Publications by authors named "Juan Ramon Gimeno-Blanes"

26 Publications

  • Page 1 of 1

Characterization of hereditary transthyretin cardiac amyloidosis in Spain.

Rev Esp Cardiol (Engl Ed) 2021 Oct 25. Epub 2021 Oct 25.

Unidad de Cardiopatías Familiares y Unidad Multidisciplinar de Amiloidosis TTR, Servicio de Cardiología, Hospital Universitario Son Llàtzer, Instituto de Investigación Sanitaria Illes Balears (IdISBa), Palma de Mallorca, Balearic Islands, Spain; Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Spain. Electronic address:

Introduction And Objectives: Hereditary transthyretin amyloidosis (hATTR) is a disease caused by mutations in the transthyretin gene that frequently shows cardiac involvement due to amyloid deposition in the myocardium. Our objective was to identify cardiac involvement in a Spanish cohort.

Methods: Retrospective multicenter study of patients diagnosed with hATTR with cardiac involvement from Spanish centers. We collected demographic, clinical, and genetic data.

Results: A total of 181 patients from 26 centers were included (65.2% men, with a median age at diagnosis of 62 years). The most frequent mutations were Val50Met (67.7%) and Val142Ile (12.4%). The main reason for consultation was extracardiac symptoms (69%), mainly neurological. The mean N-terminal pro-B-type natriuretic peptide level was 2145±3586 pg/mL. The most characteristic electrocardiogram findings were a pseudoinfarct pattern (25.9%) and atrioventricular block (25.3%). Mean ventricular thickness was 15.4±4.1mm. Longitudinal strain was reduced in basal segments by 29.4%. Late diffuse subendocardial enhancement was observed in 58.8%. Perugini grade 2 or 3 uptake was observed in 75% of scintigraphy scans. During follow-up, 24.9% of the patients were admitted for heart failure, 34.3% required a pacemaker, and 31.6% required a liver transplant. One third (32.5%) died during follow-up, mainly due to heart failure (28.8%). The presence of non-Val50Met mutations was associated with a worse prognosis.

Conclusions: HATTR cardiac amyloidosis in Spain shows heterogeneous genetic and clinical involvement. The prognosis is poor, mainly due to cardiac complications. Consequently early diagnosis and treatment are vital.
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http://dx.doi.org/10.1016/j.rec.2021.07.020DOI Listing
October 2021

Association of Genetic Variants With Outcomes in Patients With Nonischemic Dilated Cardiomyopathy.

J Am Coll Cardiol 2021 10;78(17):1682-1699

Department of Cardiology, Área del Corazón, Complejo Hospitalario de Navarra, Pamplona, Spain.

Background: The clinical relevance of genetic variants in nonischemic dilated cardiomyopathy (DCM) is unsettled.

Objectives: The study sought to assess the prognostic impact of disease-causing genetic variants in DCM.

Methods: Baseline and longitudinal clinical data from 1,005 genotyped DCM probands were retrospectively collected at 20 centers. A total of 372 (37%) patients had pathogenic or likely pathogenic variants (genotype positive) and 633 (63%) were genotype negative. The primary endpoint was a composite of major adverse cardiovascular events. Secondary endpoints were end-stage heart failure (ESHF), malignant ventricular arrhythmia (MVA), and left ventricular reverse remodeling (LVRR).

Results: After a median follow-up of 4.04 years (interquartile range: 1.70-7.50 years), the primary endpoint had occurred in 118 (31.7%) patients in the genotype-positive group and in 125 (19.8%) patients in the genotype-negative group (hazard ratio [HR]: 1.51; 95% confidence interval [CI]: 1.17-1.94; P = 0.001). ESHF occurred in 60 (16.1%) genotype-positive patients and in 55 (8.7%) genotype-negative patients (HR: 1.67; 95% CI: 1.16-2.41; P = 0.006). MVA occurred in 73 (19.6%) genotype-positive patients and in 77 (12.2%) genotype-negative patients (HR: 1.50; 95% CI: 1.09-2.07; P = 0.013). LVRR occurred in 39.6% in the genotype-positive group and in 46.2% in the genotype-negative group (P = 0.047). Among individuals with baseline left ventricular ejection fraction ≤35%, genotype-positive patients exhibited more major adverse cardiovascular events, ESHF, and MVA than their genotype-negative peers (all P < 0.02). LVRR and clinical outcomes varied depending on the underlying affected gene.

