Review Article

Clinical Evidence and Proposed Mechanisms of Sodium–Glucose Cotransporter 2 Inhibitors in Heart Failure with Preserved Ejection Fraction: A Class Effect?

Abstract

Effective treatment for heart failure with preserved ejection fraction (HFpEF) is an unmet need in cardiovascular medicine. The pathophysiological drivers of HFpEF are complex, differing depending on phenotype, making a one-size-fits-all treatment approach unlikely. Remarkably, sodium– glucose cotransporter 2 inhibitors (SGLT2is) may be the first drug class to improve cardiovascular outcomes in HFpEF. Randomised controlled trials suggest a benefit in mortality, and demonstrate decreased hospitalisations and improvement in functional status. Limitations in trials exist, either due to small sample sizes, differing results between trials or decreased efficacy at higher ejection fractions. SGLT2is may provide a class effect by targeting various pathophysiological HFpEF mechanisms. Inhibition of SGLT2 and Na+ /H+ exchanger 3 in the kidney promotes glycosuria, osmotic diuresis and natriuresis. The glucose deprivation activates sirtuins – protecting against oxidation and beneficially regulating metabolism. SGLT2is reduce excess epicardial adipose tissue and its deleterious adipokines. Na+ /H+ exchanger 1 inhibition in the heart and lungs reduces sodium-induced calcium overload and pulmonary hypertension, respectively.

Disclosure: The authors have no conflicts of interest to declare.

Received:

Accepted:

Published online:

Correspondence: Brent Deschaine, University of Florida College of Medicine, 1104 Newell Dr, Gainesville, FL 32601, US. E: brent.deschaine@ufl.edu

Open access:

This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

In randomised controlled trials (RCTs), treatment with β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and mineralocorticoid receptor antagonists reduce mortality and/or hospitalisation of patients with heart failure with reduced ejection fraction (HFrEF), but these various drugs have not similarly benefited those with heart failure with preserved ejection fraction (HFpEF). Recently, several RCTs have shown clinical benefit in HFpEF with sodium–glucose cotransporter 2 inhibitors (SGLT2is; Table 1), potentially being the first drug class to provide relief for this heterogenous and difficult to treat patient population. This is a critical review of the RCTs of SGLT2is in HFpEF, and the numerous SGLT2i proposed underlying mechanisms of action in HFpEF.

Randomised Controlled Trials of SGLT2 Inhibitors in Patients with HFpEF

Phase III Randomised Controlled Trials

In November 2020, the SOLOIST-WHF trial results were groundbreaking. For the first time, a RCT treatment effect was demonstrated with SGLT2is in HFpEF patients.1 A prespecified subgroup analysis suggested a significant decrease in the modified primary outcome of cardiovascular (CV) deaths, hospitalisation for heart failure (HHF) and urgent visits for heart failure (HF) in HFpEF patients with diabetes (HR 0.48; 95% CI [0.27–0.86]) receiving sotagliflozin versus placebo, and it was achieved in 28 days.1,2 SOLOIST-WHF was also the first to show initiation of SGLT2 inhibition in HFpEF patients with acute HF, in stabilised patients preceding discharge or shortly afterwards – resulting in a lower total number of CV deaths and HHF, and urgent visits for HF versus placebo.1 However, due to the small sample size of HFpEF patients (n=256) with ejection fraction (EF) ≥50% and an early cessation of the trial due to the COVID-19 pandemic, firm conclusions were cautioned against, and the completion of future RCTs, such as EMPEROR-Preserved, PRESERVED-HF, CHIEF-HF and DELIVER, were highly anticipated.1

In August 2021, the results of EMPEROR-Preserved were released. The RCT assigned 5,988 patients with class II–IV HF and an EF >40% to receive empagliflozin versus control, and demonstrated a significant reduction in the primary outcome (composite of CV death or HHF); however, that was mostly related to a 29% lower risk of hospitalisations (HR 0.79; 95% CI [0.69–0.90]; p<0.001).3 These protective effects were observed in patients with and without diabetes.3 Importantly, empagliflozin appeared to have less effect as left ventricular EF increased (EF ≥50%) – still demonstrating a significant reduction in first HHF, but without significant reductions in CV mortality or total HHF.3,4 Empagliflozin may be more beneficial for HFpEF patients with mildly reduced EFs (HFmrEF; EF 40–49%), because they have clinical features more similar to those of HFrEF; further analysis and future RCTs should clarify the effectiveness of SGLT2is in patients with ‘true’ HFpEF on the higher end of the EF spectrum (EF ≥50%).3–6

Summary of Phase III Randomised Controlled Trials of SGLT2 Inhibitors in Heart Failure with Preserved Ejection Fraction

Article image

EMPEROR-Preserved also demonstrated a reduction in the incidence of outpatient visits for worsening HF, including the need for urgent care visits, reaching significance at 18 days and remaining significant throughout follow-up.7 In addition, empagliflozin was associated with a decreased risk of HHF requiring intensive care, or vasopressor or inotropic therapy, and a reduced need of increasing diuretic therapy in the outpatient setting.7 Within days of these significant EMPEROR-Preserved results, the Food and Drug Administration (FDA) granted Breakthrough Therapy designation to empagliflozin for the treatment of HFpEF, the first of the SGLT2is granted this status.8 Soon after, the FDA approved and expanded the HF indication for empagliflozin from HFrEF to also include HFmrEF and HFpEF.

In September 2021, PRESERVED-HF was the first trial to demonstrate SGLT2 inhibition (dapagliflozin) improves symptoms, physical limitations and 6-minute walking distance in patients with HFpEF.9 Functional status in patients with HFpEF improved in just 12 weeks regardless of diabetes status, and importantly, with a median EF of 60%.9 Of the 324 patients receiving dapagliflozin or placebo, the treatment group demonstrated an improvement in the Kansas City Cardiomyopathy Questionnaire (KCCQ)-Clinical Summary Score of 5.8 points (95% CI [2.3–9.2]; p=0.001), due to enhancements in both the KCCQ-Total Symptom Score of 5.8 points (95% CI [2.0–9.6]; p=0.003) and the physical limitations score of 5.3 points (95% CI [0.7–10.0]; p=0.026).9 Dapagliflozin also increased the 6-minute walk test by a mean of 20.1 m (95% CI [5.6–34.7]; p=0.007) and a KCCQ-Overall Summary Score of 4.5 points (95% CI [1.1–7.8]; p=0.009).9

Interestingly, the similar EMPERIAL-Preserved trial reported a non-significant 2.0-point increase in KCCQ-Total Symptom Score with empagliflozin versus placebo, and also did not demonstrate a significant change from baseline in the 6-minute walk test.9,10 The larger and significant functional status effect observed in PRESERVED-HF versus EMPERIAL-Preserved possibly has to do with the types of patients enrolled that had characteristics indicating substantial symptomatic and functional impairment at baseline (42 versus 22% with New York Heart Association class III/IV, and 244 versus 298 m in median 6-minute walk test, respectively).9,11 In addition, PRESERVED-HF versus EMPERIAL-Preserved included a higher percentage of patients necessitating loop diuretic therapy (88% versus 72%, respectively), and a higher amount with AF (53% versus 30%, respectively), which is associated with more right-sided HF and pulmonary hypertension with less cardiac reserve.12 Finally, PRESERVED-HF included larger proportions of women and African-Americans, with markedly higher BMI (34.7 versus 29.6, respectively), which is more representative of the US population.13

