Focus on heart failure: sex-related differences, new light shed on SGLT2i mechanism of action, and heart failure after myocardial infarction

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This Issue opens with the Special Article entitled ‘Priorities for medical device regulatory approval: a report from the European Society of Cardiology Cardiovascular Round Table’ by Stephan Windecker from the University of Bern in Switzerland, and colleagues.¹ The authors note that the European Union (EU) Medical Device Regulation increased regulatory scrutiny to improve the safety and performance of new medical devices. An equally important goal is providing timely access to innovative devices to benefit patient care. The European Society of Cardiology strongly advocates for the evolution of the Medical Device Regulation system to facilitate priority access for innovative devices for unmet needs and orphan cardiovascular (CV) medical devices in EU countries. Although device approval is currently executed by Notified Bodies in the EU, it will be advantageous in the mid-term to consider a single EU regulatory agency for devices. In the short term, steps can be taken to transform the current system into a more efficient, predictable, cost-effective, and user-friendly service. Key strategies include the following: enhancing predictability of the approval process through use of early scientific advice from regulators; establishing unique regulatory pathways for CV orphan, paediatric, and innovative devices; promoting more efficient (re)certification of essential legacy CV devices; improving transparency of sponsor interactions with Notified Bodies; expanding the roles of the Expert Panels to assist in the approval of CV devices; promoting global regulatory harmonization, considering streamlined authorization of CV medical technologies across selected jurisdictions; developing an efficient system to monitor device safety; and ensuring funding for data collection platforms. Some strategies that could help include considering a pilot programme for joint approval processes of selected devices in partnership with other regions (i.e. the US Food and Drug Administration); developing priority pathways for accelerated access to innovative or orphan devices; and increasing recognition of the importance of early feasibility studies in the EU.

Figure 1

The decision on When to implement temporary mechanical circulatory support (MCS) hinges on the patient’s haemodynamic status, and the underlying burden of comorbidity, age, and frailty. Early decision and intervention are probably crucial to prevent multi-organ failure and improve outcomes. The How involves selecting the appropriate device and technique tailored to the patient’s condition. Common devices include intra-aortic balloon pumps, percutaneous ventricular assist devices (pVADs), such as Impella, and veno-arterial extracorporeal membrane oxygenation (V-A ECMO). The choice of device depends on factors such as the severity of cardiac dysfunction, involvement of the right ventricle, underlying aetiology, and the patient’s anatomical and haemodynamic characteristics. A pVAD will unload the heart, while V-A ECMO will often increase afterload. A left ventricular pVAD will require right ventricular function and oxygenation, whereas V-A ECMO is reserved for the most critical scenarios due to its ability to provide both biventricular cardiac and respiratory support. For Whom encompasses a broad range of patients, including those with acute myocardial infarction complicated by cardiogenic shock (CS), decompensated acute de novo or decompensated chronic heart failure, and refractory cardiac arrest. Mechanical circulatory support should be reserved for patients with a potential reversible cause of CS and patients who are potential candidates for heart transplantation or those requiring a bridge to more definitive therapy. Effective use of temporary MCS necessitates a multidisciplinary approach involving a shock team¹⁰

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This Issue continues with a focus on heart failure (HF) and cardiomyopathies. Cardiogenic shock represents a critical condition in which the heart is unable to maintain adequate circulation, leading to insufficient tissue perfusion and end-organ failure.^2–9 In a State of the Art Review article entitled ‘Mechanical circulatory support: when, how, and for whom’, Jacob Eifer Møller from the Copenhagen University Hospital Rigshospitalet in Denmark, and colleagues note that temporary mechanical circulatory support offers the potential to stabilize patients, provide a bridge-to-recovery, provide a bridge-to-decision, or facilitate definitive heart replacement therapies.¹⁰ Although randomized controlled trials have been performed in infarct-related cardiogenic shock and refractory cardiac arrest, the optimal timing, appropriate patient selection, and optimal implementation of these devices remain complex and predominantly based on observational data and expert consensus, especially in non-ischaemic shock. This review explores the details of ‘when, how, and for whom’ temporary mechanical circulatory support devices should be used, examining specific clinical scenarios, the mechanisms by which they operate, and the patient populations that may benefit. The review also highlights the many gaps in evidence and need for better understanding of the interaction between human biology and these devices (Figure 1).

