The syndrome of heart failure with preserved ejection fraction (HFpEF) undoubtedly interacts with cardiometabolic contributors to cellular aging, but previous tendencies toward oversimplification have challenged our understanding of the pathophysiology. One excessively myopic and historically cardiac-focused paradigm has largely come and gone: so-called "diastolic heart failure" (a term best relegated to documentation code language) was a term that attempted to describe a syndrome involving congestive signs and symptoms (eg, "the patient is wet") while assembling loose connections to aging, hypertension, and other risk factors purportedly leading to left ventricular impaired relaxation.
A more contemporary conceptual framework for trying to understand HFpEF includes recognizing the complex and heterogenous contributions of cellular aging (eg, oxidative stress, metabolic disease and inflammation, cellular senescence), along with both cardiovascular (eg, endothelial, myocardial, vascular, and so on) and noncardiovascular (eg pulmonary disease, anemia, skeletal muscle dysfunction, chronic kidney disease, and so on) mechanisms leading to the clinical syndrome of heart failure (HF), but with an ejection fraction (EF) that is not <40% (Figure 1). Clinical manifestation occurs in concert with upward and leftward shifting of the diastolic pressure-volume relationship culminating in blunted cardiac output during exercise often exacerbated by chronotropic incompetence, supranormal arterial stiffness, and ventricular-arterial uncoupling.[1,2]
Cellular Aging Contributors and Proposed Mitigation by SGLT2 Inhibition
Major molecular regulators of cellular lifespan are sirtuin-1 (SIRT1) and mammalian target of rapamycin complex 1 (mTORC1). In a nutrient-deficient or calorie-restricted state, SIRT1 activation, along with adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) set forth a cascade of downstream target activations culminating in deceleration of cell aging. Suppression of the mTORC1 pathway further augments SIRT1-activated autophagy, the lysosome-utilizing process of clearing misfolded proteins from the cytosol. Without healthy autophagy, oxidative stress contributes to impaired endothelial nitric oxide (NO) pathways, inflammation, cell death, fibrosis, and cardiomyopathy (adapted from Gevaert et al1). SGLT2 inhibitors are hypothesized to contribute to activation of SIRT1 and suppression of mTORC1 pathways.10 Akt = protein kinase B; HFpEF = heart failure with preserved ejection fraction; ROS = reactive oxygen species.
More advanced age is a recognized risk factor and pathophysiologic contributor to the HFpEF syndrome, which often provokes an adverse impact on quality of life. The mean age of patients with HFpEF enrolled in contemporary trials markedly exceeds that of clinical trial patients with reduced EF. Meanwhile, the mode of death in HFpEF is more frequently noncardiac in etiology, making the pursuit of survival-extending pharmacotherapy for affected persons daunting. Additionally, elderly individuals with HFpEF are more commonly White women with comorbidities such as atrial fibrillation, hypertension, and chronic kidney disease, which may make therapies less likely to be effective, especially when compared with younger patients. Concerns with aging also include potential waning efficacy of pharmacotherapy and concomitant increase in risk of adverse events or intolerance of medication detrimental to quality of life.
The recently published 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure provides a recommendation supporting the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for nearly all patients with symptomatic HF. For patients with HFpEF (specified as left ventricular ejection fraction [LVEF] ≥50%) and HF with mildly reduced EF (specified as LVEF 41%-49%), a moderate (Class IIa) endorsement is based largely on the results of the landmark EMPEROR-Preserved (Empagliflozin in Heart Failure with a Preserved Ejection Fraction) clinical trial. Nearly 6,000 patients with symptomatic HF and EF >40% were randomly assigned to receive empagliflozin (10 mg once daily) or placebo on top of standard background therapy. The significant 21% hazard reduction for the primary endpoint of cardiovascular death or HF hospitalization represented a barrier break—the first observation of its kind in the history of clinical trials involving patients with HFpEF. But, were older individuals similarly benefitted by use of empagliflozin?
In this issue of the Journal of the American College of Cardiology, Bohm et al explore the relative safety and efficacy of empagliflozin compared with placebo as influenced by advanced age among patients enrolled in EMPEROR-Preserved. The authors focused the substudy investigation on primary outcomes, hospitalization for HF, change in estimated glomerular filtration rate (eGFR), health-related quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score, and adverse events across 4 baseline age subgroups.
The key finding is the consistent and clinically relevant efficacy of empagliflozin across all age groups for reducing the primary endpoint of cardiovascular death and HF hospitalization, including recurrent HF hospitalization, as well as an attenuation of eGFR decline in concert with a meaningful improvement in quality of life as measured by Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score. The most elderly group of study participants (age ≥80 years) was remarkably sized, including 1,299 patients of which 52.4% were women. The elderly enrolled with the most preserved LVEF, highest N-terminal pro–B-type natriuretic peptide, most reduced eGFR, highest proportion of atrial arrhythmias, and highest proportion of New York Heart Association functional class III symptomatology at baseline. Importantly, major adverse events leading to discontinuation of medication were not significantly different between treatment and placebo groups across all age groups.
So how is empagliflozin able to preserve both long-term tolerability and clinically meaningful benefit on quality of life while also reducing cardiovascular death, recurrent hospitalizations, and progression of eGFR decline across all age groups? The favorable safety and efficacy profile of empagliflozin extending well into ≥85 years of age, particularly when used in compliment with mineralocorticoid antagonists (which is associated with further reduced HF hospitalizations and less frequent serum potassium derangements), provides hopeful encouragement for patients experiencing HFpEF along with their clinical care providers.
Aside from the obvious bedside clinical implications, the findings of Bohm et al cause us to wonder more about the mechanistic impact of SGLT2 inhibition on multiple cardiovascular and noncardiovascular therapeutic targets. SGLT2 inhibitors induce glycosuria and reduce insulin levels, which promotes a ketogenic and fatty acid oxidation state, mimicking calorie restriction physiology, which has been associated with cellular stress resistance, attenuation of cellular senescence, and reduced oxidative stress-induced tissue damage. Such pathway activation is hypothesized to assuage metabolic disease, alleviate endothelial and vascular inflammation, and mitigate the clinically observed arterial stiffness associated with the HFpEF syndrome (Figure 1).
So, in summary, we have come to appreciate the complex heterogeneous nature of HFpEF as a syndrome that includes cardiovascular and noncardiovascular risk factors and contributors to the disease progression. This has historically challenged our efforts to identify a precise therapeutic target associated with robust clinical effectiveness outcomes in clinical trials. Considering the plethora of favorable cardiometabolic effects of SGLT2 inhibitors (like other calorie restriction mimetics such as metformin, resveratrol, and others), we should not be surprised by the preserved clinical benefit and safety of empagliflozin across all age groups even into the most advanced ages. Whether or not one believes age is just a number, SGLT2 inhibition may very well represent a novel opportunity to better understand how we may slow or even reverse the process of cardiometabolic cellular aging. And, patient age should not deter us from pushing forward with optimizing guideline-directed medical therapies, which now include SGLT2 inhibitors for any patient experiencing HFpEF and without clear contraindication.
J Am Coll Cardiol. 2022;80(1):19-21. © 2022 American College of Cardiology Foundation