Further support for the impact SGLT2is may have on functional status in HFpEF was demonstrated in CHIEF-HF.14 Regardless of diabetes status, canagliflozin significantly improved symptoms and quality of life, as demonstrated by a KCCQ-Total Symptom Score of 4.5 points from baseline (95% CI [–0.3, 9.4]) for those with HFpEF (n=267; EF >40%) in as little as 2 weeks, and these improvements were sustained throughout the 3-month trial.14 However, as discussed earlier with EMPEROR-Preserved, data for CHIEF-HF included patients with HFmrEF (EF 40–49%) who appeared to be more similar to HFrEF in their clinical characteristics, and data may be less convincing in patients with EF ≥50.15

Finally, the highly anticipated DELIVER is a large RCT of 6,263 HFpEF (EF >40%) patients evaluating the effect of dapagliflozin versus control in reducing the composite of CV death, HHF and urgent HF visits, with an estimated completion date of March 2022.16 DELIVER should further clarify the possibility of SGLT2is reducing CV death in HFpEF patients.17 As stated earlier, uncertainty still remains regarding the effect of SGLT2is on mortality in HFpEF patients, as SOLOIST-WHF had a small sample size representing EF ≥50 (n=256), and EMPEROR-Preserved met its primary outcome mostly due to a reduction in the risk of hospitalisations, not mortality.1,3 DELIVER was also designed to recognise heterogeneity in the HF population at the higher end of the EF spectrum, and is powered with large sample sizes across the EF spectrum (41–49%, n=2,111; 50–59%, n=2,256; ≥60%, n=1,892).17 This should further elucidate the effect of SGLT2is in those at the higher end of the EF spectrum, where EMPEROR-Preserved data showed attenuation of benefit versus those with HFmrEF in reducing hospitalisations.3

Notably, DELIVER also included patients with recent acute decompensated HF requiring intravenous HF therapies or mechanical support, and should provide further data helping guide the role of SGLT2is in the inpatient and early post-discharge settings.17 More evidence for the use of SGLT2is in acute HF is emerging since the SOLOIST-WHF results (discussed earlier); post hoc and pre-specified analysis of the EMPULSE trial found that initiation of empagliflozin in patients hospitalised with acute HF produced clinical benefit regardless of EF.18 Results of the DELIVER trial will be available in 2022.17

Phase II Randomised Controlled Trials

Evaluation of the CAMEO-DAPA is a prospective, double-blind study (NCT04730947) with an estimated 46 participants and a primary outcome measuring the change in pulmonary capillary wedge pressure at baseline and 7 months during exercise. Patients included will have EF ≥50, BMI ≥30 and elevated pulmonary capillary wedge pressure (≥25 mmHg) during exercise at baseline. SGLT2is may reduce pulmonary capillary wedge pressure partly due to its unique diuretic ability (discussed in the next section) of decongesting fluid accumulation in the interstitial compartment without activation of the sympathetic nervous system.19,20 The trial is currently recruiting and has an estimated completion date of July 2023.

SGLT2i and KNO3 in HFpEF, the SAK HFpEF trial (NCT05138575) is a randomised crossover assignment trial in the recruiting stage with an estimated 53 participants, testing whether empagliflozin with and without potassium nitrate, improves submaximal exercise endurance, skeletal muscle oxidative phosphorylation capacity, intramuscular perfusion, and changes in the skeletal muscle metabolome, proteome and respiration in participants with HFpEF. Potential mechanisms regarding SGLT2i-induced metabolic changes in skeletal muscle and improvements in exercise capacity are discussed in the next section. The estimated completion date is September 2026.

The STADIA-HFpEF trial (NCT04475042) is in the recruiting stages, and is a randomised quadruple masked crossover study with a washout period, with an estimated 26 participants, investigating the effect of treatment with dapagliflozin on left ventricular distensibility in patients with early HFpEF. Proposed mechanisms of action of the effect of SGLT2is on cardiac stiffness are described in the next section. The estimated completion date is May 2022.

Proposed Mechanisms of Action of SGLT2is in HFpEF

SGLT2is Target SGLT2 and Na+/H+ Exchanger 3 in the Kidney

In the healthy kidney, most filtered glucose is reabsorbed in the proximal tubule by SGLT2, and most filtered sodium is reabsorbed by Na+/H+ exchanger 3 (NHE3).21–23 SGLT2 colocalises with NHE3, thereby SGLT2 inhibition also interferes with the function of NHE3.24 SGLT2is’ direct inhibition of SGLT2 and indirect inhibition of NHE3 induces glycosuria, osmotic diuresis, and natriuresis – mechanisms commonly proposed as providing potential benefit in HFpEF (Figure 1).7,24,25

The glucose-lowering and weight loss properties of SGLT2is alone cannot fully explain the CV benefits seen in HFpEF, since glycaemic control and other antihyperglycaemics that promote weight loss do not appear to decrease CV death or HF hospitalisations in HFpEF.26–28 The osmotic diuresis with resultant free water loss has been projected to explain the beneficial relatively higher interstitial versus intravascular fluid losses with a reduced reflexive neurohormonal activation thought to make SGLT2is unique when compared with conventional diuretics.20,29,30 SGLT2i-induced osmotic diuresis may improve myocardial oedema by increasing plasma oncotic pressure and stimulating plasma refill, thereby pulling fluid from the cardiac interstitium through Starling’s forces.25 A reduction in myocardial oedema is associated with a rightward shift in end-diastolic pressure volume relationship with decreases in left ventricular (LV) mass on cardiac magnetic resonance, and may be contributory in the early improvement of functional status demonstrated by PRESERVED-HF and CHIEF-HF, and may also partly explain EMPEROR-Preserved reaching significance in just 18 days with a reduction in worsening HF events.7,9,31 SGLT2is may also be a novel diuretic in that patient fluid response can vary depending on the baseline volume status of the patient, with less extracellular fluid loss in patients without fluid retention, potentially helping maintain a suitable body fluid status with lower risk of volume depletion.32

SGLT2i-induced natriuresis via inhibition of NHE3, which is upregulated in HF and implicated in diuretic resistance, may explain the reduced need for increasing outpatient diuretic therapy demonstrated by the EMPEROR-Preserved trial.7,33 Natriuresis may also be partly responsible for the reduced progression of kidney disease seen in people with diabetes, by increasing the sodium load to the macula densa with a resultant afferent arteriolar constriction and reduced glomerular hyperfiltration via tubuloglomerular feedback.34 Interestingly, SGLT2is (dapagliflozin) are also displaying prevention against the progression of chronic kidney disease in people without diabetes.35 Considering the bidirectional relationship of the heart and kidney, the kidney protection provided by SGLT2is may confer cardiac benefit indirectly, but this is speculative. In addition, long-term negative sodium balances associated with natriuresis have been shown to reduce aortic stiffness, potentially reducing the symptoms and progression of HFpEF.36,37

SGLT2i-induced natriuresis and diuresis may partly explain the reduced hospitalisations, and the easing of symptoms and physical limitations seen in HFpEF patients, but evidence suggests that SGLT2i mechanisms acting more directly on the heart may also play a significant role in their CV protection.7,9 SGLT2is activate sirtuins, reduce epicardial adipose tissue and its associated pro-inflammatory adipokines, promote cardiomyocyte sodium and calcium homeostasis, and relieve the right ventricle of pulmonary hypertension – all of which will now be discussed.24,38–41