Conclusions: In this study, DCM patients with pathogenic or likely pathogenic variants had worse prognosis than genotype-negative individuals. Clinical course differed depending on the underlying affected gene.
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http://dx.doi.org/10.1016/j.jacc.2021.08.039DOI Listing
October 2021

Clinical Risk Prediction in Patients With Left Ventricular Myocardial Noncompaction.

J Am Coll Cardiol 2021 08;78(7):643-662

Gasthuisberg University Hospital, Leuven, Belgium.

Background: Left ventricular noncompaction (LVNC) is a heterogeneous entity with uncertain prognosis.

Objectives: This study sought to develop and validate a prediction model of major adverse cardiovascular events (MACE) and to identify LVNC cases without events during long-term follow-up.

Methods: This is a retrospective longitudinal multicenter cohort study of consecutive patients fulfilling LVNC criteria by echocardiography or cardiovascular magnetic resonance. MACE were defined as heart failure (HF), ventricular arrhythmias (VAs), systemic embolisms, or all-cause mortality.

Results: A total of 585 patients were included (45 ± 20 years of age, 57% male). LV ejection fraction (LVEF) was 48% ± 17%, and 18% presented late gadolinium enhancement (LGE). After a median follow-up of 5.1 years, MACE occurred in 223 (38%) patients: HF in 110 (19%), VAs in 87 (15%), systemic embolisms in 18 (3%), and 34 (6%) died. LVEF was the main variable independently associated with MACE (P < 0.05). LGE was associated with HF and VAs in patients with LVEF >35% (P < 0.05). A prediction model of MACE was developed using Cox regression, composed by age, sex, electrocardiography, cardiovascular risk factors, LVEF, and family aggregation. C-index was 0.72 (95% confidence interval: 0.67-0.75) in the derivation cohort and 0.72 (95% confidence interval: 0.71-0.73) in an external validation cohort. Patients with no electrocardiogram abnormalities, LVEF ≥50%, no LGE, and negative family screening presented no MACE at follow-up.

Conclusions: LVNC is associated with an increased risk of heart failure and ventricular arrhythmias. LVEF is the variable most strongly associated with MACE; however, LGE confers additional risk in patients without severe systolic dysfunction. A risk prediction model is developed and validated to guide management.
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http://dx.doi.org/10.1016/j.jacc.2021.06.016DOI Listing
August 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 between new-onset right bundle branch block and primary or secondary ventricular fibrillation in ST-segment elevation myocardial infarction.

Eur Heart J Acute Cardiovasc Care 2021 Oct;10(8):918-925

Coronary Care Unit, Department of Intensive Care Medicine, Hospital Clínico Universitario Virgen de la Arrixaca, Ctra. Madrid-Cartagena, s/n, 30120 El Palmar, Murcia, Spain.

Aims: New-onset right bundle branch block (RBBB) in myocardial infarction (MI) is often associated with ventricular fibrillation (VF) but the nature of this relationship has not been determined.

Methods And Results: Between 1998 and 2014, among other data, incidence and duration of RBBB and VF occurrence were prospectively collected in 5301 patients with ST-segment elevation MI (STEMI) admitted to two University Hospitals in Murcia (Spain). Multinomial adjusted logistic regression analyses were used to examine the association between RBBB, attending to its duration, and VF according to its primary VF (PVF) or secondary VF (SVF) character. Among 284 (5.4%) patients with new-onset RBBB, 158 were transient and 126 permanent. VF occurred in 339 (6.4%) patients, 201 PVF and 138 SVF, documented within the first 2 h of symptoms-onset in 78% and 60%, respectively. New-onset RBBB was more frequent in PVF (11.4%) and SVF (20.3%), than in non-VF (4.7%). Transient RBBB incidence was higher in PVF (9.0%) and SVF (9.4) than in non-VF (2.6%), whereas permanent RBBB was higher in SVF (10.9%) than PVF (2.5%) and non-VF (2.1%). New-onset RBBB 1.83 [95% confidence interval (CI): 1.07-3.11] and new-onset transient RBBB 2.39 (95% CI: 1.32-4.32) were independently associated with PVF. New-onset 3.03 (95% CI: 1.83-5.02), transient 2.40 (95% CI: 1.27-4.55), and permanent 2.99 (95% CI: 1.52-5.86) RBBB were independently associated with SVF.

