Heart failure with preserved ejection fraction (HFpEF) in type 2 diabetes mellitus

Introduction

The prevalence of type 2 diabetes mellitus (T2DM or T2D) rose dramatically over the past decades, afflicting ∼8% adults globally (Ren et al., 2010^; Lascar et al., 2018^; Zhang et al., 2018). The ever-rising T2D prevalence imposes profound sequelae on the cardiovascular system (Ceylan-Isik et al., 2008^; Yang et al., 2015^; Tan et al., 2020^; Ren et al., 2021). Cardiovascular disease (CVD) becomes the leading cause of death in T2D, with coronary artery disease (CAD) and ischemic cardiomyopathy being the main culprits (Jia et al., 2018^; Tan et al., 2020^; Jankauskas et al., 2021). In addition to CAD, small vessel disease and diminished cardiac capillary density also occur (Zhou et al., 2018).

T2D evokes unique changes in myocardium independent of classical risk factors, including CAD, hypertension, and valvular heart disease. This is a condition termed as diabetic cardiomyopathy (DCM) (Jia et al., 2018^; Tan et al., 2020). Early-stage DCM is usually characterized by structural and functional abnormalities, including myocardial hypertrophy, stiffening, interstitial fibrosis, and diastolic dysfunction (Ren and Ceylan-Isik, 2004^; Wold et al., 2005^; Ren et al., 2010^; Jia et al., 2018^; Tan et al., 2020). Similar findings were observed in animal models of T2D, including compromised diastolic and systolic function accompanied by changes in cardiomyocyte function and intracellular Ca²⁺ (Wold et al., 2005^; Li et al., 2006^; Ghosh et al., 2007^; Ren and Anversa, 2015^; Wang et al., 2021).

Patients with T2D exhibit an increased risk of heart failure (HF). Of note, 25% of T2D patients exhibit various types of HF, including HF with preserved, reduced, and midrange ejection fraction (HFpEF, HFrEF, and HFmrEF, respectively), with mortality increased by 30%–50% and worsened prognosis (Cosentino et al., 2020). The two predominant types of HF in DCM are HFrEF and HFpEF, with concentric left ventricular (LV) remodeling and diastolic dysfunction. HFpEF accounts for approximately half of the HF incidence in T2D, characterized by a normal or near-normal LV ejection fraction (LVEF) ≥50% and exercise intolerance as the chief complaint (McDonagh et al., 2021). Other than T2D, various complications, including obesity, hypertension, dyslipidemia, renal disease, and atrial fibrillation, also closely correlate with HFpEF (Taqueti et al., 2018). Given the high prevalence and poor prognosis of HFpEF, intensive therapy is pertinent for the management of cardiovascular anomalies in patients with T2D (Lalic, 2021^; Tadic et al., 2021). Nonetheless, current treatment modality remains dismal largely due to the poorly defined pathophysiology of HFpEF in T2D. In this review, we discuss potential pathophysiological mechanisms and treatment options for HFpEF in T2D patients. We will also summarize recent clinical trials.

Epidemiology and prognosis of HFpEF in T2D

T2D plays an essential role in the onset of HFpEF (Lalic, 2021^; Tadic et al., 2021). Compared with non-diabetics, the incidence and mortality of CVD and HF are much higher in T2D patients (Bullard et al., 2018^; Xu et al., 2018). Patients with T2D initially present with normal systolic but progressively impaired diastolic function, indicative of HFpEF. Approximately 45% of T2D patients develop HFpEF, and the prevalence of co-morbid T2D is more abruptly increased in T2D patients with new-onset HFpEF (Patel et al., 2016).

T2D in combination with HFpEF greatly enhances CVD risk and mortality (Cavender et al., 2015). TOPCAT (LVEF > 40%) is a multicenter, randomized, double-blind, placebo-controlled study of microvascular complications in T2D patients, including neuropathy, nephropathy, and retinopathy (Sandesara et al., 2018^; De Marco et al., 2021). According to the CHARM Trial, 3023 patients were defined as LVEF > 40%, with an average follow-up of 37.7 months. Patients with T2D display greater volume overload, more severe myocardial injury, higher body mass index, hypertension (especially systolic pressure), coronary microvascular dysfunction, and renal abnormality (McHugh et al., 2019). The I-PRESERVE Study with LVEF ≥ 50% revealed that HFpEF patients with T2D had higher rates of cardiovascular mortality, hospitalization, and all-cause mortality (MacDonald et al., 2008^; Kristensen et al., 2017; Table 1). Overall, these clinical trials denote a close tie between HFpEF-associated mortality and T2D, favoring a positive correlation between T2D and HFpEF-associated morbidity and mortality. Possible contributions from T2D-induced cellular, molecular, and metabolic abnormalities are considered the major driving forces for the worsened HFpEF pathology.