SGLT2is Activate Sirtuins

Inhibiting SGLT2 in the proximal tubule produces glycosuria with calorie loss and a perceived state of starvation, thereby inducing a fasting-like state in tissues throughout the body, including the heart, skeletal muscle and kidney.24,42 Nutrient deprivation activates proteins called sirtuins (Sirt1, Sirt3, Sirt6), which are predominantly NAD+-dependent deacetylases involved in regulating autophagy, metabolism and mitochondrial function, thereby helping to alleviate cellular stress and inflammation.24,42–44 Autophagy, meaning self-eating, is cellular housekeeping to remove and/or recycle proteins and dysfunctional organelles – protecting the cells from oxidative stress, which is dysfunctional in the hearts of HFpEF patients.43–45 Increases in sirtuin activity are complex, but there may be a relationship between nutrient deprivation and a rise in NAD+ levels that activate sirtuins.42 Interestingly, HFpEF patients have reduced availability of NAD+, and impaired actions of Sirt1, Sirt3 and Sirt6.44 SGLT2i-induced increases in the abundance and activity of Sirt1, Sirt3 and Sirt6 in numerous tissues may explain some of the mechanisms behind their clinical benefits in HFpEF patients.40,44,46

Sirtuin 1

In cardiomyocytes, Sirt1 may induce autophagy directly by deacetylation of autophagy-related genes Atg5, Atg7 and Atg8, and may also increase autophagic flux by deacetylating the transcription factor forkhead box, class O isoform 1, increasing the expression of autophagy regulatory genes.47 The balance between the redox state and autophagy is crucial for cellular homeostasis, and inadequate basal autophagic flux and/or too many oxidants leads to a loss of redox balance that is related to the development of maladaptive cardiac remodelling.45 HFpEF pathophysiology includes damaged mitochondria with increases in reactive oxygen species (ROS), and also involves the downregulation of genes involved in autophagy.48,49 This cellular imbalance leads to oxidative damage, and promotes hallmarks of HFpEF: contractile dysfunction, cardiac stiffness, microvascular rarefaction, apoptosis, fibrosis and ECM remodelling.50 SGLT2i-induced calorie loss and resultant increases in autophagic flux through Sirt1 may mitigate HFpEF pathology by the clearance of dysfunctional mitochondria and alleviation of oxidative stress.40

SGLT2 Inhibitors Target SGLT2 and Na+ /H+ Exchanger 3 in the Kidney

Article image

Sirt1 can also deacetylate and activate the transcriptional coactivator, peroxisome proliferator-activated receptor-γ coactivator 1-α.51–53 Like other Sirt1 interactions, this pathway may increase autophagic flux, but could also provide HFpEF patients benefit through the reprogramming of metabolism and driving ketosis through regulation of its rate-limiting step.52 The pro-inflammatory state induced by comorbidities in HFpEF is associated with increased ROS and cytokine production that overwhelm the anti-inflammatory defences of the myocardium and vasculature, contributing to cardiac fibrosis.54,55 Increased ROS in HF promotes depletion of anti-oxidants with mitochondrial DNA damage and a reduction in adenosine triphosphate (ATP) synthesis.56,57 It is hypothesised that SGLT2is induce mild persistent hyperketonaemia, specifically through the SIRT1/PCG-1α pathway, whereby b-hydroxybutyrate is oxidised in preference to fatty acids, with improvement of cardiac function and efficiency, although this is controversial.40,58,59 It does appear SGLT2is improve cardiac energy efficiency by recycling cellular constituents through autophagy and thereby increasing ATP stores.40 Interestingly, ketone bodies themselves may also have anti-inflammatory properties and stimulate autophagy.60,61 The contribution of ketone metabolism in HFpEF remains to be established, but SGLT2i mediated ketosis may improve cardiac energy efficiency, reduce pro-inflammatory cytokine-induced mitochondrial damage and protect against cardiac fibrosis in HFpEF patients.62

Another possible source of ROS in failing hearts is xanthine oxidase (XO), which is stimulated by oxidative stress.63,64 An important statistical determinant of CV benefit with SGLT2is is the lowering of uric acid, particularly in those with type 2 diabetes, which may apply to the cardiometabolic phenotype of HFpEF, although this is speculative.65–67 Notably, empagliflozin lowered uric acid levels, and consistently reduced CV outcomes in those with type 2 diabetes and CV disease versus placebo.67 SGLT2is may blunt XO activity by relieving oxidative stress. Furthermore, Sirt1 activation may also downregulate XO, which in turn, may beneficially upregulate PCG-1α protein expression.68,69 The complex relationship between XO, Sirt1 and peroxisome proliferator-activated receptor-γ coactivator 1-α could explain the uric acid-lowering effects of SGLT2is.40

Activation of Sirt1 through SGLT2i-induced nutrient deprivation signals also leads to deacetylation of hypoxia-inducible factor-2α, a transcription factor with the erythropoietin gene as its main target.66,70 This may be the mechanism responsible for increases in haematocrit seen clinically with SGLT2 inhibitors.71 An increase in red cell mass may improve myocardial oxygen delivery and help alleviate LV hypertrophy in HFpEF patients, and importantly, haematocrit is a significant statistical determinant associated with the reduction in adverse cardiac events seen with SGLT2is.65,72–75

Finally, in regard to Sirt1, Sirt1-mediated deacetylation of SMAD3 may provide HFpEF patients protection by downregulation of transforming growth factor-beta (TGF-β)-mediated fibrosis through inhibition of fibrotic transcriptional activity, and also by inhibiting myofibroblasts.44,76–79 Cardiac fibrosis plays an important role in HFpEF pathology, and contributes to cardiomyocyte stiffness and cardiac remodelling.80 In addition, fibrosis is linked to AF, which occurs in up to two-thirds of HFpEF patients prior to, concurrent with or subsequent to HF diagnosis, and is associated with higher mortality rates.81,82

Sirtuin 3

HFpEF is also associated with disrupted activity of Sirt3, a mitochondrial deacetylase with tissue-specific roles that is expressed in highly metabolically active tissues, such as the heart.44,83 Sirt3 is involved in regulating the acetylation of mitochondrial proteins involved in ATP generation, and like Sirt1, appears to be increased in activity and number with SGLT2 inhibition.42,46

In cardiomyocytes, HFpEF pathology includes complex energy metabolic changes, with decreases in both glucose oxidation and mitochondrial oxidative capacity, resulting in decreased ATP production with cardiac remodelling, and this may be rescued by Sirt3 activity.84,85 Angiotensin II-induced HFpEF mice resulted in decreased glucose oxidation with reduced pyruvate dehydrogenase (PDH) activity, and Sirt3 has the ability to deacetylate and activate PDH.84,85 Related to this, increased microRNA-195 in failing hearts appears to inhibit Sirt3 by binding to its mRNA 3’-UTR, increasing the acetylation and deactivation of mitochondrial proteins, including PDH and ATP synthase.85 Therefore, increasing Sirt3 activity with SGLT2is may promote the deacetylation and activation of these enzymes, and improve mitochondrial respiration.42,46,85 This also suggests miR-195 as a potential target in HFpEF therapy through its relationship with Sirt3.44,85

In endothelial cells, Sirt3 may regulate a metabolic switch between glycolysis and mitochondrial respiration, protecting against coronary microvascular rarefaction – an emerging major contributor in HFpEF that involves endothelial cell apoptosis, cardiomyocyte hypoxia, titin-based cardiomyocyte stiffness and myocardial fibrosis.44,83,86 Endothelial cells rely predominantly on glycolysis for energy production, and Sirt3 deficiency in endothelial cells exhibit reduced glycolysis and higher levels of endothelial mitochondrial respiration, with increased production of ROS and increased acetylation of p53.83 Sirt3, which is increased with SGLT2 inhibition, may restore glycolytic predominance in endothelial cells, and also has potential to deacetylate p53, thus protecting against coronary microvascular rarefaction in HFpEF.83,87

