COMPUTER ASSISTED RETINAL VESSEL TORTUOSITY EVALUATION IN NOVEL MUTATION FABRY DISEASE: Towards New Prognostic Markers.

PURPOSE: Fabry disease is a rare lysosomal storage disorder with systemic involvement. The authors report on a large Fabry family with GLA p.M187R mutation and exhaustive ophthalmologic assessment. METHODS: Comprehensive systemic evaluation and genetic diagnosis were performed. Ophthalmologic evaluation included intraocular pressure/visual acuity measurement, refractometry, slit lamp examination, retinography, and optical coherence tomography. Three parameters quantified retinal vessel tortuosity: sum of angle metrics, product of angle distance, and triangular index. Calculations were semiautomatized using dedicated software. RESULTS: Ten individuals (2 males and 8 females) were described. Seventy-five percent had retinal vessel tortuosity. One hundred percent had cornea verticillata. Perimacular vessels were predominantly involved. The correlation between the right and left eye tortuosity measurements was very tight. A significant correlation between retinal vessel tortuosity and systemic severity measured by general Mainz Severity Score Index (MSSI), renal MSSI, and neurological MSSI but no cardiac MSSI was observed. Right sum of angle metrics value was an independent statistical predictor of the general-MSSI score in presence of age. CONCLUSION: p.M187R mutation causes a severe systemic and ophthalmologic phenotype, in both male and female patients. Semiautomatic assessment of retinal vessel tortuosity is an objective and reproducible tool. All three parameters of tortuosity are closely associated with Fabry severity scores. Studies of larger series are being awaited to establish the role of retinal vessel tortuosity as a noninvasive marker of disease progression.

A novel clinical risk prediction model for sudden cardiac death in hypertrophic cardiomyopathy (HCM risk-SCD).

AIMS: Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death (SCD) in young adults. Current risk algorithms provide only a crude estimate of risk and fail to account for the different effect size of individual risk factors. The aim of this study was to develop and validate a new SCD risk prediction model that provides individualized risk estimates. METHODS AND RESULTS: The prognostic model was derived from a retrospective, multi-centre longitudinal cohort study. The model was developed from the entire data set using the Cox proportional hazards model and internally validated using bootstrapping. The cohort consisted of 3675 consecutive patients from six centres. During a follow-up period of 24 313 patient-years (median 5.7 years), 198 patients (5%) died suddenly or had an appropriate implantable cardioverter defibrillator (ICD) shock. Of eight pre-specified predictors, age, maximal left ventricular wall thickness, left atrial diameter, left ventricular outflow tract gradient, family history of SCD, non-sustained ventricular tachycardia, and unexplained syncope were associated with SCD/appropriate ICD shock at the 15% significance level. These predictors were included in the final model to estimate individual probabilities of SCD at 5 years. The calibration slope was 0.91 (95% CI: 0.74, 1.08), C-index was 0.70 (95% CI: 0.68, 0.72), and D-statistic was 1.07 (95% CI: 0.81, 1.32). For every 16 ICDs implanted in patients with ≥4% 5-year SCD risk, potentially 1 patient will be saved from SCD at 5 years. A second model with the data set split into independent development and validation cohorts had very similar estimates of coefficients and performance when externally validated. CONCLUSION: This is the first validated SCD risk prediction model for patients with HCM and provides accurate individualized estimates for the probability of SCD using readily collected clinical parameters.

A cost-effectiveness analysis of hypertrophic cardiomyopathy sudden cardiac death risk algorithms for implantable cardioverter defibrillator decision-making.

AIMS: To conduct a contemporary cost-effectiveness analysis examining the use of implantable cardioverter defibrillators (ICD) for primary prevention in patients with hypertrophic cardiomyopathy (HCM). METHODS: A discrete-time Markov model was used to determine the cost-effectiveness of different ICD decision-making rules for implantation. Several scenarios were investigated including the reference scenario of implantation rates according to observed real world practice. A 12-year time horizon with an annual cycle length was used. Transition probabilities used in the model were obtained using Bayesian analysis. The study has been reported according to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. RESULTS: Using a 5-year SCD risk threshold of 6% was cheaper than current practice and has marginally better total quality adjusted life years (QALYs). This is the most cost-effective of the options considered, with an incremental cost effectiveness ratio of £834 per QALY. Sensitivity analyses highlighted that this decision is largely driven by what health related quality of life (HRQL) is attributed to ICD patients and time horizon. CONCLUSION: We present a timely new perspective on HCM ICD cost-effectiveness, using methods reflecting real-world practice. While we have shown that a 6% 5-year SCD risk cut-off provides the best cohort stratification to aid ICD decision-making, this will also be influenced by the particular values of costs and HRQL for subgroups or at a local level. The process of explicitly demonstrating the main factors which drive conclusions from such an analysis will help to inform shared decision-making in this complex area for all stakeholders concerned.

