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This Focus Issue on heart failure (HF) and cardiomyopathies contains the Special Article ‘European position paper on the management of patients with patent foramen ovale. Part II—Decompression sickness, migraine, arterial deoxygenation syndromes and select high-risk clinical conditions’, authored by Christian Pristipino from the San Filippo Neri Hospital in Italy, and colleagues.1 The authors note that patent foramen ovale (PFO) is implicated in the pathogenesis of a number of medical conditions. However, the high prevalence of a PFO in the normal population (20–30%) implies that PFO can often be an incidental finding rather than a causative one.2 To help clinicians with decision-making, the European Association of Percutaneous Cardiovascular Interventions Scientific Documents and Initiatives Committee invited eight European scientific societies and international experts to develop interdisciplinary position statements on the management of PFO, based on systematic assessments of the literature. A first position paper has already been published addressing issues related to cryptogenic thrombo-embolism.3,4 This second paper reports on the approach for patients with PFO and decompression sickness, desaturation syndromes, migraine, and other clinical presentations. Despite being based on limited and observational or low-certainty randomized data, a number of position statements have been made to frame PFO management in different clinical settings, along with suggestions for new research avenues. This interdisciplinary position paper, recognizing the low or very low certainty of existing evidence, provides the first approach to several PFO-related clinical scenarios beyond left circulation thrombo-embolism, and strongly stresses the need for fresh high-quality evidence on these topics.
Although considered a rare disease, recent data suggest that cardiac amyloidosis is underappreciated as a cause of common cardiac diseases.5,6 In a second Special Article entitled ‘Diagnosis and treatment of cardiac amyloidosis. A position statement of the ESC Working Group on Myocardial and Pericardial Diseases’, Pablo Garcia-Pavia from the Hospital Universitario Puerta de Hierro in Madrid, Spain, and colleagues note that cardiac amyloidosis is characterized by the extracellular deposition of misfolded proteins in the heart with the pathognomonic histological property of green birefringence when viewed under cross-polarized light after staining with Congo red.7 Recent advances in cardiac imaging, diagnostic strategies, and therapies have improved the recognition and treatment of cardiac amyloidosis. The aim of this position paper by the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases is to help cardiologists and other physicians in recognizing, diagnosing, and treating patients with cardiac amyloidosis.
The number of chronic heart failure (HF) patients is constantly increasing due to ageing populations and better survival of patients experiencing an acute coronary syndrome. The mainstay of HF treatment is stabilization of cardiac function, but identification and targeting of disease-modifying comorbidities is a rapidly emerging field in HF research.8 Numerous cross-sectional studies reported that >40% of HF patients showed cognitive deficits which are thought to relate to adverse outcomes.9 In a clinical research article entitled ‘Temporal changes in total and hippocampal brain volume and cognitive function in patients with chronic heart failure: the COGNITION.MATTERS-HF cohort study’ Anna Frey from the University and University Hospital Würzburg in Germany, and colleagues quantified the concurring dynamics affecting total and hippocampal brain volume and cognitive function in 148 patients with mild stable HF (mean age 64.5 years; 16.2% female; 77% in NYHA functional class I–II).10 The assessment included cardiological, neurological, and psychological work-up, and brain magnetic resonance imaging. Total and regional brain volumes were quantified using an operator-independent fully automated approach and reported normalized to the mean estimated intracranial volume. At baseline, the mean hippocampal volume was ∼13% lower than expected. However, the 3-year progressive hippocampal volume loss was small although significant (–62 mm3, P < 0.0001). This corresponded to a mean relative change of –1.8% which was similar in magnitude to that observed with physiological ageing. Cognitive function during the 3-year observation period remained stable, with ‘intensity of attention’ as the only domain significantly declining (P = 0.004) (Figure 1). After 3 years, performance in all domains of cognition remained significantly associated with hippocampal volume.
