Early diagnosis, disease stage and prognosis in wild-type transthyretin amyloid cardiomyopathy: The DIAMOND study.

AIMS: Disease staging and prognostic scoring in wild-type transthyretin-related cardiac amyloidosis (ATTRwt-CA) can be captured by two systems (NAC and Columbia scores). However, uncertainty remains as epidemiology of the disease is evolving rapidly. We evaluated features associated with staging systems across ATTRwt-CA patients from different diagnostic pathways, and their association with prognosis. METHODS: We performed an analysis on DIAMOND patients with available data to evaluate NAC and Columbia score. DIAMOND was a retrospective study from 17 Italian referral centres for CA, enrolling 1281 patients diagnosed between 2016 and 2021, and aimed at describing characteristics of pathways leading to ATTRwt-CA diagnosis. Of the original cohort, 811 patients were included in this analysis. Each patient had NAC and Columbia score calculated. Patients were grouped according to NAC and Columbia scoring classes. We described characteristics of patients according to staging classes and diagnostic pathways at diagnosis. Prevalence of early diagnoses, defined as NAC Ia, NYHA class I, no use of diuretics, no history of heart failure (HF) hospitalizations nor of atrial fibrillation prior to diagnosis, was investigated. Finally, prognostic variables were tested alone and grouped as NAC or Columbia scores in Cox univariate and multivariate regression analyses. Prognosis was investigated as all-cause mortality, in the whole population and dividing patients in HF versus other diagnostic pathways. RESULTS: Only 1% of the study population had an early ATTRwt-CA diagnosis. Distribution of prognostic variables and of NAC and Columbia classes was heterogeneous across diagnostic pathways. The prevalence of NAC III and Columbia III was higher in the HF diagnostic pathway, but all NAC and Columbia classes were present in all pathways. Both NAC and Columbia scores were associated with all-cause mortality at univariate Cox regression analysis in the whole population, in patients from the HF diagnostic pathway and in those from other pathways. At multivariate analysis, Columbia score remained significantly associated with the outcome, together with age at diagnosis, left ventricular ejection fraction and maximal wall thickness. CONCLUSIONS: In this contemporary nationwide cohort, an ATTRwt-CA early diagnosis was very rare. Disease staging with NAC and Columbia scoring systems determined classes of patients with heterogeneous features. Both scores were significantly associated with mortality, but other variables also had prognostic significance.

Clinical features and outcomes in carriers of pathogenic desmoplakin variants.

BACKGROUND AND AIMS: Pathogenic variants in the desmoplakin (DSP) gene are associated with the development of a distinct arrhythmogenic cardiomyopathy phenotype not fully captured by either dilated cardiomyopathy (DCM), non-dilated left ventricular cardiomyopathy (NDLVC), or arrhythmogenic right ventricular cardiomyopathy (ARVC). Prior studies have described baseline DSP cardiomyopathy genetic, inflammatory, and structural characteristics. However, cohort sizes have limited full clinical characterization and identification of clinical and demographic predictors of sustained ventricular arrhythmias (VAs), heart failure (HF) hospitalizations, and transplant/death. In particular, the relevance of acute myocarditis-like episodes for subsequent disease course is largely unknown. METHODS: All patients with pathogenic/likely pathogenic (P/LP) DSP variants in the worldwide DSP-ERADOS Network (26 academic institutions across nine countries) were included. The primary outcomes were the development of sustained VA and HF hospitalizations during follow-up. Fine-Gray regressions were used to test association between clinical and instrumental parameters and the development of outcomes. RESULTS: Eight hundred patients [40.3 ± 17.5 years, 47.5% probands, left ventricular ejection fraction (LVEF) 49.5 ± 13.9%] were included. Over 3.7 [1.4-7.1] years, 139 (17.4%, 3.9%/year) and 72 (9.0%, 1.8%/year) patients experienced sustained VA and HF episodes, respectively. A total of 32.5% of individuals did not fulfil diagnostic criteria for ARVC, DCM, or NDLVC; their VA incidence was 0.5%/year. In multivariable regression, risk features associated with the development of VA were female sex [adjusted hazard ratio (aHR) 1.547; P = .025], prior non-sustained ventricular tachycardia (aHR 1.721; P = .009), prior sustained VA (aHR 1.923; P = .006), and LVEF ≤ 50% (aHR: 1.645; P = .032), while for HF, they were the presence of T-wave inversion in 3+ electrocardiogram leads (aHR 2.036, P = .007) and LVEF ≤ 50% (aHR 3.879; P < .001). Additionally, 70 (8.8%) patients experienced a myocardial injury episode at presentation or during follow-up. These episodes were associated with an increased risk of VA and HF thereafter (HR 2.394; P < .001, and HR 5.064, P < .001, respectively). CONCLUSIONS: Patients with P/LP DSP variants experience high rates of sustained VA and HF hospitalizations. These patients demonstrate a distinct clinical phenotype (DSP cardiomyopathy), whose most prominent risk features associated with adverse clinical outcomes are the presence of prior non-sustained ventricular tachycardia or sustained VA, T-wave inversion in 3+ leads on electrocardiogram, LVEF ≤ 50%, and myocardial injury events.

