Standard Therapy in Cardiac Amyloidosis: What is Known, What is "Gray".

Amyloidosis is a systemic disease due to the accumulation of misfolded amyloid fibrils that damage the heart and worsen the prognosis. Heart failure (HF), a condition frequently linked with an advanced stage of this disease, is the most prevalent clinical manifestation that leads to its diagnosis. However, due to the growing awareness of the occurrence of cardiac amyloidosis (CA), it is now possible to perform an early diagnosis and have a positive impact on its natural course. This study aims to highlight the most compelling issues concerning patients' clinical management with HF and CA.

Natural history and clinical outcomes of patients with hypertrophic cardiomyopathy from thin filament mutations.

Hypertrophic cardiomyopathy (HCM) due to thick filament variants is more common; however, HCM due to thin filament variants (HCM-Thin) may be associated with a more malignant phenotype with an increased risk of sudden cardiac death. The aim of this study was to review all the published cases of HCM-Thin to better understand the natural history and clinical outcomes of this disease. A literature review of HCM-Thin identified 21 studies with a total of 177 patients that were suitable for analysis. There were three outcomes of interest, which included a heart failure composite, a ventricular arrhythmia composite and a heart failure and arrhythmia composite outcome. Kaplan-Meier (KM) survival analyses for freedom from each of the abovementioned composite outcomes were completed for the entire cohort and stratified by age of onset and sarcomeric variant. The heart failure composite occurred in 24 (13.6%) patients, the ventricular arrhythmia composite occurred in 30 patients (16.9%) and the combined heart failure and arrhythmia composite occurred in 50 patients (28.2%). In regard to left ventricular ejection fraction (LVEF), the majority of patients were preserved (LVEF > 50%) compared with mildly reduced (LVEF 41%-50%) and reduced (LVEF ≤ 40%) (respectively 26.6% vs. 0.6% vs. 3.4%). The median maximal left ventricular wall thickness (LVWT) was 19.0 mm [interquartile range (IQR) 5.3]. Only 10.7% of the cohort had evidence of left ventricular outflow tract (LVOT) obstruction. Those with paediatric-onset HCM had earlier onset and were at higher risk for each endpoint than their adult counterparts. When stratified by genetic variant, patients with TNNI3 and TPM1 were at a higher risk of the heart failure composite endpoint and the combined heart failure and arrhythmia composite endpoint in comparison with those with the other genetic variants. HCM-Thin is associated with significant morbidity and mortality, with a high arrhythmia burden despite low rates of cardiac obstruction and mild hypertrophy. The paediatric onset of disease and certain sarcomeric variants appear to be associated with a worse prognosis than their adult-onset and other sarcomeric variant counterparts. HCM-Thin seems to have a distinct phenotype, which may require a different management approach.

Screening for cardiac amyloidosis in patients with tenosynovial red flags: A collaboration between family medicine and cardiology.

BACKGROUND: Amyloid deposition in tenosynovial structures precedes cardiac involvement up to 20 years. Therefore, a cardiological screening in patients with a history of tenosynovial manifestations of cardiac amyloidosis (CA) could lead to an increased number of early diagnoses. METHODS: Patients with tenosynovial manifestations of CA (carpal tunnel syndrome, atraumatic biceps tendon rupture, lumbar spinal stenosis) have been identified by general practitioners and evaluated in a Referral Center for CA. Patients with a high suspicion of CA underwent the CA diagnostic pathway. RESULTS: Among 50 General Practitioners (GP) contacted, 10 (20%) agreed to participate in the study for a total of 5615 patients ≥60 years. One hundred forty-five patients met the inclusion criteria, 2 of them already had a diagnosis of CA, and 57 agreed to undergo a cardiological evaluation (electrocardiography, echocardiography, NTproBNP assay). The median age was 73 [67-80] years and 31 (54%) were women. Eight patients were suggested to start the CA diagnostic pathway, five of them underwent a complete diagnostic evaluation for CA, three refused to complete the diagnostic exams and no new diagnoses were made. CONCLUSION: A screening program for CA in patients with tenosynovial manifestations identified by general practitioners is feasible, but may not yield a high rate of new diagnosis. In this study, we identified two patients who already had a diagnosis of CA, and among patients at high risk for CA, 37% refused to complete the diagnostic pathway. Increased awareness of CA among patients might increase participation and diagnostic yield in screening studies. Further validation of this protocol is needed to evaluate its diagnostic performance.

