Heart failure with preserved ejection fraction in patients with moderate/severe aortic stenosis: what harms our patients most?

This editorial refers to ‘Cardiac dysfunction rather than aortic valve stenosis severity drives exercise intolerance and adverse haemodynamics’, by S. Hoedemakers et al., https://doi:10.1093/ehjci/jead276. Elderly patients have a high risk of developing heart failure (HF); measurement of the heart failure biomarker N-terminal pro-brain-natriuretic-peptide establishes the diagnosis followed by echocardiography to define HFrEF/HFmrEF or HFpEF according to the ESC Guideline classification with ejection fraction (EFs) of <40, 40–49, and ≥ 50%, respectively. HF with reduced EF (HFrEF) and HF with mildly reduced EF (HFmrEF) diagnosis and treatment are well established including the ‘fantastic four’ guideline-directed medical therapy, device therapy with cardiac resyncrhonisation therapy, transcutaneous aortic valve implantation, mitral transcutaneous edge-to-edge therapy, and pulmonary vein isolation.1 In comparison, HFpEF treatment is less well established: the recently focused update of the ESC heart failure guidelines recommend treatment of comorbidities including arterial hypertension and add SGLT2 inhibitors with a Class I, Level A recommendation. Both empagliflozin and dapagliflozin were the first drugs in 20 years to show positive results in large-scale, randomized, double-blind studies in this population. It is in this context that the manuscript by Hoedemakers et al.2 from the University Hospital Ziekenhuis in Brussels is of particular interest. The authors studied 206 patients with moderate or severe aortic stenosis (AS) identified by an aortic valve area of ≤ 0.85 cm/m2. The patients were classified regarding HFpEF defined by the ESC H2FPEF score: patients receive points for a body mass index > 30 kg/m2 (H, +2), hypertension on >2 drugs (+1), paroxysmal or persistent atrial fibrillation (+3 points), pulmonary hypertension (sys PAP > 35 mmHg, +1 point), age (elderly > 60 years, +1 point), and increased filling pressure (E/e′> 9, +1 point). Patients with a score of ≥ 6 (i.e. atrial fibrillation, adipositas and hypertension, or age > 60 years) have a 90% probability of HFpEF diagnosis if exercise-induced increase in pulmonary wedge pressure is regarded as the gold standard.3 The current prospective study analysed cardiopulmonary exercise testing with simultaneous echocardiography (CPETecho) in patients with moderate-to-severe AS and EF ≥ 50%. Patients received a baseline echo and a 10–15 min exercise test until a respiratory exchange ratio (RER) of ≥1.1 was achieved; 88% of patients were able to reach an RER ≥1. This parameter describes the metabolic production of carbon dioxide (CO2) and the uptake of oxygen (O2). If RER is above 1, patients start to accumulate lactate and are nearing exhaustion; RER correlates to VO2 max. Impaired exercise capacity with a significantly reduced peak VO2 of 11.5 ± 3.7 vs. 15.9 ± 5.9 mL/min/kg was correlated to HFpEF diagnosis but not the severity of AS. This result was also true if AS severity was not adjudicated by a vmax of ≥ 4 m/s but employing the valvular calcium score in CT measurements with an Agatson score of >2000 and >1200 for man and woman as the cut-off for severe stenosis, respectively. The latter analysis though was available only for a subpopulation of 41 patients. A similar prospective study on 150 patients with degenerative moderate-to-severe AS, 148 patients with HFpEF, and 65 age- and sex-matched healthy controls found very similar impairment of functional capacity in a cardiopulmonary exercise echo stress test between AS and HFpEF vs. control patients.4 The authors further characterized their HFpEF population and detected impaired left ventricular diastolic dysfunction, more pronounced left atrial myopathy, and right ventricular dysfunction with right ventricular–pulmonary arterial uncoupling in the HFpEF population. During exercise, this HFpEF population but not the severe vs. moderate AS patients showed higher pulmonary arterial pressures. The authors discuss in detail the impact of their data regarding the importance of cardiac damage and dysfunction related to HFpEF rather than the severity of the AS. This editorial aims to put these data into the context of therapeutic options in this patient population (Figure 1). Diagnostic workflow and therapeutic options in heart failure patients with AS and preserved ejection fraction. The timing and indication for TAVR is currently studied in several prospective, randomized trials. Recent data suggest that low-flow, low-gradient AS patients might profit from the lower gradient achieved with self-expanding valves and a supra-annular valve position compared with surgical patients.5 Several studies including the TAVR UNLOAD, PROGRESS and Evolut EXPAND TAVR II Pivotal trial include patients with moderate AS aiming to reduce clinical endpoints and improve quality of life. A modified H2FPEF score for patients with AS has been described with a prognostic impact on TAVR outcomes.6,7 In summary, HFpEF and AS are closely linked and probably should both be targeted to achieve symptomatic relief and improved clinical outcomes. Several new therapeutic options have become available or are under development regarding HFpEF. The recent focused update of the ESC heart failure guidelines now include a Class IA recommendation of SGLT2 inhibitors and a Class IIb recommendation for ACE, ARNI, or ARB treatment in this population (Figure 1).1 Further treatment options are currently studied including interventional inter-atrial shunt therapy for LA pressure release during exercise.8,9 In summary, the newly available data on exercise capacity in AS patients with HFpEF broaden our understanding of this complex disease. Both improved diagnostic tools including the H2FPEF score, valvular calcium score in CT, and possibly exercise testing with simultaneous echocardiography allow us to better understand the predominant disease and tailor our therapeutic options to the individual patients. None declared. No new data were generated or analysed in support of this research.