Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mineralocorticoid receptor (MR) and the enzyme 11betahydroxysteroid dehydrogenase type 2, which confers aldosterone specificity to the MR, are present in endothelium and vascular smooth muscle. In several pathological conditions aldosterone promotes vascular damage by formation of reactive oxygen species. The effect of aldosterone on vascular function, however, is far from clear. By rapid non-genomic mechanisms aldosterone may cause calcium mobilization and vasoconstriction, or may stimulate nitric oxide formation through the PI-3 kinase/Akt pathway and thereby counteract vasoconstriction. Vasoconstrictor, vasodilator or no effects of aldosterone have been reported from studies on human forearm blood flow. Inhibition of MR with spironolactone improves endothelial function in patients with heart failure but worsens endothelial function in type 2 diabetic patients. The aim of the present review is to reconcile some of the apparently conflicting data. A key observation is that reactive oxygen and nitrogen species serve as physiological signaling molecules at low concentrations, while they initiate pathological processes at higher concentrations. The net effect of aldosterone, which stimulates ROS production, therefore depends on the ambient level of oxidative stress. Thus, in situations with low levels of oxidative stress aldosterone may promote vasodilatation, while at higher oxidative stress (high NaCl intake, pre-existing vascular pathological conditions, high oxygen tension in vitro) aldosterone is likely to be associated with vasoconstriction and oxidative damage, and in this setting inhibition of the MR is likely to be beneficial.
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PMID:Rapid actions of aldosterone in vascular health and disease--friend or foe? 1641 9

Although the specific roles of nitric oxide (NO) in the heart in general and on cardiac mitochondria in particular remain controversial, it is now clear that both endogenous and exogenous sources of NO exert important modulatory effects on mitochondrial function. There is also growing evidence that NO can be produced within the mitochondria themselves. NO can influence respiratory activity, both through direct effects on the respiratory chain or indirectly via modulation of mitochondrial calcium accumulation. At pathological concentrations, NO can cause irreversible alterations in respiratory function and can also interact with reactive oxygen species (ROS) to form reactive nitrogen species, which may further impair mitochondrial respiration and can even lead to opening of the mitochondrial permeability transition pore and cell death. Diabetes, aging, myocardial ischemia, and heart failure have all been associated with altered ROS generation, which can alter the delicate regulatory balance of effects of NO in the mitochondria. As NO competes with oxygen at cytochrome oxidase, it can be argued that experiments exploring the roles of NO on mitochondrial respiration should be performed at physiological (i.e. relatively low) oxygen tensions. Improvements in techniques, and a gradual appreciation of the many potential pitfalls in studying mitochondrial NO, are leading to a recognition of the role of NO in the regulation of mitochondrial function in the heart in health and disease.
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PMID:Effects of NO on mitochondrial function in cardiomyocytes: Pathophysiological relevance. 1651 74

Circulation time (Ct) between lung and periphery may be a surrogate for cardiac output, estimated here, for the most part, as the time between taking a breath of nitrogen and peripheral detection of a desaturation pulse. Use of pulse oximetry involves an internal, instrument delay; however, using the ear, we found shortening with exercise (12.1 +/- 0.37 sec, at rest; 9.1 +/- 0.25 sec at 100 watts), lengthening after beta-blockade, and lengthening in patients with echocardiographic and clinical left heart failure (8 patients 16.2 +/- 1.1 sec; 6 controls 12.0 +/- 0.5 sec). Pulse oximetry failed, however, to discriminate heart failure from normal in several patients. In patients referred to a department of nuclear medicine for assessment of chest pain, pulse oximetry (finger and ear) showed unacceptable variability. Nuclide delays between lung and carotid artery correlated significantly with the reciprocal of gated SPECT estimated cardiac output (Q(gs)); not so, however, for lung to finger. In normal subjects, an old Waters fast response oximeter gave short, reproducible Ct estimates and a significant correlation with the reciprocal of (indirect Fick) cardiac output (Q(if)). The relationship for normal subjects was: Ct = 0.28 x 60/Q(if) + 2.8 sec (Q(if) in L min.; P slope < .001).
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PMID:Circulation time in man from lung to periphery as an indirect index of cardiac output. 1659 67