Conclusion: New-onset RBBB and VF in STEMI are independently associated and show particularities based on the duration of the conduction disturbance and/or the primary or secondary character of the arrhythmia.
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http://dx.doi.org/10.1093/ehjacc/zuab026DOI Listing
October 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

A Primary Prevention Clinical Risk Score Model for Patients With Brugada Syndrome (BRUGADA-RISK).

JACC Clin Electrophysiol 2021 02 28;7(2):210-222. Epub 2020 Oct 28.

Department of Cardiology, Santa Maria University Hospital, Lisbon Academic Medical Centre and Cardiovascular Centre of the University of Lisbon, Faculty of Medicine, Lisbon, Portugal.

Objectives: The goal of this study was to develop a risk score model for patients with Brugada syndrome (BrS).

Background: Risk stratification in BrS is a significant challenge due to the low event rates and conflicting evidence.

Methods: A multicenter international cohort of patients with BrS and no previous cardiac arrest was used to evaluate the role of 16 proposed clinical or electrocardiogram (ECG) markers in predicting ventricular arrhythmias (VAs)/sudden cardiac death (SCD) during follow-up. Predictive markers were incorporated into a risk score model, and this model was validated by using out-of-sample cross-validation.

Results: A total of 1,110 patients with BrS from 16 centers in 8 countries were included (mean age 51.8 ± 13.6 years; 71.8% male). Median follow-up was 5.33 years; 114 patients had VA/SCD (10.3%) with an annual event rate of 1.5%. Of the 16 proposed risk factors, probable arrhythmia-related syncope (hazard ratio [HR]: 3.71; p < 0.001), spontaneous type 1 ECG (HR: 3.80; p < 0.001), early repolarization (HR: 3.42; p < 0.001), and a type 1 Brugada ECG pattern in peripheral leads (HR: 2.33; p < 0.001) were associated with a higher risk of VA/SCD. A risk score model incorporating these factors revealed a sensitivity of 71.2% (95% confidence interval: 61.5% to 84.6%) and a specificity of 80.2% (95% confidence interval: 75.7% to 82.3%) in predicting VA/SCD at 5 years. Calibration plots showed a mean prediction error of 1.2%. The model was effectively validated by using out-of-sample cross-validation according to country.

Conclusions: This multicenter study identified 4 risk factors for VA/SCD in a primary prevention BrS population. A risk score model was generated to quantify risk of VA/SCD in BrS and inform implantable cardioverter-defibrillator prescription.
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http://dx.doi.org/10.1016/j.jacep.2020.08.032DOI Listing
February 2021

Current use of cardiac magnetic resonance in tertiary referral centres for the diagnosis of cardiomyopathy: the ESC EORP Cardiomyopathy/Myocarditis Registry.

Eur Heart J Cardiovasc Imaging 2021 06;22(7):781-789

Members of the European Reference Network on Heart Diseases (ERN GUARD-HEART), Coordinating Centre: Academic Medical Center, Amsterdam, the Netherlands.

Aims: Cardiac magnetic resonance (CMR) is recommended in the diagnosis of cardiomyopathies, but it is time-consuming, expensive, and limited in availability in some European regions. The aim of this study was to determine the use of CMR in cardiomyopathy patients enrolled into the European Society of Cardiology (ESC) cardiomyopathy registry [part of the EURObservational Research Programme (EORP)].

Methods And Results: Three thousand, two hundred, and eight consecutive adult patients (34.6% female; median age: 53.0 ± 15 years) with cardiomyopathy were studied: 1260 with dilated (DCM), 1739 with hypertrophic (HCM), 66 with restrictive (RCM), and 143 with arrhythmogenic right ventricular cardiomyopathy (ARVC). CMR scans were performed at baseline in only 29.4% of patients. CMR utilization was variable according to cardiomyopathy subtypes: from 51.1% in ARVC to 36.4% in RCM, 33.8% in HCM, and 20.6% in DCM (P < 0.001). CMR use in tertiary referral centres located in different European countries varied from 1% to 63.2%. Patients undergoing CMR were younger, less symptomatic, less frequently had implantable cardioverter-defibrillator (ICD)/pacemaker implanted, had fewer cardiovascular risk factors and comorbidities (P < 0.001). In 28.6% of patients, CMR was used along with transthoracic echocardiography (TTE); 67.6% patients underwent TTE alone, and 0.9% only CMR.