Impact of the Noninvasive Diagnostic Algorithm on Clinical Presentation and Prognosis in Cardiac Amyloidosis.

Background: The introduction of a noninvasive diagnostic algorithm in 2016 led to increased awareness and recognition of cardiac amyloidosis (CA). Objectives: The purpose of this study was to analyze the impact of the introduction of the noninvasive diagnostic algorithm on diagnosis and prognosis in a multicenter Italian CA cohort. Methods: This was a retrospective analysis of 887 CA patients from 5 Italian Cardiomyopathies Referral Centers: 311 light-chain CA, 87 variant transthyretin (TTR)-related CA, 489 wild-type TTR-related CA. Clinical characteristics and outcomes (all-cause mortality and heart failure [HF] hospitalizations) were compared overall and for each CA subtype between patients diagnosed before versus after 2016. Outcomes were further compared by propensity score weighted Kaplan-Meier analysis and Cox regression analysis. Results: CA diagnoses increased after 2016, in particular for wild-type TTR-related CA. Patients diagnosed after versus before 2016 were older, had less frequently a history of HF prior to diagnosis, and NYHA functional class III-IV at diagnosis. Over a median follow-up of 18 months, 172 (86%) patients diagnosed before 2016 died or had an HF hospitalization, versus 300 (44%) diagnosed after 2016. Propensity score weighted Kaplan-Meier analysis showed worse outcomes (P < 0.001) for patients diagnosed before 2016. At Cox regression analysis, CA diagnosis after 2016 was an independent protective factor for the composite outcome (HR: 0.69; P = 0.001), with interaction by CA subtype (significant in TTR-related CA and null in light-chain). Conclusions: CA patients diagnosed after 2016 showed a less severe phenotype and a better prognosis. The impact of the noninvasive diagnostic algorithm on outcomes was particularly relevant in TTR-related CA.

Degenerative Mitral Regurgitation Outcomes in Asian Compared With European-American Institutions.

Background: Clinical outcome and interventional thresholds for degenerative mitral regurgitation (DMR) were developed in studies of patients at European and American institutions (EAIs), but little is known about patients at Asian institutions (AsIs). Objectives: This study sought to contrast DMR presentation/management/outcomes of AsI patients vs EAI patients. Methods: Patients with DMR due to flail leaflet from Hong Kong and Singapore (AsI cohort, n = 737) were compared with EAI patients (n = 682) enrolled in the MIDA (Mitral regurgitation International Database) registry with similar eligibility criteria. Results: AsI patients presented similar DMR lesion/consequences vs EAI patients, but they were younger, with fewer symptoms (74% vs 44% Class I), more sinus rhythm (83% vs 69%), and lower EuroSCORE II (European System for Cardiac Operative Risk Evaluation II) (0.9 ± 0.5 vs 1.4 ± 1.5; all P < 0.0001). Imaging showed smaller absolute left atrial/ventricular dimensions in AsI patients, belying cardiac dilatation with larger body surface area-indexed diameters (all P < 0.01). Surgical/interventional mitral repair was similarly predominant (90% vs 91%; P = 0.47), and early repair was similarly beneficial (for AsI patients, adjusted HR: 0.28; 95% CI: 0.16-0.49; for EAI patients, HR: 0.32; 95% CI: 0.20-0.49; both P < 0.0001). However, AsI patients underwent fewer interventions (55% ± 2% vs 77% ± 2% at 1 year; P < 0.0001) and incurred excess mortality (adjusted HR: 1.60 [95% CI: 1.13-2.27] vs EAI patients; P = 0.008) at long-term postdiagnosis. Propensity score matching (434 patient pairs), which balanced all clinical characteristics, confirmed that there was undertreatment and excess mortality in the long term in AsI patients with DMR (P < 0.0001). Conclusions: Imaging may underestimate volume overload in AsI patients due to smaller cardiac cavities related to smaller body size compared with EAI patients with similar mitral lesions and DMR severity. AsI patients enjoy similar mitral repair predominance and early intervention benefits but undergo fewer mitral interventions than EAI patients and incur subsequent excess mortality, suggesting the need to account for imaging and cultural specificity to improve DMR outcomes worldwide.

A novel tool for arrhythmic risk stratification in desmoplakin gene variant carriers.

