Despite optimal treatment of high low density lipoprotein (LDL) cholesterol with statins many cardiovascular events are not prevented. Additional therapeutic strategies are required to reduce the residual cardiovascular risk. Large epidemiological studies show an inverse correlation between the plasma concentration of high density lipoprotein (HDL) cholesterol and the incidence of cardiovascular events. Under physiological conditions, HDL is vasculoprotective and mediates the reverse cholesterol transport. However, new studies suggest that HDL particles represent a heterogeneous population. Under several pathophysiological conditions, HDL was shown to promote atherogenesis and inflammation. Interventional studies and metaanalyses examining the effect of increasing HDL cholesterol have reported mixed results. Inhibition of cholesteryl ester transfer protein (CETP) is a new and potent strategy to increase HDL concentrations. However, the first CETP-inhibitor torcetrapib increased blood-pressure and increased cardiovascular events despite increasing HDL. The blood-pressure increasing effects are not known for more recently developed CETP inhibitors such as dalcetrapib and anacetrapib nor in patients with genetic CETP deficiency. An increase of HDL cholesterol does not necessarily imply an improvement of the functional properties of HDL such as reverse cholesterol transport. An important open question remains the functional characterization of HDL generated by CETP inhibition. Important current clinical endpoint studies with new CETP inhibitors will elucidate whether increasing HDL by CETP inhibition leads to a reduction of cardiovascular events.

BACKGROUND: The SENIORS trial demonstrated that nebivolol has beneficial effects in patients with heart failure. However, the role of beta-blocker therapy in patients with heart failure and preserved left ventricular ejection fraction (HFPEF) is still unsettled. OBJECTIVE: To assess the long-term effects of administration of nebivolol, compared to placebo, on the clinical symptoms, exercise capacity and parameters of left ventricular (LV) function in patients with HFPEF. METHODS: The Effect of Long-term Administration of Nebivolol on clinical symptoms, exercise capacity and left ventricular function in patients with Diastolic Dysfunction (ELANDD) study is a prospective multicenter European trial in 120 patients with HFPEF randomised to nebivolol or placebo. HFPEF is defined as symptoms or signs of heart failure, a LV ejection fraction >45% and evidence of diastolic LV dysfunction by Doppler echocardiography. Procedures include a baseline clinical examination, 6-min walk test (6MWT), electrocardiography, Doppler echocardiography and Minnesota QoL questionnaire. Nebivolol or placebo is started at 2.5 mg/day and gradually uptitrated to 10 mg/day. After initiation of the study, patients are assessed at 1, 2, 5 and 6 weeks (titration phase) and at weeks 12 and 26. The primary endpoint is the change from baseline in the 6MWT distance with nebivolol versus placebo. Sample size calculations are based on an anticipated 15% difference (70 m) in the 6MWT distance between nebivolol and placebo-treated patients. This study will allow the collection of data regarding the possible clinical benefits and the effects on LV function of nebivolol administration in patients with HFPEF.

Summary Background Alopecia areata (AA) is a common hair loss disorder with a complex mode of inheritance. Autoimmune mechanisms are presumed to be crucial aetiologically. It is plausible that a number of autoimmune disorders may share a common genetic background. This phenomenon has been demonstrated in previous studies, which have shown an overlap of susceptibility alleles between AA and other autoimmune disorders. Recent studies have shown that genetic variants on the TRAF1/C5 (tumor necrosis factor receptor-associated factor 1, complement component 5) locus confer susceptibility to rheumatoid arthritis (RA). Objectives To examine the role of the TRAF1/C5 locus in the development of AA using a large sample of 1195 patients with AA and 1280 controls. Methods We genotyped the two most significant single nucleotide polymorphisms (SNPs)(rs10818488, rs2416808) from a former RA candidate gene study. After having obtained evidence for association, we performed a fine-mapping study and genotyped the locus with an additional 27 SNPs. Results While no significant result was obtained for the overall sample, rs2416808 showed significant associations in the analysis of the subgroups with severe AA and with a positive family history. The most significant P-value for rs2416808 was in familial cases (P = 0.004, P(corr)= 0.026). The fine mapping revealed significant associations for four additional SNPs in the analysis of subgroups, with rs2416808 remaining the most significant marker. Conclusions Our results point to the involvement of the TRAF1/C5 locus in the aetiology of familial and severe AA, and provide further support for a shared aetiology between AA and other autoimmune disorders.

Tissue distribution and segregation and the functional consequences of heteroplasmic mitochondrial DNA mutation A3243G were studied in 30 carriers. The mutation load in hair follicles was higher in 20 patients with a broad spectrum of clinical symptoms than in 10 nonaffected carriers. The onset of the disease negatively correlated with the mutation load in blood and muscle. The activities of respiratory chain complexes in isolated muscle mitochondria did not decrease in all patients and were normal in isolated platelets. Changes in the heteroplasmy level between pairs of mothers and offspring suggest that random genetic drift is the mechanism associated with the intergenerational transmission of the A3243G mutation. In conclusion, detailed clinical investigations and mitochondrial DNA analyses in several tissues are of the highest diagnostic value for the prognosis of the disease in carriers of the A3243G mutation.

