New drugs in preclinical and early stage clinical development in the treatment of heart failure.

INTRODUCTION: Heart failure (HF) represents a major health problem because of its high prevalence, high rates of hospitalizations, and mortality and significant healthcare costs. HF comprises a heterogeneous group of syndromes with different pathophysiology, clinical presentations, and response to therapy. Basic research has identified multiple putative therapeutic targets involved in the pathogenesis of HF and many promising drugs are under development. AREAS COVERED: This review summarizes the main drugs currently in preclinical and clinical development for HF treatment. Drugs were identified by search of MEDLINE and PubMed and trials from registries (clinicaltrials.gov, clinicaltrialsregister.eu, pubmed.gov) from 2010. EXPERT OPINION: Despite significant advances in the pharmacological treatment of HF with reduced ejection fraction, no treatment has yet convincingly shown to improve outcomes in patients with HF with preserved ejection fraction and acute HF. Many promising drugs emerged in preclinical models and small phase 2 trials, but with a few exceptions, they fail to meet the primary endpoints in larger adequately powered phase 3 trials. Which new drugs will prove valuable remains uncertain. Improving clinical outcomes, delaying or preventing HF worsening and reducing hospital admissions should be prioritized in future drug development programs.

Brugada syndrome trafficking-defective Nav1.5 channels can trap cardiac Kir2.1/2.2 channels.

Cardiac Nav1.5 and Kir2.1-2.3 channels generate Na (INa) and inward rectifier K (IK1) currents, respectively. The functional INa and IK1 interplay is reinforced by the positive and reciprocal modulation between Nav15 and Kir2.1/2.2 channels to strengthen the control of ventricular excitability. Loss-of-function mutations in the SCN5A gene, which encodes Nav1.5 channels, underlie several inherited arrhythmogenic syndromes, including Brugada syndrome (BrS). We investigated whether the presence of BrS-associated mutations alters IK1 density concomitantly with INa density. Results obtained using mouse models of SCN5A haploinsufficiency, and the overexpression of native and mutated Nav1.5 channels in expression systems - rat ventricular cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) - demonstrated that endoplasmic reticulum (ER) trafficking-defective Nav1.5 channels significantly decreased IK1, since they did not positively modulate Kir2.1/2.2 channels. Moreover, Golgi trafficking-defective Nav1.5 mutants produced a dominant negative effect on Kir2.1/2.2 and thus an additional IK1 reduction. Moreover, ER trafficking-defective Nav1.5 channels can be partially rescued by Kir2.1/2.2 channels through an unconventional secretory route that involves Golgi reassembly stacking proteins (GRASPs). Therefore, cardiac excitability would be greatly affected in subjects harboring Nav1.5 mutations with Golgi trafficking defects, since these mutants can concomitantly trap Kir2.1/2.2 channels, thus unexpectedly decreasing IK1 in addition to INa.

Chronic (-)-epicatechin improves vascular oxidative and inflammatory status but not hypertension in chronic nitric oxide-deficient rats.

The present study analysed the effects of the flavanol (-)-epicatechin in rats after chronic inhibition of NO synthesis with NG-nitro-L-arginine methyl ester (L-NAME), at doses equivalent to those achieved in the studies involving human subjects. Wistar rats were randomly divided into four groups: (1) control-vehicle, (2) L-NAME, (3) L-NAME-epicatechin 2 (L-NAME-Epi 2) and (4) L-NAME-epicatechin 10 (L-NAME-Epi 10). Rats were daily given by oral administration for 4 weeks: vehicle, (-)-epicatechin 2 or 10 mg/kg. Animals in the L-NAME groups daily received L-NAME 75 mg/100 ml in drinking-water. The evolution in systolic blood pressure and heart rate, and morphological and plasma variables, proteinuria, vascular superoxide, reactivity and protein expression at the end of the experiment were analysed. Chronic (-)-epicatechin treatment did not modify the development of hypertension and only weakly affected the endothelial dysfunction induced by L-NAME but prevented the cardiac hypertrophy, the renal parenchyma and vascular lesions and proteinuria, and blunted the prostanoid-mediated enhanced endothelium-dependent vasoconstrictor responses and the cyclo-oxygenase-2 and endothelial NO synthase (eNOS) up-regulation. Furthermore, (-)-epicatechin also increased Akt and eNOS phosphorylation and prevented the L-NAME-induced increase in systemic (plasma malonyldialdehyde and urinary 8-iso-PGF2α) and vascular (dihydroethidium staining, NADPH oxidase activity and p22phox up-regulation) oxidative stress, proinflammatory status (intercellular adhesion molecule-1, IL-1ß and TNFα up-regulation) and extracellular-signal-regulated kinase 1/2 phosphorylation. The present study shows for the first time that chronic oral administration of (-)-epicatechin does not improve hypertension but reduced pro-atherogenic pathways such as oxidative stress and proinflammatory status of the vascular wall induced by blockade of NO production.

Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death.

