Publications by authors named "Pablo Garcia-Pavia"

144 Publications

Diagnosis and treatment of cardiac amyloidosis. A position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.

Eur J Heart Fail 2021 Apr 7. Epub 2021 Apr 7.

2nd Department of Medicine, Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic.

Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.
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http://dx.doi.org/10.1002/ejhf.2140DOI Listing
April 2021

Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases.

Eur Heart J 2021 Apr;42(16):1554-1568

2nd Department of Medicine, Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic.

Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.
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http://dx.doi.org/10.1093/eurheartj/ehab072DOI Listing
April 2021

Apical myectomy in patients with apical hypertrophic cardiomyopathy and advanced heart failure.

Rev Esp Cardiol (Engl Ed) 2021 Feb 27. Epub 2021 Feb 27.

Servicio de Cardiología, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain.

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http://dx.doi.org/10.1016/j.rec.2020.11.021DOI Listing
February 2021

Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant.

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

Departamento de Cardiología, Health in Code, La Coruña, Spain.

Introduction And Objectives: TPM1 is one of the main hypertrophic cardiomyopathy (HCM) genes. Clinical information on carriers is relatively scarce, limiting the interpretation of genetic findings in individual patients. Our aim was to establish genotype-phenotype correlations of the TPM1 p.Arg21Leu variant in a serie of pedigrees.

Methods: TPM1 was evaluated by next-generation sequencing in 10 561 unrelated probands with inherited heart diseases. Familial genetic screening was performed by the Sanger method. We analyzed TPM1 p.Arg21Leu pedigrees for cosegregation, clinical characteristics, and outcomes. We also estimated the geographical distribution of the carrier families in Portugal and Spain.

Results: The TPM1 p.Arg21Leu variant was identified in 25/4099 (0.61%) HCM-cases, and was absent in 6462 control individuals with other inherited cardiac phenotypes (P<.0001). In total, 83 carriers (31 probands) were identified. The combined LOD score for familial cosegregation was 3.95. The cumulative probability of diagnosis in carriers was 50% at the age of 50 years for males, and was 25% in female carriers. At the age of 70 years, 17% of males and 46% of female carriers were unaffected. Mean maximal left ventricular wall thickness was 21.4 ±7.65mm. Calculated HCM sudden death risk was low in 34 carriers (77.5%), intermediated in 8 (18%), and high in only 2 (4.5%). Survival free of cardiovascular death or heart transplant was 87.5% at 50 years. Six percent of carriers were homozygous and 18% had an additional variant. Family origin was concentrated in Galicia, Extremadura, and northern Portugal, suggesting a founder effect.

Conclusions: TPM1 p.Arg21Leu is a pathogenic HCM variant associated with late-onset/incomplete penetrance and a generally favorable prognosis.
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http://dx.doi.org/10.1016/j.rec.2021.01.001DOI Listing
February 2021

Benefits of cardiac pacing in ICD recipients with hypertrophic cardiomyopathy.

J Interv Card Electrophysiol 2021 Feb 16. Epub 2021 Feb 16.

Electrophysiology Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Calle Manuel de Falla 1, 28222 Majadahonda, Madrid, Spain.

Purpose: Implantable cardiac defibrillator (ICD) is the only definitive therapy for prevention of sudden cardiac death in hypertrophic cardiomyopathy (HCM). Conventional transvenous ICDs can provide cardiac pacing unlike new subcutaneous ICD, but the usefulness of cardiac pacing in HCM patients is not well defined. We sought to assess the usefulness of ICD pacing in HCM.

Methods: We retrospectively analyzed 93 HCM patients who had undergone ICD implantation at our center. Usefulness of pacing was defined as follows: 1) need of pacing due to bradycardia or AV conduction disturbances, 2) improvement of LV outflow tract obstruction by sequential AV pacing, 3) need for CRT pacing, or 4) successful antitachycardia pacing without a subsequent shock. Independent predictors of useful pacing were investigated by multivariable analysis.

Results: During a mean follow-up of 91.3 ± 5.5 months, 43 patients (46.2%) reached the composite endpoint. Independent predictors of pacing usefulness were older age (HR 1.36; 95%CI: 1.088-1.709; p=0.007) and NYHA functional class ≥ II (HR 2.15; 95%CI: 1.083-4.301; p=0.029). Twenty-eight (30.1%) patients had appropriate ICD interventions, triggered by a monomorphic ventricular tachycardia (MVT) in 22 of them (78.5%). In 17 individuals with MVT (77%), antitachycardia pacing successfully treated MVT.

Conclusions: In our HCM series of patients with ICD, 46% of individuals benefitted from cardiac pacing. MVT were documented in nearly 80% of the patients with ventricular arrhythmias and antitachycardia pacing successfully treated them in 77% of cases.
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http://dx.doi.org/10.1007/s10840-021-00961-9DOI Listing
February 2021

Are 18F-fluorodeoxyglucose positron emission tomography results reliable in patients with ascending aortic grafts? A prospective study in non-infected patients.

Eur J Cardiothorac Surg 2021 Feb 4. Epub 2021 Feb 4.

Cardiac Surgery Department, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain.

Objectives: Our goal was to define characteristic patterns of 18F-fluorodeoxyglucose in non-infected patients with ascending aortic prosthetic grafts during the first year after surgery.

Methods: 18F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) was performed at 3, 6 and 12 months postoperatively in 26 uninfected patients. Clinical, analytical and microbiological (blood culture) assessments were performed to confirm the absence of infection. FDG uptake intensity [measured through maximum standardized uptake values (SUVmax) and the target-to-background ratio] and distribution patterns were obtained. Models of generalized estimating equations were used to assess the evolution of the SUVmax over time. The results were compared to those in our endocarditis-over-ascending-aortic-graft series database. The receiver operating characteristic curves of the control group and the 12-month group were assessed.

