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Low levels of high-density lipoprotein cholesterol (HDL-C) are frequently encountered in patients with coronary artery disease (CAD), most often in combination with elevated triglycerides as part of a dysmetabolic syndrome. Although no large secondary prevention trials with statin therapy with special emphasis on low HDL-C have been performed, some guidance can be extracted from a number of post-hoc analyses on how to treat patients with low levels of HDL-C. In terms of risk reduction, statin therapy appears to be at least as effective in patients with low compared to normal HDL-C levels. Fibrate therapy seems only effective when low HDL-C coincides with a level of low-density lipoprotein cholesterol (LDL-C) in the low-normal range. Before considering combination therapy of statins with fibrates, much emphasis should be put on dietary changes, weight reduction, smoking cessation and regular exercise, since these measures are effective tools to raise HDL-C levels. Moreover, one should be aware of the fact that combination therapy of statins and fibrates is not evidence-based and confers some potential risk of myopathy. Future therapy options may include CETP (cholesterol ester transfer protein) inhibitors, but these agents are still in an experimental phase. As most patients with low HDL-C levels share features of the dysmetabolic syndrome, one could also consider a combination therapy of statins and ACE-inhibitors, since this combination is not only safe, but the individual preventive effects of these compounds appear to be cumulative.

Constant vasodilatation, inhibition of platelet and leukocyte adhesion, and local thrombolysis are the mechanisms through which an intact endothelial layer exerts its protective action on coronary circulation. A loss in these features is not only the first step in the development of atherosclerosis, but also a potent trigger for complications after revascularisation procedures. Percutaneous coronary interventions, particularly in the course of stenting, induce endothelial injury that can last up to months after the procedure. On the other hand, the preservation of endothelial function appears the best feature of arterial versus venous grafts after coronary bypass surgery. An early diagnosis either by invasive or non-invasive techniques has important implications for prognosis, and endothelial dysfunction can be effectively counteracted by medical treatment (ACE inhibitors, statins). Activated circulating platelets are present in the course of coronary artery disease, increasing the risk of thrombotic occlusion and/or plaque regrowth, after both percutaneous and surgical revascularisation. New antiplatelet agents are under development to reduce endothelium-platelet interaction. On the basis of the latest studies, coronary revascularisation should be integrated in a more complete treatment, which would take into account the complex processes involving the underlying atherosclerotic plaque.

Objectives: We sought to study the effect of angiotensin-converting enzyme inhibition on exercise-induced myocardial ischemia., Background: Although angiotensin-converting enzyme inhibitors have been shown to reduce ischemic events after myocardial infarction, few data are available regarding their direct anti-ischemic effects in patients with coronary artery disease., Methods: We studied 43 patients (average age 63 +/- 8 years) with exercise-induced myocardial ischemia (> or =0.1 mV ST depression, despite optimal beta blockade) and normal left ventricular function (ejection fraction >0.50). In a double-blind, placebo-controlled parallel design, patients were treated with angiotensin-converting enzyme inhibitor (enalapril 10 mg twice daily) or placebo. Assessments were made after three weeks (short-term) and 12 weeks (long-term)., Results: At baseline, the groups were well matched for all clinical characteristics. After three weeks, there was a slight but not significant increase in time to 0.1 mV ST depression in both groups (p = NS); rate pressure product (RPP = heart rate x systolic blood pressure) was also unaffected. After 12 weeks, however, time to 0.1 mV ST depression further increased in the enalapril group (5.6 +/- 1.9 min) but was unchanged in the placebo group (4.4 +/- 1.3 min; p < 0.05 between groups). In contrast, RPP was not affected. Concentrations of both atrial and brain natriuretic peptides at peak exercise tended to be lower by enalapril, if compared to placebo (p = NS)., Conclusions: Angiotensin-converting enzyme inhibition may reduce exercise-induced myocardial ischemia in patients with normal left ventricular function. Further studies are needed to elucidate the mechanisms involved.

