Double somatic mosaicism in Marfan syndrome.

Marfan syndrome (MFS) is a hereditary systemic connective tissue disorder with great clinical variability. It is caused by heterozygous pathogenic variants in the FBN1 gene. Cardinal manifestations involve the cardiovascular, ocular, and skeletal systems. Clinical diagnosis is based on the revised Ghent nosology. We present the case of a child with a Marfan systemic score of 9 whose genetic study revealed two pathogenic mosaic frameshift variants in the FBN1 gene. Mosaicism is very rare in patients diagnosed with MFS, and this is the first description of a patient with two pathogenic mosaic variants in the FBN1 gene. Both variants are present in cells derived from ectodermal (buccal swab) and mesodermal (leukocyte) tissues, suggesting a mutation prior to gastrulation. We propose a defective repair of the de novo variant in the complementary strand as the mechanism that led this individual to be a carrier of two different populations of mutant cells carrying adjacent variants.

Role of TBX20 Truncating Variants in Dilated Cardiomyopathy and Left Ventricular Noncompaction.

BACKGROUND: Less than 40% of patients with dilated cardiomyopathy (DCM) have a pathogenic/likely pathogenic genetic variant identified. TBX20 has been linked to congenital heart defects; although an association with left ventricular noncompaction (LVNC) and DCM has been proposed, it is still considered a gene with limited evidence for these phenotypes. This study sought to investigate the association between the TBX20 truncating variant (TBX20tv) and DCM/LVNC. METHODS: TBX20 was sequenced by next-generation sequencing in 7463 unrelated probands with a diagnosis of DCM or LVNC, 22 773 probands of an internal comparison group (hypertrophic cardiomyopathy, channelopathies, or aortic diseases), and 124 098 external controls (individuals from the gnomAD database). Enrichment of TBX20tv in DCM/LVNC was calculated, cosegregation was determined in selected families, and clinical characteristics and outcomes were analyzed in carriers. RESULTS: TBX20tv was enriched in DCM/LVNC (24/7463; 0.32%) compared with internal (1/22 773; 0.004%) and external comparison groups (4/124 098; 0.003%), with odds ratios of 73.23 (95% CI, 9.90-541.45; P<0.0001) and 99.76 (95% CI, 34.60-287.62; P<0.0001), respectively. TBX20tv was cosegregated with DCM/LVNC phenotype in 21 families for a combined logarythm of the odds score of 4.53 (strong linkage). Among 57 individuals with TBX20tv (49.1% men; mean age, 35.9±20.8 years), 41 (71.9%) exhibited DCM/LVNC, of whom 14 (34.1%) had also congenital heart defects. After a median follow-up of 6.9 (95% CI, 25-75:3.6-14.5) years, 9.7% of patients with DCM/LVNC had end-stage heart failure events and 4.8% experienced malignant ventricular arrhythmias. CONCLUSIONS: TBX20tv is associated with DCM/LVNC; congenital heart defect is also present in around one-third of cases. TBX20tv-associated DCM/LVNC is characterized by a nonaggressive phenotype, with a low incidence of major cardiovascular events. TBX20 should be considered a definitive gene for DCM and LVNC and routinely included in genetic testing panels for these phenotypes.

Intermediate-effect size p.Arg637Gln in FHOD3 increases risk of HCM and is associated with an aggressive phenotype in homozygous carriers.

Formin homology 2 domain-containing 3 (FHOD3) gene has emerged as one of the main non-sarcomeric genes associated with hypertrophic cardiomyopathy (HCM), but no cases of biallelic variants associated with disease have been described to date. From 2014 until 2021, FHOD3 was evaluated in our center by next-generation sequencing in 22 806 consecutive unrelated probands. The p.Arg637Gln variant in FHOD3 was enriched in our HCM cohort (284 of 9668 probands; 2.94%) compared with internal controls (64 of 11 480; 0.59%) and gnomAD controls (373 of 64 409; 0.58%), with ORs of 5.40 (95% CI: 4.11 to 7.09) and 5.19 (95% CI: 4.44 to 6.07). The variant affects a highly conserved residue localised in a supercoiled alpha helix considered a clustering site for HCM variants, and in heterozygosis can act as a predisposing factor (intermediate-effect variant) for HCM, with an estimated penetrance of around 1%. Additionally, seven homozygous carriers of p.Arg637Gln in FHOD3 were identified. All but one (unaffected) showed an early presentation and a severe HCM phenotype. All this information suggest that p.Arg637Gln variant in FHOD3 is a low-penetrant variant, with an intermediate effect, that contributes to the development of HCM in simple heterozygosis, being associated with a more severe phenotype in homozygous carriers.