Results: All patients showed increased uptake in all areas. The uptake pattern was heterogeneous in 47.4%, 43.5% and 42.3% at 3, 6 and 12 months. The means and standard deviations of the SUVmax in the graft were 4.80 (±0.99), 4.28 (±0.88) and 4.14 (±0.87) at 3, 6 and 12 months after surgery. A comparison of all values obtained in the 6th and 12th months compared to those from the 3rd month revealed a slow decrease that may persist after the first year. The cut-off value of SUVmax of 4.24 had an overall sensitivity of 84.6% and specificity of 57.7% for patients seen at 12 months.

Conclusions: Non-infected ascending aortic grafts showed no predominant uptake pattern; they also showed increased 18F-fluorodeoxyglucose activity that could persist beyond the first year. Caution is therefore recommended when interpreting PET/CT images obtained during the first year after surgery.
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http://dx.doi.org/10.1093/ejcts/ezab017DOI Listing
February 2021

Screening of Fabry Disease in Patients with Chest Pain Without Obstructive Coronary Artery Disease.

J Cardiovasc Transl Res 2021 Jan 20. Epub 2021 Jan 20.

Hospital Universitario Puerta de Hierro Majadahonda, CIBERCV, Manuel de Falla, 2. Majadahonda, 28222, Madrid, Spain.

Identification of Anderson-Fabry disease (AFD) in cardiac patients has been restricted so far to patients with left ventricular hypertrophy. Coronary microvascular dysfunction has been described in AFD with and without cardiac hypertrophy and may represent the only manifestation in AFD patients, offering a possible earlier diagnosis. We studied the prevalence of AFD in 663 patients with chest pain with normal or non-obstructive coronary arteries. The overall prevalence of AFD in this cohort was only 0.15% (1/663). AFD is not a frequent cause of chest pain without obstructive coronary artery disease and screening efforts should not be conducted in this patient population.
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http://dx.doi.org/10.1007/s12265-020-10097-2DOI Listing
January 2021

Usefulness of natriuresis to predict in-hospital diuretic resistance.

Am J Cardiovasc Dis 2020 15;10(4):350-355. Epub 2020 Oct 15.

Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda Madrid, Spain.

Background: Urinary sodium excretion predicts long-term adverse events after discharge in patients with acute heart failure (AHF). The role of natriuresis as an early marker of poor diuretic response during an AHF episode has been scarcely investigated. We sought to evaluate whether early natriuresis or its change during heart failure hospitalization is associated with the development of in-hospital diuretic resistance (DR).

Methods: This was a prospective, observational single center study of consecutive patients with AHF. Urine electrolytes were estimated from a spot urine sample within the first 6 hours following the first diuretic dose and 48 hours after admission. In-hospital DR was defined as poor diuretic response based on diuretic efficiency metrics and persistent congestion despite an intensive diuretic protocol.

Results: Between January and December 2018, 143 patients were admitted for AHF. Of these, 102 fulfilled the inclusion criteria (60% males, median age 77 years [interquartile range [IQR]: 69-83), and 20 patients (19.6%) met the definition of DR. Early natriuresis was lower in patients with DR than in non-resistant patients (46 mEq/L [IQR: 38.5-80.0] vs 97.5 mEq/L [IQR: 70.5-113.5], P<0.001). Urinary sodium <50 mEq/L increased the risk of developing in-hospital DR (risk ratio: 5.011 [95% confidence interval 2.408-10.429], P<0.001). The area under the receiver operating characteristic curve for early natriuresis to predict DR was 0.791 (95% confidence interval 0.681-0.902, P<0.001).

Conclusions: Initial natriuresis can predict in-hospital DR. Patients with urinary sodium <50 mEq/L have an increased risk of early resistance to diuretic treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675170PMC
October 2020

Phenotypic clustering of dilated cardiomyopathy patients highlights important pathophysiological differences.

Eur Heart J 2021 Jan;42(2):162-174

Department of Cardiology, Cardiovascular Research Institute (CARIM), Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands.

Aims: The dilated cardiomyopathy (DCM) phenotype is the result of combined genetic and acquired triggers. Until now, clinical decision-making in DCM has mainly been based on ejection fraction (EF) and NYHA classification, not considering the DCM heterogenicity. The present study aimed to identify patient subgroups by phenotypic clustering integrating aetiologies, comorbidities, and cardiac function along cardiac transcript levels, to unveil pathophysiological differences between DCM subgroups.

Methods And Results: We included 795 consecutive DCM patients from the Maastricht Cardiomyopathy Registry who underwent in-depth phenotyping, comprising extensive clinical data on aetiology and comorbodities, imaging and endomyocardial biopsies. Four mutually exclusive and clinically distinct phenogroups (PG) were identified based upon unsupervised hierarchical clustering of principal components: [PG1] mild systolic dysfunction, [PG2] auto-immune, [PG3] genetic and arrhythmias, and [PG4] severe systolic dysfunction. RNA-sequencing of cardiac samples (n = 91) revealed a distinct underlying molecular profile per PG: pro-inflammatory (PG2, auto-immune), pro-fibrotic (PG3; arrhythmia), and metabolic (PG4, low EF) gene expression. Furthermore, event-free survival differed among the four phenogroups, also when corrected for well-known clinical predictors. Decision tree modelling identified four clinical parameters (auto-immune disease, EF, atrial fibrillation, and kidney function) by which every DCM patient from two independent DCM cohorts could be placed in one of the four phenogroups with corresponding outcome (n = 789; Spain, n = 352 and Italy, n = 437), showing a feasible applicability of the phenogrouping.

Conclusion: The present study identified four different DCM phenogroups associated with significant differences in clinical presentation, underlying molecular profiles and outcome, paving the way for a more personalized treatment approach.
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http://dx.doi.org/10.1093/eurheartj/ehaa841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813623PMC
January 2021

Clinical Profile of Cardiac Involvement in Danon Disease: A Multicenter European Registry.

Circ Genom Precis Med 2020 12 5;13(6):e003117. Epub 2020 Nov 5.

Leviev Heart Center, Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Israel (D.L., Y.W., M.A.).

Background: The X-linked Danon disease manifests by severe cardiomyopathy, myopathy, and neuropsychiatric problems. We designed this registry to generate a comprehensive picture of clinical presentations and outcome of patients with Danon disease in cardiomyopathy centers throughout Europe.

