Abstract 15258: Radiation Induced Coronary Microvascular Compromise; a Novel Rodent Model of Heart Failure With Preserved Ejection Fraction

• Published in: Circulation (New York, N.Y.) Vol. 134; no. Suppl_1 Suppl 1; p. A15258
• Main Authors: Saiki, Hirofumi, Moulay, Gilles T, Guenzel, Adam J, Liu, Weibin, Chaanine, Antoine H, Pham, Linh, Classic, Kelly L, Decklever, Teresa D, Chen, Horng H, Burnett, John C, Russell, Stephen J, Redfield, Margaret M
• Format: Journal Article
• Language: English
• Published: by the American College of Cardiology Foundation and the American Heart Association, Inc 11-11-2016
• ISSN: 0009-7322; 1524-4539

IntroductionComorbidity-driven, coronary microvascular endothelial inflammation may be the fundamental pathophysiologic mechanism in heart failure with preserved ejection fraction (HFpEF). Cardiomyocytes are resistant to radiation but radiation specifically induces microvascular endothelial cell damage and inflammation.HypothesisCardiac radiation exposure produces isolated coronary microvascular compromise (RMVC) and recapitulates the HFpEF phenotype.MethodsCardiac expression of rat sodium iodide symporter (NIS) was induced by cardiotropic gene delivery (AAV9-NIS; 2*10 vg/rat, tail vein injection) to Sprague Dawley rats at age 5 wks. SPECT-CT (I) measured cardiac iodine uptake to calculate appropriate I doses to deliver 10 or 20 Gy cardiac radiation at age 10 wks (+ chronic T4 replacement). RMVC and Control rats were studied at age 30 wks.ResultsTable. Body weight, heart rate and blood pressure were similar across groups. EF was similar but LV diastolic volume (EDV) tended to be smaller and treadmill exercise capacity was markedly reduced in RMVC. Invasive pressure-volume analysis showed increased LV diastolic stiffness (β) and LV end-diastolic (EDP), central venous (CVP) and mean circulatory filling (Mcfp) pressures but similar preload recruitable stroke work and peak +dP/dt in RMVC, consistent with isolated diastolic dysfunction. Pathology revealed similar heart weight but reduced microvascular density and increased LV fibrosis in RMVC. In RMVC myocardium, fetal gene expression (ANP mRNA) was increased and correlated inversely with microvascular density (p<0.001) but not heart weight. Myocardial MnSOD protein was reduced in RMVC suggesting oxidative stress.ConclusionIn the absence of pressure overload, isolated coronary microvascular compromise produces a HFpEF phenotype. This model may be useful for testing HFpEF therapeutic strategies targeting microvascular compromise and its sequella.