Determinants of health status in older patients with transthyretin cardiac amyloidosis: a prospective cohort study.

BACKGROUND: Whether, and to what extent, frailty and other geriatric domains are linked to health status in patients with transthyretin cardiac amyloidosis (ATTR-CA) is unknown. AIMS: To determine the association of frailty with health status [defined by the Kansas City Cardiomyopathy Questionnaire (KCCQ)] in patients with ATTR-CA. METHODS: Consecutive ATTR-CA patients undergoing cardiovascular assessment at a tertiary care clinic from September 2021 to September 2023 were invited to participate. KCCQ, frailty and social environment were recorded. Frailty was assessed using the modified Frailty Index (mFI), mapping 11 variables from the Canadian Study of Health and Aging (frailty ≥0.36). RESULTS: Of 168 screened ATTR-CA patients, 138 [83% men, median age of 79 (75-84) years] were enrolled in the study. Median KCCQ was 66 (50-75). wtATTR-CA was the most prevalent form (N = 113, 81.9%). The most frequent cardiac variant was Ile68Leu (17/25 individuals with vATTR-CA). Twenty (14.5%) patients were considered frail, and prevalence of overt disability was 6.5%. At multivariable linear regression analysis, factors associated with worsening KCCQ were age at evaluation, the mFI, NYHA Class, and NAC Score. Gender, ATTR-CA type, phenotype, and LVEF were not associated with health status. DISCUSSION: In older patients diagnosed with ATTR-CA, frailty, symptoms, and disease severity were associated with KCCQ. CONCLUSIONS: Functional status is a determinant of quality of life and health status in older individuals with a main diagnosis of ATTR-CA. Future research may provide more in-depth knowledge on the association of frailty in patients with ATTR-CA with respect to quality of life and prognosis.

Patient-reported outcome measures for transthyretin cardiac amyloidosis: the ITALY study.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR-CA) has a deep impact on the quality of life (QoL), yet no specific patient-reported outcome measures (PROMs) for ATTR-CA exist. METHODS: The ITALY study involved 5 Italian referral centres (Pisa, Pavia, Ferrara, Florence, Messina) enrolling consecutive outpatients with ATTR-CA. RESULTS: Two 30-item questionnaires were created for wild-type (wt) and variant (v) ATTR-CA. Scores ranged from 100 (best condition) to 0 (worst condition). Out of 140 patients enrolled (77% with ATTRwt-CA), 115 repeated the re-evaluation at 6 months. At baseline, only 30% of patients needed help to fill out the questionnaires. Among baseline variables, all KCCQ and SF-36 domains were univariate predictors of ITALY scores in ATTRwt-CA patients, with the KCCQ Symptom Summary score (beta coefficient 0.759), Social Limitations (0.781), and Overall summary score (0.786) being the strongest predictors. The SF-36 Emotional well-being score (0.608), the KCCQ Overall summary score (0.656), and the SF-36 Energy/fatigue score (0.669) were the strongest univariate predictors of ITALY scores in ATTRv-CA. Similar results were found at 6 months. CONCLUSIONS: The ITALY questionnaires are the first specific PROMs for ATTRwt- and ATTRv-CA. Questionnaire completion is feasible. ITALY scores display close relationships with non-ATTR-specific measures of QoL.

Applications of Gene Therapy in Cardiomyopathies.

