Publications by authors named "Maria Sabater Molina"

31 Publications

CRITICAL STEPS FOR HUMAN GUT EXFOLIOME RNA PROFILING ANALYSIS USING NON-INVASIVE STOOL SAMPLES.

Ann Nutr Metab 2021 Nov 17. Epub 2021 Nov 17.

Introduction: Dietary exposure and drug treatments influence gut cellular pathways and hence growth and potentially even the gut-brain-microbiome axis. Since eukaryotic mRNA presents poly A sequence that distinguishes them from the prokaryotes mRNA, we could analyze the gene expression of human gut cells using exfoliated gut cells available in stool samples. However, the impact of the critical steps of these non-invasive methods must be analyzed.

Methods: We tested prokaryote contamination in all the steps of different procedures to analyze human exfoliome by microarrays and the influence of the fecal sampling collection process.

Results & Conclusion: The least bacterial contamination was found using RNA amplified with oligo dT from GeneChip 3´ IVT Pico Reagent kit or using RNA purified by both Oligotex® + oligodT. RNA later® collection of feces affects the microarray results compared to directly frozen fecal samples, although both methods produce similar cDNA quality. This technique is a potential non-invasive diagnostic tool that can be applied to larger studies to quantify intestinal gene expression in humans with non-invasive samples, but samples should always be collected and analyzed under the same procedure.
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http://dx.doi.org/10.1159/000520968DOI Listing
November 2021

Facts and Gaps in Exercise Influence on Arrhythmogenic Cardiomyopathy: New Insights From a Meta-Analysis Approach.

Front Cardiovasc Med 2021 18;8:702560. Epub 2021 Oct 18.

Cardiology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain.

Arrhythmogenic cardiomyopathy (ACM) is a genetic cardiac condition characterized by fibrofatty myocardial replacement, either at the right ventricle, at the left ventricle, or with biventricular involvement. Ventricular arrhythmias and heart failure represent its main clinical features. Exercise benefits on mental and physical health are worldwide recognized. However, patients with ACM appear to be an exception. A thorough review of the literature was performed in PubMed searching for original papers with the terms "ARVC AND sports/exercise" and "sudden cardiac death AND sports/exercise." Additional papers were then identified through other sources and incorporated to the list. All of them had to be based on animal models or clinical series. Information was structured in a regular format, although some data were not available in some papers. A total of 34 papers were selected and processed regarding sports-related sudden cardiac death, pre-clinical models of ACM and sport, and clinical series of ACM patients engaged in sports activities. Eligible papers were identified to obtain pooled data in order to build representative figures showing the global incidence of the most important causes of sudden cardiac death in sports and the global estimates of life-threatening arrhythmic events in ACM patients engaged in sports. Tables and figures illustrate their major characteristics. The scarce points of controversy were discussed in the text. Fundamental concepts were summarized in three main issues: sports may accelerate ACM phenotype with either structural and/or arrhythmic features, restriction may soften the progression, and these rules also apply to phenotype-negative mutation carriers. Additionally, remaining gaps in the current knowledge were also highlighted, namely, the applicability of those fundamental concepts to non-classical ACM phenotypes since left dominant ACM or non-plakophillin-2 genotypes were absent or very poorly represented in the available studies. Hopefully, future research endeavors will provide solid evidence about the safest exercise dose for each patient from a personalized medicine perspective, taking into account a big batch of genetic, epigenetic, and epidemiological variables, for instance, in order to assist clinicians to provide a final tailored recommendation.
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http://dx.doi.org/10.3389/fcvm.2021.702560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8558346PMC
October 2021

The EP300/TP53 pathway, a suppressor of the Hippo and canonical WNT pathways, is activated in human hearts with arrhythmogenic cardiomyopathy in the absence of overt heart failure.

Cardiovasc Res 2021 Jun 16. Epub 2021 Jun 16.

Center for Cardiovascular Genetics, Institute of Molecular Medicine and Department of Medicine, University of Texas Health Sciences Center at Houston, Texas, 77030.

Aim: Arrhythmogenic cardiomyopathy (ACM) is a primary myocardial disease that typically manifests with cardiac arrhythmias, progressive heart failure and sudden cardiac death (SCD). ACM is mainly caused by mutations in genes encoding desmosome proteins. Desmosomes are cell-cell adhesion structures and hubs for mechanosensing and mechanotransduction. The objective was to identify the dysregulated molecular and biological pathways in human ACM in the absence of overt heart failure.

Methods And Results: Transcriptomes in the right ventricular endomyocardial biopsy samples from three independent individuals carrying truncating mutations in the DSP gene and 5 control samples were analyzed by RNA-Seq (discovery group). These cases presented with cardiac arrhythmias and had a normal right ventricular function. The RNA-Seq analysis identified ∼5,000 differentially expressed genes (DEGs), which predicted suppression of the Hippo and canonical WNT pathways, among others.Dysregulated genes and pathways, identified by RNA-Seq, were tested for validation in the right and left ventricular tissues from 5 independent autopsy-confirmed ACM cases with defined mutations (validation group), who were victims of SCD and had no history of heart failure. Protein levels and nuclear localization of the cWNT and Hippo pathway transcriptional regulators were reduced in the right and left ventricular validation samples. In contrast, levels of acetyltransferase EP300, known to suppress the Hippo and canonical WNT pathways, were increased and its bona fide target TP53 was acetylated. RNA-Seq data identified apical junction, reflective of cell-cell attachment, as the most disrupted biological pathway, which was corroborated by disrupted desmosomes and intermediate filament structures. Moreover, the DEGs also predicted dysregulation of over a dozen canonical signal transduction pathways, including the Tec kinase and integrin signaling pathways. The changes were associated with increased apoptosis and fibro-adipogenesis in the ACM hearts.

Conclusion: Altered apical junction structures is associated with activation of the EP300-TP53 and suppression of the Hippo/cWNT pathways in human ACM caused by defined mutations in the absence of an overt heart failure. The findings implicate altered mechanotransduction in the pathogenesis of ACM.

Translational Perspective: The findings suggest that altered mechanosensing at the cell-cell junction instigates a cascade of molecular events through the activation of acetyltransferase EP300/TP53 and suppression of gene expression through the Hippo/canonical WNT pathways in human arrhythmogenic cardiomyopathy (ACM) caused by defined mutations. These molecular changes occur early and in the absence of overt heart failure. Consequently, one may envision cell type-specific interventions to target the dysregulated transcriptional, mechanosensing, and mechanotransduction pathways to prevent the evolving phenotype in human ACM.
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http://dx.doi.org/10.1093/cvr/cvab197DOI Listing
June 2021

Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy.

