications in systolic heart failure and HFPEF, routine assessment is warranted.