The Spanish Fabry women study: a retrospective observational study describing the phenotype of females with GLA variants.

BACKGROUND: Fabry disease (FD) is an X-linked condition caused by variants in the GLA gene. Since females have two X chromosomes, they were historically thought to be carriers. Although increased knowledge has shown that females often develop the disease, data from Spain and other countries reported that females were undertreated. The aim of this study was to provide a wider and more recent description of the disease characteristics and associated management of females with a GLA variant in a Spanish cohort. RESULTS: Ninety-seven females from 12 hospitals were included in this retrospective study. Mean age was 50.1 ± 17.2 years. Median follow-up time from GLA variant identification was 36.1 months, and most (70.1%) were identified through family screening. Variants associated with classic/non-classic phenotypes were similarly distributed (40.2%/53.6%). Missense variants were the most prevalent (n = 84, 86.6%). In the overall group, 70.4% had major organ involvement (i.e., cardiac, renal, cerebrovascular, peripheral nervous system or gastrointestinal), and 47.3% also had typical Fabry signs (angiokeratoma, cornea verticillata or increased plasma lyso-Gb3). Cardiac involvement was the most prevalent (49.5%) and the main reason for treatment initiation. A total of 33 (34%) patients received disease-specific therapy, 55% of whom were diagnosed by family screening. Females carrying variants associated with a classic phenotype had higher frequencies of clinical manifestations (92.3%) and were predominant in the treated subgroup (69.7%). Despite this, there were 34 untreated females (56.7% of total untreated), with both phenotypes represented, who had major organ involvement, with 27 of cardiac, renal or cerebrovascular nature. Age or comorbidities in this subgroup were comparable to the treated subgroup (P = 0.8 and P = 0.8, respectively). CONCLUSIONS: Efforts have been made in recent years to diagnose and treat timely Fabry females in Spain. A high percentage of females with pathogenic variants, regardless of their associated phenotype, will likely develop disease. A proportion of females with severe disease in this cohort received specific treatment. Still a significant number of females, even with same profile as the treated ones, who may be eligible for treatment according to European recommendations, remained untreated. Reasons for this merit further investigation.

Validation of multiparametric approaches for the prediction of sudden cardiac death in patients with Brugada syndrome and electrophysiological study.

INTRODUCTION AND OBJECTIVES: Multiparametric scores have been designed for better risk stratification in Brugada syndrome (BrS). We aimed to validate 3 multiparametric approaches (the Delise score, Sieira score and the Shanghai BrS Score) in a cohort with Brugada syndrome and electrophysiological study (EPS). METHODS: We included patients diagnosed with BrS and previous EPS between 1998 and 2019 in 23 hospitals. C-statistic analysis and Cox proportional hazard regression models were used. RESULTS: A total of 831 patients were included (mean age, 42.8±13.1; 623 [75%] men; 386 [46.5%] had a type 1 electrocardiogram (ECG) pattern, 677 [81.5%] were asymptomatic, and 319 [38.4%] had an implantable cardioverter-defibrillator). During a follow-up of 10.2±4.7 years, 47 (5.7%) experienced a cardiovascular event. In the global cohort, a type 1 ECG and syncope were predictive of arrhythmic events. All risk scores were significantly associated with events. The discriminatory abilities of the 3 scores were modest (particularly when these scores were evaluated in asymptomatic patients). Evaluation of the Delise and Sieira scores with different numbers of extra stimuli (1 or 2 vs 3) did not substantially improve the event prediction c-index. CONCLUSIONS: In BrS, classic risk factors such as ECG pattern and previous syncope predict arrhythmic events. The predictive capabilities of the EPS are affected by the number of extra stimuli required to induce ventricular arrhythmias. Scores combining clinical risk factors with EPS help to identify the populations at highest risk, although their predictive abilities remain modest in the general BrS population and in asymptomatic patients.

