bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiovascular phenotyping of the first mouse model of Sarcoidosis
Authors: Bueno Beti C , Lim C , Protonotarios A , Kiss A , Sheppard M.N , Szabo P.L , Behr E , Hamza O , Podesser B , Weichhart T , Asimaki A 
Published: November 2020

Abstract

Introduction
Sarcoidosis is a potentially life-threatening, inflammatory, granulomatous disease that affects multiple organs including the heart. Heretofore, its unknown etiology had hindered the creation of experimental models and the understanding of the molecular mechanisms of pathogenesis behind it.

Purpose
To extensively phenotype the heart of the first mouse model of sarcoidosis created through deletion of the tuberous sclerosis 2 (Tsc2) gene in the CD11c-positive macrophage population.

Methods
Tsc2 fl/fl CD11c Cre+ (Tsc2-KO; n=7) and Tsc2 fl/fl CD11c Cre- (Tsc2-WT; n=7) mice were subjected to echocardiography at 25 weeks of age (woa) to assess myocardial dimensions and function. Hearts of 13 and 25woa animals were subjected to histological and immunological stains to assess tissue changes, subtype inflammatory infiltrates and examine the localization of key proteins shown to be re-distributed in patients.

Results
At 13 woa, Tsc2-KO animals show inflammatory infiltrates; subtyped mainly as macrophages as well as evidence of myocyte destruction. At 25 woa, the number of inflammatory cells is significantly higher and there is heavy fibrotic replacement primarily in the septum and trabeculae. Older animals also show giant cells and non-necrotizing granulomas. The hearts show heterogeneous gap junction remodeling known to constitute an arrhythmogenic substrate and lack of immunoreactive signal for the desmosomal protein plakoglobin from the cell-cell junctions just as described in patients. The left ventricular ejection fraction and LV morphology was not significantly different between the two groups (EF: 64±4% in Tsc2-KO vs 64±2% in Tsc2-WT; LV end-systolic diameter: 4.51±0.54 mm in Tsc2-KO vs 4.59±0.29 mm in Tsc2-WT). However, there was a strong trend towards increasing filling pressure (E/e'ratio; 14.24±4.01 vs 12.15±2.54) and mean pulmonary pressure (21±6 vs 18±3 mmHg) in Tsc2-KO mice compared to controls suggesting diastolic dysfunction.

Conclusion
Hearts of the Tsc2 fl/fl CD11c Cre+ animals show a phenotype highly reminiscent of cardiac sarcoidosis in patients. We anticipate that this model will be very useful in deciphering molecular mechanisms of pathogenesis as well as testing much-needed mechanism-based therapies.

Funding Acknowledgement
Type of funding source: Foundation. Main funding source(s): British Heart Foundation - PG/18/27/33616
High sensitive troponin T as gatekeeper for cardiac magnetic resonance imaging in patients with suspected acute myocarditis
Authors: Frick M , Bauermann K , Kirschfink A , Hamada S , Weber O , Marx N , Altiok E 
Published: November 2020

Abstract

Background
The diagnosis of acute (AM) is difficult because of the variable, unspecific clinical presentation. Cardiac magnetic resonance (CMR) is the noninvasive gold standard diagnostic tool, but limited availability and high costs make a quick and inexpensive test necessary to clarify the need for CMR. Quantification of high sensitive Troponin T (hsTNT) is a broadly available, specific blood test for cardiomyocyte damage.

Aim
The aim of this study was to evaluate hsTNT as a gatekeeper for CMR with a lower cut off-value for exclusion and an upper cut-off value for confirmation of acute myocarditis as defined by CMR.

Methods
This retrospective analysis included 244 patients (age 39±17 years, 71% male) who received CMR for clinically suspected AM and quantification of hsTNT within 28 days (Median: 2 days) of CMR. CMR (1.5 Tesla) consisted of cine-sequences, edema-sensitive T2 and late gadolinium enhancement (LGE) imaging. AM was diagnosed in presence of both, myocardial edema and LGE consistent with acute myocarditis.

