Early autonomic dysfunction assessed by baroreflex sensitivity in transthyretin cardiac amyloidosis
K Yonezu, H Kondo, M Hayashi, M Miyoshi, S Saito, Y Murozono, T Shinohara, K Yufu, N TakahashiAbstract
Background
Systemic amyloidosis is characterized by progressive multi-organ involvement, in which autonomic dysfunction may precede overt structural damage. Assessment of autonomic function may therefore enable early diagnosis and risk stratification. In cardiac amyloidosis, impaired compensatory heart rate responses have been reported, suggesting early autonomic dysregulation; however, whether baroreflex sensitivity (BRS) is already reduced in early-stage transthyretin cardiac amyloidosis (ATTR-CM) remains unclear.
Purpose
To compare BRS values between patients with early-stage ATTR-CM and patients with diabetes mellitus, a condition with established autonomic dysfunction, and to clarify whether autonomic impairment is present from an early phase of amyloidosis.
Methods
Phenylephrine (2–3 μg/kg) was administered intravenously, and continuous arterial blood pressure was measured using tonometry. BRS was calculated as the slope of the linear regression line relating changes in systolic blood pressure to RR intervals (cardiac cycle length). BRS values were compared between 185 patients with diabetes mellitus without heart failure and 24 patients with NYHA class I–II ATTR-CM. To minimize confounding, propensity score matching was performed using age, sex, hypertension, β-blocker use, and baseline heart rate.
Results
Before matching, patients with ATTR-CM were significantly older (median age 75 [72–82] vs. 58 [51–66] years, P<0.0001), more frequently male (88% vs. 51%, P=0.0007), had lower median systolic blood pressure (119 [109–126] vs. 126 [112–140] mmHg, P=0.0239), and were more likely to receive β-blockers (42% vs. 2%, P<0.0001) than diabetic patients. Baseline heart rate did not differ between groups. BRS values were markedly lower in the ATTR-CM group (1.70 [−0.17 to 3.34] vs. 6.15 [3.43 to 10.31], P<0.0001). Propensity scores were estimated using logistic regression (c-index 0.962), and 1:1 matching with a caliper width of 0.10 yielded 13 well-balanced pairs (standardized difference <0.20). After matching, body mass index, serum creatinine, estimated glomerular filtration rate, and left ventricular ejection fraction were comparable between groups. Although HbA1c levels were significantly lower in the ATTR-CM group (5.9 [5.6–6.1] vs. 8.1 [6.7–9.4], P=0.0005), BRS values remained significantly reduced (1.14 [−0.42 to 3.28] vs. 5.73 [2.30 to 11.87], P=0.0089). In contrast, delayed heart-to-mediastinum ratios on sympathetic nerve scintigraphy were preserved and significantly higher in the ATTR-CM group (2.84 [2.26–3.19] vs. 1.95 [1.47–2.27], P=0.0141).
Conclusions
Despite preserved sympathetic innervation on scintigraphy, patients with early-stage ATTR-CM exhibited significantly reduced BRS compared with propensity score–matched diabetic patients. These findings suggest that functional autonomic dysregulation precedes overt organ damage in amyloidosis. BRS assessment may serve as a sensitive physiological marker for early autonomic involvement.