Endogenous endothelin-1 depresses left ventricular systolic and diastolic performance in congestive heart failure.
(9/12919)
Endothelin-1 (ET-1) is a positive inotrope in normal hearts; however, the direct cardiac effects of endogenous ET-1 in congestive heart failure (CHF) are unknown. We evaluated the cardiac responses to endogenous ET-1 using an ETA and ETB receptor blocker (L-754,142) in seven conscious dogs before and after pacing-induced CHF. Before CHF, when the plasma ET-1 was 7.3 +/- 1.7 fmol/ml, L-754,142 caused no significant alterations in heart rate, left ventricular (LV) end-systolic pressure, total systemic resistance, and the time constant of LV relaxation (tau). LV contractile performance, measured by the slopes of LV pressure (P)-volume (V) relation (EES), dP/dtmax-end-diastolic V relation (dE/dtmax), and stroke work-end-diastolic V relation, was also unaffected. After CHF, when the plasma ET-1 was significantly increased to 14.1 +/- 3.0 fmol/ml (p <.05), L-754,142 produced a significant decreases in LV end-systolic pressure (101 +/- 11 versus 93 +/- 8 mm Hg) and total systemic resistance (0.084 +/- 0.022 versus 0.065 +/- 0.15 mm Hg/ml/min). The tau (42 +/- 12 versus 38 +/- 10 ms), mean left atrial P (22 +/- 5 versus 18 +/- 4 mm Hg) (p <.05), and minimum LVP were also significantly decreased. After CHF, the slopes of P-V relations, EES (3.4 +/- 0.4 versus 4.8 +/- 0.8 mm Hg/ml), dE/dtmax (42.4 +/- 7.8 versus 50.0 +/- 7.8 mm Hg/s/ml), and stroke work-end-diastolic V relation (58.1 +/- 3.3 versus 72.4 +/- 5.2 mm Hg) (p <.05) all increased after L-754,142, indicating enhanced contractility. Before CHF, low levels of endogenous ET-1 have little cardiac effect. However, after CHF, elevated endogenous ET-1 produces arterial vasoconstriction, slows LV relaxation, and depresses LV contractile performance. Thus, elevated endogenous ET-1 may contribute to the functional impairment in CHF in this canine model. (+info)
Investigation of distal aortic compliance and vasodilator responsiveness in heart failure due to proximal aortic stenosis in the guinea pig.
(10/12919)
Hypotension and syncope are recognized features of chronic aortic stenosis. This study examined vasomotor responses and dynamic compliance in isolated abdominal aortae after chronic constriction of the ascending aorta. Guinea pigs underwent constriction of the ascending aorta or sham operation. Sections of descending aorta were removed for studies of contractile performance and compliance. Dynamic compliance was measured using a feedback-controlled pulsatile pressure system at frequencies of 0.5, 1.5 and 2.5 Hz and mean pressures from 40 to 100 mmHg. Chronic (149+/-6 days) aortic constriction resulted in significant increases in organ weight/body weight ratios for left ventricle (58%), right ventricle (100%) and lung (61%). The presence of heart failure was indicated by increased lung weights, left ventricular end-diastolic pressure and systemic vascular resistance, reduced cardiac output and increased levels of plasma atrial natriuretic peptide (166%), adrenaline (x20), noradrenaline (106%) and dopamine (x3). Aortic rings showed similar constrictor responses to phenylephrine and angiotensin II, but maximal vasodilator responses to acetylcholine and isoprenaline were significantly increased (144% and 48% respectively). Dilator responses to sodium nitroprusside, forskolin and cromokalim were unchanged. Compliance of all vessels decreased with increasing pulsatile frequency and to a lesser extent with increased mean pressure, but were similar in aortic-constricted and control groups. Chronic constriction of the ascending aorta resulted in heart failure and increased vasodilator responses to acetylcholine and isoprenaline in the distal aorta while dynamic compliance was unchanged. We hypothesize that increased endothelium-mediated vasodilatation may contribute to hypotension and syncope in patients with left ventricular outflow obstruction. (+info)
Racial differences in the outcome of left ventricular dysfunction.
