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Background: Atrial fibrillation (AF) and heart failure (HF) often coexist. We investigated the prognostic impact of biomarkers on the development of HF and death in patients with AF and different left ventricular systolic function considering the influence of competing events., Methods: The study included 11,818 patients with AF from the ARISTOTLE trial who at entry had information on history of HF, an estimate of left ventricular function and plasma samples for determination of biomarkers representing cardiorenal dysfunction (NT-proBNP, troponin T, cystatin C) and inflammation (GDF-15, IL-6, CRP). Patients were categorized into: (I) HF with reduced ejection fraction (HFrEF, n = 2,048), (II) HF with preserved ejection fraction (HFpEF, n = 2,520), and (III) No HF (n = 7,250). Biomarker associations with HF hospitalization and death were analyzed using a multi-state model accounting also for repeated events., Results: Baseline levels of NT-proBNP, troponin T, cystatin C, GDF-15, IL-6, and CRP were highest in HFrEF and lowest in No HF. During median 1.9 years follow-up, 546 patients were hospitalized at least once for HF and 819 died. Higher levels of all investigated biomarkers were associated with both outcomes (all P< .0001), with highest event rates in HFrEF and lowest in No HF. The associations remained after adjustments and were more pronounced for first than for recurrent events., Conclusions: In anticoagulated patients with AF, biomarkers indicating cardiorenal dysfunction and inflammation improve the identification of patients at risk of developing HF or worsening of already existing HF. These biomarkers might be useful for targeting novel HF therapies in patients with AF., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: To determine if an intensified form of heart failure management programme (INT-HF-MP) based on individual profiling is superior to standard management (SM) in reducing health care costs during 12-month follow-up (primary endpoint)., Methods and Results: A multicentre randomized trial involving 787 patients (full analysis set) discharged from four tertiary hospitals with chronic HF who were randomized to SM (n = 391) or INT-HF-MP (n = 396). Mean age was 74 ± 12 years, 65% had HF with a reduced ejection fraction (31.4 ± 8.9%) and 14% were remote-dwelling. Study groups were well matched. According to Green, Amber, Red Delineation of rIsk And Need in HF (GARDIAN-HF) profiling, regardless of location, patients in the INT-HF-MP received a combination of face-to-face (home visits) and structured telephone support (STS); only 9% (`low risk') were designated to receive the same level of management as the SM group. The median cost in 2017 Australian dollars (A$1 equivalent to ∼EUR €0.7) of applying INT-HF-MP was significantly greater than SM ($152 vs. $121 per patient per month; P < 0.001), However, at 12 months, there was no difference in total health care costs for the INT-HF-MP vs. SM group (median $1579, IQR $644 to $3717 vs. $1450, IQR $564 to $3615 per patient per month, respectively). This reflected minimal differences in all-cause mortality (17.7% vs. 18.4%; P = 0.848) and recurrent hospital stay (18.6 ± 26.5 vs. 16.6 ± 24.8 days; P = 0.199) between the INT-HF-MP and SM groups, respectively., Conclusion: During 12-months follow-up, an INT-HF-MP did not reduce healthcare costs or improve health outcomes relative to SM., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology)

