An increasing awareness of the disease, new diagnostic tools and novel therapeutic opportunities have dramatically changed the management of patients with amyloid transthyretin cardiomyopathy (ATTR-CM). Supportive therapies have shown limited benefits, mostly related to diuretics for the relief from signs and symptoms of congestion in patients presenting heart failure (HF). On the other hand, huge advances in specific (disease-modifying) treatments occurred in the last years. Therapies targeting the amyloidogenic cascade include several pharmacological agents that inhibit hepatic synthesis of TTR, stabilize the tetramer, or disrupt fibrils. Tafamidis, a TTR stabilizer that demonstrated to prolong survival and improve quality of life in the ATTR-ACT trial, is currently the only approved drug for patients with ATTR-CM. The small interfering RNA (siRNA) patisiran and the antisense oligonucleotide (ASO) inotersen have been approved for the treatment of patients with hereditary ATTR polyneuropathy regardless of the presence of cardiac involvement, with patisiran also showing preliminary benefits on the cardiac phenotype. Ongoing phase III clinical trials are investigating another siRNA, vutrisiran, and a novel ASO formulation, eplontersen, in patients with ATTR-CM. CRISPR–Cas9 represents a promising strategy of genome editing to obtain a highly effective blockade of TTR gene expression.

The aorta and aortic wall have a complex biological system of structural, biochemical, biomolecular, and hemodynamic elements. Arterial stiffness could be considered a manifestation of wall structural and functional variations, and it has been revealed to have a strong connection with aortopathies and be a predictor of cardiovascular risk, especially in patients affected by hypertension, diabetes mellitus, and nephropathy. Stiffness affects the function of different organs, especially the brain, kidneys, and heart, promoting remodeling of small arteries and endothelial dysfunction. This parameter could be easily evaluated using different methods, but pulse-wave velocity (PWV), the speed of transmission of arterial pressure waves, is considered the gold standard for a good and precise assessment. An increased PWV value indicates an elevated level of aortic stiffness because of the decline in elastin synthesis and activation of proteolysis and the increase in fibrosis that contributes to parietal rigidity. Higher values of PWV could also be found in some genetic diseases, such as Marfan syndrome (MFS) or Loeys-Dietz syndrome (LDS). Aortic stiffness has emerged as a major new cardiovascular disease (CVD) risk factor, and its evaluation using PWV could be very useful to identify patients with a high cardiovascular risk, giving some important prognostic information but also being used to value the benefits of therapeutic strategies.

Background Echocardiographic reference values for interventricular septal (IVS) thickness (upper reference limit [URL] 11.2 mm in women vs. 12.4 mm in men), and posterior wall (PW) thickness (URL 11.5 mm vs. 12.3 mm, respectively) exist. According to a European Society of Cardiology position statement, cardiac amyloidosis (CA) should be suspected when left ventricular (LV) wall thickness is ≥12 mm and at least one red flag is present. Given the normal difference between men and women, a same cut–off might cause a diagnostic delay in women. Methods Consecutive patients diagnosed with amyloid transthyretin (ATTR)–CA at 3 centers were evaluated. Results The cohort included 302 patients (Pisa, n=215; Brescia, n=58; Trieste, n=29). Women (n=49, 16%) were older than men (median age 83 years [interquartile range 80–85] vs. 80 years [76–84], p=0.009), but their survival free from all–cause death (p=0.380) or heart failure (HF) hospitalization (p=0.381) did not differ significantly. N–terminal pro–B–type natriuretic peptide values (p=0.897), the proportion of patients with variant ATTR (p=0.369), the prevalence of hypertension (p=0.659), diabetes (p=0.629), or New York Heart Association class III–IV (p=0.613) were not different. LV ejection fraction was 53% (43–60%) in women vs. 50% (43–65%) in men (p=0.066), and tricuspid annular plane systolic excursion was 16 mm (13–20) in women vs. 16 mm (14–19) in men (p=0.674). Even relative wall thickness (RWT) did not differ significantly (0.61 [0.49–0.98] in women vs. 0.69 [0.57–0.87] in men; p=0.448). Conversely, women had lower IVS (15 mm [14–18] vs. 17 mm [15–20]) and PW thickness (13 mm [12–16] vs. 15 mm [13–17]). These differences disappeared when IVS and PW thicknesses were indexed for height (as m), height2,7, or body surface area: IVS, p=0.150, 0.212, 0.325, respectively; PW, p=0.309, 0.107, 0.743, respectively. Conclusions At the time of diagnosis, women with ATTR–CA are older, but their biventricular function, the pattern of LV remodeling, and final outcome did not differ significantly from men, suggesting a similar disease stage. Even indexed IVS or PW thicknesses are similar, while non–indexed measures may point to a less advanced disease and then be misleading. Indexed measures or sex–specific cut–offs (e.g., 11 mm in women vs. 12 mm in men) to suspect CA might be considered.