Although loop diuretics are widely used in heart failure (HF), their effect on outcomes has not been evaluated in large clinical trials. This study sought to determine the dose-dependent relation between loop diuretic use and HF prognosis. A cohort of 1,354 patients with advanced systolic HF referred to a single center was studied. Patients were divided into quartiles of equivalent total daily loop diuretic dose: 0 to 40, 41 to 80, 81 to 160, and >160 mg. The cohort was 76% male, with a mean age of 53+/-13 years and a mean ejection fraction of 24+/-7%. The mean diuretic dose equivalence was 107+/-87 mg. The diuretic quartile groups were similar in terms of gender, body mass index, ischemic cause of HF, history of hypertension, and spironolactone use, but the highest quartile was associated with a smaller ejection fraction and lower serum sodium and hemoglobin levels but higher serum blood urea nitrogen and creatinine levels. There was a decrease in survival with increasing diuretic dose (83%, 81%, 68%, and 53% for quartiles 1, 2, 3, and 4, respectively). Even after extensive co-variate adjustment (age, gender, ischemic cause of HF, the ejection fraction, body mass index, pulmonary capillary wedge pressure, peak oxygen consumption, beta-blocker use, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use, digoxin use, statin use, serum sodium, blood urea nitrogen, creatinine, hemoglobin, cholesterol, systolic blood pressure, and smoking history), diuretic quartile remained an independent predictor of mortality (quartile 4 vs quartile 1 hazard ratio 4.0, 95% confidence interval 1.9 to 8.4). In conclusion, in this cohort of patients with advanced HF, there was an independent, dose-dependent association between loop diuretic use and impaired survival. Higher loop diuretic dosages identify patients with HF at particularly high risk for mortality.
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PMID:Relation of loop diuretic dose to mortality in advanced heart failure. 1713 42

The use of aggressive treatments and the modification of current treatment in patients with heart failure (HF) relies heavily on the assessment of disease severity using prognostic markers. However, many such markers are unavailable in routine clinical practice, and others have little prognostic value. This study tested the hypothesis that low body temperature could predict short-term survival after discharge in patients hospitalized for HF. Data from the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF) trial, which randomized 319 patients hospitalized for HF to receive placebo or tolvaptan, were retrospectively analyzed. Hypothermia was defined a priori as an oral body temperature <35.8 degrees C at randomization. Cox regression was used to analyze survival within a 60-day follow-up period. Hypothermia was observed in 32 patients (10%). Mortality rates at 60 days after discharge were 6.3% (20 of 319) overall, 9.4% (3 of 32) in hypothermic patients, and 5.9% (17 of 287) in nonhypothermic patients. Hypothermia was a strong multivariate predictor of mortality; hypothermic patients were 3.9 times more likely to die within 60 days than nonhypothermic patients (95% confidence interval 1.002 to 15.16, p = 0.0497) after adjustment for treatment group, age, and other confounders. Hypothermia was associated with such indicators of low cardiac output as an elevated blood urea nitrogen/creatinine ratio, narrow pulse pressure, and a reduced ejection fraction. In conclusion, hypothermia appears to be a strong predictor of mortality in patients with HF.
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PMID:Comparison of 60-day mortality in hospitalized heart failure patients with versus without hypothermia. 1712 55

Anemia is prevalent in patients with chronic heart failure and is associated with worse symptoms and poor prognosis. The authors reviewed the charts of all patients (N=467) treated at Texas Heart Institute from January 2000 to October 2003, during which time a clinical protocol offered treatment with erythropoiesis-stimulating proteins. Post-treatment, the authors observed a significant increase in mean +/- SD hemoglobin, from 9.9+/-1.1 g/dL to 11.7+/-1.5 g/dL (P<.0001), improvement of renal function (a decrease in mean levels of creatinine and blood urea nitrogen), and fewer hospital admissions (1.0+/-1.4 vs 1.8+/-1.6; P=.0003) without an increase in adverse clinical events, compared with pretreatment and compared with an untreated control group. These results suggest a potential benefit of anemia treatment with recombinant erythropoiesis-stimulating proteins in patients with chronic heart failure.
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PMID:The effect of administering erythropoiesis-stimulating proteins in patients with chronic heart failure: results from a retrospective study. 1717 May 81

Nitric oxide (nitrogen monoxide) (NO) plays an important role in a wide range of physiologic processes. A major mediator of endothelial function, NO regulates vasodilatory and antithrombotic actions in the vasculature and plays a role in reproductive functions, bronchodilation, bone formation, memory, insulin sensitivity, and gastrointestinal relaxation. NO is formed from NO synthase. Impaired NO bioactivity is strongly associated with endothelial dysfunction and cardiovascular disease, but is also implicated in a broad range of other disorders, including pulmonary hypertension, insulin resistance, erectile dysfunction, and preeclampsia. Numerous therapies designed to target NO are being investigated and developed, including NO donors and stimulants. The recent African-American Heart Failure Trial (A-HeFT) showed that the NO donor isosorbide dinitrate, combined with the vasodilator hydralazine, significantly reduced morbidity and mortality in black patients with moderate-to-severe heart failure. Antihypertensive drugs, including angiotensin-converting enzyme inhibitors, calcium channel blockers, and third-generation beta-blockers, are NO stimulants that have demonstrated significant improvement of endothelial function and NO bioactivity. Other cardiovascular therapies that may improve NO bioactivity include statins, l-arginine, and nonpharmacologic approaches such as exercise and dietary changes.
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PMID:Aspects of nitric oxide in health and disease: a focus on hypertension and cardiovascular disease. 1717 Jun 2

