Investigations of statins in heart failure: inflammatory biomarkers and hormones

The primary role of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) is to treat dyslipidemia. The clinical benefits with statin therapy have been demonstrated in the primary and secondary prevention of atherosclerotic vascular diseases. More recently, it has been observed that pleiotropic effects of statins (which may or may not be associated with lipid lowering) have been described as treatment of various cardiovascular disease processes and in noncardiac disease processes. This article evaluates the potential mechanisms for these effects in the management of heart failure and postulates their clinical and beneficial use.     

Pleiotropic effects: Should statins be considered an essential component in the treatment of dyslipidemia?

Cardiovascular disease (CVD) is the leading cause of death in the developed world. Lower risks of morbidity and mortality in trials of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) have changed the conventional wisdom regarding lipid lowering. Since 2001, there have been surprising results concerning the early benefits of stain therapy, which suggest that some benefits may be derived from effects other than those of simply improving dyslipidemias. The earlier than expected CVD benefits from statin trials have led to the theory that statins have effects other than, or concomitant to, the benefits on serum lipid levels, and that these effects may be at least partly responsible for their early and often significant reduction in CVD risk. These have been defined as pleiotropic effects. Possible means by which statins reduce CVD risk independent of their lipid regulation may include antithrombotic and anti-inflammatory effects, antioxidation, plaque stabilization, and endothelial wall relaxation resulting in lower intra-arterial pressure and increased blood flow.     

The evolving role of statins in the management of atherosclerosis

Significant advances in the management of cardiovascular disease have been made possible by the development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors--"statins." Initial studies explored the impact of statin therapy on coronary artery disease (CAD) progression and regression. Although the angiographic changes were small, associated clinical responses appeared significant. Subsequent large prospective placebo-controlled clinical trials with statins demonstrated benefit in the secondary and primary prevention of CAD in subjects with elevated cholesterol levels. More recently, the efficacy of statins has been extended to the primary prevention of CAD in subjects with average cholesterol levels. Recent studies also suggest that statins have benefits beyond the coronary vascular bed and are capable of reducing ischemic stroke risk by approximately one-third in patients with evidence of vascular disease. In addition to lowering low-density lipoprotein (LDL) cholesterol, statin therapy appears to exhibit pleiotropic effects on many components of atherosclerosis including plaque thrombogenicity, cellular migration, endothelial function and thrombotic tendency. Growing clinical and experimental evidence indicates that the beneficial actions of statins occur rapidly and yield potentially clinically important anti-ischemic effects as early as one month after commencement of therapy. Future investigations are warranted to determine threshold LDL values in primary prevention studies, and to elucidate effects of statins other than LDL lowering. Finally, given the rapid and protean effects of statins on determinants of platelet reactivity, coagulation, and endothelial function, further research may establish a role for statin therapy in acute coronary syndromes.     

Statins as Adjunctive Therapy in the Management of Hypertension

The effective optimization of the modifiable risk factors for the development of atherosclerosis is the cornerstone preventive cardiology. Risk factor clustering has been demonstrated to occur in a higher prevalence than would be expected by chance alone. The common cardiovascular risk factors frequently share metabolic pathways. Inflammation and oxidative stress are demonstrable in the major cardiovascular risk factors. Hypertension and dyslipidemia frequently co-exist in an individual. The advent of statin therapy has allowed optimization of the lipid profile and achievement of therapeutic goals advocated by the Adult Treatment Panel of the National Cholesterol Education Program. Statin therapy has been demonstrated to exhibit a wide variety of nonlipid or pleiotropic effects. Observational studies have demonstrated that statin therapy may cause a small but statistically significant alteration of blood pressure. Prospective clinical trials have demonstrated that statin therapy reduces this cardiovascular risk in both hypertensive and normotensive individuals. The potential role of statin therapy in blood pressure reduction is compatible with several pleiotropic mechanisms of statin therapy. However, a significant body of data from prospective, well-designed, controlled clinical trials that have analyzed the effect of statin therapy on blood pressure as the primary end point is lacking. This review examines the observational relationship between hypertension and dyslipidemia, the potential mechanisms by which statin therapy may lower blood pressure, and selected clinical trial data.     

Statins and coronary artery disease: clinical evidence and future perspective

Many clinical trials have demonstrated the beneficial effects of statins on cardiovascular risk, both in patients with history of coronary heart disease and in healthy subjects with risk factors, because of a significant reduction in acute coronary events. The introduction of more powerful statins in the market offered the opportunity to study whether an intensive lipid lowering treatment could yields even better cardiovascular outcomes than a moderate statin therapy and several clinical trial confirmed this hypothesis. Statins have also pleiotropic effect behind their lipid lowering function: they reduce inflammation, which plays an important role in the atherosclerotic process.     

