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Background: Alterations in myocardial mitochondrial function and metabolism have been implicated in the pathophysiology of heart failure with reduced ejection fraction (HFrEF). The impact of mechanical dyssynchrony and its alleviation through cardiac resynchronization therapy (CRT) on myocardial mitochondrial function and metabolism remain poorly understood.Methods: HFrEF patients with an indication for CRT underwent targeted metabolomic analysis of 84 energetic substrates at baseline (coronary sinus and peripheral venous blood). Mitochondrial membrane potential (Ψm) as an indicator of mitochondrial function was assessed non-invasively through 99mTC-sestamibi myocardial washout. Changes in peripheral metabolism and Ψm were assessed 6-months after CRT and their association with left ventricular remodeling and peakVO2 was assessed. Principle component analysis (PCA) was used as dimension reduction strategy for metabolic analysis.Results: Forty-five HFrEF-patients underwent CRT-implant (76% male, ejection fraction 29±6%). At baseline, PCA of coronary (CS) vs peripheral blood (PB) illustrated preferred cardiac uptake of β-hydroxybutyrate (CS vs PB-ratio=-78%; p<0.005) together with anaplerotic amino-acids, and glycolytic pyruvate breakdown to lactate. Baseline Ψm-dysfunction was associated with shift away from free fatty acids oxidation (FAO). Myocardial β-hydroxybutyrate extraction strongly associated with peakVO2 (-0.836; p<0.001). CRT improved Ψm (25±5% vs 18±6%; p=0.002), in parallel with metabolic remodeling, with increased reliance on FAO, and less reliance on β-hydroxybutyrate and glycolytic pyruvate breakdown to lactate. Changes in myocardial mitochondrial function and metabolism were associated with left ventricular reverse remodeling.Conclusion: HFrEF-patients exhibit baseline mitochondrial dysfunction, which is associated with alterations in myocardial substrate utilization, including less FAO, more reliance on ketone bodies, anaplerotic amino-acids and the breakdown of glycolytic pyruvate to lactate. CRT is capable of inducing mitochondrial and metabolic reverse remodeling which is associated with cardiac morphology changes. [ABSTRACT FROM AUTHOR]

Objectives: This study investigated the effects of 17β-estradiol (E2) on gene regulation in human cardiac tissues. We hypothesized that a candidate E2 effect is cardiomyocyte (CM)- and sex-specific, conserved between humans and mice, and that E2 impairs contractile function in male CMs only. Background: Both men and women produce E2 locally from androgenic precursors. E2 regulates cardiovascular function, but specific mechanisms, protective or harmful, are not fully understood. Methods: We performed genome-wide expression profiling of E2-treated cardiac tissues from men and women, and studied gene expression and function in CMs from hearts of male and female E2-treated mice. Results: We found 36 E2-dependent genes regulated in a sex-specific manner. Of these, after E2 exposure, the myosin regulatory light chain interacting protein (MYLIP) gene was induced in tissues of men only. Focusing on Mylip and employing isolated mouse CMs, we confirmed our hypotheses that the E2 effect is CM- and sex-specific and conserved between humans and mice. The E2-treatment led to impaired contractile function in male CMs only, which was characterized by increased Mylip mRNA and protein levels, and decreased myosin regulatory light chain (Mrlc) protein. Our report is the first to our knowledge to show that cardiac Mrlc is an in vivo substrate for Mylip, leading to augmented Mrlc ubiquitination. Of relevance, we found that MYLIP expression levels rise with increasing age in hearts of men. Conclusions: E2 directly influences cardiac gene regulation, and E2 actions may be different between the sexes. Since E2 levels rise in older and/or obese men, pharmacological targeting of MYLIP in men with elevated E2 levels could possibly decrease their risk for the development or progression of cardiovascular disease. [Copyright &y& Elsevier]