Objectives: The aim of this study was to determine whether short-term treatment with perhexiline improves cardiac energetics, left ventricular function, and symptoms of heart failure by altering cardiac substrate utilization., Background: Perhexiline improves exercise capacity and left ventricular ejection fraction (LVEF) in patients with heart failure (HF). (31)P cardiac magnetic resonance spectroscopy can be used to quantify the myocardial phosphocreatine/adenosine triphosphate ratio. Because improvement of HF syndrome can improve cardiac energetics secondarily, we investigated the effects of short-term perhexiline therapy., Methods: Patients with systolic HF of nonischemic etiology (n = 50, 62 ± 1.8 years of age, New York Heart Association functional class II to IV, LVEF: 27.0 ± 1.44%) were randomized to receive perhexiline 200 mg or placebo for 1 month in a double-blind fashion. Clinical assessment, echocardiography, and (31)P cardiac magnetic resonance spectroscopy were performed at baseline and after 1 month. A substudy of 22 patients also underwent cross-heart blood sampling at completion of the study to quantify metabolite utilization., Results: Perhexiline therapy was associated with a 30% increase in the phosphocreatine/adenosine triphosphate ratio (from 1.16 ± 0.39 to 1.51 ± 0.51; p < 0.001) versus a 3% decrease with placebo (from 1.36 ± 0.31 to 1.34 ± 0.31; p = 0.37). Perhexiline therapy also led to an improvement in New York Heart Association functional class compared with placebo (p = 0.036). Short-term perhexiline therapy did not change LVEF. Cross-heart measures of cardiac substrate uptake and respiratory exchange ratio (which reflects the ratio of substrates used) did not differ between patients who received perhexiline versus placebo., Conclusions: Perhexiline improves cardiac energetics and symptom status with no evidence of altered cardiac substrate utilization. No change in LVEF is seen at this early stage. (Metabolic Manipulation in Chronic Heart Failure; NCT00841139)., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Nitrite has emerged as an important bioactive molecule that can be biotransformed to nitric oxide (NO) related metabolites in normoxia and reduced to NO under hypoxic and acidic conditions to exert vasodilatory effects and confer a variety of other benefits to the cardiovascular system. Abundant research is currently underway to understand the mechanisms involved and define the role of nitrite in health and disease. In this review we discuss the impact of nitrite and dietary nitrate on vascular function and the potential therapeutic role of nitrite in acute heart failure., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aims: To describe the rationale and design of the Which Heart failure Intervention is most Cost-effective & consumer friendly in reducing Hospital care (WHICH?) trial., Methods: WHICH? is a pragmatic, multicentre, randomized controlled trial that seeks to determine if multidisciplinary management of chronic heart failure (CHF) patients post-acute hospitalization delivered in a patient's own home is superior to care delivered via a specialist CHF outpatient clinic. The composite primary endpoint is all-cause, unplanned recurrent hospitalization or death during 12-18 months of follow-up. Of 688 eligible patients, 280 patients (73% male and 66% principal diagnosis of CHF) with a mean age of 71 ± 14 years have been randomized to home- (n = 143) or clinic-based (n = 137) post-discharge management. This will provide 80% power (two-sided alpha of 0.05) to detect a 15% absolute difference in both the primary end-point and rate of all-cause hospital stay. Preliminary data suggest that the two groups are well matched in nearly all baseline socio-economic and clinical parameters. The majority of patients have significant co-morbidity, including hypertension (63%), coronary artery disease (55%), and atrial fibrillation (53%) with an accordingly high Charlson Index of Comorbidity Score (6.1 ± 2.4)., Perspective: Despite its relatively small size, the WHICH? trial is well placed to examine the relative impact of two of the most commonly applied forms of face-to-face management designed to reduce recurrent hospitalization and prolong survival in CHF patients.

Background: Chronic heart failure (CHF) is a major cause of morbidity and mortality that requires a novel approach to therapy. Perhexiline is an antianginal drug that augments glucose metabolism by blocking muscle mitochondrial free fatty acid uptake, thereby increasing metabolic efficiency. We assessed the effects of perhexiline treatment in CHF patients., Methods and Results: In a double-blind fashion, we randomly assigned patients with optimally medicated CHF to either perhexiline (n=28) or placebo (n=28). The primary end point was peak exercise oxygen consumption (VO2max), an important prognostic marker. In addition, the effect of perhexiline on myocardial function and quality of life was assessed. Quantitative stress echocardiography with tissue Doppler measurements was used to assess regional myocardial function in patients with ischemic CHF. 31P magnetic resonance spectroscopy was used to assess the effect of perhexiline on skeletal muscle energetics in patients with nonischemic CHF. Treatment with perhexiline led to significant improvements in VO2max (16.1+/-0.6 to 18.8+/-1.1 mL . kg(-1) . min(-1); P<0.001), quality of life (Minnesota score reduction from 45+/-5 to 34+/-5; P=0.04), and left ventricular ejection fraction (24+/-1% to 34+/-2%; P<0.001). Perhexiline treatment also increased resting and peak dobutamine stress regional myocardial function (by 15% and 24%, respectively) and normalized skeletal muscle phosphocreatine recovery after exercise. There were no adverse effects during the treatment period., Conclusions: In patients with CHF, metabolic modulation with perhexiline improved VO2max, left ventricular ejection fraction, symptoms, resting and peak stress myocardial function, and skeletal muscle energetics. Perhexiline may therefore represent a novel treatment for CHF with a good safety profile, provided that the dosage is adjusted according to plasma levels.