Statin therapy in heart failure: prognostic effects and potential mechanisms

The use of statins as therapy for heart failure remains controversial. Nevertheless, many of the pleiotropic effects of statins are potentially applicable in heart failure. Although early statin trials excluded patients with heart failure because of concerns that lowering serum cholesterol could worsen an already poor prognosis, statin treatment has not been shown to have adverse effects on either cardiovascular events or mortality, and recent experimental and clinical studies have shown promise of benefit. Two large, ongoing trials should provide definitive evidence of the value of statin therapy for patients with heart failure. Pending those results, it is reasonable to follow current National Cholesterol Education Program guidelines in this high-risk population.     

Statins in acute coronary syndromes

Statins are the main resource available to reduce LDL-cholesterol levels. Their continuous use decreases cardiovascular morbidity and mortality due to atherosclerosis. The administration of these medications demonstrated to be effective in primary and secondary prevention clinical trials in low and high risk patients. Specialists believe that a possible benefit of hypolipidemic therapy in preventing complications of atherosclerotic diseases is in the reduction of deposition of atherogenic lipoproteins in vulnerable areas of the vasculature. Experimental studies with statins have shown an enormous variety of other effects that could extend the clinical benefit beyond the lipid profile modification itself. Statin-based therapies benefit other important components of the atherothrombotic process: inflammation, oxidation, coagulation, fibrinolysis, endothelial function, vasoreactivity and platelet function. The demonstration of the effects that do not depend on cholesterol lowering or the pleiotropic effects of statins provides the theoretical basis for their potential role as adjunctive therapy in acute coronary syndromes. Retrospective analyses of a variety of studies indicate the potential benefit of statins during acute coronary events. Recent clinical studies have addressed this important issue in prospective controlled trials showing strong evidence for the administration of statins as adjunctive therapy in acute coronary syndromes.     

Beyond lipid lowering: the role of statins in vascular protection

The introduction of the hydroxy methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in 1987 was a major advance in the prevention and treatment of cardiovascular disease. Several landmark clinical trials have demonstrated the benefit of lipid lowering with statins for the primary and secondary prevention of coronary heart disease (CHD), namely The Scandinavian Simvastatin Survival Study (4S), Cholesterol And Recurrent Events (CARE), Long-term Intervention with Pravastatin in Ischemic Disease (LIPID), West of Scotland Coronary Prevention Study (WOSCOPS) and Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Although it is widely accepted that the majority of clinical benefit obtained with statins is a direct result of their lipid-lowering properties, these agents appear to display additional cholesterol-independent or pleiotropic effects on various aspects of cardiovascular disease, including improving endothelial function, decreasing vascular inflammation and enhancing plaque stability. Although the full impact of statin therapy on each of these processes is not fully understood, ongoing studies with current and new statins are likely to shed further light on the potential cholesterol-independent benefits of these agents.     

New insights in the treatment of dyslipidemia: A focus on cardiovascular event reduction and the antiatherosclerotic effects of atorvastatin

The identification and treatment of dyslipidemia is a critical component of ongoing efforts to reduce the incidence of atherosclerotic disease in both men and women. Several recent large-scale atorvastatin trials provide a plethora of information that expands the current body of literature describing the pathophysiology of cardiovascular disease and the prevention of acute cardiovascular events. These trials demonstrate the benefit of statin therapy in a broad variety of patient populations, explore the clinical efficacy of more intensive statin regimens, and suggest that the pleiotropic effects of statins may contribute to cardiovascular endpoint reduction. In addition, these studies have challenged whether current guidelines for low-density lipoprotein cholesterol levels provide optimal risk reduction for cardiovascular events. Additional studies with atorvastatin are underway to further explore the extent to which statins can provide cardiovascular benefits.     

Current questions regarding the use of statins in patients with coronary heart disease

The discovery of statins caused a revolution in the field of lipid intervention. Statins are drugs with a good safety profile. Their clinical benefit has been extensively documented in primary and secondary prevention of coronary heart disease. There is substantial evidence that the clinical outcome can be improved with aggressive statin treatment both in patients with unstable as well as with stable coronary heart disease. Also, early administration of statins in acute coronary syndromes is accompanied by rapid clinical benefits, mainly through their "pleiotropic" action (anti-inflammatory, anti-thrombotic, improvement of endothelial function, etc) which is probably a lipid-independent effect. Moreover, emerging data indicate that statins can achieve additional benefit when low density lipoprotein (LDL) cholesterol reduction is coupled with C-reactive protein reduction (<2 mg/L). The prevailing message from the recent statin trials is that intensive LDL cholesterol lowering treatment with statins achieves further clinical benefit beyond that achieved with standard statin therapy. This should encourage the medical community to consider prescribing statins in every coronary patient, aiming at LDL cholesterol levels <100 mg/dL, preferably in the range of 70-80 mg/dL in stable coronary patients, while in coronary patients at very high risk, the optional target for LDL cholesterol levels should be in the range of 50-70 mg/dL.     

