Pregnancy in women with dilated cardiomyopathy genetic variants.

INTRODUCTION AND OBJECTIVES: Limited information is available on the safety of pregnancy in patients with genetic dilated cardiomyopathy (DCM) and in carriers of DCM-causing genetic variants without the DCM phenotype. We assessed cardiac, obstetric, and fetal or neonatal outcomes in this group of patients. METHODS: We studied 48 women carrying pathogenic or likely pathogenic DCM-associated variants (30 with DCM and 18 without DCM) who had 83 pregnancies. Adverse cardiac events were defined as heart failure (HF), sustained ventricular tachycardia, ventricular assist device implantation, heart transplant, and/or maternal cardiac death during pregnancy, or labor and delivery, and up to the sixth postpartum month. RESULTS: A total of 15 patients, all with DCM (31% of the total cohort and 50% of women with DCM) experienced adverse cardiac events. Obstetric and fetal or neonatal complications were observed in 14% of pregnancies (10 in DCM patients and 2 in genetic carriers). We analyzed the 30 women who had been evaluated before their first pregnancy (12 with overt DCM and 18 without the phenotype). Five of the 12 (42%) women with DCM had adverse cardiac events despite showing NYHA class I or II before pregnancy. Most of these women had a history of cardiac events before pregnancy (80%). Among the 18 women without phenotype, 3 (17%) developed DCM toward the end of pregnancy. CONCLUSIONS: Cardiac complications during pregnancy and postpartum were common in patients with genetic DCM and were primarily related to HF. Despite apparently good tolerance of pregnancy in unaffected genetic carriers, pregnancy may act as a trigger for DCM onset in a subset of these women.

Gut Microbiota and Derived Short-Chain Fatty Acids Are Linked to Evolution of Heart Failure Patients.

There is a lack of direct evidence regarding gut microbiota dysbiosis and changes in short-chain fatty acids (SCFAs) in heart failure (HF) patients. We sought to assess any association between gut microbiota composition, SCFA production, clinical parameters, and the inflammatory profile in a cohort of newly diagnosed HF patients. In this longitudinal prospective study, we enrolled eighteen newly diagnosed HF patients. At admission and after 12 months, blood samples were collected for the assessment of proinflammatory cytokines, monocyte populations, and endothelial dysfunction, and stool samples were collected for analysis of gut microbiota composition and quantification of SCFAs. Twelve months after the initial HF episode, patients demonstrated improved clinical parameters and reduced inflammatory state and endothelial dysfunction. This favorable evolution was associated with a reversal of microbiota dysbiosis, consisting of the increment of health-related bacteria, such as genus Bifidobacterium, and levels of SCFAs, mainly butyrate. Furthermore, there was a decrease in the abundance of pathogenic bacteria. In vitro, fecal samples collected after 12 months of follow-up exhibited lower inflammation than samples collected at admission. In conclusion, the favorable progression of HF patients after the initial episode was linked to the reversal of gut microbiota dysbiosis and increased SCFA production, particularly butyrate. Whether restoring butyrate levels or promoting the growth of butyrate-producing bacteria could serve as a complementary treatment for these patients deserves further studies.

El electrocardiograma en la amiloidosis cardíaca: un arma para la sospecha diagnóstica de esta enfermedad / The electrocardiogram in cardiac amyloidosis: a weapon for the diagnosis suspect of this disease / O electrocardiograma na amiloidose cardíaca: uma arma para a suspeita diagnóstica desta doença

La amiloidosis cardíaca (AC) es una enfermedad con mal pronóstico si el tratamiento no se inicia de forma temprana, por lo que una de las asignaturas pendientes en esta enfermedad consiste en realizar un diagnóstico precoz. El electrocardiograma (ECG) es una prueba diagnóstica de bajo costo y amplia disponibilidad que nos permite sospechar esta enfermedad, dado que resulta normal en < 5% de los pacientes. El hallazgo clásico es la presencia de bajos voltajes en relación con la gran hipertrofia que se observa en las pruebas de imagen, así como el conocido patrón de pseudoinfarto. Ambos hallazgos son más frecuentes en el subtipo de amiloidosis por cadenas ligeras, que era el más frecuentemente diagnosticado en el pasado. Sin embargo, con la expansión del diagnóstico no invasivo del subtipo a transtiretina, su identificación ha crecido de forma exponencial y se convirtió en el más diagnosticado con más frecuencia en nuestro medio. Se debe prestar especial atención a todos estos hallazgos electrocardiográficos, con el fin de que esta prueba diagnóstica de sencilla obtención pueda contribuir de forma importante a la sospecha y al diagnóstico precoz de la AC.