BACKGROUND AND AIMS: Pathogenic desmoplakin (DSP) gene variants are associated with the development of a distinct form of arrhythmogenic cardiomyopathy known as DSP cardiomyopathy. Patients harbouring these variants are at high risk for sustained ventricular arrhythmia (VA), but existing tools for individualized arrhythmic risk assessment have proven unreliable in this population. METHODS: Patients from the multi-national DSP-ERADOS (Desmoplakin SPecific Effort for a RAre Disease Outcome Study) Network patient registry who had pathogenic or likely pathogenic DSP variants and no sustained VA prior to enrolment were followed longitudinally for the development of first sustained VA event. Clinically guided, step-wise Cox regression analysis was used to develop a novel clinical tool predicting the development of incident VA. Model performance was assessed by c-statistic in both the model development cohort (n = 385) and in an external validation cohort (n = 86). RESULTS: In total, 471 DSP patients [mean age 37.8 years, 65.6% women, 38.6% probands, 26% with left ventricular ejection fraction (LVEF) < 50%] were followed for a median of 4.0 (interquartile range: 1.6-7.3) years; 71 experienced first sustained VA events {2.6% [95% confidence interval (CI): 2.0, 3.5] events/year}. Within the development cohort, five readily available clinical parameters were identified as independent predictors of VA and included in a novel DSP risk score: female sex [hazard ratio (HR) 1.9 (95% CI: 1.1-3.4)], history of non-sustained ventricular tachycardia [HR 1.7 (95% CI: 1.1-2.8)], natural logarithm of 24-h premature ventricular contraction burden [HR 1.3 (95% CI: 1.1-1.4)], LVEF < 50% [HR 1.5 (95% CI: .95-2.5)], and presence of moderate to severe right ventricular systolic dysfunction [HR 6.0 (95% CI: 2.9-12.5)]. The model demonstrated good risk discrimination within both the development [c-statistic .782 (95% CI: .77-.80)] and external validation [c-statistic .791 (95% CI: .75-.83)] cohorts. The negative predictive value for DSP patients in the external validation cohort deemed to be at low risk for VA (<5% at 5 years; n = 26) was 100%. CONCLUSIONS: The DSP risk score is a novel model that leverages readily available clinical parameters to provide individualized VA risk assessment for DSP patients. This tool may help guide decision-making for primary prevention implantable cardioverter-defibrillator placement in this high-risk population and supports a gene-first risk stratification approach.

Survival loss linked to guideline-based indications for degenerative mitral regurgitation surgery.

AIMS: Operating on patients with severe degenerative mitral regurgitation (DMR) is based on ACC/AHA or ESC/EACTS-guidelines. Doubts persist on best surgical indications and their potential association with postoperative survival loss. We sought to investigate whether guideline-based indications lead to late postoperative survival loss in DMR-patients. METHODS AND RESULTS: : We analyzed outcome of 2833 patients from the MIDA-registry undergoing surgical correction of DMR. Patients were stratified by surgical indications: Class-I-trigger (symptoms, left ventricular end-systolic diameter≥40mm, or left ventricular ejection fraction<60%, n=1677), isolated-Class-IIa-trigger (atrial fibrillation [AF], pulmonary hypertension [PH], or left atrial diameter≥55mm, n=568), or no-trigger (n=588). Postoperative survival was compared after matching for clinical differences. Restricted-mean-survival time (RMST) was analyzed. During a median 8.5-year follow-up, 603 deaths occurred. Long-term postoperative survival was lower with Class-I-trigger than in Class-IIa-trigger and no-trigger (71.4±1.9%, 84.3±2.3%, 88.9±1.9% at 10 years, p<0.001). Having at least one Class-I-criterion led to excess mortality (p<0.001), while several Class-I-criteria conferred additional death-risk (HR:1.53, 95%CI:1.42-1.66). Isolated-Class-IIa-triggers conferred an excess mortality risk versus those without (HR:1.46, 95%CI:1.00-2.13, p=0.05). Among these patients, isolated-PH led to decreased postoperative-survival versus those without (83.7%±2.8% vs. 89.3%±1.6%, p=0.011), with the same pattern observed for AF (81.8%±5.0% vs. 88.3%±1.5%, p=0.023). According to RMST-analysis, compare to those operated on without triggers, operating on Class-I-trigger patients led to 9.4-month survival-loss (p<0.001) and operating on isolated-Class-IIa-trigger patients displayed 4.9-month survival loss (p=0.001) after 10-years. CONCLUSIONS: : Waiting for the onset of Class-I or isolated-Class-IIa-triggers before operating on DMR patients is associated with postoperative survival loss. These data encourage an early surgical-strategy.

Temporal implementation of a regional referral pathway in transthyretin cardiac amyloidosis: Emilia-Romagna experience.

