Novel oral anticoagulants in the treatment of acute coronary syndromes: Is there any room for new anticoagulants?

Thrombosis plays a key role in the pathophysiology of acute coronary syndromes (ACS). The management of patients with ACS includes interventional procedures and use of antithrombotic agents acutely, and dual antiplatelet therapy (aspirin and a P2Y12 receptor antagonist) for secondary prevention. However, patients with recent ACS remain at a substantial residual risk for recurrent ischemic events or death. The idea of follow-up treatment with an oral anticoagulant on top of standard therapy seems promising. Warfarin was the first oral anticoagulant thoroughly investigated in this direction, but the widespread long-term use of warfarin in ACS has been limited by challenges associated with pharmacodynamic/pharmacokinetic deficiencies of the drug and the risk of bleeding. Novel oral anticoagulants, such as direct thrombin inhibitors (DTIs) and FXa inhibitors overcome the downsides of VKAs. Ximelagatran was the first DTI, investigated and proven to be effective in prevention of recurrent ischemic events in ACS patients, but the drug association with hepatotoxicity prompted its withdrawal. Dabigatran etexilate, apixaban, darexaban (YM150) and TAK-442 were studied in phase II dose-escalation trials in order to determine the balance between clinical effectiveness and bleeding risk in daily use with dual antiplatelet therapy, with both positive and negative results. Rivaroxaban is the only agent that completed a phase III trial, showing reduction in recurrent ischemic events rate and death from cardiovascular causes as well as all-cause death. This review summarizes the data from completed and ongoing clinical trials of the new oral anticoagulants in patients with ACS. © 2012 Bentham Science Publishers

Novel direct factor IIa and Xa inhibitors: Mechanisms of action and preclinical studies

The need to overcome certain limitations of the existing anticoagulant agents (heparin, LMWH and VKAs) and to achieve more convenient long-term anticoagulation has fueled the quest for the "ideal anticoagulant", an agent that would exert at least similar antithrombotic effects with a substantially improved pharmacologic profile and significantly less bleeding complications. The major disadvantages of the traditional agents were the narrow therapeutic window with serious drug and food interactions and the need for regular blood monitoring. Coagulation factors IIa and Xa have proved the most attractive pharmacologic targets due to their key role in the coagulation process and the opportunity of blocking thrombin generation before the level of thrombin production that results in amplification of the anticoagulant effect while preserving some of thrombin hemostatic effect. This review summarizes the mechanism of action of some of the most promising novel oral direct factor IIa and Xa inhibitors with a focus on published preclinical trials that led to their clinical development. © 2012 Bentham Science Publishers

Cystatin C: An emerging biomarker in cardiovascular disease

Cystatin C (cys-C) is a small protein molecule (120 amino acid peptide chain, approximately 13kDa) produced by virtually all nucleated cells in the human body. It belongs to the family of papain-like cysteine proteases and its main biological role is the extracellular inhibition of cathepsins. It's near constant production rate, the fact that it is freely filtered from the glomerular membrane and then completely reabsorbed without being secreted from the proximal tubular cells, made it an almost perfect candidate for estimating renal function. The strong correlation between chronic kidney disease (CKD) and cardiovascular disease (CVD) along with the growing understanding of the role of cysteinyl cathepsins in the pathophysiology of CVD inspired researchers to explore the potential association of cys-C with CVD. Throughout the spectrum of CVD (peripheral arterial disease, stroke, abdominal aortic aneurysm, heart failure, coronary artery disease) adverse outcomes and risk stratification have been associated with high plasma levels of cys-C. The exact mechanisms behind the observed correlations have not been comprehensively clarified. Plausible links between high cys-C levels and poor cardiovascular outcome could be impaired renal function, atherogenesis and inflammatory mediators, remodeling of myocardial tissue and others (genetic factors, aging and social habits). The scope of the present article is to systematically review the current knowledge about cys-C biochemistry, metabolism, methods of detection and quantification and pathophysiological associations with different aspects of CVD. © 2013 Bentham Science Publishers

Myocardial deformation imaging unmasks subtle left ventricular systolic dysfunction in asymptomatic and treatment-naïve HIV patients

Background: Patients infected by the human immunodeficiency virus (HIV) and receiving highly active antiretroviral therapy have a higher incidence of cardiovascular disease than healthy subjects, but little is known about cardiac function in asymptomatic and treatment-naïve patients. We sought to study cardiac function in asymptomatic HIV-infected, treatment-naïve patients. Methods: We studied 41 HIV-infected and treatment-naïve patients and 20 age- and sex-matched healthy controls. Patients with cardiac symptoms, history of cardiac disease or NT-proBNP >100 pg/mL were excluded. We addressed cardiac function using standard echocardiography along with tissue Doppler (TDI) measurements, including strain/strain rate assessment. Results: Standard echocardiographic parameters did not differ between groups, except for transmitral E wave velocity (64.8 ± 14 cm/s in HIV vs 76.1 ± 10 cm/s in controls, p = 0.002). In contrast, TDI mitral and tricuspid annulus s velocity and all strain/strain rate measurements were significantly lower in HIV patients: s lateral, 10.2 ± 2.4/11.3 ± 0.7, p = 0.011; s septal, 8.1 ± 1.6/8.7 ± 0.8, p = 0.045; s tricuspid, 13.4 ± 2.3/14.9 ± 1.3, p = 0.002; strain/strain rate, septal (strain/strain rate, 15.1 ± 5.7/−0.9 ± 0.3, 25.3 ± 1.7/−1.9 ± 0.2, p < 0.001), anterior (16.7 ± 3/−1.0 ± 0.1, 26.7 ± 1.7/−1.9 ± 0.2, p < 0.001), lateral (16.0 ± 6/−1.0 ± 0.1, 27.5 ± 1.8/−2.2 ± 0.3, p < 0.001) and posterior (15.2 ± 5.8/−1.0 ± 0.2, 26.2 ± 1.8/−2.2 ± 0.3, p < 0.001) left ventricular wall. Conclusions: HIV infection itself is accompanied by subclinical systolic dysfunction, not apparent to standard echocardiography that can be unmasked though using sensitive echocardiographic techniques. © 2015, Springer-Verlag Berlin Heidelberg

