Exercise ventilation inefficiency in heart failure: pathophysiological and clinical significance.

Heart failure (HF) is a complex syndrome characterized by myocardial dysfunction and a poor prognosis. Among multiple markers of severity, an exercise ventilation inefficiency has important clinical and prognostic value. The pathophysiology determining exercise ventilatory inefficiency is complex and not definitively clarified. Three different mechanisms have been identified: (i) increased dead space, (ii) early occurrence of lactic acidosis, and (iii) abnormal chemoreflex and/or metaboreflex activity. Besides its prognostic value, abnormal ventilation can be influenced by pharmacological and non-pharmacological therapies such as beta-blockers, selective cyclic 3'-5' guanosine monosphosphate phosphodiesterase inhibitors, physical training, and nocturnal continuous positive airway pressure. There is an increasing interest for the exercise periodic breathing, which is frequently associated with HF syndrome and has prognostic importance. The precise mechanisms sustaining exercise periodic breathing are not fully defined but ventilatory and metabo-haemodynamic hypotheses have been proposed.     

Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial.

AIMS: Chronic heart failure is associated with maladaptive and prolonged neurohormonal and pro-inflammatory cytokine activation causing a metabolic shift favouring catabolism, vasodilator incapacity, and loss of skeletal muscle bulk and function. In men, androgens are important determinants of anabolic function and physical strength and also possess anti-inflammatory and vasodilatory properties. METHODS AND RESULTS: We conducted a randomized, double-blind, placebo-controlled parallel trial of testosterone replacement therapy (5 mg Androderm) at physiological doses in 76 men (mean+/-SD, age 64+/-9.9) with heart failure (ejection fraction 32.5+/-11%) over a maximum follow-up period of 12 months. The primary endpoint was functional capacity as assessed by the incremental shuttle walk test (ISWT). At baseline, 18 (24%) had serum testosterone below the normal range and bioavailable testosterone correlated with distance walked on the initial ISWT (r=0.3, P=0.01). Exercise capacity significantly improved with testosterone therapy compared with placebo over the full study period (mean change +25+/-15 m) corresponding to a 15+/-11% improvement from baseline (P=0.006 ANOVA). Symptoms improved by at least one functional class on testosterone in 13 (35%) vs. 3 (8%) on placebo (P=0.01). No significant changes were found in handgrip strength, skeletal muscle bulk by cross-sectional computed tomography, or in tumour necrosis factor levels. Testosterone therapy was safe with no excess of adverse events although the patch preparation was not well tolerated by the study patients. CONCLUSION: Testosterone replacement therapy improves functional capacity and symptoms in men with moderately severe heart failure.     

Antithrombotic therapy in heart failure: a randomized comparison of warfarin vs. aspirin (HELAS)

It is uncertain whether anti-thrombotic treatment reduces the incidence of thrombo-embolism in patients with heart failure, so there is a need for a large scale controlled study to assess the effects of anti-thrombotic therapy in this setting. We report the design of a randomized controlled multicenter double blind trial examining the effects of aspirin, warfarin and placebo in patients with heart failure on the risk of thrombo-embolism. We planned to recruit 6000 patients with heart failure without contraindications to anticoagulants or antiplatelet agents and to follow them for a mean time of 2 years following randomization. The study was planned to determine the rate of thrombo-embolic and haemorrhagic events and death among patients randomized to aspirin, warfarin and placebo, stratified according to the presence or absence of underlying coronary disease. Ancillary studies parallel to the main study will attempt to identify clinical and echocardiographic risk factors for thrombo-embolism and will also examine whether hemostatic or neurohormonal mechanisms contribute to an increase in the risk of thrombo-embolism in patients with heart failure. We hoped that the results of the study would improve the clinical management and cost-effectiveness of treatment for patients with heart failure. However, the recruitment of patients proved more difficult than expected and a number of centers decided not to participate. To avoid a great delay it was decided by the principal investigators and submitted to the executive committee to terminate enrolment in this study when 300 patients had been enrolled, and accept that this is a pilot study.     

Placebo controlled trial of felodipine in patients with mild to moderate heart failure. UK Study Group.