AIMS: Transthyretin cardiac amyloidosis (ATTR-CA) is a rare and progressive cardiomyopathy caused by amyloid fibril deposition in myocardial tissue. Diagnostic challenges have historically hampered timely detection. Recent advances in noninvasive diagnostic techniques have facilitated ATTR-CA diagnosis. We aimed to examine the development of a regional network for the diagnosis and management of ATTR-CA and describe a cohort of patients with ATTR-CA, investigate diagnostic pathways and assess clinical outcomes according to diagnosis periods. METHODS: We performed a survey study analyzing answers from 11 cardiology centers and we conducted a retrospective study including patients with ATTR-CA attending a referral center between 1 January 2012 and 31 December 2022, and categorized by the period of diagnosis (2012-2016 and 2017-2022). RESULTS: Over the years, a growing number of patients reached a diagnosis and were treated in the surveyed nonreferral centers of the region. The retrospective study showed a more significant diagnostic delay in the earlier period rather than the later one [13.4 (5-30.2) vs. 10.6 (5.0-17.9) months, P = 0.04]. Patients diagnosed after 2017 showed a greater survival rate than those diagnosed earlier ( P = 0.02). In the multivariate analysis, the year of diagnosis from 2017 remained independently associated with mortality [hazard ratio (HR) 0.46, 95% confidence interval (CI) 0.28-0.79; P = 0.005]. CONCLUSION: This study emphasized the shift toward noninvasive diagnostic criteria. It revealed a positive impact on patient survival and disease management with the use of disease-modifying therapies and diagnostic developments in more recent years. The findings underscore the importance of disease awareness and networking to reduce diagnostic delays and enhance patient journeys for ATTR-CA.

The Italian Fabry Disease Cardiovascular Registry (IFDCR).

AIMS: The Italian Fabry Disease Cardiovascular Registry (IFDCR) comprises 50 Italian centres with specific expertise in managing cardiovascular manifestations and complications of patients with Fabry disease (FD). The primary aim of the IFDCR is to examine and improve the clinical care and outcomes of patients with FD by addressing several knowledge gaps in the epidemiology, natural history, genotype-phenotype correlations, diagnosis, and management of this condition, with particular focus on cardiovascular manifestations and complications. METHODS AND RESULTS: The IFDCR is an international, longitudinal, multicentre, non-interventional, observational study. Consecutive patients aged ≥2 years with a diagnosis of FD will be included in the study. The recruitment period consists of two parts: the retrospective enrolment period, from January 1981 to December 2023, and the prospective enrolment period, spanning from January 2024 to December 2031. The registry collects baseline and follow-up data, including the enrolment setting, patient demographics, family history, symptoms, clinical manifestations, electrocardiogram, cardiovascular imaging, laboratory assessment, medical therapy, genetic testing results, and outcomes. CONCLUSIONS: The IFDCR is a national, multicentre, registry that includes patients with FD. It holds detailed and multiparametric data across the patient pathway and clinical manifestations, acting as a powerful tool for improving the quality of care and conducting high-impact research.

[Cardiac amyloidosis and aortic stenosis: what do we know?] / Amiloidosi cardiaca e stenosi valvolare aortica: quale legame?

Aortic valve stenosis and cardiac amyloidosis, particularly transthyretin-related, often coexist and share a common clinical and demographic profile. Several pathophysiological hypotheses have been proposed regarding the causes of this association, neither of which fully substantiated in practice. The key to detect the coexistence of cardiac amyloidosis and aortic valve stenosis lies in clinical suspicion. It is possible to hypothesize concurrent cardiac amyloidosis in patients with aortic valve stenosis with the aid of clinical, electrocardiographic, echocardiographic, and extracardiac "red flags". Subsequent non-invasive diagnostic steps are often sufficient to establish a definitive diagnosis. The early diagnosis of this condition is pivotal since the presence of dual pathology worsens patient's prognosis, especially without intervention. Available data on treatment show a better outcome in terms of survival and cardiovascular events in patients undergoing percutaneous correction of valvular heart disease rather than medical therapy alone, regardless of the presence of cardiac amyloidosis. Furthermore, it seems that cardiac amyloidosis does not impact survival after transcatheter aortic valve replacement, even if higher rates of rehospitalizations have been described. Indeed, percutaneous treatment of valvular heart disease is currently considered the primary therapeutic option. Subsequently a disease-modifying treatment for transthyretin amyloidosis may be considered in order to delay disease progression and improve outcomes, even if specific data are still lacking.

Long-Term Arrhythmic Follow-Up and Risk Stratification of Patients With Desmoplakin-Associated Arrhythmogenic Right Ventricular Cardiomyopathy.