Cardiac amyloidosis (CA) is a serious disease with a poor prognosis if treatment is not started early, so one of the pending issues in this condition is to make an early diagnosis. The electrocardiogram (EKG) is an inexpensive and widely available diagnostic test that can offer differential data when suspecting this disease, being normal in < 5% of these patients. The classic EKG finding is the presence of low voltages in relation to the large hypertrophy seen on imaging tests, as well as the well-known pseudoinfarct pattern. Both findings are more frequent in the light chain subtype of CA, which was the most frequently diagnosed in the past. However, with the growth of noninvasive diagnostic tests, the identification of the transtyretin subtype has grown exponentially, becoming the most frequently diagnosed in our setting. Special attention should be paid to all these electrocardiographic findings, so that this simple diagnostic test can make an important contribution to the early suspicion and diagnosis of CA.

A amiloidose cardíaca (AC) é uma doença grave com um mau prognóstico no caso de não se iniciar tratamento de forma precoce, pelo que a necessidade de um pronto diagnóstico é imperiosa. Quando se suspeita desta doença, o eletrocardiograma (ECG) é um teste de diagnóstico pouco dispendioso e disponível em todo o mundo, que pode fornecer dados discriminativos importantes, sendo normal em menos de 5% dos casos. O achado clássico do ECG é a presença de baixas voltagens em relação à grande hipertrofia vista na imagem, bem como o conhecido padrão de pseudoinfarte. Ambos os resultados são mais frequentes no subtipo a cadenas ligeras, o mais frequentemente diagnosticado no passado. No entanto, com o aumento dos testes de diagnóstico não-invasivos, o diagnóstico ddo subtipo a transtirretina, o mais cresceu de forma exponencial, tornando-se o mais frequentemente diagnosticado no nosso meio. Deve ser dada especial atenção a todos estes achados eletrocardiográficos já que esta prova de diagnóstico de fácil obtenção pode contribuir de forma importante para a suspeição de diagnóstico precoce de AC.

Natural History of MYH7-Related Dilated Cardiomyopathy.

BACKGROUND: Variants in myosin heavy chain 7 (MYH7) are responsible for disease in 1% to 5% of patients with dilated cardiomyopathy (DCM); however, the clinical characteristics and natural history of MYH7-related DCM are poorly described. OBJECTIVES: We sought to determine the phenotype and prognosis of MYH7-related DCM. We also evaluated the influence of variant location on phenotypic expression. METHODS: We studied clinical data from 147 individuals with DCM-causing MYH7 variants (47.6% female; 35.6 ± 19.2 years) recruited from 29 international centers. RESULTS: At initial evaluation, 106 (72.1%) patients had DCM (left ventricular ejection fraction: 34.5% ± 11.7%). Median follow-up was 4.5 years (IQR: 1.7-8.0 years), and 23.7% of carriers who were initially phenotype-negative developed DCM. Phenotypic expression by 40 and 60 years was 46% and 88%, respectively, with 18 patients (16%) first diagnosed at <18 years of age. Thirty-six percent of patients with DCM met imaging criteria for LV noncompaction. During follow-up, 28% showed left ventricular reverse remodeling. Incidence of adverse cardiac events among patients with DCM at 5 years was 11.6%, with 5 (4.6%) deaths caused by end-stage heart failure (ESHF) and 5 patients (4.6%) requiring heart transplantation. The major ventricular arrhythmia rate was low (1.0% and 2.1% at 5 years in patients with DCM and in those with LVEF of ≤35%, respectively). ESHF and major ventricular arrhythmia were significantly lower compared with LMNA-related DCM and similar to DCM caused by TTN truncating variants. CONCLUSIONS: MYH7-related DCM is characterized by early age of onset, high phenotypic expression, low left ventricular reverse remodeling, and frequent progression to ESHF. Heart failure complications predominate over ventricular arrhythmias, which are rare.

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

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.

Benefits of cardiac pacing in ICD recipients with hypertrophic cardiomyopathy.

