CLIC4 localizes to mitochondrial-associated membranes and mediates cardioprotection.

Mitochondrial-associated membranes (MAMs) are known to modulate organellar and cellular functions and can subsequently affect pathophysiology including myocardial ischemia-reperfusion (IR) injury. Thus, identifying molecular targets in MAMs that regulate the outcome of IR injury will hold a key to efficient therapeutics. Here, we found chloride intracellular channel protein (CLIC4) presence in MAMs of cardiomyocytes and demonstrate its role in modulating ER and mitochondrial calcium homeostasis under physiological and pathological conditions. In a murine model, loss of CLIC4 increased myocardial infarction and substantially reduced cardiac function after IR injury. CLIC4 null cardiomyocytes showed increased apoptosis and mitochondrial dysfunction upon hypoxia-reoxygenation injury in comparison to wild-type cardiomyocytes. Overall, our results indicate that MAM-CLIC4 is a key mediator of cellular response to IR injury and therefore may have a potential implication on other pathophysiological processes.

Inhibition of BKCa channels protects neonatal hearts against myocardial ischemia and reperfusion injury.

BKCa channels are large-conductance calcium and voltage-activated potassium channels that are heterogeneously expressed in a wide array of cells. Activation of BKCa channels present in mitochondria of adult ventricular cardiomyocytes is implicated in cardioprotection against ischemia-reperfusion (IR) injury. However, the BKCa channel's activity has never been detected in the plasma membrane of adult ventricular cardiomyocytes. In this study, we report the presence of the BKCa channel in the plasma membrane and mitochondria of neonatal murine and rodent cardiomyocytes, which protects the heart on inhibition but not activation. Furthermore, K+ currents measured in neonatal cardiomyocyte (NCM) was sensitive to iberiotoxin (IbTx), suggesting the presence of BKCa channels in the plasma membrane. Neonatal hearts subjected to IR when post-conditioned with NS1619 during reoxygenation increased the myocardial infarction whereas IbTx reduced the infarct size. In agreement, isolated NCM also presented increased apoptosis on treatment with NS1619 during hypoxia and reoxygenation, whereas IbTx reduced TUNEL-positive cells. In NCMs, activation of BKCa channels increased the intracellular reactive oxygen species post HR injury. Electrophysiological characterization of NCMs indicated that NS1619 increased the beat period, field, and action potential duration, and decreased the conduction velocity and spike amplitude. In contrast, IbTx had no impact on the electrophysiological properties of NCMs. Taken together, our data established that inhibition of plasma membrane BKCa channels in the NCM protects neonatal heart/cardiomyocytes from IR injury. Furthermore, the functional disparity observed towards the cardioprotective activity of BKCa channels in adults compared to neonatal heart could be attributed to their differential localization.

Inhibition of BKCa negatively alters cardiovascular function.

Large conductance calcium and voltage-activated potassium channels (BKCa ) are transmembrane proteins, ubiquitously expressed in the majority of organs, and play an active role in regulating cellular physiology. In the heart, BKCa channels are known to play a role in regulating the heart rate and protect it from ischemia-reperfusion injury. In vascular smooth muscle cells, the opening of BKCa channels results in membrane hyperpolarization which eventually results in vasodilation mediated by a reduction in Ca2+ influx due to the closure of voltage-dependent Ca2+ channels. Ex vivo studies have shown that BKCa channels play an active role in the regulation of the function of the majority of blood vessels. However, in vivo role of BKCa channels in cardiovascular function is not completely deciphered. Here, we have evaluated the rapid in vivo role of BKCa channels in regulating the cardiovascular function by using two well-established, rapid-acting, potent blockers, paxilline and iberiotoxin. Our results show that BKCa channels are actively involved in regulating the heart rate, the function of the left and right heart as well as major vessels. We also found that the effect on BKCa channels by blockers is completely reversible, and hence, BKCa channels can be exploited as potential targets for clinical applications for modulating heart rate and cardiac contractility.

Recent technological advancements in cardiac ultrasound imaging.

About 92.1 million Americans suffer from at least one type of cardiovascular disease. Worldwide, cardiovascular diseases are the number one cause of death (about 31% of all global deaths). Recent technological advancements in cardiac ultrasound imaging are expected to aid in the clinical diagnosis of many cardiovascular diseases. This article provides an overview of such recent technological advancements, specifically focusing on tissue Doppler imaging, strain imaging, contrast echocardiography, 3D echocardiography, point-of-care echocardiography, 3D volumetric flow assessments, and elastography. With these advancements ultrasound imaging is rapidly changing the domain of cardiac imaging. The advantages offered by ultrasound imaging include real-time imaging, imaging at patient bed-side, cost-effectiveness and ionizing-radiation-free imaging. Along with these advantages, the steps taken towards standardization of ultrasound based quantitative markers, reviewed here, will play a major role in addressing the healthcare burden associated with cardiovascular diseases.

