Factores de la coagulación y de la fibrinolisis relacionados con la cardiopatía isquémica precoz.

RESUMEN y con frecuencia los factores de riesgo cardiovascular (FRCV) no justifican su desarrollo clínico. La hemostasia juega un papel clave en la sintomatología derivada de placas complicadas, pues pueden resolverse silentes o manifestarse como angina inestable o IM. OBJETIVOS: Analizar distintos agentes la coagulación y fibrinolisis [lipoproteína (a)- Lp(a)-, inhibidor del activador del plasminógeno tipo 1-PAI-1-, inhibidor de la fibrinolisis activable por trombina-TAFI-, proteína C activada circulante-APC-, mutación del factor V Leiden-FVL- y G20210A de la protrombina-PTG20210A], nexos entre estos sistemas y los FRCV, en el desarrollo de IM precoz, patrones coronariográficos desfavorables (extensión/severidad) y eventos trombóticos. · Describir las características basales de la población joven con IM. · Comparar en pacientes y controles los niveles de los parámetros seleccionados [PAI- 1, TAFI, Lp(a) y APC] y ciertas características genéticas [polimorfismo 4G/5G PAI-1, C1040T TAFI, isoforma mayoritaria de apo(a) de Lp(a), mutación FVL y PTG20210A]. · Evaluar la asociación de estos aspectos (niveles/genética) con la coronariografía (extensión/gravedad) y los eventos en pacientes. MATERIAL Y MÉTODOS: Las variables genéticas se estudiaron en 237 pacientes <51 años ingresados en el Hospital La Fe por IM agudo; en 222 se estudiaron los niveles tras ³3meses. Paralelamente se estudiaron (niveles/genética) 200 controles (similar edad y sexo) sin historia de coronariopatía. Buscamos diferencias entre estos grupos, analizamos la asociación de las variables con la coronariografía y los eventos trombóticos (seguimiento 30 meses: exitus, reingreso y evento combinado de ambos). RESULTADOS: Ambos grupos estuvieron formados prioritariamente por hombres (pacientes-81%, controles-90%). Según sus OR (crudas y ajustadas al resto de FRCV), el tabaquismo (11,5 y 12,7) fue el FRCV más importante. 14,8% de pacientes presentaron antecedentes de coronariopatía familiar precoz, 75,5% elevación del segmento ST (fibrinolisis 81%), a 86,5% se realizó coronariografía y 58,9% se revascularizaron. Comparados con controles, los pacientes presentaron más alelo 4G e isoformas de apo(a) de bajo peso molecular (BPM) (OR 2 cruda y ajustada, p<0,05), así como un estado hipofibrinolítico (por mayor concentración de PAI-1, TAFI y Lp(a), p<0,01) y procoagulante (por menor concentración de APC, p<0,001). En ellos, los niveles altos de Lp(a) y bajos de APC se asociaron (p<0,05) con coronariografías desfavorables (presencia de lesiones, mayor número de coronarias afectas y mayor extensión/gravedad). Hubo una tendencia entre el PAI-1 (alelo 4G y niveles altos) con los patrones desfavorables y el desarrollo de eventos. CONCLUSIONES: 1) El IM precoz afecta prioritariamente a hombres, el FRCV más prevalente es el tabaquismo y los antecedentes clínicos de aterotrombosis son <15%. 2) En ellos, el debut electrocardiográfico más frecuente es el ascenso del ST (75%) y la fibrinolisis el tratamiento más habitual (81%). Acorde con la disponibilidad de Hemodinámica, se realizó coronariografía en 86,5% y se revascularizaron casi 60%. 3) Comparados con controles, en ellos existe un perfil genético desfavorable (hipofibrinolítico y proaterogénico) con mayor presencia del alelo 4G e isoformas de BPM. 4) En pacientes, niveles aumentados de PAI-1, TAFIfuncional y Lp(a) reducen la fibrinolisis, y la concentración aumentada de Lp(a) y disminuida de APC promueven la aterotrombosis. 5) Sus niveles altos de PAI-1 son parcialmente explicables por los FRCV, mayor presencia del alelo 4G y/o otros mecanismos 4G-independientes. 6) Sus niveles altos de TAFIfuncional no pueden atribuirse a una mayor presencia del genotipo TT comparada con controles y probablemente sí a su hipofibrinolisis, que reduce la degradación del TAFI, reforzando dicha hipofibrinolisis. 7) Sus niveles bajos de APC parecen consecuencia de una menor generación, quizás por alteraciones cuantitativas/cualitativas de los integrantes de su complejo de activación. 8) En ellos, los niveles incrementados de Lp(a) y disminuidos de APC se asocian con coronariografías desfavorables. 9) Existe una tendencia entre el desarrollo de eventos y el alelo 4G, PAI-1antigénico y Lp(a) elevados. 10) Nuestros resultados sugieren que en jóvenes con IM un desequilibrio hemostático primordialmente genético podría aconsejar mayor control de los FRCV y matizar los resultados de las exploraciones complementarias. __________________________________________________________________________________________________Although coronary atherothrombosis is the first cause of myocardial infarction (MI), often cardiovascular risk factors (CVRF) fail to explain its clinical onset. Haemostatic balance is crucial in determining the clinical impact of complicated plaques. Our aim was to assess haemostatic factors (plasmatic levels and genetic aspects) in young patients (<51 years) with MI and controls in order to study their possible role as risk factors of precocious MI, severe angiographic patterns and future thrombotic events. 237 patients were genetically studied at admission for acute MI [polymorphism 4G/5G of the plasminogen activator inhibitor type 1-PAI-1, C1040T of the thrombin activatable fibrinolysis inhibitor-TAFI, major apo(a) isoform of lipoprotein(a)-Lp(a), Factor V Leiden-FVL and prothrombin G20210A mutation-PTG20210A]. 222 of them fulfilled the protocol 3 months after (levels of PAI-1, TAFI, Lp(a) and activated protein C-APC- were quantified). All these parameters were studied in 200 healthy controls (similar age and sex distribution). In patients, 81% were men, smoking was the most important CVRF (OR 11,5), 14,8% had familial precocious ischemic heart disease, 75,5% had acute MI with ST-segment elevation (81% thrombolysed), 86,6% underwent angiography and 58,9% were revascularized. In patients, a genetic risk profile (OR for the presence of 4G allele and low molecular weight apo(a) isoforms 2) and a plasmatic risk profile [increased PAI-1, TAFI and Lp(a) levels; decreased APC levels] were found promoting hypofibrinolysis, coagulation and atherogenesis. PAI-1 and TAFI levels werent explained by the genetic substrate or CVRF. Levels of APC seemed to be due to a reduced production. High Lp(a) and low APC were associated to adverse angiographic patterns. No parameter was associated with adverse events during the follow-up. Evidence of haemostatic disbalance may benefit the clinical management (reinforce CVRF control and modulate results of complementary tests)