In skeletal muscle, HFpEF is associated with a rapid depletion of high-energy phosphates early in exercise, contributing to exercise intolerance and early fatigue, hallmarks of HFpEF.88 Enhanced acetylation due to diminished Sirt3 may have inhibitory impacts on fatty acid β-oxidation enzymes in skeletal muscle, impairing mitochondrial oxidative capacity and contributing to exercise intolerance.89 Empagliflozin restored lowered exercise endurance capacity by activating skeletal muscle fatty acid oxidation in a murine model of HF.90 Importantly, dapagliflozin and canagliflozin improves symptoms and physical limitations in HFpEF, and beneficial skeletal muscle alterations may be involved with SGLT2 inhibition.11,14

Sirtuin 6

Sirt6 is predominantly a nuclear deacetylase that is downregulated in HF, and has demonstrated a role in protection against ventricular hypertrophy by modulating insulin-like growth factor (IGF)/protein kinase B (Akt) signalling.91 Sustained activation of IGF/Akt signalling due to hyperinsulinaemia, especially in the cardiometabolic phenotype of HFpEF, may lead to pathological hypertrophy through surplus energy signalling in cardiomyocytes.24,91 Sirt6 controls IGF/Akt signalling at the level of chromatin through the stress response transcription factor, c-Jun, and by deacetylation of H3K9.91 Thus, increased activity of Sirt6 may dampen IGF/Akt signalling and protect against this pathological hypertrophy.91 SGLT2is may also indirectly decrease signalling through this pathway by lowering serum insulin levels.24

SGLT2 Inhibitors Target Na+ /H+ Exchanger 1 in the Heart and Lungs

Article image

SGLT2is Decrease Epicardial Adipose Volume and Actions of Pro-inflammatory Adipocytokines

In addition to the beneficial activation of sirtuins, the glucose-deprived state generated by blocking SGLT2 in the proximal tubule leads to increased serum glucagon and decreased serum insulin levels, thereby enhancing lipolysis with subsequent reduction of epicardial adipose tissue (EAT).36 Excess EAT especially contributes to the cardiometabolic phenotype of HFpEF as a mechanical obstacle to LV filling (pericardial restraint), and thereby aggravating diastolic dysfunction by enhanced diastolic ventricular interaction.36,44 The EAT also shares a common blood supply with the myocardium, with no fascia separating the two tissues, possibly allowing EAT-secreted pro-inflammatory (interleukin-6, interleukin-1β, tumour necrosis factor-α), pro-oxidant (H2O2, superoxide) and profibrotic (TGF-β) mediators to act on the surrounding myocardium – inducing extracellular matrix remodelling, hypertrophy and defective autophagic flux.44,92,93

Lipolysis of EAT may positively modify energy metabolism in the myocardium by providing it with free fatty acids and ketone bodies.36 Decreasing EAT can relieve pericardial restraint and improve end-diastolic pressure volume relationship in HFpEF, but also has other potential protective mechanisms due to the reduction of EAT-secreted adipokines. For example, decreased TGF-β and tumour necrosis factor-α may result in less diffuse interstitial fibrosis and hypertrophy with decreased LV stiffness – potentially contributing to the reduced LV mass on cardiac magnetic resonance demonstrated with SGLT2 inhibition, albeit this would be a longer-term mechanism versus the immediate effects of decreases in myocardial oedema due to osmotic diuresis (discussed earlier).36,72,94,95 Reduced TGF-β may also protect the atrial myocardium from fibrosis and AF.96 In addition, reducing EAT decreases superoxide production and its scavenging effects attributed to impairing the nitric oxide/cyclic guanosine monophosphate/protein kinase G pathway, resulting in decreased titin hypophosphorylation and a subsequent reduction in LV stiffness – potentially providing haemodynamic relief in HFpEF patients with a rightward shift in the end-diastolic pressure volume relationship.36,93,97,98

Notably, the EAT also secretes leptin, and circulating levels of leptin are increased in HFpEF.99,100 EAT-derived leptin induces myocardial remodelling in high-fat diet-induced obese rats, partly by stimulating upregulation of type I collagen via the JAK2/STAT3-TGF-β1/Smad3 pathway in cardiac fibroblasts.101 SGLT2i-induced increases of Sirt1, which has the ability to inhibit TGF-β1 signalling via deacetylation of Smad3 (discussed earlier), may mechanistically contribute to the ability of SGLT2is to counterbalance the deleterious actions of leptin-mediated fibrosis in HFpEF patients, especially in those who are obese. 102,103 Leptin may also increase oxidative stress in the heart through increased activity of NHE1, and SGLT2is have been shown to inhibit NHE1 (discussed later), thereby potentially protecting the heart against the paracrine effects of leptin-induced oxidative damage.104 Finally, it has been hypothesised in obesity-related HFpEF patients, that leptin enhances SGLT2 expression in the renal tubules and augments the secretion of aldosterone by the adrenal glands – leading to sodium retention and plasma volume expansion.103,105,106 The beneficial natriuretic actions of SGLT2is via inhibition of SGLT2/NHE3 and decreases in aldosterone levels are the opposite of the pathological sodium retention encouraged by leptin in HFpEF patients.103 Interestingly, decreased leptin levels seen with SGLT2 inhibition may not be only due to a reduction in adipose tissue, but could also be because of direct interference with leptin synthesis.107 This may explain why SGLT2i-induced decreases in leptin levels are out of proportion to their modest effects on weight loss.108

SGLT2s Target Na+/H+ Exchanger 1 in the Heart and Lungs

Increasing evidence supports SGLT2is’ inhibition of NHE1 in the heart, either directly and/or indirectly, explaining some of the cardioprotective mechanisms in HFpEF (Figure 2).38,109,110 Enhanced activity of NHE1 has been detected in HFpEF pathology, such as in pressure overload and hypertensive hypertrophy.111–113 When pathologically activated in cardiomyocytes, NHE1 exchanges hydrogen for an intrusion of sodium with reversal of the Na+/Ca2+ exchanger, resulting in sodium-dependent calcium overload, pH alterations and oxidative stress.59

Sodium-dependent calcium overload is injurious to cardiomyocytes, and leads to contractile dysfunction, arrhythmogenicity and apoptosis.114 Intracellular sodium overload also facilitates mitochondrial calcium efflux through the mitochondrial Na+/Ca2+ exchanger, impairing calcium-induced Krebs cycle dehydrogenases that are responsible for ATP production and the regeneration of reducing equivalents that preserve anti-oxidative capacity.115 This leads to inadequate energy supplies and to the deleterious release of ROS.115

Pathological activation of NHE1 also induces intracellular alkalosis, possibly increasing myofilament calcium responsiveness and contributing to diastolic dysfunction.116,117 Furthermore, NHE1 hyperactivation is associated with the activation of Ca2+/calmodulin-dependent protein kinase II, which phosphorylates and activates various sodium channels, including NHE1 – leading to further sodium and calcium overload, and oxidative damage.38 Calmodulin-dependent protein kinase II activity may play a role in the development and progression of HF by interfering with the fine-tuning of myocardial excitation-contraction coupling, and also by altering gene expression in hypertrophic signalling.118,119 Interestingly, mechanistic evidence supports SGLT2is’ inhibition of calmodulin-dependent protein kinase II, which could be responsible for the indirect inhibition of NHE1 by decreasing its phosphorylation.38,109

