Dose-related beneficial long-term hemodynamic and clinical efficacy of irbesartan in heart failure.
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OBJECTIVES: The primary purpose of this study was to determine the acute and long-term hemodynamic and clinical effects of irbesartan in patients with heart failure. BACKGROUND: Inhibition of angiotensin II production by angiotensin-converting enzyme (ACE) inhibitors reduces morbidity and mortality in patients with heart failure. Irbesartan is an orally active antagonist of the angiotensin II AT1 receptor subtype with potential efficacy in heart failure. METHODS: Two hundred eighteen patients with symptomatic heart failure (New York Heart Association [NYHA] class II-IV) and left ventricular ejection fraction < or = 40% participated in the study. Serial hemodynamic measurements were made over 24 h following randomization to irbesartan 12.5 mg, 37.5 mg, 75 mg, 150 mg or placebo. After the first dose of study medication, patients receiving placebo were reallocated to one of the four irbesartan doses, treatment was continued for 12 weeks and hemodynamic measurements were repeated. RESULTS: Irbesartan induced significant dose-related decreases in pulmonary capillary wedge pressure (average change -5.9+/-0.9 mm Hg and -5.3+/-0.9 mm Hg for irbesartan 75 mg and 150 mg, respectively) after 12 weeks of therapy without causing reflex tachycardia and without increasing plasma norepinephrine. The neurohormonal effects of irbesartan were highly variable and none of the changes was statistically significant. There was a significant dose-related decrease in the percentage of patients discontinuing study medication because of worsening heart failure. Irbesartan was well tolerated without evidence of dose-related cough or azotemia. CONCLUSIONS: Irbesartan, at once-daily doses of 75 mg and 150 mg, induced sustained hemodynamic improvement and prevented worsening heart failure. (+info)
Mortality remains high for outpatient transplant candidates with prolonged (>6 months) waiting list time.
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OBJECTIVES: The study aimed to determine the risk of death or urgent transplant for patients who survived an initial 6 months on the outpatient heart transplant waiting list when criteria emphasizing reduced peak oxygen consumption are used for transplant candidate selection. BACKGROUND: Waiting time is a key criterion for heart donor allocation. A recent single-center investigation described decreasing survival benefit from transplant for patients who survived an initial 6 months on the outpatient waiting list. METHODS: Kaplan-Meier survival analyses were performed for 80 patients from the Hospital of the University of Pennsylvania (HUP) listed from July 1986 to January 1991, and 132 patients from Columbia-Presbyterian Medical Center (CPMC) listed from September 1993 to September 1995. Survival from the time of outpatient listing for the entire group (ALL) was compared to subsequent survival from 6 months onward for those patients who survived the initial 6 months after placement on the outpatient list (6M). Both urgent transplant and left ventricular assist device implantation were considered equivalent to death; elective transplant was censored. RESULTS Survival for 6M was not significantly better than ALL at HUP (subsequent 12 months: 60+/-7 vs. 60+/-6% [mean+/-SD]; p = 0.89) nor at CPMC (subsequent 12 months: 60+/-6 vs. 48+/-5%; p = 0.35). Survival for 6M at both centers was substantially lower than survival following transplant from the outpatient list in the United States in 1995. CONCLUSIONS: When high-risk patients are selected for nonurgent transplant listing, mortality remains high, even among those who survive the initial six months after listing. Time accrued on the waiting list remains an appropriate criterion for donor allocation. (+info)
Cerebral metabolic abnormalities in congestive heart failure detected by proton magnetic resonance spectroscopy.
