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Published in final edited form as: Curr Opin Pharmacol. 2024 May 16;76:102461. doi: 10.1016/j.coph.2024.102461

In the heart and beyond: mitochondrial dysfunction in heart failure with preserved ejection fraction (HFpEF)

Nisha Bhattarai 1,2,3, Iain Scott 1,2,3
PMCID: PMC11176012  NIHMSID: NIHMS1990222  PMID: 38759430

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.

Keywords: Mitochondria, bioenergetics, fatty acid oxidation, glucose, acetylation, heart failure

HFpEF: 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 (Redfield et al, 2003; Shah et al, 2017). While the etiology of the diastolic dysfunction in HFpEF is multifactorial, deleterious changes in cardiac energy metabolism underpin the development of both (Lopaschuk et al, 2021). Patients with HFpEF typically have a normal left ventricle ejection fraction (EF > 50%), with only subtle contractile dysfunction observed in most patients. HFpEF patients also have a reduced cardiac output reserve, which leads to impaired organ perfusion and exercise intolerance (Shah et al, 2017). Along with diastolic dysfunction, a complex set of biological mechanisms promote cardiac dysfunction in HFpEF, including atrial and ventricular stiffness, and reduced arterial compliance. In addition, a number of comorbidities such as diabetes/hyperglycemcia, hypertension, and aging drive HFpEF progression (Gevaert et al, 2022). These features of HFpEF pathophysiology, which are all metabolic in nature, suggest that the greatest therapeutic benefit may be derived from treatments that focus on metabolic dysfunction.

In this regard, a lack of treatment options for HFpEF represents one of the greatest unmet clinical needs in modern cardiology. HFpEF accounts for around half of the heart failure cases in the United States (about three million cases per year), with an average mortality of ~50% within five years (Shah et al, 2017). In addition to mortality, HFpEF costs the United States over $15 billion per year in terms of treatment cost and lost economic activity. There are currently no first line medications specifically approved for HFpEF, with the management of comorbidities, RAAS inhibitors, and diet/exercise modifications representing the current standard of care (Gevaert et al, 2022). Exciting results in clinical trials involving heart failure with reduced ejection fraction (HFrEF; where EF < 40%) suggested that SGLT2 inhibition (e.g. with empagliflozin or dapagliflozin) may represent a novel metabolic target to treat HFpEF (Zinman et al, 2015). However, results from the EMPEROR-Preserved trial showed mixed results, with no protection from cardiovascular death observed versus placebo treatment (Anker et al, 2021). More recently, a trial with the GLP-1 receptor agonist semaglutide, approved for use in glucose control and weight loss, showed an improvement in clinical outcomes (e.g. exercise tolerance and questionnaire-based impacts on patient health) (Kosiborod et al, 2023). However, the study was underpowered to examine hard clinical endpoints such as death from cardiovascular events, and did not examine cardiac functional improvements (Pinto, 2023).

As mentioned above, there remains no first-line treatment approved to directly tackle HFpEF in the clinic. However, these drugs (SGLT2 inhibitors and GLP-1 receptor agonists) and other metabolism-directed therapies remain a core focus of translational research (Shah et al, 2020). In this regard, one novel therapeutic (ninerafaxstat; a partial fatty acid oxidation inhibitor) is currently undergoing Phase 2 clinical trials in patients with HFpEF and related conditions (e.g. diabetic cardiomyopathy). Previous studies using 31P magnetic resonance spectroscopy demonstrated that hearts from patients with HFpEF had a reduced bioenergetic reserve compared to normal controls (Phan et al, 2009). Preliminary results suggest that decreasing fatty acid oxidation leads to improved diastolic function and restored glucose oxidation, along with improved PCr/ATP levels measured by 31P spectroscopy (Hundertmark et al, 2022). As preclinical models suggest that cardiac fuel metabolism is a key component of HFpEF pathophysiology (discussed below), it is likely that further therapeutic approaches in this arena will yield promising results.

