Heart failure with preserved ejection fraction: innovative diagnostic approaches and therapeutic targets

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 State of the Art Review article entitled ‘Cardiac sarcoidosis: phenotypes, diagnosis, treatment, and prognosis’ by Jukka Lehtonen from the Helsinki University Central Hospital and University of Helsinki, and colleagues.1 The authors note that cardiac sarcoidosis (CS) results from epithelioid cell granulomas infiltrating the myocardium and predisposing to conduction disturbances, ventricular tachyarrhythmias, and heart failure (HF).2–4 Manifest CS, however, constitutes only the tip of an iceberg as advanced imaging uncovers cardiac involvement 4–5 times more commonly than what is detectable clinically. Definite diagnosis of CS requires myocardial biopsy and histopathology, but a sufficient diagnostic likelihood can be achieved by combining extracardiac histology of sarcoidosis with clinical manifestations and findings on cardiac imaging. CS can appear as the first or only organ manifestation of sarcoidosis or on top of pre-existing extracardiac disease. Due to the lack of controlled trials, the care of CS is based on observational evidence of low quality. Currently, the treatment involves corticosteroid-based, tiered immunosuppression to control myocardial inflammation, with medical and device-based therapy for symptomatic atrioventricular block, ventricular tachyarrhythmias, and HF. Recent outcome data indicate 90–96% 5-year survival in manifest CS, with the 10-year figures ranging from 80% to 90%. Major progress in the care of CS awaits the key to its molecular–genetic pathogenesis and large-scale controlled clinical trials. Cardiac rehabilitation remains the ‘Cinderella’ of treatments for heart failure. In a State of the Art Review article entitled ‘Cardiac rehabilitation for heart failure: “Cinderella” or evidence-based pillar of care?’, Rod Taylor from the University of Glasgow in the UK, and colleagues provide a contemporary update on the evidence base, clinical guidance, and status of cardiac rehabilitation delivery for patients with HF.5 Given that cardiac rehabilitation participation results in important improvements in patient outcomes, including health-related quality of life, this review argues that an exercise-based rehabilitation is a key pillar of HF management alongside drug and medical device provision. To drive future improvements in access and uptake, health services should offer HF patients a choice of evidence-based modes of rehabilitation delivery, including at home, supported by digital technology, alongside traditional centre-based programmes (or combinations of modes, ‘hybrid’) and according to stage of disease and patient preference. Hypertrophic cardiomyopathy (HCM) is a common heart muscle disorder which causes premature death from ventricular arrhythmia, HF, and stroke.6–9 In a Viewpoint article entitled ‘Do apical aneurysms predict sudden cardiac death in hypertrophic cardiomyopathy?’, Massimiliano Lorenzini and Perry Elliott from the University College London in the UK note that while left ventricular (LV) apical aneurysms are probably associated with monomorphic ventricular tachycardia, significant selection bias and the presence of important confounders such as previous severe ventricular tachyarrhythmias or reduced LV ejection fraction suggest that the available data do not support their use as an independent predictor of sudden cardiac death in HCM.10 Prospective studies of large cohorts that represent the full spectrum of disease may help resolve the debate. Until then, clinicians should continue to make individualized decisions based on well-established risk factors, and an implantable cardioverter defibrillator (ICD) should be considered for secondary prevention and in those with an aneurysm large enough to cause a reduced LV ejection fraction, but ICD decisions should not be based solely on the presence or absence of an LV apical aneurysm. In a Viewpoint article entitled ‘Drugs that slow the progression of diabetic kidney disease: are renoprotective effects attenuated in heart failure?’, Milton Packer from the Baylor University Medical Center in Dallas, TX, USA, and colleagues point out that in large-scale randomized controlled trials (RCTs), several classes of drugs have been shown to reduce major adverse renal outcomes in Type 2 diabetes.11 As compared