Aim: Autonomic impairment is related to the incidence of sudden death in chronic heart failure (CHF). Our objective was to study autonomic profiles in patients with mild CHF due to coronary artery disease, and to investigate the value of add-on beta-blockade., Methods and Results: Measures of autonomic function (plasma norepinephrine, heart rate [HR] variability, autonomic function testing), and exercise capacity, were compared between 24 patients with mild CHF, and 24 healthy controls. In this mechanistic study, we assessed the effect of 26 weeks metoprolol treatment in a double-blind, randomized, placebo-controlled design. All patients received metoprolol sustained release (200 mg; n=12) or placebo (n=12). Assessments were made at baseline and after 10 and 26 weeks' treatment. At baseline, norepinephrine levels were elevated, while HR variability parameters were decreased in patients vs. controls (both P<0.05). Autonomic function testing showed only small differences, although significant alterations were observed with deep breathing and head up tilting (both P<0.05). After 26 weeks', metoprolol did not affect exercise capacity or norepinephrine concentrations. In contrast, HR variability was markedly improved in metoprolol-treated patients vs. placebo-treated patients (P<0.05). In particular, a shift toward normal in the sympathovagal balance was observed (P<0.05). Autonomic function testing showed only small, and generally non-significant trends after metoprolol., Conclusions: Marked autonomic abnormalities are already present in mild CHF, which may be (partially) reversed by metoprolol. These observations support the reported reduction of sudden death by beta-blockade in patients with CHF.

Objectives: We sought to study the influence of frequency of exercise training during cardiac rehabilitation on functional capacity (i.e., peak oxygen consumption [VO2] and ventilatory anaerobic threshold [VAT]) and quality of life (QoL)., Background: Although the value of cardiac rehabilitation is now well established, the influence of the different program characteristics on outcome has received little attention, and the effect of frequency of exercise training is unclear. Functional capacity is regularly evaluated by peak VO2 but parameters of submaximal exercise capacity such as VAT should also be considered because submaximal exercise capacity is especially important in daily living., Methods: Patients with coronary artery disease (n = 130, 114 men; mean age 52 +/- 9 years) were randomized to either a high- or low-frequency program of six weeks (10 or 2 exercise sessions per week of 2 h, respectively). Functional capacity and QoL were assessed before and after cardiac rehabilitation. Global costs were also compared., Results: Compared with baseline, mean exercise capacity increased in both programs: for high- and low-frequency, respectively: peak VO2 = 15% and 12%, Wmax = 18% and 12%, VAT = 35% and 12% (all p < 0.001). However, when the programs were compared, only VAT increased significantly more during the high-frequency program (p = 0.002). During the high-frequency program, QoL increased slightly more, and more individuals improved in subjective physical functioning (p = 0.014). We observed superiority of the high-frequency program, especially in younger patients. Mean costs were estimated at 4,455 and 2,273 Euro, respectively, for the high- and low-frequency programs., Conclusions: High-frequency exercise training is more effective in terms of VAT and QoL, but peak VO2 improves equally in both programs. Younger patients seem to benefit more from the high-frequency training.

Aims: In patients with coronary artery disease acetylcholine (a muscarinic agonist) causes vasoconstriction. The effect of atropine (a muscarinic antagonist) on coronary vasotone in patients with normal or impaired left ventricular function is unknown., Methods and Results: Twenty-four patients who required atropine infusion (to supplement heart rate response) during atrial pacing (pacing was conducted to assess ischaemia as part of an experimental protocol) were studied; 17 patients had normal and seven impaired left ventricular function (ejection fraction < or =0.40). Two control groups were selected from a large database (from patients in whom atrial pacing was carried out but to whom atropine was not administered) to match the normal (n=20) and dysfunction (n=10) groups. In the normal left ventricular function group atropine increased rate pressure product by 12 +/- 4%, as compared to those without atropine (P < 0.05). Left ventricular end diastolic pressure increased less in the atropine group (+40 +/- 8% vs +78 +/- 6%;P < 0.05). Arterial norepinephrine increased similarly in both groups, but coronary flow (as assessed by using a thermodiluting method in the coronary sinus) increased 23 +/ -4% more in the atropine group (P < 0.05). Further, there were lower levels of myocardial lactate production and ST-segment depression in the atropine group [lactate extraction +13 +/- 6% (atropine) vs -19 +/- 4% (controls), ST-segment depression 1. 3 +/- 0.6 (atropine) vs 1.8 +/- 0.2 mm (control), both P < 0.05 between groups]. In contrast, in the dysfunction group the overall effect of atropine was less pronounced., Conclusion: In patients with normal left ventricular function atropine improves coronary flow and reduces myocardial lactate production and ST-segment depression during atrial pacing, suggesting a reduction in myocardial ischaemia., (Copyright 1999 The European Society of Cardiology.)

