The electrophysiological substrate of biopsy-proven cardiac amyloidosis

Abstract

Abstract Background Cardiac amyloidoses (CA) are an increasingly recognized group of infiltrative cardiomyopathies associated with high risk of major adverse cardiac events. Endomyocardial biopsy (EMB) may be required to differentiate the amyloid type (mainly, Immunoglobulin light chain [AL] versus transthyretin-related [ATTR]) in some cases. Purpose The aim of this study was to provide the first description of the right ventricular (RV) electroanatomical substrate of CA, and assess its association with EMB findings and clinical outcomes. Methods We enrolled ten consecutive patients undergoing EMB for suspected CA (median age, 68[63-77]; male, 50%) in a monocentric, observational, retrospective study. All patients had a clinical diagnosis of CA, but a diagnosis of CA type was hampered by the presence of inconclusive or discordant laboratory-imaging findings (abnormal serum free light chain assay and positive bone scintigraphy, n=5; ambiguous imaging results, n=4; abnormal serum free light chain assay and TTR gene mutation, n=1). Therefore, each patient underwent RV high-density electroanatomical voltage mapping (EVM) and EMB. The primary outcome was death or hospitalization at 1-year follow-up. We recorded electrogram features at EMB sampling sites and in the overall RV, and explored their correlations with histopathological findings and primary outcomes events. Results A final EMB-proven diagnosis of AL or ATTR CA was formulated in 6 and 4 patients, respectively. Electrogram amplitudes in the bipolar and unipolar configurations averaged 1.58±0.65 mV, and 5.38±1.41 in the overall RV. We found a significant inverse correlation between unipolar electrogram amplitude and amyloid burden at EMB (p<0.001); the unipolar voltage cutoff that best identified regions with >15% amyloid tissue infiltration according to Youden index was 9.1 mV (sensitivity, 43%; specificity, 100%; accuracy, 77%). At 1-year follow-up, 6 patients (60%) experienced a primary outcome event. Compared to subjects with uneventful follow-up, patients with a primary outcome event had larger unipolar low-voltage zones (32.3 [6.1] cm2 vs. 20.7 [6.5] cm2, p=0.043) and bipolar dense scar areas (6.1 [2.3] cm2 vs. 1.8 [0.7] cm2, p=0.005), and after pooling mapping points from all patients, unipolar electrogram amplitude was moderately associated with primary outcome events (AUC: 0.65 [95% CI, 0.64-0.65]). Conclusions In CA, electrogram amplitudes are around the lower limit of normal, yet disproportionately low compared to the increased wall thickness. We found evidence that unipolar electrogram amplitude may be a quantitative marker of amyloid burden, possibly associated with adverse clinical outcomes.EVM and EMB in ATTR cardiac amyloidosisEVM and EMB in AL cardiac amyloidosis