Challenges in heart failure: from actionability of genetic variants in cardiopmyopathies to new therapeutic targets

With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article. For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on heart failure and cardiomyopathies contains a Special Article entitled ‘Interpretation and actionability of genetic variants in cardiomyopathies: a position statement from the European Society of Cardiology Council on cardiovascular genomics’ by Eloisa Arbustini from the Fondazione IRCCS Policlinico San Matteo in Pavia, Italy, and colleagues.1 The specific aim of this document is to show how clinical and family data are essential for the correct interpretation of genetic variants. Indeed, broadening of the sequencing capacity of molecular genetic tests calls for an even more stringent clinical assessment (i.e. clinical phenotyping) to provide the correct interpretation of any finding.2–7 Mendelian cardiomyopathies are used as a reference to show how detailed, systematic, and iterative evaluation of patients and relatives not only can establish the pathogenicity of genetic variants but can also provide a basis for personalized medicine in heritable cardiovascular (CV) conditions. Correct clinical interpretation of genetic variants will be one of the key contributors to precision cardiology of the future, but requires effective partnerships between clinicians, patients, scientists, and industry to maximize the benefits of genetic knowledge. Importantly, a genetic test supports and confirms, but does not substitute for, a clinical diagnosis. Upper panel: schematic representation of the interaction between the various arrhythmia and conduction abnormalities with four electrical abnormalities and their consequences for remodelling and developing heart failure. Red text in boxes indicates the therapeutic approaches that treat the electrical abnormalities and thereby also heart failure. CRT, cardiac resynchronization therapy. Lower panel: flow chart of recommended checks for the eligibility of heart failure with reduced ejection fraction patients for the various electrical therapies based on the evidence presented in the upper panel and guidelines.14 AF, atrial fibrillation; AT, atrial tachicardia; AV, atrioventricular; HFreEF, heart failure with preserved ejection fraction; LBBB, left bundle branch block; PV pulmonary veins; PVC, premature ventricular beats; RV, right ventricle; VT, ventricular tachicardia. Electrical disturbances, such as atrial fibrillation (AF), dyssynchrony, tachycardia, and premature ventricular contractions (PVCs), are present in most patients with heart failure (HF).8–13 In a State of the Art Review article entitled ‘Electrical management of heart failure: from pathophysiology to treatment’, Frits W. Prinzen from Maastricht University in the Netherlands, and colleagues note that while these disturbances may be the consequence of HF, increasing evidence suggests that they may also cause or aggravate HF. Animal studies show that long lasting left bundle branch block, tachycardia, AF, and PVCs lead to functional derangements at the organ, cellular, and molecular level.14 Conversely, electrical treatment may reverse or mitigate HF. Clinical studies have shown the superiority of atrial and pulmonary vein ablation for rhythm control and atrioventricular nodal ablation for rate control in AF patients when compared with medical treatment. Ablation of PVCs can also improve left ventricular function. Cardiac resynchronization therapy (CRT) is an established adjunct therapy currently undergoing several interesting innovations (Figure 1). The current guideline recommendations reflect the safety and efficacy of these ablation therapies and CRT, but currently these therapies are greatly underutilized. This review focuses on the electrical treatment of HF with reduced ejection fraction (HFrEF). The authors believe that the team of specialists treating an HF patient should include an electrophysiologist in order to achieve a more widespread use of electrical therapies in the management of HFrEF and should also include individual conditions of the patient, such as sex, in therapy fine-tuning. Cardiovascular toxicities of anticancer therapies is a topic of growing interest.15–19 In a second State of the Art Review article entitled ‘Cardiotoxicity from chimeric antigen receptor–T cell therapy for advanced malignancies’, Matthias Totzeck from the University Hospital Essen in Germany, and colleagues indicate that chimeric antigen receptor (CAR)–T cell therapy is approved for patients suffering from advanced and refractory B cell and plasma cell malignancies, and is undergoing testing for various other haematological and solid malignancies.20 In the process of triggering an anticancer immune reaction, a systemic inflammatory response can emerge as cytokine release syndrome (CRS). The severity of CRS is highly variable across patients, ranging from mild flu-like symptoms to fulminant hyperinflammatory states with excessive