Myofilament calcium regulation in human myocardium.
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BACKGROUND: We investigated whether decreased myofilament calcium contractile activation may, in part, contribute to heart failure. METHODS AND RESULTS: Calcium concentration required for 50% activation and Hill coefficient for fibers from nonfailing and failing human hearts at pH 7.1 were not different. Maximum calcium-activated force (F(max)) was also not different. However, at pH 6.8 and 6.9, differences were seen in myofilament calcium activation between nonfailing and failing hearts. At lower pH, failing myocardium was shifted left on the calcium axis compared with nonfailing myocardium, which suggested an increase in myofilament calcium responsiveness. Increased inorganic phosphate concentration decreased maximal force development by 56% in nonfailing and 36% in failing myocardium and shifted the calcium-force relationship by 2.01+/-0.22 versus 0.86+/-0.13 micromol/L, respectively (P<0.05). Addition of cAMP resulted in a 0. 56 micromol/L shift toward higher intracellular calcium concentrations in nonfailing myocardium and a 1.04 micromol/L shift in failing myocardium. Protein kinase A in the presence of cAMP resulted in a further rightward shift in nonfailing human myocardium but did not further shift the calcium-force relationship in fibers from failing hearts. cGMP also resulted in a greater decrease in myofilament calcium sensitivity in fibers from failing hearts. CONCLUSIONS: We propose that changes at the level of the thin myofilaments result in differential responses to changes in the intracellular milieu in nonfailing versus failing myocardium. (+info)
Early and delayed consequences of beta(2)-adrenergic receptor overexpression in mouse hearts: critical role for expression level.
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BACKGROUND: Transgenic cardiac beta(2)-adrenergic receptor (AR) overexpression has resulted in enhanced signaling and cardiac function in mice, whereas relatively low levels of transgenically expressed G(alphas) or beta(1)AR have resulted in phenotypes of ventricular failure. Potential relationships between the levels of betaAR overexpression and biochemical, molecular, and physiological consequences have not been reported. METHODS AND RESULTS: We generated transgenic mice expressing beta(2)AR at 3690, 7120, 9670, and 23 300 fmol/mg in the heart, representing 60, 100, 150, and 350 times background betaAR expression. All lines showed enhanced basal adenylyl cyclase activation but a decrease in forskolin- and NaF-stimulated adenylyl cyclase activities. Mice of the highest-expressing line developed a rapidly progressive fibrotic dilated cardiomyopathy and died of heart failure at 25+/-1 weeks of age. The 60-fold line exhibited enhanced basal cardiac function without increased mortality when followed for 1 year, whereas 100-fold overexpressors developed a fibrotic cardiomyopathy and heart failure, with death occurring at 41+/-1 weeks of age. Adenylyl cyclase activation did not correlate with early or delayed decompensation. Propranolol administration reduced baseline +dP/dt(max) to nontransgenic levels in all beta(2)AR transgenics except the 350-fold overexpressors, indicating that spontaneous activation of beta(2)AR was present at this level of expression. CONCLUSIONS: These data demonstrate that the heart tolerates enhanced contractile function via 60-fold beta(2)AR overexpression without detriment for a period of >/=1 year and that higher levels of expression result in either aggressive or delayed cardiomyopathy. The consequences for enhanced betaAR function in the heart appear to be highly dependent on which signaling elements are increased and to what extent. (+info)
Therapy of heart failure.
