Temporal Progression of Coronary Microvascular Dysfunction in Swine with Repetitive Pressure Overload-Induced Heart Failure with Preserved Ejection Fraction
Authors: Hudson Emily , Rolland Tyler , Palka Beth , Nsumbu Dorcas , Canty John , Weil Brian 
Published: May 2023

Objective: We have previously shown that swine subjected to 2-weeks of intermittent repetitive pressure overload (RPO) develop a cardiac phenotype seen in many patients with heart failure with preserved ejection fraction (HFpEF), characterized by an increase in left ventricular (LV) diastolic stiffness, myocyte hypertrophy, and interstitial fibrosis without an increase in LV mass. Given emerging evidence of a potential role for coronary microvascular dysfunction (CMD) in the pathophysiology of HFpEF, we serially measured adenosine (ADO)-mediated coronary vasodilation in swine subjected to RPO to evaluate the time course of CMD relative to changes in LV stiffness in this model. Methods: Swine (n=23) were subjected to up to 2 weeks of RPO via daily infusions of phenylephrine (PE; 400 μg/min; 30-60 min/day). Regional myocardial blood flow (BF) was assessed via administration of fluorescent microspheres at rest and during submaximal ADO-mediated vasodilation (0.15 mg/kg/min) at baseline, 1 hour and 24 hours after the initial episode of pressure overload (n=7), after 3 days of RPO (n=6), and after 2 weeks of RPO (n=10). Echocardiography and invasive hemodynamic analysis were performed during PE infusion at selected timepoints to assess LV diastolic stiffness (ΔLVEDP/ΔLVEDV). Results: Impaired ADO-mediated coronary vasodilation was apparent following a single episode of transient pressure overload, as coronary flow reserve (CFR) fell from 2.1±0.3 at baseline to 1.2±0.1 one hour after the first PE infusion (p=0.03). This effect was temporary, however, as CFR normalized 24 hours later (2.3±0.4; p=0.60 vs. baseline). After 3 days of RPO, the impairment in ADO-mediated coronary vasodilation was no longer reversible, with a persistent reduction in CFR (1.4±0.1; p=0.03 vs. baseline) that was still evident after 2 weeks of RPO (1.2±0.1; p<0.01 vs. baseline). The development of persistent CMD occurred before significant changes in LV stiffness, as ΔLVEDP/ΔLVEDV rose gradually from 0.6±0.1 mmHg/mL at baseline to 0.8±0.1 mmHg/mL after 3 days of RPO (p=0.12 vs. baseline) and 2.0±0.4 mmHg/mL after 2 weeks of RPO (p<0.01 vs. baseline). Conclusions: Although transient hypertension-induced CMD is initially reversible, persistent impairments in ADO-mediated coronary vasodilation are apparent as soon as 3 days after the onset of RPO in swine. The onset of CMD precedes the increase in LV diastolic stiffness in this model, suggesting that microvascular dysfunction may be mechanistically involved in the pathogenesis of LV stiffening. Future studies are necessary to test this hypothesis, as well as determine whether impaired coronary responsiveness to ADO compromises myocardial perfusion during episodes of increased metabolic demand. Supported by funding from the National Institutes of Health (1R56HL14135901, 1RO1HL60538) and the United States Department of Veteran's Affairs (1IOBX002659). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.