Heart Rate Variability And Chronotropic Incompetence As Prognostic Markers In A Preclinical Model Of HFpEF

The prevalence of heart failure with preserved ejection fraction (HFpEF) in developed countries is increasing alarmingly. This is in part due to an increase in comorbid diseases (obesity, diabetes, hypertension), and risk factors (age, stress, and low physical activity). HFpEF patients often present with chronotropic incompetence (CI) and impaired heart rate variability (HRV), and both CI and decreased HRV are used as prognostic markers of heart disease and sudden cardiac death in clinical studies. In preclinical HFpEF models, however, CI and HRV are not commonly evaluated, and the efficacy of novel compounds is determined primarily through echocardiography results. Thus, there is a need to align efficacy readouts to enhance the translatability of novel compounds from preclinical to clinical stages. Here we sought to determine the utility of CI and HRV in preclinical HFpEF studies in a novel 2-hit HFpEF model; the metabolic syndrome non-alcoholic steatohepatitis mouse with AAV overexpression of renin (MS-NASH+Renin). To collect continuous and conscious electrocardiogram and blood pressure data, C57BL/6 (n=10) and MS-NASH (formerly FATZO, n=32) male mice were implanted with radiotelemeters at 20 weeks and iv injected with either AAV-Vector or AAV-Renin. To assess disease burden, CI and HRV, we acquired and analyzed body weight, electrocardiography, peak VO2, exercise HR, and echocardiography data once a month for 5 months. We found that MS-NASH mice have increased body weight regardless of treatment, and that renin treatment increased blood pressure for both C57BL/6 and MS-NASH mice. Peak VO2, time to exhaustion, distance traveled, and maximum and recovery HR are significantly decreased in MS-NASH mice, indicating CI. HRV is also significantly decreased in MS-NASH mice when compared to C57BL/6. Interestingly, renin treatment did not further decrease treadmill performance or HRV for MS-NASH mice. However, MS-NASH+Renin mice did have decreased functional capacity with preserved ejection fraction and altered heart structure. These results suggest that MS-NASH+Renin is a model for HFpEF, and that CI and HRV are translatable markers for HFpEF. In the future, we will evaluate the use of CI and HRV in preclinical HFpEF drug development studies.