bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lamin A/C cardiomyopathy in children
Authors: Smedsrud M , Chivulescu M , Hasselberg N E , Albinski M , Barnes A , Field E , Fruh A , Kaski J P , Haugaa K H 
Published: November 2023

Abstract

Background
Lamin A/C gene (LMNA) variants cause familial dilated cardiomyopathy (DCM) with a malignant cardiac phenotype characterized by atrioventricular (AV) block and supraventricular and ventricular arrhythmias, often preceding cardiac dilatation and dysfunction. Current guidelines recommend genetic and clinical screening of family members, starting at 10-12 years of age. However, children with LMNA variants are underrepresented in research publications and data are lacking on both the onset of a cardiac phenotype and the prevalence of cardiac events in this population.

Purpose
The study aimed to investigate the prevalence of cardiac events in LMNA genotype positive children and penetrance of LMNA cardiac phenotype in genotype positive paediatric relatives.

Methods
We conducted a longitudinal cohort study including consecutive genotype-positive LMNA patients and genotype positive relatives, all ≤18 years of age, followed between 2009 and 2022. The patients were examined by electrocardiography, Holter monitoring, and echocardiography. A cardiac phenotype was defined as the presence of either atrioventricular (AV) block, prolonged sinus arrest, atrial fibrillation/ flutter (AF), ventricular tachycardia (VT), or echocardiographic DCM. Cardiac events were defined as AF, VT, cardiac syncope, sudden cardiac arrest (SCA) or heart transplantation (Htx). Childhood-onset disease was defined as the presence of a cardiac phenotype ≤12 years of age.

Results
Among 44 LMNA genotype-positive children (age 10.4 [IQR 6.5-12.9] years, 34 relatives), 12 (27 %) became phenotype-positive at a median age of 12.8 [IQR 7.9-14.1] years, of which 7 (58 %) had childhood-onset disease (Figure 1). Nine (18 %) of the children experienced a cardiac event and 44 % of these were ≤12 years of age (Figure 2). Three children had AF, 5 had VT, and one had cardiac syncope. Htx was performed in two unrelated children, at 6 and 8 years of age, respectively.
Among the 34 genotype-positive paediatric relatives, 21 % (n=7) became phenotype-positive at a median age of 10.9 [IQR 7.5-15.1] years, of which 57 % (n=4) had childhood-onset disease.

Conclusions
In a cohort of LMNA genotype children, there was a high prevalence of cardiac events and 44 % of these occurred in children ≤12 years of age. The penetrance of LMNA cardiac phenotype in genotype positive paediatric relatives was 21 %, highlighting the importance of early family screening and cardiological follow-up.
Contribution of copy number variants to the genetic etiology of dilated cardiomyopathy
Authors: Cardenas Reyes I , Gomez Diaz I , De La Higuera Romero L , Amor Salamanca A , Garcia Hernandez S , Valverde Gomez M , Cabrera Argana D , Fernandez Fernandez X , Ortiz Genga M , Cazon Varela L , Perez Barbeito M , Peteiro Deben R , Sanchez Flores M , Ochoa J P 
Published: November 2023

Abstract

Background/Introduction
Dilated cardiomyopathy (DCM) is one of the most common cardiomyopathies, with a prevalence of 1 in 250. Single nucleotide variants (missense, nonsense, or frameshift) in definitive DCM genes are the most frequently identified in positive genetic studies. Despite major advances in genetic diagnostic technologies in recent decades, and more than 100 genes potentially associated with DCM identified to date, the diagnostic yield is still lower than 40%. Copy number variants (CNVs) have been identified as cause of the disease in several studies, especially in genes intolerant to haploinsufficiency. However, the contribution of CNVs to the etiology of DCM has not been evaluated in large cohorts of DCM patients and remains unknown.

Purpose
To determine the percentage of cases in which CNVs have been identified as the cause of disease in a large cohort of DCM patients evaluated genetically.

Methods
Retrospective study in which the presence of CNVs was evaluated in a cohort of patients diagnosed with DCM and studied by next-generation-sequencing (NGS). CNVs were detected using a read depth approach and confirmed by an orthogonal molecular technique (Sanger sequencing, MLPA, or dPCR).