Methods: Clinical and genetic data were collected in 16 cardiology centers from 8 European countries.

Results: The cohort comprised 30 male and 27 female patients. The age at diagnosis was birth to 42 years in men and 2 to 65 in women. Cardiac involvement was observed in 96%. Extracardiac manifestations were prominent in men but not in women. Left ventricular (LV) hypertrophy was reported in 73% of male and 74% of female patients. LV systolic dysfunction was reported in 40% of men (who had LV ejection fraction, 34±11%) and 59% of women (LV ejection fraction, 28±13%). The risk of arrhythmia and heart failure was comparable among sexes. The age of first heart failure hospitalization was lower in men (18±6 versus 28±17 years; <0.003). Heart failure was the leading cause of death (10 of 17; 59%), and LV systolic dysfunction predicted an adverse outcome. Eight men and 8 women (28%) underwent heart transplantation or received an LV assist device. Our cohort suggests better prognosis of female compared with male heart transplant recipients.

Conclusions: Danon disease presents earlier in men than in women and runs a malignant course in both sexes, due to cardiac complications. Cardiomyopathy features, heart failure and arrhythmia, are similar among the sexes. Clinical diagnosis and management is extremely challenging in women due to phenotypic diversity and the absence of extracardiac manifestations.
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http://dx.doi.org/10.1161/CIRCGEN.120.003117DOI Listing
December 2020

Transthyretin amyloid cardiomyopathy.

Med Clin (Barc) 2021 02 31;156(3):126-134. Epub 2020 Oct 31.

Unidad de Insuficiencia Cardíaca y Cardiopatías Familiares, Servicio de Cardiología, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, España; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, España.

Transthyretin (TTR) cardiac amyloidosis is a severe, progressive, infiltrative disease caused by the deposition of TTR at cardiac level. It may be due to a genetic alteration in its hereditary form (ATTRv) or as a consequence of an age-related degenerative process (ATTRwt). Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that ATTR is more frequent than traditionally considered and that it is particularly relevant in patients over 65 years with heart failure or with aortic stenosis. With the appearance of several treatment options capable of modifying the natural history of ATTR, it is necessary for clinicians to be familiar with the diagnostic process and treatment of this disease. This review will cover the clinical spectrum of presentation of ATTR, its diagnosis and treatment.
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http://dx.doi.org/10.1016/j.medcli.2020.06.064DOI Listing
February 2021

Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study.

Eur J Heart Fail 2021 Feb 12;23(2):277-285. Epub 2020 Nov 12.

Stanford University School of Medicine, Stanford, CA, USA.

Aims: Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). While ATTR-ACT was not designed for a dose-specific assessment, further analysis from ATTR-ACT and its long-term extension study (LTE) can guide determination of the optimal dose.

Methods And Results: In ATTR-ACT, patients were randomized (2:1:2) to tafamidis 80 mg, 20 mg, or placebo for 30 months. Patients completing ATTR-ACT could enrol in the LTE (with placebo-treated patients randomized to tafamidis 80 or 20 mg; 2:1) and all patients were subsequently switched to high-dose tafamidis. All-cause mortality was assessed in ATTR-ACT combined with the LTE (median follow-up 51 months). In ATTR-ACT, the combination of all-cause mortality and cardiovascular-related hospitalizations over 30 months was significantly reduced with tafamidis 80 mg (P = 0.0030) and 20 mg (P = 0.0048) vs. placebo. All-cause mortality vs. placebo was reduced with tafamidis 80 mg [Cox hazards model (95% confidence interval): 0.690 (0.487-0.979), P = 0.0378] and 20 mg [0.715 (0.450-1.137), P = 0.1564]. The mean (standard error) change in N-terminal pro-B-type natriuretic peptide from baseline to Month 30 was -1170.51 (587.31) (P = 0.0468) with tafamidis 80 vs. 20 mg. In ATTR-ACT combined with the LTE there was a significantly greater survival benefit with tafamidis 80 vs. 20 mg [0.700 (0.501-0.979), P = 0.0374]. Incidence of adverse events in both tafamidis doses were comparable to placebo.

Conclusion: Tafamidis, both 80 and 20 mg, effectively reduced mortality and cardiovascular-related hospitalizations in patients with ATTR-CM. The longer-term survival data and the lack of dose-related safety concerns support tafamidis 80 mg as the optimal dose.

Clinical Trial Registration: ClinicalTrials.gov NCT01994889; NCT02791230.
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http://dx.doi.org/10.1002/ejhf.2027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048553PMC
February 2021

Identification of a peripheral blood gene signature predicting aortic valve calcification.

Physiol Genomics 2020 12 12;52(12):563-574. Epub 2020 Oct 12.

Intercellular Signaling in Cardiovascular Development and Disease Laboratory, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.

Calcific aortic valve disease (CAVD) is a significant cause of illness and death worldwide. Identification of early predictive markers could help optimize patient management. RNA-sequencing was carried out on human fetal aortic valves at gestational , , and and on a case-control study with adult noncalcified and calcified bicuspid and tricuspid aortic valves. In dimension reduction and clustering analyses, diseased valves tended to cluster with fetal valves at rather than normal adult valves, suggesting that part of the disease program might be due to reiterated developmental processes. The analysis of groups of coregulated genes revealed predominant immune-metabolic signatures, including innate and adaptive immune responses involving lymphocyte T-cell metabolic adaptation. Cytokine and chemokine signaling, cell migration, and proliferation were all increased in CAVD, whereas oxidative phosphorylation and protein translation were decreased. Discrete immune-metabolic gene signatures were present at fetal stages and increased in adult controls, suggesting that these processes intensify throughout life and heighten in disease. Cellular stress response and neurodegeneration gene signatures were aberrantly expressed in CAVD, pointing to a mechanistic link between chronic inflammation and biological aging. Comparison of the valve RNA-sequencing data set with a case-control study of whole blood transcriptomes from asymptomatic individuals with early aortic valve calcification identified a highly predictive gene signature of CAVD and of moderate aortic valve calcification in overtly healthy individuals. These data deepen and broaden our understanding of the molecular basis of CAVD and identify a peripheral blood gene signature for the early detection of aortic valve calcification.
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http://dx.doi.org/10.1152/physiolgenomics.00034.2020DOI Listing
December 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.

