bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving the yield of genetic testing in dilated cardiomyopathy using late gadolinium enhancement
Authors: Ferreira A , Antunes M M , Cardoso I , Viegas J , Bras P , Almeida I , Ferreira V , Antunes D , Ferreira R C , Rosa S A 
Published: October 2024

Abstract

Background
Genetic testing has become an important tool in the work-up of dilated cardiomyopathy (DCM), aiding in family screening and providing information about prognosis and arrhythmic risk. Nonetheless, a significant proportion of patients with DCM present negative genetic test results. The "Madrid Score" was created to evaluate the likelihood of positive genetic tests and increase their yield in DCM patients.

Purpose
To determine if late gadolinium enhancement (LGE) assessment can improve the Madrid Score accuracy and increase the yield of genetic tests for DCM.

Methods
A single-centre retrospective study of patients diagnosed with DCM who underwent cardiac magnetic resonance (CMR) and genetic test between January 2017 and October 2023. The CMR imaging included the assessment of LGE. Multivariate logistic regression was performed and the model’s change in performance was evaluated when adding LGE.

Results
A total of 90 patients with the diagnosis of DCM underwent CMR and genetic test during the study period. Patient’s mean age was 51.0±14.6 years, and 57.1% were male. The genetic test was positive (G+) in 42 (46.7%), and negative (G-) in 48 (53.3%) patients. A variant of uncertain significance was present in 31 (34.4%), and these were included in the G- group. Most of the known independent predictors of a G+ given by the Madrid Score were significant in our cohort: Family history of DCM (OR: 4.82; CI: 1.73-11.60; p &lt; 0.001), absence of hypertension (OR: 0.19; CI: 0.06-0.58; p &lt; 0.001), absence of left bundle branch block (OR: 0.22; CI: 0.05-0.98; p = 0.047), and low electrocardiogram voltage in peripheral leads (OR: 3.13; CI: 0.87-11.26; p = 0.081). When analyzing the effect of LGE in the regression model (R2 = 0.622, p &lt; 0.001), we found that the number of LGE segments (OR: 2.54; CI: 1.10-5.90; p = 0.031), and the presence of LGE in the anterior wall (OR: 3.01; CI: 1.42-12.04; p = 0.041), were associated with a higher rate of positive genetic tests. When comparing both regression models, the incorporation of LGE increased the prediction power of the standard Madrid Score, correctly predicting 82.0% of the tests in our sample, with a probability of a G+ result ranging from 2% when all predictors were absent to 84% when ≥6 predictors, including LGE, were present.

Conclusion
Our study suggests that LGE assessment may enhance the Madrid Score performance and consequently improve genetic testing decisions in DCM, potentially leading to better use of the limited resources in our health care system.
AI-enabled cardiac chambers volumetry in non-contrast coronary artery calcium CT scans vs. contrast-enhanced coronary CT angiography scans in the same patients
Authors: Naghavi M , Atlas K , Zhang C , Mao S S , Reeves A P , Budoff M J , Henschke C , Yankelevitz D 
Published: October 2024

Abstract

Introduction
We have developed an AI-enabled automated volumetry of cardiac chambers (AutoChamber) that works both on non-contrast ECG-gated cardiac CT scans used for coronary artery calcium (CAC) score, and non-contrast non-gated lung cancer screening CT scans. We have recently reported the agreement between AutoChamber measurements vs cardiac MRI measurements. Here we report AutoChamber results on non-contrast CAC scans and contrast enhanced coronary CT angiography (CTA).

Methods
We have obtained CT images from a previously published study in which 131 cases underwent non-contrast CAC and contrast enhanced CCTA at research institute. The cases consisted of 52.4% women with ages 55.0 ± 10.1 years. The cardiac chambers volume in 131 cases of contrast enhanced CCTA were measured using automated chamber volumetry by Philips Brilliance Volume v 4.5; Philips Healthcare.

Results
The correlations between Philips’ automated chamber volumetry in contrast enhanced CCTA scans versus AutoChamber automated volumetry in non-contrast CAC scans for left atrium (LA), left ventricle (LV), right atrium (RA), right ventricle (RV), and left ventricular wall (LVW) volume were 0.73, 0.65, 0.85, 0.93, 0.90, respectively (P for all &lt;0.01).