J Biol Chem 2021 07 5;297(1):100854. Epub 2021 Jun 5.

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. Electronic address:

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. Variants in MYBPC3, the gene encoding cardiac myosin-binding protein C (cMyBP-C), are the leading cause of HCM. However, the pathogenicity status of hundreds of MYBPC3 variants found in patients remains unknown, as a consequence of our incomplete understanding of the pathomechanisms triggered by HCM-causing variants. Here, we examined 44 nontruncating MYBPC3 variants that we classified as HCM-linked or nonpathogenic according to cosegregation and population genetics criteria. We found that around half of the HCM-linked variants showed alterations in RNA splicing or protein stability, both of which can lead to cMyBP-C haploinsufficiency. These protein haploinsufficiency drivers associated with HCM pathogenicity with 100% and 94% specificity, respectively. Furthermore, we uncovered that 11% of nontruncating MYBPC3 variants currently classified as of uncertain significance in ClinVar induced one of these molecular phenotypes. Our strategy, which can be applied to other conditions induced by protein loss of function, supports the idea that cMyBP-C haploinsufficiency is a fundamental pathomechanism in HCM.
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http://dx.doi.org/10.1016/j.jbc.2021.100854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260873PMC
July 2021

Cardiopulmonary Exercise Test in Patients with Hypertrophic Cardiomyopathy: A Systematic Review and Meta-Analysis.

J Clin Med 2021 May 25;10(11). Epub 2021 May 25.

Human Physiology Area, Faculty of Sport Sciences, University of Murcia, Santiago de la Ribera-San Javier, 30720 Murcia, Spain.

Background: Patients with chronic diseases frequently adapt their lifestyles to their functional limitations. Functional capacity in Hypertrophic Cardiomyopathy (HCM) can be assessed by stress testing. We aim to review and analyze the available data from the literature on the value of Cardiopulmonary Exercise Test (CPET) in HCM. Objective measurements from CPET are used for evaluation of patient response to traditional and new developing therapeutic measurements.

Methods: A systematic review of the literature was conducted in PubMed, Web of Science and Cochrane in Mar-20. The original search yielded 2628 results. One hundred and two full texts were read after the first screening, of which, 69 were included for qualitative synthesis. Relevant variables to be included in the review were set and 17 were selected, including comorbidities, body mass index (BMI), cardiac-related symptoms, echocardiographic variables, medications and outcomes.

Results: Study sample consisted of 69 research articles, including 11,672 patients (48 ± 14 years old, 65.9%/34.1% men/women). Treadmill was the most common instrument employed ( = 37 studies), followed by upright cycle-ergometer ( = 16 studies). Mean maximal oxygen consumption (VO2max) was 22.3 ± 3.8 mL·kg·min. The highest average values were observed in supine and upright cycle-ergometer (25.3 ± 6.5 and 24.8 ± 9.1 mL·kg·min; respectively). Oxygen consumption in the anaerobic threshold (ATVO2) was reported in 18 publications. Left ventricular outflow tract gradient (LVOT) > 30 mmHg was present at baseline in 31.4% of cases. It increased to 49% during exercise. Proportion of abnormal blood pressure response (ABPRE) was higher in severe (>20 mm) vs. mild hypertrophy groups (17.9% vs. 13.6%, < 0.001). Mean VO2max was not significantly different between severe vs. milder hypertrophy, or for obstructive vs. non-obstructive groups. Occurrence of arrhythmias during functional assessment was higher among younger adults (5.42% vs. 1.69% in older adults, < 0.001). Twenty-three publications (9145 patients) evaluated the prognostic value of exercise capacity. There were 8.5% total deaths, 6.7% cardiovascular deaths, 3.0% sudden cardiac deaths (SCD), 1.2% heart failure death, 0.6% resuscitated cardiac arrests, 1.1% transplants, 2.6% implantable cardioverter defibrillator (ICD) therapies and 1.2 strokes (mean follow-up: 3.81 ± 2.77 years). VO2max, ATVO2, METs, % of age-gender predicted VO2max, % of age-gender predicted METs, ABPRE and ventricular arrhythmias were significantly associated with major outcomes individually. Mean VO2max was reduced in patients who reached the combined cardiovascular death outcome compared to those who survived (-6.20 mL·kg·min; CI 95%: -7.95, -4.46; < 0.01).

Conclusions: CPET is a valuable tool and can safely perform for assessment of physical functional capacity in patients with HCM. VO2max is the most common performance measurement evaluated in functional studies, showing higher values in those based on cycle-ergometer compared to treadmill. Subgroup analysis shows that exercise intolerance seems to be more related to age, medication and comorbidities than HCM phenotype itself. Lower VO2max is consistently seen in HCM patients at major cardiovascular risk.
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http://dx.doi.org/10.3390/jcm10112312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198116PMC
May 2021

Electrocardiographic Screening of Arrhythmogenic Cardiomyopathy in Genotype-Positive and Phenotype-Negative Relatives.

Front Cardiovasc Med 2021 7;8:646391. Epub 2021 May 7.

Department of Cardiology, Virgen de la Arrixaca University Hospital, Murcia, Spain.

Arrhythmogenic cardiomyopathy is a hereditary cause of ventricular arrhythmias and sudden death. Identifying the healthy genetic carriers who will develop the disease remains a challenge. A novel approach to the analysis of the digital electrocardiograms of mutation carriers through signal processing may identify early electrocardiographic abnormalities. A retrospective case-control study included a population of healthy genetics carriers and their wild-type relatives. Genotype-positive/phenotype-negative individuals bore mutations associated with the development of arrhythmogenic cardiomyopathy. The relatives included had a non-pathological 12-lead electrocardiogram, echocardiogram, and a cardiac magnetic resonance. Automatic digital electrocardiographic analyses comprised QRS and terminal activation delay duration, the number of QRS fragmentations, ST slope, and T-wave voltage. Digital 12-lead electrocardiograms from 41 genotype-positive/ phenotype-negative (29 simple carriers and 12 double mutation carriers) and 73 wild-type relatives were analyzed. No differences in the QRS length, the number of QRS fragmentations, and the voltage of the T-wave were observed. After adjusting for potential confounders, double carriers showed an average ST-slope flatter than those of the simple carriers and wild type [5.18° (0.73-8.01), 7.15° (5.14-11.05), and 11.46° (3.94-17.49), respectively, = 0.005]. There was a significant negative correlation between the ST slope and the age in genotype-positive/phenotype-negative relatives ( = 0.376, = 0.021) not observed in their wild-type counterparts ( = 0.074, = 0.570). A flattened ST segment may be an early sign of electrical remodeling that precedes T-wave inversion in healthy genetic carriers. A thorough analysis of the digital electrocardiographic signal may help identify and measure early electrical abnormalities.
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http://dx.doi.org/10.3389/fcvm.2021.646391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137826PMC
May 2021

Association of Left Ventricular Systolic Dysfunction Among Carriers of Truncating Variants in Filamin C With Frequent Ventricular Arrhythmia and End-stage Heart Failure.