Results
Of 244 patients, 78 (32%) were CMR-positive (CMR+) for AM. 166 (68%) were CMR negative (CMR−). Mean hsTNT was 206±454 pg/ml.
HsTNT was significantly higher in CMR+ than in CMR− (604±639 pg/ml vs 20±56 pg/ml, p&lt;0.001, see figure A). 8 CMR+ patients (10%) had hsTNT in the normal range (&lt;14 ng/ml).
HsTNT showed good discriminatory performance in the Receiver Operator Characteristic (ROC) analysis (AUC 0.91, see figure B).
A lower cut-off value of 4 pg/ml had a sensitivity of 98.7% for diagnosis of AM (hsTNT ≥4 pg/ml) and a negative predictive value of 98.2% for rule out of AM (hsTNT&lt;4 pg/ml) as defined by CMR, leading to a reduction of 23.4% of CMR exams. An upper cut-off value of &gt;343 pg/ml had a specificity of 99.4% and positive predictive value of 97.8% for diagnosis of AM, leading to a reduction of 18.4% of CMR exams (see table).

Conclusions
hsTNT showed good discriminatory capacity for acute myocarditis (AM) as defined by CMR. However, 10% of patients had hsTNT in the normal range (&lt;14 pg/ml). A lower cut-off value of &lt;4 pg/ml ruled out AM with very high negative predictive value, whereas an upper cut-off of &gt;343 pg/ml had a very high positive predictive value for confirmation of AM as defined by CMR. Performing CMR only in patients with hsTNT between 4 and 343 pg/ml would have led to a reduction of 41.8% of CMR exams.

Funding Acknowledgement
Type of funding source: None
Regional disparities in the clinical profiles of patients with peripartum cardiomyopathy in Nigeria: results from the peripartum cardiomyopathy in Nigeria Registry
Authors: Karaye K , Sai'du H , Balarabe S.A , Ishaq N.A , Adamu U.G , Mohammed I.Y , Oboirien I , Umuerri E.M , Mankwe A.C , Shidali V.Y , Dodiyi-Manuel S , Olunuga T , Josephs V , Mbakwem A.C , Ogah O.S 
Published: November 2020

Abstract

Background
Peripartum cardiomyopathy (PPCM) seems to have varied epidemiology within and between countries. We recently reported that Kano (North-West Nigeria) has the highest known incidence of PPCM in the world, but the clinical profiles of the patients by regions have not been previously reported. In this study, we aimed to describe the regional differences (if any) in the clinical profiles of patients with PPCM in Nigeria.

Methods
We consecutively recruited 244 PPCM patients over 9 months from 3 hospitals in Kano (n=199; 81.6%) and from 11 hospitals spread across the North-Central, South-West, South-East and South-South zones (n=45; 18.4%) of Nigeria.

Results
The baseline characteristics of the patients are summarised in Table 1. 35 (17.6%) patients in Kano and 10 (23.2%) patients in other zones died (p=0.0523) after a median of 17 months.

Conclusion
PPCM patients in Kano were younger, had lower socio-economic status, presented to hospitals later, were less symptomatic, had larger sizes of cardiac chambers, worse right ventricular systolic function, higher pulmonary artery systolic pressure and were receiving less treatment at enrolment, than those in other zones in Nigeria. This information will be used for advocacy and interactions with healthcare providers.

Funding Acknowledgement
Type of funding source: Private company. Main funding source(s): Dantata Group of Companies (Nigeria). Ammasco International Ltd. (Nigeria). Fortune Oil Mills Nigeria Ltd.
Penetrance of hypertrophic cardiomyopathy and outcome in sarcomeric mutation carriers
Authors: Lorenzini M , Norrish G , Field E , Ochoa J.P , Cicerchia M , Akhtar M.M , Syrris P , Lopes L.R , Kaski J.P , Elliott P.M 
Published: November 2020

Abstract

Background
Predictive genetic screening of the first degree relatives of patients with hypertrophic cardiomyopathy (HCM) caused by sarcomere protein (SP) gene mutations is current standard of care, but there are few data on long-term outcomes in mutation carriers without HCM.

Purpose
To establish the role of sex and genotype in HCM penetrance as well as the rate of major adverse clinical events in SP mutation carriers and following the diagnosis of HCM.