Readmission rate after ultrafiltration in acute decompensated heart failure: a systematic review and meta-analysis.

Significance of ultrafiltration in acute decompensated heart failure remains unclear. We performed meta-analysis to determine its role in reducing readmissions after acute decompensated heart failure. MEDLINE was searched using PUBMED from inception to March 22, 2017 for prospective randomized control trials comparing ultrafiltration to diuretics in acute decompensated heart failure. Five hundred ninety studies were found; nine studies with 820 patients were included. Studies with renal replacement therapy bar ultrafiltration, chronic decompensated heart failure, and non-English language were excluded. RevMan Version 5.3 was used for analysis. The primary outcomes analyzed were cumulative and 90 days readmissions secondary to heart failure and all-cause readmissions. Baseline characteristics were similar. One hundred eighty-eight patients were readmitted with heart failure, 77 vs 111 favoring ultrafiltration; risk ratio (RR) = 0.71 (95% confidence interval (CI), 0.49-1.02, p = 0.07, I 2  = 47%). Ninety days readmissions were 43 vs 67 favoring ultrafiltration; RR = 0.65 (95%CI, 0.47-0.90, p = 0.01, I 2  = 0%). Ultrafiltration showed significantly higher fluid removal and weight loss. Hypotension was common in ultrafiltration (24 vs 13, OR = 2.06, 95%CI = 0.98-4.32, p = 0.06, I 2  = 0%). Ultrafiltration showed reduced 90 days heart failure readmissions and trend towards reduced cumulative hospital readmissions. Renal and cardiovascular outcomes and hospital stay were similar.

Magnetic Nanoparticle-Mediated Targeting of Cell Therapy Reduces In-Stent Stenosis in Injured Arteries.

Although drug-eluting stents have dramatically reduced the recurrence of restenosis after vascular interventions, the nonselective antiproliferative drugs released from these devices significantly delay reendothelialization and vascular healing, increasing the risk of short- and long-term stent failure. Efficient repopulation of endothelial cells in the vessel wall following injury may limit complications, such as thrombosis, neoatherosclerosis, and restenosis, through reconstitution of a luminal barrier and cellular secretion of paracrine factors. We assessed the potential of magnetically mediated delivery of endothelial cells (ECs) to inhibit in-stent stenosis induced by mechanical injury in a rat carotid artery stent angioplasty model. ECs loaded with biodegradable superparamagnetic nanoparticles (MNPs) were administered at the distal end of the stented artery and localized to the stent using a brief exposure to a uniform magnetic field. After two months, magnetic localization of ECs demonstrated significant protection from stenosis at the distal part of the stent in the cell therapy group compared to both the proximal part of stent in the cell therapy group and the control (stented, nontreated) group: 1.7-fold (p < 0.001) less reduction in lumen diameter as measured by B-mode and color Doppler ultrasound, 2.3-fold (p < 0.001) less reduction in the ratios of peak systolic velocities as measured by pulsed wave Doppler ultrasound, and 2.1-fold (p < 0.001) attenuation of stenosis as determined through end point morphometric analysis. The study thus demonstrates that magnetically assisted delivery of ECs is a promising strategy for prevention of vessel lumen narrowing after stent angioplasty procedure.

The potential of ultrasound in cardiac pacing and rhythm modulation.

INTRODUCTION: This review examines the potential for ultrasound to induce or otherwise influence cardiac pacing and rhythm modulation. AREAS COVERED: Of particular interest is the possibility of developing new, truly non-invasive, nonpharmacological, acute and chronic, ultrasound-based arrhythmia treatments. Such approaches would not depend upon implanted or indwelling devices of any kind and would use ultrasound at diagnostic exposure levels (so as not to harm the heart or surrounding tissues). It is known that ultrasound can cause cardiomyocyte depolarization and a variety of underlying mechanisms have been proposed. Expert commentary: Questions still remain regarding the effect of exposure parameters and work will also be necessary to identify the optimal target regions within the heart if ultrasound energy is to be used to induce safe and reliable pacing in a clinical setting.

Ultrasound-induced modulation of cardiac rhythm in neonatal rat ventricular cardiomyocytes.

