Non-Invasive Technology That Improves Cardiac Function after Experimental Myocardial Infarction: Whole Body Periodic Acceleration (pGz)

March Non-Invasive Technology That Improves Cardiac Function after Experimental Myocardial Infarction: Whole Body Periodic Acceleration (pGz) Arkady Uryash 0 1 2 Jorge Bassuk 0 1 2 Paul Kurlansky 0 1 2 Francisco Altamirano 0 1 2 Jose R. Lopez 0 1 2 Jose A. Adams 0 1 2 0 1 Division of Neonatology, Mount Sinai Medical Center , Miami Beach, FL , United States of America, 2 Columbia Heart Source, Columbia University College of Physicians and Surgeons , New York, NY , United States of America, 3 Departments of Molecular Bioscience, School of Veterinary Medicine, University of California Davis , Davis, CA , United States of America 1 Funding: This work was funded by a grant from the Florida Heart Research Institute (http://www. floridaheart.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript 2 Academic Editor: Jun Yu, Yale University School of Medicine, UNITED STATES Myocardial infarction (MI) may produce significant inflammatory changes and adverse ventricular remodeling leading to heart failure and premature death. Pharmacologic, stem cell transplantation, and exercise have not halted the inexorable rise in the prevalence and great economic costs of heart failure despite extensive investigations of such treatments. New therapeutic modalities are needed. Whole Body Periodic Acceleration (pGz) is a noninvasive technology that increases pulsatile shear stress to the endothelium thereby producing several beneficial cardiovascular effects as demonstrated in animal models, normal humans and patients with heart disease. pGz upregulates endothelial derived nitric oxide synthase (eNOS) and its phosphorylation (p-eNOS) to improve myocardial function in models of myocardial stunning and preconditioning. Here we test whether pGz applied chronically after focal myocardial infarction in rats improves functional outcomes from MI. Focal MI was produced by left coronary artery ligation. One day after ligation animals were randomized to receive daily treatments of pGz for four weeks (MI-pGz) or serve as controls (MI-CONT), with an additional group as non-infarction controls (Sham). Echocardiograms and invasive pressure volume loop analysis were carried out. Infarct transmurality, myocardial fibrosis, and markers of inflammatory and anti-inflammatory cytokines were determined along with protein analysis of eNOS, p-eNOS and inducible nitric oxide synthase (iNOS).At four weeks, survival was 80% in MI-pGz vs 50% in MI-CONT (p< 0.01). Ejection fraction and fractional shortening and invasive pressure volume relation indices of afterload and contractility were significantly better in MI-pGz. The latter where associated with decreased infarct transmurality and decreased fibrosis along with increased eNOS, p-eNOS. Additionally, MI-pGz had significantly lower levels of iNOS, inflammatory cytokines (IL-6, TNF-), and higher level of anti-inflammatory cytokine (IL-10). pGz improved survival and contractile - Competing Interests: Jose A. Adams has read the journals policy and the authors of this manuscript have the following competing interests: the following authors AU, JB, PK, FA, and JRL have declared that no competing interests exist. JAA owns minimal number of stocks in Noninvasive Monitoring Systems (NIMS), a company which manufactures a platform similar to the one described in this study. This does not alter the authors adherence to PLOS ONE policies on sharing data and materials. performance, associated with improved myocardial remodeling. pGz may serve as a simple, safe, non-invasive therapeutic modality to improve myocardial function after MI. Myocardial Infarction (MI) and its associated functional derangements may lead to heart failure that affects 23% of the population in industrialized countries with a marked rise in those aged >65yr. A combined estimate of ~ 20 million people suffer from heart failure in Europe and the US and its prevalence is increasing. In the US alone direct medical costs approximate $25 billion dollars per year and expected to triple by 2030 [14]. Attempts to ameliorate myocardial dysfunction after MI, using pharmacologic, stem cell transplantation, and exercise have been widely explored in experimental and in clinical trials. The search for simple inexpensive therapeutic interventions continues. Whole Body Periodic Acceleration (pGz) is the repetitive, sinusoidal head-foot motion of the body provided by a motion platform. As the body accelerates and decelerates, low amplitude pulses are added to the circulation as a function of platform frequency thereby increasing pulsatile shear stress to the endothelium [58, 9]. pGz through its increase of pulsatile shear stress upregulates eNOS and increases its phosphorylation p-eNOS (Ser 1177) [10] eNOS phosphorylation after pGz is responsible for shear stress dependent vasodilatation and subsequent increase nitric oxide (eNO) release into the circulation [9, 1113]. pGz applied in a swine model of myocardial stunning induced by whole body ischemia reperfusion injury, acutely improves myocardial function due to increase eNO as well as other cardioprotective mediators [6, 8, 10, 14]. The purpose of this investigation was to test whether pGz applied chronically after focal myocardial infarction in rats would improve functional outcomes from MI. Materials and Methods Animals and Experimental Design The experimental protocol No. 13-08-A-03 was approved by the Mount Sinai Medical Center Animal Care and Use Committee and conforms to the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health [NIH Publication No. 85-23, revised 1996]. Adult male Sprague-Dawley rats (300350 g) were randomly assigned to (n = 60): 1) pGz started 24 hr after MI, 1 hr per day 5 days per week for four weeks (MI-pGz) (n = 20); 2) A control group (MI-CONT) animals were placed on the pGz platform starting at 24 hr after MI but the platform was not actuated (n = 20); 3) Sham group, animals where anesthetized but no MI was induced (Sham) (n = 10) (Fig. 1). After experimental MI was induced by permanent ligation of the left coronary artery, the animals recovered for 24 hr. Awake animals were placed in a restraint for 1hr/day 5 days per week for four weeks. Optimal pGz frequency of 360 cpm and peak acceleration amplitude of Gz 2.9 m/sec2 in rats for increased release of eNO was utilized [10, 13]. pGz was administered at the same time of the day for the various study groups. Animals who did not receive pGz were placed in the same restraint for the same number of days as the experimental groups. Fig 1. Myocardial Infarction Protocol Schematic. Permanent ligation of left coronary artery without reperfusion was done. pGz or Control were begun 24 hr after MI, and continued for four weeks. Post-MI echocardiograms (Echo) were done immediately post MI, at 1,3,4 weeks. Invasive Pressure Volume Loops were collected at end of study. Myocardial Infar (...truncated)