Abstract
Testing new therapies in heart failure (HF) requires a chronic stable model of HF in large animals. Microembolization of the coronary arteries has been used to model HF previously; however, neural control has not been previously explored in this model. Thus the aim of this study was to further characterize neural control in this model of HF. HF was induced by infusion of microspheres (45 micron; 1.3 ml) into the proximal left coronary artery or left descending coronary arteries, with three sequential embolizations over 3 weeks. Twelve to 14 weeks after the final embolization, and when ejection fraction had decreased below 45%, animals were instrumented to record blood pressure and heart rate. Baroreflex control of heart rate was investigated in conscious animals. Additionally, pressure-volume loops were constructed under anesthesia. Embolization-induced HF was associated with a decrease in mean arterial pressure (67 ± 2 vs. 85 ± 4 mmHg, p < 0.05), an increase in heart rate (108 ± 4 vs. 94 ± 4 bpm, p < 0.05), and a significant increase in left ventricular end-diastolic pressure (11.4 ± 2 vs. 6.2 ± 1 mmHg, p < 0.01). Under conscious conditions, there was a significant decrease in the gain (−8.2 ± 2 vs. −4.1 ± 1 beats/min/mmHg, p < 0.05) as well as the lower plateau of the baroreflex in HF compared to control animals. HF was also associated with significantly increased respiratory rate (107 ± 4 vs. 87 ± 4 breaths/min, p < 0.01) and incidence of apneas (520 ± 24 vs. 191 ± 8 apnea periods >4 s, p < 0.05), compared to control sheep. The microembolization model of heart failure is associated with an increase in left ventricular end-diastolic pressure, impaired cardiac function, and altered baroreflex control of the heart. These findings suggest this chronic model of HF is appropriate to use for investigating interventions aimed at improving neural control in HF.
Highlights
Heart failure with reduced ejection fraction (HFrEF) is characterized by progressive dysfunction of left ventricular muscle, myocyte remodeling, and activation of autonomic and hormonal systems (Jackson et al, 2000; Kemp and Conte, 2012)
heart failure (HF) was associated with a significant decrease in mean arterial pressure (MAP) (67 ± 2 vs. 85 ± 4 mmHg, p < 0.01), and an increase in heart rate (108 ± 4 vs. 94 ± 4 bpm, p < 0.05) compared to the control animals
Infusion of propranolol reduced heart rate more in the HF group compared with control (9 ± 1 vs. 3 ± 1, bpm, change in HR before and after propranolol, p < 0.001) and there was no significant change in MAP between the groups after propranolol infusion
Summary
Heart failure with reduced ejection fraction (HFrEF) is characterized by progressive dysfunction of left ventricular muscle, myocyte remodeling, and activation of autonomic and hormonal systems (Jackson et al, 2000; Kemp and Conte, 2012). There are significant differences between small animal models of HF and human HF beyond scale. These include differences in baseline heart rate, oxygen consumption, and excitation-contraction coupling in cardiac tissue (Haghighi et al, 2003; Dixon and Spinale, 2009). A clinically relevant large animal model of HF with similar anatomy and physiology of the heart is crucial. In this context, a number of different large animal models of HF have been studied
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