Acute Myocarditis Associated With Desmosomal Gene Variants.

BACKGROUND: The risk of adverse cardiovascular events in patients with acute myocarditis (AM) and desmosomal gene variants (DGV) remains unknown. OBJECTIVES: The purpose of this study was to ascertain the risk of death, ventricular arrhythmias, recurrent myocarditis, and heart failure (main endpoint) in patients with AM and pathogenic or likely pathogenetic DGV. METHODS: In a retrospective international study from 23 hospitals, 97 patients were included: 36 with AM and DGV (DGV[+]), 25 with AM and negative gene testing (DGV[-]), and 36 with AM without genetics testing. All patients had troponin elevation plus findings consistent with AM on histology or at cardiac magnetic resonance (CMR). In 86 patients, CMR changes in function and structure were re-assessed at follow-up. RESULTS: In the DGV(+) AM group (88.9% DSP variants), median age was 24 years, 91.7% presented with chest pain, and median left ventricular ejection fraction (LVEF) was 56% on CMR (P = NS vs the other 2 groups). Kaplan-Meier curves demonstrated a higher risk of the main endpoint in DGV(+) AM compared with DGV(-) and without genetics testing patients (62.3% vs 17.5% vs 5.3% at 5 years, respectively; P < 0.0001), driven by myocarditis recurrence and ventricular arrhythmias. At follow-up CMR, a higher number of late gadolinium enhanced segments was found in DGV(+) AM. CONCLUSIONS: Patients with AM and evidence of DGV have a higher incidence of adverse cardiovascular events compared with patients with AM without DGV. Further prospective studies are needed to ascertain if genetic testing might improve risk stratification of patients with AM who are considered at low risk.

Long-term prognosis of women with Brugada syndrome and electrophysiological study.

BACKGROUND: A male predominance in Brugada syndrome (BrS) has been widely reported, but scarce information on female patients with BrS is available. OBJECTIVE: The purpose of this study was to investigate the clinical characteristics and long-term prognosis of women with BrS. METHODS: A multicenter retrospective study of patients diagnosed with BrS and previous electrophysiological study (EPS) was performed. RESULTS: Among 770 patients, 177 (23%) were female. At presentation, 150 (84.7%) were asymptomatic. Females presented less frequently with a type 1 electrocardiographic pattern (30.5% vs 55.0%; P <.001), had a higher rate of family history of sudden cardiac death (49.7% vs 29.8%; P <.001), and had less sustained ventricular arrhythmias (VAs) on EPS (8.5% vs 15.1%; P = .009). Genetic testing was performed in 79 females (45% of the sample) and was positive in 34 (19%). An implantable cardioverter-defibrillator was inserted in 48 females (27.1%). During mean (± SD) follow-up of 122.17 ± 57.28 months, 5 females (2.8%) experienced a cardiovascular event compared to 42 males (7.1%; P = .04). On multivariable analysis, a positive genetic test (18.71; 95% confidence interval [CI] 1.82-192.53; P = .01) and atrial fibrillation (odds ratio 21.12; 95% CI 1.27-350.85; P = .03) were predictive of arrhythmic events, whereas VAs on EPS (neither with 1 or 2 extrastimuli nor 3 extrastimuli) were not. CONCLUSION: Women with BrS represent a minor fraction among patients with BrS, and although their rate of events is low, they do not constitute a risk-free group. Neither clinical risk factors nor EPS predicts future arrhythmic events. Only atrial fibrillation and positive genetic test were identified as risk factors for future arrhythmic events.

Mortality Among Referral Patients With Hypertrophic Cardiomyopathy vs the General European Population.

