Heart failure and ischaemic heart disease: new challenges and opportunities

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This Focus Issue on heart failure and cardiomyopathies, ischaemic heart disease contains the Special article ‘Management of cardiac sarcoidosis: a clinical consensus statement of the Heart Failure Association, the European Association of Cardiovascular Imaging, the ESC Working Group on Myocardial & Pericardial Diseases, and the European Heart Rhythm Association of the ESC’ by Rakesh Sharma from the Imperial College London in the UK, and colleagues.1 The authors point out that cardiac sarcoidosis (CS) is a frequently underdiagnosed form of inflammatory cardiomyopathy associated with significant clinical complications such as high-degree atrioventricular block, ventricular tachycardia, and heart failure (HF), as well as sudden cardiac death.2–6 It is therefore important to provide an expert consensus statement summarizing the role of different available diagnostic tools and emphasizing the importance of a multidisciplinary approach. By integrating clinical information and the results of diagnostic tests, an accurate, validated, and timely diagnosis can be made, while alternative diagnoses can be reasonably excluded. This clinical expert consensus statement reviews the evidence on the management of different CS manifestations and provides advice to practising clinicians on the role of immunosuppression and on the treatment of cardiac complications based on limited published data and the experience of international CS experts. The monitoring and risk stratification of patients with CS is also covered, while controversies and future research needs are explored. Hypertrophic cardiomyopathy is a prevalent and challenging disease which is gathering growing interest also because of the recent introduction of specific pharmacological treatments.7–13 In a State of the Art Review article entitled ‘Genetics of hypertrophic cardiomyopathy: established and emerging implications for clinical practice’, Luis Lopes from the University College London in the UK, and colleagues note that pathogenic variation in genes encoding proteins of the cardiac sarcomere is responsible for 30%–40% of cases of hypertrophic cardiomyopathy.14 The main clinical utility of genetic testing is to provide diagnostic confirmation and facilitation of family screening. It also assists in the detection of aetiologies, which require distinct monitoring and treatment approaches. Other clinical applications, including the use of genetic information to guide risk prediction have been limited by the challenge of establishing robust genotype–phenotype correlations with actionable consequences, but new data on the interaction between rare and common genetic variants as well as the emergence of therapies targeting disease-specific pathogenic mechanisms, herald a new era for genetic testing in routine practice. Acute ST-elevation myocardial infarction (STEMI) and acute ischaemic stroke (AIS) share a number of similarities. In a State of the Art Review article entitled ‘Acute myocardial infarction and ischaemic stroke: differences and similarities in reperfusion therapies—a review’, Lauranne Scheldeman from the University Hospitals Leuven in Belgium, and colleagues note that important differences in pathophysiology demand a disease-tailored approach.15 In both conditions, fast treatment plays a crucial role as ischaemia and eventually infarction develop rapidly. Furthermore, in both fields, the introduction of fibrinolytic treatments historically preceded the implementation of endovascular techniques. However, in contrast to STEMI, only a minority of AIS patients will eventually be considered eligible for reperfusion treatment. Non-invasive cerebral imaging always precedes cerebral angiography and thrombectomy, whereas coronary angiography is not routinely preceded by non-invasive cardiac imaging in patients with STEMI. In the late or unknown time window, the presence of specific patterns on brain imaging may help to identify AIS patients who benefit most from reperfusion treatment. For STEMI, a uniform time window for reperfusion up to 12 h after symptom onset, based on old placebo-controlled trials, is still recommended in guidelines and generally applied. Bridging fibrinolysis preceding endovascular treatment remains the mainstay of reperfusion treatment in AIS, while primary percutaneous coronary intervention (PCI) is the strategy of choice in STEMI. Shortening ischaemic times by fine-tuning collaboration networks between ambulances, community hospitals, and tertiary care hospitals, optimizing bridging fibrinolysis, and reducing ischaemia–reperfusion injury are important topics for further research. The aim of this review is to provide insights into the common as well as diverging pathophysiology behind current reperfusion strategies and to explore new ways to enhance their clinical benefit (Figure 1). In contrast to ST-elevation myocardial infarction (STEMI), the aetiology of acute ischaemic stroke (AIS) is more heterogeneous. Undetermined aetiology refers to the group of patients in whom no single cause is identified. More rare causes of AIS are categorized as AIS of other determined aetiologies (e.g. dissection or hypercoagulable state). Although