Noninvasive Mapping of the Electrophysiological Substrate in Cardiac Amyloidosis and Its Relationship to Structural Abnormalities

Abstract

Background The relationship between structural pathology and electrophysiological substrate in cardiac amyloidosis is unclear. Differences between light-chain (AL) and transthyretin (ATTR) cardiac amyloidosis may have prognostic implications. Methods and Results ECG imaging and cardiac magnetic resonance studies were conducted in 21 cardiac amyloidosis patients (11 AL and 10 ATTR). Healthy volunteers were included as controls. With respect to ATTR, AL patients had lower amyloid volume (51.0/37.7 versus 73.7/16.4 mL, P=0.04), lower myocardial cell volume (42.6/19.1 versus 58.5/17.2 mL, P=0.021), and higher T1 (1172/64 versus 1109/80 ms, P=0.022) and T2 (53.4/2.9 versus 50.0/3.1 ms, P=0.003). ECG imaging revealed differences between cardiac amyloidosis and control patients in virtually all conduction-repolarization parameters. With respect to ATTR, AL patients had lower epicardial signal amplitude (1.07/0.46 versus 1.83/1.26 mV, P=0.026), greater epicardial signal fractionation (P=0.019), and slightly higher dispersion of repolarization (187.6/65 versus 158.3/40 ms, P=0.062). No significant difference between AL and ATTR patients was found using the standard 12-lead ECG. T1 correlated with epicardial signal amplitude (cc=-0.78), and extracellular volume with epicardial signal fractionation (cc=0.48) and repolarization time (cc=0.43). Univariate models based on single features from both cardiac magnetic resonance and ECG imaging classified AL and ATTR patients with an accuracy of 70% to 80%. Conclusions In this exploratory study cardiac amyloidosis was associated with ventricular conduction and repolarization abnormalities, which were more pronounced in AL than in ATTR. Combined ECG imaging-cardiac magnetic resonance analysis supports the hypothesis that additional mechanisms beyond infiltration may contribute to myocardial damage in AL amyloidosis. Further studies are needed to assess the clinical impact of this approach.

Keywords: T1 mapping; amyloid; arrhythmia; electrophysiology mapping; imaging.

Figure 1

Representative example of epicardial potentials in cardiac amyloidosis reconstructed by ECGI. A, Local activation time (LAT) map in different angiographic views. B and C, Unipolar electrograms (continuous lines) from cardiac sites P₁ and P₂. Dots represent activation and repolarization times, and dashed lines represent local action potentials (schematic, for illustration purposes only). D, Unipolar electrogram from cardiac site P₃ exhibiting fractionated QRS complex with 4 negative deflections (bold gray line) and low voltage. Amplitude (Amp) is measured as the difference between the maximum and minimum values of the unipolar electrogram within the QRS complex (vertical dashed line). AT indicates activation time; ECGI, ECG imaging; LAO, Left Anterior Oblique; RAO, Right Anterior Oblique; RT, repolarization time; UEG, Unipolar Electrogram.

Figure 2

Late gadolinium enhancement (LGE), extracellular volume (ECV), native T1 and T2 maps for ATTR (top), AL (middle), and control (bottom) patients. ECV, T1, and T2 are higher in the 2 amyloid patients than in the control patient. T1 and T2 are higher in the AL than in the ATTR patient despite similar degree of cardiac amyloid infiltration (similar ECV). AL indicates light‐chain amyloidosis; ATTR, transthyretin amyloidosis; T1 and T2, magnetic fields in magnetic resonance imaging.

Figure 3

Example of a control (left), ATTR (center) and AL (right) patients showing marked differences in ECGI parameters, which are more pronounced in the AL group. A through C, Epicardial signal amplitude is lower in cardiac amyloidosis vs control and lower in AL vs ATTR. D through F, Total activation time (ΔAT) is longer in cardiac amyloidosis than in controls. G through I, Dispersion of repolarization (color coded as the difference between local and minimum repolarization time) is higher in cardiac amyloidosis vs control and higher in AL vs ATTR. J through L, Signal fractionation, measured as number of negative deflections in the QRS complex of the unipolar electrogram, is more elevated in AL patients. AL indicates light‐chain amyloidosis; Amp, amplitude; ATTR, transthyretin amyloidosis; ECGI, ECG imaging; Frac, fractionation; RT, repolarization time.

Figure 4

Pairwise comparison of 3 ECGI parameters (A through C) between controls and cardiac amyloidosis patients (ie, AL+ATTR patients, left) and cardiac AL and ATTR patients (right). Central line is the median, the edges of the box are the first (Q1) and third (Q3) quartiles, and the whiskers extend to the most extreme data points not considered outliers. P‐values are reported on top of the horizontal lines. AL indicates light‐chain amyloidosis; Amp, epicardial signal amplitude; ATTR, transthyretin amyloidosis; Frac, maximum number of negative deflections in fractionated epicardial signals; ΔRT, dispersion of repolarization.

Figure 5

Correlations between ECGI (vertical axis) and CMR (horizontal axis) parameters, where ρ indicates the correlation coefficient. A, Signal amplitude (Amp) vs T1; (B) mean number of negative deflections (FracN) in fractionated QRS complexes vs extracellular volume (ECV); (C) mean repolarization time (RT) corrected for heart rate vs extracellular volume. CMR indicates cardiac magnetic resonance imaging; ECGI, ECG imaging.