immune activation, associated multiorgan failure, and high mortality risk. CRS is also an important factor for adverse CV events. Sinus tachycardia and hypotension are the most common reflections, similar to what is seen with other systemic inflammatory response syndromes. Corrected QT interval prolongation and tachyarrhythmias, including ventricular arrhythmias and AF, also show a close link with CRS. Events of myocardial ischaemia and venous thrombo-embolism can be provoked during CAR–T cell therapy. Although not as closely related to CRS, changes in cardiac function can also be observed. This may also be encountered in patients with severe valvular heart disease in the setting of CRS. This review discusses the pertinent CV risks of the growing field of CAR–T cell therapy for today's cardiologists, including incidence, characteristics, and treatment options, and concludes with an integrated management algorithm. As compared with control subjects without heart failure (black), patients with heart failure with preserved ejection fraction (HFpEF) and low NT-proBNP levels (<125 ng/L, green) displayed increased risk for the combined endpoint of heart failure hospitalization or death, with greater reliance on an increase in left ventricular transmural pressure (LVTMP) to increase cardiac output (CO) during exercise. As compared with patients with HFpEF and lower NT-proBNP, those with elevated NT-proBNP (red) displayed the greatest risk for heart failure hospitalization or death, with more severely impaired cardiac output reserve, greater right ventricular (RV) remodelling, and higher prevalence of secondary (functional) mitral and tricuspid insufficiency.21 A substantial proportion of patients with HF with preserved ejection fraction (HFpEF) present with normal natriuretic peptide (NP) levels. In a Clinical Research article entitled ‘Heart failure with preserved ejection fraction in patients with normal natriuretic peptide levels is associated with increased morbidity and mortality’, Frederik H. Verbrugge from the Mayo Clinic in Rochester, MN, USA, and colleagues note that the pathophysiology and natural history for this phenotype remain unclear.21 Consecutive subjects undergoing invasive cardiopulmonary exercise testing for unexplained dyspnoea at the Mayo Clinic in 2006–2018 were studied. HFpEF was defined as a pulmonary arterial wedge pressure (PAWP) ≥15 mmHg (rest) or ≥25 mmHg (exercise). Patients with HFpEF and normal NP [N-terminal probrain type NP (NT-proBNP) <125 ng/L] were compared with those with HFpEF with high NT-proBNP (≥125 ng/L) and controls with normal haemodynamics. Patients with HFpEF and normal (n = 157) vs. high NT-proBNP (n = 263) were younger, yet were older than controls (n = 161), with an intermediate comorbidity profile. Normal NP HFpEF was associated with more left ventricular hypertrophy and worse diastolic function compared with controls, but better diastolic function, lower left atrial volumes, superior right ventricular function, and less mitral/tricuspid regurgitation compared with high NT-proBNP HFpEF. Cardiac output (CO) reserve with exercise was preserved in normal NT-proBNP HFpEF (101% predicted), but this was achieved only at the cost of higher left ventricular transmural pressure (LVTMP) (14 ± 6 mmHg vs. 7 ± 4 mmHg in controls, P < 0.001). In contrast, CO reserve was decreased in high NT-proBNP HFpEF (85% predicted). Patients with high NP HFpEF displayed the highest event rates, but those with normal NP HFpEF still had a 2.7-fold higher risk for mortality or HF readmissions compared with controls [hazard ratio (HR) 2.74] after adjusting for age, sex, and body mass index (Figure 2). The authors conclude that patients with HFpEF and normal NP display mild diastolic dysfunction and preserved CO reserve during exercise, despite marked elevation in filling pressures. While clinical outcomes are not as poor compared with patients with high NP, patients with normal NP HFpEF exhibit increased risk of death or HF readmissions compared with patients without HF, emphasizing the importance of this phenotype. This manuscript is accompanied by an Editorial by Sanjiv J. Shah from the Northwestern University Feinberg School of Medicine in Chicago, IL, USA.22 Shah notes that to prevent diagnostic errors, clinicians would be well served by remembering the following mnemonic when ordering the BNP test: Biomarker Not Perfect. The importance of the initial discovery and subsequent wealth of publications on NPs over the past 40+ years in the realms of diagnosis, prognosis, therapeutics, and HF biology cannot be understated; nevertheless, NPs remain only one aspect of our diagnosis and prognosis toolbox. Like any clinical test, NPs should be carefully evaluated within the context of all other clinical information, and invasive exercise haemodynamics should be performed in patients with unexplained dyspnoea if the underlying diagnosis is in question. Obesity is a global health problem, associated with significant morbidity and mortality, often