Adjunctive interventions in myocardial infarction: The role of statin therapy

Statin therapy has reduced cardiovascular morbidity and mortality across the spectrum of atherosclerosis. The administration of statins has been demonstrated to be effective in primary and secondary prevention clinical trials evaluating patients with high and low risk-factor profiles. The presumed mechanism of benefit of hypolipidemic therapy in the prevention of atherosclerotic disease was a reduction in the deposition of atherogenic lipoproteins in vulnerable areas of the coronary vasculature. Subsequent experimental studies with statins demonstrated a variety of potentially beneficial effects that would extend clinical benefit beyond lipid-lowering per se. Statin therapy beneficially alters inflammation, coagulation and fibrinolytic parameters, endothelial function, vasoreactivity, and platelet function. The demonstration of the non-lipid or pleiotropic effects provided the theoretical basis for a possible role as an adjunctive therapy in acute coronary syndromes. Retrospective analysis of a variety of early trials indicated a potential benefit of statins during acute ischemic syndromes. Recent clinical trials have addressed this important clinical question in a prospective controlled manner. The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) and the Thrombolysis In Myocardial Infarction (TIMI)-22 studies present strong clinical evidence in favor of the administration of statins as adjunctive therapy in acute ischemic syndromes.     

The Use of Fibric Acid Derivatives in Cardiovascular Prevention

Clinical trials have demonstrated the benefit of reduction of low-density lipoprotein (LDL) cholesterol levels in the prevention of atherosclerotic cardiovascular disease. Evidence is less robust for the effect of reduction of triglyceride levels and increase of high-density lipoprotein (HDL) cholesterol levels. In spite of the decrease of cardiovascular events in trials of LDL cholesterol–lowering medications, considerable residual risk remains, even with the use of high-dose statins. The fibric acid derivatives or fibrates reduce triglyceride and increase HDL cholesterol levels, effects that would be expected to affect cardiovascular events. However, clinical outcomes trials with fibrates have shown mixed results. Post-hoc analyses of fibrate trials as well as several meta-analyses suggest an overall decrease in primarily non-fatal coronary events without decrease in total mortality. The effects are most apparent in patients with elevated triglycerides and low HDL cholesterol levels. Statin therapy is the treatment of choice for most patients with dyslipidemia. The addition of a fibrate appears to be most beneficial in high-risk patients who continue to have significant dyslipidemia on statin therapy, most notably patients with diabetes mellitus or the metabolic syndrome. Thus, fibrates are not first-line drugs, but they do have a place in the management of the atherogenic lipid profile.     

The role of statins in preventing stroke

Epidemiological studies have not demonstrated a clear relationship between stroke risk and hypercholesterolemia. Clinical trials using statins have demonstrated a reduction in stroke, in particular, in patients with established coronary artery disease. The disparity between epidemiological and clinical studies suggests hypercholesterolemia is a true risk factor for stroke that evaded detection in epidemiological studies, or that statins possess other properties that render them useful in stroke prevention. These effects have been loosely termed "pleiotropic" in the lipid literature and revolve around putative effects of statins on endothelial function, inflammation, thrombosis, plaque stability, and immune regulation. Questions remain as to the mechanisms of benefit of statin therapy in stroke prevention, the role of statins in the primary prevention of stroke, and the role of statins in modulating the immune system in the brain.     

Pathological Changes in Acute Coronary Syndromes: The Role of Statin Therapy in the Modulation of Inflammation,Endothelial Function and Coagulation

Considerable progress has been made in our understanding of the pathophysiology of coronary artery disease (CAD), their acute presentations as acute coronary syndromes (ACS) and the role of LDL cholesterol. In particular there is clear evidence that atherosclerosis is far from being a process that leads to an amorphous flow limiting lesion on an angiogram, but rather involves a complex interplay between the endothelium, inflammatory cells and the coagulation cascade occurring throughout the coronary vascular bed. While a culprit flow limiting lesion may be effectively treated by a drug eluting stent or coronary bypass surgery, this will have little impact on the global molecular processes that determine recurrent plaque instability at non-culprit sites. The search for systemic long term therapy, which is safe and effective and reduces the changes in inflammation, endothelial function and thrombosis that are the hallmark of ACS, has pushed statins to the forefront. A number of recent clinical trials have shown the benefits of early statin therapy in the treatment of ACS. In addition to their effects on LDL cholesterol, statins have a number of properties collectively referred to as pleiotropic effects, which enable them to modulate the adverse biological changes that are associated with ACS. The purpose of this review is to acquaint the reader with the biological changes that accompany ACS, highlight how these pathways may be modulated for clinical benefit by statins and identify potential novel targets for future therapy.Abbreviated abstract. Acute coronary syndromes are associated with pathological changes in inflammation, endothelial function, and coagulation, and many of these are attenuate by statins in a lipid independent manner. In light of recent clinical trials showing the early benefit of statin therapy in ACS, this review discusses how the pleiotropic effects of statins may result in early clinical benefit.     