OBJECTIVE--To compare the effects of felodipine and placebo in patients with New York Heart Association functional class II or III and stable congestive heart failure despite treatment with an angiotensin converting enzyme inhibitor, diuretic, or digoxin, or any combination of these three drugs. PATIENTS AND DESIGN--252 patients were randomised in a double blind, parallel group study after a 2-4 week placebo run-in to oral treatment with either felodipine extended release formulation or placebo 2.5-10 mg twice daily given in addition to existing background medication for a further 12 weeks. METHODS--Patients aged 18-75 years of either sex with chronic congestive heart failure due to ischaemic heart disease, hypertensive heart disease, or dilated cardiomyopathy with or without secondary mitral insufficiency that was stable during the preceding two months were included in the study. Treadmill exercise tests according to the modified Naughton protocol were performed at baseline, and after six, 11, and 12 weeks of treatment. Signs and symptoms of heart failure were assessed at every visit. Physical examination was performed and left ventricular ejection fraction measured at baseline and after 12 weeks. RESULTS--Mean (SD) baseline exercise test times increased from 434 (162) s and 480 (157) s for felodipine and placebo groups respectively to 541 (217) s and 591 (218) s at 12 weeks or the last visit. The change in exercise from baseline to last visit was 107 (141) s for patients given felodipine and 112 (128) s for those given placebo (P > 0.20). There was also no difference between treatments with respect to the other efficacy variables. There were few deaths in the study (felodipine n = 3, placebo n = 2). More patients who received felodipine were withdrawn from treatment (n = 29) than those who received placebo (n = 17). The most common adverse events of the 54 and 28 cited as reasons for withdrawal in the felodipine and placebo groups respectively were increased need for non-study heart failure treatment (n = 10; 8%)--that is, starting new medication or changes in the dosage of existing treatment for patients given felodipine, and nausea (n = 4; 3%) for those given placebo. Patients withdrawn from the study due to increased need for non-study heart failure treatment rapidly stabilised and recovered. CONCLUSION--Felodipine has not been shown to be of benefit in patients with mild to moderate heart failure.     

The effect of aspirin on the ventilatory response to exercise in chronic heart failure

INTRODUCTION: Patients with chronic heart failure (CHF) experience breathlessness and fatigue on exercise. One of the abnormalities seen on maximal exercise testing is an increased ventilatory response to exercise (VE/VCO(2) slope). The cause of this is unknown, but is likely to be due to a combination of interacting peripheral and central factors. Recent data have demonstrated a relation between VE/VCO(2) slope and prostaglandin levels in contracting muscles. The present study examined the influence of the presence of a potent non-selective prostaglandin inhibitor, aspirin, on the ventilatory response to exercise in a group of patients with CHF. METHODS: We investigated the ventilatory response to exercise of 120 consecutive patients in sinus rhythm attending a specialist heart failure clinic. We excluded those taking clopidogrel (six patients) and those on both warfarin and aspirin or taking other non-steroidal anti-inflammatory agents (five patients). The other 109 patients were grouped according to whether they were taking aspirin (n=52 (48%)) or not (n=57 (52%)). Each patient underwent echocardiography to assess left ventricular function, and exercise testing with metabolic gas exchange to derive peak oxygen consumption (pVO(2)) and the VE/VCO(2) slope. RESULTS: The groups were similar in terms of age, (67 (13) vs. 66 (12) years; P=0.34) drug use, heart failure aetiology, left ventricular function (ejection fraction; 33.3 (9.4) vs. 31.8 (9.9)%; P=0.05)) and exercise tolerance (pVO(2); 20.4 (5.3) vs. 19.9 (6.0); P=0.68, and VE/VCO(2) slope; 35.4 (6.2) vs. 35.7 (9.3); P=0.73). There was no difference in the ventilatory response to exercise or the symptoms of breathlessness between the two groups. CONCLUSIONS: Aspirin does not appear to affect exercise performance in CHF.     

Preload-dependent hemodynamic effects of milrinone in moderate heart failure.