Ambulatory patients presenting with signs or symptoms of HF should undergo natriuretic peptide testing. In a Clinical Research article entitled ‘Suspected de novo heart failure in outpatient care: the REVOLUTION HF study’, Lisa Anderson from the University of London and St George’s University Hospitals NHS Foundation Trust in the UK, and colleagues examined rates of death, HF hospitalization, and healthcare costs in patients identified with suspected de novo HF.¹¹ This population-based study (REVOLUTION HF) encompassing two large healthcare regions in Sweden examined patients who presented to outpatient care for the first time between 2015 and 2020, who had a recorded sign (peripheral oedema) or symptom (dyspnoea) of HF, and whose N-terminal probrain natriuretic peptide (NT-proBNP) measured >300 ng/L within ±30 days of that sign or symptom. Characteristics, outcomes, healthcare patterns, and healthcare costs for these patients were followed for 1 year. Comparisons were made with matched controls without history of HF, its signs, its symptoms, or elevated NT-proBNP. Overall, ∼6000 patients (median age 79 years; 54% women) presented with suspected de novo HF. Within 1 year, 29% had received a HF diagnosis. Patients with suspected de novo HF had higher rates of all-cause death (11.7 vs 6.5 events/100 person-years) and HF hospitalizations (12.5 vs 2.2 events/100 person-years) than 2048 matched controls, with the highest event rates in the weeks after presentation. Rates were higher with higher NT-proBNP levels. Although some patients already used HF guideline-directed medical therapies for other indications, initiation of new medications was variable. Healthcare costs were higher in patients with suspected de novo HF than in matched controls, driven mostly by HF and chronic kidney disease.

The authors conclude that patients with suspected HF and elevated NT-proBNP have high mortality and morbidity in the months after presentation, and accrued substantial healthcare costs, highlighting an urgent need for prompt identification, evaluation, and treatment of HF. The contribution is accompanied by an Editorial by Stefan Störk from the Comprehensive Heart Failure Center in Würzburg, Germany.¹² Störk notes that Anderson and colleagues present, for the first time, data on the trajectories of individuals without a history of HF who were identified in outpatient care with initial findings suggestive of HF. Such information has previously been lacking. As they identify important actionable items that will affect individual patient prognosis and healthcare system performance, appropriate collection of respective data in linked databases needs to become a readily available element in the armamentarium of healthcare services. The call is out to readily implement what has been learnt from REVOLUTION HF into clinical practice.

Figure 2

Among 80 participants of the EMPATROPISM-FE study, who had symptomatic heart failure and a left ventricular ejection fraction (LVEF) < 50%, 30% had anaemia at baseline. At baseline and 6 months after randomization to empagliflozin or placebo, all patients underwent cardiac magnetic resonance imaging (MRI) for determination of T2* as an estimate of myocardial iron content and for quantification of cardiac morphology and function, and had assessment of exercise capacity using maximum oxygen consumption (peak VO₂) and 6 min walking distance (6MWD), and laboratory evaluation of systemic iron status, norepinephrine, and haematopoiesis (left panel). Comparison of subgroups at baseline revealed that patients with vs without anaemia had higher T2* (indicating a lower myocardial iron content [MIC]), peak VO₂, and hepcidin, and higher erythropoietin and norepinephrine (middle panel, top). Across subgroups, lower MIC correlated with higher left ventricular (LV) volumes and norepinephrine, and lower LVEF, peak VO₂, and haemoglobin/haematocrit, while associations with systemic iron status (e.g. transferrin saturation) were poor (middle panel, bottom). Empagliflozin increased MIC and haematopoiesis, and decreased norepinephrine, regardless of anaemia status. Left ventricular reverse remodelling, an increase in erythropoietin, and progressive systemic iron depletion were greater in individuals with anaemia, while exercise capacity improved more in those without anaemia (right panel). Close inter-relationships between MIC and norepinephrine levels suggest that sympatholytic effects of sodium–glucose co-transporter 2 (SGLT2) inhibitors might help explain their diverse cardiac and systemic benefits. LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume¹⁵

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Sodium–glucose co-transporter 2 inhibitors (SGLT2i) play a key role in the treatment of diabetes and HF.^13,14 SGLT2i impact iron metabolism in patients with HF, but the mechanisms are incompletely understood. In a Clinical Research article entitled ‘Anaemia predicts iron homoeostasis dysregulation and modulates the response to empagliflozin in heart failure with reduced ejection fraction: the EMPATROPISM-FE trial’, Christiane Angermann from the University and University Hospital Würzburg in Germany, and colleagues explored inter-relationships between iron homeostasis, cardiac structure/function, exercise capacity, haematopoiesis, and sympathetic activity at baseline, and the effects of 6 months of treatment with empagliflozin vs placebo by anaemia status in EMPATROPISM-FE study participants.¹⁵ Adult outpatients with confirmed HF and left ventricular ejection fraction (LVEF) < 50% were eligible if on stable guideline-directed medical therapy (GDMT) for ≥3 months. Myocardial iron content (MIC; estimated by cardiac magnetic resonance T2* imaging), LV volumes and LVEF, exercise capacity, laboratory iron markers (LIMs), haemoglobin/haematocrit, erythropoietin, and plasma norepinephrine were determined at baseline and 6 months. At baseline, 24/80 participants (30%) had anaemia. Patients with vs without anaemia had higher T2* (indicating lower MIC, P < .001), lower peak oxygen consumption (VO_2max, P = .024) and hepcidin (P = .017), and higher erythropoietin (P = .040) and norepinephrine (P = .016). Across subgroups, lower MIC correlated with higher LV volumes (P < .01) and norepinephrine (P < .001), and lower LVEF (P < .01), VO_2max (P < .001), and haemoglobin/haematocrit (P < .001). Associations with LIMs were poor (all P > .10). Empagliflozin increased MIC (P < .012), improved exercise capacity, and activated haematopoiesis. Left ventricular reverse remodelling was greater in individuals with anaemia (Figure 2).

