bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies
Authors: Lipov A , Jurgens S J , Mazzarotto F , Allouba M , Pirruccello J P , Aguib Y , Gennarelli M , Yacoub M , Ellinor P T , Bezzina C R , Walsh R 
Published: November 2023

Abstract

Background
Cardiomyopathies are a set of cardiac diseases which are typically thought to have an autosomal dominant mode of inheritance and usually present in adulthood. However, their genetic architecture is increasingly recognised to be more complex, characterised by incomplete penetrance, variable expressivity and high genetic heterogeneity. In addition, there has been a recent rapid rise in genes associated with cardiomyopathy via a recessive, rather than dominant, mode of inheritance. However, there is increasing evidence that the classical recessive/dominant dichotomy in many Mendelian-like diseases is an oversimplification, with reports of clinically relevant phenotypes, albeit milder, in heterozygous carriers of known recessive variants.

Purpose
Investigate the genetic landscape of recessive cardiomyopathy and explore the putative spectrum of dominance and recessiveness in cardiomyopathies.

Methods
Published genetic studies of cardiomyopathies caused by biallelic genotypes were systematically analysed. For established recessive cardiomyopathy genes, monoallelic associations with relevant cardiac phenotypes were investigated using the UK Biobank.

Results
After appraisal, we characterised 17 genes that are robustly associated with recessive cardiomyopathy based on exome or genome sequencing across multiple pedigrees. The recessive cases were characterised by early age of onset (mean (SD) 12.5±15.1 years), poor outcomes (42.8% reported deceased) and predominance of dilated cardiomyopathy (11/17 genes). Studies in understudied groups, particularly bottleneck populations and regions of high consanguinity, were particularly informative for novel gene discovery. For several of the recessive genes, monoallelic variants were associated with cardiac phenotypes in the UK BioBank, for example, ALPK3 and SLC30A5 with hypertrophic cardiomyopathy and LMOD2 with dilated cardiomyopathy, the latter two are novel monoallelic associations. Analysing individuals with biallelic variants in established dominant sarcomeric cardiomyopathy genes revealed an earlier age of onset compared to monoallelic carriers (median (IQR) 13.5 (1.0-30.0) vs 37.5 (23.6-49.8) years), although with variability between genes and variant classes.

Conclusions
Disease genes associated with recessive inheritance are becoming an increasingly important aspect of the genetic architecture of cardiomyopathies, but there is also evidence of the presence, and spectrum, of phenotypes in monoallelic carriers of variants for several of these same genes. These findings illustrate the complexities of genotype-phenotype associations in cardiomyopathy and the need for more comprehensive and informed clinical genetic testing, particularly for patients from diverse and understudied ancestries.Recessive cardiomyopathy cases
Cardiac Sarcoidosis treated with non-steroidal immunosuppressive therapy
Authors: Suwa K , Naruse Y , Nabeta T , Kitai T , Taniguchi T , Yoshioka K , Tanaka H , Okumura T , Baba Y , Matsue Y , Maekawa Y 
Published: November 2023

Abstract

Background
Non-steroidal immunosuppressive therapy is a potential treatment strategy for cardiac sarcoidosis. However, due to the lack of robust evidence, it is not recommended as an established treatment option in the guideline.

Purpose
The purpose of the study is to demonstrate the clinical outcome of the patients with cardiac sarcoidosis using non-steroidal immunosuppressive therapy in a retrospective registry entitled ILLUMINATE-CS (ILLUstration of the Management and prognosIs of JapaNese pATiEnts with Cardiac Sarcoidosis).

Methods
Of an entire cohort of 512 patients, 26 who received immunosuppressive therapy other than steroids were recruited for the analysis. The clinical outcome included all-cause death, fatal ventricular arrhythmic event (FVAE), and worsening heart failure with hospitalization.

