Glycoprotein IIb/IIIa Antagonists in Acute Coronary Syndromes Undergoing PCI: A Long Way to Select Optimal Agent and Route

Antiplatelet treatment in patients with an acute coronary syndrome (ACS), without or with ST segment elevation myocardial infarction (STEMI), forces to keep the balance between potential threats and optimal clinical advantages. Apart from clopidogrel, glycoprotein (GP) IIb/IIIa inhibitors (abciximab and 2 small molecules, tirofiban and eptifibatide) have come to the clinical scene. Recent evidence (2009–2011) is reviewed pointing to pharmacoeconometric considerations of concern in times of budget restrictions worldwide. In ACS, when clopidogrel plus aspirin are on, there might be no advantage to add small molecules. Whereas in STEMI patients treated by primary PCI, all 3 GP IIb/IIIa antagonists might be superimposable, when only ACS is present and PCI is elective, definite distinction among the 3 agents, both pharmacoeconomically and pharmacodynamically, might be invoked. There are still points open to debate. Among these the route (upstream versus downstream) is still a matter of uncertainties. Moreover, theoretically, there might be differences not only between abciximab and small molecules (mostly superimposable) but also between tirofiban and eptifibatide (the former being potentially more potent). Thus, a long way is needed before a prominent agent among GPIIb/IIIa inhibitors may be selected. The game is still open, a role will be played soon by new agents

The molecular sources of reactive oxygen species in hypertension.

In both animal models and humans, increased blood pressure has been associated with oxidative stress in the vasculature, i.e. an excessive endothelial production of reactive oxygen species (ROS), which may be both a cause and an effect of hypertension. In addition to NADPH oxidase, the best characterized source of ROS, several other enzymes may contribute to ROS generation, including nitric oxide synthase, lipoxygenases, cyclo-oxygenases, xanthine oxidase and cytochrome P450 enzymes. It has been suggested that also mitochondria could be considered a major source of ROS: in situations of metabolic perturbation, increased mitochondrial ROS generation might trigger endothelial dysfunction, possibly contributing to the development of hypertension. However, the use of antioxidants in the clinical setting induced only limited effects on human hypertension or cardiovascular endpoints. More clinical studies are needed to fully elucidate this so called "oxidative paradox" of hypertension

Translational Cardiology: defining limits and targets at the International Archives of Medicine

The Merriam-Webster dictionary reports the first use of “Translational Research†as early as 1986 and the definition given for this term was: “medical research that is concerned with facilitating the practical application of scientific discoveries to the development and implementation of new ways to prevent, diagnose, and treat disease, called also translational medicine†.The adjective “translational†stems from Classical Latin “translatioâ€, then probably Middle French â€translationâ€, to reach Middle English “translaciounâ€. The idea is to make a transfer from one idiom to another, yet keeping the intimate significance and sense, which is common to language translation methods. It properly stresses the relation to the transfer of scientific knowledge into practical applications. It is obvious how, in less than 30 years, translational research has pervaded all Science domains and how large is the interest of scientists and lay people for this subjec

Rapid and MR-Independent IK1 activation by aldosterone during ischemia-reperfusion

In ST elevation myocardial infarction (STEMI) context, clinical studies have shown the deleterious effect of high aldosterone levels on ventricular arrhythmia occurrence and cardiac mortality. Previous in vitro reports showed that during ischemia-reperfusion, aldosterone modulates K+ currents involved in the holding of the resting membrane potential (RMP). The aim of this study was to assess the electrophysiological impact of aldosterone on IK1 current during myocardial ischemia-reperfusion. We used an in vitro model of “border zone” using right rabbit ventricle and standard microelectrode technique followed by cell-attached recordings from freshly isolated rabbit ventricular cardiomyocytes. In microelectrode experiments, aldosterone (10 and 100 nmol/L, n=7 respectively) increased the action potential duration (APD) dispersion at 90% between ischemic and normoxic zones (from 95±4ms to 116±6 ms and 127±5 ms respectively, P<0.05) and reperfusion-induced sustained premature ventricular contractions occurrence (from 2/12 to 5/7 preparations, P<0.05). Conversely, potassium canrenoate 100 nmol/L and RU 28318 1 μmol/l alone did not affect AP parameters and premature ventricular contractions occurrence (except Vmax which was decreased by potassium canrenoate during simulated-ischemia). Furthermore, aldosterone induced a RMP hyperpolarization, evoking an implication of a K+ current involved in the holding of the RMP. Cell-attached recordings showed that aldosterone 10 nmol/L quickly activated (within 6.2±0.4 min) a 30 pS K+-selective current, inward rectifier, with pharmacological and biophysical properties consistent with the IK1 current (NPo =1.9±0.4 in control vs NPo=3.0±0.4, n=10, P<0.05). These deleterious effects persisted in presence of RU 28318, a specific MR antagonist, and were successfully prevented by potassium canrenoate, a non specific MR antagonist, in both microelectrode and patch-clamp recordings, thus indicating a MR-independent IK1 activation. In this ischemia-reperfusion context, aldosterone induced rapid and MR-independent deleterious effects including an arrhythmia substrate (increased APD90 dispersion) and triggered activities (increased premature ventricular contractions occurrence on reperfusion) possibly related to direct IK1 activation

