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Objectives We examined the association between systemic lupus erythematosus (SLE) and the risk of heart failure and cardiomyopathy (HF/CM) and assessed whether initiation and duration of hydroxychloroquine (HCQ) influence this risk.Methods This population-based cohort study utilized Swedish nationwide register data to identify all individuals aged 18-80 with newly diagnosed SLE in Sweden between 2006-08-01 and 2022-12-31, and matched general population comparators without SLE on sex, residence, and age at 1st SLE diagnosis. The primary outcome was a composite of HF or CM. Secondary outcomes included HF, CM, ischemic, and non-ischemic HF. Flexible parametric survival models estimated time-varying hazard ratios and 95% confidence intervals (HR 95%CI) comparing SLE vs. non-SLE. In patients with SLE, we applied two target trial emulations with the cloning-censoring-weighting approach to estimate the effect of HCQ initiation within 6 months of diagnosis compared to no initiation and the effect of treatment duration (<3 years, 3–6 years, >6 years) on 10-year risk of HF/CM. Weighted pooled logistic models derived risk difference and risk ratio (RR). Analyses were adjusted for time-fixed (e.g., baseline age, sex) and time-varying confounders (e.g., glucocorticoids, immunosuppressants, comorbidities).Results We included 3,468 patients with incident SLE and 33,210 matched comparators. Over a median follow-up of 9 years, HF/CM incidence rate was 8.5 per 1,000 person-years for SLE vs. 3.7 per 1,000 person-years for non-SLE. The HRs (95%CIs) were 3.28 (2.58-4.18) at 1 year, 1.81 (1.53–2.14) at 5 years, and 1.59 (1.28–1.96) at 10 years. Associations were consistent across secondary outcomes ( table 1). In patients, the 10-year risk of HF/CM was 8.9% among HCQ initiators vs. 15.3% among non-initiators (RR 0.59 [0.46–0.74] and risk difference -8.6% [-11.9 to -5.0%]) (figure 1). Among initiators, treatment duration was not associated with HF/CM: the 10-year RRs were 0.88 (0.63–1.25) for 3-6 years and 0.92 (0.65–1.27) for >6 years vs. <3 years.Abstract PT6:02 Table 1Associations between systemic lupus erythematosus and heart failure and cardiomyopathyAbstract PT6:02 Figure 1Risk of heart failure and cardiomyopathy as a composite outcome: (A) SLE vs. general population without SLE matched on age, sex, and residence; (B) SLE with HCQ initiation within six months vs. non-initiation; (C) SLE with different HCQ treatment durations.The 95% confidence intervals were not illustrated in panel C due to substantial overlap.SLE Systemic lupus erythematosus; HCQ: HydroxychloroquineConclusions SLE was associated with an increased risk of HF/CM, especially during the first year after diagnosis. In SLE, HCQ initiation within 6 months significantly reduced the risk of HF/CM, and the risk did not vary by treatment duration.