Number 28, 2005
Sex and the Heart
Featured research
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Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial
Nissen SE, Tuzcu EM, Libby P, et al, for the CAMELOT Investigators. JAMA. 2004;292:2217–2226.
The effect of antihypertensive drugs on cardiovascular events in patients with coronary artery disease (CAD) and normal blood pressure remains uncertain. In a double-blind, randomized, multicenter, 24-month trial (enrollment April 1999–April 2002), we compared amlodipine or enalapril with placebo in 1991 patients with angiographically documented CAD (>20% stenosis by coronary angiography) and diastolic blood pressure <100 mm Hg. A substudy of 274 patients measured progression of atherosclerosis by intravascular ultrasound (IVUS). Patients were allocated randomly to groups to receive amlodipine 10 mg, enalapril 20 mg, or placebo. IVUS was performed at baseline and study completion.
The primary efficacy parameter was incidence of cardiovascular events for amlodipine compared with placebo. Other outcomes included comparisons of amlodipine and enalapril, and enalapril and placebo. Events included cardiovascular death, nonfatal myocardial infarction, resuscitated cardiac arrest, coronary revascularization, admission to hospital for angina pectoris or congestive heart failure, fatal or nonfatal stroke or transient ischemic attack, and new diagnosis of peripheral vascular disease. The IVUS endpoint was change in percent atheroma volume.
Baseline blood pressure averaged 129/78 mm Hg for all patients; it increased by 0.7/0.6 mm Hg in the placebo group and decreased by 4.8/2.5 mm Hg and 4.9/2.4 mm Hg in the amlodipine and enalapril groups, respectively (P < 0.001 for both compared with placebo). Cardiovascular events occurred in 151 (23.1%) placebo-treated patients, 110 (16.6%) amlodipine-treated patients (hazard ratio [HR] 0.69; 95% confidence interval [CI] 0.54 to 0.88; P = 0.003), and in 136 (20.2%) enalapril-treated patients (HR 0.85; 95% CI 0.67 to 1.07; P = 0.16). Primary endpoint comparison between enalapril and amlodipine was not significant (HR 0.81; 95% CI 0.63 to 1.04; P = 0.10). The IVUS substudy showed a trend toward less progression of atherosclerosis in the amlodipine group compared with placebo (P = 0.12), with significantly less progression in the subgroup with systolic blood pressures greater than the mean (P = 0.02). Compared with baseline, IVUS showed progression in the placebo group (P < 0.001), a trend toward progression in the enalapril group (P = 0.08), and no progression in the amlodipine group (P = 0.31). For the amlodipine group, correlation between blood pressure reduction and progression was r = 0.19 (P = 0.07).
Administration of amlodipine to patients with CAD and normal blood pressure resulted in reduced adverse cardiovascular events. Directionally similar, but smaller and nonsignificant, treatment effects were observed with enalapril. For amlodipine, IVUS showed evidence of slowing of atherosclerosis progression.
Commentary
Guidelines for risk reduction that recommend target blood pressures of less than 140/85 mm Hg in patients without diabetes and 130/80 mm Hg in those with diabetes, chronic renal disease, and established cardiovascular disease perhaps do not give the qualification “less than” sufficient emphasis to have an impact on practice. Risk reduction to a low-density lipoprotein cholesterol concentration of 2 mmol/L or less in the Treating to New Targets (TNT) [1] and Pravastatin or Atorvastatin Evaluation Infection Therapy (PROVE-IT) [2] trials has demonstrated clinical benefit from a more aggressive statin regimen (atorvastatin 80 mg) and setting a lower target. In the case of hypertension, the risk-reduction benefit continues to a blood pressure of 115/75 mm Hg, so a study looking at decreasing blood pressure in the “normal range” in those with CAD is highly relevant to clinical practice. We already know from the European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA) trial [3] in individuals at high cardiovascular risk (documented CAD, previous myocardial infarct) that the addition of perindopril to the drug regimen reduced overall mortality by 14% and myocardial infarction by 24%. This benefit may well be explained by a blood pressure reduction of 5/2 mm Hg from a baseline 137/82 mm Hg. Participants in the (The comparison of Amlodipine vs Enapril to limit occurences of Thrombosis [CAMELOT]) trial [4] had a mean baseline blood pressure of 129/78 mm Hg; this was reduced by an additional 4.8/2.5 mm Hg with amlodipine 5–10 mg compared with placebo, and by an additional 4.9/2.4 mm Hg with enalapril 10–20 mg compared with placebo. Both regimens were once-daily, so the benefit recorded for amlodipine over enalapril (and placebo) may be a consequence of the longer half-life of amlodipine and therefore better 24 h blood pressure control. The importance of the study is the identification of clinical benefit with a lower pressure in the normal range, confirming that a lower blood pressure is a better blood pressure in patients with CAD.
It is difficult to know whether the better effect of amlodipine compared with that of enalapril is a direct one, as enalapril should have been administered twice daily (perindopril would have been a better agent for comparison). The IVUS substudy showed no progression of atheroma in the amlodipine group compared with the placebo and enalapril groups, but again this may have been a 24 h blood pressure effect, rather than drug related.