Methylprednisolone sodium succinate (MPSS) administered during reperfusion may improve myocardial function. These effects have been related to adrenergic stimulation. The present study investigated (1) the effects of ischemia and reperfusion on the beta-adrenergic response system and (2) the ability of MPSS to modify the ischemic effects on the beta-adrenergic system. Isolated perfused rat hearts were used. The ischemic protocol consisted of aerobic perfusion (20 minutes) followed by total, global normothermic (37 degrees C) ischemia (30 minutes) and reperfusion (30 minutes) with MPSS (0, 100, 500, or 1,000 mg/L). The non-ischemic protocol consisted of aerobic perfusion (20 minutes) followed by aerobic perfusion (20 minutes) with MPSS (0, 100, 500, or 1,000 mg/L). At the end of the experiments all hearts were rapidly frozen in liquid nitrogen. Crude sarcolemmal membranes were prepared and stimulated at the beta-receptor, at the coupling (G.- or N-) protein, or directly at the adenylate cyclase enzyme (AC). Results were assessed by cyclic adenosine monophosphate (cAMP) production. Tissue specimens were analyzed for myocardial content of cAMP and methylprednisolone (MP). In the ischemic protocol, the responsiveness of the beta-adrenergic system was significantly reduced at the G.-protein level. The treatment with MPSS (100 or 500 mg/L) during reperfusion preserved the beta-adrenergic response. MPSS (1,000 mg/L) offered no protection. In the non-ischemic protocol, MPSS reduced the response of the beta-adrenergic system in a dose-dependent manner at the same level. The hearts in the ischemic protocol had significantly higher contents of MP than the hearts in the non-ischemic protocol at corresponding concentrations of MPSS. The present study suggests that postischemic cardiac failure may result in part from beta-adrenergic dysfunction. This loss of function, probably at the level of the protein connecting the receptor and AC, can successfully be prevented by an optimal dose of MPSS during reperfusion after ischemia.
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PMID:Steroids protect the beta-adrenergic system during reperfusion after ischemia: effects of methylprednisolone on the beta-adrenergic response system. 1717 88

There is growing evidence that altered production and/or spatio-temporal distribution of reactive oxidant species and reactive nitrosative species in blood creates oxidative and/or nitrosative stresses in the failing myocardium and endothelium. This contributes to the abnormal cardiac and vascular phenotypes that characterize cardiovascular disease. These derangements at the system level can now be interpreted at the integrated cellular and molecular levels in terms of effects on signaling elements in the heart and vasculature. The end results of nitric oxide/redox disequilibrium have implications for cardiac and vascular homeostasis and may result in the development of atherosclerosis, myocardial tissue remodelling and hypertrophy. Reactive oxygen species/reactive nitrogen species generation is also attributed to the transit from hypertrophic to apoptotic phenotypes, a possible mechanism of myocardial failure. In this review, we highlight the possible roles of altered production and/or spatio-temporal distribution of reactive oxidant species and reactive nitrosative species in blood on the pathogenesis of the failing cardiovascular system.
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PMID:Nitric oxide in blood. The nitrosative-oxidative disequilibrium hypothesis on the pathogenesis of cardiovascular disease. 1724 98

Diabetic nephropathy (DN) is one of the main causes of end stage renal disease (ESRD) and a leading cause of diabetes mellitus related morbidity and mortality. Recently, sirtuin are reported to have emerging pathogenetic roles in cancer, muscle differentiation, heart failure, neurodegeneration, diabetes and aging. The aim of the present study was to study the role of intermittent fasting (IF) on DN and studying the expression of Sir2 and p53. At biochemical level, we found that IF causes significant improvement in blood urea nitrogen (BUN), creatinine, albumin and HDL cholesterol, parameters that are associated with the development of DN. Diabetic rats on IF also show significant improvement in onset of hypertension. Interestingly, the expression of Sir2, a NAD dependent histone deacetylase, decreases in diabetic rat kidney and this decrease is overcome by IF. Moreover, we provide evidence for involvement of mitogen activated protein kinases (MAPK) cascade in mediating the effects of IF as there is reduction in the expression of p38 which gets induced under diabetic condition. This was further accompanied by the concomitant decrease in cleavage of caspase3 and p53 expression. These findings suggest that IF significantly improves biochemical parameters associated with development of DN and changes the expression of Sir2 and p53.
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PMID:Intermittent fasting prevents the progression of type I diabetic nephropathy in rats and changes the expression of Sir2 and p53. 1731 25


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