JAMA Cardiol 2021 08;6(8):891-901

Heart Failure and Heart Transplantation Unit, Virgen del Rocio University Hospital, Sevilla, Spain.

Importance: Truncating variants in the gene encoding filamin C (FLNCtv) are associated with arrhythmogenic and dilated cardiomyopathies with a reportedly high risk of ventricular arrhythmia.

Objective: To determine the frequency of and risk factors associated with adverse events among FLNCtv carriers compared with individuals carrying TTN truncating variants (TTNtv).

Design, Setting, And Participants: This cohort study recruited 167 consecutive FLNCtv carriers and a control cohort of 244 patients with TTNtv matched for left ventricular ejection fraction (LVEF) from 19 European cardiomyopathy referral units between 1990 and 2018. Data analyses were conducted between June and October, 2020.

Main Outcomes And Measures: The primary end point was a composite of malignant ventricular arrhythmia (MVA) (sudden cardiac death, aborted sudden cardiac death, appropriate implantable cardioverter-defibrillator shock, and sustained ventricular tachycardia) and end-stage heart failure (heart transplant or mortality associated with end-stage heart failure). The secondary end point comprised MVA events only.

Results: In total, 167 patients with FLNCtv were studied (55 probands [33%]; 89 men [53%]; mean [SD] age at baseline evaluation, 43 [18] years). For a median follow-up of 20 months (interquartile range, 7-60 months), 29 patients (17.4%) reached the primary end point (19 patients with MVA and 10 patients with end-stage heart failure). Eight (44%) arrhythmic events occurred among individuals with baseline mild to moderate left ventricular systolic dysfunction (LVSD) (LVEF = 36%-49%). Univariable risk factors associated with the primary end point included proband status, LVEF decrement per 10%, ventricular ectopy (≥500 in 24 hours) and myocardial fibrosis detected on cardiac magnetic resonance imaging. The LVEF decrement (hazard ratio [HR] per 10%, 1.83 [95% CI, 1.30-2.57]; P < .001) and proband status (HR, 3.18 [95% CI, 1.12-9.04]; P = .03) remained independent risk factors on multivariable analysis (excluding myocardial fibrosis and ventricular ectopy owing to case censoring). There was no difference in freedom from MVA between FLNCtv carriers with mild to moderate or severe (LVEF ≤35%) LVSD (HR, 1.29 [95% CI, 0.45-3.72]; P = .64). Carriers of FLNCtv with impaired LVEF at baseline evaluation (n = 69) had reduced freedom from MVA compared with 244 TTNtv carriers with similar baseline LVEF (for mild to moderate LVSD: HR, 16.41 [95% CI, 3.45-78.11]; P < .001; for severe LVSD: HR, 2.47 [95% CI, 1.04-5.87]; P = .03).

Conclusions And Relevance: The high frequency of MVA among patients with FLNCtv with mild to moderate LVSD suggests that higher LVEF values than those currently recommended should be considered for prophylactic implantable cardioverter-defibrillator therapy in FLNCtv carriers.
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http://dx.doi.org/10.1001/jamacardio.2021.1106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117057PMC
August 2021

Prevented Sudden Cardiac Death and Neurologic Recovery in Inherited Heart Diseases.

Front Cardiovasc Med 2021 15;8:634300. Epub 2021 Mar 15.

Instituto Murciano, de Investigación Biosanitaria (IMIB), Murcia, Spain.

Inherited cardiovascular diseases are an important cause of sudden cardiac death (SD). The use of risk scores identify high risk patients who would benefit from an implantable cardioverter-defibrillators (ICDs). The development of automated devices for out-of-hospital cardiac arrest improves early resuscitation. The objective of the study is to quantify prevented SD and the neurological recovery of patients with inherited cardiovascular diseases. Two hundred fifty-seven cases of SD (age 42 ± 18 years, 79.4% men) of non-ischemic cardiac cause were prospectively collected during the study period (2009-17). Fifty three (20.6%) had a resuscitated cardiac arrest (RCA) (age 40 ± 18 years, 64.2% male). Epidemiological, clinical and autopsy aspects were analyzed. Prevented SD was defined as a combination of RCA and appropriate ICD therapy cases. An autopsy was performed in 157/204 (77.0%) cases who died. There were 19 (12.1%) cases with a negative autopsy. The diagnosis of cardiomyopathy and channelopathy was 58.0 and 18.7%, respectively. Female sex and confirmed or suspected channelopathy were associated with successful resuscitation. The percentage of prevented SD remained low during the study period (mean 35.6%). 60.4% of RCA cases presented good neurological outcome. There was no association between neurological recovery and therapeutic hypothermia, but there was association with time of resuscitation (min). A fifth part of non-ischemic cardiac arrests were resuscitated. Female sex and channelopathies were more prevalent among RCA. Two thirds of RCA had a good neurological recovery.
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http://dx.doi.org/10.3389/fcvm.2021.634300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005516PMC
March 2021

Trabeculated Myocardium in Hypertrophic Cardiomyopathy: Clinical Consequences.

J Clin Med 2020 Sep 30;9(10). Epub 2020 Sep 30.

Departamento de Ingeniería y Tecnología de Computadores, Universidad de Murcia, Espinardo, 30100 Murcia, Spain.

Aims: Hypertrophic cardiomyopathy (HCM) is often accompanied by increased trabeculated myocardium (TM)-which clinical relevance is unknown. We aim to measure the left ventricular (LV) mass and proportion of trabeculation in an HCM population and to analyze its clinical implication.