Conclusion: Less than one-third of patients enrolled in the registry underwent CMR and the use varied greatly between cardiomyopathy subtypes, clinical profiles of patients, and European tertiary referral centres. This gap with current guidelines needs to be considered carefully by scientific societies to promote wider availability and use of CMR in patients with cardiomyopathies.
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http://dx.doi.org/10.1093/ehjci/jeaa329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219354PMC
June 2021

Catheter ablation of ventricular arrhythmias in left ventricular noncompaction cardiomyopathy.

Heart Rhythm 2021 04 17;18(4):545-552. Epub 2020 Dec 17.

Arrhythmia Unit and Electrophysiology, Department of Cardiology, Virgen de la Arrixaca University Hospital, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain; Red de Investigación Cardiovascular (CIBERCV) Instituto de Salud Carlos III, Spain.

Background: There are limited data on ventricular arrhythmias (VAs) associated with left ventricular noncompaction (LVNC) cardiomyopathy.

Objectives: This study aims to analyze the clinical and electrocardiographic characteristics of VAs in a group of patients with LVNC.

Methods: Forty-two nonrelated patients with LVNC and VAs were included that were evaluated at the Inherited Cardiac Disease Unit of the University Hospital Virgen Arrixaca (Murcia-Spain) (ERN Guard-Heart Centre, European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart).

Results: Thirteen patients (30.9%) had isolated LVNC, 27 (64.3%) had LVNC associated with dilated cardiomyopathy, and 2 (4.8%) had LVNC associated with hypertrophic cardiomyopathy. Among isolated LVNC individuals, 9 (69.2%) had premature ventricular complexes (PVCs)/nonsustained ventricular tachycardias (VTs), and 4 (30.8%) VTs (1 VT degenerating in ventricular fibrillation). In the dilated cardiomyopathy group, 11 (40.7%) patients had PVCs, 14 (51.9%) VTs, and 2 (7.4%) ventricular fibrillation. In the hypertrophic cardiomyopathy group, one patient had PVCs and the other VTs. Endocardial mapping and ablation were performed in 19 patients (45.2%): 7 ventricular outflow tracts (4 right ventricular outflow tract, 1 left coronary cusp, and 2 right coronary cusp), 2 in the left ventricular summit, 5 related to Purkinje potentials at the mid inferoseptal area, and 5 associated with endocardial scar localized in the basal anterolateral and inferolateral segments. Epicardial ablation was performed in 3 cases.

Conclusion: The substrate of VAs in LVNC cardiomyopathy is heterogeneous, with origin in ventricular outflow tracts, Purkinje system related, and resembling scar patterns in nonischemic cardiomyopathy.
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http://dx.doi.org/10.1016/j.hrthm.2020.12.014DOI Listing
April 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

Sex-related differences in cardiomyopathies.

Int J Cardiol 2019 07 30;286:239-243. Epub 2018 Oct 30.

Institute of Cardiovascular Science, University College London and St. Bartholomew's Hospital, London, United Kingdom.

Cardiomyopathies (CMPs) are a heterogeneous group of heart muscle diseases with several different phenotypes defined as myocardial disorders in which the heart muscle is structurally and functionally abnormal in the absence of coronary artery disease, hypertension, valvular heart disease and congenital heart disease sufficient to explain the observed myocardial abnormality. CMPs can be classified into one of the following, i.e. hypertrophic CMP (HCM), dilated CMP (DCM), arrhythmogenic right ventricular CMP (ARVC), restrictive CMP (RCM), and unclassified CMPs. Although an increasing number of CMPs are now recognized to have a genetic basis, single mutations are associated with phenotypic variability and may cause not only a specific CMP, but also several different CMPs. Recently, it has become evident that, along with environmental interactions, age and sex may affect the penetrance of disease genes thus determining the phenotypic expression of CMPs. Noteworthy, an increasing body of data indicates that sex plays an important role in various forms of CMPs. The mode of inheritance may affect the sex-related occurrence of CMPs. Also, sex is a relevant determinant of the clinical manifestation of CMPs, and sex-related characteristics can be found in all forms. Sex-specific aspects of clinical disease expression as well as potential modes of inheritance should be therefore taken into proper consideration in order to improve the diagnostic work-up and treatment strategy of CMPs in both sexes.
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http://dx.doi.org/10.1016/j.ijcard.2018.10.091DOI Listing
July 2019

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

Comments on the New International Criteria for Electrocardiographic Interpretation in Athletes.