Importance: It is unclear whether hypertrophic cardiomyopathy (HCM) conveys excess mortality when compared with the general population. Objective: To compare the survival of patients with HCM with that of the general European population. Design, Setting, and Participants: Retrospective cohort study of 4893 consecutive adult patients with HCM presenting at 7 European referral centers between 1980 and 2013. The data were analyzed between April 2018 and August 2019. Main Outcomes and Measures: Survival was compared using standardized mortality ratios (SMRs) calculated with data from Eurostat, stratified by study period, country, sex, and age, and using a composite end point in the HCM cohort of all-cause mortality, aborted sudden cardiac death, and heart transplant. Results: Of 4893 patients with HCM, 3126 (63.9%) were male, and the mean (SD) age at presentation was 49.2 (16.4) years. During a median follow-up of 6.2 years (interquartile range, 3.1-9.8 years), 721 patients (14.7%) reached the composite end point. Compared with the general population, patients with HCM had excess mortality throughout the age spectrum (SMR, 2.0, 95% CI, 1.48-2.63). Excess mortality was highest among patients presenting prior to the year 2000 but persisted in the cohort presenting between 2006 and 2013 (SMR, 1.84; 95% CI, 1.55-2.18). Women had higher excess mortality than men (SMR, 2.66; 95% CI, 2.38-2.97; vs SMR, 1.68; 95% CI, 1.52-1.85; P < .001). Conclusions and Relevance: Among patients referred to European specialty centers, HCM was associated with significant excess mortality through the life course. Although there have been improvements in survival with time, potentially reflecting improved treatments for HCM, these findings highlight the need for more research into the causes of excess mortality among patients with HCM and for better risk stratification.

Trabeculated Myocardium in Hypertrophic Cardiomyopathy: Clinical Consequences.

AIMS: Hypertrophic cardiomyopathy (HCM) is often accompanied by increased trabeculated myocardium (TM)-which clinical relevance is unknown. We aim to measure the left ventricular (LV) mass and proportion of trabeculation in an HCM population and to analyze its clinical implication. METHODS AND RESULTS: We evaluated 211 patients with HCM (mean age 47.8 ± 16.3 years, 73.0% males) with cardiac magnetic resonance (CMR) studies. LV trabecular and compacted mass were measured using dedicated software for automatic delineation of borders. Mean compacted myocardium (CM) was 160.0 ± 62.0 g and trabecular myocardium (TM) 55.5 ± 18.7 g. The percentage of trabeculated myocardium (TM%) was 26.7% ± 6.4%. Females had significantly increased TM% compared to males (29.7 ± 7.2 vs. 25.6 ± 5.8, p < 0.0001). Patients with LVEF < 50% had significantly higher values of TM% (30.2% ± 6.0% vs. 26.6% ± 6.4%, p = 0.02). Multivariable analysis showed that female gender and neutral pattern of hypertrophy were directly associated with TM%, while dynamic obstruction, maximal wall thickness and LVEF% were inversely associated with TM%. There was no association between TM% with arterial hypertension, physical activity, or symptoms. Atrial fibrillation and severity of hypertrophy were the only variables associated with cardiovascular death. Multivariable analysis failed to demonstrate any correlation between TM% and arrhythmias. CONCLUSIONS: Approximately 25% of myocardium appears non-compacted and can automatically be measured in HCM series. Proportion of non-compacted myocardium is increased in female, non-obstructives, and in those with lower contractility. The amount of trabeculation might help to identify HCM patients prone to systolic heart failure.

Alcohol septal ablation for hypertrophic obstructive cardiomyopathy: a contemporary reappraisal.

Percutaneous alcohol septal ablation (ASA) is an effective and minimally invasive therapeutic strategy to resolve left ventricular outflow tract obstruction (LVOTO) in patients with hypertrophic cardiomyopathy who remain symptomatic on maximally tolerated medical therapy. First performed by Sigwart in 1994, the procedure consists in determining an iatrogenic infarction of the basal interventricular septum to reduce LVOTO and alleviate symptoms. Since its first description, numerous studies have demonstrated its efficacy and safety, proposing ASA as a valid and attractive alternative to surgical septal myectomy. The success rate of the intervention is profoundly affected by patient selection and centre experience. In this review, we sought to summarise current evidence on ASA, describing the procedure and proposing a cardiomyopathy team-based approach to resolve clinical disputes in clinical practice.

Effectiveness of the 2014 European Society of Cardiology guideline on sudden cardiac death in hypertrophic cardiomyopathy: a systematic review and meta-analysis.