Prevalence of cardiac amyloidosis among elderly patients with systolic heart failure or conduction disorders.

Objective: Cardiac amyloid infiltration can lead to systolic heart failure (HF) or to conduction disorders (CD). Patients with transthyretin (ATTR) amyloidosis are particularly exposed. We sought to determine the prevalence of ATTR and AL among patients >60 years admitted with CD or unexplained systolic HF and increased wall thickness. Materials and Methods: We studied 143 patients (57% males, 79 ± 9 years) with HF (N = 28) or CD requiring pacemaker implantation (N = 115). In total, 139 (97%) patients (28 with HF and 111 with CD) underwent 99mTc-DPD scintigraphy to detect ATTR, and 105 (73%; 19 HF and 86 CD) underwent AL screening. Results: Five patients (4%; 95%CI:0-7%) exhibited wild-type ATTR (ATTRwt) amyloidosis, 2 (2%; 95%CI:0-4%) had CD and 3 (11%; 95%CI:0-23%) HF. No patient showed AL. The 2 ATTRwt patients with CD were previously asymptomatic, did not show classical ECG signs and exhibited mild LV hypertrophy with preserved LVEF. By contrast, all ATTRwt patients with HF had ECG and echocardiographic signs of amyloid. During a mean follow-up of 18 ± 11 months, 3(60%) patients with ATTRwt amyloidosis (1 CD and 2 HF) and 14(10.4%) without died. Conclusion: Prevalence of ATTRwt amyloidosis in patients with CD requiring pacemaker is low. Although, additional studies are needed, prevalence seems to be higher in elderly patients with systolic HF.

Impacto pronóstico y factores predictores de la recuperación de la fracción de eyección en pacientes con miocardiopatía dilatada alcohólica / Prognostic impact and predictors of ejection fraction recovery in patients with alcoholic cardiomyopathy

Introducción y objetivos: La recuperación de la fracción de eyección del ventrículo izquierdo (FEVI) está descrita en la miocardiopatía alcohólica (MCA) tras la abstinencia alcohólica. Sin embargo, se desconoce el impacto pronóstico de esta recuperación y los factores con que se asocia. El objetivo es definir el papel pronóstico a largo plazo de la mejoría de la FEVI en la MCA e identificar sus predictores. Métodos: Se evaluó a 101 pacientes con MCA, con una mediana de seguimiento de 82 [intervalo intercuartílico, 36-134] meses. Resultados: Al final del seguimiento, 42 pacientes (42%) mostraron una recuperación significativa de la FEVI, definida como un incremento absoluto ≥ 10% y FEVI final ≥ 40%. Estos pacientes mostraron mejor pronóstico que aquellos sin recuperación de la FEVI (trasplante cardiaco o muerte cardiovascular, el 1 frente al 30%; p < 0,001). La duración del QRS < 120 ms (OR = 6,68; IC95%, 2,30-19,41), el tratamiento bloqueador beta (OR = 3,01; IC95%, 1,09-8,28) y no necesitar diuréticos (OR = 3,35; IC95%, 1,08-10,42) predijeron la recuperación de la FEVI en el análisis multivariable. Aunque el cese del consumo de alcohol no fue predictor, ninguno de los pacientes (n = 6) que mantuvieron un consumo excesivo recuperó la FEVI. Entre los abstemios y quienes mantuvieron un consumo moderado, hubo similar número de pacientes que recuperaron la FEVI (el 44 frente al 45%; p = 0,9). Conclusiones: La recuperación de la FEVI se asocia con un excelente pronóstico en la MCA. El tratamiento con bloqueadores beta, un QRS < 120 ms y no tomar diuréticos son predictores independientes de esta recuperación. La recuperación de la FEVI es similar entre bebedores moderados y abstemios