Conclusion
AI-enabled AutoChamber volumetry based on non-contrast cardiac scans is feasible, and correlates reasonably well with contrast-enhanced cardiac CT scans. Further studies are warranted to reproduce these results and explore the add-on value of AutoChamber to CAC scans.
Subclinical myocardial phenotype in genotype-positive relatives attending clinical and genetic screening for familial dilated cardiomyopathy
Authors: Tellefsen S , Vissing C R , Dybro A M , Bundgaard H , Poulsen S H , Jensen M S K , Christensen A H , Rasmussen T B 
Published: October 2024

Abstract

Aim
To investigate if asymptomatic relatives carrying genetic variants associated with familial dilated cardiomyopathy (DCM) show early signs of myocardial disease assessed by echocardiography.

Methods and Results
Asymptomatic relatives without a DCM-phenotype (n=176, 46% males, mean age 39 years ± 16) of 111 DCM index patients carrying likely pathogenic or pathogenetic variants in TTN, RBM20, and FLNC genes were recruited from two tertiary referral centers for inherited cardiac diseases. All participants underwent echocardiographic examinations focusing on left ventricular (LV) ejection fraction (LVEF), LV global longitudinal strain (LVGLS), and LV end-diastolic diameter (LVEDD), with operators blinded to genetic results. The participants were grouped into genotype positive ([G+], n=82) or genotype negative relatives ([G-], n=94) carrying or not carrying the disease-causing variant.
The G+ group had significantly lower systolic LV parameters compared to G- individuals with a mean LVGLS of -18.7% ± 2.4 versus -20.1% ± 2.8, p: 0.0029; and a mean ejection fraction of 57.8% ± 3.7 versus 59.7% ± 2.4, p: &lt;0.0001. The proportion of G+ individuals with an abnormal LVGLS (defined as less than -18%) was 46% compared to 18% in the G- group. 26 % of G+ individuals had an LVEF in the interval between 50 - 55% compared to of 5% G- individuals[MOU1] . Mean LVEDD did not differ significantly between G+ and G-groups (49.7 mm ± 4.9 versus 48.8 mm ± 4.7). However, LVEDD indexed to BSA were significantly increased in G+ individuals (26.7 mm/m2 ± 2.8 versus 25.4 mm/m2 ± 2.5, p-value 0.001).

Conclusion
Overall, the absolute mean values of LVGLS, LVEF, and LVEDD were within normal ranges in both G+ and G- groups of individuals. However, compared to non-carrier relatives, almost half of the asymptomatic G+ DCM relatives had signs of subclinical myocardial dysfunction with significantly lower values of LVGLS, LVEF, and larger left ventricular dimensions.
Protein redistribution in buccal cells as a prognostic marker for arrhythmogenic cardiomyopathy in paediatric patients
Authors: Moscatelli S , Jager J , Field E , Barnes A , Heenan I , Kaski J P , Asimaki A 
Published: October 2024

Abstract

Background
Mutations in genes encoding desmosomal proteins [plakoglobin (JUP), desmoplakin (DSP), plakophilin-2 (PKP2), desmoglein-2 (DSG2) and desmocollin-2 (DSC2)] cause complex genetic heart muscle disorders collectively described as arrhythmogenic cardiomyopathies (ACM). Diagnosis and risk stratification, particularly in the paediatric population, remain challenging owing to heterogeneous phenotypic manifestations and reduced genetic penetrance. Immunohistochemical analysis of heart muscle samples has shown that several junctional and signalling molecules are redistributed in patients with ACM, offering diagnostic information. However, the use of this approach in living patients was limited by need for heart samples. Recent studies in adults with ACM showed that the same set of proteins re-localised in the ACM heart also do so in the buccal epithelium.

Purpose
Given the ease of analysing serial cheek smears, we sought to establish how protein redistribution in buccal cells relates to disease onset and progression in children bearing desmosomal gene mutations.

Methods
Serial cheek smears from children with desmosomal variants were subjected to immunocytochemistry and confocal microscopy to study the distribution of JUP, DSP and PKP-1 as well as the major gap junction protein connexin43 (Cx43; GJA1) and the major subunit of the NFκB inflammatory pathway; RelA.