Isolated neonatal rat ventricular cardiomyocytes were used to study the influence of ultrasound on the chronotropic response in a tissue culture model. The beat frequency of the cells, varying from 40 to 90 beats/min, was measured based upon the translocation of the nuclear membrane captured by a high-speed camera. Ultrasound pulses (frequency = 2.5 MHz) were delivered at 300-ms intervals [3.33 Hz pulse repetition frequency (PRF)], in turn corresponding to 200 pulses/min. The intensity of acoustic energy and pulse duration were made variable, 0.02-0.87 W/cm(2) and 1-5 ms, respectively. In 57 of 99 trials, there was a noted average increase in beat frequency of 25% with 8-s exposures to ultrasonic pulses. Applied ultrasound energy with a spatial peak time average acoustic intensity (Ispta) of 0.02 W/cm(2) and pulse duration of 1 ms effectively increased the contraction rate of cardiomyocytes (P < 0.05). Of the acoustic power tested, the lowest level of acoustic intensity and shortest pulse duration proved most effective at increasing the electrophysiological responsiveness and beat frequency of cardiomyocytes. Determining the optimal conditions for delivery of ultrasound will be essential to developing new models for understanding mechanoelectrical coupling (MEC) and understanding novel nonelectrical pacing modalities for clinical applications.

Extracorporeal acute cardiac pacing by high intensity focused ultrasound.

Ultrasound has been shown to produce Premature Ventricular Contractions (PVC's). Two clinical applications in which acute cardiac pacing by ultrasound may be valuable are: (1) preoperative patient screening in cardiac resynchronization therapy surgery; (2) Emergency life support, following an event of sudden death, caused by cardiac arrest. Yet, previously the demonstrated mean success rate of extra-systole induction by High Intensity Focused Ultrasound (HIFU) in rats is below 4.5% (Miller et al., 2011). This stands in contrast to previous work in rats using ultrasound (US) and ultrasound contrast agents (UCAs), where success rates of close to 100% were reported (Rota et al., 2006). Herein, bi-stage temporal sequences of accentuated negative pressure (rarefaction) and positive pressure HIFU transmission (insonation) patterns were applied to anaesthetized rats under real-time vital-signs monitoring and US imaging. This pattern of insonation first produces a gradual growth of dissolved gas cavities in tissue (cavitation) and then an ultrasonic impact. Results demonstrate sequences of successive successful HIFU pacing. Triggering insonation at different delays from the preceding ECG R-wave demonstrated successful HIFU pacing induction from mid ECG T-wave till the next ECG complex's PR interval. Spatially focusing the beam at different locations allows cumulative coverage of the whole left ventricle. Analysis of the acoustic wave patterns and temporal characteristics of paced PVCs is suggested to provide new insight into the mechanisms of HIFU cardiac pacing. Specifically, the observed HIFU pacing temporal success rate distribution suggests against sarcomere length modulation current being the dominant cellular level mechanism of HIFU cardiac pacing and may allow postulating that membrane deformation currents are dominant at the applied insonation conditions.

Percutaneous extraction of ePTFE-coated ICD leads: a single center comparative experience.

BACKGROUND: Percutaneous extraction of standard implantable cardioverter-defibrillator leads is often complicated by ingrowth of fibrotic tissue into the shocking coils. Leads with GORE™ expanded polytetrafluoroethylene (ePTFE) coating (W. L. Gore & Associates, Inc., Newark, DE, USA) designed to inhibit fibrosis are in use, but clinical data regarding their extraction are lacking. The study's purpose was to examine the feasibility, efficacy, and safety of percutaneous extraction involving defibrillator leads coated with ePTFE. METHODS: We analyzed our database to identify all percutaneously extracted leads with ePTFE-coated shocking coils. Lead and procedure characteristics were compared to a cohort of noncoated leads of similar implant duration. RESULTS: One hundred fifty-six leads were extracted from 145 patients; 57 ePTFE-coated leads, with a mean implant duration of 621 days, were extracted and compared to 99 noncoated leads, with a mean implant duration of 763 days (P = 0.0641). Mean extraction time was 5 minutes for coated leads versus 9.75 minutes for noncoated leads (P = 0.0001). Extraction time of less than 1 minute was more frequent with coated leads (61% vs 35%, P = 0.0025). Adjunct extraction tools were required less frequently with coated leads than noncoated leads (39% vs 63%, P = 0.0071). There was no fibrosis where ePTFE covered the shocking coils. Alternatively, 23 of 99 (23%) noncoated leads demonstrated fibrosis adherent to the shock coil. There were no procedure-related complications in either group. CONCLUSIONS: Compared to noncoated leads, ePTFE-coated leads are associated with shorter extraction times and are less likely to require extraction tools for removal. The difference is likely related to the absence of fibrosis over the ePTFE-coated high-energy coils.