both intravenous fibrinolysis and mechanical reperfusion strategies [primary percutaneous coronary intervention (PCI) for STEMI and thrombectomy for AIS] are available for treatment of both STEMI and AIS, differences in pathophysiology (in part) explain disease-specific management, with a predominant role for primary PCI in STEMI, in contrast to the persisting relevance of fibrinolysis in the majority of AIS patients who are not eligible for mechanical thrombectomy. Topics for future research should focus on ways to increase the number of treatment-eligible patients, increase the success of reperfusion treatment, and reduce complications after reperfusion treatment.15 Treatment options for HF with preserved ejection fraction (HFpEF) have expanded in recent years.16–18 In a Viewpoint article entitled ‘Heart failure with preserved ejection fraction therapy: combining sodium–glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists’, John Ostrominski from Harvard Medical School in Boston, MA, USA, and colleagues indicate that sodium–glucose co-transporter 2 inhibitors (SGLT2is) are now strongly recommended for all individuals with HFpEF.19 Sacubitril/valsartan is also approved in the USA for use in selected patients with HFpEF. More recently, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to improve health status and body weight in patients with HFpEF and a body mass index (BMI) ≥ 30 kg/m2. Although dedicated outcome trials are needed to further establish the safety and efficacy of GLP-1RAs and other incretin-based therapies in HF, the high burden of cardiovascular–kidney–metabolic and other modifiable obesity-related morbidity in this population emphasizes that this class may be adopted alongside SGLT2is in patients with HF and obesity, independent of potential HF-specific indications. Herein, the authors discuss practical considerations and research gaps relating to the integration of GLP-1RAs in patients with HFpEF, especially on a background of SGLT2i use. Incident HF among individuals with chronic kidney disease (CKD) incurs hospitalizations that burden patients and healthcare systems alike. In a Clinical Research article entitled ‘Incident heart failure in chronic kidney disease: proteomics informs biology and risk stratification’, Ruth Dubin from the University of Texas in the USA, and colleagues indicate that there are few preventative therapies, and the Pooled Cohort equations to Prevent Heart Failure (PCP-HF) perform poorly in the setting of CKD. New drug targets and better risk stratification are urgently needed.20 In this analysis of incident HF, SomaScan V4.0 (4638 proteins) was analysed in 2906 participants of the Chronic Renal Insufficiency Cohort (CRIC) with validation in the Atherosclerosis Risk in Communities (ARIC) study. The primary outcome was 14-year incident HF (390 events). Mendelian randomization and Gene Ontology were applied to examine causality and pathways. The performance of novel multiprotein risk models was compared with the PCP-HF risk score. More than 200 proteins were associated with incident HF after adjustment for estimated glomerular filtration rate at P < 1 × 10−5. After adjustment for covariates including N-terminal probrain natriuretic peptide, 17 proteins remained associated at P < 1 × 10−5. Mendelian randomization associations were found for six proteins, of which four are druggable targets: FCG2B, IGFBP3, CAH6, and ASGR1. For the primary outcome, the C-statistic for the protein model in CRIC was 0.790 vs. 0.703 for the PCP-HF model (P = .001). The C-statistic for the protein model in ARIC was 0.747. The authors conclude that large-scale proteomics reveal novel circulating protein biomarkers and potential mediators of HF in CKD. Proteomic risk models improve upon the PCP-HF risk score in this population. The contribution is accompanied by an Editorial by Faiez Zannad and João Pedro Ferreira from INSERM in Paris, France.21 The authors conclude by noting that Dubin et al. must be praised for their work advancing the field of clinical proteomics. Still, future refinements are expected in this field, integrating proteomics with multiomics data. Trial sponsors must be encouraged to provide access to major clinical trials data and bio-samples, since trial data, although potentially lacking generalizability, are usually of better quality. Major unmet needs such as integrating the multiorgan dimension of cardiovascular–renal–liver–metabolism disease, developing enrichment methods for targeted clinical trials, validation of surrogate endpoints which may substitute for hard outcomes, and finally fulfilling the gestalt of personalized cardiovascular–renal–metabolism medicine are exciting areas of investigations which may be significantly advanced with omics biomarker research. In patients with de novo HF with reduced ejection fraction (HFrEF), improvement of left ventricular ejection fraction (LVEF) is expected to occur when started on guideline-recommended medical therapy (GRMT). In a Clinical Research article entitled ‘Therapy duration and improvement of ventricular function in de novo heart failure: the Heart Failure Optimization study’, Christian Veltmann from the Hannover Medical School in Germany, and colleagues point out that improvement may not be completed within 90 