Results
37 patients

Conclusion
These data indicate that shifts in junctional/signalling proteins precede the onset of clinical disease. Indeed, in the majority of pre-clinical children, Cx43 and RelA seem to be redistributed first, suggesting that onset of abnormalities in electrical conductivity and inflammatory pathways occur first in the natural disease progression, in agreement with previous clinical observations. Moreover, the data suggest that additional proteins are shifted as the disease progresses. Although further verification is required, this study suggests that analysis of buccal smears may be used as a prognostic/risk stratification test in children with desmosomal variants.
Amplicon-based long-read sequencing is useful for confirming zygosity of DSG2 variants associated with Japanese ARVC
Authors: Sonoda K , Horie M , Ohno S 
Published: October 2024

Abstract

Background
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy mainly caused by desmosomal gene variants. Previously, we reported that DSG2 variants were the most common in 153 Japanese ARVC probands (DSG2 multiple, n=62 and single, n=4; PKP2, n=28; others, n=7). Among the multiple DSG2 variant carriers, 22 probands were compound heterozygous carriers, and 25 were homozygous, which were confirmed by genetic testing for family members (Figure A). On the other hand, 88% of their family members with single DSG2 variant carriers were not diagnosed with ARVC, which meant that recessive DSG2 variants were the major cause of ARVC in Japan. However, zygosities in remaining 15 probands with multiple DSG2 variants were unknown due to the lack of genome data from their parents.

Purpose
This study aimed to clarify the zygosities of multiple DSG2 variants using amplicon-based long-read sequencing.

Methods
Genomic DNA was extracted from whole blood using standard protocols. The range containing multiple variants was amplified by long-range PCR. Sequencing libraries were prepared using ONT Ligation Sequencing Kit. Each library was loaded onto a flow cell for sequencing on ONT GridION Mk1 running MinKNOW control software. FASTQ files were aligned to hg38 using minimap2. Variants were called using Clair3 and phased using WhatsHap. Integrative Genomics Viewer (IGV) was used for visualization of the phased variants.

Results
We successfully phased all the multiple DSG2 variants found in the 15 proband. A typical result of amplicon-based LRS was shown in Figure B. It was IGV screen shot of reads at DSG2 containing c.874C&gt;T (p.R292C) and c.1481A&gt;C (p.D494A). The reads colored in red belonged to one haplotype, while the ones in blue belonged to the other. Each of the two variants was on different color reads, indicating they were compound heterozygous variants. Using LRS, we confirmed all the 15 probands had compound heterozygous variants in DSG2. Overall, the 62 probands (40.5%) with DSG2 variants were recessive variant carriers (Figure A).

Conclusions
Japanese ARVC was mainly caused by autosomal recessive variants in DSG2. Clarifying the zygosity of causative variants is crucial for the diagnosis in recessive diseases including Japanese ARVC. Amplicon-based LRS was helpful for phasing the multiple DSG2 variants directly without genetic testing of the parents.Figure AFigure B
Natural course and effect of tafamidis treatment in real-life octogenarians with wild-type transthyretin cardiac amyloidosis: an international multi-centre analysis
Authors: Debonnaire P , Dujardin K , Verheyen N , Pouleur A C , Droogmans S , Claeys M , El Haddad M , Christiaen E , Zach D , Buytaert L , Jacobs A , Buysschaert I , Trenson S , Van Hoeyweghen R , Tavernier R 
Published: October 2024

Abstract

Background and aims
In real-life, wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is increasingly diagnosed in elderly patients above 80 years old. Nevertheless, specific data on natural course and outcome under tafamidis treatment in octogenarians are particularly scarce. We aimed to study tafamidis impact on mortality and its determinants in real-life ATTRwt-CM octogenarians.

Methods
International multi-centric cohort study of 710 consecutive ATTRwt-CM patients, stratified between octogenarians and non-octogenarians at diagnose and tafamidis naive or treatment. Mean follow-up was 2.2±1.8 years to all-cause mortality endpoint.

Results
The cohort consisted of 58.3% octogenarians (median 84 years, 74.2% male). Before tafamidis availability, natural course in octogenarians (148/257) versus non-octogenarians (109/257) was poor with 41% three-year and 70% five-year mortality versus 19% and 42%, respectively (p&lt;0.001). Since tafamidis availability, 70.1% (253/361) octogenarians were initiated on tafamidis, less than 83.7% (231/276) non-octogenarians (p&lt;0.001). Tafamidis discontinuation was similar (octogenarians 11.4%, non-octogenarians 7.9%, p=0.260). Overall tafamidis treated octogenarians had better survival than untreated octogenarians (p&lt;0.001) and untreated non-octogenarians (p=0.026), with 23% three-year and 51% five-year mortality. Tafamidis treatment related to lower mortality in octogenarians (HR 0.37, 95%CI 0.20-0.67, p=0.001), after correcting for age, NAC stage and NYHA class, the other independent predictors. Propensity-score matching for those variables in 218 subjects confirmed tafamidis mortality benefit in octogenarians (p&lt;0.001). Octogenarians had poorer survival under tafamidis, when initiated at ≥90 years old (p&lt;0.001), NAC stage ≥3 (p=0.001) or NYHA class ≥3 (p=0.055).