Results
6,512 DCM patients referred for genetic testing were sequenced in our center by NGS, and the median age at the time of genetic study was 51.1 years (range 0-93). A pathogenic (P) or likely-pathogenic (LP) disease-causing variant was identified in 1,495 of the patients (diagnostic yield of 22.9%). In 67 (1.02%) of the cases, a CNV classified as P/LP was identified. DMD was the gene with the highest number of CNVs identified (n=40), followed by TTN (n=7) and LMNA (n=5). Of the 67 cases, 45 (67%) corresponded to deletions, with a lesser extent to duplications (n=9; 13%), complex alterations (n=7; 11%), and deletion/insertion (n=6; 9%). Only two of the patients harboring disease-causing CNVs had other variants potentially associated with DCM: a likely-pathogenic variant in MYH7 and a homozygous pathogenic variant in the ALMS1 gene.

Conclusion
In our cohort of DCM patients, 1.02% harbored CNVs considered P/LP, being DMD the most frequently identified gene. These results show that systematic CNVs analysis in NGS studies improves the yield of genetic testing in DCM and highlights the importance of a complete genetic study that includes structural variant detection in the diagnosis of the disease.
Disease penetrance in genotype-positive relatives from families with dilated cardiomyopathy
Authors: Cannie D , Syrris P , Protonotarios A , Bakalakos A , Lorenzini M , Guttmann O , Lopes L , O'mahony C , Sekhri N , Savvatis K , Mohiddin S , Elliott P 
Published: November 2023

Abstract

Background
Genetic testing of patients with dilated cardiomyopathy (DCM) results in identification of a causative gene variant in around 19-37% of individuals [1]. Serial clinical assessment of relatives found to carry genetic variants is recommended, but there are no data to guide screening intervals or to better understand the influence of age, sex and genotype on disease expression.

Purpose
To evaluate the trajectory of disease development in clinically unaffected relatives with a positive genetic test.

Methods
Families with a likely pathogenic or pathogenic variant in DCM related genes were identified from the database at a cardiomyopathy unit. Families were included only where phenotypes were consistent with DCM or hypokinetic non-dilated cardiomyopathy [2]. Consecutive relatives from these families were retrospectively recruited where they had tested positive for the familial genetic variant and were clinically unaffected at baseline evaluation. Incidence rates of disease penetrance during follow-up were stratified by sex and genotype.

Results
131 relatives (59 male (45%) with median age 28.6 [21.5 – 42.0] years at first evaluation) representing 75 families were included. The most prevalent genotypes were DSP (46/131, 35.1%), TTN (32/131, 24.4%) , LMNA (22/131, 16.8%), RBM20 (14/131, 10.7%) and BAG3 (8/131, 6.1%). The overall incident rate of phenotype development during follow-up was 11.6 [8.9 – 14.2] per 100 person years and rates were significantly different between males and females (16.1 versus 8.8 per 100 person-years, log-rank p value = 0.006; Figure 1). LMNA variant-carriers had the highest incidence rate of disease penetrance at 17.7 [9.8 – 25.7] per 100 person-years and disease penetrance occurred at a younger age than DSP and TTN variant-carriers (Figure 2).

Conclusions
Disease development during follow-up is common in genotype-positive relatives, particularly in males and in LMNA variant-carriers. Genotype-positive relatives should be rescreened at least once each year.Figure 1Figure 2
Skeletal muscle involvement in patients with truncations of titin and familial dilated cardiomyopathy
Authors: Vissing C R , Skriver S V , Krett B , Poulsen N S , Krag T , Walas H R , Christensen A H , Bundgaard H , Vissing J 
Published: November 2023

Abstract

Background
Variants in TTN are associated with dilated cardiomyopathy (DCM) and skeletal myopathy with or without cardiac affection. However, the skeletal muscle phenotype has not been systematically evaluated in patients with predisposition to or manifest cardiac involvement due to heterozygous truncating TTN variants (TTNtv), the most common cause of DCM.

Purpose
Assess the skeletal muscle phenotype associated with TTNtv.

Methods
This cross-sectional study examined skeletal muscle involvement in individuals with TTNtv by quantifying and comparing fat fraction from muscle magnetic resonance imaging to controls (matched on body-size, sex, and age), and evaluating muscle strength by dynamometry and features from muscle biopsies.

Results
Twenty-five participants (11 women, age 51±15 years, left ventricular ejection fraction 45±10%) with TTNtv were included (19 had DCM). Compared to controls, participants with TTNtv had higher fat fraction in calf- (12.5% vs 9.9%, p=0.013), thigh- (12.2% vs 9.3%, p=0.004) and paraspinal muscles (18.8% vs 13.9%, p=0.008), see figure. Muscle strength was relatively intact (within 1 SD of normal values). Muscle biopsies in 21 participants showed that 13 (62%) displayed myopathic features, most notably an increased proportion of central nuclei. Electron microscopy showed well-ordered Z-lines and T-tubuli but uneven and discontinuous M-lines and excessive glycogen depositions flanked by large autophagosomes, lysosomes, and abnormal mitochondria with mitophagy.

