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.

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.

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.

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.

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.

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.

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.

Right lateral versus left lateral view for forearm coronary angiography. An operator radiation exposure and image quality study.

OBJECTIVES: The aim of this study was to analyze the operator radiation exposure (ORE) and the image quality in a coronary angiography (CA) of the standard left lateral view (LLV) and compare it with an alternative right lateral view (RLV). BACKGROUND: Interventional cardiologists are exposed to high doses of scatter radiation, especially in angulated projections. METHODS: We prospectively included consecutive patients who underwent diagnostic CA. A standard +90° LLV and an alternative RLV (-90°) were done in each patient with the same protocol. The operator effective dose rate (mSv/h) was determined for each projection with digital dosimeters located in the collar, waist and knee. The image quality of both the LLV and RLV was analyzed and compared to a standard projection. RESULTS: 116 patients were enrolled; left coronary artery (LCA) was assessed in 52 patients and right coronary artery (RCA) in 64 patients. The ORE was significantly lower with the RLV compared to the conventional LLV with a maximum ORE reduction of 91.5% in the operator waist (LLV: 6.84 mSv h-1 versus RLV: 0.58 mSv h-1, p < 0.001). No significant differences in image quality were observed for the RCA in both projections. For the LCA, a slight loss of quality was observed with the RLV. CONCLUSIONS: -90° RLV is associated with a significant decrease in ORE compared to the conventional +90° LLV without losing image resolution for the RCA and resulting in a slight quality loss for the LCA evaluation. The RLV should be the first choice for RCA evaluation. For the LCA, the RLV loss of resolution should be balanced with the benefit of minimizing ORE, mainly in cases with long fluoroscopy times, such as complex percutaneous coronary interventional procedures.

Post-traumatic ventricular septal defect: a rare indication for extracorporeal membrane oxygenation as a bridge to transplant.

A ventricular septal defect (VSD) is a rare complication of blunt chest trauma. This report presents the case of a 44-year-old man who developed a VSD as a result of high-energy closed chest trauma. We describe the initial surgical and medical management of the cardiac rupture. After failed repair surgery, extracorporeal membrane oxygenation (ECMO) was used as a bridge to heart transplantation. We discuss the successful use of ECMO to improve the prognosis results in this rare and complex entity.

Impact of Coronary Collaterals on Long-term Prognosis in Patients Treated With Primary Angioplasty.

INTRODUCTION AND OBJECTIVES: The beneficial effect of coronary collateral circulation (CC) in patients with ST-segment elevation myocardial infarction is controversial. The aim of this study was to evaluate the impact of CC before reperfusion with primary angioplasty (PA) on the long-term prognosis of these patients. METHODS: Retrospective observational study of a cohort of 947 patients treated with PA and TIMI grade ≤ 1 flow in a single center from 2005 to 2013. Propensity score matching was used to create 2 groups of 175 patients each, matched by the degree of CC (Rentrop 0-1 vs Rentrop 2-3). In the matched cohort, we determined the impact of CC on total mortality, cardiovascular mortality, and a combined adverse cardiovascular event endpoint for a median follow-up of 864 (interquartile range, 396-1271) days. RESULTS: Of a total of 947 patients included, 735 (78%) had Rentrop 0 to 1 and 212 (22%) had Rentrop 2 to 3. During follow-up, 105 patients died, 71 from cardiovascular causes. In the matched cohort, the total mortality rate was similar between the 2 groups (Rentrop 0-1 [8.8%] vs Rentrop 2-3 [6.3%]; HR = 1.22; 95%CI, 0.50-2.94; P = .654). There were no differences in cardiovascular mortality (Rentrop 0-1 [4.6%] vs Rentrop 2-3 [2.3%]; sHR = 0.49; 95%CI, 0.14-1.62; P = .244) or the composite endpoint including cardiovascular death, reinfarction, target vessel revascularization, and coronary artery bypass surgery (Rentrop 0-1 [18.8%] vs Rentrop 2-3 [13.1%]; sHR = 0.68; 95%CI, 0.40-1.15; P = .157). CONCLUSIONS: In this contemporary series, the presence of good CC before PA was not associated with better long-term clinical outcomes.

Two-Dimensional Speckle Tracking Echocardiography in Heart Transplant Patients: Two-Year Follow-Up of Right and Left Ventricular Function.

BACKGROUND: Evolution of left and right ventricular (LV and RV) function after heart transplantation (HT) has not been well described. Our objective was to evaluate the evolution of echocardiographic parameters of both ventricles along the first 2 years after HT. METHODS: We followed 31 HT recipients with serial echocardiograms for up to 2 years. Echocardiograms with AR ≥2R were excluded. We analyzed LV global longitudinal strain (LV GLS) by speckle tracking in 12 segments in four- and two-chamber views and RV global longitudinal strain (RV GLS) in four-chamber view. Control group included 25 healthy volunteers. RESULTS: Even though LVEF was preserved, LV GLS was reduced early post-HT (-17.7 ± 3.0 in HT vs. -20.7 ± 2.8 in controls, P = 0.02), improving progressively until its complete normalization 2 years after HT (-20.0 ± 3.7 vs. -20.7 ± 2.8, P = 0.60). TAPSE was impaired in the early post-HT period and increased progressively (11.9 ± 2.9 mm at baseline vs. 19.0 ± 3.6 mm at 2 years, P < 0.001). RV GLS rose during follow-up as well (-17.4 ± 3.5 at baseline vs. -22.6 ± 3.3 at 2 years, P = 0.001), reaching normal values 1 year after HT. CONCLUSION: In this series of HT recipients with uneventful postoperative course, LV and RV GLS values were significantly reduced early after HT and improved progressively until their complete normalization two and 1 year after HT, respectively. This is the first study to show a full recovery of LV and RV deformation parameters and offers "normal" strain values that, if confirmed in larger studies, could be useful for monitoring the evolution of HT recipients.