Conclusions
Tafamidis treatment in real-life octogenarians independently improves survival, with better effect of early initiation at lower disease stage and age.Structured graphical abstractDistributions within age category
Endomyocardial biopsy in the diagnosis of cardiac sarcoidosis
Authors: Malkonen H , Lehtonen J , Poyhonen P , Uusitalo V , Mayranpaa M I , Kupari M 
Published: October 2024

Abstract

Background
Definite diagnosis of cardiac sarcoidosis (CS) requires proof of sarcoid granulomas in the heart. Endomyocardial biopsy (EMB) is considered a risky procedure with poor sensitivity (&lt;25%) in CS (1), although comprehensive studies on its diagnostic performance are not available.

Purpose
We investigated the sensitivity, complications, and prognostic significance of EMB in a large cohort of patients with CS to help to choose diagnostic strategy when the disease is suspected.

Methods
We analysed the data of 260 consecutive patients diagnosed with CS in 1988-2022 at our institution. All met the diagnostic criteria of the Heart Rhythm Society (1). The use, findings, and complications of EMB were retrospectively noted in addition to patients’ demographics, presenting phenotype, diagnostic examinations, and future serious cardiac events. The data were retrieved from hospital records and an ongoing CS registry (2). Advanced imaging studies (cardiac magnetic resonance, positron emission tomography) were re-analysed and the follow-up information was updated until June 2023. EMB’s performance was assessed also in 30 cardiac transplant recipients having CS at the histopathologic study of the explanted heart.

Results
Of the 260 patients (mean age 49, 60% females), 216 (83%) underwent diagnostic EMB, 48 with repeat procedures. The sensitivity of EMB was 38%, rising to 49% after repeats. The predictors of positive EMB (Table 1) included the presenting phenotype and characteristics of the activity, extent, and location of myocardial involvement. Presentation with ventricular tachyarrhythmia, left ventricular (LV) ejection fraction ≤45%, elevation of cardiac troponins, and presence of middle or apical LV septal late gadolinium enhancement on magnetic resonance imaging were independent predictors (p&lt;0.05) of positive biopsy. The sensitivity of EMB was directly related to the count of the predictors present (Figure 1). The rate of procedural complications was 9.7% overall and 0.7% for major events. One pericardial effusion needed drainage, but no deaths or long-term sequels followed the biopsies. Minor complications included 10 paroxysms of ventricular tachycardia and 6 small pericardial effusions. The 10-year rate (95% CI) of the composite of cardiac death, end-stage heart failure, or ventricular tachyarrhythmia was 55% (44-67%) with positive EMB vs 29% (17-44%) with negative EMB (p&lt;0.001). When adjusted for the presenting phenotype and LV ejection fraction, EMB did not predict outcome events. In the 30 patients with CS in explanted hearts, the sensitivity of EMB, including the repeats, was 60%.

Conclusion
The sensitivity of EMB is better than usually presented in CS and the higher the more extensive myocardial involvement is. Risk of serious complications is &lt;1%. In patients with suspect CS, the pre-test likelihood and value of positive EMB should be weighed against the procedural risks in shared decision-making when choosing the diagnostic pathway.
Health-related quality of life and prognosis in cardiac sarcoidosis
Authors: Raak-Tarkiainen J , Lehtonen J 
Published: October 2024

Abstract

Background
Cardiac sarcoidosis (CS) is characterized by inflammatory myocardial disease, often leading to conduction disturbances, ventricular tachycardias, and heart failure. While factors like initial symptoms, LVEF, and troponin levels are known prognostic indicators, the impact of CS on health-related quality of life (HRQoL) is not well-understood. Additionally, limited data exists on the predictive value of FDG-PET in CS.

Purpose
This study aimed to assess HRQoL in CS patients and investigate its prognostic relevance concerning cardiac events.