with placebo, angiotensin receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors, mineralocorticoid receptor antagonists (MRAs), and sodium–glucose co-transporter 2 (SGLT2) inhibitors each reduce the risk of occurrence of end-stage kidney disease by 30–35%. Therefore, many of the foundational drugs that favourably influence cardiovascular death and HF hospitalization in chronic HF12–14 act to decrease the risk of serious adverse renal outcomes in diabetic patients. Yet, surprisingly, large-scale trials have not demonstrated that these four classes of drugs reduce the risk of end-stage kidney disease in patients with HF, even though the same trials demonstrated significant benefits of these treatments on major HF outcomes. What might explain differences in the results with ARBs, ACE inhibitors, MRAs, and SGLT2 inhibitors in patients with Type 2 diabetes vs. those with HF regarding renal outcomes? In this Viewpoint, the authors propose three possible causes which might explain these remarkable differences. RCTs form the basis for guidelines, regulatory approval, and reimbursement. In a Rapid Communications article entitled ‘Participation in a clinical trial is associated with lower mortality but not lower risk of HF hospitalization in patients with heart failure: observations from the ESC EORP Heart Failure Long-Term Registry’, Chris Kapelios from the Laiko General Hospital in Athens, Greece, and colleagues assessed patients enrolled in the ESC-EORP Heart Failure Long-Term registry, a prospective registry of patients with HF conducted across 337 cardiology centres in 33 countries.15 A total of 18 247 patients were analysed. Among these, 938 (5%) participated in an RCT at index visit. Patient characteristics independently associated with a higher likelihood of RCT participation were outpatient setting, older age, less severe HF symptoms and lower ejection fraction, absence of active malignancy, and history of myocardial infarction or percutaneous coronary intervention, while those associated with a lower likelihood were history of coronary bypass grafting, hypercholesterolaemia, sleep apnoea, active smoking, peripheral congestion, moderate–severe mitral regurgitation, and HF history >12 months. Mortality rates were 9.7 vs. 12.9 deaths/100 patient-years for those enrolled vs. not in RCTs, respectively [crude hazard ratio (HR) 0.71; adjusted HR 0.81; 95% confidence interval (CI) 0.66–1.00, P = 0.051]. The authors conclude that patients in the registry participating in an RCT have lower risk of competing events, greater use of background guideline-recommended medical treatment, and indeed lower risk of all-cause mortality. Pregnancy outcomes in women with heart disease represent a growing concern.16–20 In a Clinical Research article entitled ‘Pregnancy outcomes in women with heart disease: the Madras Medical College Pregnancy And Cardiac (M-PAC) Registry from India’, Gnanaraj Justin Paul from the Rajiv Gandhi Government General Hospital in Chennai, Tamil Nadu, India, and colleagues evaluate the foeto-maternal outcome, identify the adverse outcome predictors, and test the applicability of modified World Health Organization (mWHO) classification in pregnant women with heart disease (PWWHD) from Tamil Nadu, India.21 One thousand and five pregnant women (mean age: 26.04 years) with 1029 consecutive pregnancies were prospectively enrolled from July 2016 to December 2019 in the Madras medical college pregnancy and cardiac (M-PAC) registry. The majority (60%) had heart disease diagnosed for the first time during pregnancy. Rheumatic heart disease (42%) was most common. One-third (34%) had pulmonary hypertension (PH). Maternal mortality and composite maternal cardiac events (MCEs) were the primary outcomes. Secondary outcomes were foetal loss and composite adverse foetal events (AFEs). MCEs occurred in 15.2% pregnancies. HF was the most common MCE (66%). Maternal mortality was 1.9%, with the highest rates in patients with prosthetic heart valves (PHVs) (8.6%). LV systolic dysfunction (LVSD), PHVs, severe mitral stenosis, PH, and current pregnancy diagnosis of heart disease were independent predictors of MCEs. The c-statistic of mWHO classification for predicting MCEs and maternal death were 0.794 and 0.796. A total of 91% of pregnancies resulted in live births; 34% of pregnancies reported AFEs. The authors conclude that maternal mortality is high in PWWHD from