Abstract: Malignant ventricular tachyarrhythmias are common among patients with hypertrophy and heart failure, and these arrhythmias can initiate by triggered activity. Abnormal repolarization and disturbed calcium handling due to remodeling processes are common features of the hypertrophied and failing heart that conspire to facilitate triggering events. These changes have a different cellular origin in compensated hypertrophy as compared with failure, which underscores the complexity of mechanisms that predispose the remodeled heart to arrhythmias. This hampers the identification of the vulnerable patient and adequate antiarrhythmic pharmacotherapy. Beat-to-beat variability of repolarization has been proposed as an early (noninvasive) electrographic detection method of triggered activity. An increase of variability heralds an enhanced risk of arrhythmias, and controlling this repolarization parameter by pharmacological agents is antiarrhythmic. Different drugs (flunarizine, ranolazine, K201, calmodulin kinase blockers) that are able to prevent and/or suppress triggered arrhythmias by specific mechanisms of action will be discussed. [Copyright &y& Elsevier]

Background The development of heart failure (HF) secondary to hypertension is a complex process related to a series of physiological and molecular factors including glucose dysregulation. The overall objective of this study was to investigate whether exercise training could improve cardiac function and insulin resistance in a rat model of hypertensive HF. Methods Seven week old Dahl salt-sensitive rats received either 8% NaCl (n = 30) or 0.3% NaCl (n = 18) diet. After a 5-week diet, animals were randomly assigned to exercise training (treadmill running at 18 m/min, 5% inclination for 60 min, 5 days/week) or kept sedentary for 6 additional weeks. 2D echocardiography was used to calculate left ventricular (LV) dimensions, volumes and global functional parameters. LV global deformation parameters were measured with speckle tracking echocardiography. Insulin resistance was assessed using 1 h oral glucose tolerance testing. Results High salt diet led to cardiac hypertrophy and HF, characterized by increased wall thicknesses and LV volumes as well as reduced deformation parameters. In addition, high salt diet was associated with the development of insulin resistance. Exercise training improved cardiac function, reduced the extent of interstitial fibrosis and reduced insulin levels 60 min post-glucose administration. Conclusions Even if not fully reversed, exercise training in HF animals improved cardiac function and insulin resistance. Adjusted modalities of exercise training might offer new insights not only as a preventive strategy, but also as a treatment for HF patients. [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a major problem worldwide. Within this patient group, cardiovascular diseases are the biggest cause of morbidity and mortality. Diabetic cardiomyopathy (DCM) is defined as diabetes-associated structural and functional changes in the myocardium, not directly attributable to other confounding factors such as coronary artery disease or hypertension. Pathophysiology of DCM remains unclear due to a lack of adequate animal models reflecting the current pandemic of diabetes, associated with a high increased sugar intake and the 'Western' lifestyle. The aim of this study was to develop an animal model mimicking this 'Western' lifestyle causing a human-like phenotype of DCM. Twenty-four Sprague-Dawley rats were randomly assigned into a normal or a 'Western' diet group for 18 weeks. Glucose and insulin levels were measured with an OGTT. Heart function was assessed by echocardiography and hemodynamic measurements in vivo. Cardiac fibrosis and inflammation were investigated in vitro. 'Western' diet given to healthy rats for 18 weeks induced hyperglycemia together with increased AGEs levels, insulin levels and hypertriglyceridemia. Heart function was altered with increased end-diastolic pressure, left ventricle hypertrophy. Changes in vivo were associated with increased collagen deposition and increased PAI-1 levels in the heart. High-sugar diet or 'Western' diet causes T2DM and the hallmarks of DCM in rats, reflecting the phenotype of the disease seen in patients. Using this new model of T2DM with DCM might open new insight in understanding the pathophysiology of DCM and on a long term, test targeted therapies for T2DM with DCM patients. [ABSTRACT FROM AUTHOR]

Background Several clinical and experimental studies have demonstrated that advanced glycation end products (AGEs) are associated with adverse cardiac outcome. Growing evidence shows that high molecular weight AGEs (HMW-AGEs) might be as important as the characterized low molecular weight AGEs. To date, the role of HMW-AGEs in the pathogenesis of cardiac remodeling remains unknown. In this study, we investigated whether HMW-AGEs are involved in cardiac dysfunction. Methods Healthy rats were daily ip injected with 20 mg/kg BSA-derived HMW-AGEs or, as a control, unmodified BSA, during 6 weeks. Cardiac function was assessed with echocardiography. Plasma levels of glucose, AGEs and soluble RAGE (sRAGE) were measured. AGEs, RAGE and lysyl oxidase (LOX) expression were determined by western blot. Results After 6 weeks, animals displayed a sustained increase in circulating total AGEs without hyperglycemia. HMW-AGEs injections induced cardiac dysfunction characterized by wall hypertrophy, increased heart sphericity, reduced strain and strain rate with preserved ejection fraction. Plasma sRAGE levels were significantly higher compared to control and correlated significantly with decreased strain. RAGE expression, TNF-α and IL-6 remained unchanged. Finally, HMW-AGEs induced prominent cardiac fibrosis associated with an increased LOX expression. Conclusion Our data demonstrate that rather than via a specific activation of RAGE, the deleterious effects of HMW-AGEs are likely mediated via an increased collagen cross-linking responsible for the observed cardiac stiffness. Additionally, we show that in the setting of elevated HMW-AGEs, increased sRAGE levels are markers of altered cardiac function. [ABSTRACT FROM AUTHOR]

