Alpha-1 adrenoceptor-angiotensin II type 1 receptor cross-talk and its relevance in clinical medicine.

The two most relevant clinical trials investigating the efficacy of multiple neurohormonal drug combinations in the treatment of chronic congestive heart failure are the Valsartan Heart Failure Trial and the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity-added studies. The Valsartan Heart Failure Trial study randomized patients with congestive heart failure to the angiotensin receptor blocker (ARB) valsartan versus placebo, in addition to baseline angiotensin-converting enzyme inhibitor (ACE-I) therapy. Overall, valsartan was found to significantly reduce the combined morbidity and mortality end point compared with placebo, mainly due to a reduction in heart failure admissions. However, a subgroup analysis showed that patients receiving triple therapy with valsartan, an ACE-I and a ß-adrenoceptor blocker, appeared to do worse. These findings led to speculation that "triple therapy" with ARB, ACE-I, and nonselective ß-blocker might be harmful, possibly due to excessive neurohormonal inhibition. In contrast, in the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity-added study, the "triple therapy" combination of ARB, ACE-I, and ß-adrenoceptor blocker was proven safe and beneficial. We propose that the discrepancy in outcomes observed in these two trials is related to the interaction between the α1-adrenoceptor and the angiotensin II type-1 receptor, and it is not just an inherent adverse event related to "triple therapy."

Statin-mediated low-density lipoprotein lowering in chronic congestive heart failure.

Many theories and clinical trials have attempted to address the effect of low-density lipoprotein (LDL) lowering in chronic congestive heart failure (CHF). The current evidence suggests that there is no convincing reason for administering statins to patients with nonischemic heart failure. Although they do not reduce the mortality rate, statins reduce LDL cholesterol and may provide some benefit to patients with ischemic heart failure. In contrast, some authors believe that statin therapy may actually worsen outcomes in patients with CHF, especially if there is excessive reduction in LDL cholesterol. This review discusses the theories attempting to link the adverse effects of statin-mediated LDL lowering in CHF to increased levels of endotoxin or reduced levels of coenzyme Q10. In addition, the 2 largest randomized, double-blind, placebo-controlled clinical trials (CORONA and GISSI-HF) were discussed. It is clear that more trials are needed to definitely ascertain the effect of statins on CHF.

Low-density lipoprotein levels in patients with acute heart failure.

Statins do not appear to have a significant benefit in heart failure (HF) as they do in coronary artery disease (CAD). Significant evidence exists that low serum cholesterol levels may be harmful in HF. This study sought to determine the optimal low-density lipoprotein (LDL) level in patients hospitalized with acute HF. Patients were included if they presented to the hospital with acute HF and had a lipid panel drawn during admission. The primary outcome was all-cause mortality, and secondary outcomes were rates of major cardiovascular (CV) events, left ventricular assist device (LVAD) implantation, and orthotopic heart transplantation (OHT). A total of 2428 patients were followed for a mean of 2.9±2.2 years. For the entire cohort, when compared with those with LDL levels >130 mg/dL, all-cause mortality was higher in those with LDL levels <71 mg/dL (hazard ratio, 1.68; 95% confidence interval, 1.31-2.167; P<.01). Results were similar when analyzing patients with LVEF ≤40%, HF of ischemic etiology only, and in statin users. The rates of CV events, LVAD implantation, or OHT in any comparison did not differ. Low LDL levels (<71 mg/dL), similar to low total cholesterol levels, were associated with a poorer prognosis and higher overall mortality in patients with HF, regardless of etiology and systolic function.

Evolution of the chronic congestive heart failure paradigm.

Paradigms are a part of our human nature. In the world of medicine and science, they allow investigators to work within a particular, previously accepted framework that provides certain constraints. This is the crux of Newton's quote, "If I've seen so far it's because I stood upon the shoulders of giants." However, in the same way that it allows us to build, it can constrain our thought processes if we fail to accept new data that are ill suited to an accepted paradigm. The physiological mechanisms to explain the phenomenon of chronic congestive heart failure are similar to other paradigms of science, in that they have undergone several shifts throughout their history, and continue to change with new evidence. Here, we seek to explore how our understanding of congestive heart failure has changed.

The neurohormonal network in the RAAS can bend before breaking.