BACKGROUND: L-type calcium channel (LTCC) mutations have been associated with Brugada syndrome (BrS), short QT (SQT) syndrome, and Timothy syndrome (LQT8). Little is known about the extent to which LTCC mutations contribute to the J-wave syndromes associated with sudden cardiac death. OBJECTIVE: The purpose of this study was to identify mutations in the α1, ß2, and α2δ subunits of LTCC (Ca(v)1.2) among 205 probands diagnosed with BrS, idiopathic ventricular fibrillation (IVF), and early repolarization syndrome (ERS). CACNA1C, CACNB2b, and CACNA2D1 genes of 162 probands with BrS and BrS+SQT, 19 with IVF, and 24 with ERS were screened by direct sequencing. METHODS/RESULTS: Overall, 23 distinct mutations were identified. A total of 12.3%, 5.2%, and 16% of BrS/BrS+SQT, IVF, and ERS probands displayed mutations in α1, ß2, and α2δ subunits of LTCC, respectively. When rare polymorphisms were included, the yield increased to 17.9%, 21%, and 29.1% for BrS/BrS+SQT, IVF, and ERS probands, respectively. Functional expression of two CACNA1C mutations associated with BrS and BrS+SQT led to loss of function in calcium channel current. BrS probands displaying a normal QTc had additional variations known to prolong the QT interval. CONCLUSION: The study results indicate that mutations in the LTCCs are detected in a high percentage of probands with J-wave syndromes associated with inherited cardiac arrhythmias, suggesting that genetic screening of Ca(v) genes may be a valuable diagnostic tool in identifying individuals at risk. These results are the first to identify CACNA2D1 as a novel BrS susceptibility gene and CACNA1C, CACNB2, and CACNA2D1 as possible novel ERS susceptibility genes.

Cinaciguat, a soluble guanylate cyclase activator for the potential treatment of acute heart failure.

The nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic guanosine-3',5'-monophosphate (cGMP) pathway plays an important role in cardiovascular regulation by producing vasodilation and inhibiting platelet aggregation and vascular smooth muscle proliferation. The NO/SGC/cGMP pathway is disrupted in patients with heart failure as a result of a decrease in NO bioavailability and an increase in NO-insensitive forms of sGC, resulting in insufficient vasodilation. Drugs that activate sGC in a NO-independent manner may provide considerable therapeutic advantages in treating these patients. Cinaciguat (BAY-58-2667), currently in development by Bayer AG, preferentially activates sGC in its oxidized or heme-free state, when the enzyme is insensitive to both NO and nitrovasodilators. Cinaciguat exhibits potent vasodilator and antiplatelet activity, a long-lasting antihypertensive effect and a hemodynamic profile similar to that of nitrates. In clinical trials in patients with acute decompensated heart failure, cinaciguat potently unloaded the heart, increased cardiac output and renal blood flow, and preserved renal function and sodium and water excretion without further neurohumoral activation. The pharmacokinetics of cinaciguat demonstrated dose-proportionality with low individual variability and a low incidence of adverse events. The phase I and II clinical trials performed with cinaciguat so far, however, are insufficient to provide convincing evidence on the efficacy and safety of the drug. Thus, caution should be exerted before extrapolating the present preliminary data to the clinical practice.

Farmacología de los ácidos grasos omega-3 / Pharmacology of omega-3 polyinsaturated fatty acids

El consumo de ácidos grasos omega-3, como el ácido eicosapentanoico (EPA) y el ácido docosahexanoico (DHA), derivados de alimentos marinos y de plantas ha demostrado, en estudios epidemiológicos y clínicos, que reduce la incidencia de mortalidad coronaria y la muerte por arritmias. Recientemente, un suplemento que contiene una concentración del 90% de ácidos omega-3 (EPA y DHA) en forma de etil ésteres (Omacor®) ha sido autorizado como tratamiento adjunto a la dieta para reducir la hipertrigliceridemia en pacientes adultos y, también, como tratamiento adjunto a la dieta y a otros tratamientos en la prevención secundaria del infarto de miocardio. En este artículo, en primer lugar, revisamos la estructura química, las acciones farmacológicas y los mecanismos por los cuales los ácidos grasos n-3 y, en particular, el Omacor ®, pueden reducir el riesgo de muerte cardiovascular. A continuación, se analizan las propiedades farmacocinéticas, la seguridad y las recomendaciones de diversos organismos para administrar suplementos de EPA+DHA u Omacor® en los pacientes con enfermedades cardiovasculares (AU)

Epidemiological and clinical trials have shown that the consumption of omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), derived from seafood and plant sources reduces the incidence of fatal coronary artery disease and death due to arrhythmia. Recently, a food supplement containing a 90% concentration of omega-3 fatty acids (i.e., EPA and DHA) in the form of ethyl esters (Omacor®) has been licensed for use as an adjunct to dietary modification for the reduction of hypertriglyceridemia in adults and as an adjuvant to standard medical treatment for the secondary prevention of myocardial infarction. In this article, we review firstly the chemical structure of omega-3 fatty acids, and the pharmacological actions and mechanisms through which they may reduce the risk of cardiovascular disease. Thereafter, we discuss the pharmacokinetics, safety profile, and the recommendations made in several guidelines concerning the use of EPA+DHA supplements or Omacor® in patients with cardiovascular disease (AU)