Further evidence for SGLT2is providing HFpEF patients benefit through NHE1 inhibition in the heart is shown by dapagliflozin ameliorating diastolic dysfunction, possibly by targeting coronary endothelium and cardiomyocytes through NHE1 in a non-diabetic model of HFpEF.120 Also, chronic inhibition of NEH1 attenuates cardiac hypertrophy, and prevents cellular remodelling after pressure and volume overloading in rabbits.114 A mechanistic study using artificial intelligence also showed empagliflozin-mediated NHE1 inhibition appears to modulate cardiomyocyte stiffness, myocardial extracellular matrix remodelling, systemic inflammation and concentric hypertrophy mechanisms.110 Validation of the data was performed by measuring declining plasma concentrations of inducible nitric oxide synthase, NLR family pyrin domain containing 3 inflammasome and TGF-β1 during 12 months of empagliflozin treatment.110

Finally, NHE1 inhibition in pulmonary artery smooth muscle cells may protect against pulmonary hypertension through repression of nuclear transcription factor, E2F transcription factor 1, leading to reduced proliferation and hypertrophy of pulmonary artery smooth muscle cells, and decreased medial wall thickness (Figure 2) in the pulmonary vasculature, as shown in mice.121 Interestingly, also in mice, SGLT2is have been shown to relax pulmonary vasculature in a dose-dependent manner akin to sodium nitroprussides (nitric oxide donor) mechanism – activation of potassium channels and hyperpolarisation of pulmonary artery smooth muscle cells.122 Clinically, empagliflozin has demonstrated rapid reductions in pulmonary artery pressures that were amplified over time.123 These SGLT2i-induced pulmonary vascular effects may aid in decongestion and improve right ventricular function in HFpEF patients, potentially contributing to the reduced symptoms and hospitalisations demonstrated in RCTs.9,41

Conclusion

SGLT2is may be the first drug class to improve cardiovascular outcomes in those suffering from HFpEF, providing hope to this heterogenous and difficult to treat population. RCTs are demonstrating a significant reduction in HF hospitalisations, with an improvement in functional status. Future trials are still needed to validate the effect of SGLT2is on mortality in HFpEF patients, and to determine their efficacy in patients at the higher end of the EF spectrum.

SGLT2is may provide a class effect by targeting a wide array of pathophysiological HFpEF pathways and mechanisms. Through inhibition of SGLT2 and NHE3 in the kidney, SGLT2is promote glycosuria, osmotic diuresis and natriuresis. The glucose deprivation is associated with a decrease in epicardial adipose volume, and SGLT2is reduce and oppose the actions of its detrimental adipocytokines. The glucose-deprived state also activates sirtuins – proteins that may protect the heart against oxidative damage, and positively regulate metabolism in the heart and skeletal muscle. Additionally, direct actions of SGLT2is via inhibition of NHE1 in the heart and lungs may protect against sodium-induced calcium overload and pulmonary hypertension, respectively.