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.

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

BACKGROUND: The clinical relevance of genetic variants in nonischemic dilated cardiomyopathy (DCM) is unsettled. OBJECTIVES: The study sought to assess the prognostic impact of disease-causing genetic variants in DCM. METHODS: Baseline and longitudinal clinical data from 1,005 genotyped DCM probands were retrospectively collected at 20 centers. A total of 372 (37%) patients had pathogenic or likely pathogenic variants (genotype positive) and 633 (63%) were genotype negative. The primary endpoint was a composite of major adverse cardiovascular events. Secondary endpoints were end-stage heart failure (ESHF), malignant ventricular arrhythmia (MVA), and left ventricular reverse remodeling (LVRR). RESULTS: After a median follow-up of 4.04 years (interquartile range: 1.70-7.50 years), the primary endpoint had occurred in 118 (31.7%) patients in the genotype-positive group and in 125 (19.8%) patients in the genotype-negative group (hazard ratio [HR]: 1.51; 95% confidence interval [CI]: 1.17-1.94; P = 0.001). ESHF occurred in 60 (16.1%) genotype-positive patients and in 55 (8.7%) genotype-negative patients (HR: 1.67; 95% CI: 1.16-2.41; P = 0.006). MVA occurred in 73 (19.6%) genotype-positive patients and in 77 (12.2%) genotype-negative patients (HR: 1.50; 95% CI: 1.09-2.07; P = 0.013). LVRR occurred in 39.6% in the genotype-positive group and in 46.2% in the genotype-negative group (P = 0.047). Among individuals with baseline left ventricular ejection fraction ≤35%, genotype-positive patients exhibited more major adverse cardiovascular events, ESHF, and MVA than their genotype-negative peers (all P < 0.02). LVRR and clinical outcomes varied depending on the underlying affected gene. CONCLUSIONS: In this study, DCM patients with pathogenic or likely pathogenic variants had worse prognosis than genotype-negative individuals. Clinical course differed depending on the underlying affected gene.

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

Importance: Truncating variants in the gene encoding filamin C (FLNCtv) are associated with arrhythmogenic and dilated cardiomyopathies with a reportedly high risk of ventricular arrhythmia. Objective: To determine the frequency of and risk factors associated with adverse events among FLNCtv carriers compared with individuals carrying TTN truncating variants (TTNtv). Design, Setting, and Participants: This cohort study recruited 167 consecutive FLNCtv carriers and a control cohort of 244 patients with TTNtv matched for left ventricular ejection fraction (LVEF) from 19 European cardiomyopathy referral units between 1990 and 2018. Data analyses were conducted between June and October, 2020. Main Outcomes and Measures: The primary end point was a composite of malignant ventricular arrhythmia (MVA) (sudden cardiac death, aborted sudden cardiac death, appropriate implantable cardioverter-defibrillator shock, and sustained ventricular tachycardia) and end-stage heart failure (heart transplant or mortality associated with end-stage heart failure). The secondary end point comprised MVA events only. Results: In total, 167 patients with FLNCtv were studied (55 probands [33%]; 89 men [53%]; mean [SD] age at baseline evaluation, 43 [18] years). For a median follow-up of 20 months (interquartile range, 7-60 months), 29 patients (17.4%) reached the primary end point (19 patients with MVA and 10 patients with end-stage heart failure). Eight (44%) arrhythmic events occurred among individuals with baseline mild to moderate left ventricular systolic dysfunction (LVSD) (LVEF = 36%-49%). Univariable risk factors associated with the primary end point included proband status, LVEF decrement per 10%, ventricular ectopy (≥500 in 24 hours) and myocardial fibrosis detected on cardiac magnetic resonance imaging. The LVEF decrement (hazard ratio [HR] per 10%, 1.83 [95% CI, 1.30-2.57]; P < .001) and proband status (HR, 3.18 [95% CI, 1.12-9.04]; P = .03) remained independent risk factors on multivariable analysis (excluding myocardial fibrosis and ventricular ectopy owing to case censoring). There was no difference in freedom from MVA between FLNCtv carriers with mild to moderate or severe (LVEF ≤35%) LVSD (HR, 1.29 [95% CI, 0.45-3.72]; P = .64). Carriers of FLNCtv with impaired LVEF at baseline evaluation (n = 69) had reduced freedom from MVA compared with 244 TTNtv carriers with similar baseline LVEF (for mild to moderate LVSD: HR, 16.41 [95% CI, 3.45-78.11]; P < .001; for severe LVSD: HR, 2.47 [95% CI, 1.04-5.87]; P = .03). Conclusions and Relevance: The high frequency of MVA among patients with FLNCtv with mild to moderate LVSD suggests that higher LVEF values than those currently recommended should be considered for prophylactic implantable cardioverter-defibrillator therapy in FLNCtv carriers.

