Volume 76, June 2024, 102461Author links open overlay panel, Abstract

Heart failure with preserved ejection fraction (HFpEF) is a major cardiovascular disorder with increasing prevalence and a limited range of targeted treatment options. While HFpEF can be derived from several different etiologies, much of the current growth in the disease is being driven by metabolic dysfunction (e.g. obesity, diabetes, hypertension). Deleterious changes in mitochondrial energy metabolism are a common feature of HFpEF, and may help to drive the progression of the disease. In this brief article we aim to review various aspects of cardiac mitochondrial dysfunction in HFpEF, discuss the emerging topic of HFpEF-driven mitochondrial dysfunction in tissues beyond the heart, and examine whether supporting mitochondrial function may be a therapeutic approach to arrest or reverse disease development.

Section snippetsHFpEF: Clinical manifestation and current treatment options

HFpEF is a structural and functional impairment of cardiac output, predominantly related to defects in organ relaxation and filling after contraction. Left ventricular diastolic dysfunction is an independent pre-clinical predictor of all-cause mortality, and is a prerequisite for the diagnosis of HFpEF [1,2]. While the etiology of the diastolic dysfunction in HFpEF is multifactorial, deleterious changes in cardiac energy metabolism underpin the development of both [3]. Patients with HFpEF

Preclinical models of HFpEF

Greater recognition of the increasing prevalence and clinical impact of HFpEF, along with the clear need to develop new therapies, has driven the development of new preclinical models of the disease for basic research. Earlier rodent models of a HFpEF-like phenotype focused on metabolic dysfunction related to diabetes/hyperglycemia, for example using the db/db leptin receptor mutant model (see, e.g, Ref. [12]). More recently, “multi-hit” models have been developed that combine diet-induced

Energy substrate utilization in cardiac mitochondria

In both the “two-hit” HFD + L-NAME [14] and “three-hit” HFD + DOCP + aging [16] mouse HFpEF models, a significant increase in mitochondrial protein lysine acetylation was observed. This reversible post-translational modification, which uses excess acetyl groups from energy fuel metabolism, was linked to an increase in both mitochondrial fatty acid uptake and impaired fatty acid oxidation enzyme activity [14,16]. Reversing mitochondrial protein acetylation, either by driving Sirtuin 3-dependent

HFpEF beyond the heart: effects on skeletal muscle mitochondria and bioenergetics

Exercise intolerance is a key clinical feature of HFpEF, and measurements of exercise capacity are one of the common outcomes measured in clinical trials of HFpEF therapeutics (for example, see the 6 min walk test used in Ref. [7]). While reduced tissue perfusion from lower cardiac output is expected to have limiting effects on exercise capacity, other tissue-specific effects of HFpEF have also been described, and these are likely to have profound effects beyond the heart. In this regard, in

Conclusions

Due to their role as regulators of cellular metabolism, mitochondria have the capacity to both protect from, and drive the progression of, metabolic disease. In terms of HFpEF, loss of mitochondrial function drives myocardial energy deficits, and may be involved at both early and late stages of the disease. Due to the comorbidity nature of HFpEF, mitochondria beyond the heart are also impacted, which can further promote disease progression and lead to worse outcomes. This is particularly true

Declaration of competing interest

The authors declared that there are no potential conflicts.

Acknowledgements

This work was supported by National Institute of Health Research Grants (R01HL147861, R0HL156874) and American Heart Association Established Investigator Award (23EIA1037834) to I.S.

References (30)S.D. Anker et al.Empagliflozin in heart failure with a preserved ejection fraction

N Engl J Med

(2021)

M.N. Kosiborod et al.Semaglutide in patients with heart failure with preserved ejection fraction and obesity

N Engl J Med

(2023)

Y.M. PintoHeart failure with preserved ejection fraction - a metabolic disease?

N Engl J Med

(2023)

S.J. Shah et al.Research priorities for heart failure with preserved ejection fraction: national heart, lung, and blood Institute working group summary

Circulation

(2020)

T.T. Phan et al.Heart failure with preserved ejection fraction is characterized by dynamic impairment of active relaxation and contraction of the left ventricle on exercise and associated with myocardial energy deficiency

J Am Coll Cardiol

(2009)

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