Methods
Retrospective analysis of consecutive adult and paediatric SP mutation carriers identified during family screening and who did not fulfill diagnostic criteria for HCM at first evaluation.

Results
321 individuals from 170 families [median age first evaluation 15.2 years (IQR 7.3–32.6); 153 (47.7%) males] were evaluated. Causal SP genes were: MYBPC3 (n=133 (41.4%)), MYH7 (n=77 (24.0%)), TNNI3 (n=51 (15.9%)), TNNT2 (n=40 (12.5%)), TPM1 (n=9 (2.8%)), MYL2 (n=6 (1.9%)), and ACTC1 (n=1 (0.3%)); 4 (1.3%) carried multiple mutations.
After a median follow up of 7.4 years (IQR 2.5–12.7), 89 (27.7%) patients developed HCM. Disease penetrance at the age of 50 years was 47% (95% CI 38%-56%). One hundred and fifty three (47.7%) individuals underwent cardiac magnetic resonance (CMR) imaging; among those diagnosed with HCM, 22/89 (24.7%) fulfilled criteria on CMR but not echocardiography.
In a multivariable model adjusted for genotype, follow up duration and evaluation with CMR, independent predictors of HCM development were male sex (HR 3.11; CI 1.82–5.32) and abnormal ECG (HR 7.87; CI 4.43–13.97). Patients with MYH7 and multiple mutations were more likely to develop HCM than those with MYBPC3 mutations (HR 2.03; CI 1.04–3.96 and HR 10.13; CI 1.40–72.92, respectively). Disease penetrance was lowest in carriers of TNNI3 mutations (HR 0.13; CI 0.03–0.48).
There were no major adverse events in individuals without HCM. Following the diagnosis of HCM, the combined rate of all-cause death, appropriate defibrillator shock or resuscitated cardiac arrest was 1.1%/year [median follow up 4.0 years (IQR 2.1–8.9)].

Conclusions
Approximately 50% of SP mutation carriers develop HCM by the age of 50 and become prone to disease complications during long-term follow-up. Sex, MYH7 mutations and the presence of an abnormal ECG are associated with a higher risk of disease development. CMR should be employed systematically in long-term screening.
HCM penetrance by sex

Funding Acknowledgement
Type of funding source: None
Prognostic impact of atrial fibrillation in patients with hypertrophic cardiomyopathy in a community-based Japanese cohort: results from Kochi RYOMA study
Authors: Kubo T , Sugiura K , Ochi Y , Takahashi A , Baba Y , Hirota T , Yamasaki N , Doi Y.L , Kitaoka H 
Published: November 2020

Abstract

Background
The prognostic impact of atrial fibrillation (AF) in patients with hypertrophic cardiomyopathy (HCM) is not fully elucidated.

Purpose
The aim of this study was to examine the prevalence and prognostic impact of AF in a prospectively assembled community-based HCM patient cohort in an aged Japanese community.

Methods
In 2004, we established a cardiomyopathy registration network in Kochi Prefecture, Japan, consisting of 9 hospitals, and finally 293 patients with HCM were followed.

Results
The ages at registration and at diagnosis were 63±14 and 56±16 years, respectively, and 197 patients (67%) were men. 86 patients (29%) showed AF. During follow-up period of 6.1±3.2 years, 44 patients died. In those patients, HCM-related deaths occurred in 23 patients with an annual mortality rate of 1.3%. Regarding HCM-related adverse events including HCM-related deaths, appropriate ICD discharge, heart failure admission and hospitalization for embolic events, a total of 77 cardiovascular events in 70 patients occurred. Multivariate analysis revealed that presence of AF, left ventricular (LV) outflow obstruction, NYHA functional class III, and lower LV fractional shortening at registration were significant predictors of these adverse events. During the follow-up period, additional 31 patients (11%) developed new-onset AF. Importantly, the incidence of HCM-related adverse events was significantly higher in patients with new AF observed from its onset compared with those with AF at registration (log-rank p=0.029) (Figure 1).

