Left ventricular wall thickness and severity of cardiac disease in women and men with transthyretin amyloidosis.

AIMS: Cardiac amyloidosis (CA) is due to a deposition of amyloid fibrils in the heart causing an increase in wall thickness. A left ventricular (LV) wall thickness ≥12 mm plus at least one red flag should raise the suspicion of CA. As normal values of LV wall thickness are lower in women, the adoption or the same cut-off values for men and women could lead to underdiagnosis or delayed diagnosis in women. We investigated the relationship between LV wall thickness and the severity of cardiac involvement in women and men with transthyretin (ATTR) CA. METHODS AND RESULTS: We evaluated 330 consecutive patients diagnosed with ATTR-CA at three centres (Pisa, n = 232; Brescia, n = 69; Trieste, n = 29). Interventricular septum (IVS) and posterior wall (PW) thickness values were lower in women (n = 53, 16%) than men, but most differences were abolished when indexing by body surface area (BSA), height, or height2.7 , suggesting similar disease severity when accounting for the smaller body size of women. PW thickness indexed for height2.7 was even higher in women. We also searched for correlations between IVS and PW thickness and other indicators of the severity of cardiac disease. IVS values indexed by height2.7 displayed tighter associations with N-terminal pro-B-type natriuretic peptide values than non-indexed IVS values. Similarly, indexed values displayed closer relationships with relative wall thickness, E/e' ratio, and tricuspid annular plane systolic excursion. CONCLUSIONS: Indexed LV wall thickness values, particularly by height2.7 , reflect more accurately the severity of cardiac involvement than non-indexed values.

Evolving trends in epidemiology and natural history of cardiac amyloidosis: 30-year experience from a tertiary referral center for cardiomyopathies.

Objective: Natural history of cardiac amyloidosis (CA) is poorly understood. We aimed to examine the changing mortality of different types of CA over a 30-year period. Patients and methods: Consecutive patients included in the "Trieste CA Registry" from January 1, 1990 through December 31, 2021 were divided into a historical cohort (diagnosed before 2016) and a contemporary cohort (diagnosed after 2016). Light chain (AL), transthyretin (ATTR) and other forms of CA were defined according to international recommendations. The primary and secondary outcome measures were all-cause mortality and cardiac death, respectively. Results: We enrolled 182 patients: 47.3% AL-CA, 44.5% ATTR-CA, 8.2% other etiologies. The number of patients diagnosed with AL and ATTR-CA progressively increased over time, mostly ATTR-CA patients (from 21% before 2016 to 67% after 2016) diagnosed non-invasively. The more consistent increase in event-rate was observed in the long-term (after 50 months) in ATTR-CA compared to the early increase in mortality in AL-CA. In the contemporary cohort, during a median follow up of 16 [4-30] months, ATTR-CA was associated with improved overall and cardiac survival compared to AL-CA. At multivariable analysis, ATTR-CA (HR 0.42, p = 0.03), eGFR (HR 0.98, p = 0.033) and ACE-inhibitor therapy (HR 0.24, p < 0.001) predicted overall survival in the contemporary cohort. Conclusion: Incidence and prevalence rates of ATTR-CA and, to a less extent, of AL-CA have been increasing over time, with significant improvements in 2-year survival of ATTR-CA patients from the contemporary cohort. Reaching an early diagnosis and starting disease-modifying treatments will improve long-term survival in CA.

Re-Definition of the Epidemiology of Cardiac Amyloidosis.

The epidemiology of cardiac amyloidosis (CA), traditionally considered a rare and incurable disease, has changed drastically over the last ten years, particularly due to the advances in diagnostic methods and therapeutic options in the field of transthyretin CA (ATTR-CA). On the one hand, the possibility of employing cardiac scintigraphy with bone tracers to diagnose ATTR-CA without a biopsy has unveiled the real prevalence of the disease; on the other, the emergence of effective treatments, such as tafamidis, has rendered an early and accurate diagnosis critical. Interestingly, the following subgroups of patients have been found to have a higher prevalence of CA: elderly subjects > 75 years, patients with cardiac hypertrophy hospitalized for heart failure with preserved ejection fraction, subjects operated on for bilateral carpal tunnel syndrome, patients with cardiac hypertrophy not explained by concomitant factors and individuals with aortic valve stenosis. Many studies investigating the prevalence of CA in these particular populations have contributed to rewriting the epidemiology of the disease, increasing the awareness of the medical community for a previously underappreciated condition. In this review, we summarized the latest evidence on the epidemiology of CA according to the different clinical settings typically associated with the disease.

Incidence and risk factors for pacemaker implantation in light-chain and transthyretin cardiac amyloidosis.

AIMS: The incidence and risk factors of pacemaker (PM) implantation in patients with cardiac amyloidosis (CA) are largely unexplored. We sought to characterize the trends in the incidence of permanent PM and to identify baseline predictors of future PM implantation in light-chain (AL) and transthyretin (ATTR) CA. METHODS AND RESULTS: Consecutive patients with AL and ATTR-CA diagnosed at participating centres (2017-2020) were included. Clinical data recorded within ±1 month from diagnosis were collected from electronic medical records. The primary study outcome was the need for clinically-indicated PM implantation. Patients with PM (n = 41) and/or permanent defibrillator in situ (n = 13) at CA diagnosis were excluded. The study population consisted of 405 patients: 29.4% AL, 14.6% variant ATTR and 56% wild-type ATTR; 82.5% were male, median age 76 years. During a median follow-up of 33 months (interquartile range 21-46), 36 (8.9%) patients experienced the primary outcome: 10 AL-CA, 2 variant ATTR-CA and 24 wild-type ATTR-CA (p = 0.08 at time-to-event analysis). At multivariable analysis, history of atrial fibrillation (hazard ratio [HR] 3.80, p = 0.002), PR interval (HR 1.013, p = 0.002) and QRS >120 ms (HR 4.7, p = 0.001) on baseline electrocardiogram were independently associated with PM implantation. The absence of these three factors had a negative predictive value of 92% with an area under the curve of 91.8% at 6 months. CONCLUSION: In a large cohort of AL and ATTR-CA patients, 8.9% received a PM within 3 years after diagnosis. History of atrial fibrillation, PR >200 ms and QRS >120 ms predicted future PM implantation.

