Heart failure in cardio-oncology and adult congenital heart disease: new challenges and 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 (HF) and cardiomyopathies contains the State of the Art Review entitled ‘Cardiovascular complications of immune checkpoint inhibitors for cancer’ by Franck Thuny from the University Mediterranean Center of Cardio-Oncology, and colleagues.1 The authors point out that over the last decade or so, there has been a paradigm shift in the oncological care of patients with a range of solid tumour and haematological malignancies, away from traditional cytotoxic chemotherapy and towards personalized cancer treatments, using both targeted therapy and immunotherapy. This shift has contributed to the remarkable and sustained increase in the number of cancer survivors and in the longevity of patients with a cancer diagnosis, but also to an exponential increase of patients suffering cardiovascular events.2–9 This review focuses on the cardiovascular effects of immune checkpoint inhibitors and presents a background on immune checkpoint inhibition for cancer, the epidemiology, potential mechanisms, the potential insights into cardiovascular biology, and a diagnostic and therapeutic approach to potential cases. The general understanding of the cardiovascular effects of immune checkpoint inhibitors needs to improve rapidly. Initial observations noted that immune checkpoint inhibitor therapy can lead to a fulminant myocarditis. Recent reports have expanded the effect of immune checkpoint inhibitor therapy on the cardiovascular system to include an increase in cardiac dysfunction without myocarditis, as well as arrhythmias, venous thrombo-embolic disease, accelerated atherosclerosis, and atherosclerosis-related cardiovascular events. The association between immune checkpoint inhibitor therapy and an increase in these cardiovascular events is not only limited to events occurring within the first few weeks after starting therapy but can also include events that occur months to years after therapy. The latter observation is of particular relevance in those treated with adjuvant or neoadjuvant therapy. There is a need for shifting from the mere recognition of an increase in cardiovascular events associated with currently approved immune checkpoint inhibitor therapies to understanding the mechanisms that lead to adverse cardiovascular effects, understanding who is at risk, and understanding what we can do about it (Figure 1). Proposed eight-point-based management of patients with a suspicion for a cardiovascular immune-related adverse event. aTroponin testing may be positive if troponin I or T is >99th percentile of the upper reference limit. Concomitant myositis may result in significant elevations of CK, CK isoforms, and even troponin T. In patients with pre-therapeutic troponin elevation, a 50% increase of the level may be used as a cut-off, but no evidence currently supports this recommendation. bHaemodynamic instability, heart failure requiring non-invasive or invasive ventilation, complete or high-grade heart block, and/or significant ventricular arrhythmia. cArrhythmias, conduction abnormalities, acute coronary syndromes, stroke, thrombo-embolic events, and heart failure should be managed urgently according to the international guidelines. dEndomyocardial biopsy should be performed especially in unstable patients who cannot undergo urgent CMR and in patients with uncertain diagnosis. eSee Table 2. fDefined as haemodynamic instability or electrical instability or increasing troponin or decreasing left ventricular ejection fraction. gThere are no data to recommend a standardized initial treatment strategy for the intensification of immunosuppressive therapy. For now, case series and case reports have shown the potential efficacy of antithymocyte globulin, intravenous immunoglobulin, plasma exchange, mycophenolate mofetil, tacrolimus, tocilizumab, abatacept, alemtuzumab, and tofacitinib. The decision regarding optimal therapy must be multidisciplinary, involving specialists in immunology and organ rejection. Infliximab was also proposed but was not incorporated into the algorithm because of its contraindication in acute heart failure. iTroponin elevation without cardiovascular signs/symptoms and negative investigations including EMB. ACS, acute coronary syndrome; CCU, coronary care unit; CK, creatine kinase; AchR, acetylcholine receptor antibodies; CMR, cardiac magnetic resonance; EMB, endomyocardial biopsy; irAE, immune-related adverse event; ICI, immune checkpoint inhibitor; NT-proBNP, N-terminal-probrain natriuretic peptide; SMB, skeletal muscle biopsy; TSH, thyroid-stimulating