Methods And Results: We evaluated 211 patients with HCM (mean age 47.8 ± 16.3 years, 73.0% males) with cardiac magnetic resonance (CMR) studies. LV trabecular and compacted mass were measured using dedicated software for automatic delineation of borders. Mean compacted myocardium (CM) was 160.0 ± 62.0 g and trabecular myocardium (TM) 55.5 ± 18.7 g. The percentage of trabeculated myocardium (TM%) was 26.7% ± 6.4%. Females had significantly increased TM% compared to males (29.7 ± 7.2 vs. 25.6 ± 5.8, < 0.0001). Patients with LVEF < 50% had significantly higher values of TM% (30.2% ± 6.0% vs. 26.6% ± 6.4%, = 0.02). Multivariable analysis showed that female gender and neutral pattern of hypertrophy were directly associated with TM%, while dynamic obstruction, maximal wall thickness and LVEF% were inversely associated with TM%. There was no association between TM% with arterial hypertension, physical activity, or symptoms. Atrial fibrillation and severity of hypertrophy were the only variables associated with cardiovascular death. Multivariable analysis failed to demonstrate any correlation between TM% and arrhythmias.

Conclusions: Approximately 25% of myocardium appears non-compacted and can automatically be measured in HCM series. Proportion of non-compacted myocardium is increased in female, non-obstructives, and in those with lower contractility. The amount of trabeculation might help to identify HCM patients prone to systolic heart failure.
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http://dx.doi.org/10.3390/jcm9103171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600439PMC
September 2020

Clinical Phenotypes and Prognosis of Dilated Cardiomyopathy Caused by Truncating Variants in the Gene.

Circ Heart Fail 2020 10 23;13(10):e006832. Epub 2020 Sep 23.

Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Centro de Investigación en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain (M.A.R.-C., P.G.-P.).

Background: Truncating variants in the gene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers.

Methods: Five hundred thirty-seven individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 [69%] with baseline left ventricular systolic dysfunction [LVSD]). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%).

Results: Median follow-up was 49 (18-105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively; =0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 [68%] end-stage heart failure events, 24 [32%] malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 [95% CI, 1.04-3.44]; =0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 [95% CI, 1.30-2.04]; <0.001) were independent predictors of the primary end point. Two hundred seven of 300 (69%) patients with LVSD had evidence of left ventricular reverse remodeling. In a subgroup of 29 of 74 (39%) patients with initial left ventricular reverse remodeling, there was a subsequent left ventricular ejection fraction decrement. TTNtv location was not associated with statistically significant differences in baseline clinical characteristics, left ventricular reverse remodeling, or outcomes on multivariable analysis (=0.07).

Conclusions: TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006832DOI Listing
October 2020

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

Genet Med 2021 01 7;23(1):47-58. Epub 2020 Sep 7.

Member of the European Reference Network for rare, low prevalence and/or complex diseases of the heart: ERN GUARD-Heart, Amsterdam, Netherlands.

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.

Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.

Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.

Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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http://dx.doi.org/10.1038/s41436-020-00946-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790744PMC
January 2021

Reasons for refusing diagnostic tests and therapeutic recommendations and associated complications in inherited heart diseases. The RELUCTANT study.

Rev Esp Cardiol (Engl Ed) 2021 Jun 22;74(6):526-532. Epub 2020 Jul 22.

Unidad de Cardiopatías Hereditarias, Servicio de Cardiología, Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain; European Reference Networks (Guard-Heart), European Commission, Brussels, Belgium; Instituto Murciano de Investigación Biosanitaria (IMIB), El Palmar, Murcia, Spain; Red de Investigación Cardiovascular (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain; Facultad de Medicina, Universidad de Murcia, Campus de El Palmar, El Palmar, Murcia, Spain.

Introduction And Objectives: Study of inherited heart diseases (IHD) involves performing diagnostic tests, which are sometimes inconvenient or stressful, in asymptomatic relatives. The aim of this study was to analyze refusal to undergo various diagnostic tests and follow therapeutic recommendations.

Methods: We assessed 1992 consecutive families with IHD to analyze refusal to undergo family screening. The study included 1539 individuals who were recommended to undergo cardiac magnetic resonance, and 837 who were recommended a drug challenge test. To study treatment refusal, we assessed 395 patients with an indication for an implantable cardioverter-defibrillator (ICD) and 402 patients with an indication for anticoagulation.

Results: A total of 28% of families who were recommended to undergo screening for suspected IHD did not attend, but refusal was lower if there was a family history of sudden cardiac death. In all, 23% did not undergo magnetic resonance, and the 2 main reasons were administrative problems (53%) and claustrophobia (18%). Refusal was more common in older people, women, symptomatic persons, individuals with arrhythmias, and relatives. Nearly one fifth (19%) did not take the drug challenge test, due to fear (46%) or administrative issues (25%). Refusal was more frequent in older individuals, asymptomatic persons, those with a history of arrhythmias, relatives, and those with a positive genetic study. Only a minority of patients rejected the treatments (5.1% ICD, 2.5% anticoagulation). The percentage of sudden cardiac death in persons rejecting ICD implantation was high (4.5% per year).

Conclusions: One fifth of people attending screening for IHD refused to undergo more sophisticated and stressful tests. This study identified several independent predictors associated with refusal. Only a minority of high-risk patients refused treatments such as ICD implantation and anticoagulation.
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http://dx.doi.org/10.1016/j.rec.2020.06.014DOI Listing
June 2021

Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.

Hum Genet 2020 Nov 8;139(11):1443-1454. Epub 2020 Jun 8.

Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany.

Dilated cardiomyopathy (DCM) belongs to the most frequent forms of cardiomyopathy mainly characterized by cardiac dilatation and reduced systolic function. Although most cases of DCM are classified as sporadic, 20-30% of cases show a heritable pattern. Familial forms of DCM are genetically heterogeneous, and mutations in several genes have been identified that most commonly play a role in cytoskeleton and sarcomere-associated processes. Still, a large number of familial cases remain unsolved. Here, we report five individuals from three independent families who presented with severe dilated cardiomyopathy during the neonatal period. Using whole-exome sequencing (WES), we identified causative, compound heterozygous missense variants in RPL3L (ribosomal protein L3-like) in all the affected individuals. The identified variants co-segregated with the disease in each of the three families and were absent or very rare in the human population, in line with an autosomal recessive inheritance pattern. They are located within the conserved RPL3 domain of the protein and were classified as deleterious by several in silico prediction software applications. RPL3L is one of the four non-canonical riboprotein genes and it encodes the 60S ribosomal protein L3-like protein that is highly expressed only in cardiac and skeletal muscle. Three-dimensional homology modeling and in silico analysis of the affected residues in RPL3L indicate that the identified changes specifically alter the interaction of RPL3L with the RNA components of the 60S ribosomal subunit and thus destabilize its binding to the 60S subunit. In conclusion, we report that bi-allelic pathogenic variants in RPL3L are causative of an early-onset, severe neonatal form of dilated cardiomyopathy, and we show for the first time that cytoplasmic ribosomal proteins are involved in the pathogenesis of non-syndromic cardiomyopathies.
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http://dx.doi.org/10.1007/s00439-020-02188-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519902PMC
November 2020

Genetic Factors Involved in Cardiomyopathies and in Cancer.

