Targeting sudden death in heart failure with preserved ejection fraction: promise or pipedream?

KEYWORDS:

• Heart failure with preserved ejection fraction
• risk prediction
• sudden cardiac death

1. Introduction

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome that continues to expand in prevalence as the global population ages, and as cardiometabolic risk factors increase worldwide. Currently, half of patients with chronic heart failure (HF) have a preserved ejection fraction, and hospitalized patients with HFpEF have a similar long-term mortality as patients hospitalized with HF with reduced ejection fraction (HFrEF) [1]. Despite comparable mortality rates among the two HF phenotypes, there remain no medical or device therapies to definitively alter disease progression in HFpEF. Sudden death (SD) represents a relatively frequent mode of death among patients with HFpEF, accounting for ~40% of cardiovascular (CV) deaths in contemporary randomized clinical trials and ~20–25% of CV deaths in epidemiologic studies [2]. Indeed, SD has emerged as an attractive target for therapy to reduce mortality in the HFpEF cohort. As knowledge of the HFpEF disease state accrues, it has become clear that SD in HFpEF is a variably defined entity, reflective of multiple potential pathophysiologic pathways, and may be as heterogeneous as HFpEF itself. In addition, HFpEF patients demonstrate relatively high competing risks of both non-sudden CV death and non-CV death, limiting the scope of benefit of therapies solely targeting SD. We explore the complexities surrounding SD in HFpEF and identify necessary steps prior to consideration of targeted therapy toward SD in this cohort.

2. Complexities of identifying SD in HFpEF

SD has traditionally been synonymous with sudden cardiac death (SCD) due to malignant ventricular tachycardia/fibrillation (VT/VF) resulting from underlying myocardial pathology, acute myocardial infarction, or an inherited predisposition to arrhythmia (e.g. Brugada syndrome). Due to variable definitions of SD in contemporary randomized clinical trials and epidemiological studies, the syndrome of SD encompasses a far broader pathophysiologic basis than SCD alone. According to a National Heart Lung and Blood Institute (NHLBI) and Heart Rhythm Society (HRS) working group, both (1) rapidity of death (usually within 1 hour of symptoms) and (2) absence of extra-cardiac symptoms to explain death are hallmarks of SCD [3]. Such stringent criteria have been inconsistently used in both trials and epidemiologic studies of HFpEF. For example, SD was defined as ‘the unexpected death of an otherwise stable patient’ in the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM)-Preserved trial, one of the earliest large-scale trials of HFpEF [4]. Subsequent contemporary trials, including the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, have incorporated rapidity of death into working definitions of SD [5].

Variable definitions of SD in trials and registry studies result in a composite of deaths that are not necessarily arrhythmic in origin, and may in fact be inclusive of non-VT/VF related SDs, including acute pulmonary embolism, cerebrovascular accident, acute aortic syndromes, or bradyarrhythmia/asystole. Furthermore, stringent definitions of SCD, even if implemented in future trials, are imperfect in identifying true mode of death. In the landmark Postmortem Systematic Investigation of Sudden Cardiac Death (POST SCD) study, 46% of patients who met the World Health Organization definition of SCD, defined as death within 1 hour of symptoms or within 24 hours of having been observed alive/symptom free, were ultimately deemed to have a non-cardiac or non-arrhythmic mode of death upon extensive autopsy review [6].

3. How do patients with HFpEF die?

Given the discrepancy between adjudicated SCD and autopsy findings among the general population, further efforts are required to understand the mechanistic basis of SD in HFpEF and several ongoing investigations offer promise. The Ventricular Tachyarrhythmia Detection by Implantable Loop Recording in Patients with Heart Failure and Preserved Ejection Fraction (VIP-HF) will investigate the incidence of sustained VT among HFpEF patients with New York Heart Association (NYHA) class II or III symptoms and recent HF hospitalization (ClinicalTrials.gov Identifier NCT01989299). While potentially cumbersome, autopsy studies similar to POST SCD amongst the HFpEF cohort may provide a more comprehensive understanding of mode of death and warrant consideration. Although interrogation of preexisting cardiac implantable electronic devices in patients with HFpEF is an intuitively appealing approach, device implantation is relatively infrequent in this population.

Finally, despite the inherent limitations of SCD definitions, a cohesive effort to incorporate rigorous definitions of SCD by trained adjudication committees in large-scale epidemiologic studies and clinical trials will provide important insights into prevalent modes of death. The PRE-DETERMINE cohort study (ClinicalTrials.gov Identifier NCT01114269) recently reported rates of SCD among patients with coronary artery disease and left ventricular ejection fraction (LVEF) >35%, which were carefully adjudicated using next-of-kin/witnessed accounts of death and medical records, when available [7]. The application of these techniques in future registries of HFpEF may add precision to current estimates of SD in HFpEF.

