Pro-Inflammatory Biomarkers in Stable Versus Acutely Decompensated Heart Failure With Preserved Ejection Fraction.

Background: Underlying inflammation has been increasingly recognized in heart failure with a preserved ejection fraction (HFpEF). In this study we tested the hypothesis that pro-inflammatory biomarkers are elevated in patients with acutely decompensated HFpEF (AD-HFpEF) compared with patients with stable HFpEF (S-HFpEF).

Methods And Results: Using a post hoc analysis the serum biomarkers tumor necrosis factor-alpha, high-sensitivity C-reactive protein interleukin 6 and pentraxin 3 (PTX3) and clinical, demographic, echocardiographic-Doppler and clinical outcomes data were analyzed in HFpEF patients enrolled in NHLBI Heart Failure Research Network clinical trials which enrolled patients with either AD-HFpEF or S-HFpEF.

Abundance, localization, and functional correlates of the advanced glycation end-product carboxymethyl lysine in human myocardium.

Advanced glycation end-products (AGEs) play a role in the pathophysiology of diabetes mellitus (DM) and possibly hypertension (HTN). In DM, AGEs accumulate in myocardium. Little is known about AGEs in myocardium.

Human epicardial cell-conditioned medium contains HGF/IgG complexes that phosphorylate RYK and protect against vascular injury.

Aims: The aim of this study was to evaluate the paracrine activity of human epicardial-derived cells (hEPDCs) to screen for secreted vasoprotective factors and develop therapeutics to treat vascular reperfusion injury.

Methods And Results: Epicardial cells support cardiac development, repair, and remodelling after injury in part, through paracrine activity. We hypothesized that secreted ligands from hEPDCs would protect vascular integrity after myocardial infarction (MI) with reperfusion.

Cardiac myosin isoforms exhibit differential rates of MgADP release and MgATP binding detected by myocardial viscoelasticity.

We measured myosin crossbridge detachment rate and the rates of MgADP release and MgATP binding in mouse and rat myocardial strips bearing one of the two cardiac myosin heavy chain (MyHC) isoforms. Mice and rats were fed an iodine-deficient, propylthiouracil diet resulting in ~100% expression of β-MyHC in the ventricles. Ventricles of control animals expressed ~100% α-MyHC.

Zinc-induced cardiomyocyte relaxation in a rat model of hyperglycemia is independent of myosin isoform.

It has been reported previously that diabetic cardiomyopathy can be inhibited or reverted with chronic zinc supplementation. In the current study, we hypothesized that total cardiac calcium and zinc content is altered in early onset diabetes mellitus characterized in part as hyperglycemia (HG) and that exposure of zinc ion (Zn2+) to isolated cardiomyocytes would enhance contraction-relaxation function in HG more so than in nonHG controls. To better control for differential cardiac myosin isoform expression as occurs in rodents after β-islet cell necrosis, hypothyroidism was induced in 16 rats resulting in 100% β-myosin heavy chain expression in the heart.

Myosin cross-bridge dynamics in patients with hypertension and concentric left ventricular remodeling.

Background: Hypertension (HTN) causes concentric left ventricular remodeling, defined as an increased relative wall thickness or overt left ventricular hypertrophy, and associated diastolic dysfunction. HTN and concentric remodeling are also common precursors to heart failure with a preserved ejection fraction. It is not known whether the myofilament contributes to diastolic dysfunction in patients with concentric remodeling.

Resistance training alters skeletal muscle structure and function in human heart failure: effects at the tissue, cellular and molecular levels.

Reduced skeletal muscle function in heart failure (HF) patients may be partially explained by altered myofilament protein content and function. Resistance training increases muscle function, although whether these improvements are achieved by correction of myofilament deficits is not known. To address this question, we examined 10 HF patients and 14 controls prior to and following an 18 week high-intensity resistance training programme.

Erythropoietin induces positive inotropic and lusitropic effects in murine and human myocardium.

Initial clinical studies indicate a potential beneficial effect of erythropoietin (EPO) in patients with anemia and heart failure. Here, we investigate the direct contractile effects of erythropoietin on myocardial tissue. Treatment with EPO (50U/mL) using excitable murine and human left ventricular muscle preparations resulted in a 37% and 62% increase in twitch tension, respectively (P<0.

Unique single molecule binding of cardiac myosin binding protein-C to actin and phosphorylation-dependent inhibition of actomyosin motility requires 17 amino acids of the motif domain.

Cardiac myosin binding protein-C (cMyBP-C) has 11 immunoglobulin or fibronectin-like domains, C0 through C10, which bind sarcomeric proteins, including titin, myosin and actin. Using bacterial expressed mouse N-terminal fragments (C0 through C3) in an in vitro motility assay of myosin-generated actin movement and the laser trap assay to assess single molecule actin-binding capacity, we determined that the first N-terminal 17 amino acids of the cMyBP-C motif (the linker between C1 and C2) contain a strong, stereospecific actin-binding site that depends on positive charge due to a cluster of arginines. Phosphorylation of 4 serines within the motif decreases the fragments' actin-binding capacity and actomyosin inhibition.