Introduction and objectives: Recovery of left ventricular ejection fraction (LVEF) has been described in alcoholic cardiomyopathy (ACM) after a period of alcohol withdrawal. Nevertheless, the prognostic impact of LVEF recovery in ACM and its determinants have not been studied. We sought to define the role of LVEF improvement in the long-term outcome of ACM and to identify predictors of LVEF recovery in these patients. Methods: We evaluated 101 ACM patients during a median follow-up period of 82 months [interquartile range 36-134]. Results: At latest follow-up, 42 patients (42%) showed substantial LVEF recovery defined as an absolute increase in LVEF ≥ 10% to a final value of ≥ 40%. Patients who recovered LVEF had better outcomes than patients who did not (heart transplant or cardiovascular death 1% vs 30%; P < .001). A QRS with < 120 ms (OR, 6.68; 95%CI, 2.30-19.41), beta-blocker therapy (OR, 3.01; 95%CI, 1.09-8.28), and the absence of diuretics (OR, 3.35; 95%CI, 1.08-10.42) predicted LVEF recovery in multivariate analysis. Although alcohol cessation did not predict LVEF recovery, none of the patients (n = 6) who persisted with heavy alcohol consumption recovered LVEF. The rate of patients who recovered LVEF did not differ between abstainers and moderate drinkers (44% vs 45%; P = .9). Conclusions: The LVEF recovery is associated with an excellent prognosis in ACM. Beta-blocker treatment, QRS < 120 ms and absence of diuretics are independent predictors of LVEF recovery. LVEF recovery is similar in moderate drinkers and abstainers

Genetic Etiology for Alcohol-Induced Cardiac Toxicity.

BACKGROUND: Alcoholic cardiomyopathy (ACM) is defined by a dilated and impaired left ventricle due to chronic excess alcohol consumption. It is largely unknown which factors determine cardiac toxicity on exposure to alcohol. OBJECTIVES: This study sought to evaluate the role of variation in cardiomyopathy-associated genes in the pathophysiology of ACM, and to examine the effects of alcohol intake and genotype on dilated cardiomyopathy (DCM) severity. METHODS: The authors characterized 141 ACM cases, 716 DCM cases, and 445 healthy volunteers. The authors compared the prevalence of rare, protein-altering variants in 9 genes associated with inherited DCM. They evaluated the effect of genotype and alcohol consumption on phenotype in DCM. RESULTS: Variants in well-characterized DCM-causing genes were more prevalent in patients with ACM than control subjects (13.5% vs. 2.9%; p = 1.2 ×10-5), but similar between patients with ACM and DCM (19.4%; p = 0.12) and with a predominant burden of titin truncating variants (TTNtv) (9.9%). Separately, we identified an interaction between TTN genotype and excess alcohol consumption in a cohort of DCM patients not meeting ACM criteria. On multivariate analysis, DCM patients with a TTNtv who consumed excess alcohol had an 8.7% absolute reduction in ejection fraction (95% confidence interval: -2.3% to -15.1%; p < 0.007) compared with those without TTNtv and excess alcohol consumption. The presence of TTNtv did not predict phenotype, outcome, or functional recovery on treatment in ACM patients. CONCLUSIONS: TTNtv represent a prevalent genetic predisposition for ACM, and are also associated with a worse left ventricular ejection fraction in DCM patients who consume alcohol above recommended levels. Familial evaluation and genetic testing should be considered in patients presenting with ACM.

Prognostic Impact and Predictors of Ejection Fraction Recovery in Patients With Alcoholic Cardiomyopathy.

