Abstract Background Electrocardiographic (ECG) abnormalities are common in patients presenting with Light-Chain (AL) or Transthyretin (ATTR) related Cardiac Amyloidosis (CA). Type of amyloid may differently affect electrical properties of the heart being responsible for variable patterns of ECG anomalies at presentation. Purpose In this retrospective, observational study we sought to compare prevalence of ECG abnormalities between AL and ATTR patients with CA. Methods Clinical files from two Referral Centres were reviewed; ECG recordings were analysed by trained cardiologists and relevant findings were reported about rhythm (sinus vs atrial fibrillation [AF]), grade I or grade II atrio-ventricular (AV) delays, intra-ventricular (IV) conduction abnormalities, low-voltage QRS and pseudo-necrosis pattern. Presence of pace-maker (PM) and stimulated QRS were regarded to as clinical equivalents for AV block, after review of indications to implantation. Results Two hundred and fifty-one patients were identified (127 ATTR vs 124 AL; among ATTR, 27 patients had mutation in TTR gene: 10 Val142Ile, 11 Ile88Leu, 6 other). As expected, most ATTR patients were male (89% vs 56% in AL, p: <0.001), and AL patients were younger (mean age 64 [53–70] vs 79 [73–83]; p: <0.001). Pathological ECG findings were common in both subgroups, involving more than three-quarters of the overall population (82% in ATTR, vs 72% in AL, p: 0.06). Atrial fibrillation was more common in ATTR, prevailing in 39% vs 5.6% (p: <0.001). ATTR had a higher burden of AV block (53% vs 13%, p: <0.001) and IV conduction delays (43% vs 21%, p: <0.001), and consistently presented a higher prevalence of PMs (24 patients vs 1). Low-voltage QRS was more prevalent in AL patients (52% vs 28%, p: <0.001), while no significant difference was found in prevalence of pseudo-necrosis patterns (ATTR: 29%, AL: 40%; p: ns). Due to imbalance in age and gender and relative possible confounding effect on rhythm disturbances, adjusted odds ratios (OR) were calculated. It resulted that ATTR was independently associated with a higher prevalence of AF and AV conduction delays when compared to AL (adjusted OR: 4 [95% CI: 1.4–11.2], p: 0.008, and 6.2 [95% CI: 2.6–14.9], p: <0.001; respectively), while being inversely associated with low-voltage QRS (adjusted OR: 0.4 [95% CI: 0.2–0.9], p: 0.026). Conclusions ECG abnormalities are common in CA. Rhythm disturbances are more prevalent in ATTR, while AL more often results in low-voltage QRS. Such differences remain relevant after adjustment for age and gender imbalance, thus suggesting an aetiology-specific link.

Abstract Background Left atrial function (AEF) is a parameter of paramount importance that has a prognostic value in a number of heart conditions. Cardiac involvement in both light-chain and transthyretin amyloidosis is the main driver of prognosis and influences treatment strategies. Cardiac magnetic resonance (CMR) provides high quality images of the left and right atria using high temporal resolution steady state free precession (SSFP) cine sequences. Purpose The aim of our study was to assess by CMR left atrial function and his correlation with prognosis in patients with cardiac amyloidosis. Method We enrolled 80 consecutive patients with diagnosis of cardiac amyloidosis: 38 patients (47%) with light-chain and 42 patients (53%) with transthyretin one. CMR was performed using a 1.5-T scanner. In all subjects, the study of atria was obtained by acquiring cine steady-state free precession (SSFP). Left Atrial function was evaluated by the ratio between the maximum and the minimum LA volume. A median follow up of 937 days was performed and 36 patients (44%) died of cardiac causes. We evaluated cardiac death as endpoint. We split out all the patient in 4 different quartiles depending on left atrial function: in the first quartile patients with AEF≤14% that reflects severe atrial dysfunction, in the second quartile patients with AEF between 14 and 19%, in the third quartile patients with AEF between 19 and 36% and in the last one patients with AEF≥36% that represent patients with normal value of left atrial function. Results We found that CMR assessed left atrial function allowed to individuate and stratify the prognosis in patients with cardiac amyloidosis. The most effective parameter to evaluate cardiac death was left atrial function with a cut off ≤14% that could predict cardiac related mortality with the same accuracy in both light-chain and transthyretin amyloidosis patients. Kaplan Meier analysis showed that patients with AEF≤14% had a worse prognosis as compared to patient with AEF≥14% (log rank p. 0001). Furthermore patients with AEF≤14% have a cardiac death risk of 32% at 1 year and 61% at 3 years. Kaplan Meier analysis Conclusion Cardiac magnetic resonance is an imaging modality that allows to individuate with great accuracy left atrial function in patients with various heart conditions and especially cardiac amyloidosis. CMR left atrial function assessment clearly identifies a subgroup of cardiac amyloid patients with an increased risk of death.

Abstract Background Transthyretin amyloidosis is a life-threatening disorder caused by the deposition of TTR amyloid in various tissues and organs. The most common worldwide pathogenic variant with almost exclusive cardiac involvement is Val122Ile (rs76992529), with an allele frequency of 3.5% in the U.S. African-American population, but rare in Caucasians. Unexpectedly, we identified 23 Caucasian individuals with Val122Ile in our amyloidosis referral center (9 affected patients, 14 carriers), belonging to 9 unrelated families. Purpose To determine the ancestral origin of the Tuscan founder population of TTR Val122Ile carriers. Methods A total of 24 individuals were included in the analysis (our 23 probands and relatives from Val122Ile families and the Caucasian reference sample NA10851 (CEU – Utah resident with European ancestry). All samples were genotyped using the EUROFORGEN Global AIM-SNP array1, inclusive of 127 highly informative SNPs to infer genetic ancestry. We have performed a principal component analysis (PCA) of the 9 unrelated probands and NA10851, compared with the Phase 3 of the 1000 Genomes Project data, comprising 2504 unrelated individuals from >20 distinct populations.(Figure 1). Results As shown in Figure 1, all our samples but one (from Argentina) cluster very close to the super-cluster of European populations, and distant from the populations of African ancestry. The proband from Argentina and the Caucasian reference sample NA10851 cluster close to Mexicans and Peruvians, and the super-cluster of European populations, respectively, confirming the robustness of the analysis. Conclusion Based on this result, we can confidently conclude that our samples from Tuscan families in which the TTR Val122Ile variant segregates are of ancestral European origin, with no mixed African ancestry, implying that the same variant originated in Africans and Europeans independently and not as result of genetic admixture. These findings suggest the presence of a mutational hot spots in TTR, with potential impact on the epidemiology of amyloidosis worldwide. Acknowledgement/Funding The present study was supported by an Investigator-Initiated Research to Azienda Ospedaliero Universitaria Careggi from Pfizer Srl.