The renin-angiotensin-aldosterone system (RAAS) has evolved in humans as one of the main physiological networks by which blood pressure and blood flow to vital organs is maintained. The RAAS has evolved to circumvent life-threatening events such as hemorrhage and starvation. Although short-term activation of this system had been well suited to counteract such catastrophes of early man, excessive chronic activation of the RAAS plays a fundamental role in the development and progression of cardiovascular disease in modern man. The RAAS is an intricate network comprising a number of major organ systems (heart, kidney, and vasculature) and signaling pathways. The main protagonists are renin, angiotensinogen (Ang), angiotensin I (Ang I), angiotensin II (Ang II), and aldosterone (Aldo). The study and delineation of each of these substances has allowed modern medicine to create targets by which cardiovascular disease can be treated. The main modulators that have been synthesized in this respect are angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor blockers (MRBs), and direct renin inhibitors (DRIs). Over the past few decades, each of these substances has proven efficacious to varying degrees amongst a number of clinical settings. Additionally, there exists data for and against the use of these agents in combination. The use of these agents in combination poses a larger question conceptually: can excessive pharmacological inhibition of the RAAS lead to patient harm? This perspective will examine the concept of a neurohormonal inhibition ceiling in pertinent experimental and clinical trials.

An update on diastolic dysfunction.

Diastolic dysfunction refers to abnormal diastolic filling properties of the left ventricle regardless of whether systolic function is normal or the patient has symptoms. Diastolic heart failure (HF), or more accurately, HF with preserved systolic function, is a distinct clinical entity characterized by the presence of the triad of impaired diastolic function, normal systolic function (left ventricular ejection fraction > 50%), and symptoms of HF. Patients with HF with preserved systolic function are frequently symptomatic from both acute and chronic elevations in left ventricular end-diastolic pressure and/or left atrial pressure.

A perspective on obesity cardiomyopathy.

SUMMARY: Obesity is a major health concern worldwide as obese individuals have a greater risk of death from any cause than normal-weight individuals. As the number of overweight children and adolescents continues to rise, so too has the scope of the obesity epidemic grown substantially. In this article, the authors discuss the role of obesity in the development of heart failure and the pathophysiology of obesity cardiomyopathy, as well as explore the potential role of bariatric surgery and mechanical circulatory support devices (MCSD) as potential therapeutic targets.:

Pathophysiology and treatment options for cardiac anorexia.

The anorexia-cachexia syndrome (ACS) occurs in many chronic illnesses, such as cancer, AIDS, and chronic obstructive pulmonary disease in addition to chronic congestive heart failure (CHF). Comparable to other chronic states, the ACS complicates CHF and impacts its prognosis; however, the available treatment options for this syndrome remain unsatisfactory. This review article focuses on the complex pathophysiology of cardiac anorexia. We focus on the recent data demonstrating the relationships between central appetite-regulating structures, inflammatory processes, and neurohormonal activation, and their respective roles in the development of anorexia. We then describe the different treatment options and discuss some future prospects for the management for cardiac anorexia.

Association between off-label use of drug-eluting stents and subsequent stent thrombosis: a case-control analysis.

OBJECTIVES: We sought to examine the association between off-label drug-eluting stent (DES) use and stent thrombosis (ST) in unselected patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: DES are frequently used in clinical and angiographic scenarios not initially tested and approved by the FDA (off-label use) resulting in lingering concerns about the higher risk of ST in these situations. METHODS: Out of 5,383 patients undergoing PCI at a single center between 2004 and 2006, 380 had death or myocardial infarction within 1 year. After adjudication using Academic Research Consortium definitions, patients with possible, probable or definite ST were termed cases. Cases were matched with controls, free of ST at 1 year, using geographic and temporal similarities. Off-label usage was defined using manufacturer's instructions and other standard criteria. RESULTS: Overall, the proportion of off-label usage was higher among cases than controls (58% vs. 43%; p = 0.002) and both cases with definite/probable ST (77% vs. 59%; p = 0.08) and possible ST (54% vs. 37%; p = 0.002) had a higher off-label use than respective controls. Off-label use among cases with ST remained higher within the following subgroups: off-label by manufacturer's criteria (36% vs. 27%; p = 0.05), left main stent implantation (2% vs. 0%; p = 0.01), ostial (12% vs. 6%; p = 0.04) and bifurcated lesions (26% vs. 9%; p < 0.001). In multivariate analysis, being a case independently predicted off-label use (OR 1.68, 95% CI: 1.10-2.57; p = 0.02). CONCLUSIONS: In this case-control analysis, off-label use of DES was independently associated with ST within 1 year, although the increased risk was moderate.