Key result
Central Angiotensin II infusion in rats induces HFpEF with ~156% higher LVEDP and cardiac fibrosis.
Why the study?
The underlying mechanisms of heart failure with preserved ejection fraction are not clear, leading to the hypothesis that enhanced central sympathetic drive induces left ventricular dysfunction and HFpEF.
Does central infusion of angiotensin II induce heart failure with preserved ejection fraction (HFpEF) characteristics in rats?
Does central infusion of angiotensin II induce heart failure with preserved ejection fraction (HFpEF) characteristics in rats?
Enhanced central sympathetic tone via Ang II infusion induces a phenotype resembling HFpEF in rats, providing a novel preclinical model for future mechanistic studies.
Hypothesis-generating for central Ang II mechanisms in HFpEF; leaves open translation to humans and requires prospective validation.
Heart failure with preserved ejection fraction (HFpEF) is a heterogenous clinical syndrome characterized by diastolic dysfunction, concentric cardiac left ventricular (LV) hypertrophy, and myocardial fibrosis with preserved systolic function. However, the underlying mechanisms of HFpEF are not clear. We hypothesize that an enhanced central sympathetic drive is sufficient to induce LV dysfunction and HFpEF in rats. Male Sprague–Dawley rats were subjected to central infusion of either saline controls (saline) or angiotensin II (Ang II, 20 ng/min, i.c.v) via osmotic mini-pumps for 14 days to elicit enhanced sympathetic drive. Echocardiography and invasive cardiac catheterization were used to measure systolic and diastolic functions. Mean arterial pressure, heart rate, left ventricular end-diastolic pressure (LVEDP), and ± dP/dt changes in responses to isoproterenol (0.5 μg/kg, iv) were measured. Central infusion of Ang II resulted in increased sympatho-excitation with a consequent increase in blood pressure. Although the ejection fraction was comparable between the groups, there was a decrease in the E/A ratio (saline: 1.5 ± 0.2 vs Ang II: 1.2 ± 0.1). LVEDP was significantly increased in the Ang II-treated group (saline: 1.8 ± 0.2 vs Ang II: 4.6 ± 0.5). The increase in +dP/dt to isoproterenol was not significantly different between the groups, but the response in -dP/dt was significantly lower in Ang II-infused rats (saline: 11,765 ± 708 mmHg/s vs Ang II: 8,581 ± 661). Ang II-infused rats demonstrated an increased heart to body weight ratio, cardiomyocyte hypertrophy, and fibrosis. There were elevated levels of atrial natriuretic peptide and interleukin-6 in the Ang II-infused group. In conclusion, central infusion of Ang II in rats induces sympatho-excitation with concurrent diastolic dysfunction, pathological cardiac concentric hypertrophy, and cardiac fibrosis. This novel model of centrally mediated sympatho-excitation demonstrates characteristic diastolic dysfunction in rats, representing a potentially useful preclinical murine model of HFpEF to investigate various altered underlying mechanisms during HFpEF in future studies.
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Nandi et al. (2023) studied Heart failure with preserved ejection fraction (HFpEF) (n=12). Angiotensin II (Ang II) intracerebroventricular infusion vs. Isotonic saline intracerebroventricular infusion was evaluated on Left ventricular end-diastolic pressure (LVEDP) (p=<0.05). Central infusion of Angiotensin II in rats induced heart failure with preserved ejection fraction, characterized by increased left ventricular end-diastolic pressure (4.6 vs 1.8 mmHg) and cardiac fibrosis.
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