Gene therapy is defined by the introduction of new genes or the genetic modification of existing genes and/or their regulatory portions via gene replacement and gene editing strategies, respectively. The genetic material is usually delivered though cardiotropic vectors such as adeno-associated virus 9 or engineered capsids. The enthusiasm for gene therapy has been hampered somewhat by adverse events observed in clinical trials, including dose-dependent immunologic reactions such as hepatotoxicity, acquired hemolytic uremic syndrome and myocarditis. Notably, gene therapy for Duchenne muscular dystrophy has recently been approved and pivotal clinical trials are testing gene therapy approaches in rare myocardial conditions such as Danon disease and Fabry disease. Furthermore, promising results have been shown in animal models of gene therapy in hypertrophic cardiomyopathy and arrhythmogenic cardiomyopathy. This review summarizes the gene therapy techniques, the toxicity risk associated with adeno-associated virus delivery, the ongoing clinical trials, and future targets.

Serial Changes in Cardiopulmonary Exercise Testing Parameters in Untreated Patients With Transthyretin Cardiac Amyloidosis.

BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM) is associated with a progressive reduction of functional capacity. The progression of cardiopulmonary exercise testing (CPET) parameters over time is still unknown. METHODS: In this study, 55 patients with ATTR-CM underwent 2 serial cardiologic evaluations and CPETs in a national referral center for cardiac amyloidosis (Careggi University Hospital, Florence). RESULTS: Forty-three patients (78%) had wild-type ATTR. Median age was 80 years (interquartile range [IQR] 76-83 years), and 50 of the patients (91%) were men. At baseline, median peak oxygen consumption (pVO2) was 15 mL/kg/min (IQR 12-18 mL/kg/min), percentage of predicted pVO2 (%ppVO2) was 71% (IQR 60%-83%) and VE/VCO2 slope was 31 (IQR 26-34). After a median follow-up of 14 months (IQR 13-16 months), pVO2, %ppVO2 and VE/VCO2 slope were significantly worsened (-1.29 mL/kg/min [95% confidence interval (CI): -1.85 to -0.74; P < 0.01], -4.5% [95% CI: -6.9 to -2.02; P < 0.01], and 8.6 [95% CI 6-11; P < 0.01], respectively). Furthermore, exercise time (-39 s, 95% CI: -59 to -19; P < 0.01), exercise tolerance (-0.47 metabolic equivalents, 95% CI: -0.69 to -0.2; P < 0.01), and peak systolic pressure (-10.8 mm Hg, 95% CI: -16.2 to -5.4; P < 0.01) were significantly reduced. The worsening in CPET variables did not correspond with a significant change in echocardiographic parameters. CONCLUSIONS: Cardiorespiratory response to exercise significantly worsened over a short period of time in patients with ATTR-CM. Serial CPET may be useful to identify early disease progression.

Electrocardiographic abnormalities in patients with cardiomyopathies.

Abnormalities in impulse generation and transmission are among the first signs of cardiac remodeling in cardiomyopathies. Accordingly, 12-lead electrocardiogram (ECG) of patients with cardiomyopathies may show multiple abnormalities. Some findings are suggestive of specific disorders, such as the discrepancy between QRS voltages and left ventricular (LV) mass for cardiac amyloidosis or the inverted T waves in the right precordial leads for arrhythmogenic cardiomyopathy. Other findings are less sensitive and/or specific, but may orient toward a specific diagnosis in a patient with a specific phenotype, such as an increased LV wall thickness or a dilated LV. A "cardiomyopathy-oriented" mindset to ECG reading is important to detect the possible signs of an underlying cardiomyopathy and to interpret correctly the meaning of these alterations, which differs in patients with cardiomyopathies or other conditions.

Gene therapy vector-related myocarditis.

Gene therapy is a technique to correct genetic abnormalities, through introduction of a functional gene or through direct genome editing. Adeno-associated virus (AAV)-mediated gene replacement shows promise for targeted therapies in treatment of inherited cardiomyopathies and is the most used approach in clinical trials. However, immune responses from the host to the virus and gene product pose delivery and safety challenges. This review explores the immunological reactions to AAV-based gene therapy, their potential toxic effects, with a focus on myocarditis, and future directions for gene therapy.

Incidence and determinants of atrial fibrillation in patients with wild-type transthyretin cardiac amyloidosis.