Rev Esp Cardiol (Engl Ed) 2017 Nov 18;70(11):983-990. Epub 2017 Sep 18.

Department of Sports Medicine, ASPETAR, Orthopaedic and Sports Medicine Hospital, Doha, Qatar.

Sudden cardiac death is the most common medical cause of death during the practice of sports. Several structural and electrical cardiac conditions are associated with sudden cardiac death in athletes, most of them showing abnormal findings on resting electrocardiogram (ECG). However, because of the similarity between some ECG findings associated with physiological adaptations to exercise training and those of certain cardiac conditions, ECG interpretation in athletes is often challenging. Other factors related to ECG findings are race, age, sex, sports discipline, training intensity, and athletic background. Specific training and experience in ECG interpretation in athletes are therefore necessary. Since 2005, when the first recommendations of the European Society of Cardiology were published, growing scientific evidence has increased the specificity of ECG standards, thus lowering the false-positive rate while maintaining sensitivity. New international consensus guidelines have recently been published on ECG interpretation in athletes, which are the result of consensus among a group of experts in cardiology and sports medicine who gathered for the first time in February 2015 in Seattle, in the United States. The document is an important milestone because, in addition to updating the standards for ECG interpretation, it includes recommendations on appropriate assessment of athletes with abnormal ECG findings. The present article reports and discusses the most novel and relevant aspects of the new standards. Nevertheless, a complete reading of the original consensus document is highly recommended.
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http://dx.doi.org/10.1016/j.rec.2017.08.015DOI Listing
November 2017

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

The TBX1 Transcription Factor in Cardiac Remodeling After Myocardial Infarction.

Rev Esp Cardiol (Engl Ed) 2016 Nov 12;69(11):1042-1050. Epub 2016 Jul 12.

Servicio de Cardiología, Grupo de Investigación Clínica y Traslacional Cardiovascular, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria (IMIB)-Arrixaca, El Palmar, Murcia, Spain; Departamento de Medicina Interna, Facultad de Medicina, Universidad de Murcia, Murcia, Spain.

Introduction And Objectives: The transcription factor TBX1 plays an important role in the embryonic development of the heart. Nothing is known about its involvement in myocardial remodeling after acute myocardial infarction (AMI) and whether its expression can be modulated by a treatment with proven benefit such as mineralocorticoid receptor blockade.

Methods: Acute myocardial infarction was induced in 60 rats via left coronary artery ligation: 50 animals were randomized to be euthanized after 1, 2, 4, 12, or 24 weeks; 10 animals were treated with eplerenone (100 mg/kg/days) 7 days before the AMI until their euthanasia (4 weeks later); 8 additional animals underwent surgery without ligation (control). We analyzed the cardiac expression of TBX1, fetal genes, and fibrosis markers.

Results: The gene and protein expression of TBX1 was increased in the infarcted myocardium, peaking 1 week after AMI (P < .01), without changes in the noninfarcted myocardium. Levels of the fetal genes and fibrosis markers also increased, peaking 4 weeks (P < .001) and 1 week (P < .01) after AMI, respectively. The TBX1 expression was correlated with that of the fibrosis markers (P < .01) but not the fetal genes. Eplerenone reduced the TBX1 increase and fibrosis induced by AMI, with an association improvement in ventricular function and remodeling in echocardiography.

Conclusions: These results show the reactivated expression of TBX1 and indicate its involvement in cardiac fibrosis and remodeling after AMI and its participation in the benefit from mineralocorticoid receptor blockade.
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http://dx.doi.org/10.1016/j.rec.2016.04.033DOI Listing
November 2016

Performance of a New Software Tool for Automatic Quantification of Left Ventricular Trabeculations.

Rev Esp Cardiol (Engl Ed) 2017 05 27;70(5):405-407. Epub 2016 Aug 27.

Unidad de Cardiopatías Familiares, Servicio de Cardiología, Hospital Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain.

