Prognostic impact of coronary flow reserve in transthyretin cardiac amyloidosis independent of coronary calcium burden

Background Transthyretin cardiac amyloidosis (ATTR-CM) is associated with myocardial infiltration and progressive heart failure. Coronary microvascular dysfunction has been increasingly recognized in ATTR-CM, even in the absence of obstructive coronary artery disease. However, the prognostic relevance of impaired coronary flow reserve (CFR) in this population remains uncertain, and the potential confounding effect of coronary atherosclerosis, assessed by coronary calcium score, is not well established. Purpose To assess coronary flow reserve in patients with ATTR-CM and evaluate its impact on prognosis, independently of coronary calcium burden. Methods Patients with confirmed ATTR-CM underwent non-invasive CFR assessment and coronary calcium scoring. Survival analyses were performed using Kaplan–Meier curves and log-rank tests. Cox proportional hazards regression models were used to evaluate the association between CFR and outcomes, with multivariable adjustment including coronary calcium score. Sensitivity analyses were conducted to assess the influence of coronary calcium on CFR measurements. Results A total of 40 patients with confirmed ATTR-CM were included (mean age 55 ± 16 years, 67.5% male). During a median follow-up of 40 months (IQR 24–44), all-cause mortality was 30%. Patients with cardiac involvement showed significantly lower global CFR compared with those without involvement (1.84 ± 0.37 vs 2.71 ± 0.77; p < 0.001), with a large effect size (Cohen’s d = 1.88). Abnormal CFR (<2.0) was more frequent among patients with cardiac involvement (55.0% vs 18.5%, p = 0.002). Coronary calcium score (CCS) was higher in patients with cardiac involvement; however, in multivariable linear regression analysis adjusting for CCS, cardiac involvement remained independently associated with reduced CFR (B = −1.07; 95% CI −1.49 to −0.66; β = −0.67; p < 0.001), whereas CCS was not significantly associated with CFR (p = 0.701). In survival analyses, patients with abnormal CFR had significantly lower survival compared with those with preserved CFR (log-rank p < 0.001). In multivariable Cox regression analysis including age, left ventricular ejection fraction, renal function, BNP, CCS, and medical therapy, CFR remained independently associated with all-cause mortality (HR 0.008; 95% CI 0.000–0.549; p = 0.025). Conclusions In patients with ATTR-CM, impaired CFR is common and strongly associated with adverse prognosis. The association between reduced CFR and mortality is independent of CCS burden, supporting a predominant role of coronary microvascular dysfunction rather than epicardial coronary atherosclerosis. Non-invasive assessment of CFR may provide incremental prognostic information and help refine risk stratification in ATTR-CM.