OBJECTIVE: In 2014, the European Society of Cardiology (ESC) recommended the use of a novel risk prediction model (HCM Risk-SCD) to guide use of implantable cardioverter defibrillators (ICD) for the primary prevention of sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HCM). We sought to determine the performance of HCM Risk-SCD by conducting a systematic review and meta-analysis of articles reporting on the prevalence of SCD within 5 years of evaluation in low, intermediate and high-risk patients as defined by the 2014 guidelines (predicted risk <4%, 4%-<6% and ≥6%, respectively). METHODS: The protocol was registered with PROSPERO (registration number: CRD42017064203). MEDLINE and manual searches for papers published from October 2014 to December 2017 were performed. Longitudinal, observational cohorts of unselected adult patients, without history of cardiac arrest were considered. The original HCM Risk-SCD development study was included a priori. Data were pooled using a random effects model. RESULTS: Six (0.9%) out of 653 independent publications identified by the initial search were included. The calculated 5-year risk of SCD was reported in 7291 individuals (70% low, 15% intermediate; 15% high risk) with 184 (2.5%) SCD endpoints within 5 years of baseline evaluation. Most SCD endpoints (68%) occurred in patients with an estimated 5-year risk of ≥4% who formed 30% of the total study cohort. Using the random effects method, the pooled prevalence of SCD endpoints was 1.01% (95% CI 0.52 to 1.61) in low-risk patients, 2.43% (95% CI 1.23 to 3.92) in intermediate and 8.4% (95% CI 6.68 to 10.25) in high-risk patients. CONCLUSIONS: This meta-analysis demonstrates that HCM Risk-SCD provides accurate risk estimations that can be used to guide ICD therapy in accordance with the 2014 ESC guidelines. REGISTRATION NUMBER: PROSPERO CRD42017064203;Pre-results.

Variables associated with contrast-enhanced cardiovascular magnetic resonance in hypertrophic cardiomyopathy: clinical implications.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) shows increased myocardial collagen and disarray. Late gadolinium enhancement in cardiovascular magnetic resonance (CMR) is observed in regions of increased myocardial collagen. The extent of late gadolinium enhancement has been associated with higher prevalence of risk factors of sudden death. The aim of the present study was to describe the clinical characteristics and the presence of risk factors for sudden death in a series of patients from 2 referral centers for HCM in relation to late gadolinium enhancement in CMR. METHODS AND RESULTS: A total of 120 patients (47 +/- 16 years) were included. All patients fulfilled conventional criteria for HCM. A complete history and clinical examination were performed. Risk factors for sudden death were evaluated. A blinded CMR was performed with late gadolinium enhancement in the left ventricular short-axis orientation. NT pro B-type natriuretic protein (BNP) and C-reactive protein were determined in serum samples. A total of 83 patients (69%) showed late gadolinium enhancement. These patients had higher maximal left ventricular wall thickness (22 +/- 5 versus 17 +/- 3 mm, P < .001), showed more frequently obstruction (42% versus 16%, P = .006), nonsustained ventricular tachycardia (38% versus 8%, P = .001), worse exercise capacity (8 +/- 4 versus 10 +/- 4 METs, P = .003) and increased levels of NT BNP (656 [300-1948] versus 290 [122-948] pg/mL, P = .020). On multivariate analysis, maximal left ventricular wall thickness (P < .001) and nonsustained ventricular tachycardia (P = .011) remained associated with gadolinium-enhanced imaging. Number of risk factors for sudden death was associated with late gadolinium enhancement (OR 2.18, 95%CI 1.45-3.20, P < .001). CONCLUSIONS: Late gadolinium enhancement in CMR is a common finding in HCM. Increased maximal left ventricular wall thickness and nonsustained ventricular tachycardia are associated with late gadolinium enhancement. Associations with risk factors for sudden death and functional status are observed.

Predictors of atrial fibrillation in hypertrophic cardiomyopathy.