Congestive heart failure (CHF) is associated with oxidative stress. Platelet responsiveness to nitric oxide (NO) donors, are impaired in patients with angina pectoris, possibly by increasing oxidative stress. We investigated the occurrence of platelet resistance to NO in patients, with ischaemic or non-ischaemic cardiomyopathy compared with normal subjects. Anti-aggregatory effects of sodium nitroprusside (SNP), oxidative stress and whole blood superoxide anion content were determined, with correlates of responsiveness to SNP. Inhibition of platelet aggregation by SNP was 65.4+/-3.55% in controls and 59.3+/-4.1% in CHF (P=ns) despite increased oxidative stress and post-aggregation O2- in CHF patients. However, subsets of CHF patients have NO-resistant platelets: this is associated with increasing age and/or increased oxidative stress (both p<0.05).

Aims: To determine the sequence of critical cardiovascular events in the progression of heart failure, and whether aetiology or high-dose vs low-dose lisinopril affected these pathways., Methods and Results: This was a post-hoc investigation of the ATLAS database, which comprised 3164 patients with chronic heart failure, randomized to low- (2.5-5.0 mg. day(-1)) or high-dose (32.5-35.0 mg. day(-1)) lisinopril, followed up for a median of 46 months. Two-thirds (64.3%) of patients had heart failure attributed to ischaemic heart disease. During the study, most patients (61.1%) had at least one cardiovascular hospitalization and 42.5% of all patients died: most deaths (88.2%) were cardiovascular. Nearly half (49.7%) of the cardiovascular deaths were considered sudden and 45.2% of cardiovascular deaths occurred as the first cardiovascular event. A third (30.2%) of deaths resulted from heart failure and were generally preceded by hospitalization, either for heart failure (85.5%), myocardial ischaemic events (21.7%) or arrhythmias (18.0%). Compared with low-dose, high-dose lisinopril was associated with a lower risk of death or hospitalization for any reason (P=0.002) and death or hospitalization with worsening heart failure (P<0.001). High-dose lisinopril delayed the time to all-cause mortality and hospitalization for chronic heart failure by 7.1 months., Conclusions: Vascular and arrhythmic events may not only be important precipitants of sudden death, but were also seen to contribute to the progression of heart failure. A reduction in vascular events, as well as benefits on ventricular remodelling, could account for the decrease in death or hospitalization with high-dose lisinopril., (Copyright 2001 The European Society of Cardiology.)

Chronic heart failure (CHF) is characterized by a prothrombotic state, which may relate to increased platelet aggregability, endothelial dysfunction, and increased oxidative stress. We investigated the effect of vitamin C in CHF on ex vivo platelet aggregation and platelet responsiveness to the anti-aggregatory effects of the nitric oxide (NO) donors glyceryl trinitrate (GTN) and sodium nitroprusside (SNP). We also examined parameters of oxidative stress and endothelial function in patients. In this double-blind, randomized, crossover study vitamin C (2 g) or placebo was given intravenously to 10 patients with CHF. We measured adenosine 5-diphosphate (ADP)-induced platelet aggregation, flow-mediated dilatation (FMD) in the brachial artery using ultrasonic wall-tracking, and plasma levels of lipid-derived free radicals using electron paramagnetic resonance spectroscopy. Vitamin C did not affect ex vivo platelet aggregability but enhanced the inhibition of platelet aggregation by SNP (62.7+/-10.2 to 82.7+/-4.8%, p = 0.03) and tended to increase responses to GTN (40.5+/-9.0 to 53.4+/-7.3, p = 0.06). The effect of vitamin C on platelet responsiveness to the antiaggregatory effects of SNP was inversely related to basal response to SNP (r = -0.9, p < 0.01); a similar trend was observed with GTN (r = -0.6, p = 0.1). Vitamin C also increased FMD (1.9+/-0.6 to 5.8+/-1.5%, p = 0.02) and reduced plasma lipid-derived free radicals by 49+/-19% (p < 0.05). In patients with CHF acute intravenous administration of vitamin C enhances platelet responsiveness to the anti-aggregatory effects of NO donors and improves endothelial function, suggesting a potential role for vitamin C as a therapeutic agent in CHF.

