A mechanistic investigation of ACE inhibitor dose effects on aerobic exercise capacity in heart failure patients.

BACKGROUND: Angiotensin converting enzyme inhibitors at high doses have been shown to improve prognosis of heart failure patients. Their beneficial effects on exercise capacity have been less convincing in large parallel group studies. The objective of this investigation was to explore the mechanisms involved in dose-related functional effects and to test the hypothesis that a trial recommended high dose of lisinopril would improve aerobic exercise capacity and cardiovascular function more than with a low dose. METHODS: Twelve patients with symptomatic heart failure completed a randomized double-blind crossover trial of lisinopril 5 mg o.d. and 20 mg o.d. for 24 weeks, crossing over the doses at 12 weeks. The primary end-point was aerobic exercise capacity, and the secondary end-points were cardiac performance at peak exercise and dobutamine stimulation. RESULTS: The aerobic exercise capacity (primary end-point) was significantly higher during the 5mg per day dosage compared to the 20 mg (1696 vs 1578 ml.min(-1), P=0.016), equivalent to a rise of 1.53 ml.kg(-1)min(-1) from the 19.6 ml.kg(-1)min(-1) with 20mg when normalized by body weight. Seventy-three percent of patients showed greater peak oxygen consumption and peak cardiac power output with the 5mg per day dose than the 20 mg, and none showed the opposite. In terms of cardiac performance, although the results were not statistically significant, there was a consistent pattern showing the same directional changes in favour of the lower dose in peak exercise cardiac power output and cardiac power output at maximal dobutamine. There were no significant differences in the resting values. A total of 24 adverse reactions were reported during the 5 mg phase compared to 38 during the 20 mg phase. CONCLUSIONS: Contrary to expectation, the aerobic exercise capacity of patients was found to be greater with the lower dose of lisinopril, suggesting that therapy with ACE inhibitors for heart failure may require tailoring the doses to the individual to optimize functional benefits in relation to the assumed prognostic benefits.

Peak exercise cardiac power output; a direct indicator of cardiac function strongly predictive of prognosis in chronic heart failure.

OBJECTIVES: This study assessed the prognostic value of peak cardiac power output, measured non-invasively during maximal cardiopulmonary exercise testing, against other exercise-derived haemodynamic variables in patients with chronic congestive heart failure. METHOD AND RESULTS: Two hundred and nineteen unselected, consecutive patients with congestive heart failure (166 men, mean (+/-SD) age of 56+/-13 years) who underwent maximal symptom limited cardiopulmonary treadmill exercise testing with non-invasive estimation of cardiac output using carbon dioxide re-breathing techniques, were followed-up for a mean period of 4.64 (4.47--4.82, 95% CI) years. Cardiac power output was calculated from the product of cardiac output and mean arterial blood pressure. All cause mortality was 12.3% (27 deaths). Peak and resting cardiac power output, peak mean arterial blood pressure, peak and resting cardiac output and peak VO(2)were all predictive of outcome on univariate analyses. Peak cardiac power output, either entered continuously or categorically with a cut-off value of 1.96 watts, was the only independent predictor of mortality (P=0.0004 for values < or >1.96 watts and P=0.001 for continuous values) using multivariate analysis. A relative risk ratio of 5.08 (1.94-13.3, 95% CI) was obtained for a cardiac power output <1.96 watts. CONCLUSION: Peak cardiac power output is an independent predictor of mortality that can be measured non-invasively using cardiopulmonary exercise testing. It can give further prognostic power to a peak VO(2)in the assessment of patients with congestive heart failure.

Disparate results of ACE inhibitor dosage on exercise capacity in heart failure: a reappraisal of vasodilator therapy and study design.

Despite manifest benefits of angiotensin converting enzyme (ACE) inhibitors on the prognosis of patients with heart failure, there is a lack of consistency in the results of trials investigating the effects of ACE inhibitors on exercise capacity. The inconsistencies cannot be readily explained by variations in effects on known neurohumoral or conventional haemodynamic factors. Drawing on insights from physiology of pump-load interactions, in a normal circulation there is an optimal extent of systemic vasodilation at which the delivery of hydraulic energy from the cardiac pump is maximal (the 'impedance matchpoint'). In heart failure, the vasoconstrictive effects shift the operating point towards mismatch at higher resistances, and optimal vasodilatory therapy would reshift the operating point to the matchpoint. Excessive dosage, however, would cause overvasodilatation leading to a reduction in cardiac power output and consequently compromising exercise ability. High levels of ACE inhibitors may not therefore improve exercise ability. Another potential reason for the observed inconsistencies is that the often used parallel-group study design (ideal for mortality studies) may not be suitable for investigating drug effects on exercise capacity because dropouts from such studies would introduce occult selection biases, thereby confounding treatment effects. In conclusion, this reappraisal of the conflicting observations reported on ACE inhibitor effects on exercise capacity has highlighted a proposition that there is an optimal dosage of ACE inhibitors which will most enhance exercise capacity, and this will require further well designed cross-over studies to elucidate.

Physiological cardiac reserve: development of a non-invasive method and first estimates in man.

OBJECTIVE: To investigate whether physiological cardiac reserve can be measured in man without invasive procedures and whether it is a major determinant of exercise capacity. DESIGN: Development of method of measurement and an observational study. SETTING: A regional cardiothoracic centre. SUBJECTS: 70 subjects with a wide range of cardiac function, from heart failure patients to athletes. METHODS: Subjects underwent treadmill, symptom limited cardiopulmonary exercise tests to measure aerobic exercise capacity (represented by VO2max) and cardiac reserve. Cardiac output was measured non-invasively using the CO2 rebreathing technique. RESULTS: Cardiac power output (CPOmax) at peak exercise was found to be significantly related to aerobic capacity: CPOmax (W) = 0.35 + 1.5 VO2max (1/min), r = 0.87, p < 0.001. It also correlated well with exercise duration (r = 0.62, p < 0.001), suggesting that cardiac reserve is a major determinant of exercise capacity. In the study, cardiac reserve ranged from 0.27 to 5.65 W, indicating a 20-fold difference between the most impaired cardiac function and that of the fittest subject. CONCLUSIONS: A non-invasive method of estimating physiological cardiac reserve was developed. The reserve was found to be a major determinant of exercise capacity in a population of normal subjects and patients with heart disease. This method may thus be used to provide a clearer definition of the extent of cardiac impairment in patients with heart failure.

Heart failure: can it be defined?

Unlike hypertension, heart failure is not readily identified, defined and evaluated. Research and clinical management of heart failure has been handicapped by the absence of a clear definition. In other branches of medicine, e.g. renal or pulmonary failure can be clearly defined with the help of direct measures of organ function. Unfortunately such a parameter does not exist in cardiology to help us with defining cardiac function or failure. Representative definitions of heart failure hitherto proposed are reviewed. A common error in these 'definitions' is the confusion between formulating a definition and giving instructions on how to identify or diagnose heart failure. Other short-comings are also recognised. From these it is possible to compile criteria which a definition of heart failure should possess. When formulating any definition, in order to avoid unnecessary detail, the importance of including only the essence and not the contingents is recognised. To find a new definition which complies best with these criteria is an important challenge facing cardiologists.