Authors Outline Potential Targeted Therapeutic Intervention for HFpEF

Authors described recent therapeutic developments in heart failure with preserved ejection fraction (HFpEF) and proposed a conceptual framework for more targeted treatment.

In a brief article published in Circulation, authors outlined therapeutic developments in heart failure with preserved ejection fraction (HFpEF) and provided a conceptual framework to help explain the potential benefits of calciotropic interventions in this patient population.

Calciotropic interventions, such as treatment with milrinone, levosimendan, or cardiac pacing, work to “increase myocardial calcium (Ca2+) handling, based on their effects on the left ventricular pressure-volume relationship (PVR),” researchers explained. In essence, the approach reduces patients’ exposure to increased cardiac stiffness, and if confirmed, it could lead to more tailored HFpEF management.

Despite a valid conceptual framework, more research is needed to confirm benefits and examine long-term outcomes. “We should remain cautious,” said study author Markus Meyer, MD. He noted, “it will be very important that we select the right patients and ascertain that these treatments are safe and indeed reduce heart failure in the long run.”

Currently, in patients with HFpEF who have a left ventricular ejection fraction less than 55%, sacubitril/valsartan and spironolactone serve as modest beneficial treatments. However, data from 2016 revealed that intravenous milrinone can provide hemodynamic benefits in HFpEF and improved chronotropy and cardiac output.

Additional data has shown that intermittent infusions with levosimendan significantly reduced aggregate pulmonary capillary wedge pressure. This treatment resulted in improved 6-minute walk distance compared with placebo and had a chronotropic effect. However, levosimendan did not increase cardiac output among patients.

Furthermore, atrial pacing, which increases patients’ heart rates, could benefit those with diastolic dysfunction and HFpEF by reducing filling pressures, authors said. Both milrinone and levosimendan are type III phosphodiesterase (PDE3) inhibitors, while “similar to the cellular response to pacing, PDE3 inhibitors augment cellular Ca2+ handling, which could provide an additional explanation for their benefit,” they added.

Researchers hypothesized that calciotropic interventions derive benefits from the leftward shift of the operating range of left ventricular (LV) filling pressure to a smaller end-systolic volume and end-diastolic volume (EDV); this effect results in a reduction in mean filling pressures, wall stress, and symptoms, they said.

An ideal treatment for HFpEF would transfer filling toward lower diastolic pressures without losing too much of the EDV. In comparison, a perfect treatment “would move EDV to the point where the end-diastolic pressure-volume relation (EDPVR) is just beginning to become exponential.”

Moving the pressure-volume loop to the left would also result in reduced pericardial restraint and enhanced diastolic recoil, potentially reducing atrial load and preventing atrial fibrillation.

Excess deaths have been reported with prolonged PDE3 inhibition. Heart failure, arrhythmias, and ischemia have also been linked with pacing.

“PDE3 inhibition and pacing result in an increase in Ca2+- dependent myofilament activation resulting in a leftward movement of the pressure-volume loop and smaller LV volumes,” authors concluded. “Thus, the ventricle begins to fill at a smaller volume and spends more of its filling on the flatter, nonexponential segment of the diastolic PVR, whereas a prolongation of diastole with heart rate–lowering drugs may do the opposite.”


Meyer M, LeWinter MM, Zile MR. A targeted treatment opportunity for HFpEF: taking advantage of diastolic tone. Circulation. Published online October 18, 2021. doi:10.1161/CIRCULATIONAHA.121.056412

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