Department of Inherited Cardiovascular Diseases, Bart's Heart Centre, St. Bartholomew's Hospital, London, United Kingdom (M.M.A., M.L., L.R.L., P.M.E.).

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

Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial.

Lancet 2020 09 29;396(10253):759-769. Epub 2020 Aug 29.

Department of Internal Medicine, Section of Cardiovascular Medicine, Yale University, New Haven, CT, USA.

Background: Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy.

Methods: In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO) and at least one NYHA class reduction or a 3·0 mL/kg per min or greater pVO increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545.

Findings: Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned to mavacamten (n=123 [49%]) or placebo (n=128 [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (-36 mm Hg, 95% CI -43·2 to -28·1; p<0·0001), greater increase in pVO (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-SoB -1·8, -2·4 to -1·2; p<0·0001). 34% more patients in the mavacamten group improved by at least one NYHA class (80 of 123 patients in the mavacamten group vs 40 of 128 patients in the placebo group; 95% CI 22·2 to 45·4; p<0·0001). Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild. One patient died by sudden death in the placebo group.

Interpretation: Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition.

Funding: MyoKardia.
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http://dx.doi.org/10.1016/S0140-6736(20)31792-XDOI Listing
September 2020

Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis.

J Am Coll Cardiol 2020 07;76(2):186-197

Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares, Madrid, Spain; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart; Universidad Francisco de Vitoria, Pozuelo de Alarcon, Spain. Electronic address:

Background: PRKAG2 gene variants cause a syndrome characterized by cardiomyopathy, conduction disease, and ventricular pre-excitation. Only a small number of cases have been reported to date, and the natural history of the disease is poorly understood.

Objectives: The aim of this study was to describe phenotype and natural history of PRKAG2 variants in a large multicenter European cohort.

Methods: Clinical, electrocardiographic, and echocardiographic data from 90 subjects with PRKAG2 variants (53% men; median age 33 years; interquartile range [IQR]: 15 to 50 years) recruited from 27 centers were retrospectively studied.

Results: At first evaluation, 93% of patients were in New York Heart Association functional class I or II. Maximum left ventricular wall thickness was 18 ± 8 mm, and left ventricular ejection fraction was 61 ± 12%. Left ventricular hypertrophy (LVH) was present in 60 subjects (67%) at baseline. Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation; 17 (19%) had pacemakers (median age at implantation 36 years; IQR: 27 to 46 years), and 16 (18%) had atrial fibrillation (median age 43 years; IQR: 31 to 54 years). After a median follow-up period of 6 years (IQR: 2.3 to 13.9 years), 71% of subjects had LVH, 29% had AF, 21% required de novo pacemakers (median age at implantation 37 years; IQR: 29 to 48 years), 14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died.

Conclusions: PRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of atrial fibrillation, conduction disease, advanced heart failure, and life-threatening arrhythmias. Classical features of pre-excitation and severe LVH are not uniformly present, and diagnosis should be considered in patients with LVH who develop atrial fibrillation or require permanent pacemakers at a young age.
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http://dx.doi.org/10.1016/j.jacc.2020.05.029DOI Listing
July 2020

Risk predictors in a Spanish cohort with cardiac laminopathies. The REDLAMINA registry.

Rev Esp Cardiol (Engl Ed) 2021 Mar 29;74(3):216-224. Epub 2020 Jun 29.

Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Departamento de Cardiología, Health in Code, A Coruña, Spain.

Introduction And Objectives: According to sudden cardiac death guidelines, an implantable cardioverter-defibrillator (ICD) should be considered in patients with LMNA-related dilated cardiomyopathy (DCM) and ≥ 2 risk factors: male sex, left ventricular ejection fraction (LVEF) <45%, nonsustained ventricular tachycardia (NSVT), and nonmissense genetic variants. In this study we aimed to describe the clinical characteristics of carriers of LMNA genetic variants among individuals from a Spanish cardiac-laminopathies cohort (REDLAMINA registry) and to assess previously reported risk criteria.

Methods: The relationship between risk factors and cardiovascular events was evaluated in a cohort of 140 carriers (age ≥ 16 years) of pathogenic LMNA variants (54 probands, 86 relatives). We considered: a) major arrhythmic events (MAE) if there was appropriate ICD discharge or sudden cardiac death; b) heart failure death if there was heart transplant or death due to heart failure.

Results: We identified 11 novel and 21 previously reported LMNA-related DCM variants. LVEF <45% (P=.001) and NSVT (P <.001) were related to MAE, but not sex or type of genetic variant. The only factor independently related to heart failure death was LVEF <45% (P <.001).

Conclusions: In the REDLAMINA registry cohort, the only predictors independently associated with MAE were NSVT and LVEF <45%. Therefore, female carriers of missense variants with either NSVT or LVEF <45% should not be considered a low-risk group. It is important to individualize risk stratification in carriers of LMNA missense variants, because not all have the same prognosis.
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http://dx.doi.org/10.1016/j.rec.2020.03.026DOI Listing
March 2021

Mutations in cause an autosomal-recessive form of hypertrophic cardiomyopathy.

Heart 2020 Sep 25;106(17):1342-1348. Epub 2020 May 25.

Cardiovascular Genetics, Health in Code, A Coruna, Spain.

Objective: Up to 50% of patients with hypertrophic cardiomyopathy (HCM) show no disease-causing variants in genetic studies. has been suggested as a candidate gene for the development of cardiomyopathies, although evidence for a causative role in HCM is limited. We sought to investigate the relationship between rare variants in and the development of HCM.

Methods: was sequenced by next generation sequencing in 4867 index cases with a clinical diagnosis of HCM and in 3628 probands with other cardiomyopathies. Additionally, 3136 index cases with familial cardiovascular diseases other than cardiomyopathy (mainly channelopathies and aortic diseases) were used as controls.