Conclusions
In an unselected HCM registry in an aged Japanese community, presence of AF, particularly new-onset AF, was associated with unfavorable clinical outcomes. AF is not just a marker of the disease stage but an important trigger of HCM-related adverse events.
Figure 1

Funding Acknowledgement
Type of funding source: None
Matrix metalloproteainase-3 polymorphism association with hypertrophic cardiomyopathy
Authors: Fourti N , Benhlima M , Guizani I , Aloui S , Zaroui A , Zidi W , Mechmeche R , Mourali M.S , Feki M , Allal Elasmi M 
Published: November 2020

Abstract

Background
Matrix metalloproteinase-3 (MMP-3) level disequilibrium in hypertrophic cardiomyopathy (HCM) may be due to a specific genetic variation. The MMP-3 gene promoter contains an insertion/deletion polymorphism characterized by an array of 5 or 6 adenosine residues (5A/6A) at –1612 positions.

Purpose
The aim was to analyze whether the MMP-3 5A/6A gene promoter polymorphism is related to its level in HCM patients.

Methods/Results
In this study, we recruited 33 HCM patients and 35 non-HCM. The ELISA sandwich assay measured MMP-3 plasmatic level. The MMP-3 –1612 5A/6A polymorphism was genotyped by RFLP-PCR. The studied population was consistentin Hardy-Weinberg equilibrium. There were 17% 5A/5A homozygotes, 65% 6A/6A homozygotes, and 17% 5A/6A heterozygotes. The HCM was related to the existence of the –1612 5A/6A polymorphism (p&lt;0.05). Patients carrying the 5A allele had a higher MMP-3 level than those with the 6A allele (16.03±9.43 vs 8.68±5.89 ng/ml, respectively; p=0.01).

Conclusion
Our data shows that the –1612 5A/6A MMP-3 gene polymorphism is associated to the hypertrophic cardiomyopathy and do influence the MMP-3 plasmatic circulating level.

Funding Acknowledgement
Type of funding source: None
Discovery and analyses of pathogenic variants in explanted hearts from primary cardiomyopathy patients
Authors: Gunnarsdottir O , Kim Y , Reichart D , Nguyen Q , Zhang H , Nikhanj A , Pereira A.C , Gorham J , Depalma S.R , Seidman J.G , Oudit G , Seidman C.E 
Published: November 2020

Abstract

Background
Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are disorders of the myocardium that affect the structure and function of the heart.

Purpose
The primary aim of this study was to discover damaging genetic variants in myocardial tissue from patients with DCM or HCM, who underwent heart transplantation.

Methods
Whole exome sequencing was performed on myocardial tissue from 103 explanted hearts with diagnosis of cardiomyopathy; 80 DCM and 13 HCM. Sanger sequencing was performed to confirm the loss-of-function variants in genes known to be linked to cardiomyopathy. RNA sequencing was conducted to confirm copy number variation deletions detected in the cohort. Burden analysis was performed by comparing the frequency of variants found in the study cohort to the frequency in the population database gnomAD.

Results
Rare (minor allele frequency &lt;1.0E-04) loss-of-function variants, deleterious missense variants, or copy number variation deletions, collectively described as damaging variants, were identified in cardiomyopathy genes in 42 of all 93 samples (45.2%). Damaging variants were identified in 37 of 80 DCM samples (46.3%) and 5 of 13 HCM samples (38.4%). The mean read depth for normal and variant allele were comparable. All the 28 loss-of-function variants in cardiomyopathy genes found in the cardiomyopathy cases were confirmed by Sanger sequencing. Two copy number variation deletions both in titin (TTN) were also detected and confirmed. Burden analyses showed that the genes TTN and lamin A/C (LMNA) had a higher frequency of loss-of function variants in the DCM cohort (17.5% and 3.75%, respectively) compared to the reference population with genome-wide significance (p=3.45E-22 and 4.34E-07, respectively). Furthermore, our analysis showed that deleterious missense variants in osteoclast-stimulating factor 1 (OSTF1), which previously has not been associated with cardiomyopathy, was highly enriched in the DCM cohort compared to the reference population (p=2.10E-06).

Conclusions
The frequency of damaging variants that are likely pathogenic (46.3%) is higher in DCM cases in this cohort compared to previous studies. These data indicate that patients with end-stage DCM are more likely to have a genetic cause for their disease. As read depth of variant and normal alleles were, these are likely germline and not mosaic variants, and can enable cascade testing in family members. Moreover, our study demonstrates that CNVs in TTN that alter the reading frame can cause DCM.