References

  1. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2021;384:117–28.
    Crossref | PubMed
  2. Shah SR, Ali A, Ikram S. Sotagliflozin and decompensated heart failure: results of the SOLOIST-WHF trial. Expert Rev Clin Pharmacol 2021;14:523–5.
    Crossref | PubMed
  3. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021;385:1451–61.
    Crossref | PubMed
  4. Drazner MH. SGLT2 inhibition in heart failure with a preserved ejection fraction – a win against a formidable foe. N Engl J Med 2021;385:1522–4.
    Crossref | PubMed
  5. Butler J, Anker SD, Packer M. Redefining heart failure with a reduced ejection fraction. JAMA 2019;322:1761–2.
    Crossref | PubMed
  6. Pascual-Figal DA, Ferrero-Gregori A, Gomez-Otero I, et al. Mid-range left ventricular ejection fraction: clinical profile and cause of death in ambulatory patients with chronic heart failure. Int J Cardiol 2017;240:265–70.
    Crossref | PubMed
  7. Packer M, Butler J, Zannad F, et al. Effect of empagliflozin on worsening heart failure events in patients with heart failure and a preserved ejection fraction: EMPEROR-Preserved trial. Circulation 2021;144:1284–94.
    Crossref | PubMed
  8. Lilly. FDA grants Jardiance® Breakthrough Therapy designation for heart failure with preserved ejection fraction. 9 September 2021. https://investor.lilly.com/news-releases/news-release-details/fda-grants-jardiancer-breakthrough-therapy-designation-heart (accessed 11 June 2022).
  9. Nassif ME, Windsor SL, Borlaug BA, et al. The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial. Nat Med 2021;27:1954–60.
    Crossref | PubMed
  10. Abraham WT, Lindenfeld J, Ponikowski P, et al. Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction, with and without type 2 diabetes. Eur Heart J 2021;42:700–10.
    Crossref | PubMed
  11. Kosiborod M. Effect of empagliflozin on worsening heart failure events in patients with heart failure and a preserved ejection fraction: the EMPEROR-Preserved trial. Presented at: Heart Failure Society of America, Denver, CO, 12 September 2021.
  12. Reddy YNV, Obokata M, Verbrugge FH, et al. Atrial dysfunction in patients with heart failure with preserved ejection fraction and atrial fibrillation. J Am Coll Cardiol 2020;76:1051–64.
    Crossref | PubMed
  13. Dunlay SM, Roger VL, Redfield MM. Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2017;14:591–602.
    Crossref | PubMed
  14. Spertus J. The Canagliflozin Impact On Health Status, Quality Of Life And Functional Status In Heart Failure (CHIEF-HF) clinical trial. Presented at: American Heart Association’s Scientific Sessions, 14 November 2021.
  15. Li P, Zhao H, Zhang J, et al. Similarities and differences between HFmrEF and HFpEF. Front Cardiovasc Med 2021;8:678614.
    Crossref | PubMed
  16. Solomon SD, de Boer RA, DeMets D, et al. Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial. Eur J Heart Fail 2021;23:1217–25.
    Crossref | PubMed
  17. Solomon SD, Vaduganathan M, Claggett BL, et al. Baseline characteristics of patients with HF with mildly reduced and preserved ejection fraction: DELIVER trial. JACC Heart Fail 2022;10:184–97.
    Crossref | PubMed
  18. Kosiborod MN, Angermann CE, Collins SP, et al. Effects of empagliflozin on symptoms, physical limitations and quality of life in patients hospitalized for acute heart failure – results from the EMPULSE trial. Circulation 2022; epub ahead of press.
    Crossref | PubMed
  19. Jensen J, Omar M, Kistorp C, et al. Effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate in patients with heart failure (Empire HF Renal): a prespecified substudy of a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2021;9:106–16.
    Crossref | PubMed
  20. Hallow KM, Helmlinger G, Greasley PJ, et al. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes Metab 2018;20:479–87.
    Crossref | PubMed
  21. Schultheis PJ, Clarke LL, Meneton P, et al. Renal and intestinal absorptive defects in mice lacking the NHE3 Na+/H+ exchanger. Nat Genet 1998;19:282–5.
    Crossref | PubMed
  22. Wang T, Yang CL, Abbiati T, et al. Mechanism of proximal tubule bicarbonate absorption in NHE3 null mice. Am J Physiol 1999;277:f298–302.
    Crossref | PubMed
  23. Zhuo JL, Li XC. Proximal nephron. Compr Physiol 2013;3:1079–123.
    Crossref | PubMed
  24. Packer M. Differential pathophysiological mechanisms in heart failure with a preserved ejection fraction in diabetes.JACC Heart Fail 2021;9:535–49.
    Crossref | PubMed
  25. Mullens W, Martens P. Empagliflozin and renal sodium handling: an intriguing smart osmotic diuretic. Eur J Heart Fail 2021;23:79–82.
    Crossref | PubMed
  26. Lejeune S, Roy C, Slimani A, et al. Diabetic phenotype and prognosis of patients with heart failure and preserved ejection fraction in a real life cohort. Cardiovasc Diabetol 2021;20:48.
    Crossref | PubMed
  27. Rasalam R, Atherton JJ, Deed G, et al. Sodium-glucose cotransporter 2 inhibitor effects on heart failure hospitalization and cardiac function: systematic review. ESC Heart Fail 2021;8:4093–118.
    Crossref | PubMed
  28. Jarnert C, Landstedt-Hallin L, Malmberg K, et al. A randomized trial of the impact of strict glycaemic control on myocardial diastolic function and perfusion reserve: a report from the DADD (Diabetes mellitus And Diastolic Dysfunction) study. Eur J Heart Fail 2009;11:39–47.
    Crossref | PubMed
  29. Aguilar-Gallardo JS, Correa A, Contreras JP. Cardio-renal benefits of SGLT2 inhibitors in heart failure with reduced ejection fraction: mechanisms and clinical evidence. Eur Heart J Cardiovasc Pharmacother 2022;8:311–21.
    Crossref | PubMed
  30. Lambers Heerspink HJ, de Zeeuw D, Wie L, et al. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab 2013;15:853–62.
    Crossref | PubMed
  31. Verbrugge FH, Bertrand PB, Willems E, et al. Global myocardial oedema in advanced decompensated heart failure. Eur Heart J Cardiovasc Imaging 2017;18:787–94.
    Crossref | PubMed
  32. Ohara K, Masuda T, Morinari M, et al. The extracellular volume status predicts body fluid response to SGLT2 inhibitor dapagliflozin in diabetic kidney disease. Diabetol Metab Syndr 2020;12:37.
    Crossref | PubMed
  33. Packer M. Activation and inhibition of sodium-hydrogen exchanger is a mechanism that links the pathophysiology and treatment of diabetes mellitus with that of heart failure. Circulation 2017;136:1548–59.
    Crossref | PubMed
  34. Hallow KM, Gebremichael Y, Helmlinger G, Vallon V. Primary proximal tubule hyperreabsorption and impaired tubular transport counterregulation determine glomerular hyperfiltration in diabetes: a modeling analysis. Am J Physiol Ren Physiol 2017;312:f819–35.
    Crossref | PubMed
  35. Persson F, Rossing P, Vart P, et al. Efficacy and safety of dapagliflozin by baseline glycemic status: a prespecified analysis from the DAPA-CKD trial. Diabetes Care 2021;44:1894–7.
    Crossref | PubMed
  36. Mullens W, Martens P. Empagliflozin-induced changes in epicardial fat: the centerpiece for myocardial protection? JACC Heart Fail 2021;9:590–3.
    Crossref | PubMed
  37. Karagodin I, Aba-Omer O, Sparapani R, Strande JL. Aortic stiffening precedes onset of heart failure with preserved ejection fraction in patients with asymptomatic diastolic dysfunction. BMC Cardiovasc Disord 2017;17:62.
    Crossref | PubMed
  38. Trum M, Riechel J, Wagner S. Cardioprotection by SGLT2 inhibitors – does it all come down to Na+? Int J Mol Sci 2021;22:7976.
    Crossref | PubMed
  39. Packer M. Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium-glucose cotransporter 2 inhibitors. Eur J Heart Fail 2020;22:618–28.
    Crossref | PubMed
  40. Packer M. Cardioprotective effects of sirtuin-1 and its downstream effectors: potential role in mediating the heart failure benefits of SGLT2 (sodium-glucose cotransporter 2) inhibitors. Circ Heart Fail 2020;13:e007197.
    Crossref | PubMed
  41. Heinzel FR, Hegemann N, Hohendanner F, et al. Left ventricular dysfunction in heart failure with preserved ejection fraction-molecular mechanisms and impact on right ventricular function. Cardiovasc Diagn Ther 2020;10:1541–60.
    Crossref | PubMed
  42. Lee IH. Mechanisms and disease implications of sirtuin-mediated autophagic regulation. Exp Mol Med 2019;51:1–11.