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OBJECTIVES: Using proton magnetic resonance spectroscopy, we investigated cerebral metabolism and its determinants in congestive heart failure (CHF), and the effects of cardiac transplantation on these measurements. BACKGROUND: Few data are available about cerebral metabolism in CHF. METHODS: Fifty patients with CHF (ejection fraction < or = 35%) and 20 healthy volunteers were included for this study. Of the patients, 10 patients underwent heart transplantation. All subjects performed symptom-limited bicycle exercise test. Proton magnetic resonance spectroscopy (1H MRS) was obtained from localized regions (8 to 10 ml) of occipital gray matter (OGM) and parietal white matter (PWM). Absolute levels of the metabolites (N-acetylaspartate, creatine, choline, myo-inositol) were calculated. RESULTS: In PWM only creatine level was significantly lower in CHF than in control subjects, but in OGM all four metabolite levels were decreased in CHF. The creatine level was independently correlated with half-recovery time and duration of heart failure symptoms in PWM (r = -0.56, p < 0.05), and with peak oxygen consumption and serum sodium concentration in OGM (r = 0.58, p < 0.05). Cerebral metabolic abnormalities were improved after successful cardiac transplantation. CONCLUSIONS: This study shows that cerebral metabolism is abnormally deranged in advanced CHF and it may serve as a potential marker of the disease severity. (+info)
Does heart failure confer a hypercoagulable state? Virchow's triad revisited.
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It is well-recognized that patients with congestive heart failure are at an increased risk of stroke and venous thromboembolism. Nevertheless, stroke, thromboembolism and myocardial infarction have generally been regarded to be end points of secondary importance in large heart failure trials, when compared with mortality or hospital readmissions. It may well have been that the incidence of thrombotic events are underestimated. The problem of thrombus formation (thrombogenesis) in heart failure may therefore be a much more significant problem than is currently recognized. The pathophysiology of thrombogenesis in heart failure could well be explained in the context of Virchow's original triad. In addition to "abnormal flow" through low cardiac output, dilated cardiac chambers and poor contractility, patients with heart failure also demonstrate abnormalities of hemostasis and platelets (that is "abnormal blood constituents") and endothelial dysfunction ("vessel wall abnormalities"). These abnormalities contribute to a prothrombotic or hypercoagulable state, which increases the risk of thrombosis in heart failure and impaired left ventricular systolic function. Some observational data are available on the role of anticoagulants in heart failure, and there is sound evidence to support the use of antithrombotic therapy in patients with heart failure and atrial fibrillation. However, there are no large-scale prospective randomized controlled trials of antithrombotic therapy in patients with heart failure who remain in sinus rhythm, although important studies are in progress. Although the results of these studies are awaited, measurement of suitable markers of thrombogenesis might prove to be valuable in identifying "high risk" patients and in determining the nature, duration and intensity of such treatment. Further information is also needed on the predictive value of various markers of hypercoagulability in patients with heart failure, the association between hemostatic variables and the severity of heart failure, and the effects of different treatments. (+info)
Enhanced peripheral chemoreflex function in conscious rabbits with pacing-induced heart failure.
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The present study aimed to determine whether peripheral and/or central chemoreflex function is altered in chronic heart failure (CHF) and whether altered chemoreflex function contributes to sympathetic activation in CHF. A rabbit model of pacing-induced CHF was employed. The development of CHF (3-4 wk of pacing) was characterized by an enlarged heart, an attenuated contractility, and an elevated central venous pressure. Renal sympathetic nerve activity (RSNA) and minute volume (MV) of ventilation in response to stimulation of peripheral chemoreceptors by isocapnic/hypoxic gases were measured in the conscious state. It was found that the baseline RSNA at normoxia was higher in CHF rabbits than in sham rabbits (35. 00 +/- 4.03 vs. 20.75 +/- 2.87% of maximum, P < 0.05). Moreover, the magnitudes of changes in RSNA and MV in response to stimulation of the peripheral chemoreceptors and the slopes of RSNA-arterial PO2 and MV-arterial PO2 curves were greater in CHF than in sham rabbits. Inhibition of the peripheral chemoreceptors by inhalation of 100% O2 decreased RSNA in CHF but not in sham rabbits. The central chemoreflex function, as evaluated by the responses of RSNA and MV to hyperoxic/hypercapnic gases, was not different between sham and CHF rabbits. These data suggest that an enhancement of the peripheral chemoreflex occurs in the rabbit model of pacing-induced CHF and that the enhanced peripheral chemoreflex function contributes to the sympathetic activation in the CHF state. (+info)
Enhanced activity of carotid body chemoreceptors in rabbits with heart failure: role of nitric oxide.
