Pressure-volume relationships in patients with transthyretin (ATTR) cardiac amyloidosis secondary to V122I mutations and wild-type transthyretin: Transthyretin Cardiac Amyloid Study (TRACS)

Abstract

Background: ATTR cardiac amyloidosis can result from a mutated variant of transthyretin (eg, V122I) or wild-type variant (ATTRwt). We evaluated pressure-volume (PV) indices at baseline and over time to further characterize abnormal pump function in these subjects.

Methods and results: Twenty-nine subjects (18 with ATTRwt and 11 with ATTRm (V122I) had 2-dimensional echocardiograms with complete Doppler measures at baseline and every 6 months for up to 2 years. PV indices were derived from echocardiographic measures of ventricular volume coupled with sphygmomanometer-measured pressure and Doppler estimates of filling pressure. The end-systolic and end-diastolic PV relations and the area between them as a function of end-diastolic pressure, the isovolumic PV area (PVA(iso)), were calculated. Clinical, demographic, and PV indices were compared between V122I and ATTRwt subjects and between survivors and nonsurvivors at baseline and over time. Cox proportional hazards model identified correlates for mortality. Stroke volume decline was associated with alterations in ventricular-vascular coupling and a decrease in ventricular capacitance with significant decrement in ejection fraction (56±12% to 48±14%, P=0.0001) over 18 months. PVA(iso) was lower in V122I subjects compared with wild-type at baseline and declined over time. Twelve (41%) subjects died or underwent a cardiac transplant after a mean follow-up of 478 days (range, 31 to 807). Multivariable survival analysis demonstrated that initial ejection fraction (a measure of ventricular-vascular coupling) <50% was associated with increased mortality (hazard ratio, 6.6; 95% confidence interval, 1.1 to 40.3).

Conclusions: In ATTR cardiac amyloidosis secondary to a V122I mutation and wild-type transthyretin, PV analysis reveals alterations that are associated with reductions in the ability of the ventricle to perform work and, ultimately, with reduced survival in these subjects.

Figures

Figure 1

Changes in echocardiographic and pressure-volume parameters. Mean changes with standard error for each parameter are shown stratified by V122I and wild-type disease. There are significant changes in EF, stroke volume, TPR, Ea, and Res in the overall group at various time points compared with baseline (noted with asterisk for wild-type and cross for V122I above time point) as determined by the generalized estimating equation (see Methods).

Figure 2

Pressure-volume relations (top) and isovolumetric pressure-volume area (PVA-iso, bottom). Baseline to 18-month follow-up (left) and V122I versus wild-type at baseline (right). There were significant (eg, P < 0.05) increases in Ea, declines in Res, and altered Ea/Res ratio from baseline to 18 months (left) and differences in baseline in Ea and Ea/Res ratio between wild-type and V122I (right). In addition, significant differences in PVA-iso curves were noted for both comparisons. See text for details.

Figure 3

Kaplan–Meier survival curve stratified by the presence of a normal (eg, EF ≥50%) or reduced (