Transthyretin amyloid cardiomyopathy in women: frequency, characteristics, and diagnostic challenges

Abstract

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, life-threatening disease characterized by deposition of insoluble amyloid fibrils in the myocardium, resulting in cardiac structural and functional abnormalities and ultimately heart failure. Disease frequency is reportedly lower in women than men, but sex-related differences have not been well established. We conducted a systematic literature review (SLR), based on PRISMA-P guidelines and registered with PROSPERO, to assess whether the epidemiology and clinical presentation of ATTR-CM differ between women and men. MEDLINE, Embase, and Cochrane databases and selected conference proceedings were searched (August 16, 2019) to identify observational and clinical studies reporting sex-specific data for patients with wild-type or hereditary ATTR-CM. Of 193 publications satisfying final eligibility criteria, 69 studies were included in our pooled analysis. Among the 4669 patients with ATTR-CM analyzed, 791 (17%) were women, including 174 (9%), 366 (29%), and 251 (18%) in studies of wild-type, hereditary, and undefined ATTR-CM, respectively. Data available on disease characteristics were limited and very heterogeneous, but trends suggested some cardiac structural/functional differences, i.e., lower interventricular septal and posterior wall thickness and left ventricular (LV) end diastolic diameter, and higher LV ejection fractions, in women versus men across ATTR-CM subtypes. Because LV wall thickness > 12 mm is generally the suggested threshold for ATTR-CM diagnosis in both sexes, smaller cardiac anatomy in women with the disease may lead to underdiagnosis. Additional research and studies are needed to elucidate potential disparities between sexes in ATTR-CM frequency, clinical characteristics, and underlying biological mechanisms. This study was registered within the International Prospective Register of Systematic Reviews (PROSPERO) database of the University of York (CRD42019146995).

Estimating the Gender Distribution of Patients with Wild-Type Transthyretin Amyloid Cardiomyopathy: A Systematic Review and Meta-Analysis

“…In cardiovascular disease, certain female sex hormones, particularly estrogen, could be cardioprotective [ 68 ]. However, similar guidelines for the identification of ATTR-CM for both sexes (LV wall thickness > 12 mm) but larger cardiac anatomy in males compared to females may result in disease underdiagnosis of the latter as they are less likely to meet this threshold [ 69 ]. Other studies suggest ATTRwt may manifest differently in female patients resulting in more atypical symptoms compared to men [ 70 , 71 ] which may pose additional diagnostic challenges.…”

“…Therefore, both the older age of presentation and milder symptoms in female patients would contribute jointly to lower diagnosis rates. Literature suggests that gender imbalances are common in ATTR-CM [ 69 ]. Increasing the awareness of these factors among clinicians, in particular, implementing non-invasive techniques such as nuclear scintigraphy, could potentially increase the diagnosis among women if currently underdiagnosed [ 72 ].…”

Drug Discovery and Development in Rare Diseases: Taking a Closer Look at the Tafamidis Story

“… 17 , 43 The expectancy that ATTR-CM predominantly occurs in men may reduce clinicians’ suspicion of the disease in women. In a recent literature review, 44 among over 4500 patients with ATTR-CM, 17% were women; the proportions of women with variant ATTR-CM (29%) and undefined disease (18%) were higher than that of women with wild-type ATTR-CM (9%). Importantly, in the referenced review, some cardiac structural/functional differences, including lower interventricular septal and posterior wall thickness and higher left ventricular ejection fractions, were observed in women versus men across all ATTR-CM subtypes.…”

Transthyretin: From Structural Stability to Osteoarticular and Cardiovascular Diseases

“…The involvement of TTR in osteoarticular disorders is an indirect indication of TTR involvement in calcification occurring in cardiovascular disease. Osteoarticular/ligament disorders precede or coincide with ATTR CA, which is associated with aortic and/or valve stenosis caused by calcification [ 127 , 146 , 147 ].…”

“…An increase in the oxidized form of TTR was observed and is correlated with arterial stiffness and cardiovascular risk in T2DM patients [ 151 ]. Additionally, in ATTR CA, a decrease in the plasma concentration or stability of TTR is associated with shorter survival [ 147 , 152 ]. Low molecular weight stabilizers (tafamidis, AG-10) bind TTR and reduce mortality, restore plasma levels, and/or improve the outcome of ATTR CA patients [ 147 , 153 ].…”