(11/12919)
BACKGROUND: Population-based studies have found that black patients with congestive heart failure have a higher mortality rate than whites with the same condition. This finding has been attributed to differences in the severity, causes, and management of heart failure, the prevalence of coexisting conditions, and socioeconomic factors. Although these factors probably account for some of the higher mortality due to congestive heart failure among blacks, we hypothesized that racial differences in the natural history of left ventricular dysfunction might also have a role. METHODS: Using data from the Studies of Left Ventricular Dysfunction (SOLVD) prevention and treatment trials, in which all patients received standardized therapy and follow-up, we conducted a retrospective analysis of the outcomes of asymptomatic and symptomatic left ventricular systolic dysfunction among black and white participants. The mean (+/-SD) follow-up was 34.2+/-14.0 months in the prevention trial and 32.3+/-14.8 months in the treatment trial among the black and white participants. RESULTS: The overall mortality rates in the prevention trial were 8.1 per 100 person-years for blacks and 5.1 per 100 person years for whites. In the treatment trial, the rates were 16.7 per 100 person-years and 13.4 per 100 person-years, respectively. After adjustment for age, coexisting conditions, severity and causes of heart failure, and use of medications, blacks had a higher risk of death from all causes in both the SOLVD prevention trial (relative risk, 1.36; 95 percent confidence interval, 1.06 to 1.74; P=0.02) and the treatment trial (relative risk, 1.25; 95 percent confidence interval, 1.04 to 1.50; P=0.02). In both trials blacks were also at higher risk for death due to pump failure and for the combined end point of death from any cause or hospitalization for heart failure, our two predefined indicators of the progression of left ventricular systolic dysfunction. CONCLUSIONS: Blacks with mild-to-moderate left ventricular systolic dysfunction appear to be at higher risk for progression of heart failure and death from any cause than similarly treated whites. These results suggest that there may be racial differences in the outcome of asymptomatic and symptomatic left ventricular systolic dysfunction. (+info)
A phase I and pharmacokinetic study of losoxantrone and paclitaxel in patients with advanced solid tumors.
(12/12919)
A Phase I and pharmacological study was performed to evaluate the feasibility, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics of the anthrapyrazole losoxantrone in combination with paclitaxel in adult patients with advanced solid malignancies. Losoxantrone was administered as a 10-min infusion in combination with paclitaxel on either a 24- or 3-h schedule. The starting dose level was 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel (as a 24- or 3-h i.v. infusion) without granulocyte colony-stimulating factor (G-CSF). Administration of these agents at the starting dose level and dose escalation was feasible only with G-CSF support. The following dose levels (losoxantrone/paclitaxel, in mg/m2) of losoxantrone and paclitaxel as a 3-h infusion were also evaluated: 50/135, 50/175, 50/200, 50/225, and 60/225. The sequence-dependent toxicological and pharmacological effects of losoxantrone and paclitaxel on the 24- and 3-h schedules of paclitaxel were also assessed. The MTD was defined as the dose at which >50% of the patients experienced DLT during the first two courses of therapy. DLTs, mainly myelosuppression, occurring during the first course of therapy were noted in four of six and five of eight patients treated with 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel over 24 and 3 h, respectively, without G-CSF. DLTs during the first two courses of therapy were observed in one of six patients at the 50/175 (losoxantrone/paclitaxel) mg/m2 dose level, two of four patients at the 50/200 mg/m2 dose level, one of four patients at the 50/225 mg/m2 dose level, and two of five patients at the 60/225 mg/m2 dose level. The degree of thrombocytopenia was worse, albeit not statistically significant, when 24-h paclitaxel preceded losoxantrone, with a mean percentage decrement in platelet count during course 1 of 80.7%, compared to 43.8% with the reverse sequence (P = 0.19). Losoxantrone clearance was not significantly altered by the sequence or schedule of paclitaxel. Cardiac toxicity was observed; however, it was not related to total cumulative dose of losoxantrone. An unacceptably high rate of DLTs at the first dose level of 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel administered as either a 24- or 3-h i.v. infusion precluded dose escalation without G-CSF support. The addition of G-CSF to the regimen permitted further dose escalation without reaching the MTD. Losoxantrone at 50 mg/m2 followed by paclitaxel (3-h i.v. infusion) at 175 mg/m2 with G-CSF support is recommended for further clinical trials. (+info)
Addition of angiotensin II receptor blockade to maximal angiotensin-converting enzyme inhibition improves exercise capacity in patients with severe congestive heart failure.