INTRODUCTION AND OBJECTIVES: Recovery of left ventricular ejection fraction (LVEF) has been described in alcoholic cardiomyopathy (ACM) after a period of alcohol withdrawal. Nevertheless, the prognostic impact of LVEF recovery in ACM and its determinants have not been studied. We sought to define the role of LVEF improvement in the long-term outcome of ACM and to identify predictors of LVEF recovery in these patients. METHODS: We evaluated 101 ACM patients during a median follow-up period of 82 months [interquartile range 36-134]. RESULTS: At latest follow-up, 42 patients (42%) showed substantial LVEF recovery defined as an absolute increase in LVEF ≥ 10% to a final value of ≥ 40%. Patients who recovered LVEF had better outcomes than patients who did not (heart transplant or cardiovascular death 1% vs 30%; P <.001). A QRS with <120ms (OR, 6.68; 95%CI, 2.30-19.41), beta-blocker therapy (OR, 3.01; 95%CI, 1.09-8.28), and the absence of diuretics (OR, 3.35; 95%CI, 1.08-10.42) predicted LVEF recovery in multivariate analysis. Although alcohol cessation did not predict LVEF recovery, none of the patients (n=6) who persisted with heavy alcohol consumption recovered LVEF. The rate of patients who recovered LVEF did not differ between abstainers and moderate drinkers (44% vs 45%; P=.9). CONCLUSIONS: The LVEF recovery is associated with an excellent prognosis in ACM. Beta-blocker treatment, QRS <120ms and absence of diuretics are independent predictors of LVEF recovery. LVEF recovery is similar in moderate drinkers and abstainers.

Genetically Confirmed Familial Hypercholesterolemia in Patients With Acute Coronary Syndrome.

BACKGROUND: Genetic screening programs in unselected individuals with increased levels of low-density lipoprotein cholesterol (LDL-C) have shown modest results in identifying individuals with familial hypercholesterolemia (FH). OBJECTIVES: This study assessed the prevalence of genetically confirmed FH in patients with acute coronary syndrome (ACS) and compared the diagnostic performance of FH clinical criteria versus FH genetic testing. METHODS: Genetic study of 7 genes (LDLR, APOB, PCSK9, APOE, STAP1, LDLRAP1, and LIPA) associated with FH and 12 common alleles associated with polygenic hypercholesterolemia was performed in 103 patients with ACS, age ≤65 years, and LDL-C levels ≥160 mg/dl. Dutch Lipid Clinic (DLC) and Simon Broome (SB) FH clinical criteria were also applied. RESULTS: The prevalence of genetically confirmed FH was 8.7% (95% confidence interval [CI]: 4.3% to 16.4%; n = 9); 29% (95% CI: 18.5% to 42.1%; n = 18) of patients without FH variants had a score highly suggestive of polygenic hypercholesterolemia. The prevalence of probable to definite FH according to DLC criteria was 27.2% (95% CI: 19.1% to 37.0%; n = 28), whereas SB criteria identified 27.2% of patients (95% CI: 19.1% to 37.0%; n = 28) with possible to definite FH. DLC and SB algorithms failed to diagnose 4 (44%) and 3 (33%) patients with genetically confirmed FH, respectively. Cascade genetic testing in first-degree relatives identified 6 additional individuals with FH. CONCLUSIONS: The prevalence of genetically confirmed FH in patients with ACS age ≤65 years and with LDL-C levels ≥160 mg/dl is high (approximately 9%). FH clinical algorithms do not accurately classify patients with FH. Genetic testing should be advocated in young patients with ACS and high LDL-C levels to allow prompt identification of patients with FH and relatives at risk.

Respuesta: La paradoja del tabaquismo: fumar o no fumar / Reply: Smoking paradox: smoking or not smoking

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La paradoja del tabaco en el síndrome coronario agudo sin elevación del ST / Smoking paradox in acute coronary syndrome without st-segment elevation