This paper reports on an international comparison of the characteristics, treatment and health outcomes of chronic heart failure (CHF) patients discharged from acute hospital care in Australia and Scotland. The baseline characteristics and treatment of 200 CHF patients recruited to a randomised study of a non-pharmacological intervention in Australia and 157 CHF patients concurrently recruited to a similar study in Scotland were compared. Subsequent health outcomes (including survival and readmission) within 3 months of discharge in those patients who received usual post-discharge care in Australia (n=100) and Scotland (n=75) were also compared. Individuals in both countries were predominantly old and frail with significant comorbidity likely to complicate treatment. Similar proportions of Australian and Scottish patients were prescribed either a 'high' (20 vs. 18%) or medium (64 vs. 66%) dose of an angiotensin-converting enzyme inhibitor. Proportionately more Australian patients were prescribed a long-acting nitrate, digoxin and/or a beta-blocker. At 3 months post-discharge, 57 of the 100 (57%: 95% CI 47--67%) Australian and 37 of the 75 (49%: 95% CI 38--61%) Scottish patients assigned to 'usual care' remained event-free (NS). Similarly, 15 vs. 12% required > or =2 unplanned readmission (NS) and 16 vs. 19% of Australian and Scottish patients, respectively, died (NS). Australian and Scottish patients accumulated a median of 0.6 vs. 0.9 days, respectively, of hospitalisation/patient/month (NS). On multivariate analysis (including country of origin), unplanned readmission or death was independently correlated with severe renal impairment (adjusted odds ratio 4.4, P<0.05), a previous hospitalisation for CHF (2.3, P<0.05), longer index hospitalisation (2.7 for >10 days, P<0.05) and greater comorbidity (1.3 for each incremental unit of the Charlson Index, P=0.05). Health outcomes among predominantly old and frail CHF patients appear to be independent of the health-care system in which the patient is managed and more likely to be dependent on the syndrome itself.

Background: Treatment with angiotensin-converting enzyme (ACE) inhibitors reduces mortality and morbidity in patients with chronic heart failure (CHF), but most affected patients are not receiving these agents or are being treated with doses lower than those found to be efficacious in trials, primarily because of concerns about the safety and tolerability of these agents, especially at the recommended doses. The present study examines the safety and tolerability of high- compared with low-dose lisinopril in CHF., Methods: The Assessment of Lisinopril and Survival study was a multicenter, randomized, double-blind trial in which patients with or without previous ACE inhibitor treatment were stabilized receiving medium-dose lisinopril (12.5 or 15.0 mg once daily [OD]) for 2 to 4 weeks and then randomized to high- (35.0 or 32.5 mg OD) or low-dose (5.0 or 2.5 mg OD) groups. Patients with New York Heart Association classes II to IV CHF and left ventricular ejection fractions of no greater than 0.30 (n = 3164) were randomized and followed up for a median of 46 months. We examined the occurrence of adverse events and the need for discontinuation and dose reduction during treatment, with a focus on hypotension and renal dysfunction., Results: Of 405 patients not previously receiving an ACE inhibitor, doses in only 4.2% could not be titrated to the medium doses required for randomization because of symptoms possibly related to hypotension (2.0%) or because of renal dysfunction or hyperkalemia (2.3%). Doses in more than 90% of randomized patients in the high- and low-dose groups were titrated to their assigned target, and the mean doses of blinded medication in both groups remained similar throughout the study. Withdrawals occurred in 27.1% of the high- and 30.7% of the low-dose groups. Subgroups presumed to be at higher risk for ACE inhibitor intolerance (blood pressure, <120 mm Hg; creatinine, > or =132.6 micromol/L [> or =1.5 mg/dL]; age, > or =70 years; and patients with diabetes) generally tolerated the high-dose strategy., Conclusions: These findings demonstrate that ACE inhibitor therapy in most patients with CHF can be successfully titrated to and maintained at high doses, and that more aggressive use of these agents is warranted.