Angermann concludes that dysregulated cellular iron uptake/availability may be a shared mechanism in myocardial structural/functional impairment, reduced exercise capacity, and restricted haematopoiesis in HF, which are worse in patients with anaemia, and improve with empagliflozin. Empagliflozin increases MIC and decreases norepinephrine. This manuscript is accompanied by an Editorial by Samira Lakhal-Littleton from the University of Oxford in the UK.¹⁶ Lakhal-Littleton concludes that the evidence is converging on the notion that anaemia, neurohormonal activation, and myocardial iron depletion form a vicious and self-sustaining circle that drives the progression of HF. SGLT2 inhibitors and iron therapy may be able to break this circle by disrupting many of the links within it.

In a Clinical Research article entitled ‘Sex-specific risk factors for new-onset heart failure: the PREVEND study at 25 years’, Bart van Essen from the University of Groningen in the Netherlands, and colleagues note that the sex-specific lifetime risk and population-attributable fraction of potentially modifiable risk factors for incident reduced (HFrEF) or preserved EF (HFpEF) are in a large European community-based cohort with 25 years of follow-up.¹⁷ A total of ∼8500 participants from the PREVEND cohort were studied at baseline from 1997 onwards and followed until 2022 for cases of new-onset HFrEF (ejection fraction <50%) and HFpEF (ejection fraction ≥50%) by assessment of hospital records. A total of 804 cases of new-onset HF were identified during 25 years of follow-up. The mean age at baseline was 50 years for men and 47 years for women. The mean age at onset of HF was 72 years in men and 74 years in women. The overall lifetime risk of developing HF was 24% in men compared with 23% in women. The lifetime risk of HFrEF was lower in women compared with men (12% vs 18%), while the lifetime risk of HFpEF was higher in women compared with men (11.5% vs 6.4%). In women, 71% of incident HFrEF cases were attributable to eight risk factors (hypertension, hypercholesterolaemia, obesity, smoking, atrial fibrillation, chronic kidney disease, myocardial infarction [MI], and diabetes mellitus) and 60% in men. In women, 64% of incident HFpEF cases were attributable to those risk factors, whereas this figure was 46% in men. More specifically, in both men and women, hypertension and hypercholesterolaemia were the strongest risk factors for HFrEF, whereas hypertension and obesity were the strongest risk factors for HFpEF.

The authors conclude that in this European cohort, the lifetime risk of developing HFrEF is greater in men than in women, while women are at greater risk of developing HFpEF. Eight directly and indirectly modifiable risk factors substantially account for the risk of developing HFrEF and HFpEF, particularly in women. The contribution is accompanied by an Editorial by Felix Lindberg and Gianluigi Savarese from the Karolinska Institutet in Stockholm, Sweden.¹⁸ The authors conclude that multinational studies incorporating patients from both specialty and primary care settings and combining sufficient characterization to discern EF phenotypes with long-term follow-up are challenging, but would provide a better picture of risk factors and lifetime risk for HF.

Recurrent MI and incident HF are the major post-MI complications. In a Clinical Research article entitled ‘Incident heart failure and recurrent coronary events following acute myocardial infarction’, Javed Butler from the Baylor Scott & White Research Institute in Dallas, TX, USA, and colleagues describe contemporary post-MI risks for recurrent MI and HF.¹⁹ A total of ∼6800 patients with a primary discharge diagnosis of MI at 28 Baylor Scott & White Health hospitals (January 2015 to December 2021) were studied. Patient characteristics, treatment, and outcomes, including incident HF, recurrent MI, all-cause death, and all-cause and CV rehospitalizations, were assessed. A landmark approach anchored at 3 months post-discharge was used to assess 1 year outcomes. Median age was 69 years, 60% were male, and 77% had non-ST-elevation MI. Comorbidities included hypertension (89%), dyslipidaemia (87%), Type 2 diabetes (48%), and chronic kidney disease (34%); 17% had a history of MI and 23% of HF; and 63% underwent percutaneous/surgical revascularization. In landmark-anchored 1 year outcomes, 6.7% of patients died, 28% had all-cause and 12% CV hospitalizations, and 3.8% had recurrent MI. Among patients without a history of HF, 24% developed incident HF (42, 27, and 31% with EF <40, 41–49, and >50%, respectively) within 3 months of discharge. Patients who developed HF had a higher risk of death and hospitalizations (all P < .001), irrespective of EF. Among patients with EF >50% without prevalent HF or HF during index hospitalization, 12% developed HF and 3.5% recurrent MI within 1 year.