BACKGROUND: Data on the incidence and factors associated with de novo atrial fibrillation (AF) in patients with wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is limited. We described the incidence and factors associated with de novo AF in patients diagnosed with ATTRwt-CA to drive tailored arrhythmia screening. METHODS: Multicenter, retrospective, observational cohort study performed in six referral centers for CA. All consecutive patients diagnosed with ATTRwt-CA between 2004 and 2020 with >6-month follow up (FU) were enrolled and divided into three groups according to presence of AF: (1)patients with 'known AF'; (2)patients in 'sinus rhythm' and (3)patients developing 'de novo AF' during FU. Incidence and factors associated with AF in patients with ATTRwt were the primary outcomes. RESULTS: Overall, 266 patients were followed for a median of 19 [11-33] months: 148 (56%) with known AF, 84 (31.6%) with sinus rhythm, and 34 (12.8%) with de novo AF. At Fine-Gray competing risk analysis to account for mortality, PR (sub-distribution hazard ratio [SHR] per Δms: 1.008, 95% C.I. 1.001-1.013, p = 0.008), QRS (SHR per Δms: 1.012, 95% C.I. 1.001-1.022, p = 0.046) and left atrial diameter ≥ 50 mm (SHR: 2.815,95% C.I. 1.483-5.342, p = 0.002) were associated with de novo AF. Patients with at least two risk factors (PR ≥ 200 ms, QRS ≥ 120 ms or LAD≥50 mm) had a higher risk of developing de novo AF compared to patients with no risk factors (HR 14.918 95% C.I. 3.242-31.646, p = 0.008). CONCLUSIONS: At the end of the study almost 70% patients had AF. Longer PR and QRS duration and left atrial dilation are associated with arrhythmia onset.

Gene therapy for heart failure and cardiomyopathies.

Gene therapy strategies encompass a range of approaches, including gene replacement and gene editing. Gene replacement involves providing a functional copy of a modified gene, while gene editing allows for the correction of existing genetic mutations. Gene therapy has already received approval for treating genetic disorders like Leber's congenital amaurosis and spinal muscular atrophy. Currently, research is being conducted to explore its potential use in cardiology. This review aims to summarize the mechanisms behind different gene therapy strategies, the available delivery systems, the primary risks associated with gene therapy, ongoing clinical trials, and future targets, with a particular emphasis on cardiomyopathies.

Frailty and caregiver relationship quality in older patients diagnosed with transthyretin cardiac amyloidosis.

Aim of the study was to explore frailty and quality of the relationship with the caregiver in a cohort of older patients with transthyretin cardiac amyloidosis (ATTR-CA). Sixty-eight consecutive ATTR-CA patients were recruited and assessed for frailty, depressive symptoms, quality of the relationship in terms of social support, or conflict toward caregivers, New York Heart Association Class (NYHA), and National Amyloid Center score (NAC Score) for grading disease severity. Results showed that 10% of patients were frail. Depressive symptoms were present in 46% of patients. Regression analyses showed that both mFI and depression were associated with worse perception of social support, and that mFI and NAC score were associated with higher levels of conflict perceived in the caregivers' relationship. Overall, the mFI score was associated with worse perceived social support and caregiver relationship quality. Tertiary care heart failure clinics should actively support the patient-caregiver relationship to improve quality of life.

Prevalence of transthyretin-related amyloidosis in Tuscany: Data from the regional population-based registry.

The limited available data regarding the prevalence of transthyretin amyloidosis, both for wild-type (ATTRwt) and hereditary form (ATTRv), is inferred from highly selected patients and subsequent extrapolations that limit the comprehension of the clinical disease impact. The Tuscan healthcare system in 2006 developed a web-based rare disease registry, to monitor and profile patients affected by rare diseases. Clinicians belonging to regional validated healthcare data centres can register patients at the diagnosis, with a rigorous approach and distinguishing the types of amyloidosis, i.e., ATTRwt versus ATTRv. Thanks to this data collection method, available from July 2006 and extended with electronic therapy plans related to a diagnosis since May 2017, we analysed prevalence and incidence of ATTR and its subtypes. On November 30th 2022, ATTRwt prevalence in Tuscany is 90.3 per 1,000,000 persons and ATTRv prevalence is 9.5 per 1,000,000 persons, whereas the annual incidence ranges from 14.4 to 26.7 per 1,000,000 persons and from 0.8 to 2.7 per 1,000,000 persons, respectively. The male gender is predominant in both forms. All except one patient showed evidence of cardiomyopathy. This epidemiological data requires attention, not only to increase the effort for the clinical management and earlier diagnosis, but also to underline the need for the disease-specific treatments.