J Clin Med 2020 Jun 2;9(6). Epub 2020 Jun 2.

Unidad de Cardiopatías Hereditarias, Servicio de Cardiología, Hospital Universitario Virgen dela Arrixaca, El Palmar, 30120 Murcia, Spain.

Cancer therapy-induced cardiomyopathy (CCM) manifests as left ventricular (LV) dysfunction and heart failure (HF). It is associated withparticular pharmacological agents and it is typically dose dependent, but significant individual variability has been observed. History of prior cardiac disease, abuse of toxics, cardiac overload conditions, age, and genetic predisposing factors modulate the degree of the cardiac reserve and the response to the injury. Genetic/familial cardiomyopathies (CMY) are increasingly recognized in general populations with an estimated prevalence of 1:250. Association between cardiac and oncologic diseases regarding genetics involves not only the toxicity process, but pathogenicity. Genetic variants in germinal cells that cause CMY (LMNA, RAS/MAPK) can increase susceptibility for certain types of cancer. The study of mutations found in cancer cells (somatic) has revealed the implication of genes commonly associated with the development of CMY. In particular, desmosomal mutations have been related to increased undifferentiation and invasiveness of cancer. In this article, the authors review the knowledge on the relevance of environmental and genetic background in CCM and give insights into the shared genetic role in the pathogenicity of the cancer process and development of CMY.
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http://dx.doi.org/10.3390/jcm9061702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356401PMC
June 2020

Genetics of feline hypertrophic cardiomyopathy.

Clin Genet 2020 09 1;98(3):203-214. Epub 2020 Apr 1.

Veterinary Teaching Hospital University of Murcia, Murcia, Spain.

Hypertrophic cardiomyopathy (HCM) is characterized by an abnormal increase in myocardial mass that affects cardiac structure and function. HCM is the most common inherited cardiovascular disease in humans (0.2%) and the most common cardiovascular disease in cats (14.7%). Feline HCM phenotype is very similar to the phenotype found in humans, but the time frame for the development of the disease is significantly shorter. Similar therapeutic agents are used in its treatment and it has the same complications, such as heart failure, thromboembolism and sudden cardiac death. In contrast to humans, in whom thousands of genetic variants have been identified, genetic studies in cats have been limited to fragment analysis of two sarcomeric genes identifying two variants in MYBPC3 and one in MYH7. Two of these variants have also been associated with human disease. The high prevalence of the reported variants in non-affected cats hinders the assumption of their pathogenicity in heterozygotes. An in-depth review of the literature about genetic studies on feline HCM in comparison with the same disease in humans is presented here. The close similarity in the phenotype and genotype between cats and humans makes the cat an excellent model for the pathophysiological study of the disease and future therapeutic agents.
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http://dx.doi.org/10.1111/cge.13743DOI Listing
September 2020

RNA sequencing-based transcriptome profiling of cardiac tissue implicates novel putative disease mechanisms in FLNC-associated arrhythmogenic cardiomyopathy.

Int J Cardiol 2020 03 6;302:124-130. Epub 2019 Dec 6.

Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK. Electronic address:

Arrhythmogenic cardiomyopathy (ACM) encompasses a group of inherited cardiomyopathies including arrhythmogenic right ventricular cardiomyopathy (ARVC) whose molecular disease mechanism is associated with dysregulation of the canonical WNT signalling pathway. Recent evidence indicates that ARVC and ACM caused by pathogenic variants in the FLNC gene encoding filamin C, a major cardiac structural protein, may have different molecular mechanisms of pathogenesis. We sought to identify dysregulated biological pathways in FLNC-associated ACM. RNA was extracted from seven paraffin-embedded left ventricular tissue samples from deceased ACM patients carrying FLNC variants and sequenced. Transcript levels of 623 genes were upregulated and 486 genes were reduced in ACM in comparison to control samples. The cell adhesion pathway and ILK signalling were among the prominent dysregulated pathways in ACM. Consistent with these findings, transcript levels of cell adhesion genes JAM2, NEO1, VCAM1 and PTPRC were upregulated in ACM samples. Moreover, several actin-associated genes, including FLNC, VCL, PARVB and MYL7, were suppressed, suggesting dysregulation of the actin cytoskeleton. Analysis of the transcriptome for dysregulated biological pathways predicted activation of inflammation and apoptosis and suppression of oxidative phosphorylation and MTORC1 signalling in ACM. Our data suggests dysregulated cell adhesion and ILK signalling as novel putative pathogenic mechanisms of ACM caused by FLNC variants which are distinct from the postulated disease mechanism of classic ARVC caused by desmosomal gene mutations. This knowledge could help in the design of future gene therapy strategies which would target specific components of these pathways and potentially lead to novel treatments for ACM.
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http://dx.doi.org/10.1016/j.ijcard.2019.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940594PMC
March 2020

Filamin C variants are associated with a distinctive clinical and immunohistochemical arrhythmogenic cardiomyopathy phenotype.

Int J Cardiol 2020 05 8;307:101-108. Epub 2019 Oct 8.

Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK.

Background: Pathogenic variants in the filamin C (FLNC) gene are associated with inherited cardiomyopathies including dilated cardiomyopathy with an arrhythmogenic phenotype. We evaluated FLNC variants in arrhythmogenic cardiomyopathy (ACM) and investigated the disease mechanism at a molecular level.

Methods: 120 gene-elusive ACM patients who fulfilled diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC) were screened by whole exome sequencing. Fixed cardiac tissue from FLNC variant carriers who had died suddenly was investigated by histology and immunohistochemistry.