Kaplan–Meier curve for clinical events. Kaplan–Meier product limit estimator (95% CI) for the combined endpoint ‘time to death or rehospitalization for heart failure’. (A) Events of the total sample. (B) Events by the presence of medial temporal atrophy (MTA). (C) Events by the presence of cognitive dysfunction at baseline (from Frey A, Homola GA, Henneges C, Mühlbauer L, Sell R, Kraft P, Franke M, Morbach C, Vogt M, Müllges W, Ertl G, Solymosi L, Pirpamer L, Schmidt R, Pham M, Störk S, Stoll G. Temporal changes in total and hippocampal brain volume and cognitive function in patients with chronic heart failure: the COGNITION.MATTERS-HF cohort study. See pages 1569–1578).
The authors conclude that in patients with predominantly mild heart failure, the markedly reduced hippocampal volume observed at baseline is associated with impaired cognitive function, but no accelerated deterioration in cognition and brain atrophy becomes evident over a mid-term period of 3 years. The manuscript is accompanied by an Editorial by Ulrich Laufs from the Universitätsklinikum Leipzig in Germany, and Arno Villringer from the Max Planck Institute for Human Cognitive and Brain Science in the same city.11 The authors note that assuming the correlations between biomarkers/proxies of cardiac function and markers of cognition and brain anatomy/function hold in all ‘directions of change’, not only could stabilization of cardiac function prevent cerebral dysfunction, but improvement of cardiac function might also—to some extent—lead to improvement of brain function. They conclude that studies such as the COGNITION.MATTERS-HF study published in this issue are therefore greatly needed not only to unravel the bidirectional pathology of the heart and cognition but also to provide the necessary visualization needed to monitor and potentially influence this process.
Although the attention of the world and the global health community specifically is deservedly focused on the coronavirus disease 2019 (COVID-19) pandemic, other determinants of health continue to have large impacts and may also interact with COVID-19. Air pollution is one crucial example.12–14 Little is known about the relationship between the long-term joint exposure to various ambient air pollutants and the incidence of HF. In a clinical research article entitled ‘Joint exposure to various ambient air pollutants and incident heart failure: a prospective analysis in UK Biobank’, Mengying Wang from Tulane University in New Orleans, LA, USA, and colleagues assess the joint association of various air pollutants with HF risk and examine the modification effect of the genetic susceptibility.15 This study included 432 530 participants free of HF, atrial fibrillation, or coronary heart disease in the UK Biobank study. All participants were enrolled from 2006 to 2010 and followed up to 2018. Information on particulate matter (PM) with diameters ≤2.5 µm (PM2.5), ≤10 µm (PM10), and between 2.5 µm and 10 µm (PM2.5–10), as well as nitrogen oxides (NO2 and NOx) was collected. The authors proposed a new air pollution score to assess the joint exposure to the five air pollutants through summing each pollutant concentration weighted by the regression coefficients with HF from single-pollutant models. The authors also calculated the weighted genetic risk score of HF. During a median of 10.1 years of follow-up, they documented 4201 incident HF. The hazard ratios (HRs) of HF were 1.16, 1.19, 1.21, and 1.31, respectively, in higher quintile groups compared with the lowest quintile of the air pollution score (P trend <0.001). In addition, they observed that the elevated risk of HF associated with a higher air pollution score was strengthened by the genetic susceptibility to HF.
Wang et al. note that their results indicate that the long-term joint exposure to various air pollutants is associated with an elevated risk of incident HF in an additive manner. The manuscript is accompanied by an Editorial by Sanjay Rajagopalan from Harrington Heart and Vascular Institute in Cleveland, OH, USA.16 The authors conclude that ultimately, questions such as whether air pollution modulates HF risk could very well be a moot point, given the accelerated pace at which transition to sustainable non-fossil fuel sources is occurring in the COVID-19 era. However, in the interim period of transition, there is a need to understand the risk associations between air pollution and HF and measures to mitigate this historic risk factor.
