Addressing Health Disparities—The Case for Variant Transthyretin Cardiac Amyloidosis Grows Stronger

Abstract

There has been a transformational change in understanding heart failure due to transthyretin cardiac amyloidosis (ATTR-CA). Previously considered a rare condition, the widespread adaptation of nuclear imaging to establish the diagnosis has led to the recognition that ATTR-CA is commonly encountered in clinical practice. Additionally, the advent of effective disease-modifying therapies that reduce morbidity and mortality among affected patients has afforded hope to those newly diagnosed. 1 Because these disease-modifying therapies are more effective when administered early in the course of the illness, before significant end-organ dysfunction has occurred, it is vital to facilitate early diagnosis.ATTR-CA results from misfolded transthyretin (TTR) protein and is associated with advancing age (typical onset at age >60 years). Mechanisms underlying misfolding of TTR are incompletely understood, but the process is accelerated by inherited variants of the TTR gene. Accordingly, ATTR-CA is subclassified by the genetic sequence of TTR into (1) normal or wild-type gene sequence (termed ATTRwt-CA, formerly termed senile cardiac amyloidosis) or (2) variant gene sequence (ATTRv-CA) associated with a single nucleotide change that results in an amino acid substitution that destabilizes TTR and induces misfolding. The most common TTR variant in the US is V142I (also known as Val122Ile or V122I under legacy nomenclature), observed in 3.4% of individuals in the US who selfidentify as Black, or approximately 1.5 million people (across all age groups). 1 While larger-scale studies have individually demonstrated an association of the allele with an increased risk for heart failure 2 and reduced survival, 3 analyses examining the association of the cardiac structural changes characteristic of ATTR-CA with observed adverse outcomes have estimated a low clinical penetrance of disease (based on echocardiographic parameters) and no association with mortality. 4 That said, most prior studies were limited by relatively small numbers of V142I carriers, among whom those that survived to advanced age were primarily women. This is an important limitation because observations from large amyloidosis referral programs have demonstrated earlier phenotypic expression of V142I in males and a more severe phenotype. 5 The current study by Selvaraj et al 6 adds meaningfully to knowledge regarding the impact of V142I in the US population.