Tackling metabolic defects in HFpEF

Abstract

The intricate pathophysiology of heart failure (HF) with preserved ejection fraction (EF) (HFpEF) is marked by its heterogeneous clinical characteristics and its variety of associated comorbidities, resulting in a disappointingly limitation of effective therapies. Heart failure with preserved ejection fraction syndrome is now recognized as a multiple-organ systemic disorder for the understanding of which the in-depth investigation of its clinical, basic, and translation characteristics across multiple organs and systems beyond cardiovascular is required. Challenges in establishing reliable animal models recapitulating different phenotypes of HFpEF, coupled with limited access to human samples, casted a shadow on our understanding of HFpEF pathophysiology and its therapeutic opportunities. Thus far, sodium–glucose cotransporter 2 inhibitor stands as the sole European Society of Cardiology HF guideline-recommended treatment option for patients with HFpEF.1 Despite a great deal of epidemiological evidence having reinforced the association between obesity and HFpEF, inclusion of obese HFpEF patients in clinical trials is still limited. This is at least partially attributed to the challenges in interpreting the lower-than-expected plasmatic levels of natriuretic peptides, which are per se affected by obesity. Indeed, the role of obesity in HFpEF should be redefined from a simple comorbidity bystander to a central player in its pathophysiology. In this context, the most recent and striking evidence related to the impact of obesity on HFpEF comes from the results of the STEP-HFpEF trial (NCT04788511) which strongly supported the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in patients with HFpEF and obesity.2 For the first time, a class of medications designed to treat obesity is effective in HFpEF. The promising results obtained with GLP-1RAs highlight the fact that correction of metabolic alterations, viz. changes in energy metabolism, is key to HFpEF treatment. ‘An engine out of fuel’.3 Failing heart—mostly HF with reduced EF (HFrEF)—has been marked by this seminal definition nearly two decades ago as the consequence of major changes in cardiac metabolism leading to the reduction of energetic equivalents, i.e. reduction in phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio. Fast forward today, the same definition might not be entirely applicable to cardiac metabolic remodelling in obese HFpEF. In obese HFpEF, overload of fatty acids (FAs) compels the heart to sustain or even increase reliance on FA oxidation lacking the anticipated shift to glucose oxidation as typically occurs in HFrEF.4 Considering FAs as the most energetic dense substrate, in the presence of FA overflow, the term ‘energy deficit’ does not accurately recapitulate the energetic changes occurring in cardiometabolic HFpEF. To avoid oversimplifying the complexity of metabolic changes in cardiometabolic HFpEF and recognizing HFpEF being probably marked by energy deficit, here, we propose the term ‘energy resilience’ to characterize the metabolic derangements in cardiometabolic HFpEF (Figure 1). Other than FAs, various substrates play a crucial role in myocardial ATP production in HFpEF. However, the prevailing dominance of one substrate (e.g. FAs in obese HFpEF) over others raises critical questions about energy imbalance and its impact on cardiac homeostasis. Instead of ‘metabolic inflexibility’ or ‘energy deficit’, HFpEF hearts rather appear to be prompt to prefer the dominant substrate available (i.e. FAs). If prolonged, increased reliance on FAs presents with unwanted effects such as lipid accumulation and consequent cardiac lipotoxicity, driving myocardial maladaptation in HFpEF. Schematic representation of putative energetic alterations in cardiometabolic heart failure with preserved ejection fraction (HFpEF). In the healthy heart (left), fatty acid (FA) is the primary energy source for adenosine triphosphate production (∼70%), together with glucose, branched chain amino acids (BCAAs), ketone bodies (KBs), and lactate. Metabolic flexibility in the healthy heart enables the switching in the oxidation among energy substrates in response to nutrient availability (box on the left). In the obese HFpEF heart (right), the overflow of FA disrupts the distribution of other energy substrates, impacting negatively on cardiac energy resilience—e.g. inhibition of glucose oxidation (box on the right). Disruption of physiological substrate oxidation leads to an imbalance redox state and changes in metabolite availability which regulates cellular signalling pathway via post-translational modification (PTMs) and increases oxidative/nitrosative stress (e.g. R/NOS production), promoting a status of cardiac hypoxia/pseudohypoxia This dynamic imbalance among energy substrates dictates metabolic remodelling beyond the competition between FAs and glucose. Infusion of ketone bodies (KBs) diminishes myocardial glucose uptake5 and inhibits FA uptake and oxidation.6 Understanding the interdependence