(13/12919)
BACKGROUND: Incomplete suppression of the renin-angiotensin system during long-term ACE inhibition may contribute to symptomatic deterioration in patients with severe congestive heart failure (CHF). Combined angiotensin II type I (AT1) receptor blockade and ACE inhibition more completely suppresses the activated renin-angiotensin system than either intervention alone in sodium-depleted normal individuals. Whether AT1 receptor blockade with losartan improves exercise capacity in patients with severe CHF already treated with ACE inhibitors is unknown. METHODS AND RESULTS: Thirty-three patients with severe CHF despite treatment with maximally recommended or tolerated doses of ACE inhibitors were randomized 1:1 to receive 50 mg/d losartan or placebo for 6 months in addition to standard therapy in a multicenter, double-blind trial. Peak aerobic capacity (V(O2)) during symptom-limited treadmill exercise and NYHA functional class were determined at baseline and after 3 and 6 months of double-blind therapy. Peak V(O2) at baseline and after 3 and 6 months were 13.5+/-0.6, 15.1+/-1.0, and 15.7+/-1.1 mL. kg-1. min-1, respectively, in patients receiving losartan and 14.1+/-0.6, 14.3+/-0.9, and 13.6+/-1.1 mL. kg-1. min-1, respectively, in patients receiving placebo (P<0.02 for treatment group-by-time interaction). Functional class improved by at least one NYHA class in 9 of 16 patients receiving losartan and 1 of 17 patients receiving placebo. CONCLUSIONS: Losartan enhances peak exercise capacity and alleviates symptoms in patients with CHF who are severely symptomatic despite treatment with maximally recommended or tolerated doses of ACE inhibitors. (+info)
Origin of contractile dysfunction in heart failure: calcium cycling versus myofilaments.
(14/12919)
BACKGROUND: Chronic congestive heart failure is a common, often lethal disorder of cardiac contractility. The fundamental pathophysiology of the contractile failure remains unclear, the focus being on abnormal Ca2+ cycling despite emerging evidence for depressed myofilament function. METHODS AND RESULTS: We measured intracellular Ca2+ concentration ([Ca2+]i) and contractile force in intact ventricular muscle from SHHF rats with spontaneous heart failure and from age-matched controls. At physiological concentrations of extracellular Ca2+ ([Ca2+]o), [Ca2+]i transients were equal in amplitude in the 2 groups, but [Ca2+]i peaked later in SHHF muscles. Twitch force peaked slowly and was equivalent or modestly decreased in amplitude relative to controls. Steady-state analysis revealed a much greater (53%) depression of maximal Ca2+-activated force in SHHF muscles, which, had other factors been equal, would have produced an equivalent suppression of twitch force. Phase-plane analysis reveals that the slowing of Ca2+ cycling prolongs the time available for Ca2+ to activate the myofilaments in failing muscle, partially compensating for the marked dysfunction of the contractile machinery. CONCLUSIONS: Our results indicate that myofilament activation is severely blunted in heart failure, but concomitant changes in [Ca2+]i kinetics minimize the contractile depression. These results challenge prevailing concepts regarding the pathophysiology of heart failure: the myofilaments emerge as central players, whereas changes in Ca2+ cycling are reinterpreted as compensatory rather than causative. (+info)
Coexistence of mitochondrial DNA and beta myosin heavy chain mutations in hypertrophic cardiomyopathy with late congestive heart failure.