The authors conclude that in a contemporary post-MI cohort, the risk for incident HF was greater than recurrent MI, even among those with normal EF and no HF at discharge. The contribution is accompanied by an Editorial by Iaian Squire from the NIHR Leicester Biomedical Research Centre, and Shirley Sze of the University of Lecester, both in Leicester, UK.²⁰ The authors highlight that translating research findings into clinical practice in patients post-MI, clinicians should be vigilant in looking out for signs and symptoms suggestive of HF, especially considering the HFpEF phenotype, beyond parameters such as a low LVEF. Biomarker testing and/or cardiac imaging should be organized in a timely fashion to confirm the diagnosis of HF, so that appropriate treatment can be initiated. The report by Butler et al. emphasizes that patients destined to develop HF are identifiable during the index admission. Patients denied these treatments are those for whom prescription is most challenging, in the context of greater age, lower blood pressure, poorer renal function, and greater comorbidity burden. The clinician’s duty is to identify and to take the time needed to address the opportunity.

In a Rapid Communications contribution entitled ‘Dapagliflozin and ventilatory control during exercise in heart failure with preserved ejection fraction: the CAMEO-DAPA trial’ by Shunichi Doi from the Mayo Clinic, Rochester, MN, USA, and colleagues, the authors note that HFpEF is characterized by exertional intolerance due to symptoms of dyspnoea and fatigue.²¹ SGLT2i improve central haemodynamics, enhance quality of life, and reduce the risk of HF hospitalization or CV death in patients with HfpEF.^22–25 The authors investigated the effect of dapagliflozin compared with placebo on metabolic and ventilatory responses to low-intensity exercise in a secondary analysis from the CAMEO-DAPA trial. Symptomatic adult patients with HF, LVEF ≥50%, and elevated pulmonary artery wedge pressure (PAWP) during exercise (≥25 mmHg) were included. Participants underwent blood sampling and invasive haemodynamic cardiopulmonary exercise testing, and were then randomized to either dapagliflozin 10 mg once daily or a matching placebo and treated for 24 weeks, after which repeat assessments were performed. A multistage incremental exercise test to exhaustion was performed as part of the study, but the present analysis focuses on changes observed at a low-intensity workload of 20 W and VO₂ peak. VO₂, carbon dioxide production (VCO₂), respiratory exchange ratio (RER = VCO₂/VO₂), tidal volume (VT), respiratory drive reflected by the tidal volume/inspiratory time ratio (VT/Ti), frequency of breathing (fb), and minute ventilation (VE) were determined breath by breath using expired gas analysis with a pneumotachometer simultaneously with catheterization. During cycle ergometry at 20 W, treatment with dapagliflozin reduced PAWP, fb, VE, arterial lactate, and RER as compared with the placebo, while there were no significant changes in ventilatory indices or arterial lactate at rest. Although dapagliflozin had no significant effect on respiratory drive at rest or peak exercise, VT/Ti was significantly reduced with dapagliflozin at 20 W exercise (P = .029), but there were no significant differences in VT at 20 W exercise between dapagliflozin and placebo.

The authors conclude that dapagliflozin attenuates the increases in respiratory drive that accompany low-intensity exercise as compared with placebo in patients with HFpEF, and these changes are associated with reduced lactate accumulation despite no significant difference in cardiac output. Most of these effects from dapagliflozin are not apparent during maximal exercise, indicating that measures during peak exertion may not fully capture effects during lower intensity exercise that more closely resembles activities of daily living.

The issue is complemented by two Discussion Forum contributions. In ‘COVID-19 vaccinations in adults and evaluation of cardiovascular events: critical methodological issues’, Serafino Fazio from the Federico II University Hospital in Napoli and Elisabetta Zanolin and Paolo Bellavite from Verona, Italy comment on the recent article entitled ‘Cardiovascular events following coronavirus disease 2019 vaccination in adults: a nationwide Swedish study’ by Yiyi Xu from the University of Gothenburg in Sweden.^26,27 Xu replies in a separate comment.²⁸

The editors hope that this issue of the European Heart Journal will be of interest to its readers.

Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, Daiichi Sankyo, enarini outside the submitted work.

With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.

References