Statins reduce mortality of patients with coronary artery disease (CAD). However, by protocol, trials have excluded patients with chronic heart failure. Since the prevalent etiology of heart failure is CAD, preventing CAD may prevent heart failure progression. Statins may have other beneficial effects besides cholesterol lowering, such as anti-inflammatory properties and improvement of endothelial function. On the contrary, high levels of cholesterol can be beneficial in heart failure patients on the basis of the ability of serum lipoproteins to modulate inflammatory response. Furthermore, statins affecting mitochondrial function can have a deleterious effect on skeletal or cardiac muscles. Despite all these conflicting data, there is no evidence from trials on the effects of statins in patients with heart failure. For this reason, the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI) investigators planned a controlled trial testing the effect of statins in patients with heart failure of different etiology.

Treatment to prevent progression of heart failure has been targeted to reverse the consequences of heart failure and to a lesser extent the cause – the atherosclerotic plaque itself. Less than 50% of patients with heart failure are treated with lipid intervention. Heart failure (New York Heart Association [NYHA] functional classes I and II) is associated with an increase in low-density lipoproteins (LDL) and triglycerides while high-density lipoproteins (HDL) is lowered. In NYHA class IV, cholesterol is reduced due to depressed production in the liver. Although lipoproteins, especially LDL and HDL, may have some protective effect in binding and neutralising endotoxins released from the intestine during terminal heart failure, observational studies in patients with heart failure strongly suggest that lipid modification with statins may reduce progression of heart failure as well as reducing heart failure mortality.

The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study was the first trial to assess whether statins might be of clinical benefit in those with recently unstable coronary disease. MIRACL found that high-dose atorvastatin was safe and reduced the incidence of the composite endpoint, death, non-fatal myocardial infarction, resuscitated sudden cardiac death or emergent rehospitalization for recurrent ischemia at 16 weeks when compared with placebo. Despite a number of important study limitations, MIRACL's findings and the prior observation that inpatient initiation of lipid-lowering therapy is associated with higher rates of subsequent utilization, suggest that it is prudent to begin statin therapy when patients present with an acute coronary syndrome.

The Myocardial Ischemia Reduction with Acute Cholesterol Lowering (MIRACL) Trial tested the hypothesis that intensive lowering of cholesterol with atorvastatin (80 mg/day) initiated 24-96 h after an acute coronary syndrome would, over 4 months, reduce the incidence of the composite endpoint of death, nonfatal infarction, resuscitated cardiac arrest, and recurrent symptomatic myocardial ischemia with new objective symptoms requiring emergency rehospitalization. This primary composite endpoint was reduced from 17.4% to 14.8% (P = 0.048) among the 3086 patients enrolled. The results of MIRACL suggest that patients with acute coronary syndromes should begin to receive this treatment before leaving hospital, irrespective of baseline levels of low-density lipoprotein-cholesterol.

Background Doxazosin and its role as an antihypertensive agent have come under recent scrutiny as a result of the early termination of that treatment arm in ALLHAT. It is unclear why the cardiovascular (CV) event rate in this randomized, controlled trial (RCT), especially heart failure, is higher in those treated with a doxazosin-based regimen than with a chlorthalidone based-regimen. There has been little work in the past to summarize information on peripheral alpha-1 antagonists that may be helpful in evaluating the results of this randomized controlled trial. Methods Using Medline and the Cochrane databases, we performed a comprehensive review of the literature on the use of peripheral alpha-1 antagonists as antihypertensive agents, focusing on available information that could explain the excess cardiovascular events observed in the Antihypertensive and Lipid-Lowering Treatment to prevent Heart Attack Trial (ALLHAT). Results Minimal data were available concerning the effects of peripheral alpha-1 antagonists on CV endpoints. A multitude of short-term studies-ranging from small observational studies to short-term moderate-sized RCTs – focused on safety, efficacy, and tolerability, and some studies investigated the physiologic effects of these agents. These previously reported studies reveal associations with weight gain, fluid retention, and neurohormonal changes among various populations of those treated with peripheral alpha-1 antagonists. Conclusion These findings suggest several possible mechanisms by which doxazosin may be inferior to low-dose diuretics as antihypertensive therapy for the prevention of heart failure.

Research Article: Current Controlled Trials in Cardiovascular Medicine

Of the associations between dietary elements and coronary artery disease (CAD), the greatest body of evidence deals with the beneficial effect of reducing the dietary intake of saturated fatty acids and cholesterol. Furthermore, it is well established, on the basis of convincing evidence, that reduction in serum total cholesterol results in reduction in coronary morbidity and mortality, as well as in regression of other atherosclerotic manifestations.In fact, dietary intervention studies revealed that it is possible to reduce the incidence of coronary death and nonfatal myocardial infarction, as well as manifestations of atherosclerosis in cerebral and peripheral arteries, by reducing dietary intake of saturated fat and cholesterol. In two recently reported dietary interventions the incidence of coronary events, especially coronary mortality, and total mortality were reduced by increased intake of n-3 long-chain polyunsaturated fatty acids and by a modification of the diet toward a Mediterranean-type diet (rich in α-linolenic acid. In addition to those findings, the potential efficacy of the dietary newcomers phytostanol and phytosterol esters on reducing coronary incidence is discussed in the present review.

The importance of low-density lipoprotein (LDL) control in the management of patients at high risk of cardiovascular events is unquestionable. The major statin trials have shown that the benefits of LDL lowering extend throughout the range of risk and the range of serum cholesterol, and have indicated that the protective effects of the intervention are mostly related to the baseline risk. Statin therapy is, for this reason, currently seen as an anti-atherogenic approach for the majority of high risk individuals and possibly all coronary heart disease patients. This debate is not about the value of statin therapy or the importance of LDL reduction, but about the goals to be set once we decide that LDL cholesterol must be reduced. With the National Cholesterol Education Program (NCEP) guidelines representing a solid middle ground, the two viewpoints in this debate try to argue, on one hand, that the LDL goals should be substantially lower than our current standards or, on the other, that a specific on-treatment LDL value may not be the most important goal to pursue. We defend the latter position by presenting the case that the most effective LDL intervention in high risk patients is to achieve a reduction of at least 30%. This strategy complies with the NCEP guidelines, as most of the high risk patients treated with an average dose of an average statin would experience a 30-40% LDL reduction that would put on-treatment LDL levels safely below goal. Our position differs from both the guidelines and the proponents of more aggressive LDL goals in the management of the two extremes of the cholesterol distribution, where our lack of interest in a predefined on-treatment LDL concentration would make us more aggressive than guidelines on low baseline LDL patients and less aggressive than guidelines on high baseline LDL patients.

The use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) to reduce serum cholesterol is well described. However, the recent finding that statins have direct effects on bone was unexpected. A number of epidemiological studies have recently been published that explore the effects of statins on bone mineral density and risk of fracture in humans. Statins may act by directly stimulating the expression of bone morphogenetic protein-2 and increasing osteoblast differentiation or, like nitrogen-containing bisphosphonates, may have effects on the mevalonate pathway that leads to inhibition of osteoclast activity and osteoblast apoptosis. In addition, the demonstration that statins can inhibit inflammation and encourage angiogenesis offers other possibilities for action.