Fundamento y objetivo: Aunque el tabaco es un conocido factor de riesgo cardiovascular, se ha descrito que en los pacientes ingresan por un infarto de miocardio parece observarse un mejor pronóstico, a corto plazo, en los que tienen antecedente de tabaquismo, lo que se conoce como “paradoja del tabaco”. El propósito de nuestro estudio es comprobar si este fenómeno se da en los pacientes con síndrome coronario agudo sin elevación del ST (SCASEST) y qué factores contribuyen a explicarlo.Pacientes y método: Se analizaron 563 pacientes consecutivos que ingresaron por SCASEST en la Unidad Coronaria de nuestro centro desde enero de 2005 hasta diciembre de 2006. Se analizaron las características clínicas y angiográficas y su relación con las complicaciones y pronóstico intrahospitalario. Resultados: Un total de 155 pacientes eran fumadores (27,53%). Lo pacientes fumadores eran más jóvenes de media que los no fumadores, con más frecuencia fueron varones, presentaban menos factores de riesgo cardiovascular y con mayor frecuencia estaban en clase Killip I (91,6 frente a 79,3%). Los pacientes fumadores tuvieron con menor frecuencia el evento combinado de muerte, reinfarto o Killip IV (6,5 frente a 13,6%, odds ratio 0,439, intervalo de confianza del 95% 0,218 a 0,885, p=0,018). Esta relación perdió la significación estadística al ajustar mediante regresión logística en la que se incluyeron los datos clínicos y angiográficos significativos.Conclusiones: Nuestro estudio confirma la existencia de la “paradoja del tabaco” en el SCASEST, pero queda explicada por la menor prevalencia de infarto previo, diabetes mellitus o enfermedad multivaso. Es fundamental aconsejar a los fumadores el abandono del tabaco (AU)

Background and objective: Although smoking habit is a well-known cardiovascular risk factor, it has been described that smokers admitted because of myocardial infarction have better prognosis than non smoker patients, which is known as “the smoking paradox”. The purpose of our work is to investigate whether this phenomenon occurs among patients admitted because of acute coronary syndrome without ST-segment elevation (NSTACS), and which factors help to explain it. Patients and Methods: We analysed 563 consecutive patients admitted because of NSTACS on the Coronary Unit of our hospital from January 2005 to December 2006. We analysed clinic and angiographic characteristics and their relationship with in-hospital complications and prognosis. Results: 155 Patients were smokers (27,53%). Smoker patients were younger, more often male, had less risk factors, and more often had a Killip I class at admission (91.6% vs. 79.3%). They had less commonly the combined endpoint of death, reinfarction or Killip Class IV (6.5 vs 13.6%, odds ratio 0,439, confidence interval 0,218 a 0,885, P=.018). This relationship was lost after adjusting to other significant clinical and angiographic data by logistic regression. Conclusions: Our study confirms the “smoking paradox” amongst NSTACS patients, which is explained by the lower prevalence of previous myocardial infarction, diabetes or multivessel disease. It is essential to recommend quitting the smoking habites (AU)

[Smoking paradox in acute coronary syndrome without ST-segment elevation]. / La paradoja del tabaco en el síndrome coronario agudo sin elevación del ST.

BACKGROUND AND OBJECTIVE: Although smoking habit is a well-known cardiovascular risk factor, it has been described that smokers admitted because of myocardial infarction have better prognosis than non smoker patients, which is known as "the smoking paradox". The purpose of our work is to investigate whether this phenomenon occurs among patients admitted because of acute coronary syndrome without ST-segment elevation (NSTACS), and which factors help to explain it. PATIENTS AND METHODS: We analysed 563 consecutive patients admitted because of NSTACS on the Coronary Unit of our hospital from January 2005 to December 2006. We analysed clinic and angiographic characteristics and their relationship with in-hospital complications and prognosis. RESULTS: 155 Patients were smokers (27.53%). Smoker patients were younger, more often male, had less risk factors, and more often had a Killip I class at admission (91.6% vs. 79.3%). They had less commonly the combined endpoint of death, reinfarction or Killip Class IV (6.5 vs 13.6%, odds ratio 0.439, confidence interval 0.218 a 0.885, P=.018). This relationship was lost after adjusting to other significant clinical and angiographic data by logistic regression. CONCLUSIONS: Our study confirms the "smoking paradox" amongst NSTACS patients, which is explained by the lower prevalence of previous myocardial infarction, diabetes or multivessel disease. It is essential to recommend quitting the smoking habit.