Erdal Safak

Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism; intervention; and long-term consequences.

Background Intrauterine growth restriction is associated with an increased future risk for developing cardiovascular diseases. Hypoxia in utero is a common clinical cause of fetal growth restriction. We have previously shown that chronic hypoxia alters cardiovascular development in chick embryos. The aim of this study was to further characterize cardiac disease in hypoxic chick embryos. Methods Chick embryos were exposed to hypoxia and cardiac structure was examined by histological methods one day prior to hatching (E20) and at adulthood. Cardiac function was assessed in vivo by echocardiography and ex vivo by contractility measurements in isolated heart muscle bundles and isolated cardiomyocytes. Chick embryos were exposed to vascular endothelial growth factor (VEGF) and its scavenger soluble VEGF receptor-1 (sFlt-1) to investigate the potential role of this hypoxia-regulated cytokine. Principal Findings Growth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis. Hypoxic hearts displayed pump dysfunction with decreased LV ejection fractions, accompanied by signs of diastolic dysfunction. Cardiomyopathy caused by hypoxia persisted into adulthood. Hypoxic embryonic hearts showed increases in VEGF expression. Systemic administration of rhVEGF165 to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass. Lowering VEGF levels in hypoxic embryonic chick hearts by systemic administration of sFlt-1 yielded an almost complete normalization of the phenotype. Conclusions/Significance Our data show that hypoxia causes a decreased cardiac performance and cardiomyopathy in chick embryos, involving a significant VEGF-mediated component. This cardiomyopathy persists into adulthood.

Dietary n-3 Polyunsaturated Fatty Acids and Direct Renin Inhibition Improve Electrical Remodeling in a Model of High Human Renin Hypertension

We compared the effect n-3 polyunsaturated fatty acids (PUFAs) with direct renin inhibition on electrophysiological remodeling in angiotensin II-induced cardiac injury. We treated double-transgenic rats expressing the human renin and angiotensinogen genes (dTGRs) from week 4 to 7 with n-3 PUFA ethyl-esters (Omacor; 25-g/kg diet) or a direct renin inhibitor (aliskiren; 3 mg/kg per day). Sprague-Dawley rats were controls. We performed electrocardiographic, magnetocardiographic, and programmed electrical stimulation. Dietary n-3 PUFAs increased the cardiac content of eicosapentaenoic and docosahexaenoic acid. At week 7, mortality in dTGRs was 31%, whereas none of the n-3 PUFA- or aliskiren-treated dTGRs died. Systolic blood pressure was modestly reduced in n-3 PUFA-treated (180±3 mm Hg) compared with dTGRs (208±5 mm Hg). Aliskiren-treated dTGRs and Sprague-Dawley rats were normotensive (110±3 and 119±6 mm Hg, respectively). Both n-3 PUFA-treated and untreated dTGRs showed cardiac hypertrophy and increased atrial natriuretic peptide levels. Prolonged QRS and QTc intervals and increased T-wave dispersion in dTGRs were reduced by n-3 PUFAs or aliskiren. Both treatments reduced arrhythmia induction from 75% in dTGRs to 17% versus 0% in Sprague-Dawley rats. Macrophage infiltration and fibrosis were reduced by n-3 PUFAs and aliskiren. Connexin 43, a mediator of intermyocyte conduction, was redistributed to the lateral cell membranes in dTGRs. n-3 PUFAs and aliskiren restored normal localization to the intercalated disks. Thus, n-3 PUFAs and aliskiren improved electrical remodeling, arrhythmia induction, and connexin 43 expression, despite a 70-mm Hg difference in blood pressure and the development of cardiac hypertrophy.