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Pathophysiology of HFpEF in T2D

Clinical reports favor a DCM phenotype distinct from dilated cardiomyopathy. T2D patients display myocardial dysfunction in the absence of coronary heart diseases (e.g. CAD) (Dei Cas et al., 2015), possibly due to metabolic abnormalities, e.g. advanced glycation end product (AGE) deposition, lipid toxicity, and microvascular rarefication (Low Wang et al., 2016). These adverse effects of T2D were more pronounced in HFpEF (Lalic, 2021^; Tadic et al., 2021). T2D with HFpEF is featured by LV diastolic dysfunction (LVDD) and decreased LV cavity with elevated LV filling pressure, as well as endothelial and coronary microvascular dysfunction (Paulus and Dal Canto, 2018). In T2D, hearts are exposed to hyperglycemic environments with abundant fatty acids and cytokines (Seferovic and Paulus, 2015^; McHugh et al., 2019). Hyperglycemia provokes adverse clinical outcomes in T2D through AGE production (Ren and Ceylan-Isik, 2004), leading to accumulation of reactive oxygen species (ROS), inflammation, mitochondrial damage, and apoptosis (Ren and Ceylan-Isik, 2004^; Wold et al., 2005). Hyperglycemia prompts endothelial dysfunction and elevated serum cholesterol, resulting myocardial dysfunction and ventricular–vascular uncoupling (Meza et al., 2019). In this context, subclinical variations develop, prompting cardiovascular events, including HFpEF (Figure 1; Kosmala et al., 2017). Rigorous glucose control is of enormous importance for the clinical outcome of HFpEF.

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Molecular mechanisms behind HFpEF in T2D

In T2D patients, decreased diastolic function accompanied by altered protein expression governing relaxation was revealed. Metabolic abnormalities in T2D seem to play a vital role in conjunction with hyperglycemia, proinflammatory responses, and lipotoxicity (Borlaug, 2014). Other confounding factors, including interstitial fibrosis, vascular damaging, dysregulated NO, and cyclic guanine monophosphate (cGMP), may also contribute to the etiology of HFpEF. For example, interruption in the cGMP–PKG signal transduction and the rise of protein kinase C alpha (PKCα) activity are deemed key regulatory factors of cardiomyocyte stiffness in DCM (Figure 2).

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LVH is a cardinal feature of HFpEF and the major reason for elevated diastolic filling pressure and diastolic dysfunction. Myocardial fibrosis, impaired Ca²⁺ handling, oxidative stress, mitochondrial dysfunction, and metabolic reprogramming are all key components of pathological cardiac hypertrophy (Liang et al., 2021^; Ren et al., 2021^; Xu et al., 2021^; Zhang et al., 2021). Crucial molecular contributors to this pathological hypertrophy in T2D with HFpEF include G protein-coupled receptors, stress hormone ligands, and signaling kinases (Nakamura and Sadoshima, 2018). The precise roles of these signaling machineries in HFpEF remain at large in humans. The ratio of NAD⁺ to NADH decreased in the hearts of patients with T2D, while NAD⁺ is required for metabolic oxidation (Atila Uslu and Uslu, 2022). These findings suggest the possible involvement of altered energy metabolism in pathological hypertrophy.

Interstitial fibrosis is commonly noted in DCM accompanied by changes in a wide variety of cell signaling cascades and extracellular matrix proteins (e.g. formation of insoluble AGEs) (Ren and Ceylan-Isik, 2004^; Tayanloo-Beik et al., 2021). In addition, aberrant activation of protein kinases such as calcium/calmodulin-dependent protein kinase type II subunit beta (CAMKII) has been shown to contribute to excitation–contraction coupling defects in T2D. CAMKII may be turned on by the Ca²⁺–calmodulin complex, cAMP, and ROS. Overactivation of CAMKII phosphorylates substrate proteins governing Ca²⁺ handling and fosters LVH, mitochondrial injury, inflammation, and arrythmia (Pyun et al., 2018^; Hegyi et al., 2019). It is believed that transient receptor potential channel 3 (TRPC3) and TRPC6 may serve as triggers for the hyperactivation of CAMKII (Klaiber et al., 2010). This is supported by the observation that ablation of TRPC3 or TRPC6 mitigates pressure overload-evoked maladaptive hypertrophy (Seo et al., 2014). Among various potential regulators for TRP channels, stimulation of calcineurin–NFAT is suggested to offer a direct link between gene expression and intracellular Ca²⁺ signaling (Hogan et al., 2003^; Molkentin, 2004).