Results: Sixteen index cases with rare homozygous or compound heterozygous variants in (15 HCM and one restrictive cardiomyopathy) were included. No homozygous or compound heterozygous were identified in the control population. Familial evaluation showed that only homozygous and compound heterozygous had signs of disease, whereas all heterozygous family members were healthy. The mean age at diagnosis was 35 years (range 15-69). Fifty per cent of patients had concentric left ventricular hypertrophy (LVH) and 45% were asymptomatic at the moment of the first examination. Significant degrees of late gadolinium enhancement were detected in 80% of affected individuals, and 20% of patients had left ventricular (LV) systolic dysfunction. Fifty per cent had non-sustained ventricular tachycardia. Twenty per cent of patients suffered an adverse cerebrovascular event (20%).

Conclusion: appears to be an uncommon cause of HCM inherited in an autosomal-recessive manner and associated with concentric LVH and a high rate of LV dysfunction.
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http://dx.doi.org/10.1136/heartjnl-2020-316913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476281PMC
September 2020

Design of the β3-Adrenergic Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure Trial.

JACC Basic Transl Sci 2020 Apr 11;5(4):317-327. Epub 2020 Mar 11.

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

Combined pre-and post-capillary hypertension (CpcPH) is a relatively common complication of heart failure (HF) associated with a poor prognosis. Currently, there is no specific therapy approved for this entity. Recently, treatment with beta-3 adrenergic receptor (β3AR) agonists was able to improve pulmonary hemodynamics and right ventricular (RV) performance in a translational, large animal model of chronic PH. The authors present the design of a phase II randomized clinical trial that tests the benefits of mirabegron (a clinically available β3AR agonist) in patients with CpcPH due to HF. The effect of β3AR treatment will be evaluated on pulmonary hemodynamics, as well as clinical, biochemical, and advanced cardiac imaging parameters. (Beta3 Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure [SPHERE-HF]; NCT02775539).
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http://dx.doi.org/10.1016/j.jacbts.2020.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188870PMC
April 2020

Clinical profile and outcome of cardiac amyloidosis in a Spanish referral center.

Rev Esp Cardiol (Engl Ed) 2021 Feb 18;74(2):149-158. Epub 2020 Apr 18.

Servicio de Cardiología, Hospital Universitario Puerta de Hierro Majadahonda, Universidad Autónoma de Madrid, Majadahonda, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain; Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcón, Madrid, Spain. Electronic address:

Introduction And Objectives: Cardiac amyloidosis (CA) is produced by amyloid fiber deposition in the myocardium. The most frequent forms are those caused by light chains (AL) and transthyretin (ATTR). Our objective was to describe the diagnosis, treatment and outcomes of CA in a specialized Spanish center.

Methods: We included all patients diagnosed with CA in Hospital Universitario Puerta de Hierro Majadahonda from May 2008 to September 2018. We analyzed their clinical characteristics, outcomes, and survival.

Results: We included 180 patients with CA, of whom 64 (36%) had AL (50% men; mean age, 65±11 years) and 116 had ATTR (72% men; mean age 79±11 years; 18 with hereditary ATTR). The most common presentation was heart failure in both groups (81% in AL and 45% in ATTR, P <.01). Other forms of presentation in ATTR patients were atrial arrhythmias (16%), conduction disorders (6%), and incidental finding (6%); 70 patients (40%), had a previous alternative cardiac diagnosis. Diagnosis was noninvasive in 75% of ATTR patients. Diagnostic delay was higher in ATTR (2.8±4.3 vs 0.6±0.7 years, P <.001), but mortality was greater in AL patients (48% vs 32%, P=.028). Independent predictors of mortality were AL subtype (HR, 6.16; 95%CI, 1.56-24.30; P=.01), female sex (HR, 2.35; 95%CI, 1.24-4.46; P=.01), and NYHA functional class III-IV (HR, 2.07; 95%CI, 1.11-3.89; P=.02).

Conclusions: CA is a clinical challenge, with wide variability in its presentation depending on the subtype, leading to diagnostic delay and high mortality. Improvements are needed in the early diagnosis and treatment of these patients.
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http://dx.doi.org/10.1016/j.rec.2019.12.020DOI Listing
February 2021

Clinical characteristics and determinants of the phenotype in TMEM43 arrhythmogenic right ventricular cardiomyopathy type 5.

Heart Rhythm 2020 06 13;17(6):945-954. Epub 2020 Feb 13.

Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; CIBERCV, Madrid, Spain; Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcón, Spain. Electronic address:

Background: Arrhythmogenic right ventricular cardiomyopathy type V (ARVC-5) is the most aggressive heterozygous form of ARVC. It is predominantly caused by a fully penetrant mutation (p.S358L) in the nondesmosomal gene TMEM43-endemic to Newfoundland, Canada. To date, all familial cases reported worldwide share a common ancestral haplotype. It is unknown whether the p.S358L mutation by itself causes ARVC-5 or whether the disease is influenced by genetic or environmental factors.

Objective: The purpose of this study was to examine the phenotype, clinical course, and the impact of exercise on patients with p.S358L ARVC-5 without the Newfoundland genetic background.

Methods: We studied 62 affected individuals and 73 noncarriers from 3 TMEM43-p.S358L Spanish families. The impact of physical activity on the phenotype was also evaluated.

Results: Haplotype analysis revealed that the 3 Spanish families were unrelated to patients with ARVC-5 with the Newfoundland genetic background. Two families shared 10 microsatellite markers in a 4.9 cM region surrounding TMEM43; the third family had a distinct haplotype. The affected individuals showed a 38.7% incidence of sudden cardiac death, which was higher in men. Left ventricular involvement was common, with 40% of mutation carriers showing a left ventricular ejection fraction of <50%. Compared with noncarriers, the R-wave voltage in lead V was lower (3.2 ± 2.8 mV vs 7.5 ± 3.6 mV; P < .001) and QRS complex in right precordial leads wider (104.7 ± 24.0 ms vs 88.2 ± 7.7 ms; P = .001). A history of vigorous exercise showed a trend toward more ventricular arrhythmias only in women (P = .053).