Results
The reasons to use non-steroidal immunosuppressant were increased fluorodeoxyglucose (FDG) accumulation on the heart suggesting worsened inflammation (n = 13), side effects of steroid (n = 7), ventricular tachycardia or frequent ventricular premature contraction (n=4), complete atrioventricular block (n = 2), worsened symptom relating to non-cardiac sarcoidosis including neuro and pulmonary sarcoidosis (n = 2), and the other reason (n = 2), with some overlapping. Used non-steroidal immunosuppressants were comprised of methotrexate (n = 20, 6.9 ± 2.1 mg/week), cyclosporine (n =2, 75 or 100 mg/day), cyclophosphamide (n = 2, 25 or 50 mg/day), and azathioprine (n = 3, 100 mg/day in each). Side effects of non-steroidal immunosuppressant were observed in six cases and included one with methotrexate-related interstitial pneumonia, one with a methotrexate-associated lymphoproliferative disorder, one with septic coxitis with methotrexate, one with methotrexate-induced acute kidney injury, one with methotrexate-induced hepatic dysfunction, and one with azathioprine-induced anemia. After the addition of a non-steroidal immunosuppressant, steroids could be reduced in 14 cases of 26 cases with a median maintenance dose of 5 (interquartile range of 5–17) mg, although no cases stopped steroids. Of 13 cases who started non-steroidal immunosuppressant for the increased FDG uptake, decreased FDG uptake was observed in seven cases at the follow-up scan. Clinical outcome events were observed in 11 cases (42.3%). Detected events included all-cause death in five cases (19.2%), FVAE in four cases (15.4%), and worsening heart failure with hospitalization in five cases (19.2%), with some overlapping.

Conclusions
Non-steroidal immunosuppressive therapy may be a possible treatment option for patients who are not stabilized using sole steroid therapy or who suffer from the side effects of steroids.
Genetic testing in presumed cardiac sarcoidosis
Authors: Castrichini M , Agboola K , Siontis K C , Abou Ezzeddine O , Giudicessi J , Rosenbaum A , Pereira N 
Published: November 2023

Abstract

Background
Cardiac sarcoidosis (CS) is a difficult to diagnose inflammatory heart disease. Certain types of genetic cardiomyopathy have been reported to masquerade as inflammatory cardiomyopathy. The utility of genetic testing in the evaluation of inflammatory cardiomyopathy is not completely explored and data regarding the prevalence of genetic cardiomyopathies in patients with presumed CS is limited.

Methods
We retrospectively analyzed patients evaluated from May 2020 to October 2022 in our Cardiac Sarcoid Clinic diagnosed with presumed CS as inferred by either fluorodeoxyglucose positron emission tomography (FDG-PET) - computed tomography (CT) or cardiac magnetic resonance (CMR) or both. Pertinent demographic, genetic, electrocardiographic, and imaging data for these patients was extracted from the electronic medical record.

Results
Genetic testing was obtained in 47 (22%) of the 213 presumed CS patients, among whom 43 (91%) presented with suspected isolated CS, and 4 (9%) with possible cardiac involvement in the setting of systemic sarcoidosis. Among the patients who underwent genetic testing, 10 (21 %) had a pathogenic or likely pathogenic (P/LP) variant(s) in a genetic cardiomyopathy-susceptibility gene, including DSP (n=2), LMNA, FHL1, TPM1, MYBPC3, NRAS, MYH7 (n=2) and TTN (n= 2) genes. All P/LP patients had FDG uptake, and in those with CMR data, 100% had late gadolinium enhancement. The seven patients with P/LP who underwent endomyocardial biopsy had no evidence of granulomatous inflammation. Immunosuppression was initiated in 60% of the P/LP patients before knowledge of genetic results.

Conclusion
Patients suspected to have CS may have concomitant or primarily genetic cardiomyopathy that may masquerade as an inflammatory phenotype Genetic testing should be considered in these patients, not only to clarify the diagnosis and its prognostic and therapeutic implications, but also to offer cascade screening for the family of patients with P/LP variants who otherwise would not have been considered to have a heritable disease.
Incidence and risk factors of myocarditis in hospitalized patients with COVID-19 in Germany
Authors: Keller K , Sagoschen I , Konstantinides S , Gori T , Munzel T , Hobohm L 
Published: November 2023

Abstract

Background
In December 2019 first patient cases of pneumonia caused by a previously unknown virus was detected in China. This began the coronavirus disease 2019 (COVID-19)-pandemic with a never seen infectious disease burden and impact on the healthcare systems worldwide. The first severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections in Germany were reported on January 27th, 2020. From this initial cluster (in Bavaria), a sustained transmission of SARS-CoV-2 was followed by a substantial spread of COVID-19 in the German population.
Although COVID-19 is frequently accompanied by symptoms like fever, cough, sore throat, malaise, myalgias, and dyspnoea, and the infection affects the lungs primarily, COVID-19 might also lead to acute cardiac, kidney, and liver injury. Cardiac complications, particularly myocarditis, and pericarditis, were associated with SARS-CoV-2 infection. Viral infections are frequent causes of myocarditis, an inflammation of the myocardium, which may result in hospitalization and heart failure and can be followed by sudden cardiac death. Myocarditis as cardiac involvement in COVID-19 infection is well known. Real-world data about incidence in hospitalized COVID-19 patients and risk factors for myocarditis in COVID-19 patients are sparse.