OBJECTIVES: Atrial fibrillation (AF) is associated with increased morbidity and mortality in patients with hypertrophic cardiomyopathy (HCM). The primary aim of this study (HCM Risk-AF) was to determine the predictors of AF in a large multicentre cohort of patients with HCM. Exploratory analyses were performed to investigate the association between AF and survival and the efficacy of antiarrhythmic therapy in maintaining sinus rhythm (SR). METHODS: A retrospective, longitudinal cohort of patients recruited between 1986 and 2008 in seven centres was used to develop multivariable Cox regression models fitted with preselected predictors. HCM was defined as unexplained hypertrophy (maximum left ventricular wall thickness of ≥15 mm or in accordance with published criteria for the diagnosis of familial disease). 28% of patients (n=1171) had coexistent hypertension. The primary end point was paroxysmal, permanent or persistent AF detected on ECG, Holter monitoring or implantable device interrogation. RESULTS: Of the 4248 patients with HCM without pre-existing AF, 740 (17.4%) reached the primary end point. Multivariable Cox regression revealed an association between AF and female sex, age, left atrial diameter, New York Heart Association (NYHA) class, hypertension and vascular disease. The proportion of patients with cardiovascular death at 10 years was 4.9% in the SR group and 10.9% in the AF group (difference in proportions=5.9%; 95% CI (4.1% to 7.8%)). The proportion of patients with non-cardiovascular death at 10 years was 3.2% in the SR group and 5.9% in the AF group (difference in proportions=2.8%; 95% CI (0.1% to 4.2%)). An intention-to-treat propensity score analysis demonstrated that ß-blockers, calcium channel antagonists and disopyramide initially maintained SR during follow-up, but their protective effect diminished with time. Amiodarone therapy did not prevent AF during follow-up. CONCLUSION: This study shows that patients with HCM who are at risk of AF development can be identified using readily available clinical parameters. The development of AF is associated with a poor prognosis but there was no evidence that antiarrhythmic therapy prevents AF in the long term.

Direct oral anticoagulants in patients with hypertrophic cardiomyopathy and atrial fibrillation.

BACKGROUND: Chronic anticoagulation with vitamin K antagonists (VKAs) is recommended in patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF). Direct oral anticoagulants (NOACs) are an alternative to VKAs but there are limited data to support their use in HCM. We sought to describe the pattern of use, thromboembolic events, bleeding and quality of life in patients with HCM and AF treated with NOACs. METHODS: Data from patients treated with NOACs (n=99) and VKA (n=433) at 9 inherited cardiac diseases units were retrospectively collected. Annual rates of embolic events, serious bleeding and death were analysed and compared. Quality of life and treatment satisfaction were evaluated with SF-36 and SAFUCA questionnaires in 80 NOAC-treated and 57 VKA-treated patients. RESULTS: After median follow-up of 63 months (IQR: 26-109), thromboembolic events (TIA/stroke and peripheral embolism) occurred in 10% of patients on oral anticoagulation. Major/clinically relevant bleeding occurred in 3.8% and the global mortality rate was 23.3%. Thromboembolic event rate was 0.62 per 100patient-years in the NOAC group vs. 1.59 in the VKA group [subhazard ratio (SHR) 0.32;95%CI:0.04-2.45; p=0.27]. Major/clinically relevant bleeding occurred in 0.62 per 100person-years in the NOAC group vs. 0.60 in the VKA group (SHR 1.28;95%CI 0.18-9.30; p=0.85). Quality of life scores were similar in both groups; however, NOAC-treated patients achieved higher scores in the SAFUCA. CONCLUSIONS: HCM patients with AF on NOACs showed similar embolic and bleeding rates to those on VKA. Although quality of life was similar in both groups, the NOAC group reported higher treatment satisfaction.

Inverted U-Shaped Relation Between the Risk of Sudden Cardiac Death and Maximal Left Ventricular Wall Thickness in Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy is associated with sudden cardiac death (SCD). Some studies have shown an association between risk of sudden death and left ventricular maximal wall thickness (MWT), but there are few data in patients with extreme hypertrophy. The aim of this study was to determine the relation between MWT and the risk of SCD. METHODS AND RESULTS: This is a multicenter, retrospective, longitudinal cohort study of 3673 adult (≥16 years) patients, previously used to develop and validate a risk prediction model for SCD (HCM Risk-SCD [hypertrophic cardiomyopathy risk-SCD]). There was an inverted U-shaped relation between MWT and the estimated 5-year risk of SCD. In patients with MWT≥35 mm (n=47; mean age, 33 years; 81% men), there was a single SCD end point (annual rate, 0.2%; 95% confidence interval, 0.03-1.60) and 3 additional cardiovascular events during a median follow-up of 9.5 years. Compared with patients with MWT≤14 mm, those with MWT≥35 mm did not have a higher risk for SCD (hazard ratio, 0.22; 95% confidence interval, 0.03-1.65), cardiovascular death (hazard ratio, 0.66; 95% confidence interval, 0.26-1.67), or all-cause mortality (hazard ratio, 0.73; 95% confidence interval, 0.32-1.69). CONCLUSIONS: The risk of SCD has a complex, nonlinear relationship to MWT. The pathophysiological mechanisms behind this observation require further study but implantable cardioverter defibrillator implantation should not be guided solely on the severity of left ventricular hypertrophy.

