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Hereditary transthyretin amyloidosis (ATTRv) is a multisystemic, rare, inherited, progressive and adult-onset disease, affecting the sensorimotor nerves, heart, autonomic function and other organs. The actual scenario of pharmaceutical approaches for ATTRv amyloidosis includes five main groups: TTR stabilizers, TTR mRNA silencers, TTR fibril disruptors, inhibitor of TTR fibril seeding and gene therapy. Patisiran is a small, double-stranded interfering RNA encapsulated in a lipid nanoparticle, able to penetrate into hepatocytes, where it selectively targets TTR mRNA, reducing TTR production. We report and discuss 9 cases of different patients with ATTRv amyloidosis successfully managed with patisiran in the real clinical practice. Literature data, as well as the above presented case reports, show that this drug is effective and safe in improving both neurological and cardiovascular symptoms of ATTRv amyloidosis, and to maintain a good QoL, independently form the stage of the disease and the involved mutation. Recent studies correlated improved functional and biochemical outcomes with a regression of amyloid burden, especially at the cardiac level. Today, patisiran can be considered a valid therapeutic option for the management of patients with ATTRv amyloidosis and polyneuropathy and cardiovascular symptoms.

Background Hereditary transthyretin amyloidosis (hATTR), alias ATTR variant (ATTRv) is a severe and disabling disease causing sensory and motor neuropathy, autonomic dysfunction, and cardiomyopathy. The progressive decline of patient’s functional autonomy negatively affects the patient’s quality of life and requires increasing involvement of relatives in the patient’s daily life. Family caregiving may become particularly demanding when the patient is no longer able to move independently. This study is focused on the psychosocial aspects of ATTRv from the patient and relative perspectives. In particular, it explored: the practical and psychological burdens experienced by symptomatic patients with ATTRv and their key relatives and the professional and social network support they may rely on; whether burden varied in relation to patients’ and relatives’ socio-demographic variables, patients’ clinical variables, and perceived professional and social network support; and, any difference in burden and support between patients and their matched relatives. Methods The study was carried out on symptomatic patients included in the ATTRv Italian national registry and living with at least one adult relative not suffering from severe illness and being free from ATTRv symptoms. Patients and relatives’ assessments were performed using validated self-reported tools. Results Overall, 141 patients and 69 relatives were evaluated. Constraints of leisure activities, feelings of loss and worries for the future were the consequences of ATTRv most frequently reported by patients and relatives. Both in patients and their relatives, the burden increased with the duration of symptoms and the level of help in daily activities needed by the patient. In the 69 matched patient-relative pairs, the practical burden was significantly higher among the patients than among their relatives, while the psychological burden was similar in the two groups. Moreover, compared to their relatives, patients with ATTRv reported higher levels of professional and social network support. Conclusions These results show that ATTRv is a disease affecting quality of life of both patients and their families. Supporting interventions should be guaranteed to patients, to facilitate their adaptation to the disease, and to their families, to cope as best as possible with the difficulties that this pathology may involve.

CardioPulmonary Exercise Test (CPET) is the gold standard to evaluate functional capacity in patients at high risk of heart failure (HF). Few studies with a limited number of subjects and conflicting results, analyzed the role of CPET in patients with systemic amyloidosis. Aims of our study were the assessment of the response to exercise in patients with Transthyretin amyloid (ATTR) cardiomyopathy (CA), and the correlation of clinical, biohumoral and echocardiographic parameters with CPET parameters, such as VO2 peak and VE/VCO2 slope. From February 2018 to March 2019, 72 cardiac ATTR patients were prospectively enrolled and underwent a complete clinical, biohumoral, echocardiographic and CPET assessment. All patients completed the exercise stress test protocol, without any adverse event. At CPET, they achieved a mean VO2 peak of 14 mL/Kg/min and a mean VE/VCO2 slope of 31. The blood pressure response to exercise was inadequate in 26 (36%) patients (flat in 25 and hypotensive in 1), while 49/72 patients (69%) showed an inadequate heart rate recovery. In multivariate analysis, s’ tricuspidalic was the only independent predictor of VO2 peak, while in the two test models performed to avoid collinearity, both TAPSE and s’ tricuspidalic were the strongest independent predictors of VE/VCO2 slope. Our data demonstrate the role of right ventricular function as an independent predictor of exercise capacity and ventilatory efficiency in ATTR. In CPET evaluation, a significant proportion of patients presented an abnormal arterial pressure response and heart rate variation to exercise.