Conclusion
Skeletal muscle involvement is prevalent in patients with cardiac involvement or predisposition to DCM due to TTNtv and is characterized by an increased muscle fat fraction, and excessive accumulation of glycogen, possibly due to reduced autophagic flux. This emphasizes the need for specialized diagnostic work-up in patients with TTNtv, especially if reporting symptoms or objective signs of muscle involvement.
Prognostic implications of family screening in Dilated and Arrhythmogenic Cardiomyopathies
Authors: Del Mestre E , Paldino A , Pio Loco C , Dal Ferro M , Gandin I , Setti M , Folgheraiter A , Rizzi J , Korkova R , Merlo M , Sinagra G 
Published: November 2023

Abstract

Introduction
Dilated cardiomyopathy (DCM) and arrhythmogenic left dominant cardiomyopathy (ALVC) are overlapping phenotypes of inherited cardiomyopathies characterized by left ventricular systolic dysfunction (LVSD), sharing the same genetic background. The risk of disease development in relatives is relevant and influenced by multiple factors. The purpose of familial screening (FS) is to early detect cardiac manifestations by ECG and echocardiogram every 2-5 years. Recent studies suggested a possible role of Holter-ECG and Global Longitudinal Strain (GLS) for disease prediction. However, these are not strongly recommended in the current FS guidelines. Moreover, it is unclear if FS represents a useful tool to prevent cardiac events in family members.

Purpose
Our study aims to 1) elucidate the role of genetic and environmental factors for cardiac disease development in relatives of probands affected by DCM/ALVC, 2) quantify the predictive role of FS for LVSD, and 3) assess the prognostic impact of FS on relatives.

Methods
Reasons for first medical contact, genetic data, baseline and follow-up (FU) clinical, ECG, echocardiogram, GLS, Holter-ECG data and outcomes were compiled. LVSD was defined as ejection fraction &lt; 50%. Moreover, a primary outcome including all-cause death (D) and heart transplantation (HT) and an arrhythmic secondary outcome including sudden cardiac death (SCD) and major ventricular arrhythmias (MVA) were evaluated in affected relatives.

Results
A total of 385 relatives (85% with a proband affected by DCM) were enrolled. Among these, 223 (58%) were unaffected at baseline. During a median follow-up of 60 (IQR 30-110) months, 81 (36%) developed LVSD. Being carrier of pathogenic variants and having a family history of SCD were the main clinical factors significantly associated with LVSD development in the multivariable model, whereas environmental factors were not. Moreover, the GLS value at baseline was significantly lower in relatives developing LVSD compared to persistent unaffected relatives (-14.9 ±3.2 vs -19.8 ±3.2, p&lt;0.001), and its value was an independent predictor of LVSD. Furthermore, in comparison to previously published predictive models which included age, ECG and echocardiographic abnormalities (C-index 0.64), adding Holter-ECG offers a better fit and increases the concordance by 20% (C-index 0.77). In conclusion, in the total population of 243 relatives (63%) with LVSD (at the baseline or at FU), cardiac events were less frequent among relatives detected by FS.

Conclusions
Genetic background plays a major role in the development of LVSD in relatives of DCM/ALVC probands. GLS and Holter-ECG could be useful tools to improve the efficiency of FS to predict LVSD, suggesting early FU visits. FS shows a significant prognostic protective impact in this study population.
Multimodality imaging in cardiac masses
Authors: Bodega F , Angeli F , Bergamaschi L , Paolisso P , Armillotta M , Fedele D , Bertolini D , Cavallo D , Ryabenko K , Casuso Alvarez M , Lovato L , Rinaldi A , Foa' A , Galie' N , Pizzi C 
Published: November 2023

Abstract

Background
Cardiac masses (CM) are an extremely heterogeneous clinical scenario, including benign and malignant neoformations. After a first echocardiographic assessment, Cardiac Computed Tomography (CCT) together with Cardiac Magnetic Resonance (CMR) and 18-Fluorodeoxyglucose Positron Emission Tomography (18- FDG-PET) represent second line and third-line imaging techniques to determine the nature of the mass. However, data regarding their diagnostic performance and a standardized imaging algorithm are lacking.