Tc-99m labelled bone scintigraphy in suspected cardiac amyloidosis.

AIMS: To perform evaluation of widely embraced bone scintigraphy-based non-biopsy diagnostic criteria (NBDC) for ATTR amyloid cardiomyopathy (ATTR-CM) in clinical practice, and to refine serum free light chain (sFLC) ratio cut-offs that reliably exclude monoclonal gammopathy (MG) in chronic kidney disease. METHODS AND RESULTS: A multi-national retrospective study of 3354 patients with suspected or histologically proven cardiac amyloidosis (CA) referred to specialist centres from 2015 to 2021; evaluations included radionuclide bone scintigraphy, serum and urine immunofixation, sFLC assay, eGFR measurement and echocardiography. Seventy-nine percent (1636/2080) of patients with Perugini grade 2 or 3 radionuclide scans fulfilled NBDC for ATTR-CM through absence of a serum or urine monoclonal protein on immunofixation together with a sFLC ratio falling within revised cut-offs incorporating eGFR; 403 of these patients had amyloid on biopsy, all of which were ATTR type, and their survival was comparable to non-biopsied ATTR-CM patients (p = 0.10). Grade 0 radionuclide scans were present in 1091 patients, of whom 284 (26%) had CA, confirmed as AL type (AL-CA) in 276 (97%) and as ATTR-CM in only one case with an extremely rare TTR variant. Among 183 patients with grade 1 radionuclide scans, 122 had MG of whom 106 (87%) had AL-CA; 60/61 (98%) without MG had ATTR-CM. CONCLUSION: The NBDC for ATTR-CM are highly specific [97% (95% CI 0.91-0.99)] in clinical setting, and diagnostic performance was further refined here using new cut-offs for sFLC ratio in patients with CKD. A grade 0 radionuclide scan all but excludes ATTR-CM but occurs in most patients with AL-CA. Grade 1 scans in patients with CA and no MG are strongly suggestive of early ATTR-type, but require urgent histologic corroboration.

Diagnostic pathways to wild-type transthyretin amyloid cardiomyopathy: a multicentre network study.

AIM: Epidemiology of wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) remains poorly defined. A better characterization of pathways leading to ATTRwt-CA diagnosis is of key importance, and potentially informative of disease course and prognosis. The aim of this study was to describe the characteristics of contemporary pathways leading to ATTRwt-CA diagnosis, and their potential association with survival. METHODS AND RESULTS: This was a retrospective study of patients diagnosed with ATTRwt-CA at 17 Italian referral centres for CA. Patients were categorized into different 'pathways' according to the medical reason that triggered the diagnosis of ATTRwt-CA (hypertrophic cardiomyopathy [HCM] pathway, heart failure [HF] pathway, incidental imaging or incidental clinical pathway). Prognosis was investigated with all-cause mortality as endpoint. Overall, 1281 ATTRwt-CA patients were included in the study. The diagnostic pathway leading to ATTRwt-CA diagnosis was HCM in 7% of patients, HF in 51%, incidental imaging in 23%, incidental clinical in 19%. Patients in the HF pathway, as compared to the others, were older and had a greater prevalence of New York Heart Association (NYHA) class III-IV and chronic kidney disease. Survival was significantly worse in the HF versus other pathways, but similar among the three others. In multivariate model, older age at diagnosis, NYHA class III-IV and some comorbidities but not the HF pathway were independently associated with worse survival. CONCLUSIONS: Half of contemporary ATTRwt-CA diagnoses occur in a HF setting. These patients had worse clinical profile and outcome than those diagnosed either due to suspected HCM or incidentally, although prognosis remained primarily related to age, NYHA functional class and comorbidities rather than the diagnostic pathway itself.