Conclusion: ARVC-5 is associated with a high risk of sudden cardiac death and characteristic clinical and electrocardiographic features irrespective of geographical origin and genetic background. Our data suggest that, as in desmosomal ARVC, vigorous physical activity could aggravate the phenotype of TMEM43 mutation carriers.
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http://dx.doi.org/10.1016/j.hrthm.2020.01.035DOI Listing
June 2020

Changes in causes of death and influence of therapeutic improvement over time in patients with heart failure and reduced ejection fraction.

Rev Esp Cardiol (Engl Ed) 2020 Jul 20;73(7):561-568. Epub 2020 Jan 20.

Servicio de Cardiología, Hospital Clínico Universitario Virgen de la Arrixaca, Universidad de Murcia, IMIB-Arrixaca, El Palmar, Murcia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Madrid, Spain; Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. Electronic address:

Introduction And Objectives: In patients with heart failure and reduced ejection fraction (HFrEF), several therapies have been proven to reduce mortality in clinical trials. However, there are few data on the effect of the use of evidence-based therapies on causes of death in clinical practice.

Methods: This study included 2351 outpatients with HFrEF (< 40%) from 2 multicenter prospective registries: MUSIC (n=641, period: 2003-2004) and REDINSCOR I (n=1710, period: 2007-2011). Variables were recorded at inclusion and all patients were followed-up for 4 years. Causes of death were validated by an independent committee.

Results: Patients in REDINSCOR I more frequently received beta-blockers (85% vs 71%; P <.001), mineralocorticoid antagonists (64% vs 44%; P <.001), implantable cardioverter-defibrillators (19% vs 2%; P <.001), and resynchronization therapy (7.2% vs 4.8%; P=.04). In these patients, sudden cardiac death was less frequent than in those in MUSIC (6.8% vs 11.4%; P <.001). After propensity score matching, we obtained 2 comparable populations differing only in treatments (575 vs 575 patients). In patients in REDINSCOR I, we found a lower risk of total mortality (HR, 0.70; 95%CI, 0.57-0.87; P=.001) and sudden cardiac death (sHR, 0.46; 95%CI, 0.30-0.70; P <.001), and a trend toward lower mortality due to end-stage HF (sHR, 0.73; 95%CI, 0.53-1.01; P=.059), without differences in other causes of death (sHR, 1.17; 95%CI, 0.78-1.75; P=.445), regardless of functional class.

Conclusions: In ambulatory patients with HFrEF, implementation of evidence-based therapies was associated with a lower risk of death, mainly due to a significant reduction in sudden cardiac death.
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http://dx.doi.org/10.1016/j.rec.2019.09.030DOI Listing
July 2020

Multiparametric Echocardiography Scores for the Diagnosis of Cardiac Amyloidosis.

JACC Cardiovasc Imaging 2020 04 18;13(4):909-920. Epub 2019 Dec 18.

National Amyloidosis Centre, University College London, Royal Free Campus, London, United Kingdom. Electronic address:

Objectives: This study aimed to investigate the accuracy of a broad range of echocardiographic variables to develop multiparametric scores to diagnose CA in patients with proven light chain (AL) amyloidosis or those with increased heart wall thickness who had amyloid was suspected. We also aimed to further characterize the structural and functional changes associated with amyloid infiltration.

Background: Cardiac amyloidosis (CA) is a serious but increasingly treatable cause of heart failure. Diagnosis is challenging and frequently unclear at echocardiography, which remains the most often used imaging tool.

Methods: We studied 1,187 consecutive patients evaluated at 3 referral centers for CA and analyzed morphological, functional, and strain-derived echocardiogram parameters with the aim of developing a score-based diagnostic algorithm. Cardiac amyloid burden was quantified by using extracellular volume measurements at cardiac magnetic resonance.

Results: A total of 332 patients were diagnosed with AL amyloidosis and 339 patients with transthyretin CA. Concentric remodeling and strain-derived parameters displayed the best diagnostic performance. A multivariable logistic regression model incorporating relative wall thickness, E wave/e' wave ratio, longitudinal strain, and tricuspid annular plane systolic excursion had the greatest diagnostic performance in AL amyloidosis (area under the curve: 0.90; 95% confidence interval: 0.87 to 0.92), whereas the addition of septal apical-to-base ratio yielded the best diagnostic accuracy in the increased heart wall thickness group (area under the curve: 0.80; 95% confidence interval: 0.85 to 0.90).

Conclusions: Specific functional and structural parameters characterize different burdens of CA deposition with different diagnostic performances and enable the definition of 2 scores that are sensitive and specific tools with which diagnose or exclude CA.
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http://dx.doi.org/10.1016/j.jcmg.2019.10.011DOI Listing
April 2020

Predictive model of in-hospital mortality in left-sided infective endocarditis.

Rev Esp Cardiol (Engl Ed) 2019 Dec 14. Epub 2019 Dec 14.

Servicio de Cardiología, Instituto de Ciencias del Corazón (ICICOR), Hospital Clínico Universitario Valladolid, Valladolid, Spain; CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.

Introduction And Objectives: Infective endocarditis (IE) is a complex disease with high in-hospital mortality. Prognostic assessment is essential to select the most appropriate therapeutic approach; however, international IE guidelines do not provide objective assessment of the individual risk in each patient. We aimed to design a predictive model of in-hospital mortality in left-sided IE combining the prognostic variables proposed by the European guidelines.

Methods: Two prospective cohorts of consecutive patients with left-sided IE were used. Cohort 1 (n=1002) was randomized in a 2:1 ratio to obtain 2 samples: an adjustment sample to derive the model (n=688), and a validation sample for internal validation (n=314). Cohort 2 (n=133) was used for external validation.