4. Identifying the enriched HFpEF cohort for SCD

At present, given the lack of understanding of the mechanistic drivers of SD in HFpEF, the routine targeting of this mode of death in all patients is not supported. However, it is conceivable that patients with certain enriched characteristics may favorably benefit from targeted therapies toward SD.

Contemporary large-scale HFpEF trials conducted to date have identified select clinical factors that appear to predict SD. In the Irbesartan in Patients with Heart Failure and Preserved Ejection Fraction (I-PRESERVE) trial, six clinical parameters (age, sex, history of diabetes mellitus, prior myocardial, left bundle branch block, and natriuretic peptides) identified patients with greater than 10% cumulative risk of SD at 5 years [8]. In a more recent analysis of the Americas region of the TOPCAT trial, only male sex and insulin-treated diabetes mellitus were significant predictors of SD, after accounting for competing risks of non-sudden modes of death [9]. The clinical implications of these findings, however, are predicated on older definitions of SD and the accuracy and completeness of source documents supporting SD adjudication.

Racial and ethnic minority patients with HFpEF also appear to have distinct structural abnormalities (including increased LV mass and hypertrophy) [10] and clustering of comorbid diseases [11], that may contribute to higher observed SD risks [12]. The ascertainment of ancillary clinical information at the time of SD may vary by race/ethnicity, such that these patients may be more likely to be classified as SD. Given systematic underrepresentation of non-white races in prior studies, SD surveillance in HFpEF communities with greater racial/ethnic diversity is needed.

Beyond these clinical predictors, precision medicine techniques including biomarkers and novel imaging modalities offer promise. Cardiac T1 mapping and quantification of regional patterns of fibrosis and late gadolinium enhancement using magnetic resonance imaging [13] may be useful in risk stratification of SD in HFpEF. The PARAPET (Prediction of ARrhythmic Events With Positron Emission Tomography) study found that regional myocardial sympathetic denervation, as assessed by positron emission tomography, was predictive of arrhythmic death or appropriate implantable cardioverter defibrillator (ICD) discharge in 204 patients with ischemic cardiomyopathy [14]. The ongoing ADMIRE-ICD (International Study to Determine if AdreView Heart Function Scan Can be Used to Identify Patients with Mild or Moderate Heart Failure that Benefit from Implanted Medical Device; ClinicalTrials.gov Identifier: NCT02656329) study is evaluating the role of AdreView™ (¹²³I meta-iodobenzylguanidine, a novel scintigraphy imaging agent) in appropriately selecting patients with HFrEF for ICD therapy. Similar approaches could be considered in HFpEF.

5. Future directions

Targeted therapy of SCD has typically referred to ICD placement in the HF population. Despite this traditional perception, neurohormonal pharmacotherapies, which serve as the cornerstone for treatment of HFrEF, exhibit impressive reductions in SCD. It is possible that pharmacotherapies under investigation in HFpEF may demonstrate similar benefits. Indeed, several medical therapies that are currently under active study in HFpEF (sodium-glucose cotransporter 2 inhibitors [ClinicalTrials.gov Identifiers: NCT03057951 and NCT03619213], sacubitril/valsartan [ClinicalTrials.gov Identifier: NCT01920711], and spironolactone [ClinicalTrials.gov Identifier: NCT02901184]) have shown promise in SCD reduction in other high-risk CV populations. SD was numerically lower in patients treated with spironolactone compared with placebo in patients enrolled in the Americas region of the TOPCAT trial, but this difference did not reach statistical significance [9]; spironolactone may be considered in well-selected patients with HFpEF. Finally, the ongoing Multicenter Automatic Defibrillator Implantation Trial–Subcutaneous Implantable Cardioverter Defibrillator (MADIT S-ICD) trial, which will evaluate subcutaneous ICD therapy in patients with diabetes mellitus, prior myocardial infarction, and LVEF of 36–50%, may have important implications in future device trials of enriched cohorts of populations with borderline or preserved LVEF [15].

As the vast heterogeneity of HFpEF has introduced significant challenges in studying the disease, our current limited knowledge of SCD in HFpEF prohibits support for routine targeted therapy. Despite this, our understanding of SCD in HFpEF can be improved with (1) rigorous adjudication of SCD, (2) mechanistic evaluation of modes of death, (3) identification of enriched cohorts with arrhythmogenic phenotypes, and (4) clinical trials of novel pharmacotherapies. Such future investigations are essential in shaping the pipedream of targeted therapy of SCD in HFpEF into a promising reality.

Declaration of interest

RB Patel is supported by the NHLBI T32 postdoctoral training grant (T32HL069771). M Vaduganathan is supported by the KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Award KL2 TR002542), and serves on advisory boards for Bayer AG and Baxter Healthcare. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This paper is not funded.