Results: Novel or rare FLNC variants, four null and five variants of unknown significance, were identified in nine ACM probands (7.5%). In FLNC null variant carriers (including family members, n = 16) Task Force diagnostic electrocardiogram repolarization/depolarization abnormalities were uncommon (19%), echocardiography was normal in 69%, while 56% had >500 ventricular ectopics/24 h or ventricular tachycardia on Holter and 67% had late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMRI). Ten gene positive individuals (63%) had abnormalities on ECG or CMRI that are not included in the current diagnostic criteria for ARVC. Immunohistochemistry showed altered key protein distribution, distinctive from that observed in ARVC, predominantly in the left ventricle.

Conclusions: ACM associated with FLNC variants presents with a distinctive phenotype characterized by Holter arrhythmia and LGE on CMRI with unremarkable ECG and echocardiographic findings. Clinical presentation in asymptomatic mutation carriers at risk of sudden death may include abnormalities which are currently non-diagnostic for ARVC. At the molecular level, the pathogenic mechanism related to FLNC appears different to classic forms of ARVC caused by desmosomal mutations.
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http://dx.doi.org/10.1016/j.ijcard.2019.09.048DOI Listing
May 2020

A study of the pathogenicity of variants in familial heart disease. The value of cosegregation.

Am J Transl Res 2019 15;11(3):1724-1735. Epub 2019 Mar 15.

Inherited Cardiac Disease Unit, Department of Cardiology, University Hospital Virgen de la Arrixaca Murcia, Spain.

With the development of deep sequencing, a significant proportion of mutations already listed in studies have inconclusive pathogenicity. We aim to establish the proportion of cases in which familial studies are possible and cosegregation analysis is informative. We also compare cosegregation analysis with in silico software and a proposed pathogenicity score. 204 consecutive positive tests were reviewed. 4 different in silico software programs were used. Spaendonck-Zwarts' pathogenicity score was also calculated. A total of 73 of the missense variants could be classified by the score as being likely or definitively pathogenic. A high percentage of nonsense variants were found in desmosomal genes and missense variants in sarcomeric genes. 36.3% of the missense variants in our cohort classified as very likely or definitively pathogenic were novel. Cosegregation analysis was positive in 19.5% and could be discarded in 15.6%. There was a significant discrepancy between the in silico tools used in the setting of inherited heart disease. Multiparametric scoring systems which include cosegregation and functional studies seem to perform better than individual prediction software.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6456527PMC
March 2019

Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy.

J Am Coll Cardiol 2018 11;72(20):2457-2467

Health in Code S.L., Scientific Department, A Coruña, Spain.

Background: The genetic cause of hypertrophic cardiomyopathy remains unexplained in a substantial proportion of cases. Formin homology 2 domain containing 3 (FHOD3) may have a role in the pathogenesis of cardiac hypertrophy but has not been implicated in hypertrophic cardiomyopathy.

Objectives: This study sought to investigate the relation between FHOD3 mutations and the development of hypertrophic cardiomyopathy.

Methods: FHOD3 was sequenced by massive parallel sequencing in 3,189 hypertrophic cardiomyopathy unrelated probands and 2,777 patients with no evidence of cardiomyopathy (disease control subjects). The authors evaluated protein-altering candidate variants in FHOD3 for cosegregation, clinical characteristics, and outcomes.

Results: The authors identified 94 candidate variants in 132 probands. The variants' frequencies were significantly higher in patients with hypertrophic cardiomyopathy (74 of 3,189 [2.32%]) than in disease control subjects (18 of 2,777 [0.65%]; p < 0.001) or in the gnomAD database (1,049 of 138,606 [0.76%]; p < 0.001). FHOD3 mutations cosegregated with hypertrophic cardiomyopathy in 17 families, with a combined logarithm of the odds score of 7.92, indicative of very strong segregation. One-half of the disease-causing variants were clustered in a small conserved coiled-coil domain (amino acids 622 to 655); odds ratio for hypertrophic cardiomyopathy was 21.8 versus disease control subjects (95% confidence interval: 1.3 to 37.9; p < 0.001) and 14.1 against gnomAD (95% confidence interval: 6.9 to 28.7; p < 0.001). Hypertrophic cardiomyopathy patients carrying (likely) pathogenic mutations in FHOD3 (n = 70) were diagnosed after age 30 years (mean 46.1 ± 18.7 years), and two-thirds (66%) were males. Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 ± 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%. Events were rare before age 30 years, with an annual cardiovascular death incidence of 1% during follow-up.

Conclusions: FHOD3 is a novel disease gene in hypertrophic cardiomyopathy, accounting for approximately 1% to 2% of cases. The phenotype and the rate of cardiovascular events are similar to those reported in unselected cohorts. The FHOD3 gene should be routinely included in hypertrophic cardiomyopathy genetic testing panels.
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http://dx.doi.org/10.1016/j.jacc.2018.10.001DOI Listing
November 2018

Phenotypic Characterization of a Family With An In-frame Deletion in the DMD Gene and Variable Penetrance.

Curr Gene Ther 2018 ;18(4):246-251

Inherited Cardiac Disease Unit, University Hospital Virgen de la Arrixaca, Murcia, Spain.

Duchenne muscular dystrophy is a disorder with variable expression caused by framedisrupting mutations in the dystrophin gene. It is characterized by progressive muscle weakness and dilated cardiomyopathy. In-frame dystrophin mutations cause a clinically moderate disorder named Becker muscular dystrophy. Our aim was to study the clinical and genetic characteristics of a family with inherited cardiomyopathy and Becker muscular dystrophy. The index case was diagnosed with psychomotor retardation at 5 years of age. Asymmetric left ventricular hypertrophy and a long QT interval were evidenced at the age of 12. Mild muscular weakness was developed subsequently. Three genetic variants were identified in the index case: p.Arg891Alafs*160 in the MYBPC3 gene, p.Thr263Met in the KCNJ5 gene, and p.Ser2437_Ile2554delinsPhe in the DMD gene. The latter was expected to generate an in-frame deletion of exons 51 and 52 of the dystrophin gene. A family study revealed that the father and 3 uncles were carriers of the MYBPC3 mutation. The mother and a maternal grandfather were carriers of the other 2 variants. The 80-year-old grandfather, who had the dystrophin mutation, showed no sign of cardiomyopathy or muscular weakness. The deletion of exons 51 and 52 in the DMD gene, which has been proposed as one of the therapeutic strategies for Duchenne, is consistent with a normal life expectancy and the absence of myopathic symptoms in hemizygous males.
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http://dx.doi.org/10.2174/1566523218666180709125346DOI Listing
August 2019

Phenotype-modifying Factors in Hypertrophic Cardiomyopathy. Response.