Diastolic function denotes myocardial relaxation capacity following a normal heartbeat (Gaasch and Zile, 2004). The relaxation period includes active and passive phases at both cellular and tissue levels (Borlaug and Kass, 2006). Upon excitation, intracellular Ca²⁺ is dumped from the intracellular sarcoplasmic reticulum (SR) store with the binding of ryanodine receptor (RyR) to troponin C. Relaxation initiates with the dissociation of Ca²⁺ ions from the troponin complex—prior to SR reuptake and efflux of Ca²⁺ through Na⁺–Ca²⁺ exchange protein (NCX). To lower cytosolic Ca²⁺ in diastole, phospholamban is phosphorylated to disinhibit sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2), enabling SR Ca²⁺ reuptake (Xu et al., 2020). This is supported by findings that cardiac overexpression of phospholamban inhibits SERCA2A and SR Ca²⁺ uptake to compromise cardiac function, while phospholamban knockout mice display better Ca²⁺ cycling and myocardial contractility. With the uptake of Ca²⁺ into SR during the diastolic period, reverse-mode NCX is increased at the sarcolemma. Decreased myocardial compliance (muscle stiffening) was due to suppressed cGMP-dependent PKG and hypo-phosphorylation of titin (Obokata et al., 2020). cGMP and its cognate kinase, PKG, are known for the maintenance of vascular and endothelial function. As such, the LV chamber becomes less compliant and fails to dilate properly courtesy of hypo-phosphorylation of titin in diastole. Activation of PKG or protein kinase A (PKA, cAMP-driven and possibly PKG-independent) may thus correct these irregularities and reinstate LV chamber compliance (Sztechman et al., 2018).

Hyperglycemia, a hallmark of T2D, is one of the key causes of endothelial dysfunction (Ren and Ceylan-Isik, 2004^; Tayanloo-Beik et al., 2021). Exposure of endothelial cells to high glucose leads to ROS production, while glycosylation inhibits eNOS activation, angiogenesis, and mitochondrial dysfunction. Quenching of NO by AGEs plays a vital role in vasodilatory impairment in T2D. Depletion of NADPH and excessive AGE production may result in elevated permeability of endothelial cells, inhibition of eNOS activity, influence of the coagulation system, and activation of NADPH oxidase and nuclear factor-κB (NF-κB) (Soro-Paavonen et al., 2010). Downregulated insulin signaling is a hallmark of T2D, and other signaling cascade changes occur, including downregulated adenosine monophosphate activated protein kinase (AMPK) signaling and increased PKC and mitogen-activated protein kinase (MAPK) signaling with undesirable effects (Ren and Anversa, 2015^; Dillmann, 2019). Downregulation of peroxisome-proliferator-activated receptor-γ coactivator 1α (PGC1α) evokes altered oxidative mitochondrial function in T2D. In plasma from HFpEF patients, metabolomic profiling exhibited altered levels of β-oxidation (Phan et al., 2009). Reduced mitochondrial oxidative metabolism is accompanied by increased glycolysis, although such change may be translated to higher glucose uptake through glycolysis from pyruvate oxidation (Berthiaume et al., 2019). Impaired insulin signaling inhibits glucose oxidation by negative feedback regulation via the Randle cycle.

Microvascular disease is also a common feature of T2D (Zhou et al., 2018). Mechanisms include depressed NO signaling, increased oxidative stress and inflammation, impaired angiogenesis, and other abnormalities. For generality, the main factor is NAD-dependent protein deacetylase sirtuin-3 (SIRT3). SIRT3 knockdown of endothelial cells in mice impairs glycolysis and angiogenesis and is associated with diastolic dysfunction. However, a role for SIRT3 in HFpEF patients is lacking. Compared with healthy controls, patients with HFpEF display a greater product of end-systolic pressure and stroke volume, myocardial blood flow, and myocardial oxygen consumption (Pillai et al., 2010). These changes denote an imbalance between demand and supply with elevated cardiac work in HFpEF with β-adrenergic stimulation.