Background: Patients with likely pathogenic/pathogenic desmoplakin (DSP) variants are poorly characterized. Some of them meet diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC), but it is unclear how risk stratification strategies for ARVC perform in this setting. Objectives: The purpose of this study was to characterize arrhythmic outcomes and to test the performance of the recently validated ARVC risk calculator in patients with DSP likely pathogenic/pathogenic variants fulfilling definite 2010 ARVC Task Force Criteria (DSP-TFC+). Methods: DSP-TFC+ patients were enrolled from 20 institutions across 3 continents. Ventricular arrhythmias (VA), defined as a composite of sustained ventricular tachycardia (VT), appropriate implantable cardioverter defibrillator therapies, and ventricular fibrillation/sudden cardiac death events in follow-up, were reported as the primary outcome. We tested the performance of the ARVC risk calculator for VA prediction, reporting c-statistics. Results: Among 252 DSP-TFC+ patients (age 39.6 ± 16.9 years, 35.3% male), 94 (37.3%) experienced VA over 44.5 [IQR: 19.6-78.3] months. Patients with left ventricle involvement (n = 194) were at higher VA risk (log-rank P = 0.0239). History of nonsustained VT (aHR 2.097; P = 0.004) showed the strongest association with VA occurrence during the first 5-year follow-up. Neither age (P = 0.723) nor male sex (P = 0.200) was associated with VAs at follow-up. In 204 patients without VA at diagnosis, incident VA rate was high (32.8%; 7.37%/y). The ARVC risk calculator performed poorly overall (c-statistic 0.604 [0.594-0.614]) and very poorly in patients with left ventricular disease (c-statistic 0.558 [0.556-0.560]). Conclusions: DSP-TFC+ patients are at substantial risk for VAs. The ARVC risk calculator performs poorly in DSP-TFC+ patients suggesting need for a gene-specific risk algorithm. Meanwhile, DSP-TFC+ patients with nonsustained VT should be considered as high-risk.

Patisiran for the treatment of patients with p.Ile88Leu hereditary transthyretin amyloidosis: an Italian real-life experience.

Objectives: Evidence on the activity of patisiran therapy in specific subgroups of patients with hereditary transthyretin amyloidosis variant (ATTRv) is still scarce. This prospective real-world study was designed to provide the first in-depth clinical data on the effectiveness of patisiran in patients with ATTRv reporting the p.Ile88Leu variant, the most widespread variant in the Emilia-Romagna regional area, which has been less represented in previous clinical trials. Patients and methods: This prospective study evaluated all the patients with genetically proven ATTRv (p.Ile88Leu) and polyneuropathy treated with patisiran in the Emilia-Romagna referral centers for ATTRv (Institute of Neurological Sciences in Bologna and Division of Neurology in Rimini) from March 2021 to April 2023. All subjects underwent clinical and neurological evaluations at baseline and after 9-12 months of treatment. Results: A total of 22 patients were included in the study; the median age was 73 years (IQR: 9), the age at diagnosis was 72 years (IQR: 10), and the disease duration was 1.6 years (IQR: 2.3). We observed stability of all considered neurological and cardiological parameters at 9-12 months after the beginning of patisiran treatment. Conclusion: Our findings support the clinical data regarding the effectiveness of patisiran in stabilizing the disease course and extend this activity to the subset of patients with the p.Ile88Leu variant.

Evaluation of the 2021 ESC recommendations for family screening in hereditary transthyretin cardiac amyloidosis.

AIMS: The 2021 European Society of Cardiology (ESC) screening recommendations for individuals carrying a pathogenic transthyretin amyloidosis variant (ATTRv) are based on expert opinion. We aimed to (i) determine the penetrance of ATTRv cardiomyopathy (ATTRv-CM) at baseline; (ii) examine the value of serial evaluation; and (iii) establish the yield of first-line diagnostic tests (i.e. electrocardiogram, echocardiogram, and laboratory tests) as per 2021 ESC position statement. METHODS AND RESULTS: We included 159 relatives (median age 55.6 [43.2-65.9] years, 52% male) at risk for ATTRv-CM from 10 centres. The primary endpoint, ATTRv-CM diagnosis, was defined as the presence of (i) cardiac tracer uptake in bone scintigraphy; or (ii) transthyretin-positive cardiac biopsy. The secondary endpoint was a composite of heart failure (New York Heart Association class ≥II) and pacemaker-requiring conduction disorders. At baseline, 40/159 (25%) relatives were diagnosed with ATTRv-CM. Of those, 20 (50%) met the secondary endpoint. Indication to screen (≤10 years prior to predicted disease onset and absence of extracardiac amyloidosis) had an excellent negative predictive value (97%). Other pre-screening predictors for ATTRv-CM were infrequently identified variants and male sex. Importantly, 13% of relatives with ATTRv-CM did not show any signs of cardiac involvement on first-line diagnostic tests. The yield of serial evaluation (n = 41 relatives; follow-up 3.1 [2.2-5.2] years) at 3-year interval was 9.4%. CONCLUSIONS: Screening according to the 2021 ESC position statement performs well in daily clinical practice. Clinicians should adhere to repeating bone scintigraphy after 3 years, as progressing to ATTRv-CM without signs of ATTRv-CM on first-line diagnostic tests or symptoms is common.