days.22 Patients with HFrEF and LVEF ≤35% prescribed a wearable cardioverter-defibrillator between 2017 and 2022 from 68 sites were enrolled, starting with a registry phase for 3 months and followed by a study phase up to 1 year. The primary endpoints was achievement of LVEF >35% between Days 90 and 180 following guideline-recommended medical therapy initiation. A total of 598 patients with de novo HFrEF (median age 59 years, 27% female) entered the study phase. During the first 180 days, a significant increase in dosage of beta-blockers, renin–angiotensin system inhibitors, and mineralocorticoid receptor antagonists was observed (P < .001). At Day 90, 46% of study phase patients exhibited LVEF >35%; 46% of those with persistently low LVEF at Day 90 exhibited LVEF >35% by Day 180, increasing the total rate of improvement >35% to 68% of patients. In 392 patients followed for 360 days, LVEF >35% was observed in 77% of the patients (Figure 2). Until Day 90, sustained ventricular tachyarrhythmias were observed in 1.8% of patients. After 90 days, no sustained ventricular tachyarrhythmia occurred in wearable cardioverter-defibrillator carriers. Summary of design and results of the Heart Failure Optimization study. Median left ventricular ejection fraction and percentage of patients with left ventricular ejection fraction >35% at baseline, Days 90, 180, and 360. GRMT, guideline-recommended medical therapy; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; WCD, wearable cardioverter-defibrillator.22 The authors conclude that continuous optimization of guideline-recommended medical therapy for at least 180 days in HFrEF is associated with an increasing prevalence of patients with LVEF > 35%. This improves decision-making regarding preventive implantable cardioverter-defibrillator (ICD) therapy. The manuscript is accompanied by an Editorial by Josip Andelo Borovac from the University Hospital of Split (KBC Split) in Croatia.23 Borovac notes that Veltmann and colleagues should be commended for delivering an important study that informs the management of patients with new-onset HFrEF. They illustrated how early initiation and ongoing optimization of GRMT in this patient cohort can lead to the recovery of LV function well beyond the conventional 90-day mark. This discovery could potentially streamline decision-making regarding the implantation of ICDs. Moreover, it is plausible that this effect could be even stronger and occur more rapidly nowadays with the full implementation of the ‘fantastic four’ medicines. However, this assumption should be rigorously tested in future trials. Finally, in a Rapid Communications contribution ‘Fractional flow reserve or optical coherence tomography for angiographically intermediate coronary stenoses: 5-year outcomes in the FORZA trial’, Francesco Burzotta from the Catholic University in Rome, Italy, and colleagues indicate that patients with angiographically intermediate coronary lesions (AICLs) have traditionally been managed with coronary angiography, which lacks information on lesion characterization and myocardial ischaemia, thereby hindering an accurate assessment of lesion severity.24 To fill this gap, adjunctive tools allowing an improved evaluation of lesion severity have been developed. Fractional flow reserve (FFR) is an invasive index providing physiological information about stenosis and representing the standard of care for guiding the management of AICLs. Concurrently, intravascular imaging devices, such as optical coherence tomography (OCT) or intravascular ultrasound (IVUS), contribute to PCI planning and optimization and, recently, have been tested as an alternative to FFR for the management of AICLs. The FORZA trial was the first to compare FFR and OCT guidance. In this extended follow-up of the FORZA trial (median follow-up of 1825 days), the primary endpoint (defined as a composite of all-cause death, myocardial infarction, or target vessel revascularization (TVR) occurred in 30 patients in the OCT group and in 33 patients in the FFR group (P = .704). Compared with the FFR group, the OCT group was associated to numerically lower rates of all-cause death and TVR. Results of the primary outcome were largely consistent across subgroups The authors conclude that the comparative clinical efficacy of FFR-guided and imaging-guided PCI for patients with AICLs found in this extended follow-up of the FORZA trial confirms the results of two recent randomized clinical trials reporting results at a maximum follow-up of 24 months and showing a similar rate of clinical outcomes between IVUS and FFR guidance. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Long-term outcomes of transcatheter vs. surgical aortic valve replacement: is there still a question to be answered?’, Kyriakos Dimitriadis from the National and Kapodistrian University of Athens in Greece and colleagues comment on the recent publication ‘Transcatheter or surgical aortic valve implantation: 10-year outcomes of the NOTION trial’ by Hans Gustav Hørsted Thyregod from the Copenhagen University Hospital in Denmark, and colleagues.25,26 Thyregod et al. respond in a separate comment.27 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, Menarini outside the submitted work. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.