Percutaneous mitral valve repair with MitraClip device in hemodynamically unstable patients: A systematic review.

BACKGROUND: Very few data exist on percutaneous mitral valve repair (PMVr) in unstable patients with concomitant moderate-severe mitral regurgitation (MR). The purpose of this systematic review was to evaluate baseline characteristics, management and clinical outcomes of critically ill patients undergoing PMVr with MitraClip. METHODS: We conducted a systematic review of the published data on MitraClip from its first use in 2003 to December 2020. Studies referring to critically ill patients in cardiogenic shock or acute refractory pulmonary edema were included. A total of 40 publications including 254 patients with significant MR (Grade 4 in 91%) were included. RESULTS: Mean age was 70 ± 12 years with mean Euroscore II and STS of 21 ± 13 and 20.5 ± 16, respectively. Clinical presentation was with cardiogenic shock and acute myocardial infarction in 72.8 and 60.0% of patients, respectively. Device success was achieved in 238 (93.7%) patients with a significant reduction in MR (Grade ≤ 2 in 91.8%, p < .001). The median weaning time from the procedure, to discontinuation of mechanical circulatory or respiratory support, was 2 days (IQR 1-4), with an in-hospital mortality and non-fatal complication rate of 12.6 and 9.1%, respectively. Kaplan-Meier curves estimated an overall mortality rate of 39.1% at 12-month follow-up, with persistent reduction in MR severity for survivors (Grade ≤ 2 in 81.3%) and one case of mitral valve reintervention. CONCLUSIONS: Percutaneous mitral valve repair with MitraClip device is a technically feasible and potentially viable management option in high-risk patients with cardiogenic shock or refractory pulmonary edema and concomitant moderate-severe MR. Prospective trials are required to confirm these findings, and definitively determine the value of MitraClip in hemodynamically unstable patients.

Predictores de riesgo en una cohorte española con cardiolaminopatías. Registro REDLAMINA / Risk predictors in a Spanish cohort with cardiac laminopathies. The REDLAMINA registry

Introducción y objetivos Según las guías de muerte súbita, se debe considerar un desfibrilador automático implantable (DAI) para los pacientes con miocardiopatía dilatada debida a variantes en el gen de la lamina (LMNA) con al menos 2 factores: varones, fracción de eyección del ventrículo izquierdo (FEVI) <45%, taquicardia ventricular no sostenida (TVNS) y variantes no missense. Nuestro objetivo es describir las características clínicas de una cohorte española de pacientes con cardiolaminopatías (registro REDLAMINA) y evaluar los criterios de riesgo vigentes. Métodos Se evaluó la relación entre factores de riesgo y eventos cardiovasculares en una cohorte de 140 portadores de variantes en LMNA (54 probandos, 86 familiares, edad ≥ 16 años). Se consideró: a) evento arrítmico mayor (EAM) si hubo descarga apropiada del DAI o muerte súbita, y b) muerte por insuficiencia cardiaca, incluidos los trasplantes. Resultados Se identificaron 11 variantes nuevas y 21 previamente publicadas. La FEVI <45% (p=0,001) y la TVNS (p <0,001) se relacionaron con los EAM, pero no el sexo o el tipo de variante (missense frente a no missense). La FEVI <45% (p <0,001) fue el único factor relacionado con la muerte por insuficiencia cardiaca. Conclusiones En el registro REDLAMINA, los únicos 2 predictores asociados con EAM fueron la TVNS y la FEVI <45%. No se debería considerar grupo de bajo riesgo a las portadoras de variantes missense con TVNS o FEVI <45%. Es importante individualizar la estratificación del riesgo de los portadores de variantes missense en LMNA, porque no todas tienen el mismo pronóstico. (AU)

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. (AU)