Long-term angiotensin-converting enzyme (ACE) inhibition may reduce ischemic events in patients with coronary artery disease, but whether it protects against acute ischemia or the effects of preexisting left ventricular (LV) dysfunction on potential anti-ischemic properties is unknown. We performed a double-blind trial in 25 patients with exercise-induced ischemia. The effects of perindoprilat on pacing-induced myocardial ischemia were examined. Fourteen patients received perindoprilat and 11 patients received placebo. Based on LV function, 2 subgroups were formed in the perindoprilat group: 7 patients with LV dysfunction (LV ejection fraction <0.40), and 7 patients with normal LV function. After receiving the study medication, the pacing test was repeated. During the first pacing test both groups developed ischemia. After perindoprilat administration, the increase in systemic vascular resistance and LV end-diastolic pressure were significantly blunted (p <0.05). Further, the ischemia-induced increase in arterial and cardiac uptake of norepinephrine was inhibited by perindoprilat, and the increase in atrial natriuretic peptide was less pronounced; also, ST-segment depression was reduced by 32% compared with placebo (all p <0.05). In the group with LV dysfunction, perindoprilat reduced LV end-diastolic pressure significantly by 67% and myocardial lactate production was prevented, but this did not happen in the group with normal LV function. In addition, the increase in arterial norepinephrine was reduced by 74% and 33%, respectively (p <0.05). These results indicate that perindoprilat reduced acute, pacing-induced ischemia in normotensive patients. In patients with (asymptomatic) LV dysfunction these effects were more pronounced than in patients with normal LV function.

Aims: Most studies in chronic heart failure have only included patients with marked left ventricular systolic dysfunction (i.e. ejection fraction < or =0.35), and patients with mild left ventricular dysfunction are usually excluded. Further, exercise capacity strongly depends on age, but age-adjustment is usually not applied in these studies. Therefore, this study sought to establish whether (age-adjusted) peak VO2 was impaired in patients with mild left ventricular dysfunction., Methods: Peak VO2 and ventilatory anaerobic threshold were measured in 56 male patients with mild left ventricular dysfunction (ejection fraction 0.35-0.55; study population) and in 17 male patients with a normal left ventricular function (ejection fraction >0.55; control population). All patients had an old (>4 weeks) myocardial infarction. By using age-adjusted peak VO2 values, a 'decreased' exercise capacity was defined as < or = predicted peak VO2 - 1 x SD (0.81 of predicted peak VO2), and a severely decreased exercise capacity as < or = predicted peak VO2 - 2 x SD (0.62 of predicted peak VO2)., Results: Patients in the study population (age 52+/-9 years; ejection fraction 0.46+/-0.06) were mostly asymptomatic (NYHA class I: n=40, 76%), while 16 patients (24%) had mild symptoms, i.e. NYHA class II. All 17 controls (age 57+/-8 years) were asymptomatic. Mean peak VO2 was lower in patients with mild left ventricular dysfunction (23.6+/-5.7 vs 27.1+/-4.6 ml x min(-1) x kg(-1) in controls, P<0.05). In 75% of the study population patients (n=42) age-adjusted peak VO2 was decreased (NYHA I/II: n=29/13) and in 18% of them severely decreased (n=10; NYHA I/II: n=6/4). In contrast, only three patients (18%) in the control population had a decreased and none a severely decreased age-adjusted peak VO2., Conclusion: In patients with mild left ventricular dysfunction, who have either no or only mild symptoms of chronic heart failure, a substantial proportion has an impaired exercise capacity. By using age-adjustment, impairment of exercise capacity becomes more evident in younger patients. Patients with mild left ventricular dysfunction are probably under-diagnosed, and this finding has clinical and therapeutic implications.