Unmasking the prevalence of amyloid cardiomyopathy in the real world: results from Phase 2 of the AC-TIVE study, an Italian nationwide survey.

AIM: To investigate the prevalence of amyloid cardiomyopathy (AC) and the diagnostic accuracy of echocardiographic red flags of AC among consecutive adult patients undergoing transthoracic echocardiogram for reason other than AC in 13 Italian institutions. METHODS AND RESULTS: This is an Italian prospective multicentre study, involving a clinical and instrumental work-up to assess AC prevalence among patients ≥55 years old with an echocardiogram suggestive of AC (i.e. at least one echocardiographic red flag of AC in hypertrophic, non-dilated left ventricles with preserved ejection fraction). The study was registered at ClinicalTrials.gov (NCT04738266). Overall, 381 patients with an echocardiogram suggestive of AC were identified among a cohort of 5315 screened subjects, and 217 patients completed the investigations. A final diagnosis of AC was made in 62 patients with an estimated prevalence of 29% (95% confidence interval 23%-35%). Transthyretin-related AC (ATTR-AC) was diagnosed in 51 and light chain-related AC (AL-AC) in 11 patients. Either apical sparing or a combination of ≥2 other echocardiographic red flags, excluding interatrial septum thickness, provided a diagnostic accuracy >70%. CONCLUSION: In a cohort of consecutive adults with echocardiographic findings suggestive of AC and preserved left ventricular ejection fraction, the prevalence of AC (either ATTR or AL) was 29%. Easily available echocardiographic red flags, when combined together, demonstrated good diagnostic accuracy.

Incidence and Characterization of Concealed Cardiac Amyloidosis Among Unselected Elderly Patients Undergoing Post-mortem Examination.

Background: The prevalence of cardiac amyloidosis (CA) is unknown. Aims and Methods: We sought to (a) determine the prevalence of CA in unselected patients ≥75 years undergoing autopsy, (b) characterize cardiological profiles of CA and non-CA patients by providing clinical-histological correlations, and (c) compare their cardiological profiles. After dedicated staining, the localization (interstitial or vascular) and the distribution (non-diffuse or diffuse) of amyloid deposition were analyzed. Cardiological data at last evaluation were retrospectively assessed for the presence of CA red-flags. Results: CA (50% light chains, 50% transthyretin) was found in 43% (n = 24/56) of the autopsied hearts. Atria were involved in 96% of cases. Amyloid localized both at the perivascular and interstitial levels (95.5 and 85%, respectively) with a slightly predominant non-diffuse distribution (58% of cases). Compared to the other patients, CA patients had a more frequent history of heart failure (HF) (79 vs. 47%, p = 0.014), advanced NYHA functional class (III-IV 25 vs. 6%, p = 0.047), atrial fibrillation (68 vs. 36%, p = 0.019), discrepancy between QRS voltage and left ventricular (LV) thickness (70 vs. 12%, p < 0.001), thicker LV walls (15 vs. 11 mm, p < 0.001), enlarged left atrium (49 vs. 42 mm, p = 0.019) and restrictive filling pattern (56 vs. 19%, p = 0.020). The presence of right ventricular amyloidosis seemed to identify hearts with a higher amyloid burden. Among the CA patients, >30% had ≥3 echocardiographic red-flags of disease. Conclusion: CA can be found in 43% of autopsied hearts from patients ≥75 years old, especially in patients with HF, LV hypertrophy and atrial fibrillation.

Prevalence and Evolution of Right Ventricular Dysfunction Among Different Genetic Backgrounds in Dilated Cardiomyopathy.

BACKGROUND: Titin (TTN)-related dilated cardiomyopathy (DCM) has a higher likelihood of left ventricular reverse remodelling compared with other genetic etiologies. No data regarding the evolution of right ventricular dysfunction (RVD) according to genetic background are available. METHODS: Consecutive 104 DCM patients with confirmed pathogenic genetic variants (51 TTN-related DCM; 53 other genetic DCM) and a control group of 139 patients with negative genetic testing and available follow-up data at 12-24 months were analysed. RVD was defined as a right ventricular fractional area change (RVFAC) < 35%. The main study end point was the comparison of the evolution of RVD and the change of RVFAC throughout the follow-up according to etiology. A composite of all-cause mortality and heart transplantation was included as outcome measure. RESULTS: At enrollment, RVD was present in 29.1% of genetically positive DCM without differences between genetic cohorts. At 14 months follow-up, 5.9% of TTN-related DCM patients vs 35.8% of other genetic DCM patients had residual RVD after treatment (P < 0.001). Accordingly, RVFAC significantly improved in the TTN-related DCM cohort and remained stably impaired in other genetic DCM patients. However, the evolution of RVD was similar between TTN-related DCM and patients without a genetic mutation. After adjusting for RVD at follow-up, no differences in the outcome measure were seen in the study cohorts. CONCLUSIONS: The evolution of RVD in DCM is heterogeneous in different genetic backgrounds. TTN-related DCM is associated with a higher chance of RVD recovery compared with other genetic etiologies.