    Crossref | PubMed
  43. Mishra S, Kass DA. Cellular and molecular pathobiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 2021;18:400–23.
    Crossref | PubMed
  44. Hamdani N, Costantino S, Mugge A, et al. Leveraging clinical epigenetics in heart failure with preserved ejection fraction: a call for individualized therapies. Eur Heart J 2021;42:1940–58.
    Crossref | PubMed
  45. Morales CR, Pedrozo Z, Lavandero S, Hill JA. Oxidative stress and autophagy in cardiovascular homeostasis. Antioxid Redox Signal 2014;20:507–18.
    Crossref | PubMed
  46. Wang CY, Chen CC, Lin MH, et al. TLR9 Binding to beclin 1 and mitochondrial SIRT3 by a sodium-glucose co-transporter 2 inhibitor protects the heart from doxorubicin toxicity. Biology (Basel) 2020;9:369.
    Crossref | PubMed
  47. Hariharan N, Maejima Y, Nakae J, et al. Deacetylation of FoxO by Sirt1 plays an essential role in mediating starvation-induced autophagy in cardiac myocytes. Circ Res 2010;107:1470–82.
    Crossref | PubMed
  48. Kumar AA, Kelly DP, Chirinos JA. Mitochondrial dysfunction in heart failure with preserved ejection fraction. Circulation 2019;139:1435–50.
    Crossref | PubMed
  49. Hahn VS, Knutsdottir H, Luo X, et al. Myocardial gene expression signatures in human heart failure with preserved ejection fraction. Circulation 2021;143:120–34.
    Crossref | PubMed
  50. Upadhya B, Taffet GE, Cheng CP, Kitzman DW. Heart failure with preserved ejection fraction in the elderly: scope of the problem. J Mol Cell Cardiol 2015;83:73–87.
    Crossref | PubMed
  51. Osataphan S, Macchi C, Singhal G, et al. SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms. JCI Insight 2019;4:e123130.
    Crossref | PubMed
  52. Swe MT, Thongnak L, Jaikumkao K, et al. Dapagliflozin not only improves hepatic injury and pancreatic endoplasmic reticulum stress, but also induces hepatic gluconeogenic enzymes expression in obese rats. Clin Sci (Lond) 2019;133:2415–30.
    Crossref | PubMed
  53. Umino H, Hasegawa K, Minakuchi H, et al. High basolateral glucose increases sodium-glucose cotransporter 2 and reduces sirtuin-1 in renal tubules through glucose transporter-2 detection. Sci Rep 2018;8:6791.
    Crossref | PubMed
  54. Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 2013;62:263–71.
    Crossref | PubMed
  55. Zhazykbayeva S, Pabel S, Mugge A, et al. The molecular mechanisms associated with the physiological responses to inflammation and oxidative stress in cardiovascular diseases. Biophys Rev 2020;12:947–68.
    Crossref | PubMed
  56. Sugamura K, Keaney JF, Jr. Reactive oxygen species in cardiovascular disease. Free Radic Biol Med 2011;51:978–92.
    Crossref | PubMed
  57. Tsutsui H, Kinugawa S, Matsushima S. Oxidative stress and heart failure. Am J Physiol Heart Circ Physiol 2011;301:h2181–90.
    Crossref | PubMed
  58. Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care 2016;39:1108–14.
    Crossref | PubMed
  59. Baker HE, Kiel AM, Luebbe ST, et al. Inhibition of sodium-glucose cotransporter-2 preserves cardiac function during regional myocardial ischemia independent of alterations in myocardial substrate utilization. Basic Res Cardiol 2019;114:25.
    Crossref | PubMed
  60. Rojas-Morales P, Tapia E, Pedraza-Chaverri J. Beta-hydroxybutyrate: a signaling metabolite in starvation response? Cell Signal 2016;28:917–23.
    Crossref | PubMed
  61. Youm YH, Nguyen KY, Grant RW, et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med 2015;21:263–9.
    Crossref | PubMed
  62. Lopaschuk GD, Karwi QG, Tian R, et al. Cardiac energy metabolism in heart failure. Circ Res 2021;128:1487–513.
    Crossref | PubMed
  63. Hajjar RJ, Leopold JA. Xanthine oxidase inhibition and heart failure: novel therapeutic strategy for ventricular dysfunction? Circ Res 2006;98:169–71.
    Crossref | PubMed
  64. McNally JS, Saxena A, Cai H, et al. Regulation of xanthine oxidoreductase protein expression by hydrogen peroxide and calcium. Arterioscler Thromb Vasc Biol 2005;25:1623–8.
    Crossref | PubMed
  65. Inzucchi SE, Zinman B, Fitchett D, et al. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care 2018;41:356–63.
    Crossref | PubMed
  66. Packer M. Mechanisms leading to differential hypoxia-inducible factor signaling in the diabetic kidney: modulation by SGLT2 inhibitors and hypoxia mimetics. Am J Kidney Dis 2021;77:280–6.
    Crossref | PubMed
  67. Verma S, Ji Q, Bhatt DL, et al. Association between uric acid levels and cardio-renal outcomes and death in patients with type 2 diabetes: a subanalysis of EMPA-REG OUTCOME. Diabetes Obes Metab 2020;22:1207–14.
    Crossref | PubMed
  68. Wang Z, Ding J, Luo X, et al. Effect of allopurinol on myocardial energy metabolism in chronic heart failure rats after myocardial infarct. Int Heart J 2016;57:753–9.
    Crossref | PubMed
  69. Alcendor RR, Gao S, Zhai P, et al. Sirt1 regulates aging and resistance to oxidative stress in the heart. Circ Res 2007;100:1512–21.
    Crossref | PubMed
  70. Chen R, Xu M, Hogg RT, et al. The acetylase/deacetylase couple CREB-binding protein/sirtuin 1 controls hypoxia-inducible factor 2 signaling. J Biol Chem 2012;287:30800–11.
    Crossref | PubMed
  71. Mazer CD, Hare GMT, Connelly PW, et al. Effect of empagliflozin on erythropoietin levels, iron stores, and red blood cell morphology in patients with type 2 diabetes mellitus and coronary artery disease. Circulation 2020;141:704–7.
    Crossref | PubMed
  72. Verma S, Mazer CD, Yan AT, et al. Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes mellitus and coronary artery disease: the EMPA-HEART CardioLink-6 randomized clinical trial. Circulation 2019;140:1693–702.
    Crossref | PubMed
  73. Verma S, Mazer CD, Bhatt DL, et al. Empagliflozin and cardiovascular outcomes in patients with type 2 diabetes and left ventricular hypertrophy: a subanalysis of the EMPA-REG OUTCOME trial. Diabetes Care 2019;42:e42–4.
    Crossref | PubMed
  74. Li J, Woodward M, Perkovic V, et al. Mediators of the effects of canagliflozin on heart failure in patients with type 2 diabetes. JACC Heart Fail 2020;8:57–66,
    PubMed
  75. Kobayashi M, Girerd N, Duarte K, et al. Prognostic impact of plasma volume estimated from hemoglobin and hematocrit in heart failure with preserved ejection fraction. Clin Res Cardiol 2020;109:1392–401.
    Crossref | PubMed
  76. Wei W, Rao F, Liu F, et al. Involvement of Smad3 pathway in atrial fibrosis induced by elevated hydrostatic pressure. J Cell Physiol 2018;233:4981–9.
    Crossref | PubMed
  77. Zhang L, Chen J, Yan L, et al. Resveratrol ameliorates cardiac remodeling in a murine model of heart failure with preserved ejection fraction. Front Pharmacol 2021;12:646240.
    Crossref | PubMed
  78. Casalena G, Daehn I, Bottinger E. Transforming growth factor-beta, bioenergetics, and mitochondria in renal disease. Semin Nephrol 2012;32:295–303.
    Crossref | PubMed
  79. Han L, Tang Y, Li S, et al. Protective mechanism of SIRT1 on Hcy-induced atrial fibrosis mediated by TRPC3. J Cell Mol Med 2020;24:488–510.
    Crossref | PubMed
  80. Sweeney M, Corden B, Cook SA. Targeting cardiac fibrosis in heart failure with preserved ejection fraction: mirage or miracle? EMBO Mol Med 2020;12:e10865.
    Crossref | PubMed
  81. Zakeri R, Chamberlain AM, Roger VL, Redfield MM. Temporal relationship and prognostic significance of atrial fibrillation in heart failure patients with preserved ejection fraction: a community-based study. Circulation 2013;128:1085–93.
    Crossref | PubMed
  82. Luong C, Barnes ME, Tsang TS. Atrial fibrillation and heart failure: cause or effect? Curr Heart Fail Rep 2014;11:463–70.
    Crossref | PubMed
  83. Zeng H, Chen JX. Sirtuin 3, endothelial metabolic reprogramming, and heart failure with preserved ejection fraction. J Cardiovasc Pharmacol 2019;74:315–23.
    Crossref | PubMed
  84. De Jong KA, Lopaschuk GD. Complex energy metabolic changes in heart failure with preserved ejection fraction and heart failure with reduced ejection fraction. Can J Cardiol 2017;33:860–71.
    Crossref | PubMed
