CETP Inhibition: Does the Future Look Promising?

Based on epidemiologic studies conducted throughout the world, it is established that there is an inverse relationship between high-density lipoprotein cholesterol (HDL-C) and risk for coronary artery disease (CAD). The incidence of low HDL-C is high and increasing throughout the world. A variety of pharmacologic approaches are being developed to therapeutically modulate serum levels of HDL-C. One controversial approach to this is the use of molecules that inhibit the activity of cholesteryl ester transfer protein (CETP), an enzyme involved in neutral lipid transfer between lipoproteins. The inhibition of CETP can lead to substantial elevations in HDL-C. Based on a number of considerations, including the complex relationship between loss of function mutations in CETP and risk for CAD and the clinical experience with torcetrapib, it is difficult to predict if CETP inhibition will be associated with reductions in rates of atherosclerosis disease progression and risk for cardiovascular events.     

INTERMACS and MedaMACS: How Will They Guide Future Therapy?

The INTERMACS registry has played a central role in the evolving field of device therapy for advanced heart failure (HF). This nationwide, prospective registry of approved assist devices has defined the boundaries of mechanical support, tracked the evolution from pulsatile to continuous flow, developed new profiles for advanced HF, and standardized adverse event definitions. INTERMACS has guided current therapy and in the future will do so aided by new insights from MedaMACS, a parallel registry of medically-managed ambulatory patients with advanced HF. Together INTERMACS and MedaMACS will leverage the power of observation research to guide patient-centered decisions about mechanical circulatory support.     

CETP Inhibitors: Will They Live up to Their Promise?

Cholesterol ester transfer protein (CETP) exchanges lipids between circulating plasma lipoproteins and has been considered as an excellent drug target for raising plasma levels of high-density lipoprotein (HDL) cholesterol. However, HDL displays considerably more complexity than low-density lipoprotein (LDL) in terms of structure, proteomics, and several physiologic functions. After the discouraging results from clinical trials of torcetrapib (an early inhibitor of CETP that dramatically raised HDL cholesterol levels), there is renewed hope that dalcetrapib and anacetrapib are sufficiently different structurally and functionally to justify large-scale clinical end point studies. In fact, such trials are already underway in the case of dalcetrapib and are imminent in the case of anacetrapib. These end point trials will show whether CETP inhibition will live up to its promise for atheroprotection.     

HDL cholesterol in cardiovascular diseases: The good,the bad,and the ugly?

Atherosclerotic cardiovascular diseases are the leading cause of death in developed and developing countries. HDL-raising therapeutic modalities (such as cholesterol ester transferase protein (CETP) inhibitors) are being developed to combat these diseases. However, recent setback of two CETP inhibitors (Torcetrapib and Dalcetrapib) has highlighted the importance of measuring qualitative functionality of HDL particles, rather than focusing quantitatively on HDL cholesterol serum concentrations. It has been known that, HDL from patients with coronary artery disease (CAD) (i.e., HDL^CAD) limits the anti-inflammatory and endothelial repair properties of normal HDL, due to the activation of lectin-like oxidized LDL receptor-1 (LOX-1), thereby causing failure in endothelial nitric oxide (NO) production. A more recent study (Immunity 2013; 38: 754–768) also demonstrates that HDL from patients with chronic kidney dysfunction (CKD) (i.e., HDL^CKD), unlike its healthy counterpart (i.e., HDL^Healthy), promotes superoxide production, reduces NO bioavailability and raises blood pressure via toll-like receptor-2 (TLR-2) activation. This study provides novel insights into understanding why HDL-raising agents failed to demonstrate beneficial effects on cardiovascular mortality in large clinical trials and why CKD accelerates the development of atherosclerosis in CAD patients. Further research is warranted to elucidate whether HDL^CKD and HDL^CAD participate in other cellular processes in atherosclerosis, such as foam cell formation, the proliferation and migration of smooth muscle cells, and most importantly, plaque destabilization.     

Angiotensin Receptor Blockers and the Kidney: Possible Advantages over ACE Inhibition?

This review deals with similarities and differences between the effects of ACE inhibitors and AT₁‐receptor blockers in the kidney. Specific receptor blockade has demonstrated that the beneficial effects of AT₁ blockers arise from two mechanisms: the reduction of the AT₁ receptor mediated response and the increase in plasma levels of Ang II through the AT₁‐receptor blockade, which leads to increased stimulation of the AT₂ receptor (the so‐called yin‐yang effect). Both ACE inhibition and AT₁‐receptor blockade provide significant renal protection in the majority of experimental animal models of kidney diseases. AT₁ receptor blockade may offer additional clinical benefits over ACE inhibitor treatment, particularly in the kidney, where AT₁‐receptor blockade does not cause the fall in glomerular filtration rate seen with ACE inhibitor treatment. A number of long‐term clinical studies currently running should show the real value of this new class of compounds in the management of hypertension and associated cardiorenal diseases.     

Anacetrapib: Hope for CETP Inhibitors?

Inhibition of cholesteryl ester transfer protein (CETP), a key protein involved in reverse cholesterol transport, can lead to increases in high‐density lipoprotein cholesterol (HDL‐C) levels and thus, is under evaluation as an antiatherogenic strategy. Several CETP inhibitors have been under development including anacetrapib, dalcetrapib, and torcetrapib. To date, anacetrapib demonstrates the greatest HDL‐C raising and low‐density lipoprotein cholesterol (LDL‐C) lowering potential. Phase I and phase II trials with anacetrapib have revealed that anacetrapib is well‐tolerated and does not seem to possess the pressor effects associated with torcetrapib. This article will briefly review the HDL‐C raising through CETP inhibition as an antiatherogenic strategy with a specific focus on anacetrapib.     

Endocardial Pacing: The Wave of the Future?

Cardiac resynchronization therapy (CRT) is a proven treatment for heart failure and requires the implantation of a left ventricular (LV) lead, usually placed in a tributary of the coronary sinus. Encouraged by the fact that approximately 30?% of the patients receiving CRT do not benefit from this therapy, LV endocardial pacing has been proposed as an alternative to traditional LV transvenous epicardial pacing. Endocardial LV pacing has a number of potential advantages over conventional LV epicardial pacing, including a more physiological endocardial-to-epicardial transmural activation sequence, a faster ventricular activation, a larger choice of stimulation sites and a potential superior hemodynamic performance. On the other hand, cardiologists will have to deal with new implant techniques' (transseptal), higher risk of thromboembolic events, and challenging extraction procedures of infected material. The future of endocardial stimulation will depend on the results of randomized studies adequately powered to assess the feasibility, the safety and the effectiveness of this new pacing strategy.