between substrate utilization is crucial to grasp the complexity of energy metabolism in HFpEF cardiac remodelling. Consequently, strategies to correct energy defects in cardiometabolic HFpEF might not be as straightforward such prioritizing one substrate over others. Instead, restoring the balance between energy substrates—i.e. resilience—will be critical to allow cardiac adaptive energy production in response to dynamic changes of energy demand (Figure 1). In addition to unbalanced energy substrates availability, energy defects in cardiometabolic HFpEF is accompanied by increased production of reactive oxygen/nitrosative oxygen species (R/NOS). A prominent downstream effect of R/NOS in HFpEF is the emergence and propagation of microvascular dysfunction (MVD). Despite the high prevalence of MVD observed in patients with HFpEF, whether MVD is a causal mechanism in HFpEF development is still uncertain. One potential link between MVD and HFpEF relates to the tissue hypo-oxygenation—i.e. cardiac hypoxia. As hypoxia is tightly linked with changes in cardiac metabolism,7 the role of hypoxia-inducible factor 1-alpha (HIF1α) on pyruvate dehydrogenase (PDH) activity—governing glucose oxidation—might provide a pathophysiological basis for the role of hypoxia in HFpEF. Under hypoxia, upregulation of HIF1α inhibits PDH activity by activating pyruvate dehydrogenase kinase (PDK4). Inhibition of PDH redirects pyruvate away from the tricarboxylic acid (TCA) cycle for oxidation, favouring its conversion to lactate through anaerobic glycolysis to sustain ATP production—a phenomenon known as Warburg effect. Intriguingly, the potential effects of HIFs on metabolic remodelling in HFpEF might not be exclusively dependent on the status of cardiac tissue oxygenation. Oxygen-independent mechanisms of HIF activation have been observed. Potentially relevant to cardiometabolic HFpEF pathogenesis might be the axis sirtuins (SIRTs)-NAD+/NADH. In HFpEF, the imbalanced redox state caused by reduction of NAD+/NADH ratio associated with the accumulation of acetyl-CoA impacts on energy metabolism and cardiac function through changes in the acetylation status of multiple mitochondrial proteins.8 Inhibition of SIRTs caused a decline in NAD+ which activates HIF1α signalling even in the presence of oxygen—a phenomenon known as pseudohypoxia9 (Figure 1). Pseudohypoxia metabolic modulators are not limited to NAD+. Changes in TCA cycle enzymatic activity modify NAD+/NADH redox state, as well as resulting in the accumulation of TCA cycle metabolites. Among these, α-ketoglutarate, succinate, and fumarate (KSF) drive pseudohypoxia signalling by inhibiting prolyl hydroxylases and initiating the HIF signalling pathway (Figure 1). Importantly, the current understanding of KSF actions in pseudohypoxia is almost exclusively limited to cancer. The contribution of pseudohypoxia modulators to the regulation of oxygen utilization capacity and associated oxidative stress in HFpEF remains unknown. We submit that mechanisms related to pseudohypoxia can occur in cardiometabolic HFpEF and might be critical for its pathogenesis. The investigation of this intriguing putative mechanism could facilitate the discovery of novel therapeutic targets for HFpEF. The notion that major energy substrates serve exclusively as energetic bricks to make ATP is incomplete. Indeed, the growing recognition of energy substrates as signalling molecules extends their role beyond their conventional function as mere energy fuels. Virtually, any metabolite can serve as a signalling molecule. One prominent mode by which metabolites exert their signalling role is through post-translational modifications (PTMs), allowing metabolites to directly modify proteins and affect their function(s). Acetyl-CoA, KBs, TCA cycle intermediates, and many others can orchestrate signalling pathways via PTMs dictating different cardiac metabolic phenotypes (Figure 1). Thus, metabolite-driven PTMs may play a role in HFpEF pathophysiology, and, so far, we are only at the beginning of their understanding in this syndrome. Furthermore, owing to their potential druggability, the prospect of targeting PTMs as a therapeutic strategy for HFpEF treatment appears promising (e.g. histone deacetylase inhibitors). The exploration of pharmacological modulation of metabolite-driven PTMs in HFpEF warrants further consideration. Many challenges remain in advancing our understanding of HFpEF pathogenesis and in identifying effective therapeutic targets. Interventions aimed to restore energy resilience and targeting metabolite-driven PTMs hold promise to combat metabolic remodelling in HFpEF. Figure 1 has been created with BioRender.com licenced to G.G.S. All authors declare no disclosure of interest for this contribution. This work was supported by grants from the DZHK (German Centre for Cardiovascular Research—81X3100210), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation—SFB-1470—A02), and the European Research Council (ERC, StG 101078307 to G.G.S.).

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