Genetics of myocarditis in arrhythmogenic right ventricular dysplasia.

BACKGROUND: Myocarditis occasionally is related to arrhythmogenic right ventricular dysplasia (ARVD) and sometimes overlaps during the early stages, which may lead to misdiagnosis. Acute myocarditis may reflect an active phase of ARVD. OBJECTIVE: The purpose of this study was to evaluate the genetic basis of myocarditis in ARVD and to investigate the association with a poorer prognosis and a higher risk of ventricular arrhythmias. METHODS: Two groups were analyzed: group A, which consisted of 131 affected patients-84 with ARVD (62% male, age 45 years [range 33-55 years]) and 47 with left-sided forms (arrhythmogenic left ventricular dysplasia [ALVD]) (47% male, age 45 years [range 25-61 years]); and group B, which consisted of 64 nonaffected mutation-carrying relatives (36% male, age 42 years [range 22-56 years]; 23 from classic ARVD families and 41 from ALVD families). RESULTS: Seven patients (3.5%) presented with a clinical diagnosis of acute myocarditis over median follow-up of 34 months. Myocarditis was the first clinical presentation in 6 of 7 cases. In 2 patients, acute myocarditis preceded worsening of left ventricular systolic function. In 1 case, myocarditis was associated with an increased gadolinium pattern in cardiac magnetic resonance. Two patients presented with ECG changes weeks after myocarditis resolution. Myocarditis preceded the development of ventricular tachycardia in 2 other patients. Myocarditis clustered in families bearing DSP Q447* and LDB3 c.1051A>G. CONCLUSION: Acute myocarditis reflects an active phase of ARVD that leads to changes in phenotype and abrupt progression of the disease. An active phase should be suspected in a patient with myocarditis associated with a family history of ARVD. Certain mutations may increase the susceptibility to superimposed myocarditis in ARVD.

Prediction of thrombo-embolic risk in patients with hypertrophic cardiomyopathy (HCM Risk-CVA).

AIMS: Atrial fibrillation (AF) and thrombo-embolism (TE) are associated with reduced survival in hypertrophic cardiomyopathy (HCM), but the absolute risk of TE in patients with and without AF is unclear. The primary aim of this study was to derive and validate a model for estimating the risk of TE in HCM. Exploratory analyses were performed to determine predictors of TE, the performance of the CHA2 DS2 -VASc score, and outcome with vitamin K antagonists (VKAs). METHODS AND RESULTS: A retrospective, longitudinal cohort of seven institutions was used to develop multivariable Cox regression models fitted with pre-selected predictors. Bootstrapping was used for validation. Of 4821 HCM patients recruited between 1986 and 2008, 172 (3.6%) reached the primary endpoint of cerebrovascular accident (CVA), transient ischaemic attack (TIA), or systemic peripheral embolus within 10 years. A total of 27.5% of patients had a CHA2 DS2 -VASc score of 0, of whom 9.8% developed TE during follow-up. Cox regression revealed an association between TE and age, AF, the interaction between age and AF, TE prior to first evaluation, NYHA class, left atrial (LA) diameter, vascular disease, and maximal LV wall thickness. There was a curvilinear relationship between LA size and TE risk. The model predicted TE with a C-index of 0.75 [95% confidence interval (CI) 0.70-0.80] and the D-statistic was 1.30 (95% CI 1.05-1.56). VKA treatment was associated with a 54.8% (95% CI 31-97%, P = 0.037) relative risk reduction in HCM patients with AF. CONCLUSIONS: The study shows that the risk of TE in HCM patients can be identified using a small number of simple clinical features. LA size, in particular, should be monitored closely, and the assessment and treatment of conventional vascular risk factors should be routine practice in older patients. Exploratory analyses show for the first time evidence for a reduction of TE with VKA treatment. The CHA2 DS2 -VASc score does not appear to correlate well with the clinical outcome in patients with HCM and should not be used to assess TE risk in this population.