Degenerative mitral regurgitation due to flail leaflet: sex-related differences in presentation, management, and outcomes.

BACKGROUND AND AIMS: Presentation, outcome, and management of females with degenerative mitral regurgitation (DMR) are undefined. We analysed sex-specific baseline clinical and echocardiographic characteristics at referral for DMR due to flail leaflets and subsequent management and outcomes. METHODS: In the Mitral Regurgitation International Database (MIDA) international registry, females were compared with males regarding presentation at referral, management, and outcome (survival/heart failure), under medical treatment, post-operatively, and encompassing all follow-up. RESULTS: At referral, females (n = 650) vs. males (n = 1660) were older with more severe symptoms and higher MIDA score. Smaller cavity diameters belied higher cardiac dimension indexed to body surface area. Under conservative management, excess mortality vs. expected was observed in males [standardized mortality ratio (SMR) 1.45 (1.27-1.65), P < .001] but was higher in females [SMR 2.00 (1.67-2.38), P < .001]. Female sex was independently associated with mortality [adjusted hazard ratio (HR) 1.29 (1.04-1.61), P = .02], cardiovascular mortality [adjusted HR 1.58 (1.14-2.18), P = .007], and heart failure [adjusted HR 1.36 (1.02-1.81), P = .04] under medical management. Females vs. males were less offered surgical correction (72% vs. 80%, P < .001); however, surgical outcome, adjusted for more severe presentation in females, was similar (P ≥ .09). Ultimately, overall outcome throughout follow-up was worse in females who displayed persistent excess mortality vs. expected [SMR 1.31 (1.16-1.47), P < .001], whereas males enjoyed normal life expectancy restoration [SMR 0.92 (0.85-0.99), P = .036]. CONCLUSIONS: Females with severe DMR were referred to tertiary centers at a more advanced stage, incurred higher mortality and morbidity under conservative management, and were offered surgery less and later after referral. Ultimately, these sex-related differences yielded persistent excess mortality despite surgery in females with DMR, while males enjoyed restoration of life expectancy, warranting imperative re-evaluation of sex-specific DMR management.

Fabry disease in W162C mutation: a case report of two patients and a review of literature.

BACKGROUND: Fabry disease is a multisystemic disorder characterized by deposition of globotriaosylceramide (Gb3) and its deacylated form in multiple organs, sometimes localized in specific systems such as the nervous or cardiovascular system. As disease-modifying therapies are now available, early diagnosis is paramount to improving life quality and clinical outcomes. Despite the widespread use of non-invasive techniques for assessing organ damage, such as cardiac magnetic resonance imaging (MRI) for patients with cardiac disease, organ biopsy remains the gold standard to assess organ involvement. CASE PRESENTATION: The cases of two patients, father and daughter with a W162C mutation, are described. The father presented with late-onset, cardiac Fabry disease, subsequently developing systolic dysfunction and heart failure. His daughter, while asymptomatic and with normal cardiac assessment (except for slightly reduced native T1 values by cardiac MRI), had already initial myocyte Gb3 deposits on the endomyocardial biopsy, allowing her to start therapy precociously and potentially modifying the course of her disease. A review of the literature concerning the W162C mutation is then provided, showing that it is usually associated to classic, multisystemic Fabry disease rather than the cardiac-restricted form as in these two cases. CONCLUSIONS: Three main points can be concluded from this report. First, the W162C mutation can present with a more variegate phenotype than that predicted on a molecular basis. Second, endomyocardial biopsy was shown in this case to precede non-invasive investigation in determining organ involvement, justifying further studies on this potentially reliable technique, Third, difficulties can arise in the management of asymptomatic female carriers.