The role of statins in clinical medicine--LDL--cholesterol lowering and beyond

In the past years, statins have emerged as the most important class of lipid lowering agents. Through inhibition of HMG-CoA reductase, they restrict the rate-limiting step of cholesterol synthesis, which leads to upregulation of LDL receptors on the cell membrane and thus reduction of atherogenic LDLs. This effect translates into clinical benefit by reducing cardiovascular events both in primary and secondary prevention settings. As an approximate rule, statin therapy leads to a relative risk reduction of 25-30% in most of the large randomised controlled trials. Stroke risk is reduced to a similar degree. Despite initial concerns, the currently available statins have a favourable safety profile; however, potential interactions with other drugs must be considered. Recently, characteristics unrelated to LDL lowering have been intensively studied. These pleiotropic statin effects result from decreased levels of isoprenoid intermediates of cholesterol synthesis. They include--among others--anti-inflammatory, anti-proliferative, and immunomodulatory actions. Pleiotropic effects favourably influence pathomechanisms of plaque formation. Furthermore, they may prove beneficial in the prevention or treatment of diseases unrelated to atherosclerosis, eg rheumatoid arthritis, multiple sclerosis, or cancer.     

Cholesterol-independent effects of statins and new therapeutic targets: ischemic stroke and dementia

The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or "statins", are used as cholesterol-lowering agents worldwide. Statins inhibit cholesterol biosynthesis, leading to enhanced uptake of low-density lipoprotein (LDL) from the circulation via LDL receptors. This strong cholesterol-lowering action contributes to the beneficial effects of statins. For example, large clinical trials have demonstrated that statins significantly reduce cardiovascular risk. Recent research has shown that statins have other multiple actions involved in endothelial function, cell proliferation, inflammatory response, immunological reactions, platelet function, and lipid oxidation. These "pleiotropic actions" of statins probably provide a significant contribution to the reduction of cardiovascular events. This review summarizes the pleiotropic actions of statins in both basic and clinical studies. It also considers the potential for statin therapy in the treatment of stroke and dementia.     

Low-density lipoprotein in the setting of congestive heart failure: Is lower really better?

Hypercholesterolemia is a risk factor for coronary artery disease (CAD), CAD mortality, and incident heart failure (HF). Lipid-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has been shown to reduce the risk of developing HF in patients with CAD. However, in patients with chronic established HF, hypercholesterolemia has not been associated with an increased risk of mortality. Several studies have demonstrated that higher lipid and lipoprotein levels, including total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides, are associated with significantly improved outcomes in HF of both ischemic and nonischemic etiologies. In light of the association between high cholesterol levels and improved survival in HF, statin or other lipid-lowering therapy in HF remains controversial. To date, large outcome trials of statin therapy in HF of multiple etiologies have not demonstrated mortality benefit.     

Chronic kidney disease and statins: Improving cardiovascular outcomes

The burden of chronic kidney disease (CKD) continues to increase worldwide. Patients with CKD are at greater risk of mortality from cardiovascular events than end-stage renal disease. This review describes the pathogenesis of dyslipidemia in CKD patients and the role of statins in reducing coronary heart disease morbidity and mortality. The major clinical trials with statins in CKD patients are reviewed along with a discussion of statin safety. Although statin dosing and safety in patients with early CKD (Stage I or II) are similar to those of the general population, dose adjustments are required in advanced CKD (Stages III–V) due to differences in statin pharmacokinetics and renal excretion. Although the use of statins to reduce cardiovascular events in patients with mild to moderate CKD is strongly supported by existing clinical trials, no clinical benefit has been demonstrated in two large clinical trials involving hemodialysis patients.     

New and emerging data from clinical trials of statins

Recent clinical trials of statins have clearly demonstrated the benefit of statin therapy in preventing both coronary and cerebral vascular events. These benefits have been demonstrated to be present without reference to older age, sex, or comorbid conditions, including hypertension and diabetes. Future trials will test the value of more aggressive low-density lipoprotein cholesterol lowering, the value of immediate statin intervention during acute coronary syndromes, the role of cholesterol lowering with or without angioplasty, and the role of cholesterol lowering in stroke prevention.