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http://dx.doi.org/10.1016/j.rec.2016.07.006DOI Listing
May 2017

The Importance of Family-genetic Screening: The Phenotype Caused by the p.L3778F Ryanodine Receptor Mutation is Likely Less Severe Than Previously Thought.

Rev Esp Cardiol (Engl Ed) 2016 Jul 16;69(7):702-4. Epub 2016 May 16.

Unidad de Cardiopatías Familiares, Servicio de Cardiología, Complexo Hospitalario Universitario A Coruña, A Coruña, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.rec.2016.04.007DOI Listing
July 2016

Genetic basis of familial dilated cardiomyopathy patients undergoing heart transplantation.

J Heart Lung Transplant 2016 05 6;35(5):625-35. Epub 2016 Jan 6.

Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; Myocardial Biology Programme, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. Electronic address:

Background: Dilated cardiomyopathy (DCM) is the most frequent cause of heart transplantation (HTx). The genetic basis of DCM among patients undergoing HTx has been poorly characterized. We sought to determine the genetic basis of familial DCM HTx and to establish the yield of modern next generation sequencing (NGS) technologies in this setting.

Methods: Fifty-two heart-transplanted patients due to familial DCM underwent NGS genetic evaluation with a panel of 126 genes related to cardiac conditions (59 associated with DCM). Genetic variants were initially classified as pathogenic mutations or as variants of uncertain significance (VUS). Final pathogenicity status was determined by familial cosegregation studies.

Results: Initially, 24 pathogenic mutations were found in 21 patients (40%); 25 patients (48%) carried 19 VUS and 6 (12%) did not show any genetic variant. Familial evaluation of 220 relatives from 36 of the 46 families with genetic variants confirmed pathogenicity in 14 patients and allowed reclassification of VUS as pathogenic in 17 patients, and as non-pathogenic in 3 cases. At the end of the study, the DCM-causing mutation was identified in 38 patients (73%) and 5 patients (10%) harbored only VUS. No genetic variants were identified in 9 cases (17%).

Conclusions: The genetic spectrum of familial DCM patients undergoing HTx is heterogeneous and involves multiple genes. NGS technology plus detailed familial studies allow identification of causative mutations in the vast majority of familial DCM cases. Detailed familial studies remain critical to determine the pathogenicity of underlying genetic defects in a substantial number of cases.
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http://dx.doi.org/10.1016/j.healun.2015.12.014DOI Listing
May 2016

Plan of Action for Inherited Cardiovascular Diseases: Synthesis of Recommendations and Action Algorithms.

Rev Esp Cardiol (Engl Ed) 2016 Mar 6;69(3):300-9. Epub 2016 Feb 6.

Unidad de Cardiopatías Familiares, Servicio de Cardiología, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain; Grupo de Trabajo de Cardiopatías Familiares, Sociedad Española de Cardiología, Madrid, Spain.

The term inherited cardiovascular disease encompasses a group of cardiovascular diseases (cardiomyopathies, channelopathies, certain aortic diseases, and other syndromes) with a number of common characteristics: they have a genetic basis, a familial presentation, a heterogeneous clinical course, and, finally, can all be associated with sudden cardiac death. The present document summarizes some important concepts related to recent advances in sequencing techniques and understanding of the genetic bases of these diseases. We propose diagnostic algorithms and clinical practice recommendations and discuss controversial aspects of current clinical interest. We highlight the role of multidisciplinary referral units in the diagnosis and treatment of these conditions.
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http://dx.doi.org/10.1016/j.rec.2015.11.029DOI Listing
March 2016

European Cardiomyopathy Pilot Registry: EURObservational Research Programme of the European Society of Cardiology.

Eur Heart J 2016 Jan 25;37(2):164-73. Epub 2015 Sep 25.

EURObservational Research Programme, European Society of Cardiology, Sophia-Antipolis, France.

Aims: Cardiomyopathies are a heterogeneous group of disorders associated with premature death due to ventricular arrhythmia or heart failure. The purpose of this study was to examine the characteristics of patients enrolled in the pilot phase of the EURObservational Research Programme (EORP) cardiomyopathy registry.

