Search

This article discusses the role of long-chain acylcarnitines (LCACs) in cardiac pathophysiology. Metabolomics studies have identified associations between LCACs and cardiovascular diseases such as heart failure and cardiac arrhythmias. The article focuses on the effects of LCACs on the ryanodine receptor (RyR2), a calcium release channel in cardiomyocytes. The study found that LCACs promote spontaneous calcium release and intracellular calcium accumulation, potentially through increased cytosolic calcium levels. The article also highlights the importance of considering methodological limitations and membrane perturbation effects when studying LCACs. The findings have implications for future research on LCACs and their potential as therapeutic targets for cardiovascular diseases. [Extracted from the article]

Diabetic patients often have impaired heart rate (HR) control. HR is regulated both intrinsically within the sinoatrial node (SAN) and via neuronal input. Previously, we found lower ex vivo HR in type 2 diabetic rat hearts, suggesting impaired HR generation within the SAN. The major driver of pacemaking within the SAN is the activity of hyperpolarisation-activated cyclic nucleotide-gated 4 (HCN(4)) channels. This study aimed to investigate whether the lower intrinsic HR in the type 2 diabetic heart is due to changes in HCN4 function, protein expression and/ or distribution. The intrinsic HR response to HCN4 blockade was determined in isolated Langendorff-perfused hearts of Zucker type 2 Diabetic Fatty (ZDF) rats (DM) and their non-diabetic ZDF littermates (nDM). HCN4 protein expression and membrane localisation were determined using western blot and immunofluorescence, respectively. We found that the intrinsic HR was lower in DM compared to nDM hearts. The change in intrinsic HR in response to HCN4 blockade with ivabradine was diminished in DM hearts, which normalised the intrinsic HR between the groups. HCN4 protein expression was decreased in the SAN of DM compared to nDM controls with no change in the fraction of HCN4 localised to the membrane of SAN cardiomyocytes. The lower intrinsic HR in DM is likely due to decreased HCN4 expression and depressed HCN4 function. Our study provides a novel understanding into the intrinsic mechanisms underlying altered HR control in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Right heart failure in pulmonary arterial hypertension (PH) is associated with mechanical ventricular dyssynchrony, which leads to impaired right ventricular (RV) function and, by adverse diastolic interaction, to impaired left ventricular (LV) function as well. However, therapies aiming to restore synchrony by pacing are currently not available. In this proof-of-principle study, we determined the acute effects of RV pacing on ventricular dyssynchrony in PH. Chronic PH with right heart failure was induced in rats by injection of monocrotaline (80 mg/kg). To validate for PH-related ventricular dyssynchrony, rats (6 PH, 6 controls) were examined by cardiac magnetic resonance imaging (9.4 T), 23 days after monocrotaline or sham injection. In a second group (10 PH, 4 controls), the effects of RV pacing were studied in detail, using Langendorff-perfused heart preparations. In PH, septum bulging was observed, coinciding with a reversal of the transseptal pressure gradient, as observed in clinical PH. RV pacing improved RV systolic function, compared with unpaced condition (maximal first derivative of RV pressure: +8.5 [+ or -] 1.3%, P < 0.001). In addition, RV pacing markedly decreased the pressure-time integral of the transseptal pressure gradient when RV pressure exceeds LV pressure, an index of adverse diastolic interaction (-24 [+ or -] 9%, P < 0.01), and RV pacing was able to resynchronize time of RV and LV peak pressure (unpaced: 9.8 [+ or -] 1.2 ms vs. paced: 1.7 [+ or -] 2.0 ms, P < 0.001). Finally, RV pacing had no detrimental effects on LV function or coronary perfusion, and no LV preexcitation occurred. Taken together, we demonstrate that, in experimental PH, RV pacing improves RV function and diminishes adverse diastolic interaction. These findings provide a strong rationale for further in vivo explorations. right ventricular dysfunction; artificial cardiac pacing; magnetic resonance imaging; Langendorff preparation doi: 10.1152/ajpheart.00555.2009.

During ischemic heart diseases and when heart failure progresses depletion of myocardial energy stores occurs. D-Ribose (R) has been shown to improve cardiac function and energy status after ischemia. Folic acid (FA) is an essential cofactor in the formation of adenine nucleotides. Therefore, we assessed whether chronic R-FA administration during the development of hypertrophy resulted in an improved cardiac function and energy status. In Wistar rats (n = 40) compensatory right ventricular (RV) hypertrophy was induced by monocrotaline (30 mg/kg; MCT), whereas saline served as control. Both groups received a daily oral dose of either 150 mg * [kg.sup.-1] * [day.sup.-1] dextrose (placebo) or R-FA (150 and 40 mg * [kg.sup.-1] * [day.sup.1], respectively). In Langendorff-perfused hearts, RV and left ventricular (LV) pressure development and collagen content as well as total RV adenine nucleotides (TAN), creatine content, and RV and LV collagen content were determined. In the control group R-FA had no effect. In the MCT-placebo group, TAN and creatine content were reduced, RV and LV diastolic pressure-volume relations were steeper, RV systolic pressures were elevated, RV and LV collagen content was increased, and RV-LV diastolic interaction was altered compared with controls. In the MCTR-FA group, TAN, RV and LV diastolic stiffness, RV and LV collagen content, and RV-LV diastolic interaction were normalized to the values in the control group while creatine content remained depressed and RV systolic function remained elevated. In conclusion, the depression of energy status in compensated hypertrophic myocardium observed was partly prevented by chronic R-FA administration and accompanied by a preservation of diastolic function and collagen deposition. energy metabolism; cardiac hypertrophy; adenine nucleotides; collagen

I. Introduction II. The Cardiac Muscle and the Coronary Vasculature A. Functional arrangement of the cardiac muscle and the coronary circulation B. Coronary pressure-flow relationships C. Summary III. The Cardiac [...]