Diagnostic delay in arrhythmogenic cardiomyopathy.

AIMS: Diagnosis of arrhythmogenic cardiomyopathy (ACM) may be challenging, as it comprises diverse phenotypes (right dominant, biventricular, and left dominant), and each may overlap with other clinical entities. The issue of differential diagnosis with conditions mimicking ACM has been previously highlighted; however, a systematic analysis of ACM diagnostic delay, and of its clinical implications, is lacking. METHODS AND RESULTS: Data of all ACM patients from three Italian Cardiomyopathy Referral Centres were reviewed to assess the time from first medical contact to definitive ACM diagnosis; a significant diagnostic delay was defined as a time to ACM diagnosis ≥2 years. Baseline characteristics and clinical course of patients with and without diagnostic delay were compared. Of 174 ACM patients, 31% experienced diagnostic delay, with a median time to diagnosis of 8 years (20% in right-dominant ACM, 33% in left-dominant ACM, and 39% in biventricular). Patients with diagnostic delay, when compared with those without, more frequently exhibited an ACM phenotype with left ventricular (LV) involvement (74 vs. 57%, P = 0.04) and a specific genetic background (none had plakophilin-2 variants). The most common initial (mis)diagnoses were dilated cardiomyopathy (51%), myocarditis (21%), and idiopathic ventricular arrhythmia (9%). At follow-up, all-cause mortality was greater in those with diagnostic delay (P = 0.03). CONCLUSION: Diagnostic delay is common in patients with ACM, particularly in the presence of LV involvement, and is associated with greater mortality at follow-up. Clinical suspicion and increasing use of tissue characterization by cardiac magnetic resonance in specific clinical settings are of key importance for the timely identification of ACM.

Almost one-third of patients with arrhythmogenic cardiomyopathy (ACM) experience a diagnostic delay >2 years. These patients are mostly affected by an ACM phenotype with left ventricular (LV) involvement and present worse mortality compared with those without diagnostic delay.Diagnostic delay is common in patients with ACM, particularly in the presence of LV involvement, and is associated with greater mortality at follow-up.The most common initial (mis)diagnoses were dilated cardiomyopathy, myocarditis, and idiopathic ventricular arrhythmia. Clinical suspicion and increasing use of tissue characterization by cardiac magnetic resonance in these specific clinical settings are of key importance to identify ACM in a timely fashion.

Anxious/Depressive Symptoms Alter the Subjective Perception of Heart Failure Severity in Transthyretin Cardiac Amyloidosis.

The subjective perception of cardiac symptom severity is considered a main treatment target in the management of transthyretin-related cardiac amyloidosis (CA), as opposed to objective prognostic markers such as N-terminal pro b-type natriuretic peptide (NT-proBNP), which objectively reflects the severity of heart disease. Nevertheless, anxious and depressive symptoms in patients with CA might affect subjects perceptions of disease, creating a potential gap between objective and subjective parameters. We assess the impact of such bias in consecutive patients with CA. A total of 60 patients aged 62 to 88 years with CA were recruited. The level of anxiety and depression was measured by the Hospital Anxiety and Depression Scale and the subjective perception of symptoms severity by the Kansas City Cardiomyopathy Questionnaire (KCCQ). Finally, NT-proBNP plasma levels at rest and glomerular filtration rate were measured. Nearly 1/2 of the patients (48%) reported clinically relevant levels of psychologic symptoms. Higher levels of anxious and depressive symptoms were significantly linked to lower KCCQ scores. Furthermore, the relation between NT-proBNP and KCCQ was significant only when anxious and depressive symptoms were low (ß = -0.86, p = 0.002; ß = -0.86, p = 0.002, respectively) and medium (ß = -0.49, p = 0.004; ß = -0.45, p = 0.004, respectively) but was otherwise lost. Depression and anxiety in patients with transthyretin-related CA required assessment and management. In conclusion, patients with depression/anxiety have a clear disconnect between their personal assessment and objective measures of cardiac symptoms, with a major influence on the patients' wellbeing and on their subjective response to treatments in clinical trials.