Left ventricular Myocardial dysfunction in arrhythmogenic cardiomyopathy with left ventricular involvement: A door to improving diagnosis.

Background: Diagnostic Task Force Criteria (TFC) for arrhythmogenic cardiomyopathy (AC) exhibit poor performance for left dominant forms. TFC only include right ventricular (RV) dysfunction (akinesia, dyssynchrony, volumes and ejection fraction). Moreover, cardiac magnetic resonance imaging (CMRI) assessment of left ventricular (LV) dyssynchrony has hitherto not been described. Thus, we aimed to comprehensively characterize LV CMRI behavior in AC patients. Methods: Thirty-five AC patients with LV involvement and twenty-three non-affected family members (controls) were enrolled. Feature-tracking analysis was applied to cine CMRI to assess LV ejection fraction (LVEF), LV endsystolic and end-diastolic volume indexes, strain values and dyssynchrony. Regions with more frequent strain and dyssynchrony impairment were also studied. Results: Radial dyssynchrony and LVEF were selected (sensitivities 54.3% and 48.6%, respectively at 100% specificity), with a threshold of 70 ms for radial dyssynchrony and 48.5% for LVEF. 71.4% of patients exceeded these thresholds (31.4% both, 22.9% only dyssynchrony and 17.1% only LVEF). Considering these cut-off values as a novel combined criterion, 30% of patients with 'borderline' or 'possible' AC following 2010 TFC would move to a 'definite' AC diagnosis. Strain was globally impaired whereas dyssynchronous regions were more often apical and located at the inferolateral wall. Conclusions: Mirroring the RV evaluation, we suggest including LVEF and LV dyssynchrony to improve the diagnosis of AC. Two independent mechanisms can be claimed in AC patients with LV involvement: 1) decreased myocardial deformation with global LV affectation and 2) delayed myocardial contraction at localized regions