Funding Acknowledgement
Type of funding source: None
First-in-world assessment of outcomes of catheter ablation for atrial arrhythmias in arrhythmogenic right ventricular cardiomyopathy
Authors: Gasperetti A , James C.A , Chen L , Compagnucci P , Casella M , Dello Russo A , Tondo C , Platonov P , Jensen H.K , Schenker N , Shibu M , Kany S , Calkins H , Duru F , Saguner A.M 
Published: November 2020

Abstract

Introduction
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically inherited disease characterized by fibro-fatty infiltrations (FFI). FFI in ARVC patients usually originates in the ventricles, but recent imaging studies showed FFI at the atrial level as well. Effectiveness of catheter ablation (CA) for atrial arrhythmias (AA) in this subset of patients is currently unknown.

Purpose
Aim of our study is to describe acute and long-term effectiveness of CA for AA in ARVC patients.

Methods
Nine ARVC registries from Europe, US, and China were retrospectively searched for ARVC patients undergoing CA for AA (namely: atrial fibrillation (AF), atrial tachycardia (AT), and cavo-tricuspid dependent atrial flutter (CTI-FL)). Baseline, procedural, and long-term outcome data were collected.

Results
Thirty-five pts (86% male, median CHA2DS2-VASc 1 [1–2], HAS-BLED 1 [0–2], and EHRA scores 2 [2–3]) were enrolled, in which a total of 45 CA procedures for AA were performed (left atrial CA: n=19 AF, n=10 AT; right atrial CA: n=16 CTI). Mean age at AA CA was 48.2±14.8 y.o. At baseline, 63% of pts were on oral anticoagulants (OAC) (n=9 warfarin; n=13 NOAC). Catheter ablation was successful and sinus rhythm obtained at the end of the procedure in all patients, with 2 (6%) AF patients requiring electrical cardioversion. Over a median follow-up of 36 [14–74] months, 12 (27%) pts experienced arrhythmia recurrence (left atrial group: n=6 AF recurrences, n=3 AT recurrences; CTI-FL group: n=1 CTI-FL recurrence; n=1 new AF with previous CTI-dependent flutter ablation), with a 1-year follow-up resulting comparable to what has been reported in the literature for the general population. [Figure 1 and 2]. 61% pts were on OAC at last follow-up.

Conclusion
Age at the time of CA for AA is about 10 years younger in patients with ARVC as compared to the general population. CA for AA in ARVC pts is safe and effective; surprisingly, long-term CA outcomes for AF and left AT result comparable to those reported in the general population, whereas recurrence rates of CTI-dependent flutter seem to be higher.

Funding Acknowledgement
Type of funding source: None
Long time clinical course of cardiac sarcoidosis with corticosteroid therapy -from Japanese nationwide questionnaire survey-
Authors: Kamada H , Ishibashi K , Nakajima K , Ueda N , Kamakura T , Wada M , Yamagata K , Inoue Y , Miyamoto K , Nagase S , Noda T , Aiba T , Isobe M , Terasaki F , Kusano K 
Published: November 2020

Abstract

Background
Sarcoidosis is a systemic inflammatory syndrome of unknown etiology and cardiac involvement has been reported to be an important prognostic factor in this disease. An autopsy study has reported that the frequency of this cardiac involvement (cardiac sarcoidosis: CS) varies in the different countries and races and very frequent in Japanese patients. We therefore performed the nationwide questionnaire survey and try to clarify the clinical characteristics and corticosteroid effect in CS, especially focused on arrhythmic events in this disease.

Methods
Total of 757 Japanese patients from 57 hospitals who diagnosed CS were examined. Patients who unsatisfied the criteria of the Japanese new guidelines, or who underwent cardiac transplantations were excluded, and 420 patients (287 females, median follow-up periods 1864 days [interquartile range: 845–3159 days]) were analyzed. The clinical outcome and corticosteroid effect were evaluated.