Nuclear factor erythroid 2-like factor 2 (Nrf2) is a master regulator of oxidative stress with a vital role in DKD (Sakashita et al., 2021). Under unstressed conditions, Nrf2 is ubiquitinated and degraded by proteasomes through Kelch-like ECH-associated protein 1 (Keap1), while Keap1 undergoes various chemical modifications to reduce its affinity for Nrf2 and inhibit its degradation under oxidative stress (Ruiz et al., 2013^; Kobayashi et al., 2016). Bardoxolone methyl is a synthetic triterpenoid, which not only upregulates Nrf2 but also retards inflammation, perhaps through additional actions on NF-κB. Currently, bardoxolone methyl is going through clinical trials for type 1 diabetic nephropathy and other renal diseases.

Treatment options for HFpEF in T2D

It is important to identify and treat potential risk factors and other comorbidities such as hypertension, CAD, atrial fibrillation, and valvular heart disease for HFpEF in T2D (Table 1). Therapeutically, mineralocorticoid receptor antagonists (MRA) were reported to reduce HFH in HFpEF, although the effects on mortality-related outcomes and quality of life remain unclear for MRA (Martin et al., 2018). On the other hand, classical β-blockers display little effectiveness in treating obesity/T2D-associated HFpEF, although larger cohorts are needed. Likewise, angiotensin converting enzyme inhibitors exhibit little or no effect on cardiovascular mortality, all-cause mortality, and HFH (Tomasoni et al., 2019). In the PARAGON-HF Trial using angiotensin receptor/neprilysin inhibitor (ARNI, sacubitril/valsartan), there was little difference in primary endpoints of HFpEF. Nonetheless, significant benefits were noted in two subgroups (women and LVEF ≤ 57%). It is suggested that ARNI may be an effective option for certain HFpEF patients (Jering et al., 2021). Comorbidities are common in HFpEF patients, including hypertension, thus necessitating intensive management for hypertension. The ACC/AHA guidelines recommend a target systolic blood pressure <130 mmHg in HFpEF patients. In addition, observational studies suggest that statins may also offer benefits in HFpEF (Yancy et al., 2017).

There are several mechanisms in T2D with HFpEF, including sodium retention and subsequent volume overload and elevated filling pressure, increased proinflammatory cytokines, impaired skeletal muscle function, and cardio–respiratory uncoupling (McHugh et al., 2019^; Kessler et al., 2021^; Tadic et al., 2021). Historically, treatment based on the cardiovascular system, with neurohormonal blockade, has been claimed unsuccessful. Specific subgroups of patients with HFpEF and those with combinations of clinical comorbidities, including T2D and metabolic dysfunction, might be more new remedies for T2D with HFpEF.

Of note, the use of new medications and combination therapies for glycemic control in T2D is rapidly evolving (Ceylan-Isik et al., 2008^; Kashiwagi et al., 2021^; Kessler et al., 2021^; Oh et al., 2021^; Tadic et al., 2021^; Kim et al., 2022). As patients with T2D often have other risk factors, including obesity, hypertension, dyslipidemia, and renal disease, current treatment strategies favor combination therapies, such as anti-hyperglycemic and anti-hypertensive therapy, to retard the progression of HFpEF. A multifactorial approach targeting multiple, if not all, risk factors has displayed better promises compared with glucose control alone. The most potent antidiabetic medications to prevent HF development in T2D include SGLT2 inhibitors, which retard the onset and progression of HF regardless of the presence of T2D or not (Anker et al., 2019; Table 2).

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Conclusion and future perspectives

Clinical trial data show that the incidence rate and long-term mortality rate of T2D patients with HFpEF are higher than those of non-diabetic patients. Treatments for T2D patients with HFpEF are urgently needed. One of the major burning obstacles for clinical therapeutics of HFpEF is the poorly understood pathophysiology behind HFpEF, making drug development a perplexing task. Several potential therapeutic targets have been identified thus far. However, individual targeting of molecular signaling pathways defined in HFpEF might not effectively restore diastolic function due to the apparent drug toxicity and off-target effects. Therefore, future drug development requires a more comprehensive approach, not only for HFpEF comorbidities but also for classification and phenotypic identification in HFpEF.