Clinical and Prognostic Implications of Right Ventricular Uptake on Bone Scintigraphy in Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: The extent of myocardial bone tracer uptake with technetium pyrophosphate, hydroxymethylene diphosphonate, and 3,3-diphosphono-1,2-propanodicarboxylate in transthyretin amyloid cardiomyopathy (ATTR-CM) might reflect cardiac amyloid burden and be associated with outcome. METHODS: Consecutive patients with ATTR-CM who underwent diagnostic bone tracer scintigraphy with acquisition of whole-body planar and cardiac single-photon emission computed tomography (SPECT) images from the National Amyloidosis Centre and 4 Italian centers were included. Cardiac uptake was defined according to the Perugini classification: 0=absent cardiac uptake; 1=mild uptake less than bone; 2=moderate uptake equal to bone; and 3=high uptake greater than bone. Extent of right ventricular (RV) uptake was defined as focal (basal segment of the RV free wall only) or diffuse (extending beyond basal segment) on the basis of SPECT imaging. The primary outcome was all-cause mortality. RESULTS: Among 1422 patients with ATTR-CM, RV uptake accompanying left ventricular uptake was identified by SPECT imaging in 100% of cases at diagnosis. Median follow-up in the whole cohort was 34 months (interquartile range, 21 to 50 months), and 494 patients died. By Kaplan-Meier analysis, diffuse RV uptake on SPECT imaging (n=936) was associated with higher all-cause mortality compared with focal (n=486) RV uptake (77.9% versus 22.1%; P<0.001), whereas Perugini grade was not associated with survival (P=0.27 in grade 2 versus grade 3). On multivariable analysis, after adjustment for age at diagnosis (hazard ratio [HR], 1.03 [95% CI, 1.02-1.04]; P<0.001), presence of the p.(V142I) TTR variant (HR, 1.42 [95% CI, 1.20-1.81]; P=0.004), National Amyloidosis Centre stage (each category, P<0.001), stroke volume index (HR, 0.99 [95% CI, 0.97-0.99]; P=0.043), E/e' (HR, 1.02 [95% CI, 1.007-1.03]; P=0.004), right atrial area index (HR, 1.05 [95% CI, 1.02-1.08]; P=0.001), and left ventricular global longitudinal strain (HR, 1.06 [95% CI, 1.03-1.09]; P<0.001), diffuse RV uptake on SPECT imaging (HR, 1.60 [95% CI, 1.26-2.04]; P<0.001) remained an independent predictor of all-cause mortality. The prognostic value of diffuse RV uptake was maintained across each National Amyloidosis Centre stage and in both wild-type and hereditary ATTR-CM (P<0.001 and P=0.02, respectively). CONCLUSIONS: Diffuse RV uptake of bone tracer on SPECT imaging is associated with poor outcomes in patients with ATTR-CM and is an independent prognostic marker at diagnosis.

Left atrial structural and functional remodelling in Fabry disease and cardiac amyloidosis: A comparative analysis.

BACKGROUND: Fabry disease (FD) and transthyretin cardiac amyloidosis (TTR CA) are cardiomyopathies with hypertrophic phenotype that share several features, including left atrial (LA) enlargement and dysfunction, but direct comparative data are lacking. Aim of the present study was to perform a comparative analysis of LA remodelling between the two diseases. METHODS AND RESULTS: In this prospective study, a total of 114 patients (31 FD and 83 TTR CA) were included; all of them had left ventricular hypertrophy (LVH), defined as left ventricular (LV) wall thickness ≥ 12 mm. Despite similar degree of LVH, patients with TTR CA showed worse LV systolic and diastolic function. LA maximal volume index was not significantly different between the two groups (p = 0.084), while patients with TTR CA showed larger LA minimal volume index (p = 0.001). Moreover, all phases of LA mechanics were more impaired in the TTR CA group vs FD (reservoir: 6.9[4.2-15.5] vs 19.0[15.5-29.5], p < 0.001). After excluding patients with atrial fibrillation (AF), these differences remained clearly significant. In multivariable regression analyses, LA reservoir strain showed an independent correlation with TTR CA, controlling for demographic characteristics, AF and LV systolic and diastolic performance (p ≤ 0.001), whereas LV global longitudinal strain did not. Finally, among echocardiographic parameters, LA function demonstrated the highest accuracy in discriminating the two diseases. CONCLUSIONS: TTR CA is characterized by a more advanced LA structural and functional remodelling in comparison to patients with FD and similar degree of LVH. The association between TTR CA and LA dysfunction remains consistent after adjustment for potential confounders.

Clinical characteristics and outcome of end stage hypertrophic cardiomyopathy: Role of age and heart failure phenotypes.

BACKGROUND: A minority of patients with hypertrophic cardiomyopathy (HCM) presents advanced heart failure (HF) during their clinical course, in the context of left ventricular (LV) remodeling with reduced LV ejection fraction (LVEF), or of severe diastolic dysfunction without impaired LVEF. Aim of this study was to describe a multicentric end stage (ES) HCM population and analyze clinical course and outcome among its different phenotypes. METHODS: Data of all HCM patients from 7 Italian referral centres were retrospectively evaluated. ES was diagnosed in presence of: LVEF <50% (ES-rEF) or NYHA functional class ≥II with severe diastolic dysfunction (ES-pEF). Outcomes were: HCM-related and all-cause mortality; combined arrhythmic events; advanced HF treatments. RESULTS: Study population included 331 ES patients; 87% presented ES-rEF and 13% ES-pEF. At ES recognition, patients with ES-pEF were more commonly females, had more frequently NYHA III/IV, atrial fibrillation and greater maximal LV wall thickness. Over a median follow-up of 5.6 years, 83 (25%) patients died, 46 (15%) experienced arrhythmic events and (26%) 85 received advanced HF treatments. Incidence of HCM-related and all-cause mortality, and of combined arrhythmic events did not differ in ES-pEF and ES-rEF patients, but ES-pEF patients were less likely to receive advanced HF treatments. Older age at ES recognition was an independent predictor of increased HCM-related mortality (p = 0.01) and reduced access to advanced HF treatments (p < 0.0001). CONCLUSIONS: Two different HCM-ES phenotypes can be recognized, with ES-pEF showing distinctive features at ES recognition and receiving less frequently advanced HF treatments. Older age at ES recognition has a major impact on outcomes.

