The cardiomyopathy of cystic fibrosis: a modern form of Keshan disease.

Introduction: We conducted a study to determine the prevalence of structural heart disease in patients with CF, the characteristics of a cardiomyopathy not previously described in this population, and its possible relationship with nutritional deficiencies in CF. Methods: We studied 3 CMP CF patients referred for heart-lung transplantation and a prospective series of 120 adult CF patients. All patients underwent a clinical examination, blood tests including levels of vitamins and trace elements, and echocardiography with evaluation of myocardial strain. Cardiac magnetic resonance imaging (CMR) was performed in patients with CMP and in a control group. Histopathological study was performed on hearts obtained in transplant or necropsy. Results: We found a prevalence of 10% (CI 4.6%-15.4%) of left ventricular (LV) dysfunction in the prospective cohort. Myocardial strain parameters were already altered in CF patients with otherwise normal hearts. Histopathological examination of 4 hearts from CF CMP patients showed a unique histological pattern of multifocal myocardial fibrosis similar to Keshan disease. Four of the five CF CMP patients undergoing CMR showed late gadolinium uptake, with a characteristic patchy pattern in 3 cases (p < 0.001 vs. CF controls). Selenium deficiency (Se < 60 µg/L) was associated with more severe LV dysfunction, higher prevalence of CF CMP, higher NTproBNP levels, and more severe pulmonary and digestive involvement. Conclusion: 10% of adults with CF showed significant cardiac involvement, with histological and imaging features resembling Keshan disease. Selenium deficiency was associated with the presence and severity of LV dysfunction in these patients.

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.

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.

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.

Spanish Heart Transplant Registry. 29th Official Report of the Spanish Society of Cardiology Working Group on Heart Failure.

INTRODUCTION AND OBJECTIVES: The present report updates the characteristics and results of heart transplantation in Spain, mainly focused in the 2008-2017 period. METHODS: We describe the recipient and donor characteristics, surgical procedures, and outcomes of heart transplants performed in 2017. The 2017 data were compared with those obtained from 2008 to 2016. RESULTS: A total of 304 cardiac transplants were performed in 2017. Between 1984 and 2017, 8173 procedures were performed, 2689 of them after 2008. Significant temporal trends were observed in recipient characteristics (lower pulmonary vascular resistance, lower use of mechanical ventilation, and a higher percentage of diabetic patients and those with previous cardiac surgery), donor characteristics (older donor age and a higher percentage of female donors and those with a prior cardiac arrest) and procedures (lower ischemia time). In 2017, 27% of patients were transplanted after undergoing mechanical ventricular assistance (P <.001 for trend). In the last decade, there was a trend to better survival. CONCLUSIONS: Around 300 transplants per year were performed in Spain in the last decade. There was a significant increase in the use of pretransplant mechanical circulatory support and a trend to improved survival.

Identification of capillary rarefaction using intracoronary wave intensity analysis with resultant prognostic implications for cardiac allograft patients.

Aims: Techniques for identifying specific microcirculatory structural changes are desirable. As such, capillary rarefaction constitutes one of the earliest changes of cardiac allograft vasculopathy (CAV) in cardiac allograft recipients, but its identification with coronary flow reserve (CFR) or intracoronary resistance measurements is hampered because of non-selective interrogation of the capillary bed. We therefore investigated the potential of wave intensity analysis (WIA) to assess capillary rarefaction and thereby predict CAV. Methods and results: Fifty-two allograft patients with unobstructed coronary arteries and normal left ventricular (LV) function were assessed. Adequate aortic pressure and left anterior descending artery flow measurements at rest and with intracoronary adenosine were obtained in 46 of which 2 were lost to follow-up. In a subgroup of 15 patients, simultaneous RV biopsies were obtained and analysed for capillary density. Patients were followed up with 1-3 yearly screening angiography. A significant relationship with capillary density was noted with CFR (r = 0.52, P = 0.048) and the backward decompression wave (BDW) (r = -0.65, P < 0.01). Over a mean follow-up of 9.3 ± 5.2 years patients with a smaller BDW had an increased risk of developing angiographic CAV (hazard ratio 2.89, 95% CI 1.12-7.39; P = 0.03). Additionally, the index BDW was lower in those who went on to have a clinical CAV-events (P = 0.04) as well as more severe disease (P = 0.01). Conclusions: Within cardiac transplant patients, WIA is able to quantify the earliest histological changes of CAV and can predict clinical and angiographic outcomes. This proof-of-concept for WIA also lends weight to its use in the assessment of other disease processes in which capillary rarefaction is involved.

