Filippo Maria Rubbo

Background: The RoMa classification, based on peak heart rate and oxygen pulse derived from cardiopulmonary exercise testing, was recently proposed to stratify patients with hypertrophic cardiomyopathy by physiological reserve during exercise. We aimed to externally validate RoMa in an independent multicenter cohort with hypertrophic cardiomyopathy and assess its association with long‐term clinical outcomes. Methods: In this retrospective multicenter cohort study patients with hypertrophic cardiomyopathy, undergoing cardiopulmonary exercise testing, were consecutively enrolled. Patients were enrolled regardless of left ventricular outflow tract obstruction and were naïve to disease‐specific therapy (eg, mavacamten). Patients were categorized into RoMa I to IV based on percentage of predicted heart rate and oxygen pulse. The primary end point was a composite of all‐cause and cardiovascular death, sudden cardiac death, or aborted sudden cardiac death, heart failure–related hospitalization, stroke, systemic embolism, surgical myectomy, and heart transplantation. Results: The study included 292 patients (age 51 [36–63] years, 70% male sex, 30% with obstructive left ventricular outflow tract). Functional capacity declined hierarchically across RoMa groups (peak oxygen uptake 29.2 to 17.9 mL/kg/min; P ‐trend P =0.019). In multivariable analysis, RoMa II to IV compared with RoMa I were independently associated with higher hazard ratios (HRs) for the composite outcome (HRs, 3.89–5.37; all P <0.05), whereas genotype, LVEF <50%, male sex, and left ventricular outflow tract obstruction were not predictive. Conclusions: The RoMa classification independently predicts long‐term, clinically relevant outcomes in hypertrophic cardiomyopathy regardless of left ventricular outflow tract obstruction and may provide a novel approach to risk stratification.

Background: Sodium/glucose cotransporter-2 inhibitors (SGLT2is), such as dapagliflozin and empagliflozin, are currently a standard therapy for heart failure (HF) patients. We report the real-world use of SGLT2is in a monocentric cohort of HF patients with reduced ejection fraction (HFrEF) and improved ejection fraction (HFimpEF), comparing patient characteristics and outcomes with those observed in large-scale randomized clinical trials (RCTs). Methods: We retrospectively analyzed a cohort of 370 stable patients with HFrEF or HFimpEF who initiated therapy with dapagliflozin or empagliflozin between June 2019 and November 2023. Baseline data, including medical history, concomitant diseases, therapy, laboratory tests, echocardiographic results and cardiopulmonary exercise tests (CPETs), were collected at the start of the therapy with SGLT2is. After a median period of 18 months, follow-up data on treatment adherence, adverse events, hospitalizations, and mortality were also reviewed. A comparison was made between patients taking dapagliflozin and those taking empagliflozin and then individual populations were compared with those from the trials. Results: Among 370 patients (81% HFrEF, 19% HFimpEF), 276 received dapagliflozin and 94 empagliflozin. Empagliflozin patients were older, had higher NYHA class and LVEF, and higher incidence of diabetes, while dapagliflozin users had greater use of sacubitril/valsartan and mineralocorticoid receptor antagonists. Both groups were older than the RCT cohorts. Dapagliflozin patients had LVEF comparable to DAPA-HF, while empagliflozin patients had higher LVEF than EMPEROR-Reduced. HF hospitalizations were more frequent in the real-world groups, but mortality was lower than in RCTs. The composite outcome of death and worsening HF was higher in the real-world dapagliflozin cohort vs. DAPA-HF but similar between the real-world empagliflozin cohort and EMPEROR-Reduced. Conclusions: In this real-world cohort, the use of empagliflozin was associated with cardio-nephro-metabolic comorbidities and dapagliflozin being prescribed more frequently for patients with isolated cardiac symptoms. While outcomes were generally favorable, they differed from those seen in RCTs, highlighting the importance of real-world data in understanding the practical application of these therapies.

The mechanisms underlying the effects of dapagliflozin in heart failure with reduced ejection fraction (HFrEF) are not yet fully understood. This study aims to evaluate the effect of the drug on cardiorespiratory function by assessing alveolar–capillary membrane characteristics, sleep apnea, pulmonary and cardiac performance in stable HFrEF patients. Seventy-three patients with stable HFrEF were enrolled, with 66 completing the six-month follow-up. Analyses included assessment of the alveolar–capillary membrane by diffusion capacity, including its membrane diffusion and capillary volume components and measurements of proSP-B in the blood, an emerging biomarker of alveolar–capillary membrane function. Pulmonary function tests, overnight respiratory monitoring, and echocardiographic parameter collection were also conducted. After 6 months, a reduction in circulating proSP-B levels was observed (32.65 ± 13.36 at baseline vs. 30.86 ± 12.45 AU at 6 months, p for trend 0.0092), accompanied by improvements in echocardiographic parameters (left ventricle ejection fraction and pulmonary pressures). Pulmonary function tests and overnight respiratory monitoring showed no significant changes in lung diffusion, spirometry, or obstructive sleep apnea (apnea hypopnea index from 5.0 [1.1–16.6] at baseline to 6.2 [0.7–13.8]/h; p = n.s.). A significant reduction in central sleep apnea (CSA) was noted in the 13 patients with at least one CSA at baseline (15 [3–48] vs. 0 [0–18.5]/h, p = 0.017). Dapagliflozin demonstrates both hemodynamic and non-hemodynamic effects, particularly improving alveolar–capillary membrane function. This study highlights the multifactorial benefits of dapagliflozin in patients with stable HFrEF and the potential of proSP-B as a sensitive marker for evaluating therapeutic response.

Recent advances in medical therapy have significantly improved the prognosis of patients with heart failure and reduced ejection fraction (HFrEF). The established four pillars of HFrEF treatment – β-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor–neprilysin inhibitors, mineralocorticoid receptor antagonists and sodium–glucose cotransporter 2 inhibitors – serve as the foundation for on-going innovations in this domain. However, these represent only the starting point for the therapy and management of heart failure. New medications, new devices and improvements in the use of diuretic therapy are fundamental and recent advancements. This article aims to highlight the latest findings in HFrEF treatment. While emphasising the optimism these developments bring, the article also addresses the significant unresolved challenges that persist in the management of this syndrome, which remains a leading global cause of mortality, morbidity and poor quality of life with high use of resources and healthcare costs.