Characterization and natural history of different phenotypes in hereditary transthyretin amyloidosis: 40-year experience at a single Italian referral centre.

AIMS: Hereditary transthyretin amyloidosis (ATTRv) is one of the leading aetiologies of systemic amyloidosis with more than 135 mutations described and a broad spectrum of clinical manifestations. We aimed to provide a systematic description of a population of individuals carrying pathogenic mutations of transthyretin (TTR) gene and to investigate the major clinical events during follow-up. METHODS AND RESULTS: This was an observational, retrospective, cohort study including consecutive patients with mutations of TTR gene, admitted to a tertiary referral centre in Bologna, Italy, between 1984 and 2022. Three hundred twenty-five patients were included: 106 asymptomatic carriers, 49 cardiac phenotype, 49 neurological phenotype, and 121 mixed phenotype. Twenty-two different mutations were found, with Ile68Leu (41.8%), Val30Met (19%), and Glu89Gln (10%) being the most common. After a median follow-up of 51 months, 111 patients (38.3%) died and 9 (11.5%) of the 78 asymptomatic carriers developed ATTRv. Carriers had a prognosis comparable with healthy population, while no significant differences were seen among the three phenotypes adjusted by age. Age at diagnosis, New York Heart Association class III, left ventricular ejection fraction, modified polyneuropathy disability score IV, and disease-modifying therapy were independently associated with survival. CONCLUSION: This study offers a wide and comprehensive overview of ATTRv from the point of view of a tertiary referral centre in Italy. Three main phenotypes can be identified (cardiac, neurological, and mixed) with specific clinical and instrumental features. Family screening programmes are essential to identify paucisymptomatic affected patients or unaffected carriers of the mutation, to be followed through the years. Lastly, disease-modifying therapy represents an evolving cornerstone of the management of ATTRv, with a great impact on mortality.

A total of 325 consecutive patients harbouring a pathogenic mutation in the TTR gene, admitted to a tertiary referral centre in Bologna, Italy, between 1984 and 2022, were included in the study.These patients exhibited significant clinical diversity: 106 were asymptomatic carriers, 49 presented with a cardiac phenotype, 49 had a neurological phenotype, and 121 had a mixed phenotype.Asymptomatic carriers demonstrated a prognosis comparable with healthy population, but some of them may develop signs and symptoms of the disease during follow-up.Survival curves adjusted by age are similar among the three phenotypes.Age at diagnosis, New York Heart Association class, modified polyneuropathy disability score, left ventricular ejection fraction, and disease-modifying therapy were identified as independent factors associated with prognosis.

ECG/echo indexes in the diagnostic approach to amyloid cardiomyopathy: A head-to-head comparison from the AC-TIVE study.

BACKGROUND AND AIMS: The discordance between QRS voltages on electrocardiogram (ECG) and left ventricle (LV) wall thickness (LVWT) on echocardiogram (echo) is a recognized red flag (RF) of amyloid cardiomyopathy (AC) and can be measured by specific indexes. No head-to-head comparison of different ECG/echo indexes among subjects with echocardiographic suspicion of AC has yet been undertaken. The study aimed at evaluating the performance and the incremental diagnostic value of different ECG/echo indexes in this subset of patients. METHODS: Electrocardiograms of subjects with LV hypertrophy, preserved ejection fraction and ≥ 1 echocardiographic RF of AC participating in the AC-TIVE study, an Italian prospective multicenter study, were independently analyzed by two cardiologists. Low QRS voltages and 8 different ECG/echo indexes were evaluated. Cohort specific cut-offs were computed. RESULTS: Among 170 patients, 55 (32 %) were diagnosed with AC. Combination of low QRS voltages with interventricular septum ≥ 1,6 cm was the most specific (specificity 100 %, positive predictive value 100 %) ECG/echo index, while the ratio between the sum of all QRS voltages and LVWT <7,8 was the most sensitive and accurate (sensitivity 94 %, negative predictive value 97 %, accuracy 82 %). When the latter index was added to a model using easily-accessible clinical variables, the diagnostic accuracy for AC greatly increased (AUC from 0,84 to 0,95; p = 0,007). CONCLUSIONS: Among patients with non-dilated hypertrophic ventricles with normal ejection fraction and echocardiographic RF of AC, easily-measurable ECG/echo indexes, mainly when added to few clinical variables, can help the physician orient second level investigations. External validation of the results is warranted.