Background: Rapid ventricular pacing is a well-established method to induce heart Failure with reduced Ejection Fraction (HFrEF) in large animal models, mainly dogs and pigs. The animals are usually paced three- to fourfold higher than spontaneous heart rate (HR) over a period of three to five weeks leading to reproducible dilated cardiomyopathy (DCM). However, animals usually suffer severe symptoms of cardiac decompensation, including tachypnoea, peripheral and pulmonary edema, weight loss, lethargy and rarely sudden death. Therefore, we set out to establish a novel pacing-induced HF model based on slower pacing and milder clinical HF progression, in accordance with the principle of refinement in animal trials.
Methods: Eight female Göttingen Minipigs (34,4±6,0kg; mean±SEM) were implanted a right-ventricular pacemaker, with two apical pacing electrodes (HF group). After recovery, the animals were paced at a rate of 180 beats per minute (bpm) for two weeks and subsequently at 200 bpm for four weeks. Further seven female Göttingen minipigs (35,8±10,8kg) served as control group (C). Echocardiographic examinations were conducted every two weeks. Blood and hair samples were taken before pacing, after four and six weeks. General condition was examined daily and animals wore jacketed external telemetry (JET) to assess respiratory rate (RR) and daily activity of life (DAL). At 6 weeks animals were anaesthetized and instrumented for extensive pressure-volume-assessment.
Results: Overall the protocol was well tolerated, with no mortality or severe arrhythmogenic events observed throughout the study protocol. The HF group progressively developed a HFrEF phenotype with decreasing LV EF over time (HF: 27±3 vs C 54±3 %), increased LV end-diastolic pressure, and pulmonary congestion. Final invasive assessment showed a dilated LV with increased enddiastolic (Ved; HF 106±10 vs C 53±6 ml) and endsystolic (Ves; HF 79±10 vs C 25±3 ml) volumina, while the maximum rate of LV pressure increase corrected by Ved were decreased (LV dPdTmax/Ved; HF 7,3±0,7 vs C 30,8±6,0 mmHg/s/ml) (all p<0,05). The recorded respiratory rate (RR) during the day was slightly elevated in the tachypaced pigs compared to control animals during the first two weeks but did not differ at 6 weeks. Daily activity of life was not altered over the course of the pacing period, i.e., all pigs had a stable fitness. Cortisol levels were not elevated compared to control and did not rise during the trial significantly (HF 1,2±0,2 at week 1-4 to 1,5±0,4 pg/mg at week 6; control 1,7 pg/mg), meaning no additional stress for the paced animals.
Conclusion: The presented protocol poses a reliable model of tachypacing induced HFrEF in pigs, resulting in loss of contractility and dilated cardiomyopathy, while drastically reducing the severity of HF symptoms compared to conventional approaches. Therefore, this protocol can be recommended in accordance with the principle of refinement in animal trials.