Methods And Results: Between 1 December 2012 and 30 November 2013, four cardiomyopathy phenotypes were studied: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and restrictive cardiomyopathy (RCM). Twenty-seven centres in 12 countries participated; 1115 patients were enrolled. The commonest cardiomyopathy was HCM (n = 681), followed by DCM (n = 346), ARVC (n = 59), and RCM (n = 29); 423 patients (46.4% of those reported) had familial disease; and 56 (5.0%) had rare disease phenocopies. Median age at enrolment and diagnosis was 54 [interquartile range (IQR), 42-64] and 46 years (IQR, 32-58), respectively; fewer patients with ARVC and more with RCM were diagnosed in the upper age quartile (P < 0.0001). There was a male predominance for all cardiomyopathies except RCM (P = 0.0023). Most patients were in New York Heart Association functional class I (n = 813) at enrolment; 139 (12.5%) reported syncope, most frequently in ARVC (P = 0.0009). Five hundred and seven (45.5%) patients underwent cardiac magnetic resonance imaging, 117 (10.6%) endomyocardial biopsy, and 462 (41.4%) genetic testing with a causative mutation reported in 236 individuals (51.1%). 1026 patients (92.0%) were receiving drug therapy; 316 (28.3%) had received an implantable cardioverter defibrillator (highest proportion in ARVC, P < 0.0001).

Conclusion: This pilot study shows that services for patients with cardiomyopathy are complex, requiring access to a large range of invasive and non-invasive investigations and involvement of multidisciplinary teams. Treatment regimens are equally multifaceted and show that patients are likely to need long-term follow-up in close liaison with expert centres.
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http://dx.doi.org/10.1093/eurheartj/ehv497DOI Listing
January 2016

Phenotype and prognostic correlations of the converter region mutations affecting the β myosin heavy chain.

Heart 2015 Jul 2;101(13):1047-53. Epub 2015 May 2.

Health in Code, A Coruña, Spain Inherited Cardiovascular Disease Unit, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas Universidade da Coruña (UDC), A Coruña, Spain.

Objectives: The prognostic value of genetic studies in cardiomyopathies is still controversial. Our objective was to evaluate the outcome of patients with cardiomyopathy with mutations in the converter domain of β myosin heavy chain (MYH7).

Methods: Clinical characteristics and survival of 117 affected members with mutations in the converter domain of MYH7 were compared with 409 patients described in the literature with mutations in the same region.

Results: Twenty-five mutations were evaluated (9 in our families including 3 novel (Ile730Asn, Asp717Gly and Arg719Pro)). Clinical diagnoses were hypertrophic (n=407), dilated (n=15), non-compaction (n=4) and restrictive (n=5) cardiomyopathies, unspecified cardiomyopathy (n=11), sudden death (n=50) and 35 healthy carriers. One hundred eighty-four had events (cardiovascular death or transplant). Median event-free survival was 50±2 years in our patients and 53±3 years in the literature (p=0.27). There were significant differences in the outcome between mutation: Ile736Thr had fewer events than other mutations in the region (p=0.01), while Arg719Gln (p<0.01) had reduced event-free survival.

Conclusions: Mutations in the converter region are generally associated with adverse prognosis although there are differences between mutations. The identification of a mutation in this particular region provides important prognostic information that should be considered in the clinical management of affected patients.
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http://dx.doi.org/10.1136/heartjnl-2014-307205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484257PMC
July 2015

Somatic MYH7, MYBPC3, TPM1, TNNT2 and TNNI3 mutations in sporadic hypertrophic cardiomyopathy.

Circ J 2013 19;77(9):2358-65. Epub 2013 Jun 19.

Instituto de Investigación Biomédica de la Universidad de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC)-Universidad de A Coruña.

Background: Hypertrophic cardiomyopathy (HCM) is a clinically heterogeneous genetic heart disease characterized by left ventricular hypertrophy in the absence of another disease that could explain the wall thickening. Elucidation of the genetic basis of HCM lead to the identification of several genes encoding sarcomeric proteins, such as MYH7, MYBPC3, TPM1, TNNT2, and TNNI3. Sarcomeric genes are mutated in approximately 40% of HCM patients and a possible explanation for the incomplete yield of mutation-positive HCM may be somatic mutations.

Methods And Results: We studied 104 unrelated patients with non-familial HCM. Patients underwent clinical evaluation and mutation screening of 5 genes implicated in HCM (MYH7, MYBPC3, TPM1, TNNT2, and TNNI3) in genomic DNA isolated from resected cardiac tissue; 41 of 104 were found to carry a mutation, but as several patients carried the same mutations, the total amount of different mutations was 37; 20 of these mutations have been previously described, and pathogenicity has been assessed. To determine the effect of the 17 new mutations an in silico assay was performed and it predicted that 4 variants were damaging mutations. All identified variants were also seen in the DNA isolated from the corresponding blood, which demonstrated the absence of somatic mutations.