The overall results suggest that the optimal blood pressure for patients with CAD needs to be re-evaluated, given that amlodipine achieved a 31% relative risk reduction and 5.6% absolute risk reduction in adverse cardiovascular events superimposed on high rates of use of statins (>80%), aspirin (95%), and β-blockers (>75%). Perhaps, after all, the classic target of 120/80 mm Hg should be our treatment objective. The “less than” component of the target guidelines needs to be emphasized, just as it is in the case of decreasing low-density lipoprotein cholesterol concentrations.
REFERENCES
1. LaRosa JC, Grundy SM, Waters DD, et al.
Intensive lipid lowering with atorvastatin in patients with stable coronary artery disease.
N Eng J Med. 2005;352:1425–1435.
2. Cannon CP, Braunwald E, McCabe CH, et al.
Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
N Engl J Med. 2004;350:1495–1504.
3. The EUROPA Study. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised double-blind, placebo-controlled multicentre trial.
Lancet. 2003;362:782–788.
4. Nissen SE, Tuzcu EM, Libby P, et al., for the CAMELOT Investigators.
Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial.
JAMA. 2004;292:2217–2226.
Graham Jackson
Influence of substrate supply on cardiac efficiency, as measured by pressure–volume analysis in ex vivo mouse hearts
How OJ, Aasum E, Kunnathu S, Severson DL, Myhre ES, Larsen TS. Am J Physiol Heart Circ Physiol. 2005;288:2979–2985.
In the present study we tested the reliability of measurements of pressure–volume area (PVA) and myocardial oxygen consumption (mVO2) in ex-vivo mouse hearts, combining the use of a miniaturized conductance catheter and a fiberoptic oxygen sensor. Secondly, we tested whether we could reproduce the influence of increased myocardial fatty acid metabolism on cardiac efficiency in the isolated working mouse heart model, which has already been documented in large animal models. The hearts were perfused with crystalloid buffer containing 11 mmol/L glucose and two different concentrations of fatty acids bound to 3% bovine serum albumin: an initial concentration of 0.3 ± 0.1 mmol/L, subsequently increased to 0.9 ± 0.1 mmol/L. End-systolic and end-diastolic pressure–volume relationships were assessed by temporarily occluding the preload line. Different steady-state PVA–mVO2 relationships were obtained by changing the loading conditions (pre- and afterload) of the heart. There were no apparent changes in baseline cardiac performance or contractile efficiency (slope of the PVA–mVO2 regression line) in response to increased concentrations of fatty acid in the perfusate. However, all hearts (n = 8) showed an increase in the Y-intercept of the PVA–mVO2 regression line after an increase in the palmitate concentration, indicating a fatty-acid-induced increase in the unloaded mVO2. In the present model, therefore, unloaded mVO2 is not independent of metabolic substrate. This is, to our knowledge, the first report of the PVA–mVO2 relationship in ex-vivo perfused murine hearts, using a PVA catheter. The methodology can be an important tool for phenotypic assessment of the relationship between metabolism, contractile performance, and cardiac efficiency in various mouse models.
Commentary
Cardiac efficiency is defined as the amount of cardiac work performed at a given level of mVO2. As the heart has a high energy demand, and almost no energy reserves, alterations in cardiac efficiency can have important consequences for heart function or heart muscle viability. This is particularly true during myocardial ischemia, when energy production in the heart is compromised as a result of a lack of adequate oxygen supply. ATP is the energy currency of the heart, and is produced by the metabolism of a variety of energy substrates, carbohydrates and fatty acids being the primary ones. The ATP produced by the heart is not only used to sustain contractile function; it is also used for noncontractile purposes, such as to maintain ionic homeostasis or basal metabolic processes in the heart. Any change in the amount of ATP needed for muscle contraction, or the amount of ATP needed for basal metabolism and ion homeostasis, has the ability to alter cardiac efficiency. One determinant of cardiac efficiency is the supply of energy substrate to the heart. In particular, an increased supply of fatty acid to the heart, and an increased use of fatty acids as a source of energy, can lead to a decrease in cardiac efficiency.
Using a sophisticated experimental approach involving the measurement of pressure–volume area (PVA) in isolated working mouse hearts, the authors of this paper have shown that exposing hearts to a high fatty acid concentration can dramatically increase the “unloaded” mVO2, which is equivalent to the oxygen used for noncontractile purposes. A 27% increase in unloaded mVO2 was seen if the fatty acid concentration was increased from 0.3 to 0.9 mmol/L. Part of this increase in mVO2 could be related to the fact that fatty acids are less efficient than glucose for the production of ATP (more oxygen is required to produce an equivalent amount of ATP). However, this would not normally account for more than 11% of the mVO2 differences. The additional difference could be the result of a high fatty-acid-induced uncoupling of oxidative phosphorylation, such that the mitochondria are less efficient at producing ATP, yet still consume oxygen. Alternatively, high fatty acid concentrations may trigger futile metabolic cycling such as an increase in triacylglycerol turnover, a process in which ATP consumption increases. A third possibility is that that high concentrations of fatty acids can inhibit glucose oxidation, which will result in an increased production of lactate and protons in the heart; many of the pathways involved in the clearance of protons in the heart require ATP. As a result, fatty acid inhibition of glucose oxidation may be another mechanism by which high concentrations of fatty acids decrease cardiac efficiency.