due to CV diseases.23–27 While bariatric surgery is increasingly performed in patients with obesity and reduces CV risk factors, its effect on CV disease is not established. In a meta-analysis article entitled ‘Bariatric surgery and cardiovascular disease: a systematic review and meta-analysis’, Sophie L. van Veldhuisen from the University of Amsterdam in the Netherlands, and colleagues conducted a systematic review and meta-analysis to evaluate the effect of bariatric surgery on CV outcomes, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline.28 PubMed and Embase were searched for literature up to August 2021 which compared bariatric surgery patients with non-surgical controls. Outcomes of interest were all-cause and CV mortality, AF, HF, myocardial infarction, and stroke. The authors included 39 studies, all prospective or retrospective cohort studies, while randomized outcome trials were not available. Bariatric surgery was associated with a beneficial effect on all-cause mortality (HR 0.55, P < 0.001 vs. controls) and CV mortality (HR 0.59, P < 0.001). In addition, bariatric surgery was also associated with a reduced incidence of HF (HR 0.50, P < 0.001), myocardial infarction (HR 0.58, P < 0.001), and stroke (HR 0.64, P < 0.001. The authors conclude that bariatric surgery is associated with reduced all-cause and CV mortality, and lowered incidence of several CV diseases. Bariatric surgery should therefore be considered in these patients. The contribution is accompanied by an Editorial by Geltrude Mingrone from the Università Cattolica del Sacro Cuore in Rome, Italy, together with Lidia Castagneto-Gissey from the University of Rome and Stefan R. Bornstein from King's College London in the UK.29 The authors conclude that this meta-analysis strengthens the evidence that bariatric surgery reduces all-cause mortality, CV-related mortality, and the incidence of CV disease in obesity as compared with standard of care. The healthcare community, insurers, and all other stakeholders should consider bariatric surgery as a viable option in subjects with CV disease and obesity. Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that was reported to target ion channel proteins. L-type voltage-dependent Ca2+ channel (LTCC) density and dysfunction are critical players in HFrEF. However, the underlying cellular mechanisms by which CRBN regulates LTCC subtype Cav1.2α during cardiac dysfunction remain unclear. In a Translational Research article entitled ‘Cereblon contributes to cardiac dysfunction by degrading Cav1.2α’, Nammi Park from the Inje University in the Republic of Korea, and colleagues explored the role of CRBN in HFrEF by investigating its direct regulatory role in Cav1.2α activity and examining how it can serve as a target to address myocardial dysfunction.30 Cardiac tissues from HFrEF patients exhibited increased levels of CRBN compared with controls. In vivo and ex vivo studies demonstrated that whole-body CRBN knockout (CRBN−/−) and cardiac-specific knockout mice (Crbnfl/fl/Myh6Cre+) exhibited enhanced cardiac contractility with increased LTCC current (ICaL) compared with their respective controls, which was modulated by the direct interaction of CRBN with Cav1.2α. Mechanistically, the Lon domain of CRBN directly interacted with the N-terminus of Cav1.2α. Increasing CRBN levels enhanced the ubiquitination and proteasomal degradation of Cav1.2α and decreased ICaL. In contrast, genetic or pharmacological depletion of CRBN via TD-165, a novel PROTAC-based CRBN degrader, increased surface expression of Cav1.2α and enhanced ICaL. Low CRBN levels protected the heart against cardiomyopathy in vivo. Nammi and colleagues conclude that CRBN selectively degrades Cav1.2α, which in turn facilitates cardiac dysfunction. Reducing CRBN levels could serve as a promising strategy for HFrEF therapeutics. The manuscript is accompanied by an Editorial by Vasco Sequeira and Christoph Maack from the University Clinic Würzburg in Germany.31 The authors conclude that CRBN is an attractive novel therapeutic target for CV disease, but potentially also metabolic and other diseases, and the presented findings will certainly stimulate the field to reveal in more detail the cardiac and systemic effects and therapeutic feasibility of targeting CRBN. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Alarmist reporting on the pandemic: time to say no!’, Ambuj Roy from the All India Institute of Medical Sciences in New Delhi, India comments on the recent publication ‘Multi-organ assessment in mainly non-hospitalized individuals after SARS-CoV-2 infection: The Hamburg City Health Study COVID programme’ by Elina Larissa Petersen et al. from the University Heart and Vascular Center in Hamburg, Germany.32,33 Twerenbold et al. respond in a separate comment.34 Dr. Crea reports speaker fees from Amgen, Astra Zeneca, Servier, BMS, other from GlyCardial Diagnostics, outside the submitted work. The editors hope that readers of this issue of the European Heart Journal will find it of interest.