Modeling the physiological roles of the heart and kidney in heart failure with preserved ejection fraction during baroreflex activation therapy

Abstract

Heart failure (HF) is a leading cause of death and is increasing in prevalence. Unfortunately, therapies that have been efficacious in patients with HF with reduced ejection fraction (HFrEF) have not convincingly shown a reduction in cardiovascular mortality in patients with HF with preserved ejection fraction (HFpEF). It is thought that high sympathetic nerve activity (SNA) in the heart plays a role in HF progression. Clinical trials demonstrate that baroreflex activation therapy reduces left ventricular (LV) mass and blood pressure (BP) in patients with HFpEF and hypertension; however, the mechanisms are unclear. In the present study, we used HumMod, a large physiology model to simulate HFpEF and predict the time-dependent changes in systemic and cardiac hemodynamics, SNA, and cardiac stresses during baroreflex activation. The baseline HFpEF model was associated with elevations in systolic BP, diastolic dysfunction, and LV hypertrophy and stiffness similar to clinical HFpEF. Simulating 12 mo of baroreflex activation resulted in reduced systolic BP (-25 mmHg) and LV mass (-15%) similar to clinical evidence. Baroreflex activation also resulted in sustained decreases in cardiac and renal SNA (-22%) and improvement in LV β₁-adrenergic function. However, the baroreflex-induced reductions in BP and improvements in cardiac stresses, mass, and function were mostly attenuated when renal SNA was clamped at baseline levels. These simulations suggest that the suppression of renal SNA could be a primary determinant of the cardioprotective effects from baroreflex activation in HFpEF.NEW & NOTEWORTHY Treatments that are efficacious in patients with HFrEF have not shown a significant impact on cardiovascular mortality in patients with HFpEF. We believe these simulations offer novel insight into the important roles of the cardiac and renal nerves in HFpEF and the potential mechanisms of how baroreflex activation alleviates HFpEF disease progression.

Keywords: HFpEF; baroreflex activation; heart failure; physiological model.

Figure 1.

Cardiac model describing diastolic and systolic function and influence of fibrosis and stiffness on diastolic function. The fibrosis variable is derived from the ratio of left ventricular (LV) fibrosis to LV contractile mass (top, right). The break variable derived from a function of baseline LV stiffness and fibrosis (bottom, right). EDP, end-diastolic pressure; EDV, end-diastolic volume; ESP, end-systolic pressure; ESV, end-systolic volume; HFpEF, heart failure with preserved ejection fraction; LAP, left atrial pressure; MAP, mean arterial pressure; SBP, systolic blood pressure; SV, stroke volume.

Figure 2.

Model relationships and equations that determine the gain and loss of ventricular contractile protein mass and fibrotic mass and their impact on cardiac function. The fibrosis effect is also a multiplier on stiffness as shown in Fig. 1. Contractile, fibrotic, and cardiac functions show baseline control (blue) and heart failure with preserved ejection fraction (HFpEF) values (black). EDP, end-diastolic pressure; ESP, end-systolic pressure; LV, left ventricular.

Figure 3.

Comparison of model response to patients with hypertension with evidence of heart failure with preserved ejection fraction treated with baroreflex activation therapy (13). Clinical data are presented as means ± SE except for ejection fraction (EF), which is expressed as medians and interquartile ranges. HR, heart rate; LV, left ventricular; SBP, systolic blood pressure.

Figure 4.

Systemic and cardiac and pressure and volumes during baroreflex activation. Heart failure with preserved ejection fraction without treatment (control, black) is compared with baroreflex activation therapy (BAT, dashed blue), BAT with cardiac sympathetic activity clamped at baseline including influence from circulating catecholamines (BAT-CSNA, red), and BAT with renal sympathetic activity clamped at baseline including influence from circulating catecholamines (BAT-RSNA, dashed red). BAT indicates start of baroreflex activation therapy at time 0. ANP, atrial natriuretic peptide; LV, left ventricular.

Figure 5.

Cardiac pressures and left ventricular (LV) thickness and resulting wall stress during baroreflex activation. LV wall stress was calculated based on pressure, intraventricular diameter, and wall thickness assuming an ellipsoidal geometry. Heart failure with preserved ejection fraction without treatment (control, black) is compared with baroreflex activation therapy (BAT, dashed blue), BAT with cardiac sympathetic activity clamped at baseline (BAT-CSNA, red), and BAT with renal sympathetic activity clamped at baseline (BAT-RSNA, dashed red). Normal (no heart failure) model values are indicated on y-axis. EDP, end-diastolic pressure; ESP, end-systolic pressure.

Figure 6.

Cardiac sympathetic nerve activity and adrenergic function during baroreflex activation. Increases in sympathetic nerve activity (SNA) from increased baseline pulmonary venous pressure is shown (top, left). Heart failure with preserved ejection fraction without treatment (control, black) is compared with baroreflex activation therapy (BAT, dashed blue), BAT with cardiac sympathetic activity clamped at baseline (BAT-CSNA, red), and BAT with renal sympathetic activity clamped at baseline (BAT-RSNA, dashed red). BAT indicates start of baroreflex activation therapy at time 0. LV, left ventricular.

Figure 7.

Changes in renal sympathetic nerve activity and renal vascular resistance during baroreflex activation. Heart failure with preserved ejection fraction without treatment (control, black) is compared with baroreflex activation therapy (BAT, dashed blue), BAT with cardiac sympathetic activity clamped at baseline (BAT-CSNA, red), and BAT with renal sympathetic activity clamped at baseline (BAT-RSNA, dashed red). Normal (no heart failure) model values are indicated on y-axis. SNA, sympathetic nerve activity.

Figure 8.

Determinants of left ventricular contractile mass. Contractile tissue mass was based on a growth constant and effect multipliers from β₁-adrenergic activity, systolic stress, and diastolic stress as shown in Fig. 2. Heart failure with preserved ejection fraction without treatment (control, black) is compared with baroreflex activation therapy (BAT, dashed blue), BAT with cardiac sympathetic activity clamped at baseline (BAT-CSNA, red), and BAT with renal sympathetic activity clamped at baseline (BAT-RSNA, dashed red). LV, left ventricular; SNA, sympathetic nerve activity.

Figure 9.

Determinants of left ventricular (LV) fibrotic mass and resultant effects on LV stiffness. Fibrotic tissue mass was based on a growth constant and effect multipliers from α₁-adrenergic activity, systolic stress, and diastolic stress as shown in Fig. 2. Heart failure with preserved ejection fraction without treatment (control, black) is compared with baroreflex activation therapy (BAT, dashed blue), BAT without contributions from cardiac sympathetic activity (BAT-CSNA, red), and BAT without contributions from renal sympathetic activity (BAT-RSNA, dashed red). Normal (no heart failure) model values are indicated on y-axis. SNA, sympathetic nerve activity.

Figure 10.

Working hypothesis on progression of heart failure with preserved ejection fraction (HFpEF) and the proposed role of baroreflex activation therapy (BAT). Impaired filling due to increased relative wall thickness and increased left ventricular stiffness leads to congestion, which increases sympathetic nerve activity (SNA) through unknown mechanisms. BAT suppresses both cardiac and renal SNA as well as potentiates atrial natriuretic peptide (ANP), all of which improve cardiac function.