Myocardial ischemia results in a situation in which a mismatch occurs between the oxygen demand of the heart and the oxygen supply to the heart. In most forms of clinical ischemia (during and after a myocardial infarction, during and after cardiac surgery, or during an angina attack), blood concentrations of fatty acids increase markedly and can readily exceed 1 mmol/L. These high concentrations of fatty acids may contribute to the severity of ischemia as a result of their effect in decreasing cardiac efficiency. It is therefore important to have a better understanding of the exact mechanism by which high concentrations of fatty acids produce the marked decrease in cardiac efficiency. Understanding these mechanisms may provide novel therapeutic approaches to the treatment of myocardial ischemia. It may also provide us with a better understanding of why inhibition of fatty acid oxidation (such as through the use of trimetazidine in patients with angina pectoris) has proved to be a useful therapeutic approach to the treatment of ischemic heart disease.
Gary D. Lopaschuk
Sildenafil effects on exercise, neurohormonal activation, and erectile dysfunction in congestive heart failure: a double-blind, placebo-controlled, randomized study followed by a prospective treatment for erectile dysfunction
Bocchi EA, Guimarães G, Mocelin A, Bacal F, Bellotti G, Ramires JF. Circulation. 2002;106:1097–1103.
Erectile dysfunction is common in patients with congestive heart failure. It reduces the quality of life, and may affect compliance, thereby impairing the success of treatment of the congestive heart failure. We have studied the effects of sildenafil in 23 men with congestive heart failure.
In the first phase (a fixed-dose, double-blind, randomized, placebo-controlled, two-way crossover study), we studied the effects of sildenafil 50 mg on exercise and neurohormonal activation. The patients underwent a 6-min treadmill-walking cardiopulmonary test (6MWT), followed by a maximal cardiopulmonary exercise test. In the second phase, patients received sildenafil, taken as required for erectile function. Sildenafil reduced the heart rate before the 6MWT from 75 ± 15 to 71 ± 14 beats/min (P < 0.02) and that before the exercise test from 75 ± 15 to 71 ± 15 (P < 0.02). It reduced the systolic blood pressure before the 6MWT from 116 ± 18 to 108 ± 18 mm Hg (P < 0.004) and that before the exercise test from 116 ± 15 to 108 ± 17 mm Hg (P < 0.001) and the diastolic blood pressure before the 6MWT from 69 ± 9 to 63 ± 11 mm Hg (P < 0.01) and that before the exercise test (from 70 ± 8 to 65 ± 10 mm Hg (P < 0.004). In addition, it reduced the Ve/VCO2 slope during the 6MWT from 32 ± 7 to 31 ± 6 (P < 0.04) and that during the exercise test from 33 ± 8 to 31 ± 5 (P < 0.03). Sildenafil attenuated the increment in heart rate during the 6MWT (P < 0.003) and the exercise test (P < 0.000), and increased the peak VO2 from 16.6 ± 3.4 to 17.7 ± 3.4 mL/kg per min (P < 0.025) and the exercise time from 12.3 ± 3.4 to 13.7 ± 3.2 min (P < 0.003). It improved most International Index of Erectile Function scores.
Sildenafil was tolerated and effective for the treatment of erectile dysfunction in congestive heart failure, and improved the exercise capacity. The reduction in heart rate during exercise that was obtained with sildenafil could, theoretically, decrease the myocardial oxygen consumption during sexual activity.
Commentary
The prevalence of heart failure is close to 10% and is expected to increase further in the near future. Congestive heart failure is often associated with impaired sexual performance, either as a result of the disease itself or as an adverse effect of drugs prescribed to reduce mortality and morbidity in patients with the condition. Many patients who value quality of life over prolonged survival may overtly refuse treatment and become noncompliant, in order to retain sexual activity.
Phosphodiesterase inhibitors, such as sildenafil, have been shown to improve erectile dysfunction in a variety of conditions, including heart failure. Concerns have been raised, however, as to the safety of sildenafil in patients with heart failure, either as a direct effect of the vasodilating property of the drug or as a consequence of increased sexual activity. In this study, the effects of sildenafil on exercise tolerance and quality of life were investigated in patients with heart failure. The authors report that inhibition of phosphodiesterase type-5 reduced heart rate and blood pressure under resting conditions and during exercise. Sildenafil increased maximal exercise capacity, was well tolerated, and improved erectile dysfunction.
Successful treatment of erectile dysfunction can improve, not only personal relationships, but also overall quality of life in patients with heart failure, both as a direct effect of resumed sexual activity and as a result of greater patient compliance to complex drug regimens.
Mario Marzilli
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