  85. Zhang X, Ji R, Liao X, et al. MicroRNA-195 regulates metabolism in failing myocardium via alterations in Sirtuin 3 expression and mitochondrial protein acetylation. Circulation 2018;137:2052–67.
    Crossref | PubMed
  86. D’Amario D, Migliaro S, Borovac JA, et al. Microvascular dysfunction in heart failure with preserved ejection fraction. Front Physiol 2019;10:1347.
    Crossref | PubMed
  87. Li S, Banck M, Mujtaba S, et al. p53-induced growth arrest is regulated by the mitochondrial SirT3 deacetylase. PLoS One 2010;5:e10486.
    Crossref | PubMed
  88. Adams V, Linke A, Winzer E. Skeletal muscle alterations in HFrEF vs. HFpEF. Curr Heart Fail Rep 2017;14:489–97.
    Crossref | PubMed
  89. Tsuda M, Fukushima A, Matsumoto J, et al. Protein acetylation in skeletal muscle mitochondria is involved in impaired fatty acid oxidation and exercise intolerance in heart failure. J Cachexia Sarcopenia Muscle 2018;9:844–59.
    Crossref | PubMed
  90. Nambu H, Takada S, Fukushima A, et al. Empagliflozin restores lowered exercise endurance capacity via the activation of skeletal muscle fatty acid oxidation in a murine model of heart failure. Eur J Pharmacol 2020;866:172810.
    Crossref | PubMed
  91. Sundaresan NR, Vasudevan P, Zhong L, et al. The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun. Nat Med 2012;18:1643–50.
    Crossref | PubMed
  92. Oikonomou EK, Antoniades C. The role of adipose tissue in cardiovascular health and disease. Nat Rev Cardiol 2019;16:83–99.
    Crossref | PubMed
  93. Payne GA, Kohr MC, Tune JD. Epicardial perivascular adipose tissue as a therapeutic target in obesity-related coronary artery disease. Br J Pharmacol 2012;165:659–69.
    Crossref | PubMed
  94. Putko BN, Wang Z, Lo J, et al. Circulating levels of tumor necrosis factor-alpha receptor 2 are increased in heart failure with preserved ejection fraction relative to heart failure with reduced ejection fraction: evidence for a divergence in pathophysiology. PLoS One 2014;9:e99495.
    Crossref | PubMed
  95. Miao K, Zhou L, Ba H, et al. Transmembrane tumor necrosis factor alpha attenuates pressure-overload cardiac hypertrophy via tumor necrosis factor receptor 2. PLoS Biol 2020;18:e3000967.
    Crossref | PubMed
  96. Venteclef N, Guglielmi V, Balse E, et al. Human epicardial adipose tissue induces fibrosis of the atrial myocardium through the secretion of adipo-fibrokines. Eur Heart J 2015;36:795–805a.
    Crossref | PubMed
  97. Kovács Á, Alogna A, Post H, Hamdani N. Is enhancing cGMP-PKG signalling a promising therapeutic target for heart failure with preserved ejection fraction? Neth Heart J 2016;24:268–74.
    Crossref | PubMed
  98. van Heerebeek L, Hamdani N, Falcao-Pires I, et al. Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation 2012;126:830–9.
    Crossref | PubMed
  99. Mizuta E, Kokubo Y, Yamanaka I, et al. Leptin gene and leptin receptor gene polymorphisms are associated with sweet preference and obesity. Hypertens Res 2008;31:1069–77.
    Crossref | PubMed
  100. Faxén UL, Hage C, Andreasson A, et al. HFpEF and HFrEF exhibit different phenotypes as assessed by leptin and adiponectin. Int J Cardiol 2017;228:709–16.
    Crossref | PubMed
  101. Tian G, Luo C, Liu L. Epicardial adipose tissue-derived leptin induce MMPS/TIMPS imbalance and promote cardiac fibrosis through JAK2/ROS/NA/K-ATPase/ERK1/2 signaling pathway in high fat diet-induced obese rats. J Am Coll Cardiol 2022;79(9 Suppl):1544.
    Crossref
  102. Bugyei-Twum A, Ford C, Civitarese R, et al. Sirtuin 1 activation attenuates cardiac fibrosis in a rodent pressure overload model by modifying Smad2/3 transactivation. Cardiovasc Res 2018;114:1629–41.
    Crossref | PubMed
  103. Packer M. Do sodium-glucose co-transporter-2 inhibitors prevent heart failure with a preserved ejection fraction by counterbalancing the effects of leptin? A novel hypothesis. Diabetes Obes Metab 2018;20:1361–6.
    Crossref | PubMed
  104. Konstantinou-Tegou A, Kaloyianni M, Bourikas D, Koliakos G. The effect of leptin on Na+-H+ antiport (NHE 1) activity of obese and normal subjects erythrocytes. Mol Cell Endocrinol 2001;183:11–8.
    Crossref
  105. Xue B, Yu Y, Zhang Z, et al. Leptin mediates high-fat diet sensitization of angiotensin II-elicited hypertension by upregulating the brain renin-angiotensin system and inflammation. Hypertension 2016;67:970–6.
    Crossref | PubMed
  106. Huby AC, Antonova G, Groenendyk J, et al. Adipocyte-derived hormone leptin is a direct regulator of aldosterone secretion, which promotes endothelial dysfunction and cardiac fibrosis. Circulation 2015;132:2134–45.
    Crossref | PubMed
  107. Teta D, Bevington A, Brown J, et al. Acidosis downregulates leptin production from cultured adipocytes through a glucose transport-dependent post-transcriptional mechanism. J Am Soc Nephrol 2003;14:2248–54.
    Crossref | PubMed
  108. Vickers SP, Cheetham SC, Headland KR, et al. Combination of the sodium-glucose cotransporter-2 inhibitor empagliflozin with orlistat or sibutramine further improves the body-weight reduction and glucose homeostasis of obese rats fed a cafeteria diet. Diabetes Metab Syndr Obes 2014;7:265–75.
    Crossref | PubMed
  109. Zuurbier CJ, Baartscheer A, Schumacher CA, et al. SGLT2 inhibitor empagliflozin inhibits the cardiac Na+/H+ exchanger 1: persistent inhibition under various experimental conditions. Cardiovasc Res 2021;117:2699–701.
    Crossref | PubMed
  110. Bayes-Genis A, Iborra-Egea O, Spitaleri G, et al. Decoding empagliflozin’s molecular mechanism of action in heart failure with preserved ejection fraction using artificial intelligence. Sci Rep 2021;11:12025.
    Crossref | PubMed
  111. Cingolani HE, Ennis IL. Sodium-hydrogen exchanger, cardiac overload, and myocardial hypertrophy. Circulation 2007;115:1090–100.
    Crossref | PubMed
  112. Mraiche F, Oka T, Gan XT, et al. Activated NHE1 is required to induce early cardiac hypertrophy in mice. Basic Res Cardiol 2011;106:603–16.
    Crossref | PubMed
  113. Pérez NG, Alvarez BV, Camilión de Hurtado MC, Cingolani HE. pHi regulation in myocardium of the spontaneously hypertensive rat. Compensated enhanced activity of the Na+–H+ exchanger. Circ Res 1995;77:1192–200.
    Crossref | PubMed
  114. Baartscheer A, Schumacher CA, van Borren MM, et al. Chronic inhibition of Na+/H+-exchanger attenuates cardiac hypertrophy and prevents cellular remodeling in heart failure. Cardiovasc Res 2005;65:83–92.
    Crossref | PubMed
  115. Maejima Y. SGLT2 inhibitors play a salutary role in heart failure via modulation of the mitochondrial function. Front Cardiovasc Med 2019;6:186.
    Crossref | PubMed
  116. Marban E, Kusuoka H. Maximal Ca2+-activated force and myofilament Ca2+ sensitivity in intact mammalian hearts. Differential effects of inorganic phosphate and hydrogen ions. J Gen Physiol 1987;90:609–23.
    Crossref | PubMed
  117. Bode D, Semmler L, Wakula P, et al. Dual SGLT-1 and SGLT-2 inhibition improves left atrial dysfunction in HFpEF. Cardiovasc Diabetol 2021;20:7.
    Crossref | PubMed
  118. Maier LS, Bers DM. Calcium, calmodulin, and calcium-calmodulin kinase II: heartbeat to heartbeat and beyond. J Mol Cell Cardiol 2002;34:919–39.
    Crossref | PubMed
  119. Maier LS, Bers DM. Role of Ca2+/calmodulin-dependent protein kinase (CaMK) in excitation-contraction coupling in the heart. Cardiovasc Res 2007;73:631–40.
    Crossref | PubMed
  120. Cappetta D, De Angelis A, Ciuffreda LP, et al. Amelioration of diastolic dysfunction by dapagliflozin in a non-diabetic model involves coronary endothelium. Pharmacol Res 2020;157:104781.
    Crossref | PubMed
  121. Yu L, Hales CA. Silencing of sodium-hydrogen exchanger 1 attenuates the proliferation, hypertrophy, and migration of pulmonary artery smooth muscle cells via E2F1. Am J Respir Cell Mol Biol 2011;45:923–30.
    Crossref | PubMed
  122. Han Y, Cho YE, Ayon R, et al. SGLT inhibitors attenuate no-dependent vascular relaxation in the pulmonary artery but not in the coronary artery. Am J Physiol Lung Cell Mol Physiol 2015;309:L1027–36.
    Crossref | PubMed
  123. Nassif ME, Qintar M, Windsor SL, et al. Empagliflozin effects on pulmonary artery pressure in patients with heart failure: results from the EMBRACE-HF trial. Circulation 2021;143:1673–86.
    Crossref | PubMed