Alterations in Myocardial Oxygen Balance, Anaerobic Metabolism and Diastolic Dysfunction in Exercising Swine with Multiple Comorbidities

Abstract

IntroductionMultiple comorbidities, including diabetes mellitus (DM), hypercholesterolemia and chronic kidney disease (CKD) are associated with diastolic dysfunction. These risk factors also cause coronary microvascular dysfunction leading to impaired myocardial perfusion and ischemia with non‐obstructive coronary artery disease (INOCA). Recently a link has been proposed between INOCA and HFpEF. We investigated the detrimental effects of DM, CKD and high fat diet (HFD) on myocardial function and perfusion.HypothesisProlonged exposure to multiple comorbidities in swine leads to diastolic dysfunction, associated with impaired myocardial perfusion and anaerobic metabolism.MethodsDM (streptozotocin 3×50mg/kg i.v.) and CKD (renal embolization) were induced in 7 female swine fed a high fat diet (DM+HFD+CKD), while 10 female healthy swine on normal diet served as controls (CON). After 6 months, myocardial perfusion and oxygen balance were studied at rest and during treadmill exercise. At sacrifice PV‐loop measurements and histology were performed.ResultsDM+HFD+CKD animals showed hyperglycemia (glucose: 19.2±1.5 vs 7.5±0.6 mmol/L), renal dysfunction (glomerular filtration rate: 132±14 vs 197±10 ml/min) and hypercholesterolemia (total cholesterol: 8.28±0.86 vs 1.65±0.06 mmol/l, all P<0.05). DM+HFD+CKD had an increased EDPVR (0.14±0.02 vs 0.09±0.01 mmHg/mL) with preserved ejection fraction, a lower cardiac index compared to CON at similar levels of exercise (fig A). Left ventricular myocardial capillary density was decreased (1229±59 vs 1502±86 #/mm2) and collagen content was increased (9.6±1.9 vs 5.0±0.6 %). Their myocardium required more oxygen for similar levels of cardiac work, suggesting cardiac inefficiency (fig B). Furthermore, they showed a lower myocardial oxygen delivery (fig C), forcing the myocardium to increase its oxygen extraction (fig D) leading to lower coronary venous oxygen saturation (fig E) both at rest and during exercise. This was accompanied by a decrease in myocardial lactate consumption at the same lactate supply as in CON (fig F), suggestive of anaerobic metabolism. Importantly, DM+HFD+CKD showed no coronary atherosclerosis.ConclusionMultiple co‐morbidities in swine result in severe perturbations in myocardial oxygen balance and anaerobic metabolism in the absence of significant atherosclerosis, indicating severe coronary microvascular dysfunction co‐occurring with diastolic dysfunction.Support or Funding InformationThis study was supported by grants from the European Commission FP7‐Health‐2010 grant MEDIA‐261409, the Netherlands CardioVascular Research Initiative: an initiative with support of the Dutch Heart Foundation [CVON2012‐08 (PHAEDRA), CVON2014‐11 (RECONNECT)]. Cardiac index (CI) of DM+HFD+CKD was lower than in CON swine (A). Myocardium of DM+HFD+CKD swine shows increased oxygen consumption (MVO2) for the same level of cardiac work (B), has a lower myocardial oxygen delivery (MDO2, C) and a higher oxygen extraction (MEO2, D), which results in lower coronary venous oxygen saturation (cv SaO2, E). Lower myocardial lactate consumption (MVlactate) at a given level of myocardial lactate delivery (MDlactate, F). *p<0.05 DM+HFD+CKD versus CONimageCardiac index (CI) of DM+HFD+CKD was lower than in CON swine (A). Myocardium of DM+HFD+CKD swine shows increased oxygen consumption (MVO2) for the same level of cardiac work (B), has a lower myocardial oxygen delivery (MDO2, C) and a higher oxygen extraction (MEO2, D), which results in lower coronary venous oxygen saturation (cv SaO2, E). Lower myocardial lactate consumption (MVlactate) at a given level of myocardial lactate delivery (MDlactate, F). *p<0.05 DM+HFD+CKD versus CONThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.