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An enhanced peripheral chemoreflex has been documented in patients with chronic heart failure (CHF). This study aimed to examine the characteristics of carotid body (CB) chemoreceptors in response to isocapnic hypoxia in a rabbit model of pacing-induced CHF and to evaluate the possible role that nitric oxide (NO) plays in the altered characteristics. The chemosensitive characteristics of the CB were evaluated by recording single-unit activity from the carotid sinus nerve in both an intact and a vascularly isolated preparation. It was found that the baseline discharge under normoxia (intact preparation: arterial PO2 90-95 Torr; isolated preparation: PO2 100-110 Torr) and the chemosensitivity in response to graded hypoxia (PO2 40-70 Torr) were enhanced in CHF vs. sham rabbits. These alterations were independent of the CB preparations (intact vs. isolated). NO synthase inhibition by Nomega-nitro-L-arginine increased the baseline discharge and the chemosensitivity in the intact preparation, whereas L-arginine (10(-5) M) inhibited the baseline discharge and the chemosensitivity in the isolated preparation in sham but not in CHF rabbits. S-nitroso-N-acetylpenicillamine, an NO donor, inhibited the baseline discharge and the chemosensitivity in both CB preparations in CHF rabbits but only in the isolated preparation in sham rabbits. The amount of NO produced in vitro by the CB under normoxia was less in CHF rabbits than in sham rabbits (P < 0.05). NO synthase-positive varicosities of nerve fibers within the CB were less in CHF rabbits than in sham rabbits (P < 0.05). These data indicate that an enhanced input from CB occurs in the rabbit model of pacing-induced CHF and that an impairment of NO production may contribute to this alteration. (+info)
Recent advances in the drug treatment of heart failure.
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A number of important questions surrounding the treatment of systolic congestive heart failure have been answered by randomised clinical trials completed within the past 2 years. In particular, these studies have established that high-dose angiotensin-converting enzyme (ACE) inhibition is more beneficial than low dose therapy, and that angiotensin II receptor antagonists are an acceptable alternative in patients unable to tolerate ACE inhibitors. Digoxin has been shown to be the only inotropic agent not associated with increased mortality, while amiodarone exerts a modest survival benefit in arrhythmiaprone patients. Beta-blockers appear to be beneficial for selected patients although their precise role remains to be defined by ongoing studies. (+info)
Sudden and cardiac death rates in hemodialysis patients.
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BACKGROUND: Sudden and cardiac death (including death from congestive heart failure, myocardial infarction, and sudden death) are common occurrences in hemodialysis patients. The intermittent nature of hemodialysis may lead to an uneven distribution of sudden and cardiac death throughout the week. The purpose of this study was to assess the septadian rhythm of sudden and cardiac death in hemodialysis patients. METHODS: Data from the United States Renal Data System (USRDS) were obtained to examine the day of death for United States hemodialysis and peritoneal dialysis patients from 1977 through 1997. The days of death were also determined for patients in the Case Mix Adequacy Study of the USRDS. RESULTS: There was an even distribution of sudden and cardiac deaths for patients on peritoneal dialysis, and hemodialysis patients dying of noncardiac deaths also had an even distribution. For all hemodialysis patients, Monday and Tuesday were the most common days of sudden and cardiac death. For patients in the Case Mix Adequacy Study designated as Monday, Wednesday, and Friday dialysis patients, 20.8% of sudden deaths occurred on Monday compared with the 14.3% expected (P = 0.002). Similarly, 20.2% of cardiac deaths occurred on Monday compared with the 14.3% expected (P = 0.0005). Similar trends were found on Tuesday for Tuesday, Thursday, and Saturday dialysis patients. CONCLUSIONS: The intermittent nature of hemodialysis may contribute to an increased sudden and cardiac death rate on Monday and Tuesday for patients enrolled in the USRDS. (+info)