Methods
Patients diagnosed with CS completed the RAND-36 general health-related questionnaire, covering eight dimensions. Clinical data were obtained from the Finnish myocardial inflammatory diseases registry. Follow-up data on cardiac events, including life-threatening ventricular tachyarrhythmias (VT/VF), heart transplant, left ventricular assist device (LVAD) implantation, pericardial tamponade, or death, were collected over 36 months.

Results
Of the 240 CS patients surveyed, 179 (75%) were female, with a median age of 56 [IQR 48 – 64]. CS patients reported significantly lower RAND-36 scores across all dimensions compared to the general Finnish population. Over the 3-year follow-up, 38 (16%) patients experienced cardiac-related adverse events, including VT/VF (26 cases), deaths (8 cases), heart transplants (2 cases), LVAD implantation (1 case), and pericardial tamponade (1 case).
We divided CS patients into those without adverse event (N=202) and with adverse events (N=38). Interestingly, in four dimensions of PF 70.0 [50.0-90.0] vs 60.0 [33.8-80.0], p=0.019, RP 50.0 [0.0-100.0] vs 0.00 [0-56.3], p=0.002, MH 76.0 [59.0-88.0] vs 66.0 [51.0-84.0], p=0.036, and SF 75.0 [50-100] vs 62.5 [37.5-78.1], p=0.037 were significantly lower scores in the event group.
Univariate Cox regression analysis (Table 1) revealed that physical functioning (PF) and role-physical (RP) dimensions, along with certain clinical factors, such as younger age, higher NYHA classification, elevated proBNP levels, lower hemoglobin levels, and the main manifestation of the disease as ventricular tachyarrhythmia, independently predicted adverse cardiac events. In the multivariate analysis, lower role-physical scores and younger age remained independent prognostic factors for adverse cardiac events.

Conclusions
Patients with CS demonstrated lower HRQoL compared to the general Finnish population. This study enhances our understanding of prognosis in CS and underscores the predictive value of HRQoL in identifying future adverse cardiac events, highlighting its relevance in the clinical management of these patients.
Sustained paradoxical vasodilation and blood pressure lowering in response to sympathetic stimulation as markers of disease severity and poor survival in primary AL amyloidosis.
Authors: Patras R , Petropoulos I , Theodorakakou F , Delialis D , Georgiopoulos G , Angelidakis L , Gavriatopoulou M , Kokkotis P , Manios E , Terpos E , Dimopoulos M A , Kastritis E , Stamatelopoulos K 
Published: October 2024

Abstract

Background
AL patients present sustained paradoxical vasodilation in response to sympathetic stimulation by cold pressor test (CPT). The clinical relevance of this finding is unknown.

Purpose
We investigated the association between CPT-induced vascular and hemodynamic responses with clinical characteristics of the disease in AL amyloidosis.

Methods
We consecutively recruited 113 newly diagnosed patients with AL amyloidosis before treatment initiation. High resolution ultrasonography was used to measure the maximum vasodilation of the brachial artery in response to a cold stimulus and 3 minutes after its withdrawal. Systolic (SBP) and diastolic blood pressure (DBP) were measured at the same timepoints. Clinical and laboratory makers of autonomic dysfunction were also measured in a subgroup of the population. All-cause and cardiovascular (CV) mortality were defined as end-points of the study.

Results
Sustained vasodilation post CPT (%pCPT) was associated with markers of autonomic dysfunction, namely dipping status (p&lt;0.05) and sudomotor dysfunction (p=0.064) and with NYHA stage, baseline NTproBNP and heart failure (p&lt;0.05 for all). DBP%pCPT was associated with the neuropathy symptom scale (NSS Autonomous, p=0.032), while SBP%pCPT was inversely associated with Mayo stage. Vasodilation%pCPT was independently associated with CV death (adjusted HR=1.154, p=0.017) while both DBP%pCPT (HR=0.955, p=0.027) and SBP%pCPT (HR=0.947, p=0.04) were independently associated with all cause death (adjusted for the core model including age, sex, SBP, Mayo stage and nerve involvement). Overall survival was worse in AL patients who demonstrated a decrease in SBP%pCPT than in those who exhibited an increase or kept it stable (log rank test, p=0.024). The same applies to DBP%pCPT(log rank test, p=0.002). Regarding CV death, Vasodilation%pCPT above 5.86% was associated with increased risk of CV death (log rank test, p=0.002).

Conclusions
In AL amyloidosis, sustained paradoxical vasodilation and decreased SBP and DBP in response to sympathetic stimulation were associated with autonomic dysfunction, more severe cardiac involvement and poor survival.