Results: The model included age, prosthetic valve IE, comorbidities, heart failure, renal failure, septic shock, Staphylococcus aureus, fungi, periannular complications, ventricular dysfunction, and vegetations as independent predictors of in-hospital mortality. The model showed good discrimination (area under the ROC curve=0.855; 95%CI, 0.825-0.885) and calibration (P value in Hosmer-Lemeshow test=0.409), which were ratified in the internal (area under the ROC curve=0.823; 95%CI, 0.774-0.873) and external validations (area under the ROC curve=0.753; 95%CI, 0.659-0.847). For the internal validation sample (observed mortality: 29.9%) the model predicted an in-hospital mortality of 30.7% (95%CI, 27.7-33.7), and for the external validation cohort (observed mortality: 27.1%) the value was 26.4% (95%CI, 22.2-30.5).

Conclusions: A predictive model of in-hospital mortality in left-sided IE based on the prognostic variables proposed by the European Society of Cardiology IE guidelines has high discriminatory ability.
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http://dx.doi.org/10.1016/j.rec.2019.11.003DOI Listing
December 2019

Predicted pathogenic mutations in STAP1 are not associated with clinically defined familial hypercholesterolemia.

Atherosclerosis 2020 01 29;292:143-151. Epub 2019 Nov 29.

Endocrinology Department, Hospital Universitario Insular de Gran Canaria, Instituto Universitario de Investigación Biomédica y de la Salud de la Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain.

Background And Aims: Autosomal dominant familial hypercholesterolemia (FH) is caused by mutations in LDLR,APOB and PCSK9. Two new putative loci causing FH have been identified recently, the p.(Leu167del) mutation in APOE and new mutations in the signal transducing adaptor family member STAP1. We aimed at investigating the role of STAP1 mutations in the etiology of FH.

Methods: We sequenced LDLR, APOB, PCSK9, LDLRAP1, APOE, LIPA and STAP1 with the LipidInCode platform in 400 unrelated subjects from Spain with a clinical diagnosis of FH. All subjects carrying rare predicted pathogenic variants in STAP1 gene, described as pathogenic by at least three bioinformatic analysis and having an allelic frequency lower than 1% in general population, were selected for family study. Available relatives were recruited, including both hypercholesterolemic and non-hypercholesterolemic family members.

Results: Sequencing analysis of STAP1 gene revealed seventeen rare variants, four of them being described as pathogenic by bioinformatic analysis. We studied the cosegregation with hypercholesterolemia of four rare predicted pathogenic variants, c.-60A > G, p.(Arg12His), p.(Glu97Asp), p.(Pro176Ser) in seven families. We did not observe any cosegregation between genotype and phenotype, even carriers of rare variants in STAP1 had lower LDL cholesterol levels than non-carriers.

Conclusions: This study analyzes the family cosegregation of four rare predicted pathogenic variants of STAP1, p.(Arg12His), p.(Glu97Asp), p.(Pro176Ser) and c.-60A > G, in seven families, showing absence of cosegregation in all of them. These results would suggest that STAP1 gene is not involved in hypercholesterolemia of these families.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.11.025DOI Listing
January 2020

Mortality Among Referral Patients With Hypertrophic Cardiomyopathy vs the General European Population.

JAMA Cardiol 2020 01;5(1):73-80

Barts Heart Centre, Institute for Cardiovascular Science, St Bartholomew's Hospital, University College London, London, United Kingdom.

Importance: It is unclear whether hypertrophic cardiomyopathy (HCM) conveys excess mortality when compared with the general population.

Objective: To compare the survival of patients with HCM with that of the general European population.

Design, Setting, And Participants: Retrospective cohort study of 4893 consecutive adult patients with HCM presenting at 7 European referral centers between 1980 and 2013. The data were analyzed between April 2018 and August 2019.

Main Outcomes And Measures: Survival was compared using standardized mortality ratios (SMRs) calculated with data from Eurostat, stratified by study period, country, sex, and age, and using a composite end point in the HCM cohort of all-cause mortality, aborted sudden cardiac death, and heart transplant.

Results: Of 4893 patients with HCM, 3126 (63.9%) were male, and the mean (SD) age at presentation was 49.2 (16.4) years. During a median follow-up of 6.2 years (interquartile range, 3.1-9.8 years), 721 patients (14.7%) reached the composite end point. Compared with the general population, patients with HCM had excess mortality throughout the age spectrum (SMR, 2.0, 95% CI, 1.48-2.63). Excess mortality was highest among patients presenting prior to the year 2000 but persisted in the cohort presenting between 2006 and 2013 (SMR, 1.84; 95% CI, 1.55-2.18). Women had higher excess mortality than men (SMR, 2.66; 95% CI, 2.38-2.97; vs SMR, 1.68; 95% CI, 1.52-1.85; P < .001).

Conclusions And Relevance: Among patients referred to European specialty centers, HCM was associated with significant excess mortality through the life course. Although there have been improvements in survival with time, potentially reflecting improved treatments for HCM, these findings highlight the need for more research into the causes of excess mortality among patients with HCM and for better risk stratification.
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http://dx.doi.org/10.1001/jamacardio.2019.4534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902239PMC
January 2020

Severe Cardiac Dysfunction and Death Caused by Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Are Improved by Inhibition of Glycogen Synthase Kinase-3β.

Circulation 2019 10 5;140(14):1188-1204. Epub 2019 Sep 5.

Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (L.P.-B., M.V.-O., J.M.G.-S., F.D., J.L.-A., P.O.-S., F.M., M.L.-O., E.B.-K., J.V., C.M.-G., D.J.S., B.P., G.G., S.P., E.L.-P.).

Background: Arrhythmogenic cardiomyopathy/arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease characterized by fibrofatty replacement of the myocardium, resulting in heart failure and sudden cardiac death. The most aggressive arrhythmogenic cardiomyopathy/ARVC subtype is ARVC type 5 (ARVC5), caused by a p.S358L mutation in TMEM43 (transmembrane protein 43). The function and localization of TMEM43 are unknown, as is the mechanism by which the p.S358L mutation causes the disease. Here, we report the characterization of the first transgenic mouse model of ARVC5.

Methods: We generated transgenic mice overexpressing TMEM43 in either its wild-type or p.S358L mutant (TMEM43-S358L) form in postnatal cardiomyocytes under the control of the α-myosin heavy chain promoter.