Methods
We used the German nationwide inpatient sample to analyze all hospitalized patients with confirmed COVID-19-diagnosis in Germany in 2020 and stratified them for myocarditis (source: RDC of the Federal Statistical Office and the Statistical Offices of the federal states, DRG Statistics 2020, own calculations).

Results
Overall, 176,137 hospitalizations (52.3%males, 53.6%aged≥70years) with confirmed COVID-19-infection were coded in Germany in 2020, and among them, 226 (0.01%) had myocarditis (incidence:1.28 per 1000 hospitalization cases). Absolute numbers of myocarditis increased, while relative numbers decreased with age. COVID-19 patients with myocarditis were younger (64.0 [IQR 43.0/78.0] vs.71.0 [56.0/82.0], P&lt;0.001). In-hospital case fatality was 1.3-fold higher in COVID-19 patients with than without myocarditis (24.3% vs. 18.9%, P=0.012). Myocarditis was independently associated with increased case fatality (OR 1.89 [95%CI 1.33-2.67], P&lt;0.001). Independent risk factors for myocarditis were age&lt;70years (OR 2.36 [95%CI 1.72-3.24], P&lt;0.001), male sex (1.68 [95%CI 1.28-2.23], P&lt;0.001), pneumonia (OR 1.77 [95%CI 1.30-2.42], P&lt;0.001) and multi-systemic inflammatory COVID-19-infection (OR 10.73 [95%CI 5.39-21.39], P&lt;0.001).

Conclusion
The incidence of myocarditis in hospitalized COVID-19 patients in Germany was 1.28 cases per 1000 hospitalizations in 2020. Risk factors for myocarditis in COVID-19 were young age, male sex, pneumonia, and multi-systemic inflammatory COVID-19 infection. Myocarditis was independently associated with increased case fatality.
Mortality in hypertrophic cardiomyopathy is unrelated to genotype
Authors: Bonaventura J , Rowin E J , Chin M T , Puchnerova V , Polakova E , Macek Jr M , Koethe B , Veselka J , Maron B J , Maron M S 
Published: November 2023

Abstract

Background
Hypertrophic cardiomyopathy (HCM) patients with a pathogenic variant are presumed to have worse prognosis than patients without a pathogenic mutation. However, the genetic basis of hypertrophic cardiomyopathy (HCM) is complex, and relationship between genotype status and outcomes have not been completely resolved.

Objective
We assessed a large international HCM cohort to define the natural history and clinical consequences of genotype status.

Methods
Consecutive patients (n=1468) with established clinical HCM diagnosis underwent genetic testing focused on HCM-related genes. Patients with pathogenic or likely pathogenic variants were considered genotype positive (G+), and those without definite disease-causing mutation or a variant of uncertain significance (VUS) were considered genotype negative (G-). Patients were followed for 9.6 ± 8.2 years for clinical outcomes.

Results
Of 1468 HCM patients, 1156 (79%) were G - and 312 (21%) were G+. Over the follow-up 116 (10%) G- patients died at 70 ± 14 years, including in 26 (2.2%) from HCM-related causes. HCM-related mortality was not significantly different in G- patients (0.3%/year) as compared to G+ patients (0.3%/year) when adjusted for age (HR 0.93, 95% CI 0.38-2.30, p=0.87). All-cause mortality was not different among these groups (0.7%/year G- vs. 0.6%/year G+) when adjusted for age (HR 0.62, 95% CI 0.3-1.2, p=0.14) or comorbidities (HR 0.78, 95% CI 0.46-1.31, p=0.35). Rate of progression to advanced heart failure NYHA class III/IV in nonobstructive patients was not different in G- (4%/ year) vs. G+ (3%/year, HR 1.20, 95% CI 0.63-2.26, p=0.58). Sudden death events (appropriate ICD shocks, aborted cardiac arrest and sudden death) were more frequent in G+ patients (1.7%/year) than in G- patients (0.5%/year), albeit of borderline statistical significance when adjusted for age and SD risk factors (HR 1.58, 95% CI 1.00-2.49, p=0.05).

