Developing Therapies for Heart Failure With Preserved Ejection Fraction

Abstract

The burden of heart failure with preserved ejection fraction (HFpEF) is considerable and is projected to worsen. To date, there are no approved therapies available for reducing mortality or hospitalizations for these patients. The pathophysiology of HFpEF is complex and includes alterations in cardiac structure and function, systemic and pulmonary vascular abnormalities, end-organ involvement, and comorbidities. There remain major gaps in our understanding of HFpEF pathophysiology. To facilitate a discussion of how to proceed effectively in future with development of therapies for HFpEF, a meeting was facilitated by the FDA and included representatives from academia, industry and regulatory agencies. This document summarizes the proceedings from this meeting.

Deleting titin’s I-band/A-band junction reveals critical roles for titin in biomechanical sensing and cardiac function

“…The increased left atrial weight is likely to reflect the increased LV stiffness and the ensuing increase in pressure and volume of the LA. It is well recognized that increased diastolic stiffness can lead to functional deficits (20,34), and this was confirmed in free-wheel running studies that showed that Ttn ΔIAjxn mice had a running deficiency (SI Appendix, Fig. S10).…”

“…A significant E-wave DT reduction was found in Ttn ΔIAjxn mice, supporting that diastolic chamber stiffness is increased. Finally, since increased left atrial (LA) size is typically seen in patients with elevated LV stiffness (20) we measured LA weights.…”

“…Deleting the IA junction moves the attachment point of titin's spring region away from the Z disk, which results in an increase in left ventricular diastolic stiffness, exercise intolerance, and modest left ventricular hypertrophy. Increased diastolic stiffness is an important feature of heart failure with preserved ejection fraction (HFpEF), a type of heart failure that occurs in ∼50% of patients with heart failure and for which currently no effective therapies exist (20). HFpEF is accompanied by preserved systolic function, reduced exercise capacity, and hypertrophy is a comorbidity (20); all of these features are present in the Ttn ΔIAjxn model.…”

“…Increased diastolic stiffness is an important feature of heart failure with preserved ejection fraction (HFpEF), a type of heart failure that occurs in ∼50% of patients with heart failure and for which currently no effective therapies exist (20). HFpEF is accompanied by preserved systolic function, reduced exercise capacity, and hypertrophy is a comorbidity (20); all of these features are present in the Ttn ΔIAjxn model. Previous studies (45) have shown that titin-based passive force is greatly increased in patients with HFpEF, due to hypophosphorylation of titin, but it is unknown whether this is a cause or an effect of HFpEF.…”

The Heart Failure Paradox: An Epidemic of Scientific Success

“…[42][43][44][45][46] One of the major challenges ahead is what the optimal care of the patient with HFpEF should entail. It is a critical issue, considering many real-world patients have been found to fare even worse than patients in clinical trials.…”