Selective heart rate (HR) reduction by I(f)-channel inhibition is a recently developed pharmacological principle in cardiovascular therapy. Among these newly identified HR-lowering drugs, only ivabradine has now become approved for clinical use. I(f)-channel inhibition mainly reduces HR, thereby improving myocardial oxygen supply, energy balance, and cardiac function. Ivabradine was well tolerated and revealed a good safety profile in the investigated study populations. The guiding experimental and clinical results of I(f)-channel inhibition were compared to those of beta-blockade as a HR reducing principle as well as cornerstone of heart failure standard therapy. Beside its use in therapy of coronary artery disease, I(f)-channel inhibition potentially exhibits beneficial effects in systolic and diastolic heart failure as well. Therefore, hemodynamic effects of ivabradine and its limitations in heart failure together with the biological impact of HR reduction will be considered in this context. Because no clinical data with specific heart-rate-reducing agents are available in heart failure patients until now, the prospective significance of I(f)-channel inhibition can only be speculated on. However, the presented results and considerations are encouraging: ivabradine may play a therapeutic role in the future protecting left ventricular function and structure from early deterioration in heart failure with reduced and preserved ventricular ejection fraction.

BACKGROUND:-The underlying molecular mechanisms of the vasculoprotective effects of physical exercise are incompletely understood. Telomere erosion is a central component of aging, and telomere-associated proteins regulate cellular senescence and survival. This study examines the effects of exercising on vascular telomere biology and endothelial apoptosis in mice and the effects of long-term endurance training on telomere biology in humans. Methods and Results-C57/Bl6 mice were randomized to voluntary running or no running wheel conditions for 3 weeks. Exercise upregulated telomerase activity in the thoracic aorta and in circulating mononuclear cells compared with sedentary controls, increased vascular expression of telomere repeat-binding factor 2 and Ku70, and reduced the expression of vascular apoptosis regulators such as cell-cycle-checkpoint kinase 2, p16, and p53. Mice preconditioned by voluntary running exhibited a marked reduction in lipopolysaccharide-induced aortic endothelial apoptosis. Transgenic mouse studies showed that endothelial nitric oxide synthase and telomerase reverse transcriptase synergize to confer endothelial stress resistance after physical activity. To test the significance of these data in humans, telomere biology in circulating leukocytes of young and middle-aged track and field athletes was analyzed. Peripheral blood leukocytes isolated from endurance athletes showed increased telomerase activity, expression of telomere-stabilizing proteins, and downregulation of cell-cycle inhibitors compared with untrained individuals. Long-term endurance training was associated with reduced leukocyte telomere erosion compared with untrained controls. Conclusions-Physical activity regulates telomere-stabilizing proteins in mice and in humans and thereby protects from stress-induced vascular apoptosis.

The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET()) was a 25,620 patient study program comparing telmisartan with ramipril or the combination thereof in patients at increased cardiovascular risk. Ramipril had previously been proven to prevent cardiovascular events in a similar population within the HOPE-trial. However, ramipril and other ACE inhibitors (ACE-Is) may have limited tolerability that might restrict their use in patients requiring secondary prevention, whereas angiotensin receptor blockers (ARBs) are suggested to be better tolerated. However, no ARB had been compared with the standard treatment, ramipril, in these cardiovascular patients at increased risk. ONTARGET showed that telmisartan was as effective as ramipril in preventing cardiovascular events, but was better tolerated. The combination of ramipril and telmisartan was not superior to either monotherapy. Taken together, ONTARGET demonstrated that telmisartan is as effective as ramipril in a broad cardiovascular increased-risk population in the middle of the cardiovascular continuum. In these patients who are intolerant to ACE-Is or who do not achieve blood pressure control, the ARB with the best evidence for secondary prevention is telmisartan according to the results of the ONTARGET trial.

This summary article provides an update on novel clinical trials in the field of cardiovascular (CV) medicine which were presented at the Transcatheter Cardiovascular Therapeutics meeting, held in San Francisco in September 2009. The data were presented by leading experts in the field with relevant positions in the trials and registries. Unpublished reports should be considered as preliminary data as the analysis may change in the final publications. This article provides the reader with comprehensive summaries of the most recent diagnostic and therapeutic developments in CV medicine.

AIMS: Elevated heart rate is a significant marker for mortality and morbidity in cardiovascular disease including heart failure. Despite background treatment with a beta-blocker, many patients with heart failure and low ejection fraction maintain a heart rate above 70 b.p.m. Ivabradine reduces heart rate directly through inhibition of the I(f) ionic current. Methods SHIFT is a randomized, double-blind study designed to compare ivabradine with placebo on outcomes in patients with symptomatic chronic heart failure (NYHA class II-IV), left-ventricular ejection fraction </=35%, and a prior hospitalization for worsening heart failure within the previous 12 months. Randomized treatment is given on top of guidelines-based therapy for chronic heart failure, including a beta-blocker at optimized dose. Resting heart rate at baseline must be >/=70 b.p.m. The primary endpoint is the composite of the time to first event of cardiovascular death or hospitalization for worsening heart failure. Secondary endpoints include all-cause, cardiovascular and heart failure mortality, and hospitalization. The randomized treatment period lasts approximately 12-48 months. The study will include approximately 6500 patients and will continue until >/=1600 primary endpoints have occurred. The first patient was randomized in October 2006, and the study is expected to end in 2010. CONCLUSION: The SHIFT study will assess if a heart rate reduction by direct sinus node inhibition can reduce cardiovascular outcomes in patients with chronic heart failure and left-ventricular systolic dysfunction.