Sudden cardiac death in obstructive hypertrophic cardiomyopathy: substrate-guided risk using fibrosis, microvascular function, and immune signatures :a systematic review

Background/Introduction Sudden cardiac death (SCD) in obstructive hypertrophic cardiomyopathy (oHCM) arises from a multifactorial arrhythmogenic substrate that extends beyond the scope of current risk-prediction models. Emerging evidence links myocardial fibrosis, coronary microvascular dysfunction, and immune/inflammatory remodelling to malignant ventricular arrhythmias. Purpose To systematically review and integrate data on SCD and arrhythmic surrogates in oHCM, identifying substrate-based risk markers across imaging, perfusion, and immune-transcriptomic domains. Methods A prospectively planned systematic review was conducted according to PRISMA standards. MEDLINE, Embase, Web of Science, and Cochrane databases were searched up to November 2025. Of 289 records screened, 25 studies met inclusion criteria: adult oHCM cohorts reporting SCD or arrhythmic outcomes (appropriate ICD therapy, sustained VT/VF, or resuscitated arrest) with quantified (a) cardiac MRI fibrosis (LGE%, extracellular volume), (b) PET myocardial blood flow or stress-perfusion CMR (myocardial flow reserve), or (c) immune/transcriptomic features (bulk, scRNA-seq, spatial, or deconvolution data), as shown in Figure 1. Risk of bias was assessed using ROBINS-I/QUIPS, and methodological quality was evaluated against CMR/PET consensus and omics preprocessing standards. Results Across included oHCM cohorts, the absolute SCD incidence was low but clustered in patients with adverse substrates. Higher LGE% independently predicted SCD and appropriate ICD therapies beyond traditional guideline variables. PET and stress-perfusion CMR revealed impaired hyperaemic flow and reduced flow reserve correlating with arrhythmic events and fibrosis burden. Transcriptomic and immune-cell studies demonstrated cytotoxic T-cell expansion, M0/M1 macrophage predominance with relative M2/Treg depletion, and activation of IL-6–JAK–STAT and necroptosis pathways, spatially co-localised with myocardial disarray and fibrotic foci. Septal reduction therapy improved gradients but did not eliminate risk when residual fibrosis or microvascular dysfunction persisted. Conclusions In oHCM, SCD risk converges where fibrosis, microvascular dysfunction, and immune dysregulation intersect. A substrate-guided EHRA framework combining clinical risk models with LGE%, perfusion (MBF/MFR), and, where available, immune-omic markers could refine ICD implantation, guide surveillance imaging, and inform septal reduction timing. Future biomarker-enriched registries are needed to validate this integrative approach in reducing arrhythmic events.