Collagen degradation is suggested to be responsible for long-term contractile dysfunction in different cardiomyopathies, but the effects of acute and specific collagen type I removal (main type in the heart muscle) on tension have not been studied. We determined the diastolic and developed tension length relations in isometric contracting perfused rat papillary muscles (perfusion pressure 60 cm[H.sub.2]O) before and after acute and specific removal of small collagen struts with the use of purified collagenase type I. At 95% of the maximal length (95%[L.sub.max]), diastolic tension increased 20.4 [+ or -] 8.1% (P < 0.05, n = 6) and developed tension increased 15.0 [+ or -] 6.7% after collagenase treatment compared with time controls. Treatment increased the diastolic muscle diameter by 7.1 [+ or -] 3.4% at 95%[L.sub.max], whereas the change in diameter due to contraction was not changed. Diastolic coronary flow and normalized coronary arterial flow impediment did not change after collagenase treatment. Electron microscopy revealed that the number of small collagen struts, interconnecting myocytes, and capillaries was reduced to ~32% after treatment. We conclude that removal of the small collagen struts by acute and specific collagen type I degradation increases diastolic and developed tension in perfused papillary muscle. We suggest that diastolic tension is increased due to edema, whereas developed tension is increased because the removal of the struts poses a lower lateral load on the cardiac myocytes, allowing more myocyte thickening. cardiac contraction; coronary flow; collagen struts; edema; flow impediment

An increase in coronary perfusion, transversal stretch of the myocardium, increases developed force ([F.sub.dev]) (Gregg effect) through activation of stretch-activated ion channels (SACs). Lengthening of the muscle, longitudinal stretch of the myocardium, causes an immediate increase in [F.sub.dev] followed by a slow [F.sub.dev] increase (Anrep effect). In isometrically contracting perfused papillary muscles of Wistar rats, we investigated whether both effects were based on similar stretch-induced mechanisms by measuring [F.sub.dev] and intracellular [Ca.sup.2+] concentration ([[[Ca.sup.2+]].sub.i]) after a muscle length increase from 85% to 95% [L.sub.max] (length at which maximal isometric force develops) at low and high coronary perfusion before and after inhibition of SACs with gadolinium (10 [micro]mol [Gd.sup.3+]). The increase of [F.sub.dev] and peak [[[Ca.sup.2+]].sub.i] by the Gregg effect was of similar magnitude as the Anrep effect (from 3.5 [+ or -] 0.8 to 3.9 [+ or -] 1.2 mN/[mm.sup.2] and from 3.0 [+ or -] 0.7% to 3.8 [+ or -] 0.9% normalized [[[Ca.sup.2+]].sub.i], means [+ or -] SE). SAC blockade completely blunted the increase of [F.sub.dev] and peak [[[Ca.sup.2+]].sub.i] by the Gregg effect; however, it did not affect the Anrep effect. The slow force response, but not the calcium response, was augmented by an increase in coronary perfusion. Therefore, increased coronary perfusion, transversal stretch of the myocardium, and muscle lengthening, longitudinal stretch of the myocardium, increase myocardial contraction in the rat through different stretch-triggered mechanisms. myocardial stretch; papillary muscles; gadolinium; streptomycin; stretch-activated ion channels

Abstract Background Injurious mechanical ventilation (MV) may augment organ injury remote from the lungs. During sepsis, myocardial dysfunction is common and increased endothelial activation and permeability can cause myocardial edema, which may, among other factors, hamper myocardial function. We investigated the effects of MV with injuriously high tidal volumes on the myocardium in an animal model of sepsis. Methods Normal rats and intraperitoneal (i.p.) lipopolysaccharide (LPS)-treated rats were ventilated with low (6 ml/kg) and high (19 ml/kg) tidal volumes (Vt) under general anesthesia. Non-ventilated animals served as controls. Mean arterial pressure (MAP), central venous pressure (CVP), cardiac output (CO) and pulmonary plateau pressure (Pplat) were measured. Ex vivo myocardial function was measured in isolated Langendorff-perfused hearts. Cardiac expression of endothelial vascular cell adhesion molecule (VCAM)-1 and edema were measured to evaluate endothelial inflammation and leakage. Results MAP decreased after LPS-treatment and Vt-dependently, both independent of each other and with interaction. MV Vt-dependently increased CVP and Pplat and decreased CO. LPS-induced peritonitis decreased myocardial function ex vivo but MV attenuated systolic dysfunction Vt-dependently. Cardiac endothelial VCAM-1 expression was increased by LPS treatment independent of MV. Cardiac edema was lowered Vt-dependently by MV, particularly after LPS, and correlated inversely with systolic myocardial function parameters ex vivo. Conclusion MV attenuated LPS-induced systolic myocardial dysfunction in a Vt-dependent manner. This was associated with a reduction in cardiac edema following a lower transmural coronary venous outflow pressure during LPS-induced coronary inflammation.