Milrinone, a bipyridine derivative with positive inotropic and balanced type vasodilating properties, acutely improves cardiac pump function in patients with severe and moderate to severe heart failure. Whether it has similar effects in patients with mild to moderate heart failure is unknown. A hemodynamic evaluation of oral milrinone in dosage of 2.5, 5 and 10 mg was carried out on 3 consecutive days in 18 patients with NYHA class 2.7 heart failure. Patients continued with diuretics and digitalis, administered 15 h before each hemodynamic study. Peak milrinone plasma levels ranged from 77 to 252 micrograms/ml and were attained at 60-90 min following administration. Concomitantly, milrinone significantly reduced pulmonary wedge and right atrial pressures with 24, 47 and 44, and 25, 42 and 38% with the 2.5-, 5- and 10-mg doses, respectively. Milrinone had no effect on cardiac or stroke indices with either dose. Moreover, systemic vascular resistance only decreased by 12% with the highest dose, together with a 7% fall in mean arterial pressure and a 13% rise in heart rate (all p less than 0.05 vs. baseline). Patients were subsequently grouped depending on baseline pulmonary wedge pressure greater than or equal to 18 mm Hg (Gr I, n = 9) or less than 18 mm Hg (Gr II, n = 9). Changes in pulmonary wedge, pulmonary artery and right atrial pressure were similar in both groups following each dose. In contrast, the effect on cardiac pump function clearly differed in patients with high versus normal baseline wedge pressure. In Gr I, cardiac index increased significantly by 16% (5 and 10 mg). In Gr II, cardiac index decreased with 13% following the 10-mg dose (p less than 0.05 vs. baseline). When maximal individual changes in cardiac index were compared, 10 mg milrinone resulted in an improvement of cardiac index in all patients with baseline wedge pressures greater than 15 mm Hg, but in a decrease in cardiac index in patients with lower wedge pressures. It is concluded that milrinone induces contrasting effects on cardiac pump function in patients with mild to moderate heart failure, which may negatively affect its early and, possibly, also late efficacy in this patient group.     

Update of REACH-1 and MERIT-HF clinical trials in heart failure. Cardio.net Editorial Team

BACKGROUND: This article reviews the design and results of REACH-1 (Research on Endothelin Antagonism in Chronic Heart Failure) and MERIT (Metoprolol controlled and Extended release, Randomised Intervention Trial in congestive Heart Failure), two recently reported clinical trials that investigated, respectively, the role of a non-selective endothelin antagonist (bosentan) and of a beta-selective blocker for the treatment of heart failure. RESULTS: The REACH-1 trial demonstrated that initiation of bosentan therapy is associated with an increased risk of worsening heart failure. However, long-term therapy with bosentan may have improved symptoms and favourably altered the progression of heart failure. The MERIT-HF clinical trial indicated that beta-blockade using metoprolol confers a significant beneficial effect on total mortality in patients with stable chronic heart failure.     

Randomized, controlled trial of integrated heart failure management: The Auckland Heart Failure Management Study.

AIMS: To determine the effect of an integrated heart failure management programme, involving patient and family, primary and secondary care, on quality of life and death or hospital readmissions in patients with chronic heart failure. METHODS AND RESULTS: This trial was a cluster randomized, controlled trial of integrated primary/secondary care compared with usual care for patients with heart failure. The intervention involved clinical review at a hospital-based heart failure clinic early after discharge, individual and group education sessions, a personal diary to record medication and body weight, information booklets and regular clinical follow-up alternating between the general practitioner and heart failure clinic. Follow-up was for 12 months. One hundred and ninety-seven patients admitted to Auckland Hospital with an episode of heart failure were enrolled in the study. There was no significant difference between the intervention and control groups for the combined end-point of death or hospital readmission. The physical dimension of quality of life showed a greater improvement in the intervention group from baseline to 12 months compared with the control group (-11.1 vs -5.8 respectively, 2 P=0.015). The main effect of the intervention was attributable to the prevention of multiple admissions (56 intervention group vs 95 control group, 2 P=0.015) and associated reduction in bed days. CONCLUSIONS: This integrated management programme for patients with chronic heart failure improved quality of life and reduced total hospital admissions and total bed days.     