Rev Esp Cardiol (Engl Ed) 2018 09 25;71(9):770-771. Epub 2018 Jun 25.

Unidad de Cardiopatías Hereditarias, Instituto Médico de Investigación Biosanitaria (IMIB-Arrixaca), El Palmar, Murcia, Spain; Departamento de Medicina Interna, Universidad de Murcia, Murcia, Spain; Departamento de Cardiología, Hospital Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain.

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http://dx.doi.org/10.1016/j.rec.2018.04.023DOI Listing
September 2018

Hypertrophic cardiomyopathy.

Med Clin (Barc) 2018 06 14;150(11):434-442. Epub 2017 Nov 14.

Unidad de Cardiopatías Familiares, Servicio de Cardiología, Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Murcia, España; Universidad de Murcia, Murcia, España. Electronic address:

Hypertrophic cardiomyopathy is the most common inherited cardiovascular disease. It is characterized by increased ventricular wall thickness and is highly complex due to its heterogeneous clinical presentation, several phenotypes, large number of associated causal mutations and broad spectrum of complications. It is caused by mutations in sarcomeric proteins, which are identified in up to 60% of cases of the disease. Clinical manifestations of Hypertrophic Cardiomyopathy include shortness of breath, chest pain, palpitations and syncope, which are related to the onset of diastolic dysfunction, left ventricular outflow tract obstruction, ischemia, atrial fibrillation and abnormal vascular responses. It is associated with an increased risk of sudden cardiac death, heart failure and thromboembolic events. In this article, we discuss the diagnostic and therapeutic aspects of this disease.
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http://dx.doi.org/10.1016/j.medcli.2017.09.013DOI Listing
June 2018

Factors Influencing the Phenotypic Expression of Hypertrophic Cardiomyopathy in Genetic Carriers.

Rev Esp Cardiol (Engl Ed) 2018 Mar 4;71(3):146-154. Epub 2017 Jul 4.

Unidad de Cardiopatías Hereditarias, Instituto Médico de Investigación Biosanitaria (IMIB-Arrixaca), Hospital Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain; Departamento de Medicina Interna, Universidad de Murcia, Murcia, Spain; Servicio de Cardiología, Hospital Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain.

Introduction And Objectives: Hypertrophic cardiomyopathy (HCM) is a disorder with variable expression. It is mainly caused by mutations in sarcomeric genes but the phenotype could be modulated by other factors. The aim of this study was to determine whether factors such as sex, systemic hypertension, or physical activity are modifiers of disease severity and to establish their role in age-related penetrance of HCM.

Methods: We evaluated 272 individuals (mean age 49 ± 17 years, 57% males) from 72 families with causative mutations. The relationship between sex, hypertension, physical activity, and left ventricular hypertrophy was studied.

Results: The proportion of affected individuals increased with age. Men developed the disease 12.5 years earlier than women (adjusted median, 95%CI, -17.52 to -6.48; P < .001). Hypertensive patients were diagnosed with HCM later (10.8 years of delay) than normotensive patients (adjusted median, 95%CI, 6.28-17.09; P < .001). Individuals who performed physical activity were diagnosed with HCM significantly earlier (7.3 years, adjusted median, 95%CI, -14.49 to -1.51; P = .016). Sex, hypertension, and the degree of physical activity were not significantly associated with the severity of left ventricular hypertrophy. Adjusted survival both free from sudden death and from the combined event were not influenced by any of the exploratory variables.

Conclusions: Men and athletes who are carriers of sarcomeric mutations are diagnosed earlier than women and sedentary individuals. Hypertensive carriers of sarcomeric mutations have a delayed diagnosis. Sex, hypertension, and physical activity are not associated with disease severity in carriers of HCM causative mutations.
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http://dx.doi.org/10.1016/j.rec.2017.06.002DOI Listing
March 2018

A Novel Founder Mutation in MYBPC3: Phenotypic Comparison With the Most Prevalent MYBPC3 Mutation in Spain.

Rev Esp Cardiol (Engl Ed) 2017 Feb 28;70(2):105-114. Epub 2016 Oct 28.

Departamento de Cardiología, Hospital Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain.

Introduction And Objectives: Mutations in MYBPC3 are the cause of hypertrophic cardiomyopathy (HCM). Although most lead to a truncating protein, the severity of the phenotype differs. We describe the clinical phenotype of a novel MYBPC3 mutation, p.Pro108Alafs*9, present in 13 families from southern Spain and compare it with the most prevalent MYBPC3 mutation in this region (c.2308+1 G>A).

Methods: We studied 107 relatives of 13 index cases diagnosed as HCM carriers of the p.Pro108Alafs*9 mutation. Pedigree analysis, clinical evaluation, and genotyping were performed.

Results: A total of 54 carriers of p.Pro108Alafs*9 were identified, of whom 39 had HCM. There were 5 cases of sudden death in the 13 families. Disease penetrance was greater as age increased and HCM patients were more frequently male and developed disease earlier than female patients. The phenotype was similar in p.Pro108Alafs*9 and in c.2308+1 G>A, but differences were found in several risk factors and in survival. There was a trend toward a higher left ventricular mass in p.Pro108Alafs*9 vs c.2308+1G>A. Cardiac magnetic resonance revealed a similar extent and pattern of fibrosis.

Conclusions: The p.Pro108Alafs*9 mutation is associated with HCM, high penetrance, and disease onset in middle age.
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http://dx.doi.org/10.1016/j.rec.2016.06.020DOI Listing
February 2017

An R1632C variant in the SCN5A gene causing Brugada syndrome.

Mol Med Rep 2016 Jun 11;13(6):4677-80. Epub 2016 Apr 11.

Department of Cardiology, Virgen de la Arrixaca University Hospital, El Palmar, 30120 Murcia, Spain.

Brugada syndrome (BS) is an electrical disease, inherited in an autosomal dominant manner. BS is caused by mutations in up to 13 different genes. SCN5A is the gene most frequently mutated in BS, although this presents an incomplete penetrance. The present case study investigated the SCN5A gene in a family exhibiting BS. Direct sequencing of the SCN5A gene was performed to identify mutations and a familial investigation was performed. A novel variant was identified in the voltage‑sensing domain of the SCN5A protein. This familial investigation revealed one novel asymptomatic carrier in the family. Genetic investigations are useful to classify individuals who require more frequent clinical monitoring and to stratify the risk of developing the disease.
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http://dx.doi.org/10.3892/mmr.2016.5100DOI Listing
June 2016

A gene variant in the transcription factor 7-like 2 (TCF7L2) is associated with an increased risk of gestational diabetes mellitus.