Objective: A cost-effectiveness analysis of high and low doses of the angiotensin-converting enzyme (ACE) inhibitor lisinopril in the treatment of chronic heart failure., Methods: A cost-effectiveness analysis using data from a randomized controlled trial, ATLAS, where 3164 patients with chronic heart failure were allocated to a high-dose (daily target dose 32.5-35 mg) or low-dose strategy (daily target dose 2.5-5.0 mg) of lisinopril. Differential costs were based on resource use data collected in the trial costed using UK unit costs. Cost-effectiveness analysis related differential costs to differential life-years during a 4-year trial follow-up., Results: The mean total number of hospital in-patient days per patient was 18. 5 in the high dose group and 22.5 in the low dose group. Over the whole duration of the trial, the mean (S.D.) daily dose of lisinopril in the high-dose group was 22.5 mg (15.7 mg) compared to 3.2 mg (2.5 mg) in the low-dose group. The mean difference in cost per patient was pound sterling 397 lower in the high-dose group [95% CI (high-dose-low-dose) - pound sterling 1263 to pound sterling 436]. Mean life-years per patient were 0.085 years higher in the high-dose group [95% CI (high-dose-low-dose) -0.0074 to 0.1706). Based on mean costs and life-years, high-dose therapy dominates low-dose (less costly and more effective). Allowing for uncertainty in mean costs and life-years, the probability of high-dose therapy being less costly than low dose was 82%. If a decision maker is willing to pay at least pound sterling 3600 per life-year gained, the probability of high-dose being more cost-effective was 92%., Conclusions: The ATLAS Study showed that the treatment of heart failure with high-doses of lisinopril has a high probability of being more cost-effective than low-dose therapy.

Aims: An analysis was designed to determine whether chronic heart failure patients at high cardiovascular risk benefited to the same extent from high-dose lisinopril as the whole ATLAS population., Methods and Results: A retrospective analysis was performed on high-risk heart failure patients in the Assessment of Treatment with Lisinopril And Survival (ATLAS) trial (total number of patients 3164) comparing highdose (32.5-35 mg. day(-1)) vs low-dose (2.5-5 mg. day(-1)) lisinopril for a median of 46 months. These high-risk patients included those with hypotension, hyponatraemia, compromised renal function, the elderly and patients with diabetes mellitus at baseline. In the whole study population, high-dose lisinopril led to a trend in risk reduction of all-cause mortality (primary end-point P=0.128) and a significant risk reduction in all-cause mortality plus hospitalization (principal secondary end-point P=0.002). Subgroup analyses were performed for these end-points. There were no consistent interactions between age, baseline sodium, creatinine or potassium values, and treatment effect. Diabetics showed a beneficial response to high-dose therapy that was at least as good as that in non-diabetics. The underlying higher morbidity/mortality rates in diabetics mean that high-dose lisinopril has potential for a larger absolute clinical impact in these patients., Conclusion: Long-term high-dose lisinopril was as effective and well-tolerated in high-risk patients, including those with diabetes mellitus, as for the ATLAS study population as a whole., (Copyright 2000 The European Society of Cardiology.)

Background: Angiotensin-converting enzyme (ACE) inhibitors are generally prescribed by physicians in doses lower than the large doses that have been shown to reduce morbidity and mortality in patients with heart failure. It is unclear, however, if low doses and high doses of ACE inhibitors have similar benefits., Methods and Results: We randomly assigned 3164 patients with New York Heart Association class II to IV heart failure and an ejection fraction < or = 30% to double-blind treatment with either low doses (2.5 to 5.0 mg daily, n=1596) or high doses (32.5 to 35 mg daily, n=1568) of the ACE inhibitor, lisinopril, for 39 to 58 months, while background therapy for heart failure was continued. When compared with the low-dose group, patients in the high-dose group had a nonsignificant 8% lower risk of death (P=0.128) but a significant 12% lower risk of death or hospitalization for any reason (P=0.002) and 24% fewer hospitalizations for heart failure (P=0.002). Dizziness and renal insufficiency was observed more frequently in the high-dose group, but the 2 groups were similar in the number of patients requiring discontinuation of the study medication. Conclusions-These findings indicate that patients with heart failure should not generally be maintained on very low doses of an ACE inhibitor (unless these are the only doses that can be tolerated) and suggest that the difference in efficacy between intermediate and high doses of an ACE inhibitor (if any) is likely to be very small.

Background: Hospital admissions among patients with congestive heart failure (CHF) are a major contributor to health-care costs. Previous investigations suggest that the therapeutic efficacy of pharmacotherapy in CHF may be improved by strategies incorporating home visits to identify and address factors precipitating deterioration and resultant readmission., Methods: Chronic CHF patients discharged home after acute hospital admission were randomly assigned usual care (n=100) or a multidisciplinary, home-based intervention (n=100), consisting of a home visit by a cardiac nurse 7-14 days after discharge. The primary endpoint of the study was frequency of unplanned readmission plus out-of-hospital death within 6 months., Findings: During 6 months' follow-up there were 129 primary endpoint events in the usual-care group and 77 in the intervention group (p=0.02). More intervention-group than usual-care patients remained event-free (38 vs 51; p=0.04). Overall, there were fewer unplanned readmissions (68 vs 118; p=0.03) and associated days in hospital (460 vs 1173; p=0.02) among intervention-group patients. Hospital-based costs were Australian $490,300 for the intervention group and A$922,600 for the usual-care group (p=0.16); the mean cost of the intervention was A$350 per patient, and other community-based costs were similar for both groups., Interpretation: A home-based intervention has the potential to decrease the rate of unplanned readmissions and associated health-care costs, prolong event-free and total survival, and improve quality of life among patients with chronic CHF.