Background This study assessed whether autologous transplantation of cardiac atrial appendage stem cells (CASCs) preserves cardiac function after myocardial infarction (MI) in a minipig model. Methods and results CASCs were isolated from right atrial appendages of Göttingen minipigs based on high aldehyde dehydrogenase activity and expanded. MI was induced by a 2 h snare ligation of the left anterior descending coronary artery. Upon reperfusion, CASCs were intramyocardially injected under NOGA guidance (MI-CASC, n = 10). Non-transplanted pigs (MI, n = 8) received sham treatment. 3D electromechanical mapping (EMM) and cardiac MRI were performed to assess left ventricular (LV) function. MI pigs developed LV dilatation at 2 months (2 M), while in the MI-CASC group volumes remained stable. Global LV ejection fraction decreased by 16 ± 8% in MI animals vs 3 ± 10% in MI-CASC animals and regional wall thickening in border areas was better preserved in the MI-CASC group. EMM showed decreased viability and wall motion in the LV for both groups POST-MI, whereas at 2 M these parameters only improved in the MI-CASC. Substantial cell retention was accompanied by cardiomyogenic differentiation in 98 ± 1% of the transplanted CASCs, which functionally integrated. Second harmonic generation microscopy confirmed the formation of mature sarcomeres in transplanted CASCs. Absence of cardiac arrhythmias indicated the safety of CASC transplantation. Conclusion CASCs preserve cardiac function by extensive engraftment and cardiomyogenic differentiation. Our data indicate the enormous potential of CASCs in myocardial repair. [ABSTRACT FROM AUTHOR]

Abstract: In the setting of regional ischemia, the “at-risk” myocardium exhibits a flow-related reduction in systolic thickening with a concomitant development of abnormal thickening after aortic valve closure (postsystolic thickening [PST]). With the introduction of high time–resolution ultrasonic-based strain/strain-rate imaging, this short lived phenomenon can be measured accurately in the clinical setting. The mechanisms underlying this ischemia-related PST are poorly understood and both active and passive etiologies have been proposed. This study aims at elucidating the potential mechanisms behind PST in the intact heart. A theoretical model, describing active force development, elasticity and segment interaction has been developed to simulate radial deformation during systole and iso-volumetric relaxation. Simulation results have been compared with experimental deformation curves obtained from postero-basal segments of a pig model undergoing varying controlled ischemic challenges. Three forms of regional ischemia could be simulated by varying the model parameters of the ischemic segments: (i) chronic regional hypo-perfusion (reduced and prolonged active force development; preserved elasticity); (ii) acute short-lived ischemia—temporary vessel occlusion (no active force development; preserved elasticity); and (iii) chronic myocardial infarction (no active force development; decreased elasticity). For all ischemic substrates, the simulated curves closely correlate to the deformation measured in the corresponding porcine models without the need for active force development during the occurrence of PST. This suggests that segment interaction is the key determinant in the development of PST. Thus, in all instances, at the time of its manifestation, ischemia-related PST could be explained in a unified way as a passive phenomenon that was the result of elastic segment interaction. Its occurrence originates from the end-systolic inhomogeneous state where neighboring segments have a different wall thickness. The occurrence of these differences at end-systole depends on the presence of regional differences within the ventricle in the magnitude and duration of the developed contraction force during the first part of systole, the elasticity of the ischemic segment and the left-ventricular pressure. (E-mail: Piet.Claus@med.kuleuven.be) [Copyright &y& Elsevier]