Valvular heart disease in transthyretin cardiac amyloidosis
Authors: Sarrazyn C , Debonnaire P , Graziani F , Donal E , Pinto F J , Droogmans S , Van De Veire N , Bertrand P , Sia C H , Ng A , Jurcut R O , Nabeta T , Van De Heyning C , Bax J J , Ajmone Marsan N 
Published: January 2025

Abstract

Introduction
Amyloidosis cardiomyopathy (CM) is known to be associated with valvular heart disease (VHD) and particularly with aortic stenosis (AS). However, previous studies included both immunoglobulin light-chain CM and transthyretin amyloid CM (ATTR-CM), with limited data focussing specifically on ATTR-CM. Furthermore, VHD assessment was mostly limited to isolated significant VHD, and the difference in outcome between isolated and multiple VHD is largely unknown.

Aim
To evaluate the prevalence and prognostic value of significant VHD in ATTR-CM patients, including the differences in outcome between isolated and multiple significant VHD, with or without AS.

Methods
Patients with ATTR-CM were retrospectively included in this multicentric study. Significant VHD was defined as at least moderate VHD. The study endpoint was a composite of heart failure hospitalisations and all-cause death.

Results
A total of 694 ATTR-CM patients (mean age 75 ±13 years, 74% male) were included, and 302 (44%) presented with significant VHD (Figure 1). These patients were older (81±9 vs. 71±13, p&lt;0. 001), had more cardiovascular risk factors, lower left ventricular ejection fraction (50±12 vs. 54±12, p&lt;0.001) and more pulmonary arterial hypertension (76% vs. 45%, p&lt;0.001), as compared to patients without significant VHD. Among patients with significant VHD, only 98 patients had VHD including AS (isolated AS in 45%; multiple VHD with AS in 55%), while the majority (n=204) had VHD without AS (isolated in 64%, multiple VHD in 36%) (Figure 1). During a median follow-up of 16 (6 - 33) months, 214 (31%) patients reached the study endpoint. Univariable Cox regression analysis identified significant VHD as a predictor of worse outcomes (HR: 3.486; 95% CI: 2.627 - 4.626; p &lt; 0.001), which remained significant in the multivariable Cox regression analysis (HR: 1.879;95%CI:1.182 - 2.987;p=0.008), after adjusting for transthyretin amyloid cardiomyopathy phenotype, disease-modifying treatment, coronary artery disease, atrial fibrillation, renal function, New York Heart Association III-IV, polyneuropathy, electrocardiographic abnormalities, left ventricular stroke volume, interventricular septum thickness, left atrial dilatation, tricuspid annular plane systolic excursion, and arterial pulmonary hypertension(Figure2). Further stratification based on the presence of significant AS, and according to isolated or multiple VHD, revealed that patients isolated significant AS (HR:2.399;95%CI 1.179 – 4.884;p=0.016), and patients with multiple VHD including significant AS, had the highest risk for adverse outcomes (HR:3.542; 95%CI: 1.809 - 6.935;p&lt;0.001)(Figure 2).

Conclusion
In ATTR-CM, significant VHD is strongly associated with poor prognosis, with the highest risk for adverse events in patients with significant multiple VHD including AS. These findings underscore the importance of VHD assessment for risk stratification and possibly targeted treatment in this patient population.
The distribution of significant VHD.