Background: The beneficial effect of ACE inhibitors on mortality has been established in a series of trials. However, in clinical practice, ACE inhibitors are commonly administered in doses much lower than those shown to be effective in the landmark trials., Aims: This report describes the baseline characteristics of the patients recruited into the ATLAS study by age and gender sub-groups., Methods: The ATLAS study compared the effects of 'low' dose (2.5-5.0 mg/day) to 'high' dose (32.5-35.0 mg/day) lisinopril in a double-blind study of 3164 patients with moderate to severe heart failure and left ventricular ejection fraction < 30% during a mean follow-up period of 46 months. The primary end-point was all cause mortality and the principal secondary end-point a composite of all-cause hospitalisation or all-cause mortality., Results: Among patients with heart failure selected for the presence of left ventricular systolic function there were few differences among age groups or between genders. Older patients were not so heavy, were more likely to have ischaemic heart disease, hypertension and atrial fibrillation contributing to their heart failure and had a higher blood urea. Women were not so heavy as men. Age and gender had no major influence on mean ejection fraction or baseline treatment in the ATLAS study., Conclusions: Weight and renal function may alter the plasma concentration of any given dose of an ACE inhibitor. Potential interactions between dose of lisinopril, weight and renal function will be explored after the study is completed.

Background: A single home-based intervention (HBI) applied immediately after hospital discharge in a cohort of "high-risk" patients with congestive heart failure has been shown to decrease numbers of unplanned readmissions plus out-of-hospital deaths during a period of 6 months. The duration of this beneficial effect remains uncertain., Methods: Hospitalized patients with congestive heart failure who had been randomly assigned to receive either usual care (n=48) or HBI 1 week after discharge (n=49) were subject to an extended follow-up of 18 months. The primary end point of the study was frequency of unplanned readmissions plus out-of-hospital deaths. Secondary end points included total hospital stay, frequency of multiple readmissions, cost of hospital-based care, and total mortality., Results: During 18-month follow-up, HBI patients had fewer unplanned readmissions (64 vs 125; P=.02) and out-of-hospital deaths (2 vs 9; P=.02), representing 1.4+/-1.3 vs 2.7+/-2.8 events per HBI and usual-care patient, respectively (P=.03). The HBI patients also had fewer days of hospitalization (2.5+/-2.7 vs 4.5+/-4.8 per patient; P=.004) and, once readmitted, were less likely to experience 4 or more readmissions (3/31 vs 12/38; P=.03). Hospital-based costs were significantly lower among HBI patients (Aust $5100 vs Aust $10600 per patient; P=.02). Unplanned readmission was positively correlated with 14 days or more of unplanned readmission in the 6 months before study entry (odds ratio [OR], 5.4; P=.006). Positive correlates of death were (1) non-English speaking (OR, 4.9; P=.008), (2) 14 days or more of unplanned readmission in the 6 months before study entry (OR, 4.9; P=.008), and (3) left ventricular ejection fraction of 40% or less (OR, 3.0; P=.03); conversely, assignment to HBI was a negative correlate (OR, 0.3; P=.02)., Conclusions: In this controlled study, among a cohort of high-risk patients with congestive heart failure, beneficial effects of a postdischarge HBI were sustained for at least 18 months, with a significant reduction in unplanned readmissions, total hospital stay, hospital-based costs, and mortality.