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The incidence and prevalence of heart failure is on the rise. It has become the single most expensive health care item in the United States and the number one discharge diagnosis in the elderly. The goals of therapy include both prevention and treatment of heart failure. In recent years research studies and randomized clinical trials have revolutionized the understanding of the pathophysiology and treatment of this disease. This article focuses on the medical management of chronic systolic heart failure based on the pathophysiology of the disease. Systolic heart failure is characterized by a decrease in left ventricular function and cardiac output, which results in activation of several neurohormonal compensatory systems. The long term effects of this neurohormonal activation leads to further deterioration of cardiac function. The use of hydralazine and nitrates to reduce the systemic vascular resistance was the first to show an improvement in mortality and morbidity. Then angiotensin converting enzyme inhibitors, by inhibiting the renin angiotensin system, demonstrated a greater improvement in mortality and morbidity. More recently the inhibition of the sympathetic stimulation with beta-blockers has been shown to have an additive effect on morbidity and mortality in combination with angiotensin-converting enzyme inhibitors. Digoxin and diuretics remain important for improving symptoms and decreasing hospitalizations but have not been shown to decrease mortality. The most recent advance in the treatment of cardiac failure is the demonstration that the aldosterone antagonists, spironolactone decreases morbidity and mortality. (+info)
Skeletal muscle dysfunction in chronic obstructive pulmonary disease and chronic heart failure: underlying mechanisms and therapy perspectives.
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Low exercise tolerance has a large influence on health status in chronic obstructive pulmonary disease and chronic heart failure. In addition to primary organ dysfunction, impaired skeletal muscle performance is a strong predictor of low exercise capacity. There are striking similarities between both disorders with respect to the muscular alterations underlying the impairment. However, different alterations occur in different muscle types. Histologic and metabolic data show that peripheral muscles undergo a shift from oxidative to glycolytic energy metabolism, whereas the opposite is observed in the diaphragm. These findings are in line with the notion that peripheral and diaphragm muscle are limited mainly by endurance and strength capacity, respectively. In both diseases, muscular impairment is multifactorially determined; hypoxia, oxidative stress, disuse, medication, nutritional depletion, and systemic inflammation may contribute to the observed muscle abnormalities and each factor has its own potential for innovative treatment approaches. (+info)
Contribution of caveolin protein abundance to augmented nitric oxide signaling in conscious dogs with pacing-induced heart failure.
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Myocardial NO signaling appears elevated in heart failure (HF). Whether this results from increased NO production, induction of the high-output NO synthase (NOS)2 isoform, or changes in NOS regulatory pathways (such as caveolae) remains controversial. We tested the hypothesis that increased abundance of caveolin-3 and/or sarcolemmal caveolae contribute to increased NO signaling in pacing-induced HF. Abundance of caveolin-3 (0.59+/-0.08 versus 0.29+/-0.08 arbitrary units, P = 0.01) but not caveolin-1 was increased in HF compared with control conditions, assessed by Western blot. Additionally, transmission electron microscopy revealed increased caveolae (2. 7+/-0.4 versus 1.3+/-0.3 per micrometer myocyte membrane, P<0.005). The association between caveolin-3 and NOS3 at the sarcolemma and T tubules was unchanged in HF compared with control myocytes. The impact of NOS inhibition with L-N(G)-methylarginine hydrochloride (L-NMMA) on beta-adrenergic inotropy was assessed in conscious dogs before and after HF. In control dogs, dobutamine (5 microg. kg(-1) x min(-1)) increased +dP/dt by 36+/-7%, and this was augmented to 66+/-24% by 20 mg/kg L-NMMA (P = 0.04 versus without L-NMMA, n = 8) but not affected by 10 mg/kg L-NMMA (34+/-10%, P = NS; n = 8). In HF, dobutamine +dP/dt response was depressed (P<0.001 versus control), and increased concentrations were required to match control inotropic responses (10 to 15 microg. kg(-1) x min(-1), 48+/-7%). L-NMMA enhanced +dP/dt responses similarly at 10 mg/kg (61+/-17%, P = 0.02; n = 4) and 20 mg/kg (54+/-7%, P = 0.04; n = 7). Caveolin-3 abundance positively correlated with L-NMMA augmentation of dobutamine inotropic responses in HF (r = 0.9, P = 0.03; n = 4). Thus, in canine pacing-induced HF, expression of caveolin-3 and of sarcolemmal caveolae is increased. This increase is associated with augmented agonist-stimulated NO signaling, likely via a compartmentation effect. (+info)
Effects of estrogen on venous function in rats with chronic heart failure.