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, Alex et al, 2018). More recently, “multi-hit” models have been developed that combine diet-induced hyperglycemia with chemical hypertensives, to better model the obesity-diabetes-hypertension phenotype common to many HFpEF patients (van Ham et al, 2022). One of the best characterized (and most replicated) of the newly developed mouse models combines a 60% high fat diet (HFD) with the NOS inhibitor L-NAME (in drinking water) for a period of 5–15 weeks. At the conclusion of the diet, mice display an increase in body weight, hyperglycemia, increased blood pressure, and cardiac diastiolic dysfunction in the absence of any systolic impairment (Schiattarella et al, 2019). Similar models, which replace L-NAME with angiotensin II (AngII; Withaar et al, 2021) or desoxycorticosterone pivalate (DOCP; Deng et al, 2020) to induce hypertension in aged mice, or overexpress Cavβ2a in combination with L-NAME to increase cardiomyocyte Ca2+ levels (Li et al, 2023), result in a similar phenotype, demonstrating the robustness of this multi-hit approach. At the large animal model level, a novel minipig model of HFpEF was developed along similar lines, where experimental animals were provided a western diet (high in fat, fructose, and cholesterol), along with 11-deoxycorticosterone acetate (DOCA) salt to induce hypertension, for 20 weeks. In addition to cardiac diastolic dysfunction, these animals developed a range of comorbidities and multi-organ dysfunction common in human HFpEF cases (Sharp et al, 2021).

In summary, the basic and translational HFpEF research field now has a number of tools at their disposal, aiding preclinical discovery. As detailed below, a number of early studies using these newer models have highlighted the central role of mitochondrial dysfunction in HFpEF development and progression.

Energy Substrate Utilization in Cardiac Mitochondria

In both the “two-hit” HFD+L-NAME (Schiattarella et al, 2019) and “three-hit” HFD+DOCP+aging (Deng et al, 2020) 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 (Schiattarella et al, 2019; Deng et al, 2020). Reversing mitochondrial protein acetylation, either by driving Sirtuin 3-dependent deacetylation with the provision of its cofactor NAD+ (Tong et al, 2021), or by supplementing with an alternative fuel source, such as the ketone β-hydroxybutyrate (Deng et al, 2020), led to a normalization fuel substrate metabolism and cardiac function.

The healthy heart typically obtains 40–60% of its energy from fatty acid oxidation, with the remainder coming from the oxidation of alternative fuels (e.g. glucose, ketones, lactate, branched chain amino acids, etc.) or non-oxidative glycolysis (Lopaschuk et al, 2021). Metabolic flexibility is key feature of the healthy heart, with the ability to shift fuel source a necessary adaptation to changes in energy demand or fuel availability (Lopaschuk et al, 2021). In the failing HFpEF heart, changes in fuel substrate utilization – largely caused by alterations in fuel availability – have the capacity to reduce both cardiac metabolic flexibility and bioenergetic output. Cardiomyocyte insulin resistance reduces the availability of glucose/pyruvate for mitochondrial oxidation, driving a fuel substrate utilization phenotype that is more heavily dependent on fatty acid oxidation (Lopaschuk et al, 2001; Sun et al, 2024). While it had previously been assumed that the heart would increase the oxidation of other substrates (e.g. ketones) or upregulate glycolysis to compensate for the loss of glucose/pyruvate oxidation, recent work in the two-hit HFD+L-NAME mouse model suggests that this is not the case (Sun et al, 2024). As a result, the fuel-type restricted HFpEF heart may develop energy deficits as the disease progresses, further restricting diastolic function.

Due to the complexity of in vivo tracer studies, details of fuel substrate metabolism in human HFpEF patients are less available. However, a combined cross-sectional transcriptomic and metabolomic approach gives some clues to potential fuel metabolism changes in affected patients. Matching the findings observed in small animal studies, HFpEF patients tended to have higher myocardial levels of pyruvate and reduced expression of genes related to glucose oxidation, suggesting a decrease in the amount of glucose used for energy metabolism (Hahn et al, 2023). In addition, an increase in amino acids (both regular and branched-chain) in the HFpEF myocardium suggests that overall, the HFpEF heart is less able to use alternative fuels for bioenergetic purposes (Hahn et al, 2023). Interestingly, transcriptomic and metabolomic data suggests that fatty acid oxidation may also be decreased in the HFpEF heart, with a reduction in fatty acid oxidation enzyme gene expression and acylcarnitines observed in the myocardium of disease patients (Hahn et al, 2023).

These data were largely corroborated in an elegant human study examining cardiac metabolism from control and HFpEF patients in vivo. Researchers in this study simultaneously sampled blood from the coronary sinus and the radial artery, and used these samples to subtractively measure the uptake and secretion of key metabolites by the heart (O’Sullivan et al, 2024). Data from this study showed that while HFpEF hearts are still able to uptake fatty acids, the amount is reduced compared to control hearts. Furthermore, there was a sex-dependent modulation of lipid use, with female HFpEF hearts metabolizing a range less common lipid classes than males under the same conditions (O’Sullivan et al, 2024).

