Background/Introduction
The constantly growing population of patients suffering from heart failure with preserved ejection fraction (HFpEF) is one of the largest unmet needs in cardiovascular medicine and predictive animal models are important for identification and profiling of novel therapeutic approaches. Apart from classical pathophysiological aspects like left ventricular (LV) hypertrophy and diastolic dysfunction comprehensive large animal models should also exhibit effort intolerance and etiological key features like components of the metabolic syndrome (MetS).

Ossabaw pigs have shown that chronic cardiac pressure overload by aortic banding (AoB), when combined with a Western diet leads to LV hypertrophy, diastolic dysfunction and MetS in the Ossabaw pig, reflecting important features of human HFpEF characteristics. But current studies often do not include exercise testing and lack a close temporal evaluation of disease relevant parameters.  

Purpose
We aim to provide proof of concept, that the disease progression of Ossabaw pigs exhibiting a cardiometabolic HFpEF phenotype can be investigated under rest and submaximal exercise testing by non-invasive techniques. This combined approach should demonstrate the ability to longitudinally evaluate hemodynamic changes due to chronic cardiac pressure overload and the development of MetS and effort intolerance in translational animal models for HFpEF.

Methods
Naive, female Ossabaw pigs were instrumented with telemetric devices followed by AoB to induce chronic cardiac pressure overload. The wound healing and acclimatization period was followed by the start of a Western diet feeding regime to mimic components of the MetS. Disease progression was characterized by monthly telemetric recordings of LV systolic pressure (LVSP), LV end diastolic pressure (LVEDP) and mean arterial pressure (MAP) for 24 h at rest over 9 months post AoB. To evaluate effort intolerance the heart rate (HR) was recorded during a treadmill exercise of 1 min at 2; 3; 4 and 5 km/h with resting periods of 4 min before and after exercise over 7 months post AoB. Changes in LVSP, LVEDP, MAP and HR were compared to a control (Ctrl) measurement in healthy animals.

Results
Compared to Ctrl LV pressures were significantly increased to maximal values 8 months post AoB (112.5 ± 15.3 to 177.5 ± 21.8 mmHg for LVSP and 10.8 ± 10.7 to 29.6 ± 7.8 mmHg for LVEDP). Compared to Ctrl (90.9 ± 13.7 mmHg) the MAP significantly increased after AoB to a maximum of 119.1 ± 13.6 mmHg 9 months post AoB. The HR was significantly increased compared to Ctrl from 1-7 months under rest (baseline and recovery) as well as during exercise. Maximum HRs of 176.4 ± 2.0 and 201.5 ± 2.2 bpm were reached 7 months post AoB under 4 and 5 km/h respectively.

Conclusion(s)
We were able to follow the long-term increase of LV pressures due to AoB and MAP potentially driven by both, AoB and the manifestation of MetS. Exercise testing was feasible to provoke submaximal HR elevations and revealed significant intolerance to effort during disease progression. This work demonstrates the opportunity to non-invasively and longitudinally characterise features that are relevant to evaluate HFpEF manifestation in translational animal models.