Immune Activation and Region-specific Myocardial Arrhythmic Substrate in Sudden Cardiac Death Victims with HIV - SUMMARY/ABSTRACT We first discovered that the rate of sudden cardiac death (SCD), the most feared manifestation of cardiovascular disease, is substantially higher in people with HIV (PWH). We established the POstmortem Systematic InvesTigation of Sudden Cardiac Death (POST SCD) study, a prospective medical examiner-based cohort using autopsy to refine presumed SCDs to true cardiac causes, with banked tissue and data on PWH and uninfected control cases. ~80% of HIV+ SCDs were on ART, thus this a one-of-a-kind resource to study the direct myocardial tissue effects of treated HIV. HIV POST SCD showed that the increased SCD risk in PWH is attributable to higher levels of myocardial fibrosis, a known substrate for fatal arrhythmias, and our updated incidence analysis confirms a significant, 2-fold higher rate of arrhythmic death in PWH (IRR 2.001, 95% CI 1.02- 3.93, p=0.044). Yet, the mechanisms by which HIV leads to myocardial fibrosis or other tissue processes to cause non-CAD SCD are poorly understood. We have generated expression, immunohistochemical, and viral persistence data in myocardial tissue sampled at the time of SCD from 20 PWH, matched to >40 HIV- control SCDs that demonstrate: (1) hearts from PWH, most on ART, exhibit higher immune activation and cardiac ion channel dysregulation; (2) PWH on ART have downregulated expression of acute heart failure (HF) genes, suggesting that SCD in PWH is less related to HF and may be due to a distinct arrhythmogenic substrate or other inflammatory process; and, (3) the level of myocardial immune upregulation in PWH on ART is comparable to the highly inflammatory myocardial state triggered by traumatic injury. Via regional digital spatial profiling, we demonstrate the first direct tissue evidence of HIV RNA in myocardial-resident macrophages (MΦ) and that HIV may preferentially affect the epicardium, a known frequent source of VT/VF triggers, in the ART-suppressed heart, suggesting a regional myocardial specificity to the effects of HIV. Our central hypothesis is that HIV- induced MΦ activation in myocardium of PWH on ART, with particular augmentation in the arrhythmogenic epicardium, leads to chronic cardiac inflammation, interstitial fibrosis, ion channel dysregulation, and disruption of normal electrical coupling. Together, these process exert a direct myocardial tissue effect beyond the vascular space, to ultimately result in arrhythmic substrate that underlies increased SCD risk due to fatal arrhythmias in PWH. Our aims are to test the following hypotheses: 1A) myocardium from PWH on ART with SCD vs. HIV- SCDs and trauma controls have a higher burden of HIV-infected or infiltrating/inflammatory MΦ, which in turn correlates with levels of myocardial inflammation, fibrosis, and electrical remodeling; 1B) myocardium from PWH on ART with SCD vs. HIV- SCDs and trauma controls demonstrate chronic immune activation and tissue remodeling specific and distinct to the highly arrhythmogenic and inflammatory epicardial layer, including its adipocytes; and 2) chronic immune activation promotes fibrosis and decreased electrical coupling in specialized conduction tissues from PWH on ART with SCD vs. HIV- SCDs and trauma controls.