Perfil clínico y evolución de la amiloidosis cardiaca en un centro español de referencia / Clinical profile and outcome of cardiac amyloidosis in a Spanish referral center

Introducción y objetivos La amiloidosis cardiaca (AC) se produce por depósito de fibras de amiloide en el miocardio. Las formas más frecuentes son la amiloidosis por cadenas ligeras (AL) y por transtiretina (ATTR). Nuestro objetivo es describir la experiencia en el diagnóstico, el tratamiento y el pronóstico en un centro especializado español. Métodos Se incluyó a todos los pacientes diagnosticados de AC en el Hospital Puerta de Hierro Majadahonda desde mayo de 2008 a septiembre de 2018 y se analizaron sus características clínicas, su evolución y su supervivencia. Resultados Se incluyó a 180 pacientes con AC, de los que 64 (36%) tenían AL (el 50% varones; edad, 65±11 años) y 116, ATTR (el 72% varones; edad, 79±11 años; 18 con ATTR hereditaria). La forma de presentación más frecuente fue la insuficiencia cardiaca en ambos grupos (el 81% con AL y el 45% con ATTR; p <0,01). Otras formas de presentación en pacientes con ATTR fueron arritmias auriculares (16%), trastornos de conducción (6%) e incidental (6%). Ya tenían otro diagnóstico establecido 70 pacientes (40%). Se pudo diagnosticar de manera no invasiva al 75% de los pacientes con ATTR. A pesar de que el retraso diagnóstico fue superior en la ATTR (2,8±4,3 frente a 0,6±0,7 años; p <0,001), la mortalidad fue mayor en los pacientes con AL (el 48 frente al 32%; p=0,028). El tipo de AL (HR=6,16; IC95%, 1,56-24,30; p=0,01), el sexo femenino (HR=2,35; IC95%, 1,24-4,46; p=0,01) y la clase funcional de la NYHA III-IV (HR=2,07; IC95%, 1,11-3,89; p=0,02) fueron predictores independientes de la mortalidad. Conclusiones La AC constituye un reto en la práctica clínica, con gran variabilidad en su presentación en función del subtipo y con un retraso diagnóstico y una mortalidad elevados. Son necesarias mejoras en el diagnóstico temprano y el tratamiento de estos pacientes. (AU)

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. (AU)

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

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.

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

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.

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

BACKGROUND: Truncating variants in the TTN 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; P=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]; P=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]; P<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 (P=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.

Multiparametric Echocardiography Scores for the Diagnosis of Cardiac Amyloidosis.

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.

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

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.

Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy.

BACKGROUND: Cancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and preexisting cardiovascular disorders. These parameters incompletely account for substantial interindividual susceptibility to CCM. We hypothesized that rare variants in cardiomyopathy genes contribute to CCM. METHODS: We studied 213 patients with CCM from 3 cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped adults with breast cancer (n=73), and prospectively phenotyped children with acute myeloid leukemia (n=41). Cardiomyopathy genes, including 9 prespecified genes, were sequenced. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas participants (n=2053), healthy volunteers (n=445), and an ancestry-matched reference population. Clinical characteristics and outcomes were assessed and stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice. RESULTS: CCM was diagnosed 0.4 to 9 years after chemotherapy; 90% of these patients received anthracyclines. Adult patients with CCM had cardiovascular risk factors similar to the US population. Among 9 prioritized genes, patients with CCM had more rare protein-altering variants than comparative cohorts ( P≤1.98e-04). Titin-truncating variants (TTNtvs) predominated, occurring in 7.5% of patients with CCM versus 1.1% of The Cancer Genome Atlas participants ( P=7.36e-08), 0.7% of healthy volunteers ( P=3.42e-06), and 0.6% of the reference population ( P=5.87e-14). Adult patients who had CCM with TTNtvs experienced more heart failure and atrial fibrillation ( P=0.003) and impaired myocardial recovery ( P=0.03) than those without. Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wild-type ( P=0.0004 and P<0.002, respectively). CONCLUSIONS: Unrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtvs, increased the risk for CCM in children and adults, and adverse cardiac events in adults. Genotype, along with cumulative chemotherapy dosage and traditional cardiovascular risk factors, improves the identification of patients who have cancer at highest risk for CCM. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01173341; AAML1031; NCT01371981.