Conclusions: Somatic mutations in MYH7, MYBPC3, TPM1, TNNT2, and TNNI3 do not represent an important etiologic pathway in HCM.
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http://dx.doi.org/10.1253/circj.cj-13-0294DOI Listing
April 2014

Emergency percutaneous coronary intervention in unprotected left main coronary arteries. Predictors of mortality and impact of cardiogenic shock.

Rev Esp Cardiol 2009 Oct;62(10):1118-24

Servicio de Cardiología, Sección de Hemodinámica, Hospital Virgen de la Arrixaca, Murcia, España.

Introduction And Objectives: Percutaneous coronary intervention (PCI) for unprotected left main coronary artery (LMCA) disease may be essential following acute myocardial infarction (AMI). However, few data are available on the use of emergency PCI in unprotected LMCAs outside of clinical trials. The objective of this study was to determine the frequency of in-hospital mortality, its predictors and its association with cardiogenic shock, and long-term outcomes in patients with unprotected LMCA disease who undergo emergency PCI because of AMI.

Methods: The study included 71 consecutive patients who underwent emergency angioplasty of the LMCA and who were followed up clinically.

Results: Overall, 42 patients (59%) had ST-elevation AMI and 47 (66%) had cardiogenic shock or developed it during PCI. Eleven patients (16%) died in the catheterization laboratory and 33 (47%) died during hospitalization. Inhospital mortality was similar in those with and without evidence of ST-segment elevation on ECG (48% vs. 45%; P=1). Multivariate analysis showed that the predictors of in-hospital mortality were cardiogenic shock (odds ratio [OR]=4.5; 95% confidence interval [CI], 1.1-18) and incomplete revascularization (OR=5.1; 95% CI, 1.0-26). After discharge, 39 patients were followed up for a median of 32 months. Mortality in the first year was 10%.

Conclusions: Emergency PCI is a viable therapeutic option for AMI due to unprotected LMCA disease. However, in-hospital mortality is high, regardless of ST-segment elevation, particularly if there is cardiogenic shock or complete revascularization has not been achieved.
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http://dx.doi.org/10.1016/s1885-5857(09)73326-2DOI Listing
October 2009

Prevalence of fabry disease in a cohort of 508 unrelated patients with hypertrophic cardiomyopathy.

J Am Coll Cardiol 2007 Dec;50(25):2399-403

Complejo Hospitalario Universitario Juan Canalejo, A Coruña, Spain.

Objectives: We aimed to study the prevalence of Fabry disease (FD) in patients with hypertrophic cardiomyopathy (HCM).

Background: There are limited and controversial data about the prevalence of FD in patients with HCM.

Methods: We screened the plasma alpha-galactosidase A activity from 508 unrelated patients with HCM (328 men, 180 women, ages 58 +/- 16 years). Patients with low activity (0% to 30% of the normal control in men, and 0% to 50% in women) underwent genetic study of the GLA gene.

Results: We found low plasma activity in 15 patients (3%). Three men had GLA mutations (0.9%): S238N (novel) in 2 and E358del (described) in 1. Two women had described mutations (1.1%): L89P and A143T. Three unrelated men had the D313Y variant previously associated with enzyme pseudo-deficiency. Two women had polymorphisms that did not segregate with the disease in their families. Five women (activity 39% to 47%) had no sequence variants. The familial studies allowed the diagnosis of 14 carriers: 6 women without Fabry manifestations, 3 women with cardiomyopathy, 2 men with renal and cardiac disease, 1 man with microhematuria, 1 woman with first-degree atrioventricular block, and a 32-year-old woman with only renal disease.

Conclusions: By means of a screening based on genotyping of patients with low plasma enzymatic activity, the prevalence of FD in our population of HCM is 1% (0.9% in men and 1.1% in women). This diagnosis is relevant, because it allows the identification of disease carriers that might benefit from enzyme replacement therapy.
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http://dx.doi.org/10.1016/j.jacc.2007.06.062DOI Listing
December 2007
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