Predictors of recurrent ischemic stroke in cardiac amyloidosis

Background Cardiac amyloidosis (CA) is associated with atrial dysfunction, atrial fibrillation (AF), and thromboembolic events. However, the prognostic relevance of a documented stroke prior to CA diagnosis and echocardiographic (echo) predictors of future ischemic cerebrovascular events remains unclear. Purpose To identify clinical and echo parameters associated with increased risk of stroke during follow-up in patients with CA in a multicenter setting. Methods A total of 1394 patients (age 71 ± 15 years, 72% male) with confirmed CA were included (transthyretin amyloidosis 73%; immunoglobulin light-chain amyloidosis 23%). Clinical and echo characteristics were compared between patients with and without documented stroke (9% vs. 91%) prior to CA diagnosis. Standard transthoracic echo study was performed at baseline. In addition to conventional parameters, measures of systolic and diastolic function were assessed, including left ventricular global longitudinal strain (LV GLS), E/e’ ratio, indexed LV mass, and left atrial volume index (LAVI), with severe LA dilatation defined as LAVI >48 mL/m² according to ESC/EACVI chamber quantification guidelines. The study endpoint was incidence of ischemic stroke during follow-up. Cox proportional hazards models were used for univariable and multivariable analyses. To reduce confounding, inverse probability of treatment weighting (IPTW) including established stroke risk factors (age, sex, hypertension (HT), diabetes (DM), hyperlipidemia (HLD) and AF) was applied. Survival free from stroke was estimated using IPTW-adjusted Kaplan–Meier curves. Additionally, a Fine–Gray sub-distribution hazards model was used to account for death as a competing risk. Results Patients with documented stroke prior to CA diagnosis were older and had higher rates of HT, DM and HLD compared to patients with no previously documented stroke (Figure 1). Furthermore, previously documented stroke was more often associated with AF, advanced heart failure related symptoms (New York Heart Association functional class ≥ III) and higher NT-proBNP at baseline. Echo of these patients also had greater indexed LV mass and LAVI, more impaired LV GLS and a lower E/e’ ratio. Over a median follow-up of 2 years (IQR 1-4), 38 (3%) patients experienced an ischemic stroke and 375 (27%) patients died. In both univariable and multivariable IPTW-adjusted Cox analyses, prior stroke and severely dilated LA were independently associated with 3-year stroke risk (prior stroke: HR 5.054; LAVI >48 mL/m²: HR 1.517) (Figure 2). After adjustment for death as a competing risk, prior stroke remained independently associated with an increased stroke risk (HR 4.299). Conclusion In CA, documented stroke prior to diagnosis and severely dilated LA (LAVI >48 mL/m²) identify a high-risk subgroup with a significantly increased risk of future ischemic cerebrovascular events, independent of and after adjustment for established stroke risk factors.