Characterizing subtypes of heart failure with preserved ejection fraction: the HeartMagic prospective observational study

IntroductionHeart failure (HF) is a life-threatening syndrome with significant morbidity and mortality. While evidence-based drug treatments have effectively reduced morbidity and mortality in HF with reduced ejection fraction (HFrEF), few therapies have been demonstrated to improve outcomes in HF with preserved ejection fraction (HFpEF). The multifaceted clinical presentation is one of the main reasons why the current understanding of HFpEF remains limited. This may be caused by the existence of several HFpEF disease subtypes that each need different treatments. There is therefore an unmet need for a holistic approach that combines comprehensive imaging with metabolomic, transcriptomic and genomic mapping to subtype HFpEF patients. This protocol details the approach employed in the HeartMagic study to address this gap in understanding. MethodsThis prospective multi-center observational cohort study will include 500 consecutive patients with actual or recent hospitalization for treatment of HFpEF at two Swiss university hospitals, along with 50 age-matched HFrEF patients and 50 age-matched healthy controls. Diagnosis of heart failure is based on clinical signs and symptoms and subgrouping HF patients is based on the left-ventricular ejection fraction. In addition to routine clinical workup, participants undergo genomic, transcriptomic, and metabolomic analyses, while the anatomy, composition, and function of the heart are quantified by comprehensive echocardiography and magnetic resonance imaging (MRI). Quantitative MRI is also applied to characterize the kidney. The primary outcome is a composite of one-year cardiovascular mortality or rehospitalization. Machine learning (ML) based multi-modal clustering will be employed to identify distinct HFpEF subtypes in the holistic data. The clinical importance of these subtypes shall be evaluated based on their association with the primary outcome. Statistical analysis will include group comparisons across modalities, survival analysis for the primary outcome, and integrative multi-modal clustering combining clinical, imaging, ECG, genomic, transcriptomic, and metabolomic data to identify and validate HFpEF subtypes. DiscussionThe integration of comprehensive MRI with extensive genomic and metabolomic profiling in this study will result in an unprecedented panoramic view of HFpEF and should enable us to distinguish functional subgroups of HFpEF patients. This approach has the potential to provide unprecedented insights on HFpEF disease and should provide a basis for personalized therapies. Beyond this, identifying HFpEF subtypes with specific molecular and structural characteristics could lead to new targeted pharmacological interventions, with the potential to improve patient outcomes.