Central obesity is a major risk factor for HF with preserved ejection fraction (HFpEF), particularly in women, but the mechanisms remain unclear.17,18 In a clinical research article entitled ‘Pathophysiological importance of visceral adipose tissue in women with heart failure and preserved ejection fraction’, Hidemi Sorimachi from the Mayo Clinic in Rochester, MN, USA, and colleagues hypothesized that sex-specific differences in visceral adipose tissue (VAT) content would differentially relate to haemodynamic severity of HFpEF in women and men.19 Abdominal computed tomography (CT) and invasive haemodynamic exercise testing were performed in 105 subjects with HFpEF (63 women) and 105 age-, sex-, and body mass index (BMI)-matched controls. VAT area was quantified by CT. As compared with control women, VAT area was 34% higher in women with HFpEF (P = 0.006), while VAT area was not significantly different in men with or without HFpEF. In addition, women with increased VAT area displayed 33% higher pulmonary capillary wedge pressure (PCWP) during exercise compared with women with normal VAT area (P = 0.001), whereas exercise PCWP was similar in men with or without excess VAT area. In women, each 100 cm2 increase in VAT area was associated with a 4.0 mmHg higher PCWP (P < 0.0001), while there was no such relationship in men (interaction P = 0.009) (Figure 2).
Relationships between exercise central haemodynamics and visceral adipose tissue (VAT) area. (A) Elevation in pulmonary capillary wedge pressure (PCWP) was related to an increase in visceral fat area in women, but not in men. (B) Parameter estimates from linear regression for the change in exercise right atrial pressure and PCWP with increasing VAT in women and men. There was a 4 mmHg increase in exercise PCWP for every 100 cm2 increase in VAT area in women, but no significant relationship was seen in men. *Sex–VAT interaction p<0.05. †Sex–VAT interaction after adjusting for BMI P < 0.05 (from Sorimachi H, Obokata M, Takahashi N, Reddy YNV, Jain CC, Verbrugge FH, Koepp KE, Khosla S, Jensen MD, Borlaug BA. Pathophysiologic importance of visceral adipose tissue in women with heart failure and preserved ejection fraction. See pages 1595--1605).
The authors conclude that accumulation of excess visceral adipose tissue plays a distinct and important role in the pathophysiology of HFpEF preferentially in women. Further research is needed to better understand the mechanisms and treatment implications for visceral fat in HFpEF in women. The manuscript is accompanied by an Editorial by Rudolf de Boer from the University Medical Center Groningen in the Netherlands.20 de Boer et al. note that the sex-specific findings of this and other studies reinforce the importance of including women as a specific cohort in clinical studies and trials. This work also underscores that besides classical measures of obesity (BMI or waist circumference), one should consider more sophisticated measures of obesity such as assessment of VAT area, as this may help to identify specific HFpEF phenotypes. Future studies are essential to better understand the sex-specific content and role of VAT, as this may allow even better phenotyping of patients, and development of designer drugs targeting specific fat depots, in both men and women with HFpEF.
Myocarditis is an inflammatory disease of the heart frequently resulting from viral infections that cause direct cardiac damage and/or post-viral immune-mediated responses.21,22 Beyond infections, myocarditis can be caused by a large variety of autoimmune disorders, drugs, and toxins.23 It is an important heart-specific inflammatory entity causing heart failure, chest pain, unexplained arrhythmias, and sudden death. Prognosis in myocarditis patients depends on the underlying aetiology. Rarely, myocarditis is associated with necrotizing coronary vasculitis (NCV) of intramural vessels.24 In a clinical research article entitled ‘Myocarditis-associated necrotizing coronary vasculitis: incidence, cause, and outcome’, Andrea Frustaci from Sapienza University in Rome, Italy, and colleagues found that among 1916 patients with biopsy-proven myocarditis, 30 had NCV.25 The NCV-myocarditis cohort was followed for 6 months with 2D-echo and/or cardiac magnetic resonance, and compared with 60 patients with non-NCV-myocarditis. Identification of an immunological pathway characterized by virus negativity, TLR4, and anti-heart autoantibody positivity was followed by immunosuppression. An increase in left ventricular ejection fraction ≥10% was classified as response to therapy. Causes of NCV-myocarditis included infectious agents (10%) and immune-mediated causes (chest trauma 3%; drug hypersensitivity 7%; hypereosinophilic syndrome 3%; primary autoimmune diseases 33%, idiopathic 44%). In-hospital mortality among NCV-myocarditis patients was 24% compared with 1.5% among non-NCV-myocarditis patients. At multivariable analysis, the presence of NCV was the only independent predictor of mortality. Immunosuppression was associated with an improvement of cardiac function in 88% of NCV-myocarditis and in 86% of non-NCV-myocarditis patients.