Background: We examined the effect of a home-based intervention (HBI) on readmission and death among "high-risk" patients with congestive heart failure discharged home from acute hospital care., Methods: Hospitalized patients with congestive heart failure and impaired systolic function, intolerance to exercise, and a history of 1 or more hospital admissions for acute heart failure were randomized to either usual care (n=48) or HBI at 1 week after discharge (n=49). Home-based intervention comprised a single home visit (by a nurse and pharmacist) to optimize medication management, identify early clinical deterioration, and intensify medical follow-up and caregiver vigilance as appropriate. The primary end point of the study was frequency of unplanned readmissions plus out-of-hospital deaths within 6 months of discharge. Secondary end points included duration of hospital stay and overall mortality., Results: During follow-up, patients in the HBI group had fewer unplanned readmissions (36 vs 63; P=.03) and fewer out-of-hospital deaths (1 vs 5; P=.11): 0.8+/-0.9 vs 1.4+/-1.8 (mean +/- SD) events per patient assigned to HBI and usual care, respectively (P=.03). Patients in the HBI group also had fewer days of hospitalization (261 vs 452; P=.05) and fewer total deaths (6 vs 12; P=.11). Patients assigned to usual care were more likely to experience 3 or more readmissions for acute heart failure (P=.02). Predictors of unplanned readmission were (1) 14 days or more of unplanned readmission during the 6 months before study entry (odds ratio [OR], 5.2; 95% confidence interval [CI], 1.8-16.2), (2) previous admission for acute myocardial ischemia (OR, 3.3; 95% CI, 1.2-9.1), and (3) an albumin plasma concentration of 38 g/L or less (OR, 2.4; 95% CI, 1.2-6.0). Home-based intervention was also associated with a trend toward reduced risk of unplanned readmission (OR, 0.4; 95% CI, 0.2-1.1)., Conclusion: Among a cohort of high-risk patients with congestive heart failure, HBI was associated with reduced frequency of unplanned readmissions plus out-of-hospital deaths within 6 months of discharge from the hospital.

Aims: This study was designed to determine regional differences in patient characteristics and medication use among patients entered into an international heart failure trial., Methods and Results: Data for this analysis were derived from the Assessment of Treatment with Lisinopril and Survival Study (ATLAS), a prospective randomized comparison of high- and low-dose therapy with lisinopril in patients with New York Heart Association class II, III, or IV chronic heart failure, which enrolled 3164 patients in 291 centers in 19 countries on 3 continents. Information was collected at baseline concerning patient demographics, etiology of heart failure, accompanying conditions, prior revascularization procedures, and medication use. The primary findings were a lower incidence of ischemic cardiomyopathy in southern and western Europe, more frequent diabetes in North America, and a greater use of coronary revascularization in the United States and Canada. There was substantial variation in medication use, particularly with regard to digoxin, anticoagulants, and amiodarone., Conclusions: Although there is considerable overlap in guidelines concerning the treatment of heart failure issued by authorities in Europe and North America, there are significant regional variations in medication use. Some, but not all, of these differences can be explained by differences in patient characteristics.

Quantitative descriptions of the mechanical restitution curve as a description of variability in ventricular performance with coupling interval in isolated tissue preparations are widely available. In humans, however, in vivo examination of the force-interval relationship is restricted to test pulse intervals shorter than the sinus cycle length (i.e., incomplete mechanical restitution). The primary objectives in this investigation were therefore to examine this aspect of mechanical restitution in patients with ischemic heart disease and to develop a quantitative description of the phenomenon. Mechanical restitution curves were constructed in 40 patients, most of whom had well-preserved left ventricular (LV) systolic function, undergoing diagnostic cardiac catheterization for the investigation of chest pain, using a single premature test pulse interval during baseline atrial pacing. The mechanical restitution curve, the relationship between LV + dP/dtmax and test pulse interval, was fitted to a rectangular hyperbolic function. From this, the parameter c, the calculated proportional decrease in LV + dP/dtmax at 60% of the resting cycle length, was derived. The mechanical restitution curve-fitting model (involving determination of c) satisfactorily described the force-interval relationship in 37 of the 40 patients studied (as a rectangular hyperbola in 31 and with simple linear regression in 6 patients). The refractory period of the atria/atrioventricular node limited accurate use of the model in the remaining three patients. The parameter c was inversely proportional to both baseline atrial pacing cycle length (P < .001) and LV ejection fraction (P < .02) In patients with normal LV ejection fractions, the derived value of c at a cycle length of 800 ms (c800) was 29.0% baseline LV + dP/dtmax (95% confidence interval, 23.0, 35.0). The presence of hemodynamically significant ischemic heart disease was not a predictor of the parameters of the model. After intravenous injection of the beta-adrenoreceptor antagonist metoprolol in seven patients, there was a significant (P < .05) reduction in both c and LV + dP/dtmax at the baseline atrial pacing cycle length. Thus, the force-interval relationship can be quantitatively studied using incomplete mechanical restitution curves in humans in vivo. This quantitative description probably reflects relative intracellular calcium availability via slow channel activity and can be used to assess effects of cardioactive drugs on frequency-dependent inotropic mechanisms in humans. The predictive value of this mechanical restitution curve model for hemodynamic instability during tachycardia in patients with impaired LV function remains to be determined.