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

Background: Pathogenic variants in the filamin C (FLNC) gene are associated with inherited cardiomyopathies including dilated cardiomyopathy with an arrhythmogenic phenotype. We evaluated FLNC variants in arrhythmogenic cardiomyopathy (ACM) and investigated the disease mechanism at a molecular level. Methods: 120 gene-elusive ACM patients who fulfilled diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC) were screened by whole exome sequencing. Fixed cardiac tissue from FLNC variant carriers who had died suddenly was investigated by histology and immunohistochemistry. Results: Novel or rare FLNC variants, four null and five variants of unknown significance, were identified in nine ACM probands (7.5%). In FLNC null variant carriers (including family members, n = 16) Task Force diagnostic electrocardiogram repolarization/depolarization abnormalities were uncommon (19%), echocardiography was normal in 69%, while 56% had >500 ventricular ectopics/24 h or ventricular tachycardia on Holter and 67% had late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMRI). Ten gene positive individuals (63%) had abnormalities on ECG or CMRI that are not included in the current diagnostic criteria for ARVC. Immunohistochemistry showed altered key protein distribution, distinctive from that observed in ARVC, predominantly in the left ventricle. Conclusions: ACM associated with FLNC variants presents with a distinctive phenotype characterized by Holter arrhythmia and LGE on CMRI with unremarkable ECG and echocardiographic findings. Clinical presentation in asymptomatic mutation carriers at risk of sudden death may include abnormalities which are currently non-diagnostic for ARVC. At the molecular level, the pathogenic mechanism related to FLNC appears different to classic forms of ARVC caused by desmosomal mutations. Keywords: ARVC; Arrhythmogenic cardiomyopathy; Filamin C variants; Immunohistochemistry; Late gadolinium enhancement

Clinical findings and prognosis of Danon’s Disease. An analysis from the Spanish multicenter Danon Registry.

Introducción y objetivos: La enfermedad de Danon (ED) es una enfermedad poco frecuente producida por mutaciones en el gen LAMP2. Se considera una enfermedad multisistémica caracterizada por: miocardiopatía hipertrófica con preexcitación y gran hipertrofia, discapacidad intelectual, miopatía, presentación infantil y peor pronóstico en varones. Existen pocas series que permitan conocer las características clínicas y el pronóstico de la ED en detalle. Métodos Estudio retrospectivo basado en el análisis de los registros clínicos de los pacientes con ED seguidos en 10 hospitales españoles. Resultados Se incluyeron 28 pacientes (3220años, 79% mujeres). Los varones demostraron una elevada prevalencia de manifestaciones extracardiacas: miopatía (80%), trastornos del aprendizaje (83%) y alteraciones visuales (60%), siendo hallazgos infrecuentes en las mujeres (5%, 0% y 24%, respectivamente). Aunque la miocardiopatía hipertrófica era la cardiopatía más habitual (67%), el grosor máximo ventricular fue 157 mm y 12 pacientes (10 mujeres) se presentaron con miocardiopatía dilatada. Sólo 11 pacientes (46%) (4 hombres y 7 mujeres) mostraron preexcitación y en 16 (67%) la enfermedad debutó por encima de los 20 años. Tras una mediana de seguimiento de 4 años (P25-752-9), 4 varones (67%) y 9 mujeres (41%) fallecieron o requirieron un trasplante. Tanto la afectación cardiaca como los eventos adversos ocurrieron más tardíamente en mujeres (37±9 vs 23±16 y 38±21 vs 20±11 años, respectivamente). Conclusiones. Las características clínicas de la ED difieren substancialmente de lo tradicionalmente considerado. La edad de presentación de la ED es más tardía, no se expresa como una patología multisistémica en mujeres y la preexcitación es poco frecuente. Aunque las mujeres presentan mal pronóstico, los eventos adversos ocurren a una edad más avanzada.Background Danon's disease (DD) is a rare disease caused by mutations in the LAMP2 gene. It is considered a multisystemic disease characterized by: hypertrophic cardiomyopathy with preexcitation and ventricular hypertrophy, intellectual disability, myopathy, childhood presentation and worse prognosis in men. Available data regarding clinical characteristics and the prognosis of the DD are scarce. Methods Retrospective study based on the analysis of the clinical records of patients with ED from 10 Spanish hospitals. Results Twenty-eight patients were included (32±20 years, 79% women). Males showed a high prevalence of extracardiac manifestations: myopathy (80%), learning disorders (837%) and visual alterations (60%), which were uncommon findings in women (5%, 0% and 24%, respectively). Although hypertrophic cardiomyopathy was the most common form of heart disease (67%), maximum wall thickness was 15±7 mm and 12 patients (10 women) presented as dilated cardiomyopathy. Only 11 patients (467%) (4 men and 7 women) showed preexcitation and in 16 (67%) the disease started above 20 years-old. After a median follow-up of 4 years (P25-75: 2-9), 4 men (67%) and 9 women (41%) died or required a heart transplant. Both cardiac involvement and adverse events occurred later in women (37 ± 9 vs 23 ± 16 and 38± 21 vs 20 ± 11 years, respectively). Conclusions Clinical characteristics of DD differ substantially from what has been traditionally considered. ED usually presents at an increased age, is not a multisystemic disease in women and preexcitation is rare. Even though, women show also a poor prognosis, adverse events occur at a later age.pre-print518 K