Eur J Obstet Gynecol Reprod Biol 2014 Sep 6;180:77-82. Epub 2014 Jul 6.

Physiology Department, Faculty of Biology, University of Murcia, Spain.

Objective: Adipokines play an important role in the pathogenesis of insulin resistance during pregnancy. We studied the association of genetic variants linked with type 2 diabetes in gestational diabetes mellitus (GDM) subjects and its influence on maternal adipokines.

Study Design: We recruited 25 healthy pregnant women (Controls) and 45 women with GDM at 24-28 weeks of gestation. Maternal blood samples were collected at recruitment and delivery. Adipokines were determined at both sampling times. Genomic DNA was extracted from recruitment samples and FTO rs9939609, TCF7L2 rs4506565, rs7901695, rs12243326, rs12255372 and rs7903146, INSIG2 rs7566605, SREBF1 rs114001633, rs45535737 and rs12941356 and FATP4 rs2003560 genotyped.

Results: Serum adiponectin was significantly lower in GDM than Controls at recruitment and showed a similar trend at delivery (p=0.060). In contrast, resistin tended to higher levels in GDM only at recruitment. TCF7L2 rs4506565 (OR=2.31, 95% CI: 1.97-5.01; p=0.031) and FTO rs9939609 (OR=2.17, 95% CI: 1.07-4.41; p=0.039) were associated with GDM risk. Women carrying the T allele of TCF7L2 rs4506565 had increases in plasma resistin of 9.38 μg/L (95% CI 1.39-17.37; p=0.022) per allele; this association remained significant after adjusting for pre-gestational body weight.

Conclusion: TCF7L2 rs4506565 variant (T/T) is associated with increased risk of GDM and plasma resistin concentrations in women with GDM.
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http://dx.doi.org/10.1016/j.ejogrb.2014.06.024DOI Listing
September 2014

Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy.

Nat Med 2013 Feb 13;19(2):193-201. Epub 2013 Jan 13.

Program of Cardiovascular Developmental Biology, Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.

Left ventricular noncompaction (LVNC) causes prominent ventricular trabeculations and reduces cardiac systolic function. The clinical presentation of LVNC ranges from asymptomatic to heart failure. We show that germline mutations in human MIB1 (mindbomb homolog 1), which encodes an E3 ubiquitin ligase that promotes endocytosis of the NOTCH ligands DELTA and JAGGED, cause LVNC in autosomal-dominant pedigrees, with affected individuals showing reduced NOTCH1 activity and reduced expression of target genes. Functional studies in cells and zebrafish embryos and in silico modeling indicate that MIB1 functions as a dimer, which is disrupted by the human mutations. Targeted inactivation of Mib1 in mouse myocardium causes LVNC, a phenotype mimicked by inactivation of myocardial Jagged1 or endocardial Notch1. Myocardial Mib1 mutants show reduced ventricular Notch1 activity, expansion of compact myocardium to proliferative, immature trabeculae and abnormal expression of cardiac development and disease genes. These results implicate NOTCH signaling in LVNC and indicate that MIB1 mutations arrest chamber myocardium development, preventing trabecular maturation and compaction.
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http://dx.doi.org/10.1038/nm.3046DOI Listing
February 2013

Effects of fructooligosaccharides on cecum polyamine concentration and gut maturation in early-weaned piglets.

J Clin Biochem Nutr 2011 May 26;48(3):230-6. Epub 2011 Apr 26.

Department of Physiology, Faculty of Biology, University of Murcia, Espinardo Campus, 30100 Murcia, Spain.

Polyamines are molecules involved in cell growth and differentiation and are produced by bacterial metabolism. However, their production and effects by the microbiota selected by fructooligosaccharides consumption are controversial. In this study, we investigated the influence of supplementation of fructooligosaccharides on the cecal polyamine production by the microflora selected, and its effect on gut maturation in newborn piglets. Twenty piglets were fed a control formula (n = 10) or a formula supplemented with fructooligosaccharides (8 g/l) (n = 10) for 13 days. Colony-forming unit's count of cecal content was done in different media. Several intestinal development parameters were measured as well as the polyamine concentration in the cecal mucosa and cecal content. A dose-dependent study on in vitro polyamine production by fructooligosaccharides addition to the isolated cecal content was performed. Bifidogenic activity of fructooligosaccharides increased polyamine concentration in the cecal content, mainly putrescine, with no beneficial effect on gut maturation. Bifidobacterium spp. were able to produce polyamines, but they were not the most significant bacterial producer of polyamines in the cecum of piglets fed fructooligosaccharides. Bifidogenic activity of fructooligosaccharides did not lead to an increase in gut maturation in piglets of 15 days of age although polyamines were increased in the cecal content.
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http://dx.doi.org/10.3164/jcbn.10-100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082079PMC
May 2011

Effects of dietary polyamines at physiologic doses in early-weaned piglets.

Nutrition 2009 Sep 28;25(9):940-6. Epub 2009 May 28.

Department of Physiology, Faculty of Biology, University of Murcia, Murcia, Spain.

Objective: Polyamines are essential for many cell functions, and they form part of the composition of maternal milk; despite this, their addition to infant formulas is currently under evaluation. The aim of the present study was to evaluate the effects of milk formulas designed to resemble sow milk supplemented with polyamines at maternal physiologic milk doses on the gut maturation of early-weaned piglets.

Methods: We fed 30 newborn piglets with maternal milk (n=10), a control milk formula (n=10), or a milk formula supplemented with polyamines (5 nmol/mL of spermine and 20 nmol/mL of spermidine, n=10) for 13 d (day 2 after birth through day 15). Several growth and intestinal development parameters were measured.

Results: The piglets fed the formula containing polyamine at physiologic doses showed significantly increased crypt depth in the small intestine compared with those fed with the control formula. Villus length was correlated to crypt depth. Although there were no differences in the disaccharidase activities between the animals fed the two formulas, alkaline phosphatase and gamma-glutamyl transferase activities tended to be higher in the jejunum of those fed the polyamine-supplemented diet. Dietary polyamines did not significantly modify the gut mucosal concentrations of putrescine, spermine, or spermidine.

Conclusion: Milk formulas supplemented with polyamines at maternal milk physiologic doses slightly enhanced gut growth and maturation in neonatal piglets.
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http://dx.doi.org/10.1016/j.nut.2009.01.017DOI Listing
September 2009
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