We prospectively studied 69 consecutive patients hospitalized with a primary diagnosis of acute left ventricular failure so as to assess the impact of vasodilators on incidence and morbidity of acute symptomatic left ventricular failure. The determinants of duration of hospitalization, in-hospital mortality and symptomatic status 2 months after discharge were examined. There were 9 in-hospital deaths (13%), and survival at 60 days was 77%. Median duration of hospitalization was 9 days, and 33% of the surviving patients remained in New York Heart Association functional class III-IV 60 days subsequent to discharge. Of the patients, 49 (76%) had previously received treatment for left ventricular failure: 30 (61%) of these had received vasodilators, most commonly angiotensin converting enzyme inhibitors and nitrates. Ischaemic chest pain was present in 34 (49%) of the patients. Acute utilization of vasodilators (45% of patients) was largely limited to nitrate therapy associated with ischaemic chest pain (P less than 0.01). Multiple logistic regression revealed previous left ventricular failure, advanced age and hypokalaemia as significant correlates of prolonged hospitalization (greater than 9 days). Previous left ventricular failure was also predictive of persistent severe disability two months subsequent to discharge. No factor was a significant predictor of in-hospital death. Although preceding treatment with digoxin and incremental angiotensin converting enzyme inhibitor therapy tended to predict brief hospitalization, the parameter of acute ischaemia, other biochemical anomalies and modes of acute or chronic therapy were not significant correlates of any end point. We conclude that preceding disability, rather than mode of treatment, predicts an adverse outcome in acute left ventricular failure.

The haemodynamic effects and pharmacokinetics of a single orally administered dose of 0.5 mg of prazosin have been compared in six patients with stable severe congestive cardiac failure. Administration of prazosin induced significant decreases in mean pulmonary capillary wedge pressure (from 27.5, s.e.m. = 4.5 to 19.4, s.e.m. = 5.1 mmHg; P less than 0.001), mean arterial blood pressure (from 94.5, s.e.m. = 6.0 to 85.4, s.e.m. = 5.0 mmHg; P less than 0.01), and systemic vascular resistance (from 1690, s.e.m. = 360 to 1420, s.e.m. = 200 dyn. s/cm5; P less than 0.05) and a rise in cardiac index from 1.98 (s.e.m. = 0.07) to 2.28 (s.e.m. = 0.16) litres/min per m2 (P less than 0.05). There was a non-significant fall in heart rate. Pharmacokinetic analysis revealed maximum plasma prazosin concentrations of 4.1 (s.e.m. = 1.4) ng/ml, occurring 2.1 (s.e.m. = 0.4) h after drug ingestion. The mean elimination half-life was 5.1 (s.e.m. = 0.8) h, which is longer than that found in our previous studies in normal subjects. There was considerable interindividual variation in peak plasma prazosin concentrations, elimination half-life and area under the concentration-time curve. While mean maximal haemodynamic effects of prazosin occurred at similar times to the peak plasma concentration of the drug, there was no significant correlation between the extent of haemodynamic response and individual pharmacokinetic parameters. It is concluded that significant and potentially beneficial haemodynamic effects occur with the initial administration of 0.5 mg oral dose of prazosin in patients with stable congestive cardiac failure and it is suggested that in many patients little advantage will be achieved with higher initial doses.

An abstract of the study "Metabolic Modulation With Perhexiline in Chronic Heart Failure," by L. Lee and colleagues is presented.

This article focuses on a study related to augmentation of glucose metabolism with perhexiline in non-ischaemic heart failure. Chronic heart failure (CHF) is a major cause of morbidity and mortality. Additional effective therapies ore needed. Glucose metabolism is more oxygen efficient than free fatty acid metabolism at generating AIP. Treatment with perhexiline leads to an improvement in the heart failure syndrome in DCM even in the absence of ischaemia. This could be linked to the observed improvement in skeletal muscle energetics. Metabolic modulation could represent a potential future treatment strategy for CHF.