Differential effect of biventricular and right ventricular DDD pacing on coronary flow reserve in patients with ischemic cardiomyopathy

CRT and Coronary Flow Reserve. Background: Cardiac resynchronization therapy (CRT) has become a mainstay in heart failure management. There are also indications that upgrading of existing pacemakers to CRT systems may be of benefit. The aim of this study was to assess the effect of biventricular (BiV), compared with right ventricular (RV), pacing, on coronary flow reserve (CFR), in patients with ischemic cardiomyopathy. Methods and Results: From our database of heart failure patients implanted with BiV pacemakers, 20 patients (10 responders and 10 non-responders to CRT) were randomly selected. Left anterior descending artery coronary flow reserve was measured invasively, under BiV and RV pacing, using intracoronary adenosine to induce hyperemia. In all the 20 patients, there was a significant difference in the pairwise comparison between CFR recorded during BiV and RV pacing (mean difference 0.15, 95% confidence interval 0.07-0.23, P = 0.001). When comparing responders to non-responders, there was a significant difference as to the effect of BiV, compared with RV, pacing on CFR: mean difference (BiV minus RV CFR) was 0.26 ± 0.06 (95% confidence interval 0.13-0.39; P = 0.002), while in non-responders the difference was 0.04 ± 0.03 (95% confidence interval -0.02 to 0.10; P = 0.168). Conclusion: BiV pacing is overall associated to higher CFR, compared with RV DDD pacing. This difference is almost exclusively attributable to the beneficial effect of CRT on coronary flow reserve in CRT-responders. This effect may contribute to the beneficial action of resynchronization in the failing heart and can be viewed in the context of reports of the usefulness of upgrading RV pacemakers to CRT systems. © 2010 Wiley Periodicals, Inc

The impact of positive airway pressure on cardiac status and clinical outcomes in patients with advanced heart failure and sleep-disordered breathing: A preliminary report

Introduction: Heart failure (HF) is a major public health problem associated with high rates of morbidity and mortality. Patients with HF exhibit a high prevalence of sleep-disordered breathing (SDB). We have investigated the long-term impact of positive airway pressure (PAP) therapy on heart function and clinical outcomes in patients with advanced HF and concomitant SDB. Materials and methods: We assessed 18 patients with advanced HF (New York Heart Association (NYHA) functional classification III-IV) and concomitant SDB (diagnosed with polysomnography) either of obstructive or central type. Eleven patients who received PAP therapy (auto-titrating PAP or adaptive servo-ventilation) for 12 months were compared with seven patients who refused this therapy. All participants were assessed at both baseline and end of follow-up for NYHA functional status, left and right ventricular function, neurohormonal activation, and exercise tolerance. The rates of hospitalization, deaths, and the combination of both were also recorded. Results: Patients treated with PAP achieved better functional status, higher left ventricular ejection fraction, improved longitudinal right ventricular contractile function, lower levels of b-type natriuretic peptide, and greater exercise performance compared to those who remained untreated. PAP-treated group had a significantly lower incidence of the prespecified combined end-point (i.e., hospital admissions and death) than the control group (87.5 vs. 18.2%, p= 0.013). Interestingly, the mortality rate was 28% (two out of seven patients) in the control group, while no deaths were recorded in the PAP-treated group. Discussion: In this preliminary study, we found that treatment of SDB, irrespective of type, in stable patients with advanced HF receiving optimal medical therapy was associated with improvement in cardiac functional status, ventricular contraction, physical performance, and neurohormonal status, leading to better clinical outcomes. © Springer-Verlag 2010

The role of the immunogenetic background in the development and recurrence of acute idiopathic pericarditis

Objectives: We assessed the role of the immunogenetic background in the development and recurrence of acute idiopathic pericarditis (AIP). Methods: Fifty-five patients with a first episode of AIP were followed for 23.8 ± 6.3 months and recurrences were recorded. The control group consisted of 246 healthy individuals. In all subjects, genomic human leukocyte antigen (HLA) typing was performed. Moreover, circulating lymphocyte subpopulations were studied in 44 randomly selected patients and in 20 controls. Results: An increased frequency of HLA-A*02, -Cw*07 and -DQB1*0202 alleles, and a decreased frequency of the -DQB1*0302 allele was detected in patients with AIP. The recurrence rate was 40% and time to recurrence was 202.8 ± 164.1 days. In patients with idiopathic recurrent pericarditis (RP), increased frequencies of HLA-A*02, -Cw*07 and -DQB1*0202 alleles were found. Notably, no patient with RP exhibited HLA-DRB1*04 and -DQB1*0302 alleles. Patients with RP exhibited lower CD4+/CD45RA+ naïve T cells (p = 0.03) than controls, and higher CD8+DR+ activated T cells (p = 0.01) than patients without recurrence and controls. Conclusions: HLA alleles may confer either susceptibility or resistance to AIP and RP. Circulating T-cell subpopulations may also predict RP. A combination of the above parameters might help to better define patients prone to recurrence. Copyright © 2011 S. Karger AG, Basel