Biomarker profiles as descriptors of left ventricular remodeling after acute myocardial infarction.

Background: Biomarker expression can predict subsequent cardiovascular events. The goal of this study was to determine the pattern of expression in blood of a broad array of cytokines and growth factors taken 24-72 h after an ST elevation myocardial infarction (STEMI) involving the left anterior descending (LAD) coronary artery.

Methods: Blood was taken from 16 patients with LAD STEMI.

Blood gene expression signatures associate with heart failure outcomes.

Gene expression signatures in blood correlate with specific diseases. Such signatures may serve as valuable diagnostic and prognostic tools in disease management. Blood gene expression signatures associated with heart failure may be applied to predict prognosis, monitor disease progression, and optimize treatment.

Effect of resistance training on physical disability in chronic heart failure.

Purpose: Patients with chronic heart failure (CHF) report difficulty performing activities of daily living. To our knowledge, however, no study has directly measured performance in activities of daily living in these patients to systematically assess their level of physical disability. Moreover, the contribution of skeletal muscle weakness to physical disability in CHF remains unclear.

Chronic heart failure reduces Akt phosphorylation in human skeletal muscle: relationship to muscle size and function.

Patients with chronic heart failure (HF) frequently lose muscle mass and function during the course of the disease. A reduction in anabolic stimuli to the muscle has been put forth as a potential mechanism underlying these alterations. The present study examined the hypothesis that skeletal muscle tissue from HF patients would show reduced IGF-1 expression and phosphorylation of signaling molecules downstream of receptor activation.

Ventricular resynchronization by implementation of direct his bundle pacing in a patient with congenital complete AV block and newly diagnosed cardiomyopathy.

Congenital complete atrioventricular block (CCAVB) is usually due to failure of AV nodal conduction with preservation of the His Purkinje system, typically present at birth. While most patients with CCAVB ultimately require pacemaker therapy to restore physiologic heart rates, recent studies have suggested that chronic right ventricular (RV) pacing in patients with CCAVB can have detrimental effects on cardiac structure and function, and may account for a 7-10% incidence of congestive heart failure in these patients. Since the His Purkinje system is preserved in CCAVB, this patient population could be uniquely well served by direct His bundle pacing (DHBP) which would be expected to restore physiologic activation of both ventricles.

Chronic heart failure decreases cross-bridge kinetics in single skeletal muscle fibres from humans.

Skeletal muscle function is impaired in heart failure patients due, in part, to loss of myofibrillar protein content, in particular myosin. In the present study, we utilized small-amplitude sinusoidal analysis for the first time in single human skeletal muscle fibres to measure muscle mechanics, including cross-bridge kinetics, to determine if heart failure further impairs contractile performance by altering myofibrillar protein function. Patients with chronic heart failure (n = 9) and controls (n = 6) were recruited of similar age and physical activity to diminish the potentially confounding effects of ageing and muscle disuse.

Atrial contractile protein content and function are preserved in patients with coronary artery disease and atrial fibrillation.

Objectives: Atrial fibrillation (AF) causes atrial contractile dysfunction. The focus of this study was to determine whether the contractile deficit of human AF is the result of altered contractile protein abundance and/or function.

Methods: Atrial tissue from patients with chronic AF undergoing open-heart surgery was compared with the tissue from patients in normal sinus rhythm (NSR).

Combined immunoelectron microscopic and computer-assisted image analyses to detect advanced glycation end-products in human myocardium.

Advanced glycation end-products (AGEs) result from oxidation-reduction reactions that ensue when a sugar becomes adducted to a protein. AGEs cause various complications of diabetes mellitus (DM). Experimental and clinical evidence suggest that AGEs also contribute to the complications of hypertension (HTN).

Effects of cardiac myosin isoform variation on myofilament function and crossbridge kinetics in transgenic rabbits.

Background: The left ventricles of both rabbits and humans express predominantly beta-myosin heavy chain (MHC). Transgenic (TG) rabbits expressing 40% alpha-MHC are protected against tachycardia-induced cardiomyopathy, but the normal amount of alpha-MHC expressed in humans is only 5% to 7% and its functional importance is questionable. This study was undertaken to identify a myofilament-based mechanism underlying tachycardia-induced cardiomyopathy protection and to extrapolate the impact of MHC isoform variation on myofilament function in human hearts.

Human actin mutations associated with hypertrophic and dilated cardiomyopathies demonstrate distinct thin filament regulatory properties in vitro.

Two cardiomyopathic mutations were expressed in human cardiac actin, using a Baculovirus/insect cell system; E99K is associated with hypertrophic cardiomyopathy whereas R312H is associated with dilated cardiomyopathy. The hypothesis that the divergent phenotypes of these two cardiomyopathies are associated with fundamental differences in the molecular mechanics and thin filament regulation of the underlying actin mutation was tested using the in vitro motility and laser trap assays. In the presence of troponin (Tn) and tropomyosin (Tm), beta-cardiac myosin moved both E99K and R312H thin filaments at significantly (p<0.