Vitronectin Concentrations Predict Risk in Patients Undergoing Coronary Stenting

Background—Vitronectin is a multifunctional protein with a multiple binding domain that interacts with a variety of plasma and cell proteins. Vitronectin binds multiple ligands, including the soluble vitronectin receptor. Abciximab binds equally well to soluble vitronectin receptor and glycoprotein IIb/IIIa, because both share the &bgr;3 subunit. We tested whether vitronectin concentrations correlate with adverse outcomes in acute coronary syndrome patients. Methods and Results—Baseline serum samples (n=233) from a randomized, placebo-controlled trial of abciximab plus stenting (Evaluation of Platelet IIb/IIIa Inhibitor for Stenting EPISTENT) were retrospectively analyzed. We stratified vitronectin concentrations into the 3 lower quartiles (n=178; <49.7 &mgr;g/mL) versus the fourth upper quartile (n=55; ≥49.7 &mgr;g/mL). The end point was a major adverse cardiovascular event defined as death, myocardial infarction or urgent revascularization at 30 days and 6 months. A higher proportion of patients with baseline vitronectin ≥49.7 &mgr;g/mL had major adverse cardiovascular event than patients with baseline vitronectin <49.7 &mgr;g/mL at 30 days (18.2% versus 5.6%; P=0.01) and 6 months (20.0% versus 6.2%; P=0.006). When baseline variables not predictive of major adverse cardiovascular event (eg, troponin positive, history of congestive heart failure, diabetes, history of hypertension, smoking status) were excluded from the multivariate model, only baseline vitronectin ≥49.7 &mgr;g/mL (at 30 days: OR, 3.23; 95% CI, 1.23, 8.49; at 6 months: OR, 3.36; 95% CI, 1.33, 8.52) and history of myocardial infarction (at 30 days: OR, 5.02; 95% CI, 1.41, 17.9; at 6 months: OR, 3.99; 95% CI, 1.28, 12.43) remained. No interaction occurred between abciximab and vitronectin. Conclusions—Our findings indicate that vitronectin may be an independent predictor of adverse cardiovascular outcomes following acute stenting.

Clinical Efficacy and Safety of an Implantable Cardioverter-Defibrillator Lead with a Floating Atrial Sensing Dipole: SINGLE-LEAD ATRIALSENSING ICD

The concept of a single‐lead implantable cardioverter‐defibrillator (ICD), with a floating dipole, has been proven safe and functional.

Safety and reliability of the insertable Reveal XT recorder in patients undergoing 3 Tesla brain magnetic resonance imaging

BACKGROUND Up to now there is little evidence about the safety and reliability of insertable cardiac monitors (ICMs) in patients undergoing magnetic resonance imaging (MRI). OBJECTIVE The purpose of this prospective single-center study (MACPAF; clinicaltrials.govNCT01061931), which we are currently performing, was to evaluate these issues for the ICM Reveal XT at a 3 Tesla MRI scanner in patients undergoing serial brain MRI. METHODS We present an interim analysis including 62 brain MRI examinations in 24 patients with paroxysmal atrial fibrillation bearing the Reveal XT. All patients were interviewed for potential ICM-associated clinical symptoms during and after MRI examination. According to the study protocol, data from the Reveal XT were transmitted before and after the MRI examination. RESULTS All patients were clinically asymptomatic during the MRI procedure. Moreover, the reliability (ability to detect signals, battery status) of the Reveal XT was unaffected, except for one MRI-induced artifact that was recorded by the ICM, mimicking a narrow complex tachycardia, as similarly recorded in a further study patient bearing the forerunner ICM Reveal DX. No loss of ICM data was observed after the MRI examination. CONCLUSIONS The 3 Tesla brain MRI scanning is safe for patients bearing the ICM Reveal XT and does not alloy reliability of the Reveal XT itself. MRI-induced artifacts occur rarely but have to be taken into account.

Long-term follow-up of patients with atherosclerotic renal artery disease

Atherosclerotic renal artery stenosis (ARAS) is a predictor of increased morbidity and mortality. However, whether ARAS itself accelerates the arteriosclerotic process or whether ARAS is solely the consequence of atherosclerosis is unclear. We imaged renal arteries of 1561 hypertensive patients undergoing coronary angiography and followed this cohort for 9 years (range, 2.4-15.1 years; median, 31.2 months, interquartile range, 13.4/52.9 months). All patients received aspirin, renin-angiotensin system blockade, statins, and beta blockade as indicated. One hundred seventy-one patients had ARAS >50% diameter stenosis and 126 patients an arteriosclerotic plaque (ARAP) without significant stenosis. Blood pressures were not different in ARAS, ARAP, and non-ARAS patients. After adjustment for cardiovascular risk factors by propensity scores and matched pair analysis, ARAS patients had a lower ejection fraction and more coronary artery disease (CAD) than non-ARAS patients. The same was true for brain natriuretic peptide values, troponin I, and highly sensitive C-reative protein. Over 9 years, more ARAS patients died of any cause (34% vs 23%; P < .05). The prevalence of CAD in ARAP patients was higher than in non-ARAS patients and lower than in ARAS patients. The mortality of the ARAP patients at 9 years was 37%, not different from the ARAS patients. Atherosclerotic renal artery disease appears to be a marker for the severity of atherosclerosis rather than a causative factor for atherosclerosis progression.