Coding mutations in TTR gene cause a rare hereditary form of systemic amyloidosis, which has a complex genotype-phenotype correlation. We investigated the role of non-coding variants in regulating TTR gene expression and consequently amyloidosis symptoms. We evaluated the genotype-phenotype correlation considering the clinical information of 129 Italian patients with TTR amyloidosis. Then, we conducted a re-sequencing of TTR gene to investigate how non-coding variants affect TTR expression and, consequently, phenotypic presentation in carriers of amyloidogenic mutations. Polygenic scores for genetically determined TTR expression were constructed using data from our re-sequencing analysis and the GTEx (Genotype-Tissue Expression) project. We confirmed a strong phenotypic heterogeneity across coding mutations causing TTR amyloidosis. Considering the effects of non-coding variants on TTR expression, we identified three patient clusters with specific expression patterns associated with certain phenotypic presentations, including late onset, autonomic neurological involvement, and gastrointestinal symptoms. This study provides novel data regarding the role of non-coding variation and the gene expression profiles in patients affected by TTR amyloidosis, also putting forth an approach that could be used to investigate the mechanisms at the basis of the genotype-phenotype correlation of the disease.

Aims The use of beta‐blocker therapy in cardiac amyloidosis (CA) is debated. We aimed at describing patterns of beta‐blocker prescription through a nationwide survey. Methods and results From 11 referral centres, we retrospectively collected data of CA patients with a first evaluation after 2016 (n = 642). Clinical characteristics at first and last evaluation were collected, with a focus on medical therapy. For patients in whom beta‐blocker therapy was started, stopped, or continued between first and last evaluation, the main reason for beta‐blocker management was requested. Median age of study population was 77 years; 81% were men. Arterial hypertension was found in 58% of patients, atrial fibrillation (AF) in 57%, and coronary artery disease in 16%. Left ventricular ejection fraction was preserved in 62% of cases, and 74% of patients had advanced diastolic dysfunction. Out of the 250 CA patients on beta‐blockers at last evaluation, 215 (33%) were already taking this therapy at first evaluation, while 35 (5%) were started it, in both cases primarily because of high‐rate AF. One‐hundred‐nineteen patients (19%) who were on beta‐blocker at first evaluation had this therapy withdrawn, mainly because of intolerance in the presence of heart failure with advanced diastolic dysfunction. The remaining 273 patients (43%) had never received beta‐blocker therapy. Beta‐blockers usage was similar between CA aetiologies. Patients taking vs. not taking beta‐blockers differed only for a greater prevalence of arterial hypertension, coronary artery disease, AF, and non‐restrictive filling pattern (P < 0.01 for all) in the former group. Conclusions Beta‐blockers prescription is not infrequent in CA. Such therapy may be tolerated in the presence of co‐morbidities for which beta‐blockers are routinely used and in the absence of advanced diastolic dysfunction.

Cardiac amyloidosis (CA) is an infiltrative cardiomyopathy divided into two types: light-chain (LA) and transthyretin (ATTR) CA. Cardiac magnetic resonance (CMR) has emerged as an important diagnostic tool in CA. While late gadolinium enhancement (LGE), T1 mapping and extracellular volume (ECV) have a consolidate role in the assessment of CA, T2 mapping has been less often evaluated. We aimed to test the value of T2 mapping in the evaluation of CA. This study recruited 70 patients with CA (51 ATTR, 19 AL). All the subjects underwent 1.5 T CMR with T1 and T2 mapping and cine and LGE imaging. Their QALE scores were evaluated. The myocardial T2 values were significantly (p < 0.001) increased in both types of CA compared to the controls. In the AL-CA group, increased T2 values were associated with a higher QALE score. The myocardial native T1 values and ECV were significantly (p < 0.001) higher in the CA patients than in the healthy subjects. Left ventricular (LV) mass, QALE score and ECV were higher in ATTR amyloidosis compared with AL amyloidosis, while the LV ejection fraction was lower (p < 0.001). These results support the concept of the presence of myocardial edema in CA. Therefore, a CMR evaluation including not only myocardial T1 imaging but also myocardial T2 imaging allows for more comprehensive tissue characterization in CA.

Cardiac amyloidosis (CA), caused by the deposition of insoluble amyloid fibrils, impairs different cardiac structures, altering not only left ventricle (LV) systo-diastolic function but also atrial function and the conduction system. The consequences of the involvement of the cardiac electrical system deserve more attention, as well as the study of the underlying molecular mechanisms. This is an issue of considerable interest, given the conflicting data on the effectiveness of conventional antiarrhythmic strategies. Therefore, this review aims at summarizing the arrhythmic burden related to CA and the available evidence on antiarrhythmic treatment in this population.