To assess the acute hemodynamic and long-term clinical effects of isradipine, a calcium antagonist of the dihydropyridine class, we performed a double-blind, placebo-controlled parallel study in 19 patients with coronary artery disease (CAD) and stable chronic heart failure (CHF). Their mean age was 56 +/- 5 years, and left ventricular ejection fraction (LVEF) was 0.18 +/- 0.05. Patients were treated with diuretics and digoxin only. All were clinically stable and in sinus rhythm. The acute hemodynamic study showed that (intravenous) isradipine increased cardiac index (+36%) and stroke volume index (+30%) (both P < 0.001), while systemic vascular resistance (-33%) and mean arterial pressure (-10%) decreased (both P < 0.005). Filling pressures and heart rate were not affected. Of the 19 patients, 17 completed the 12 week study; 2 patients on placebo (1 death, 1 side-effects) but no patient on isradipine (5 mg 3 times daily) dropped out. After 12 weeks, peak oxygen consumption (VO2), LVEF, echocardiographic indices, and other clinical parameters were unaffected by treatment. Repeat invasive hemodynamic measurements showed that the initial improvement by isradipine was not present anymore. In conclusion, despite a beneficial acute hemodynamic effect, isradipine has no favorable clinical influence during prolonged treatment in patients with mild to moderate CHF.

The present data show that HR variability has a statistically significant, but moderate, correlation with clinical variables of severity of CHF. Therefore, HR variability analysis may be a new, important tool in the clinical assessment of CHF patients.

To compare the value of the New York Heart Association (NYHA) classification and measurement of peak oxygen consumption (VO2) in the assessment of functional status and prognosis in patients with mild to moderate chronic congestive heart failure (CHF), 94 patients with clinically stable NYHA class II and III CHF were prospectively studied. In all patients, left ventricular ejection fraction was less than or equal to 40% (mean 22 +/- 9); 49 patients were in NYHA class II, and 45 were in NYHA class III. Mean peak VO2 was 17 +/- 5 ml/min/kg. During a follow-up period of 23 +/- 11 months, 21 patients died. The 1-, 2- and 3-year cumulative survival rates for the 94 patients were 88, 79 and 69%, respectively. Functional status, as assessed both by peak VO2 and NYHA classification, and left ventricular ejection fraction were significantly worse in the group of nonsurvivors. The most powerful independent predictor of mortality was peak VO2. Although mean peak VO2 was significantly higher in NYHA class II than in NYHA class III (20 +/- 4 vs 13 +/- 3 ml/min/kg, p less than 0.0001), categorization into subgroups on the basis of the attained peak VO2 revealed a marked discrepancy with the NYHA classification. Nevertheless, the survival curves of patients subdivided at a peak VO2 of 16 ml/min/kg showed a strong resemblance with survival curves of both NYHA classes.(ABSTRACT TRUNCATED AT 250 WORDS)

The article presents a double-blind study on chronic heart failure (CHF) patients to determine the effects of carvedilol on plasma vascular endothelial growth factor (VEGF). It states that carvedilol or placebo were given randomly to patients, who were treated based on an uptitration schedule. Results show the benefits of beta-blockers in ischemic heart disease (IHD) and CHF. It concludes that CHF patients using carvedilol had increased VEGF.

The effect of beta blockade on heart rate in patients with either idiopathic or ischemic cardiomyopathy was studied. It was found that beta blockade reduced the early morning increase in heart rate to a greater extent in patients with idiopathic dilated cardiomyopathy than in those with ischemic dilated cardiomyopathy. [ABSTRACT FROM AUTHOR]