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.

Clinical characteristics of wild-type transthyretin cardiac amyloidosis: disproving myths.

AIMS: Wild-type transthyretin amyloidosis (ATTRwt) is mostly considered a disease predominantly of elderly male, characterized by concentric LV hypertrophy, preserved LVEF, and low QRS voltages. We sought to describe the characteristics of a large cohort of ATTRwt patients to better define the disease. METHODS AND RESULTS: Clinical findings of consecutive ATTRwt patients diagnosed at 2 centres were reviewed. ATTRwt was diagnosed histologically or non-invasively (LV hypertrophy ≥12 mm, intense cardiac uptake at 99mTc-DPD scintigraphy and AL exclusion). Mutations in TTR were excluded in all cases. The study cohort comprised 108 patients (78.6 ± 8 years); 67 (62%) diagnosed invasively and 41 (38%) non-invasively. Twenty patients (19%) were females. An asymmetric hypertrophy pattern was observed in 25 (23%) patients. Mean LVEF was 52 ± 14%, with 39 patients (37%) showing a LVEF < 50%. Atrial fibrillation (56%) and a pseudo-infarct pattern (63%) were the commonest ECG findings. Only 22 patients fulfilled QRS low-voltage criteria while 10 showed LV hypertrophy on ECG. Although heart failure was the most frequent profile leading to diagnosis (68%), 7% of individuals presented with atrioventricular block and 11% were diagnosed incidentally. Almost one third (35; 32%) were previously misdiagnosed. CONCLUSION: The clinical spectrum of ATTRwt is heterogeneous and differs from the classic phenotype: women are affected in a significant proportion; asymmetric LV hypertrophy and impaired LVEF are not rare and only a minority have low QRS voltages. Clinicians should be aware of the broad clinical spectrum of ATTRwt to correctly identify an entity for which a number of disease-modifying treatments are under investigation.

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.

Analysis of diagnostic and therapeutic strategies in advanced cardiac light-chain amyloidosis.

BACKGROUND: Prognosis of advanced cardiac light-chain amyloidosis (ACAL) is ominous. Diagnosis of ACAL is frequently preceded by several biopsies of non-clinically affected tissues, which can result in dangerous treatment delays. Combinations of alkylators and steroids have a limited role in its therapy. Definitive efficacy of bortezomib in ACAL is not widely described. In this study we analyze the diagnostic yield of biopsies and compare the effect of bortezomib with other therapeutic strategies in ACAL patients. METHODS: This study is a retrospective analysis of 40 consecutive ACAL patients treated at our hospital (2005 to 2015). For comparison purposes, the cohort was divided into 2 groups: patients treated with bortezomib (n = 23) and those treated with other therapeutic approaches (non-bortezomib, n = 8). RESULTS: Sensitivity of biopsies of non-clinically affected organs was 23%, as compared with 97% for affected organ biopsies (p < 0.0001). The need for >2 biopsies resulted in an average delay in diagnosis of 4.1 months (p = 0.007). Hematologic response was observed in 96% of patients in the bortezomib group compared with 25% in the non-bortezomib group (relative risk = 3.8; 95% confidence interval 1.14 to 12.75; p = 0.0002). Cardiac response criteria were met by 60% of patients in the bortezomib group as compared with none in the non-bortezomib group (p = 0.005). Survival at 6 months and 1 and 2 years for bortezomib patients was 91%, 91% and 73%, as compared with 58%, 15% and 0% for non-bortezomib patients (log rank, p < 0.0001), respectively. CONCLUSION: In our experience, the sensitivity of biopsies from non-affected organs in ACAL is poor and could result in diagnostic delay. Bortezomib was associated with higher hematologic and cardiac response rates as well as survival when compared with other therapies.

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.

A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families.