Background Multiple myeloma (MM) is a malignant neoplasm associated with kidney involvement in nearly half of the patients. Cast nephropathy, monoclonal immunoglobulin deposition disease (MIDD), and light chain (AL) amyloidosis are the most common monoclonal immunoglobulin-mediated causes of renal injury. Cardiac involvement is also present in MM, characterized by restrictive cardiomyopathy generated by light chain deposit or amyloid. Thromboembolic complications such as deep vein thrombosis or pulmonary embolism are also described. Case presentation We present an unusual multidisciplinary case of a woman with a newly diagnosed MM associated with severe proteinuria and high natriuretic peptide. A renal and fat pad biopsy with Congo red staining were performed but amyloid deposition was not discovered. While immunofluorescence on fresh frozen unfixed tissue was not contributory, the immunofluorescence on fixed tissue and electron microscopy revealed the correct diagnosis. During subsequent investigations, two intracardiac right-sided masses and massive pulmonary embolism were also detected. Conclusions This case highlights that multiple organ involvement in patients with MM may result from a combination of paraprotein-dependent and -independent factors. Moreover, renal diseases induced by monoclonal gammopathies are a group of complex and heterogeneous disorders. Their subtle presentation and their potential multiorgan involvement require the expertise of a multidisciplinary team able to provide the most appropriate diagnostic and therapeutic assessment.

Abstract Aims This study aimed to evaluate the change of the main electrocardiographic (ECG) characteristics and their prognostic role across the main subtypes of cardiac amyloidosis [light-chain amyloidosis (AL) and hereditary (ATTRv) and wild-type transthyretin amyloidosis (ATTRwt)]. Methods and results This multicentre, retrospective study was performed in six referral centres for cardiac amyloidosis. Clinical and ECG data were collected at the first and last evaluations. Three hundred fifty-six patients were included (AL, n = 105; ATTRv, n = 50; ATTRwt, n = 201). The median age was 76 (67–81) years, and 271 (74%) were men. At baseline, patients with ATTRwt showed a higher prevalence of conduction abnormalities compared with those with AL [first-degree atrioventricular block, n = 51 (40%) vs. n = 13 (34%), P < 0.01; left bundle branch block, n = 23 (11%) vs. n = 2 (2%), P < 0.01], and patients with AL more often had low QRS voltage [n = 58 (55%); in ATTRv, n = 17 (34%); in ATTRwt, n = 67 (33%), P value < 0.01] and T wave inversion compared with those with ATTR [n = 39 (37%); in ATTRv, n = 9 (18%); in ATTRwt, n = 37 (18%)]. After a median follow-up of 15 (8–26) months, the adjusted differences in mean PR, QRS interval, total, peripheral, and precordial QRS scores were similar across subtypes of amyloidosis (P value for linear regression > 0.05). The adjusted odds ratios for the development of right bundle branch block were higher in AL compared with ATTRwt [odds ratio 4.7 (95% confidence interval 1.5–15), P < 0.05]. QRS duration at baseline remained independently associated with patient survival in the overall population even after adjustment for relevant clinical variables [hazard ratio 1.78 (95% confidence interval 1.13–2.8), P < 0.01]. Conclusions The progression of the ECG abnormalities seems similar across amyloidosis subtypes. QRS duration could be a marker of more advanced disease.

Orthopaedic manifestations of wild-type transthyretin amyloidosis are frequent and characteristic, including idiopathic bilateral carpal tunnel syndrome, idiopathic lumbar canal stenosis, atraumatic rupture of the brachial biceps tendon, and, more rarely, finger disease and rotator cuff. These manifestations often coexisting in the same patient, frequently male and aged, steadily precede cardiac involvement inducing a rapidly progressive heart failure with preserved ejection fraction. Although transthyretin cardiac amyloidosis remains a cardiac relevant disease, these extracardiac localisation may increase diagnostic suspicion and allow for early diagnosis assuming the role of useful diagnostic red flags, especially in light of new therapeutic opportunities that can slow or stop the progression of the disease. For the cardiologist, the recognition of these extracardiac red flags is of considerable importance to reinforce an otherwise less emerging diagnostic suspicion. For orthopedists and rheumatologists, the presence in an old patient with or without clinical manifestations of cardiovascular disease, of an unexpected and inexplicable constellation of musculoskeletal symptoms, can represent a fundamental moment for an early diagnosis and treatment is improving a patient’s outcome.