Urocortin 2 Gene Transfer in Mice Improves Diastolic Function in Heart Failure with Preserved Ejection Fraction

Patients with heart failure and preserved ejection fraction (HFpEF) comprise about 50% of patients with heart failure in the US (>3 million people). There are currently no treatments for HFpEF that prolong life, and few that reduce HF hospitalization rates. The Schlager BPH (Blood Pressure-High) mouse is a genetic model of hypertension, a major contributing factor in left ventricular (LV) diastolic dysfunction and HFpEF. This study test the hypothesis that intravenous (i.v.) delivery of a long-term expression vector encoding murine urocortin 2 (AAV8.m Ucn2) can improve LV diastolic function in mice with impaired LV diastolic function. Twelve male and 12 female BPH mice (21.3±0.5 g; 3.1±0.1 months-old) with an ejection fraction (EF) of 60±2% (echocardiography) were studied. Prior to Ucn2 gene transfer their unsedated systolic/diastolic blood pressures (tail cuff) were (183/146±2/7 mmHg, n=24), conforming the presence of severe hypertension. The BPH mice were separated into two groups (6M & 6F in each group). One group (BPH + Ucn2) received AAV8.m Ucn2 (2x1013 gc/kg, i.v) and the other group (BPH) received saline, i.v. Seven weeks after randomization, LV EF showed a group difference (BPH: 54±2%, n=12; BPH+Ucn2: 74±2%, n=12; p<.0001) that was same as with systolic/diastolic blood pressure (BPH: 183/154±4/4 mmHg, n=12; BPH +Ucn2: 142/117±4/4 mmHg; p<0.0001). In addition, physiological studies conducted in vivo showed accelerated cardiac relaxation in the Ucn2-treated mice (see Tau in Table), indicating superior LV relaxation after Ucn2 gene transfer. Conclusion: Ucn2 gene transfer improves LV diastolic and systolic function in mice with HFpEF, indicating that such a strategy may be applicable in clinical settings. [Formula: see text] Merit grant from the Department of Veterans Affairs (I01 BX003774). This is the full abstract presented at the American Physiology Summit 2024 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.