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

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

Impact of SARS-Cov-2 infection in patients with hypertrophic cardiomyopathy : results of an international multicentre registry

To describe the natural history of SARS-CoV-2 infection in patients with hypertrophic cardiomyopathy (HCM) compared with a control group and to identify predictors of adverse events. Three hundred and five patients [age 56.6 ± 16.9 years old, 191 (62.6%) male patients] with HCM and SARS-Cov-2 infection were enrolled. The control group consisted of 91 131 infected individuals. Endpoints were (i) SARS-CoV-2 related mortality and (ii) severe clinical course [death or intensive care unit (ICU) admission]. New onset of atrial fibrillation, ventricular arrhythmias, shock, stroke, and cardiac arrest were also recorded. Sixty-nine (22.9%) HCM patients were hospitalized for non-ICU level care, and 21 (7.0%) required ICU care. Seventeen (5.6%) died: eight (2.6%) of respiratory failure, four (1.3%) of heart failure, two (0.7%) suddenly, and three (1.0%) due to other SARS-CoV-2-related complications. Covariates associated with mortality in the multivariable were age {odds ratio (OR) per 10 year increase 2.25 [95% confidence interval (CI): 1.12-4.51], P = 0.0229}, baseline New York Heart Association class [OR per one-unit increase 4.01 (95%CI: 1.75-9.20), P = 0.0011], presence of left ventricular outflow tract obstruction [OR 5.59 (95%CI: 1.16-26.92), P = 0.0317], and left ventricular systolic impairment [OR 7.72 (95%CI: 1.20-49.79), P = 0.0316]. Controlling for age and sex and comparing HCM patients with a community-based SARS-CoV-2 cohort, the presence of HCM was associated with a borderline significant increased risk of mortality OR 1.70 (95%CI: 0.98-2.91, P = 0.0600). Over one-fourth of HCM patients infected with SARS-Cov-2 required hospitalization, including 6% in an ICU setting. Age and cardiac features related to HCM, including baseline functional class, left ventricular outflow tract obstruction, and systolic impairment, conveyed increased risk of mortality

Phenotypic patterns of right ventricular dysfunction: analysis by cardiac magnetic imaging