While these findings somewhat contrast with the two-hit mouse model data referenced above (Sun et al, 2024), they are consistent with previous reports in a rat model of progressive HFpEF, where animals display a decrease in cardiac fatty acid oxidation as the condition worsens (Fillmore et al, 2018). These data suggest that in the early stages of HFpEF, the heart first loses the ability to use glucose oxidation (both from insulin resistance, and from an uncoupling of glucose oxidation from glycolysis), and over time this deficit extends to a significant reduction in fatty acid oxidation. Combined, these studies suggest that an impairment in mitochondrial fuel metabolism is likely to be a key driver of HFpEF progression.

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 six minute walk test used in Kosiborod et al., 2023). 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 the following section we discuss the current research on the effects of HFpEF on mitochondrial function in skeletal muscle.

Skeletal muscle mass declines with age, however chronic conditions like cancer, diabetes, sepsis, bedrest, physical inactivity, severe burns, and heart failure can accelerate the loss of muscle mass. Patients with HFpEF have significantly reduced lean muscle mass compared to their age matched healthy controls, with losses of up to 10% (Haykowsky et al, 2013). Additionally, reduced lean mass correlates with lower peak VO2 max and exercise intolerance in HFpEF patients (Haykowsky et al, 2013). Loss of muscle mass is associated with decreased muscle strength, impaired physical function, and prolonged recovery times. Therefore, protecting against the loss of muscle mass is an important factor to consider in the treatment of individuals with advanced HFpEF.

Skeletal muscles are densely populated with mitochondria, accounting for up to 25% of resting energy expenditure (REE). Mitochondria are responsible for 90% of oxygen consumption and 80% of coupled respiration attributed to oxidative phosphorylation (Rolfe and Brown, 1997). As such, any abnormalities in skeletal muscle may be a consequence of dysfunctional mitochondria. Several pieces of evidence suggest that older patients with HFpEF indeed have altered skeletal muscle mitochondrial function. Mitochondrial porin and mitofusion 2 (MFN2) expression are significantly lower in patients with HFpEF compared to age matched healthy controls, suggesting a reduction in mitochondrial volume or altered mitochondrial dynamics. Patients with HFpEF demonstrated a reduced peak VO2 max and a significantly lower six-minute walk distance, suggestive of increased exercise intolerance. In both cases, porin and MFN2 expression were positively correlated with this whole-body energetic dysfunction, further suggesting that impaired skeletal muscle function is associated with reduced mitochondrial protein content (Molina et al, 2016). In support of these findings, a recent cross-sectional study also reported a decline in lean muscle mass, mitochondrial function, and exercise tolerance in patients with HFpEF compared to healthy controls. When adjusted for age, sex, and body mass index (BMI), skeletal muscle mitochondrial respiration at complex I, complex II, and maximal respiration were all reduced in HFpEF patients (Scandalis et al, 2023). Furthermore, lower maximal respiratory capacity correlated with lower physical function in HFpEF patients when subjected to peak VO2 max, leg strength, and six-minute walk tests (Scandalis et al, 2023).

Mechanistically, preclinical studies have linked decreased mitochondrial function and muscle mass to alterations in skeletal muscle protein turnover. Muscle RING Finger 1 (MuRF1) and MAFBx are well-identified markers of skeletal muscle proteolysis under various atrophy conditions (Bodine et al, 2001), and the use of MyoMed-205 (a MuRF1 inhibitor) in obese rats significantly attenuated the loss of muscle weight due to proteolytic degradation (Adams et al, 2022). Additionally, the authors reported a significant upregulation of mitochondrial protein synthesis of Complex I and Complex II components compared to untreated obese animals, and an upregulation in protein synthesis of Complex III and Complex V compared to lean animals following MyoMed-205 treatment (Adams et al, 2022). In accord with animal data, skeletal muscle protein expression of MuRF-1 and ubiquitinated proteins (UB-K48) were significantly augmented in patients with HFpEF, as well as overall proteasome activity, confirming enhanced skeletal muscle protein degradation in affected individuals (Adams et al, 2019).

Overall, these data suggest a clear concordance between declining muscle mass and altered mitochondrial function in patients with HFpEF. As such, the protection and enhancement of mitochondrial function may serve as an important therapeutic target in HFpEF.

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 of the impact on HFpEF on skeletal muscle, which is likely to exacerbate the exercise intolerance aspects of HFpEF in patients. However, the drivers of metabolic dysfunction in HFpEF also have a negative effect on other tissues, meaning that the interplay between HFpEF, and diseases like diabetic kidney disease and non-alcoholic fatty liver disease, are likely to become increasingly apparent. As such, treatment modalities that focus on preventing mitochondrial dysfunction, and promoting their normal homeostatic mechanisms common to many tissues and diseases, are likely to be central to future therapeutic approaches.

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.

Footnotes

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Conflict of interest: The authors declared that there are no potential conflicts.

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