Purpose
To evaluate the different roles of CCT, CMR, and PET in defining the nature of CMs and to propose an evidence-based, stepwise, diagnostic approach.

Materials and methods
Out of 312 patients with suspected mass from January 2000 and August 2022, we enrolled 87 patients who underwent CCT, CMR and 18-FDG-PET within a month from the initial evaluation. A definitive diagnosis was achieved by histological examination or, in case of cardiac thrombi, with radiological evidence of thrombus resolution after an appropriate anticoagulant treatment. For each imaging technique, we identified a model with the strongest predictors of malignancy at multivariate analysis and evaluated their ability to discriminate between benign and malignant neoformations. A multiple model with forwarding selection was performed to identify the strongest predictors of malignancy at CCT, CMR and 18-FDG-PET.

Results
CCT model included 4 variables (irregular margins, mass dimension, invasiveness, and not-hypodense lesion) with an Area Under the Curve (AUC) of 0.972, 95% Confidence Interval (CI) 0.94-1.0; CMR model included 3 parameters (invasiveness, pericardial effusion and irregular margins, AUC 0.976 with 95% CI 0.95-1.0); PET model included only cardiac maximum Standardized Uptake Value (SUVmax), with an AUC 0.87 (95% CI 0.74-0.971). When implemented with SUVmax, CCT and CMR models showed only a slight improvement in their discrimination ability (AUC 0.975 and 0.986, respectively). No statistical difference was observed between CCT and CMR models regarding their discrimination ability (AUC 0.972 vs 0.976, p=0.26). However, on a multiple model with forwarding selection evaluating CCT, CMR and PET variables, only the 3 MR parameters remained significant predictors of malignancy.

Conclusion
After a first echocardiographic assessment, the application of the CMR model may be the most accurate second-level investigation to discriminate between benign and malignant lesions. When CMR is not available, or the patient has contraindications to CMR, the CCT model performs similarly, and 18-FDG-PET provides a negligible advantage.
Prevalence of cardiac amyloidosis in patients undergoing carpal tunnel release with amyloid deposition in removed tenosynovium
Authors: Takashio S , Kato T , Tashima H , Irie H , Komohara Y , Morikawa K , Oguni T , Kuyama N , Ueda M , Tsujita K 
Published: November 2023

Abstract

Background
Carpal tunnel syndrome (CTS) is an early symptom and important clinical indicator for the diagnosis of cardiac amyloidosis. Amyloid deposition in removed tenosynovium during carpal tunnel release (CTR) is often confirmed; however, the prevalence of concomitant cardiac amyloidosis is not yet understood.

Purpose
This study aimed to evaluate the prevalence of amyloid deposition in removed tenosynovium in patients who underwent CTR and to clarify the prevalence of concomitant cardiac amyloidosis in patients who had amyloid deposition in removed tenosynovium.

Methods
Overall, 669 patients who underwent CTR were prospectively examined and evaluated for amyloid deposition after tenosynovium removal. Invitation and proposal letters for cardiac screening were sent to patients with amyloid deposition. Electrocardiography, echocardiography, and biomarkers were evaluated to assess the likelihood of cardiac amyloidosis.

Results
Amyloid deposition was observed in 261 (39%) patients, who were significantly older and predominantly male (p&lt;0.05). Among them, 111 patients (mean age; 70.8 ± 7.3 years old; men: 55%) agreed to cardiac screening. 99mTc-labeled pyrophosphate (99mTc-PYP) scintigraphy was performed in 12 patients who met the following criteria: 1) interventricular septum diameter (IVSd) ≥14 mm or 2) 12 mm ≤ IVSd &lt;14 mm with above-normal limits in high-sensitivity cardiac troponin T (hs-cTnT; &gt;0.014 ng/mL). Six patients (50%) had positive findings on 99mTc-PYP scintigraphy and were diagnosed with wild-type transthyretin cardiac amyloidosis with Mayo prognostic stage I. The prevalence of concomitant cardiac amyloidosis was observed in 6/111 (5.4%) CTR patients with amyloid deposition and 50% (6/12) in patients with left ventricular hypertrophy (≥12 mm) with increased hs-cTnT levels.