Early Invasive Strategy for Unstable Angina: a New Meta-Analysis of Old Clinical Trials

Randomized controlled trials (RCTs) were conflicting to support whether unstable angina versus non-ST-elevation myocardial infarction (UA/NSTEMI) patients best undergo early invasive or a conservative revascularization strategy. RCTs with cardiac biomarkers, in MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from 1975-2013 were reviewed considering all cause mortality, recurrent non-fatal myocardial infarction (MI) and their combination. Follow-up lasted from 6-24 months and the use of routine invasive strategy up to its end was associated with a significantly lower composite of all-cause mortality and recurrent non-fatal MI (Relative Risk [RR] 0.79; 95% confidence interval [CI], 0.70-0.90) in UA/NSTEMI. In NSTEMI, by the invasive strategy, there was no benefit (RR 1.19; 95%\u2009CI, 1.03-1.38). In the shorter time period, from randomization to discharge, a routine invasive strategy was associated with significantly higher odds of the combined end-point among UA/NSTEMI (RR 1.29; 95%\u2009CI, 1.05-1.58) and NSTEMI (RR 1.82; 95%\u2009CI, 1.34-2.48) patients. Therefore, in trials recruiting a large number of UA patients, by routine invasive strategy the largest benefit was seen, whereas in NSTEMI patients death and non-fatal MI were not lowered. Routine invasive treatment in UA patients is accordingly supported by the present study

Re-calibration of coronary risk prediction:An example of the Seven Countries Study

We aimed at performing a calibration and re-calibration process using six standard risk factors from Northern (NE, N = 2360) or Southern European (SE, N = 2789) middle-aged men of the Seven Countries Study, whose parameters and data were fully known, to establish whether re-calibration gave the right answer. Greenwood-Nam-D'Agostino technique as modified by Demler (GNDD) in 2015 produced chi-squared statistics using 10 deciles of observed/expected CHD mortality risk, corresponding to Hosmer-Lemeshaw chi-squared employed for multiple logistic equations whereby binary data are used. Instead of the number of events, the GNDD test uses survival probabilities of observed and predicted events. The exercise applied, in five different ways, the parameters of the NE-predictive model to SE (and vice-versa) and compared the outcome of the simulated re-calibration with the real data. Good re-calibration could be obtained only when risk factor coefficients were substituted, being similar in magnitude and not significantly different between NE-SE. In all other ways, a good re-calibration could not be obtained. This is enough to praise for an overall need of re-evaluation of most investigations that, without GNDD or another proper technique for statistically assessing the potential differences, concluded that re-calibration is a fair method and might therefore be used, with no specific caution

Left atrial trajectory impairment in hypertrophic cardiomyopathy disclosed by geometric morphometrics and parallel transport

The analysis of full Left Atrium (LA) deformation and whole LA deformational trajectory in time has been poorly investigated and, to the best of our knowledge, seldom discussed in patients with Hypertrophic Cardiomyopathy. Therefore, we considered 22 patients with Hypertrophic Cardiomyopathy (HCM) and 46 healthy subjects, investigated them by three-dimensional Speckle Tracking Echocardiography, and studied the derived landmark clouds via Geometric Morphometrics with Parallel Transport. Trajectory shape and trajectory size were different in Controls versus HCM and their classification powers had high AUC (Area Under the Receiving Operator Characteristic Curve) and accuracy. The two trajectories were much different at the transition between LA conduit and booster pump functions. Full shape and deformation analyses with trajectory analysis enabled a straightforward perception of pathophysiological consequences of HCM condition on LA functioning. It might be worthwhile to apply these techniques to look for novel pathophysiological approaches that may better define atrio-ventricular interaction

A personal decision support system for heart failure management (HeartMan) : study protocol of the HeartMan randomized controlled trial

Background: Heart failure (HF) is a highly prevalent chronic disease, for which there is no cure available. Therefore, improving disease management is crucial, with mobile health (mHealth) being a promising technology. The aim of the HeartMan study is to evaluate the effect of a personal mHealth system on top of standard care on disease management and health-related quality of life (HRQoL) in HF. Methods: HeartMan is a randomized controlled 1:2 (control: intervention) proof-of-concept trial, which will enrol 120 stable ambulatory HF patients with reduced ejection fraction across two European countries. Participants in the intervention group are equipped with a multi-monitoring health platform with the HeartMan wristband sensor as the main component. HeartMan provides guidance through a decision support system on four domains of disease management (exercise, nutrition, medication adherence and mental support), adapted to the patient's medical and psychological profile. The primary endpoint of the study is improvement in self-care and HRQoL after a six-months intervention. Secondary endpoints are the effects of HeartMan on: behavioural outcomes, illness perception, clinical outcomes and mental state. Discussion: HeartMan is technologically the most innovative HF self-management support system to date. This trial will provide evidence whether modern mHealth technology, when used to its full extent, can improve HRQoL in HF