(15/12919)
OBJECTIVE: To investigate the possible coexistence of mitochondrial DNA (mtDNA) mutations in patients with beta myosin heavy chain (beta MHC) linked hypertrophic cardiomyopathy (HCM) who develop congestive heart failure. DESIGN: Molecular analysis of beta MHC and mtDNA gene defects in patients with HCM. SETTING: Cardiovascular molecular diagnostic and heart transplantation reference centre in north Italy. PATIENTS: Four patients with HCM who underwent heart transplantation for end stage heart failure, and after pedigree analysis of 60 relatives, eight additional affected patients and 27 unaffected relatives. A total of 111 unrelated healthy adult volunteers served as controls. Disease controls included an additional 27 patients with HCM and 102 with dilated cardiomyopathy. INTERVENTION: Molecular analysis of DNA from myocardial and skeletal muscle tissue and from peripheral blood specimens. MAIN OUTCOME MEASURES: Screening for mutations in beta MHC (exons 3-23) and mtDNA tRNA (n = 22) genes with denaturing gradient gel electrophoresis or single strand conformational polymorphism followed by automated DNA sequencing. RESULTS: One proband (kindred A) (plus seven affected relatives) had arginine 249 glutamine (Arg249Gln) beta MHC and heteroplasmic mtDNA tRNAIle A4300G mutations. Another unrelated patient (kindred B) with sporadic HCM had identical mutations. The remaining two patients (kindred C), a mother and son, had a novel beta MHC mutation (lysine 450 glutamic acid) (Lys450Glu) and a heteroplasmic missense (T9957C, phenylalanine (Phe)-->leucine (Leu)) mtDNA mutation in subunit III of the cytochrome C oxidase gene. The amount of mutant mtDNA was higher in the myocardium than in skeletal muscle or peripheral blood and in affected patients than in asymptomatic relatives. Mutations were absent in the controls. Pathological and biochemical characteristics of patients with mutations Arg249Gln plus A4300G (kindreds A and B) were identical, but different from those of the two patients with Lys450Glu plus T9957C(Phe-->Leu) mutations (kindred C). Cytochrome C oxidase activity and histoenzymatic staining were severely decreased in the two patients in kindreds A and B, but were unaffected in the two in kindred C. CONCLUSIONS: beta MHC gene and mtDNA mutations may coexist in patients with HCM and end stage congestive heart failure. Although beta MHC gene mutations seem to be the true determinants of HCM, both mtDNA mutations in these patients have known prerequisites for pathogenicity. Coexistence of other genetic abnormalities in beta MHC linked HCM, such as mtDNA mutations, may contribute to variable phenotypic expression and explain the heterogeneous behaviour of HCM. (+info)
Reversal of severe pulmonary hypertension with beta blockade in a patient with end stage left ventricular failure.
(16/12919)
A 52 year old man with severe chronic left ventricular failure (New York Heart Association class IV) was considered unsuitable for cardiac transplantation because of high and irreversible pulmonary vascular resistance (PVR). In an attempt to produce symptomatic improvement, metoprolol was cautiously introduced, initially at 6.25 mg twice daily. This was slowly increased to 50 mg twice daily over a two month period and continued thereafter. After four months of treatment the patient's symptoms had improved dramatically. His exercise tolerance had increased and diuretic requirements reduced to frusemide 160 mg/day only. Assessment of right heart pressures was repeated and, other than a drop in resting heart rate, there was little change in his pulmonary artery pressure or PVR. His right heart pressures were reassessed showing a pronounced reduction in pulmonary artery pressure and a significant reduction in PVR, which fell further with inhaled oxygen and sublingual nitrates. He was then accepted onto the active waiting list for cardiac transplantation. A possible mechanism of action was investigated by assessing responses to beta agonists during treatment. Not only was there pronounced improvement in PVR but it was also demonstrated that beta receptor subtype cross-regulation may have contributed to the mechanism of benefit. (+info)