Results
Clinical characteristics at diagnosis was as follows: female dominant (68%), mean age of 60±13 years old, mean left ventricular ejection fraction was 49±16%. Arrhythmic events were very frequently observed as an initial cardiac manifestation in 263 patients (62%) of CS, of which atrioventricular block (AVB) in 174 (41%), ventricular tachycardia (VT) in 73 (17%) and AVB with VT in 17 (4%) (Figure 1A). Pacemaker was implanted in 166 patients (40%) and defibrillators was 137 patients (33%). Corticosteroid was prescribed in 144 (83%) of 174 patients with AVB and in 62 (85%) of 73 patients with VT. Initial dose was mean 47.9 mg and maintenance dose of mean 7.3 mg. Corticosteroid improved VT as good as AVB (27% vs. 29%). However, corticosteroid sometimes worsened VT events compared with AVB (10% vs. 2%) (Figure 1B). During the course of follow-up, 32 patients were needed to increase corticosteroid in 23 of AVB and 10 of VT cases. However, there were no difference in mortality between the groups, whether or not to increase corticosteroid. All survival rate was 92% (5-year mortality), 83% (10-year mortality) and free from all cause death and defibrillator charge was 81% (5 year), 71% (10 year).

Conclusion
Fatal arrhythmia is commonly observed in CS as a primary symptom. Corticosteroid sometimes worsen ventricular arrhythmia and appropriate defibrillator discharge was common. Thus, careful attention for activating ventricular arrhythmia would be needed during the follow-up period even after corticosteroid therapy.

Funding Acknowledgement
Type of funding source: None
Quantitative and functional evaluation of endothelial progenitor cells in patients with cardiac amyloidosis
Authors: Itzhaki Ben Zadok O , Leshem-Lev D , Ben-Gal T , Hamdan A , Schamroth-Pravda N , Steinmetz T , Kandinov I , Kornowski R , Eisen A 
Published: November 2020

Abstract

Background
Endothelial microvascular dysfunction is a known mechanism of injury in cardiac amyloidosis (CA), but evidence regarding the level and function of endothelial progenitor cells (EPCs) in patients with CA is lacking.

Methods
Study population included patients with light-chain or transthyretin (ATTR) CA. Patients with diagnosed heart failure and preserved ejection fraction (HFpEF) without monoclonal gammopathy and a 99mTc-DPD scan incompatible with TTR were used as controls. Blood circulating EPCs were assessed quantitatively by the expression of VEGFR-2(+), CD34(+) and CD133(+) using flow cytometry, and functionally by the formation of colony forming units (CFUs). MTT assay was used to demonstrate cell viability. Tests were repeated 3 months following the initiation of amyloid-suppressive therapies (either ATTR-stabilizer or targeted chemotherapy) in CA patients.

Results
Our preliminary cohort included 14 CA patients (median age 74 years, 62% ATTR CA).
Patients with CA vs. patients with HFpEF (n=8) demonstrated lower expression of CD34(+)/VEGFR-2(+) cells [0.51% (IQR 0.4, 0.7) vs. 1.03% (IQR 0.6, 1.4), P=0.043] and CD133(+)/VEGFR-2(+) cells [0.35% (IQR 0.23, 0.52) to 1.07% (IQR 0.6, 1.5), P=0.003]. Functionally, no differences were noted between groups. Following the initiation of amyloid-suppressive therapies in CA patients, we observed the up-regulation of CD34(+)/VEGFR-2(+) cells [2.47% (IQR 2.1, 2.7), P&lt;0.001] and CD133(+)/VEGFR-2(+) cells [1.38% (IQR 1.1, 1.7), P=0.003]. Moreover, functionally, active EPCs were evident microscopically by their ability to form colonies (from 0.5 CFUs [IQR 0, 1.5) to 2 CFUs (IQR 1, 3.5), P=0.023]. EPCs' viability was demonstrated by an MTT assay [0.12 (IQR 0.04, 0.12) to 0.24 (IQR 0.16, 0.3), p=0.014].

Conclusions
These preliminary results demonstrate reduced EPCs levels in CA patients indicating significant microvascular impairment. Amyloid-targeted therapies induce the activation of EPCs, thus possibly promoting endothelial regeneration. These findings may represent a novel mechanism of action of amyloid-suppressive therapies
EPCs in CA patients and during therapy

Funding Acknowledgement
Type of funding source: None