hormone; TTE, transthoracic echocardiography; TTS, takotsubo syndrome.1 Stroke is a devastating complication of atrial fibrillation (AF) but is rarely considered when the clinical consequences of heart failure (HF) are described.10 If stroke is discussed in HF, it is usually in the context of associated AF.10 However, stroke also occurs in HF patients without documented AF, although most older reports did not differentiate between individuals with and without AF. In a Fast Track Clinical Research article entitled ‘Predicting stroke in heart failure and reduced ejection fraction without atrial fibrillation’, Toru Kondo from the University of Glasgow in the UK, and colleagues note that anticoagulation reduces this risk in HF patients with and without AF, but the risk-to-benefit balance in the latter group, overall, is not favourable. Identification of patients with HFrEF, without AF, at the highest risk of stroke may allow targeted and safer use of prophylactic anticoagulant therapy.11 In a pooled patient-level cohort of the PARADIGM-HF, ATMOSPHERE, and DAPA-HF trials, a previously derived simple risk model for stroke, consisting of three variables (history of prior stroke, insulin-treated diabetes, and plasma N-terminal probrain natriuretic peptide level), was validated. Of the 20 159 patients included, 12 751 patients did not have AF at baseline. Among patients without AF, 2.7% experienced a stroke over a median follow-up of 2.0 years. The risk for stroke increased with increasing risk score: fourth quintile hazard ratio (HR) 2.35, fifth quintile HR 3.73, with the first quintile as reference. For patients in the top quintile, the rate of stroke was 21.2 per 1000 patient-years, similar to participants with AF not receiving anticoagulation (20.1 per 1000 patient-years). Model discrimination was good, with a C-index of 0.84 (Figure 2). Validation of a risk score for stroke in heart failure with reduced ejection fraction. AF, atrial fibrillation; DM, diabetes mellitus; HFrEF, heart failure with reduced ejection fraction; NT-proBNP, N-terminal probrain natriuretic peptide.11 The authors conclude that it is possible to identify a subset of HFrEF patients without AF with a stroke risk equivalent to that of patients with AF who are not anticoagulated. In these patients, the risk-to-benefit balance might justify the use of prophylactic anticoagulation, but this hypothesis needs to be tested prospectively. The contribution is accompanied by an Editorial by Dimitrios Sagris, Eduard Shantsila, and Gregory Lip from the University of Liverpool, UK.12 The authors conclude that the simple, practical, and accurate identification of HFrEF patients in sinus rhythm at high thrombo-embolic risk promotes a more patient-specific therapeutic strategy, especially in the frail and multimorbid HF population. Of note, many patients with HFrEF may develop ‘silent’ episodes of AF, which confer a poor outcome. Finally, we should also not forget the impact of a holistic or integrated care approach (that encompasses careful attention to comorbidities and lifestyle factors) in reducing adverse outcomes, including cardiovascular mortality, stroke, and bleeding. Future randomized control trials, in selected HFrEF patients with sinus rhythm at high thrombo-embolic risk (selected with refined, simple risk stratification tools that account for dynamic changes in risk profile), may provide more evidence before embracing any ‘one size fits all’ anticoagulation strategy, as well as important insights into personalized stroke risk assessments. Although life expectancy in adults with congenital heart diseases (ACHD) has increased dramatically over the past five decades, a substantial number of patients still die prematurely.13–16 In a Fast Track clinical research article entitled ‘Last year of life of adults with congenital heart diseases: causes of death and patterns of care’, Liesbet Van Bulck from the KU Leuven–University of Leuven in Belgium, and colleagues try to gain understanding of the trajectories of dying in ACHD and for this the last year of life warrants further investigation.17 To this end, the authors’ study aimed to (i) define the causes of death and (ii) describe the patterns of healthcare utilization in the last year of life of adults with CHD. This retrospective mortality follow-back study used healthcare claims and clinical data from BELCODAC, which includes patients with ACHD from Belgium. Healthcare utilization comprises cardiovascular procedures, ACHD physician contacts, general practitioner visits, hospitalizations, emergency department (ED) visits, intensive care unit (ICU) admissions, and specialist palliative care, and was identified