Introduction
Metabolic diseases like obesity, diabetes and hypercholesterolemia are major risk factors for the development and progression of heart failure (HF). HF is associated with impaired autonomic reflexes, sympathetic activation and impaired parasympathetic outflow, suggesting that autonomic dysfunction (AD) is involved in the pathogenesis of HF. However, little is known to which extent the progression of the cardiometabolic HF phenotype leads to the development of AD. Aim of this study was to develop a disease model in large animals of cardiometabolic HF to evaluate AD during disease progression.
Material and methods
14 Ossabaw pigs were included in the study and were implanted with telemetry sensors to measure cardiac and systemic hemodynamics, ECG, and physical activity. The animals were divided into two groups: The first group underwent aortic banding (AOB) to increase cardiac afterload and was fed a western diet (WD) to mimic relevant components of the metabolic sytdrome, while the other served as a Sham group. To monitor disease progression, echocardiographic parameters, hemodynamics, autonomic function (e.g. SDNN, RMSSD), body weight, and biomarkers were regularly assessed over a follow-up of 10 months.
Results
The AOB/WD group showed a persistent pressure overload with increased LV systolic pressure, LVEDP, and arterial hypertension when compared to the Sham group while diastolic dysfunction (maximum LV relaxation and Tau) was not significantly altered.
After 10 months, body weight was significantly higher in the AOB/WD group compared to the Sham group (143.0 ± 19.1 kg vs. 113.0 ± 11.9 kg; p≤ 0.05). Physical activity was significantly reduced in the AOB/WD group after 8 – 10 months (p<0.05). From 2 months onwards, the AOB/WD group was characterized by significantly elevated plasma levels of CHOL (>10 mmol/L), LDL (>9.5 mmol/L), HDL (>2.9 mmol/L), and the LDL/HDL ratio (>3.0), when compared to the Sham group (p< 0.01, each).
Echocardiography demonstrated a preserved LVEF, while altered measures of diastolic dysfunction and cardiac hypertrophy attributable to the AOB/WD.
The disease progression was accompanied by an early onset of AD: After 2 months SDNN was significantly lower in the AOB/WD group in comparison to the Sham group (73.1 ± 18.4 ms vs. 101.2 ± 32.9 ms; p< 0.05).
Additional HRV parameters showed significant differences throughout the study, such as alteration in RMSSD (5, 7, 8, and 10 months post AOB) and PNN50 (4, 5, and 7 – 10 months after AOB).
Conclusion
Reduced autonomic function occurred 2 months after AOB and persisted throughout the study. Additional findings, such as hypercholesterolemia, overweight, and reduced physical activity, confirmed the presence of a metabolic syndrome. The animals showed signs of congestion (elevated LVEDP); however, no LV dysfunction or LV hypertrophy. This data suggests that AD occurs during the progression and development of a cardiometabolic HF phenotype even before measurable signs of HF appear. Therefore, this animal model provides important insides into the pathogenesis of cardiometabolic HF and can serve as a model to characterize novel therapies targeting AD in HF.
