Background Ventricular expression of phosphodiesterase-5 (PDE5), an enzyme responsible for cGMP catabolism, is increased in human right ventricular hypertrophy, but its role in left ventricular (LV) failure remains incompletely understood. We therefore measured LV PDE5 expression in patients with advanced systolic heart failure and characterized LV remodeling after myocardial infarction (MI) in transgenic mice with cardiomyocyte-specific over-expression of PDE5 (PDE5-TG). Methods and Results Immunoblot and immunohistochemistry techniques revealed that PDE5 expression was greater in explanted LVs from patients with dilated and ischemic cardiomyopathy than in control hearts. To evaluate the impact of increased ventricular PDE5 levels on cardiac function, PDE5-TG mice were generated. Confocal and immunoelectron microscopy revealed increased PDE5 expression in cardiomyocytes predominantly localized to Z-bands. At baseline, myocardial cGMP levels, cell shortening and calcium handling in isolated cardiomyocytes, and LV hemodynamic measurements were similar in PDE5-TG and wild-type littermates (WT). Ten days after MI, LV cGMP levels increased to a greater extent in WT than PDE5-TG (P<0.05). Ten weeks after MI, LV end-systolic and -diastolic volumes were larger in PDE5-TG than in WT (57±5 vs 39±4 and 65±6 vs 48±4 µL, respectively, P<0.01 for both). LV systolic and diastolic dysfunction was more marked in PDE5-TG than WT associated with enhanced hypertrophy and reduced contractile function in isolated cardiomyocytes from remote myocardium. Conclusions Increased PDE5 expression predisposes mice to adverse LV remodeling after MI. Increased myocardial PDE5 expression in patients with advanced cardiomyopathy may contribute to the development of heart failure and represents an important therapeutic target.
Background-The impact of interleukin (IL)-6 on skeletal muscle function remains the subject of controversy. Methods and Results-The effects of 7-day subcutaneous administration of recombinant human IL-6 were examined at 3 doses, 50, 100, or 250 g · kg Ϫ1 · d Ϫ1 , in rats. Skeletal muscle mass decreased dose-dependently (with increasing dose: in the diaphragm, Ϫ10%, PϭNS; Ϫ15%, Pϭ0.0561; and Ϫ15% PϽ0.05; and in the gastrocnemius, Ϫ9%, PϭNS; Ϫ9%, PϭNS; and Ϫ18%, PϽ0.005) because of decreases in cross-sectional area of all fiber types without alterations in diaphragm contractile properties. Cardiovascular variables showed a dose-dependent heart dilatation (for end-diastolic volume: control, 78 L; moderate dose, 123 L; and high dose, 137 L, PϽ0.001), reduced end-systolic pressure (control, 113 mm Hg; moderate dose, 87 mm Hg; and high dose, 90 mm Hg; Pϭ0.037), and decreased myocardial contractility (for preload recruitable stroke work: control, 79 mm Hg; moderate dose, 67 mm Hg; and high dose, 48 mm Hg; PϽ0.001). Lung edema was confirmed by an increased wet-to-dry ratio (control, 4.2; moderate dose, 4.6; and high dose, 4.5; PϽ0.001) and microscopy findings. These cardiovascular alterations led to decreases in organ blood flow, particularly in the diaphragm (control, 0.56 mL · min Ϫ1 · g
Hypertension is an underlying risk factor for cardiovascular disease. Despite this, its pathogenesis remains unknown in most cases. Recently, the transient receptor potential (TRP) channel family was associated with the development of several cardiovascular diseases linked to hypertension. The melastatin TRP channels TRPM4 and TRPM5 have distinct properties within the TRP channel family: they form nonselective cation channels activated by intracellular calcium ions. Here we report the identification of TRPM4 proteins in endothelial cells, heart, kidney, and chromaffin cells from the adrenal gland, suggesting that they have a role in the cardiovascular system. Consistent with this hypothesis, Trpm4 gene deletion in mice altered long-term regulation of blood pressure toward hypertensive levels. No changes in locomotor activity, renin-angiotensin system function, electrolyte and fluid balance, vascular contractility, and cardiac contractility under basal conditions were observed. By contrast, inhibition of ganglionic transmission with either hexamethonium or prazosin abolished the difference in blood pressure between Trpm4 -/-and wild-type mice. Strikingly, plasma epinephrine concentration as well as urinary excretion of catecholamine metabolites were substantially elevated in Trpm4 -/-mice. In freshly isolated chromaffin cells, lack of TRPM4 was shown to cause markedly more acetylcholineinduced exocytotic release events, while neither cytosolic calcium concentration, size, nor density of vesicles were different. We therefore conclude that TRPM4 proteins limit catecholamine release from chromaffin cells and that this contributes to increased sympathetic tone and hypertension.
It is well accepted that strain and strain rate deformation parameters are not only a measure of intrinsic myocardial contractility but are also influenced by changes in cardiac load and structure. To date, no information is available on the relative importance of these confounders. This study was designed to investigate how strain and strain rate, measured by Doppler echocardiography, relate to the individual factors that determine cardiac performance. Echocardiographic and conductance measurements were simultaneously performed in mice in which individual determinants of cardiac performance were mechanically and/or pharmacologically modulated. A multivariable analysis was performed with radial and circumferential strains and peak systolic radial and circumferential strain rates as dependent parameters and preload recruitable stroke work (PRSW), arterial elastance (E(a)), end-diastolic pressure, and left ventricular myocardial volume (LVMV) as independent factors representing myocardial contractility, afterload, preload, and myocardial volume, respectively. Radial strain was most influenced by E(a) (β = -0.58, R(2) = 0.34), whereas circumferential strain was strongly associated with E(a) and moderately with LVMV (β = 0.79 and -0.52, respectively, R(2) = 0.54). Radial strain rate was related to both PRSW and LVMV (β = 0.79 and -0.62, respectively, R(2) = 0.50), whereas circumferential strain rate showed a prominent correlation only with PRSW (β = -0.61, R(2) = 0.51). In conclusion, strain (both radial and circumferential) is not a good surrogate measure of intrinsic myocardial contractility unless the strong confounding influence of afterload is considered. Strain rate is a more robust measure of contractility that is less influenced by changes in cardiac load and structure. Thus, peak systolic strain rate is the more relevant parameter to assess myocardial contractile function noninvasively.
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