The aim of this study was to use magnetic resonance imaging (MRI) to classify the morphological changes and remodeling of the right ventricle (RV) that occur in different clinical situations and that have an impact on RV function. Most literature has traditionally focused on the left ventricle (LV) and as a result, few studies analyze RV behavior and remodeling. The study evaluated all cardiac MRI performed at our center from 2008 to 2010. We retrospectively identified 159 patients who had some sign of right ventricular dysfunction (RVD) based on MRI findings. We classified patients according to a combination of criteria for RVD and the presence of left ventricle dysfunction (LVD). We considered RVD as any of the following abnormalities: i) depressed RV function; ii) RV dilatation; iii) RV hypertrophy. LVD was considered when there was atrial dilatation, LV hypertrophy, LV dilatation and/or depressed LV function. We obtained 6 pathophysiological patterns: RV pressure overload (1.9%), RV volume overload (15.7%), RV volume overload + LVD (32.7%), depressed RV function + LVD (42.1%), mixed RV overload + LVD (6.9%) and other (0.6%). The most frequent etiology was congenital heart disease (33.3%), followed by idiopathic dilated cardiomyopathy (18.2%), left valvular disease (17.6%), ischemic heart disease (15%), pulmonary disease (9.8%), and other (6.1%). This study helps to classify the different patterns that RV can adopt in different clinical situations and can, therefore, help us to understand the RV pathophysiology

Factores psicosociales y de adaptación en familiares de pacientes fallecidos por muerte súbita cardíaca

Introduction: Although grief is a natural process that, in most cases, develops without complications, 10-20% of people who suffer a significant loss will experience complicated grief and percentages are much higher in relatives bereaved by sudden cardiac death.Objective: To study the relationship between attachment styles, stressful life events accumulation and psychopathology development, especially complicated grief, in relatives of patients who died of sudden cardiac death. Method: The sample consisted of 16 mourners of deceased from this cause. Questionnaires were used to evaluate, among other variables, stressful life events, psychopathological symptoms, attachment and grief. Results: Sixty-two percent of the cases were middle-aged women (average 49 years), predominantly married or with unmarried partner (60%), and 31% widows (of the deceased). Prior to death, most of the mourners (81%) did not have a histo-ry of anxious-depressive symptoms. At present more than 50% attend psychotherapy sessions, showing clear signs of risk to their physical-psychological health, with sleep disturbances, anxious-depressive symptoms and general exhaustion. Particularly relevant in our study is the fact that half of them have very high levels of chronic stress. About 40% of family members have insecure attachment style: 15% anxious and 25% avoidant. Conclusions: Presenting insecure attachment style is considered a risk factor for developing complicated grief. Its indicators show 56% of subjects at clear risk of suffering it.Introducción: Aunque el duelo es un proceso natural que, en la mayoría de los casos, se desarrolla sin complicaciones, un 10-20% de los individuos que sufren una pérdida significativa experimentarán duelo complicado y los porcentajes son muy superiores en los familiares en duelo por muerte súbita cardíaca.Objetivo: Estudiar la relación entre los estilos de apego, la acumulación de acontecimientos vitales estresantes y el desarrollo de psicopatología, especialmente duelo complicado, en familiares de pacientes fallecidos por muerte súbita cardíaca.Método: La muestra estuvo conformada por 16 dolientes de fallecidos por esta causa. Se utilizaron cuestionarios para evaluar, entre otras variables, los sucesos vitales estresantes, la sintomatología psicopatológica, el apego y el duelo.Resultados: El 62% de los casos eran mujeres de mediana edad (media 49 años), predominantemente casadas o en pareja (60%), y un 31% viudas (del fallecido). Previo al fallecimiento, la mayoría de los dolientes (81%) no contaban con antecedentes de clínica ansioso-depresiva. Actualmente más del 50% acude a psicoterapia, y presentan claros signos de riesgo para su salud física-psicológica, con dificultades para dormir, síntomas ansioso-depresivos y agotamiento general. Un dato especialmente relevante de nuestro estudio es que la mitad tiene niveles muy elevados de estrés crónico. Cerca del 40% de los familiares presenta un estilo de apego inseguro: 15% ansioso y 25% evitativo.Conclusiones: El presentar un estilo de apego inseguro se considera factor de riesgo para el desarrollo de duelo complicado. Sus indicadores muestran un 56% de sujetos con un claro riesgo de padecerlo