Cardiac angiosarcoma (CAS) is a rare malignant tumour whose genetic basis is unknown. Here we show, by whole-exome sequencing of a TP53-negative Li-Fraumeni-like (LFL) family including CAS cases, that a missense variant (p.R117C) in POT1 (protection of telomeres 1) gene is responsible for CAS. The same gene alteration is found in two other LFL families with CAS, supporting the causal effect of the identified mutation. We extend the analysis to TP53-negative LFL families with no CAS and find the same mutation in a breast AS family. The mutation is recently found once in 121,324 studied alleles in ExAC server but it is not described in any other database or found in 1,520 Spanish controls. In silico structural analysis suggests how the mutation disrupts POT1 structure. Functional and in vitro studies demonstrate that carriers of the mutation show reduced telomere-bound POT1 levels, abnormally long telomeres and increased telomere fragility.

Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome with multiple underlying causes. Wild-type transthyretin (TTR) amyloidosis (ATTRwt) is an underdiagnosed cause of HFpEF that might benefit from new specific treatments. ATTRwt can be diagnosed non-invasively by (99m)Tc-3,3-diphosphono-1,2-propanodicarboxylic acid ((99m)Tc-DPD) scintigraphy. We sought to determine the prevalence of ATTRwt among elderly patients admitted due to HFpEF. METHODS AND RESULTS: We prospectively screened all consecutive patients ≥60 years old admitted due to HFpEF [left ventricular (LV) ejection fraction ≥50%] with LV hypertrophy (≥12 mm). All eligible patients were offered a (99m)Tc-DPD scintigraphy. The study included 120 HFpEF patients (59% women, 82 ± 8 years). A total of 16 patients (13.3%; 95% confidence interval: 7.2-19.5) showed a moderate-to-severe uptake on the (99m)Tc-DPD scintigraphy. All patients with a positive scan underwent genetic testing of the TTR gene, and no mutations were found. An endomyocardial biopsy was performed in four patients, confirming ATTRwt in all cases. There were no differences in age, gender, hypertension, diabetes, coronary artery disease, or atrial fibrillation between ATTRwt patients and patients with other HFpEF forms. Although patients with ATTRwt exhibited higher median N-terminal pro-brain natriuretic peptide (6467 vs. 3173 pg/L; P = 0.019), median troponin I (0.135 vs. 0.025 µg/L; P < 0.001), mean LV maximal wall thickness (17 ± 3.4 vs. 14 ± 2.5 mm; P = 0.001), rate of pericardial effusion (44 vs. 19%; P = 0.047), and rate of pacemakers (44 vs. 12%; P = 0.004), clinical overlap between ATTRwt and other HFpEF forms was high. CONCLUSION: ATTRwt is an underdiagnosed disease that accounts for a significant number (13%) of HFpEF cases. The effect of emerging TTR-modifying drugs should be evaluated in these patients.

Usefulness of Two-Dimensional Strain Parameters to Diagnose Acute Rejection after Heart Transplantation.

BACKGROUND: Acute cellular rejection (ACR) is still a relevant complication after orthotopic heart transplantation. The diagnosis of ACR is based on endomyocardial biopsy (EMB). Recent advances in two-dimensional strain imaging may allow early noninvasive detection of ACR. The objective of this study was to analyze the usefulness of conventional and new echocardiographic parameters to exclude ACR after orthotopic heart transplantation. METHODS: Thirty-four consecutive adult heart transplant recipients admitted to a single center between January 2010 and December 2012 for orthotopic heart transplantation were prospectively included. A total of 235 pairs of EMB and echocardiographic examination were performed. A median of seven studies per patient (interquartile range, six to eight studies per patient) were performed during the first year of follow-up. Classic echocardiographic parameters; speckle-tracking-derived left ventricular (LV) longitudinal, radial, and circumferential strain; and global and free wall right ventricular (RV) longitudinal strain were analyzed. RESULTS: ACR was detected in 26.4% of EMB samples (n = 62); 5.1% (n = 12) required specific treatment (ACR degree ≥ 2R). Lower absolute values of global LV longitudinal strain and free wall RV longitudinal strain were present in patients with ACR degree ≥ 2R compared with those without ACR (13.7 ± 2.7% vs 17.8 ± 3.4% and 16.6 ± 3.6% vs 23.3 ± 5.2%, respectively). An average LV longitudinal strain < 15.5% had 85.7% sensitivity, 81.4% specificity, 98.8% negative predictive value, 25.0% positive predictive value, and 81.7% accuracy for the presence of ACR degree ≥ 2R. Free wall RV longitudinal strain < 17% had 85.7% sensitivity, 91.1% specificity, 98.8% negative predictive value, 42.9% positive predictive value, and 90.7% accuracy for ACR degree ≥ 2R. Both variables were normal in 106 echocardiograms (57.6%); none of these patients presented with ACR degree ≥ 2R. CONCLUSIONS: The combination of two new echocardiographic measures, global LV and RV free wall longitudinal strain, may be able to identify a group of heart transplant patients who are unlikely to have ACR. If these findings are confirmed independently, it may be possible to use LV and RV strain measures as reliable tools to exclude ACR and to reduce the burden of repeated EMB.

