Experimental cardiac radiation exposure induces ventricular diastolic dysfunction with preserved ejection fraction

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 313; no. 2; pp. H392 - H407
• Main Authors: Saiki, Hirofumi, Moulay, Gilles, Guenzel, Adam J, Liu, Weibin, Decklever, Teresa D, Classic, Kelly L, Pham, Linh, Chen, Horng H, Burnett, John C, Russell, Stephen J, Redfield, Margaret M
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.08.2017
• Series: Integrative Cardiovascular Physiology and Pathophysiology
• Subjects: Animals; Blood pressure; Body weight; Breast cancer; Cardiomyocytes; Cells; Cyclic GMP - metabolism; Cyclic GMP-Dependent Protein Kinases - metabolism; Dependovirus - genetics; Diastole; Dose-Response Relationship, Radiation; Endothelial cells; Experiments; Fibrosis; Gene expression; Genetic Vectors; Heart failure; Heart rate; Iodine; Life Sciences; Male; Myocardium; Myocardium - metabolism; Myocardium - pathology; Oxidative stress; Oxidative Stress - radiation effects; Radiation; Radiation effects; Radiation Injuries, Experimental - etiology; Radiation Injuries, Experimental - genetics; Radiation Injuries, Experimental - metabolism; Radiation Injuries, Experimental - physiopathology; Radiation therapy; Rarefaction; Rats, Sprague-Dawley; Signal Transduction - radiation effects; Stiffness; Stroke Volume - drug effects; Symporters - genetics; Symporters - metabolism; Time Factors; Transduction, Genetic; Ventricular Dysfunction, Left - etiology; Ventricular Dysfunction, Left - genetics; Ventricular Dysfunction, Left - metabolism; Ventricular Dysfunction, Left - physiopathology; Ventricular Function, Left - drug effects; Viruses; diastolic dysfunction; heart failure with preserved ejection fraction; coronary microvasculature; animal model; radiation
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00124.2017

Breast cancer radiotherapy increases the risk of heart failure with preserved ejection fraction (HFpEF). Cardiomyocytes are highly radioresistant, but radiation specifically affects coronary microvascular endothelial cells, with subsequent microvascular inflammation and rarefaction. The effects of radiation on left ventricular (LV) diastolic function are poorly characterized. We hypothesized that cardiac radiation exposure may result in diastolic dysfunction without reduced EF. Global cardiac expression of the sodium-iodide symporter (NIS) was induced by cardiotropic gene (adeno-associated virus serotype 9) delivery to 5-wk-old rats. SPECT/CT ( I) measurement of cardiac iodine uptake allowed calculation of the I doses needed to deliver 10- or 20-Gy cardiac radiation at 10 wk of age. Radiated (Rad; 10 or 20 Gy) and control rats were studied at 30 wk of age. Body weight, blood pressure, and heart rate were similar in control and Rad rats. Compared with control rats, Rad rats had impaired exercise capacity, increased LV diastolic stiffness, impaired LV relaxation, and elevated filling pressures but similar LV volume, EF, end-systolic elastance, preload recruitable stroke work, and peak +dP/d Pathology revealed reduced microvascular density, mild concentric cardiomyocyte hypertrophy, and increased LV fibrosis in Rad rats compared with control rats. In the Rad myocardium, oxidative stress was increased and in vivo PKG activity was decreased. Experimental cardiac radiation exposure resulted in diastolic dysfunction without reduced EF. These data provide insight into the association between cardiac radiation exposure and HFpEF risk and lend further support for the importance of inflammation-related coronary microvascular compromise in HFpEF. Cardiac radiation exposure during radiotherapy increases the risk of heart failure with preserved ejection fraction. In a novel rodent model, cardiac radiation exposure resulted in coronary microvascular rarefaction, oxidative stress, impaired PKG signaling, myocardial fibrosis, mild cardiomyocyte hypertrophy, left ventricular diastolic dysfunction, and elevated left ventricular filling pressures despite preserved ejection fraction.