Conclusions
In this large consecutive genotyped cohort, all-cause and HCM-related mortality was unrelated to genotype status. Substantial proportion of G- patients experienced progressive HF, at a similar rate when compared to G+ patients. Although G- patients had less frequently SD events, genotype negative status could not be considered benign.FiguresTable
Epigenetic study of the differential phenotypic expression of a hypertrophic cardiomyopathy-related pathological variant at MYBPC3 in a cohort of monozygotic twins
Authors: Penarroya A , Fraga M , Rodriguez Reguero J J , Gomez J , Moris C , Lorca R 
Published: November 2023

Abstract

Introduction
Hypertrophic cardiomyopathy (HCM) is a inherited cardiac disease with a variable penetrance and expressivity. Epigenetics orchestrates the interplay between the environment and the molecular changes that lead to the development of the pathological phenotype. It is of great interest to identify the changes that determine the magnitude of left ventricular hypertrophy (LVH) in patients carrying a given pathogenic variant.

Methods
In this work, we used peripheral blood samples from a cohort of three homozygous twin pairs carrying the p.Gly263Ter pathogenic variant at MYBPC3 gene to suppress the underlying genetic effect and isolate the role of DNA methylation in its divergent phenotypic expressivity.

Results
We found a poorer life-style and a more anxious personality among the more severely affected patients. Using a pair-matched model corrected by cell type proportions, a total of 2486 differentially methylated positions (DMP) were extracted with moderate but proportional methylation changes to the LVH of the patients. DMP were enriched in functional regions controlled by repressor histone marks (H3K27me3, H3K9me3) and tended to colocalise forming differentially methylated regions (DMR) across genes mainly related to homophilic surface adhesion molecules and Ca2+ transport. Strikingly, many affected genes were found to be involved in LVH development, such as PLSCR2, ELMO3, TRIM68, HOXA5, UCN3, PCDHGA3, PAX8-AS1, suggesting that the analysis of blood samples could be able to recapitulate alterations at cardiac tissue level. Furthermore, the relationship of the observed changes with the development of the pathology was successfully validated with an external cohort of peripheral blood samples from healthy patients. Further studies are needed to validate the observed changes at cardiac tissue and to verify their causal role.

Conclusions
In this cohort of monozygotic twins we were able to identify promising epigenetic peripheral blood changes that relate to the expressivity of the HCM. Anxious personalities and lifestyle divergences could lie behind our findings. DNA methylation changes tend to locate at key positions related to cell-to-cell communication and Ca2+ metabolism, as well as at other loci already described to regulate LVH and stress.
Association of left atrial strain with long-term cardiovascular mortality in hypertrophic cardiomyopathy
Authors: Kim J , Lee H J , Kim H K , Lee S C 
Published: November 2023

Abstract

Background
Hypertrophic cardiomyopathy (HCM) is a relatively common genetic cardiac disease affecting 1 in 200 people. Although sudden cardiac death (SCD) is considered the most devastating event in patients with HCM, cardiovascular death (CVD) is the leading cause of death in this population. Little is known about the predictors of cardiovascular mortality.

Purpose
The aim of this study was to investigate prognostic implication of left atrial (LA) strain on long-term cardiovascular mortality in patients with HCM.

Methods
Peak longitudinal LA strain was measured on echocardiography at initial evaluation using vendor-independent speckle-tracking software. Among a prospective cohort of 865 HCM patients collected at two large tertiary centers, 697 with adequate echocardiographic images to measure biplane LA strain were included in the analysis. The primary endpoint was CVD during 10 years after initial evaluation.

Results
The median age was 56.0 years and 74.6% were male. Among the 697 patients, 25 died due to cardiovascular cause for 10 years. Among clinical and echocardiographic variables, older age, female sex, previous myocardial infarction, previous stroke, higher SCD risk score by European Society of Cariology, presence of SCD risk factors by American College of Cardiology, obstructive HCM, larger LA diameter, and lower LA strain were associated with CVD. LA strain had the highest predictive power for CVD occurrence, with a c-statistic of 0.79 (Figure 1). In multivariable Cox analysis, LA strain remains an independent predictor of CVD (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.82–0.94). Patients with LA strain &lt;19.4% (the lowest quartile), compared with those with LAS ≥19.4%, had a significantly higher risk of CVD (19.5% vs. 2.1%, HR 7.31, 95% CI 3.15–16.95), as well as death by any cause, SCD, and a composite of CVD, heart failure admission, and stroke (Figure 2).

Conclusions
In patients with HCM, LA strain is an independent predictor of long-term CVD.
Prognostic role of the progression of late gadolinium enhancement in hypertrophic cardiomyopathy
Authors: Todiere G , Aquaro G D , Barison A , Grigoratos C , Parisella M L , Amedei M , Grilli G , Faggioni L , Cioni D , Lencioni R , Neri E , Emdin M 
Published: November 2023

Abstract

Background
Late Gadolinium Enhancement (LGE) extent ≥15% of left ventricular (LV) mass is a widely accepted prognostic risk factor in hypertrophic cardiomyopathy (HCM). However, LGE extent increases over time and the clinical role of the progression of LGE (LGE-rate) was not prospectively evaluated in previous studies.