Malignant ventricular arrhythmias in alcoholic cardiomyopathy.

BACKGROUND: Excessive alcohol consumption is a well-known aetiology of atrial arrhythmias but there is little information concerning the prevalence or incidence of malignant ventricular arrhythmias in alcoholic cardiomyopathy (ACM). This study sought to investigate incidence and predictive factors of ventricular arrhythmias in ACM. METHODS: Retrospective observational study of the clinical characteristics and long-term arrhythmic events in 282 consecutive patients with ACM (94 individuals) and idiopathic dilated cardiomyopathy (IDCM) (188 individuals) evaluated between 1993 and 2011. RESULTS: During a median follow-up of 38months (IQR:12-77), 42 patients died and 79 underwent heart transplantation [31 (33%) with ACM vs 90 (48%) with IDCM; p=0.017]. A total of 37 (13%) patients [18 (19%) ACM vs 20 (11%) IDCM; p=0.048] suffered malignant ventricular arrhythmias. On multivariate analysis, left bundle branch block (LBBB) (OR 2.4; CI95%: 1.2-5; p=0.015) and alcoholic aetiology (OR 2.3; CI95%: 1.1-4.5; p=0.026) were the only independent predictors of malignant ventricular arrhythmic events. A total of 18 (19%) ACM patients experienced 20 malignant ventricular arrhythmic events (4 aborted SCD, 8 SCD and 8 appropriate ICD therapies). At baseline evaluation, the only independent predictor of malignant ventricular arrhythmias in ACM patients was LBBB (OR 11.2; CI95%: 2.6-50; p=0.001). No malignant ventricular arrhythmias were recorded during follow-up in ACM patients if left ventricular ejection fraction (LVEF) had increased or remained ≥40%. CONCLUSIONS: Malignant ventricular arrhythmias are more frequent in ACM than in IDCM. LBBB identifies ACM patients with increased risk of SCD. No malignant ventricular arrhythmias were found during follow-up in ACM patients when LVEF was ≥40%.

Stop-gain mutations in PKP2 are associated with a later age of onset of arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a cardiac disease characterized by the presence of fibrofatty replacement of the right ventricular myocardium, which may cause ventricular arrhythmias and sudden cardiac death. Pathogenic mutations in several genes encoding mainly desmosomal proteins have been reported. Our aim is to perform genotype-phenotype correlations to establish the diagnostic value of genetics and to assess the role of mutation type in age-related penetrance in ARVC. METHODS AND RESULTS: Thirty unrelated Spanish patients underwent a complete clinical evaluation. They all were screened for PKP2, DSG2, DSC2, DSP, JUP and TMEM43 genes. A total of 70 relatives of four families were also studied. The 30 patients fulfilled definite disease diagnostic criteria. Genetic analysis revealed a pathogenic mutation in 19 patients (13 in PKP2, 3 in DSG2, 2 in DSP, and 1 in DSC2). Nine of these mutations created a truncated protein due to the generation of a stop codon. Familial assessment revealed 28 genetic carriers among family members. Stop-gain mutations were associated to a later age of onset of ARVC, without differences in the severity of the pathology. CONCLUSIONS: Familial genetic analysis helps to identify the cause responsible for the pathology. In discrepancy with previous studies, the presence of a truncating protein does not confer a worse severity. This information could suggest that truncating proteins may be compensated by the normal allele and that missense mutations may act as poison peptides.