Results: We found that mice expressing TMEM43-S358L recapitulate the human disease and die at a young age. Mutant TMEM43 causes cardiomyocyte death and severe fibrofatty replacement. We also demonstrate that TMEM43 localizes at the nuclear membrane and interacts with emerin and β-actin. TMEM43-S358L shows partial delocalization to the cytoplasm, reduced interaction with emerin and β-actin, and activation of glycogen synthase kinase-3β (GSK3β). Furthermore, we show that targeting cardiac fibrosis has no beneficial effect, whereas overexpression of the calcineurin splice variant calcineurin Aβ1 results in GSK3β inhibition and improved cardiac function and survival. Similarly, treatment of TMEM43 mutant mice with a GSK3β inhibitor improves cardiac function. Finally, human induced pluripotent stem cells bearing the p.S358L mutation also showed contractile dysfunction that was partially restored after GSK3β inhibition.

Conclusions: Our data provide evidence that TMEM43-S358L leads to sustained cardiomyocyte death and fibrofatty replacement. Overexpression of calcineurin Aβ1 in TMEM43 mutant mice or chemical GSK3β inhibition improves cardiac function and increases mice life span. Our results pave the way toward new therapeutic approaches for ARVC5.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.040366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784777PMC
October 2019

POT1 and Damage Response Malfunction Trigger Acquisition of Somatic Activating Mutations in the VEGF Pathway in Cardiac Angiosarcomas.

J Am Heart Assoc 2019 09 12;8(18):e012875. Epub 2019 Sep 12.

Human Genetics Group Spanish National Cancer Research Center (CNIO) Madrid Spain.

Background Mutations in the gene explain abnormally long telomeres and multiple tumors including cardiac angiosarcomas (CAS). However, the link between long telomeres and tumorigenesis is poorly understood. Methods and Results Here, we have studied the somatic landscape of 3 different angiosarcoma patients with mutations in the gene to further investigate this tumorigenesis process. In addition, the genetic landscape of 7 CAS patients without mutations in the gene has been studied. Patients with CAS and nonfunctional did not repress ATR (ataxia telangiectasia RAD3-related)-dependent DNA damage signaling and showed a constitutive increase of cell cycle arrest and somatic activating mutations in the VEGF (vascular endothelial growth factor)/angiogenesis pathway ( gene). The same observation was made in mutation carriers with tumors different from CAS and also in CAS patients without mutations in the gene but with mutations in other genes involved in DNA damage signaling. Conclusions Inhibition of POT1 function and damage-response malfunction activated DNA damage signaling and increased cell cycle arrest as well as interfered with apoptosis, which would permit acquisition of somatic mutations in the VEGF/angiogenesis pathway that drives tumor formation. Therapies based on the inhibition of damage signaling in asymptomatic carriers may diminish defects on cell cycle arrest and thus prevent the apoptosis deregulation that leads to the acquisition of driver mutations.
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http://dx.doi.org/10.1161/JAHA.119.012875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818007PMC
September 2019

Development of a Novel Risk Prediction Model for Sudden Cardiac Death in Childhood Hypertrophic Cardiomyopathy (HCM Risk-Kids).

JAMA Cardiol 2019 09;4(9):918-927

Centre for Inherited Cardiovascular Diseases, Department of Cardiology, Great Ormond Street Hospital, London, United Kingdom.

Importance: Sudden cardiac death (SCD) is the most common mode of death in childhood hypertrophic cardiomyopathy (HCM), but there is no validated algorithm to identify those at highest risk.

Objective: To develop and validate an SCD risk prediction model that provides individualized risk estimates.

Design, Setting, And Participants: A prognostic model was developed from a retrospective, multicenter, longitudinal cohort study of 1024 consecutively evaluated patients aged 16 years or younger with HCM. The study was conducted from January 1, 1970, to December 31, 2017.

Exposures: The model was developed using preselected predictor variables (unexplained syncope, maximal left-ventricular wall thickness, left atrial diameter, left-ventricular outflow tract gradient, and nonsustained ventricular tachycardia) identified from the literature and internally validated using bootstrapping.

Main Outcomes And Measures: A composite outcome of SCD or an equivalent event (aborted cardiac arrest, appropriate implantable cardioverter defibrillator therapy, or sustained ventricular tachycardia associated with hemodynamic compromise).

Results: Of the 1024 patients included in the study, 699 were boys (68.3%); mean (interquartile range [IQR]) age was 11 (7-14) years. Over a median follow-up of 5.3 years (IQR, 2.6-8.3; total patient years, 5984), 89 patients (8.7%) died suddenly or had an equivalent event (annual event rate, 1.49; 95% CI, 1.15-1.92). The pediatric model was developed using preselected variables to predict the risk of SCD. The model's ability to predict risk at 5 years was validated; the C statistic was 0.69 (95% CI, 0.66-0.72), and the calibration slope was 0.98 (95% CI, 0.59-1.38). For every 10 implantable cardioverter defibrillators implanted in patients with 6% or more of a 5-year SCD risk, 1 patient may potentially be saved from SCD at 5 years.

Conclusions And Relevance: This new, validated risk stratification model for SCD in childhood HCM may provide individualized estimates of risk at 5 years using readily obtained clinical risk factors. External validation studies are required to demonstrate the accuracy of this model's predictions in diverse patient populations.
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http://dx.doi.org/10.1001/jamacardio.2019.2861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694401PMC
September 2019

Correction to: Usefulness of Genetic Testing in Hypertrophic Cardiomyopathy: an Analysis Using Real-World Data.

J Cardiovasc Transl Res 2019 Aug;12(4):389-390

Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Manuel de Falla 2, Majadahonda, 28222, Madrid, Spain.

The name of author M. Alejandra Restrepo-Cordoba was parsed incorrectly (in such a way as to suggest that her surname is "Alejandra Restrepo-Cordoba") in this article as published.
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http://dx.doi.org/10.1007/s12265-019-09901-5DOI Listing
August 2019