Increased index of microcirculatory resistance, capillary rarefaction, elevated troponin levels, and their association with transthyretin amyloidosis cardiomyopathy

Abstract Background The pathophysiology of coronary microvascular disease (CMD) in patients with transthyretin amyloidosis cardiomyopathy (ATTR-CM) remains unclear. Objective This study aims to functionally and pathologically assess coronary microvasculature to elucidate the underlying mechanisms of myocardial injury in patients with ATTR-CM. Methods Fifty patients (median age, 74 years; men, n=46, 92%) with echocardiographic evidence of left ventricular hypertrophy (≥12 mm) who underwent endomyocardial biopsy (EMB) and invasive coronary physiological assessments following coronary angiography were enrolled between October 2021 and September 2023 and divided into ATTR-CM (n=30) and non-cardiac amyloidosis (CA) (n=20) groups according to EMB results. All patients with ATTR-CM exhibited positive heart-to-contralateral (H/CL) ratios (>1.5) on technetium 99m pyrophosphate scintigraphy. Fractional flow reserve (FFR), coronary flow reserve (CFR), and index of microcirculatory resistance (IMR) were measured using the PressureWire X guidewire in the left anterior descending artery. Capillary density (/mm2) was determined with EMB tissues by counting the number of CD31 immunopositive luminal structures, whereas the amyloid deposition burden was assessed by measuring the transthyretin immunopositive areas. Circulating cardiac troponin T (hs-cTnT) and brain natriuretic peptide (BNP) were measured. Results Compared to the non-CA group, the ATTR-CM group exhibited lower CFR (2.4±0.3 vs. 3.6±0.4, p=0.01), higher IMR (35.4±3.0 vs. 18.7±3.7, p=0.0009), lower capillary density (255.3±24.9 /mm2 vs. 408.6±29.5 /mm2 , p=0.0002), and elevated hs-cTnT levels (0.056±0.006 ng/mL vs. 0.036±0.004 ng/mL, p=0.01), with similar FFR (0.87±0.015 vs. 0.84±0.013, p=0.1) and BNP levels (229.6±38.1 pg/mL vs. 210.2±46.7 pg/mL, p=0.75). In the overall and ATTR-CM groups, capillary density had no significant correlation with IMR (r=0.16, p=0.41 and r=0.04, p=0.84, respectively) and a significant inverse correlation with hs-cTnT (r=-0.47, p=0.001, and r=-0.48, p=0.009, respectively). In the ATTR-CM group, capillary density was not significantly correlated with the H/CL ratio (r=-0.23, p=0.09); nevertheless, transthyretin immunopositive areas were positively correlated with the H/CL ratio (r=0.47, p=0.01). Conclusion Capillary rarefaction correlates with elevated hs-cTnT levels but not with elevated IMR, and H/CL ratios, suggesting that CMD is involved at the capillary level in ATTR-CM-related myocardial injury independent of the amyloid deposition burden.