India. The highest death rates occur in women with PHVs, PH, and LVSD. The mWHO classification for risk stratification may require further adaptation and validation in India. The contribution is accompanied by an Editorial by Jolien Roos-Hesselink and Johanna van der Zande from the University Medical Center Rotterdam in the Netherlands, and Mark Johnson from the Imperial College London in the UK.22 The authors conclude that it is likely that differences in pregnancy outcomes described in registries are due to variations in the nature and severity of the underlying heart disease, the access to medical care, and the underlying socio-cultural environment. The study of Gnanaraj et al. highlights the need for better access to cardiac care in low–medium income countries for women of childbearing age. Only if underlying heart disease is identified before pregnancy can the clinical state be optimized, and accurate pre-conception counselling given. In the absence of antenatal diagnosis, it is essential that pregnant women with heart disease have access to advanced medical care in the form of pregnancy heart teams as described by Gnanaraj et al. in their timely and important paper. Set-up of the different components of a dedicated dyspnoea clinic for heart failure with preserved ejection fraction. For patients with a confirmed diagnosis according to either the HFA-PEFF score, the H2FPEF score, or both, downstream implications of testing are presented. CT, computed tomography; ECG, electrocardiogram.23 HF with preserved ejection fraction (HFpEF) is a syndrome with a heterogeneous presentation. In a Clinical Research article entitled ‘Heart failure with preserved ejection fraction: relevance of a dedicated dyspnoea clinic’, Jan Verwerft from Hasselt University in Belgium, and colleagues provide an in-depth description of haemodynamic and metabolic alterations revealed by systematic assessment through cardiopulmonary exercise testing combined with exercise echocardiography (CPETecho) within a dedicated dyspnoea clinic.23 Consecutive patients (n = 297), referred to a dedicated dyspnoea clinic using a standardized workup including CPETecho, with HFpEF diagnosed through a H2FPEF score ≥6 or HFA-PEFF score ≥5, were evaluated. A median of four haemodynamic/metabolic alterations was uncovered per patient: impaired stroke volume reserve (73%), impaired chronotropic reserve (72%), exercise pulmonary hypertension (65%), and impaired diastolic reserve (64%) were the most frequent cardiac alterations. Impaired peripheral oxygen extraction and a ventilatory limitation were present in 40% and 39%, respectively. In 267 patients (90%), 575 further diagnostic examinations were recommended (median of two tests per patient). Cardiac magnetic resonance imaging, coronary or amyloidosis workup, ventilation–perfusion scanning, and pulmonology referral were each recommended in approximately one out of three patients. In 293 patients (99%), 929 cardiovascular drug optimizations were needed (median of three modifications per patient). In 110 patients (37%), 132 cardiovascular interventions were performed, with ablation as the most frequent procedure (Figure 1). Verwerft et al. conclude that holistic work up of HFpEF patients within a multidisciplinary, dedicated dyspnoea clinic, including systematic implementation of CPETecho, reveals various haemodynamic/metabolic alterations, leading to further diagnostic testing and potential treatment changes in most cases. The manuscript is accompanied by an Editorial by Carolyn Lam and Jennifer Ho from the Duke-National University of Singapore Medical School.24 Lam and Ho conclude by noting that Verwerft et al. provide compelling data on the diagnostic and therapeutic implications of a systematic approach to patients with HFpEF in a dedicated multidisciplinary clinic. Yet, many questions remain. What is the best way to implement this multidisciplinary clinic in a fragmented care setting? What resources are needed? What are the roles for cardiologists/HF specialists/general practitioners? How scalable is this model, and can we improve access to key tests, e.g. biomarkers, spirometry, echo, or CPET? What is the impact of such a specialized clinic on clinical outcomes, and what is its cost-effectiveness? These unanswered questions remain in stark contrast to treatment pathways for patients with HFrEF, where referrals to a HF clinic, for instance, are