using nomenclature codes. Of the 390 included patients, almost half of the study population (45%) died from a cardiovascular cause. In the last year of life, 87% of patients were hospitalized, 78% of patients had an ED visit, and 19% of patients had an ICU admission. Specialist palliative care was provided to 17% of patients, and to only 4% when looking at the patients with cardiovascular causes of death. The authors conclude that there is a high use of intensive and potentially avoidable care at the end of life. This may imply that end-of-life care provision can be improved. Future studies should further examine end-of-life care provision in the light of a patient's needs and preferences, and how the healthcare system can adequately respond. The contribution is accompanied by an Editorial by Jill M. Steiner and James Kirkpatrick from the University of Washington.18 The authors point out that as we look toward future ACHD research needs, we must keep in mind the importance of first understanding patients’ palliative care needs: what are their care preferences and expectations, illness understanding and their self-perceived ability to manage their care, and the impact of their symptoms on quality of life? We must work to determine what might be ACHD-specific goals of care, how these change as patients approach end of life, and how healthcare systems can best respond to and support patients’ needs. Then, we must invest in the development and dissemination of interventions to target improvements in these areas of need. Examining the end of life for patients with ACHD provides a great opportunity to learn about the potential applications of palliative care in this unique patient population, guided by the experiences of those who have come before. This ‘view from the end’ provided by Van Bulck et al. can help chart future journeys. Cardiotoxicity leading to HF is a growing problem in many cancer survivors.19 In a Clinical Research article entitled ‘A circular RNA derived from the insulin receptor locus protects against doxorubicin-induced cardiotoxicity’, Dongchao Lu from the Hannover Medical School, Germany looked at this question more closely.20 The authors found that the highly species-conserved circRNA insulin receptor (Circ-INSR) participates in HF processes, including those provoked by cardiotoxic anticancer treatments. Chemotherapy-provoked cardiotoxicity led to the down-regulation of Circ-INSR in rodents and patients, which mechanistically contributed to cardiomyocyte cell death, cardiac dysfunction, and mitochondrial damage. In contrast, Circ-INSR overexpression prevented doxorubicin-mediated cardiotoxicity in both rodent and human cardiomyocytes in vitro and in a mouse model of chronic doxorubicin cardiotoxicity. Breast cancer type 1 susceptibility protein (Brca1) was identified as a regulator of Circ-INSR expression. Detailed transcriptomic and proteomic analyses revealed that Circ-INSR regulates apoptotic and metabolic pathways in cardiomyocytes. Circ-INSR physically interacts with the single-stranded DNA-binding protein (SSBP1) mediating its cardioprotective effects under doxorubicin stress. Importantly, in vitro transcribed and circularized Circ-INSR mimics also protected against doxorubicin-induced cardiotoxicity. The authors conclude that Circ-INSR is a highly conserved non-coding RNA which is down-regulated during cardiotoxicity and cardiac remodelling. Adeno-associated virus and circRNA mimics-based Circ-INSR overexpression prevent and reverse doxorubicin-mediated cardiomyocyte death, and improve cardiac function. The results of this study highlight a novel and translationally important Circ-INSR-based therapeutic approach for doxorubicin-induced cardiac dysfunction. This manuscript is accompanied by an Editorial by Carlo G. Tocchetti from the Federico II University in Naples, Italy and colleagues.21 The authors note that the body of pre-clinical data provided by Lu et al. suggests altogether a strong translational potential of Circ-INSR. This novel approach may retain its potential not only in doxorubicin-induced cardiomyopathy but also in response to other cardiotoxic common anticancer agents, such as, for example, taxanes. Further detailed investigations are warranted in this context, but the group of Thomas Thum has unveiled a novel avenue towards treatment of cardiotoxicity which deserves to be pursued in a further drug discovery process as well as clinical testing. The editors hope that this issue of the European Heart Journal will be of interest to its readers. Dr. Crea reports speaker fees from Amgen, Astra Zeneca, Servier, BMS, other from GlyCardial Diagnostics, outside the submitted work.