The authors conclude that NCV is histologically detectable in 1.5% of myocarditis. NCV-myocarditis includes viral- and immune-mediated causes, and is characterized by high in-hospital mortality which might be improved by immunosuppression when caused by immune-mediated mechanisms. The contribution is accompanied by an Editorial by Alida Caforio from the University of Padua in Italy.26 Caforio and colleagues note that Frustaci et al. should be appreciated for their long-lasting pioneering work in the myocarditis field and that using endomyocardial biopsy and new refined tissue and serum biomarkers of immune-mediated pathogenesis, we will rapidly implement new and effective tailored treatments for myocarditis.
In the last decade, immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of many cancers including malignant melanoma and lung cancer. ICIs have been shown to significantly improve prognosis but may induce immune-related side effects.27,28 Among the known immune-related side effects are pneumonitis, dermatitis, colitis, hepatitis, nephritis, and endocrine toxicities. Case studies and pharmacovigilance data suggest that the immune-related cardiac side effects are mainly affecting cardiac conduction and myocyte function, which may result in arrhythmias, peri- or myocarditis, HF, and sudden cardiac arrest. However, the risk of cardiac side effects outside these selected populations is widely uninvestigated. In a clinical research article entitled ‘The risk of cardiac events in patients receiving immune checkpoint inhibitors: a nationwide Danish study’, Maria D’Souza from the University Hospital Herlev-Gentofte in Hellerup, Denmark, and colleagues aimed to estimate the risk of cardiac events in ICI-treated patients with lung cancer or malignant melanoma.29 In this nationwide study in Denmark, the authors enrolled consecutive patients with lung cancer or malignant melanoma in the period 2011–2017. The main composite outcome was cardiac events (arrhythmia, peri- or myocarditis, HF) or cardiovascular death. They included >25 500 patients with lung cancer. Of these, 743 were treated with programmed cell death-1 inhibitor (PD1i) and their 1-year absolute risk of cardiac events was 9.7%. Of the >13 500 patients with malignant melanoma, 145 received PD1i and 212 received Cytotoxic T-Lymphocyte-Associated Protein-4 inhibitor (CTLA-4i) treatment. Their 1-year risks of cardiac events were 6.6% and 7.5%, respectively. The hazard rates (HR) of cardiac events were higher in patients with vs. without ICI treatment. Within 6 months from first ICI administration, the HRs were 2.14 in patients with lung cancer and 4.30 and 4.93 in patients with malignant melanoma on PD1i or CTLA-4i, respectively. After 6 months, HRs were 2.26 for patients with lung cancer and 3.48 for patients with malignant melanoma receiving CTLA-4i.
The authors conclude that among patients with lung cancer and malignant melanoma, ICI-treated patients exhibit increased rates of cardiac events. The absolute risks are higher in this study compared with previous pharmacovigilance studies. The article is accompanied by an Editorial by Thomas Neilan from the Massachusetts General Hospital in Boston, MA, USA, and colleagues.30 The authors conclude that perhaps it is time for a broader description of ICI-induced cardiovascular complications to include the term ‘ICI-related cardiovascular disease’, and this is supported by the important insights presented by D’Souza and colleagues. Immediate steps include increasing our awareness for a broader range of potential cardiac toxicities related to ICI treatment. Longer term steps include broadening collaborations with our oncology and pharmaceutical partners, and expanded clinical research efforts in parallel and based on innovative basic experimental insights. These and other steps are needed to move this forward so that we can improve cardiovascular outcomes among our cancer patients treated with an ICI.
The issue is complemented by two Discussion Forum articles: in a contribution entitled ‘Cardiac events associated with ICI therapy: the devil is in the detail’ Markus Anker from the Charité in Berlin, Germany comments on the contribution also published in this issue entitled ‘The risk of cardiac events in patients receiving immune checkpoint inhibitors: a nationwide Danish study’.29,31 D’Souza et al. respond in a separate comment.32
The editors hope that readers of this issue of the European Heart Journal will find it of interest.
With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.