centred around clear and delineated goals, including medication management and evaluation of advanced therapies. With one of the primary challenges in HFpEF being around diagnosis itself, as well as the identification of masqueraders and recognition of treatable comorbid conditions, the clinical approach is invariably more complex, drawing from multiple disciplines. While the ‘how’ needs clarification from further studies, the ‘why’ remains clear. In fact, the need for dedicated HFpEF clinics today is arguably even more urgent than 16 years ago when the first HFpEF clinical programme was established, as HFpEF becomes the dominant form of HF worldwide, and continues to be underdiagnosed and undertreated. Tangle-like aggregates of hyperphosphorylated tau are present in the heart of patients with dilated cardiomyopathy or Alzheimer’s disease. A mouse model of tauopathy recapitulates the pathological findings of the human disease. Disruption of microtubule de-/tyrosination causes myocardial diastolic dysfunction observed in the mouse model and it can be targeted with immunotherapy. Abbreviations: iDCM, idiopathic dilated cardiomyopathy; PAO, pre-amyloid oligomers; TOMA, tau oligomer monoclonal antibody.25 Amyloid plaques and neurofibrillary tangles, the molecular lesions that characterize Alzheimer’s disease (AD), are emerging as determinants of proteinopathies ‘beyond the brain’. In a Translational Research article entitled ‘Big tau aggregation disrupts microtubule tyrosination and causes myocardial diastolic dysfunction: from discovery to therapy’, Federica del Monte from the Medical University of South Carolina in Charleston, NC, USA, and colleagues aim to establish tau’s putative pathophysiological mechanistic roles and potential future therapeutic targeting of tau in HF.25 A mouse model of tauopathy and human myocardial and brain tissue from patients with HF, AD, and controls were employed in this study. Tau protein expression was examined together with the distribution. In addition, tau-related pathophysiological mechanisms were identified in vitro using a variety of biochemical, imaging, and functional approaches. A novel tau-targeting immunotherapy was tested to explore tau-targeted therapeutic potential in HF. Tau was expressed in normal and diseased human hearts, in contradistinction to the current often-cited observation that tau is expressed specifically in the brain. Notably, the main cardiac isoform was the high-molecular-weight (HMW) tau (also known as big tau) and hyperphosphorylated tau segregated in aggregates in HF and AD hearts. Perturbation in tubulin code, specifically a loss of tyrosinated microtubules, emerged as a potential mechanism of myocardial tauopathy. Monoclonal anti-tau antibody therapy improved myocardial function and clearance of toxic aggregates in mice, supporting tau as a potential target for novel HF immunotherapy (Figure 2). The authors conclude that the study presents new mechanistic evidence and potential treatment for the brain–heart tauopathy axis in myocardial and brain degenerative diseases and ageing. The contribution is accompanied by an Editorial by Carmen Sucharov and Obed Nyarko from the University of Colorado Denver, CO, USA.26 The authors note that tau proteins have been extensively studied in neurodegenerative diseases. The current study is relevant, and novel, and highlights the contribution of tau proteins to HF. The results of this study may provide an effective novel therapeutic option for patients with tauopathies and HFpEF. Furthermore, > 30% of AD patients suffer from HFpEF, suggesting a strong link between the AD and the effect of tau modification and aggregation in the heart. The study of tau proteins holds tremendous promise not only in the field of neurodegenerative diseases but also in the field of cardiology by potentially improving HF outcomes in patients with HFpEF. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘The TANSNIP-PESA trial is not the end of the story’, Ulf Näslund, Patrik Wennberg, and Margareta Norberg from the Umeå University in Sweden comment on the recent publication ‘Effects of a comprehensive lifestyle intervention on cardiovascular health: the TANSNIP-PESA trial’ by Ines Garcia-Lunar from the Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid, Spain.27,28 Garcia-Lunar et al. respond in a separate comment. 29 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.