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The effect of 17beta-estradiol on venous function was investigated in ovariectomized rats with heart failure. Rats (50-60 days old) were ovariectomized and implanted with 60-day-release pellets that contain 17beta-estradiol (1.5 mg) or vehicle. The left coronary artery was ligated 7 days later. Another group of ovariectomized rats was given vehicle pellets and then a sham operation was performed. The rats were studied while under pentobarbital anesthesia at 7 wk after ligation. Ligated rats, relative to sham groups, had lower mean arterial pressure (MAP, -34 mmHg) and cardiac output (CO, -38%); higher arterial resistance (R(A), +12%) and venous resistance (R(V), +116%); mean circulatory filling pressure (MCFP, +40%) and left ventricular end-diastolic pressure (LVEDP, +11 mmHg); and similar cardiovascular responses to norepinephrine (NE). Treatment of ligated rats with 17beta-estradiol increased CO (+16%); reduced R(A) (-16%), R(V) (-35%), MCFP (-23%), and LVEDP (-3 mmHg); and augmented MAP, R(V,) and MCFP responses to NE. Therefore, 17beta-estradiol reduced MCFP, and this reduced preload (LVEDP). 17beta-Estradiol decreased R(V), which, along with decreased R(A) (afterload), led to an increase in CO. 17beta-Estradiol likely augmented vasoconstriction to NE through an improvement on the cardiovascular status. (+info)
Near-maximal fractional oxygen extraction by active skeletal muscle in patients with chronic heart failure.
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Systemic oxygen uptake and deep femoral vein oxygen content were determined at peak exercise in 53 patients with chronic heart failure with impaired systolic function (mean left ventricular ejection fraction 0.18; n = 41) or preserved systolic function (mean left ventricular ejection fraction 0.70; n = 12) and in 6 age-matched sedentary normal subjects. At peak exercise, deep femoral vein oxygen content in heart failure patients with impaired systolic function and preserved systolic function were similar, both significantly lower than that of normal subjects (2.5 +/- 0.1, 2.9 +/- 0.2, and 5.0 +/- 0.1 ml/100 ml, respectively; P < 0.05). Deep femoral venous oxygen content was lower in patients with the greater impairment of aerobic capacity, regardless of the underlying systolic function (r = 0.72, P < 0.01). Fractional oxygen extraction in the skeletal muscle at peak exercise is enhanced in patients with chronic heart failure when compared with normal subjects, in proportion to the degree of aerobic impairment. (+info)
A mechanistic analysis of reduced mechanical performance in human heart failure.
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In failing human hearts (FHH) (NYHA IV) the cardiac output is inadequate to meet the metabolic needs of the peripheral systems. By means of thermo-mechanical analysis we have shown that epicardial strips from FHH (37 degrees C) have a depressed tension independent heat (TIH) and tension independent heat rate (dTIH / dt) liberation that correlates with depression in peak isometric force and the rate of relaxation. Furthermore, in response to a change in frequency of stimulation, FHH shows a severe blunting of the force-frequency relationship resulting in a decrease in myocardial reserve and in the frequency at which optimum force is obtained. We used ventricular ANF as an index of the severity of myocardial disease and demonstrated an inverse relationship between ANF mRNA and the sarcoplasmic reticulum (SR) calcium cycling proteins (SERCA 2, Phospholamban, Ryanodine Receptor) while these latter proteins all had a positive correlation with each other. At the same time there was an increase in sarcolemmal sodium calcium exchange protein. The decrease in SR pump proteins correlates with the decrease in myocardial reserve and optimum frequency of contraction. The latter mechanical changes are explainable in terms of a frequency dependent decrease in calcium concentration (aequorin light) in FHH. (+info)