Prognostic value of cardiopulmonary exercise testing in patients with transthyretin cardiac amyloidosis.

The aim of this study is to evaluate the prognostic value of cardiopulmonary testing (CPET) in a cohort of patients with transthyretin cardiac amyloidosis (ATTR-CA). ATTR-CA is associated with a progressive reduction in functional capacity. The prognostic role of CPET parameters and in particular of normalized peak VO2 (%ppVO2) remains to be thoroughly evaluated. In this study, 75 patients with ATTR-CA underwent cardiological evaluation and CPET in a National Referral Center for cardiac amyloidosis (Careggi University Hospital, Florence). Fifty-seven patients (76%) had wild-type ATTR. Median age was 80 (75-83) years, 68 patients (91%) were men. Peak oxygen consumption (14.1 ± 4.1 ml/kg/min) and %ppVO2 (68.4 ± 18.8%) were blunted. Twenty-seven (36%) patients had an abnormal pressure response to exercise. After a median follow-up of 25 (12-31) months, the composite outcome of death or heart failure hospitalization was registered in 19 (25.3%) patients. At univariate analysis %ppVO2 was a stronger predictor for the composite outcome than peak VO2. %ppVO2 and NT-proBNP remained associated with the composite outcome at multivariate analysis. The optimal predictive threshold for %ppVO2 was 62% (sensitivity: 71%; specificity: 68%; AUC: 0.77, CI 0.65-0.88). Patients with %ppVO2 ≤ 62%and NT-proBNP > 3000 pg had a worse prognosis with 1- and 2-year survival of 69 ± 9% and 50 ± 10%, respectively. CPET is a safe and useful prognostic tool in patients with ATTR-CA. CPET may help to identify patients with advanced disease that may benefit from targeted therapy.

Investigation on the high recurrence of the ATTRv-causing transthyretin variant Val142Ile in central Italy.

The p.Val142Ile variant in transthyretin (encoded by the TTR gene) is the most common genetic cause of transthyretin-related amyloidosis. This allele is particularly prevalent in communities ofAfrican descent compared with populations of different ancestries, where its frequency is two orders of magnitude lower. For this reason, p.Val142Ile has always been considered an "African" variant, with limited studies performed on individuals of European descent. However, recent reports of higher-than-expected prevalence in European-ancestry populations question the African specificity of this allele. Here we show that the high recurrence of p.Val142Ile in central Italy is due to a founder effect and not to recent admixture from African populations, highlighting how this may be the case in other communities. This suggests a probable underestimate of the global prevalence of p.Val142Ile, and further emphasizes the importance of routine inclusion of TTR in gene panels used for clinical genetic testing in hypertrophic cardiomyopathy (independently of the patient's geographical origin), that transthyretin-related amyloidosis can mimic.

Does a standard myectomy exist for obstructive hypertrophic cardiomyopathy? From the Morrow variations to precision surgery.

OBJECTIVES: The purpose of this work is to revisit the history of surgical treatment for obstructive hypertrophic cardiomyopathy (oHCM) over the last 60 years, in the light of advancing knowledge of the pathophysiology of obstruction. METHODS: In this narrative review the contribution of the different surgical approaches to the field will be assessed in our personal experience in Florence. RESULTS: Septal myectomy is the treatment of choice in patients with obstructive hypertrophic cardiomyopathy who remain symptomatic despite optimal medical treatment. Over the decades, numerous "theme variations" of the Morrow operation have been proposed, each of them targeting a specific pathophysiological determinant of left ventricular outflow tract obstruction. CONCLUSIONS: Precision surgery in oHCM patients today depends on the ability of the surgeon to combine and master these variations, with the bird's eye view allowed by climbing on the shoulders of giants.