Purpose
We evaluated the clinical and prognostic role of LGE-rate in HCM.

Methods
105 patients with HCM underwent cardiac-MR at baseline (CMR-I) and after ≥2 years of follow-up (CMR-II). LGE extent was measured in both the examinations (LGE was defined using threshold validated method of ≥6 SD exceeding the mean of normal myocardium (1)).
LGE-rate was defined as the ratio between the increase of LGE extent (g) and the time interval (months) between CMR-I and CMR-II. A combined endpoint of sudden cardiac death (SCD), resuscitated cardiac arrest, appropriate ICD intervention and sustained ventricular tachycardia was used (hard events).

Results
The percentage of patients with LGE extent ≥15% increased from 9% to 20% at CMR-II (p=0.03), compared to CMR-I. During a median follow-up of 52 months, 25 hard events were recorded. The presence of LGE≥15% at CMR-II allowed a significant reclassification of the risk of patients than at LGE≥15% at CMR-I (NRI 0.21, p=0.046). At maximally selected rank statistical analysis the optimal prognostic cut-point for LGE-rate was &gt;0.07 g/months. At Kaplan-Meier curve analysis patients with LGE-rate&gt;0.07 had significant worse prognosis than those without (p&lt;0.0001) (figure 1). LGE-rate&gt;0.07 allowed a significant reclassification of the risk compared to LGE≥15% at CMR-I and at CMR-II (NRI 0.49, p=0.003) (figure 2). At Cox regression multivariable analysis, LGE-rate&gt;0.07 was the best independent predictor of hard events.

Conclusions
LGE-rate is heterogenous among patients with HCM and a follow-up CMR should be performed after 2 years to reclassify the risk of SCD of those patients. High LGE-rate should be considered as a novel prognostic risk factor in HCM.Figure 1Figure 2
Assessment of Myocardial Work in sarcomere gene mutation carriers and overt hypertrophic cardiomyopathy
Authors: Marques Pires C , Triantafyllou M , Monteiro R P , Joy G , Ferreira A , Savvatis K , Lopes L R 
Published: November 2023

Abstract

Introduction
Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease defined by unexplained hypertrophy and often characterized by diastolic and systolic dysfunction. In recent studies, HCM patients were found to have impaired left ventricular (LV) myocardial work (MW), a more load-independent parameter compared to global longitudinal strain (GLS). MW was never studied in sarcomere mutation carriers.

Aim
To compare MW between sarcomere mutation carriers, healthy controls and overt HCM.

Methods
A single centre study with a case-control design. The study population comprised 3 groups: overt HCM patients with a likely pathogenic/pathogenic sarcomere gene variant (n=51), carriers (n=51) and age and sex matched (to the carriers) healthy controls (n=32). All participants (pts) underwent a transthoracic echocardiogram including myocardial deformation analysis to calculate global longitudinal strain (GLS) and MW. MW was calculated from same-day non-invasive blood pressure evaluation. Global work index (GWI), Global constructive work (GCW), Global work efficiency (GWE) and Global wasted work (GWW) were obtained.

Results
GWI (1695mmHg% vs 1869mmHg%, p=0.001) and GCW (1993mmHg% vs 2244mmHg%, p&lt;0.001) were lower in sarcomere mutation carriers compared to controls. LVEF and GLS were similar between the two groups (p=0.233). HCM pts were older (p&lt;0.001), less likely female (p=0.01) and had a higher prevalence of cardiovascular (Cv) comorbidities, including hypertension (p&lt;0.001), compared with sarcomere gene mutation carriers. Global work index (GWI) (1209mmHg%vs1695mmHg%), global constructive work (1456mmHg% vs 1993mmHg%, p&lt;0.001) and global work efficiency (GWE) (89% vs 95%, p&lt;0.001) were significantly lower in overt HCM compared with sarcomere mutation carriers. GWW was higher (117mmHg% vs 95mmHg%, p=0.006) in overt HCM.

Conclusion
In this study, we show for the first time that MW indexes were significantly worse in sarcomere gene mutation carriers compared to controls. GLS and MW indexes were also significantly different between overt HCM and sarcomere gene mutation carriers. These data suggest that MW is more sensitive to early changes than GLS and could play a major role in the evaluation and follow-up of sarcomere mutation carriers.