A large-scale trial of captopril for mild to moderate heart failure in the primary care setting

A large-scale, prospective, 8-week, office-based study was conducted to evaluate the effects of adding captopril to a therapeutic regimen of diuretic and digoxin or diuretic alone in the management of patients with mild to moderate congestive heart failure (CHF). A total of 2218 primary care physicians evaluated 6669 patients over the study period for efficacy parameters, which included changes in a modified New York Heart Association (NYHA) functional classification, symptomatology, and daily activity levels. Overall, 63.8% of evaluated patients improved with regard to functional ability, with 19% improving two or more modified NYHA classes. Symptoms of CHF, including dyspnea on exertion, fatigue, and orthopnea and signs, including rales and peripheral edema, were reduced in 86% of these patients: 41.5% demonstrated mild improvement; 30.0%, moderate improvement; and 14.5%, marked improvement. Three parameters, with which patients reported having difficulty at study entry, were assessed serially to evaluate changes in functional capacity; 78.5% of patients reported an increased walking distance, 72.3% had increased capacity for climbing stairs, and 60.2% had improved capacity for individual recreational activities. Adverse experiences were reported in 18.1% of all patients; 4.9% of patients withdrew from the study because of an adverse effect. Combination therapy with captopril and diuretic for CHF was shown to be safe and effective regardless of patient age (less than 70 years vs. greater than or equal to 70 years), duration of heart failure (less than 1 year vs. greater than 1 year), presence of digoxin treatment, or the dosing schedule employed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Multicenter randomized comparison of direct vs. conventional stenting: the DIRECTO trial.

With conventional stenting, predilatation frequently induces dissections that require deploying stents longer than originally planned. To assess whether direct stenting is safe and may prevent dissections and reduce the length of stents implanted, we conducted a randomized study comparing direct (n = 73) and conventional (n = 78) stenting. Direct stenting was successful in 89% of cases, 11% crossed over to predilation without complications. Dissections occurred more frequently in conventional stenting group (10.3% vs. 1.4%; P = 0.034), but did not translate to a significant stent length difference (16.31 +/- 7.6 vs. 15.31 +/- 5.5; P = NS). Periprocedure creatine kinase elevation and number of balloons utilized were lower with direct stenting.     

Comparison of captopril and ibopamine in mild to moderate heart failure.

OBJECTIVE: To determine the effects of ibopamine 100 mg three times daily compared with captopril 25 mg three times daily on exercise capacity in patients with chronic heart failure. DESIGN: A randomised, double blind, parallel group comparison of the addition of ibopamine versus captopril during a period of 24 weeks. SETTING: 26 outpatient cardiology clinics in seven European countries. PATIENTS: 266 patients, with mild to moderate chronic heart failure (New York Heart Association (NYHA) functional class II, 81% and III, 19%) and evidence of an enlarged left ventricle. Patients received concomitant treatment with diuretics and/or digitalis. MAIN OUTCOME MEASURE: Exercise duration after 24 weeks of treatment, compared with baseline. RESULTS: Mean (SD) ejection fraction was 29 (8)% and the baseline exercise duration in the captopril and ibopamine groups 665 (160) and 675 (174) seconds, respectively. At the end of the study, exercise duration had improved in both groups, by 29 seconds in the ibopamine group (P < 0.01), and by 24 seconds in the captopril group (P < 0.05). There was no difference between groups (P = 0.69, 95% confidence interval -22 to 33). NYHA class, signs and symptoms score, and dyspnoea and fatigue index improved equally in both groups. The total number of adverse events was the same in both treatment groups, but gastrointestinal complaints occurred more often in the ibopamine group. The number of patients with premature withdrawals was no different. CONCLUSIONS: No difference was detected between the effect of captopril and ibopamine on exercise time in patients with mild to moderate heart failure during a treatment period of 24 weeks.     

机械通气在重度急性左心衰竭患者中的治疗作用

目的观察机械通气在重度急性左心衰竭患者治疗中的作用。方法将60例重度急性左心衰竭患者随机分为两组,第1组应用BiPAP呼吸机进行机械通气,第2组予气管插管呼吸机机械通气,比较两组病人治疗前后心率、呼吸频率、血气分析等指标的变化。结果第1组30例患者经BiPAP呼吸机治疗2小时后,多数患者明显好转,12例病人低氧血症不能纠正,最终行气管插管呼吸机通气治疗,9例病人死亡,死亡率为30．O％。第2组30例患者经机械通气治疗2小时后,各项观察指标显著好转,5例病人死亡,死亡率为16．7％。结论机械通气支持治疗是抢救重度急性左心衰竭患者的有效措施。同时应根据患者的不同情况选择不同的通气方式。