Conclusion
Amyloid deposition in removed tenosynovium was frequently observed in elderly men with CTS. Cardiac screening may be useful for the early diagnosis of cardiac amyloidosis in patients undergoing CTR with amyloid deposition. This knowledge should be shared with orthopedic surgeons and cardiologists for the early diagnosis of cardiac amyloidosis.Flowchart of participant selectionGraphical Abstract
Transtyretin cardiac amyloidosis in the elderly patient: always a wild type?
Authors: Costantino J , Ballatore F , Ajmone F M , Manguso G , Ciaramella P , Maggio E , Alfarano M , Vizza C D , Chimenti C 
Published: November 2023

Abstract

Background
Transthyretin amyloidosis (ATTR) exists in two forms: a genetic form transmitted by autosomal dominant inheritance (ATTRv) and a wild type form (ATTRwt). Clinically, the hereditary form tends to have an early onset in adulthood and it is characterized by a particular tropism for nervous as well as cardiac tissue. In contrast, the "wild type" form has a later onset with major cardiac involvement and neurological manifestations usually limited to carpal tunnel syndrome (1).

Methods and results
in our centre, from January to October 2022, 20 patients older than 75 years received a diagnosis of cardiac ATTR (73% male, 27% female, mean age 83±5). In all patients, blood tests showed a significant and stable increase in the values of troponin Ths (0.070± 0.074 ng/mL) and NT-proBNP (1533±1204 pg/ml), with the absence of a monoclonal component in the blood and urine, and miocardial bisphosphonate scintigraphy positive grade 2/3. All patients showed absence of peripheral neuropathy with the presence of carpal tunnel syndrome in 9 cases. Before starting therapy with Tafamidis all patients underwent genetic testing by amplification of exons 2,3 and 4 of the TTR gene with subsequent sequencing. Unexpectedly, in 3 elderly male patients (15%) the genetic test resulted positive with 3 different mutations of pathogenetic significance (Val50Met; Ile88Leu; Val142Ile). First-degree relatives (10 consanguineous, average age 49±12 years) agreed to be subjected to genetic screening; of these 4 (1 male and 3 females, age 47±8 years) were positive for the corresponding mutation and underwent echocardiogram, MRI and myocardial scintigraphy. All of these tests were normal and they were included in an annual follow-up protocol at the to identify an early manifestation of the disease.

Conclusions
our experience shows that 15% of patients older than 75 years and diagnosed with cardiac ATTR may be affected by a genetic form. Making genetic diagnosis in this context is particularly important for screening family members: current therapies are in fact much more effective if started early before organ damage can occur (2).
Temporal trends and outcomes of heart failure patients between light-chain cardiac amyloidosis and transthyretin cardiac amyloidosis: insights from the national inpatient sample database
Authors: Gandhi K , Moras E , Correa A , Mahmood K 
Published: November 2023

Abstract

Background
Systemic amyloidosis comprises a family of diseases caused by deposition of misfolded fibrillar proteins in the extracellular space. Cardiac involvement is the leading cause of morbidity and mortality in systemic amyloidosis and a major determinant of survival, regardless of the underlying pathogenesis of amyloid production. Data regarding the clinical outcomes in immunoglobulin light-chain (AL) va amyloid transthyretin (ATTR) cardiac amyloidosis (CA) is scarce.

Purpose
We aimed to investigate the trends, baseline clinical characteristics, and clinical outcomes of AL CA vs ATTR CA in heart failure (HF) patients.

Methods
Data from United States National Inpatient Sample database from 2017-2020 was used to identify hospitalizations for CA with concurrent cardiomyopathy in HF patients and were further subclassified into AL vs ATTR CA. Outcomes were compared using univariate and multivariate logistic regression analysis.

Results
During 2017-2020, there were 12430 hospitalizations of CA of which 96.3% were ATTR CA and 3.7% were AL CA. Patients with ATTR-CA when compared to AL-CA were older, predominantly male, more blacks, and had a higher prevalence of co-morbidities including atrial arrythmias, sick sinus syndrome, and aortic stenosis. Patients with AL CA had significantly increased in-hospital mortality, length of stay, total charges, acute heart failure exacerbations, and cardiopulmonary resuscitation. After adjustment for baseline characteristics, AL CA patients had significantly increased odds of in-hospital mortality and HF hospitalizations when compared to ATTR CA cohort. There is an increasing trend in hospitalizations in AL CA from 2017-2019.

Conclusion
AL cardiac amyloidosis had significantly higher odds of in-hospital mortality and HF hospitalizations in comparison to ATTR cardiac amyloidosis cohort. AL CA had lower incidence of stroke, thromboembolism and major bleeding with similar need for cardiac device implantation.Figure 1Figure 2