166 Risk stratification in cardiomyopathies: what’s new and clinically relevant?

RISK STRATIFICATION IN CARDIOMYOPATHIES: WHAT’SNEW AND CLINICALLY RELEVANT?

863 | BEDSIDEHigh-throughput genotyping and phenotyping reveals new geneticdeterminants of clinical phenotype in hypertrophic cardiomyopathy

L. Rocha Lopes1, C. Giambartolomei2, P. Syrris1, C. O’Mahony1,C. Dalageorgou1, S. Jenkins1, M. Hubank3, W. Mc Kenna1, V. Plagnol2,P. Elliott1. 1University College London, Institute of Cardiovascular Science,London, United Kingdom; 2UCL Genetics Institute, London, United Kingdom;3UCL Genomics, London, United Kingdom

Background: A major barrier for the clinical application of genetics in hyper-trophic cardiomyopathy (HCM) is a lack of data on the relation between genotypeand phenotype.Aim: Discover new genetic determinants of HCM phenotype using high-through-put genotyping.Methods: Unrelated and consecutive patients (pts) were studied. High-throughput sequencing was used to analyze 41 genes. Rare variants (vts) weretested for associations with the phenotype.Results: The cohort comprised 384 pts (46.3±15.1 years at initial evaluation,71.4% males). Candidate sarcomere or sarcomere-associated vts were presentin 240 pts (63%). Seventy-five percent were either previously published or novelloss-of-function or insilico predicted to be pathogenic. Rare vts in desmosomaland ion-channel genes were each present in 88 (23%) pts. Table 1 shows someof the significant genotype-phenotype associations.Conclusions: Genotype-phenotype relationships, some of them novel, wereidentified for sarcomere and related genes. Non-sarcomeric vts seem to havea phenotype-modifier effect.

864 | BEDSIDEOutcome of hypertrophic cardiomyopathy associated withsarcomere protein gene mutations: impact of the implantablecardioverter-defibrillator

B. Tomberli1, C. Ferrantini2, R. Coppini3, F. Girolami4, G. Castelli1, A. Fornaro1 ,P. Pieragnoli5, I. Olivotto1, L. Padeletti5, F. Cecchi6. 1Careggi University Hospital,Referral Center for Cardiomyopathies, Florence, Italy; 2University of Florence,Department of Human Physiology, Florence, Italy; 3University of Florence,Department of Pharmacology, Florence, Italy; 4Careggi University Hospital,Genetic Unit, Florence, Italy; 5Careggi University Hospital, ElectrophysiologyUnit, Florence, Italy; 6University of Florence, Department of Clinical andExperimental Medicine, Florence, Italy

Purpose: To date, clinical studies on hypertrophic cardiomyopathy (HCM) haveassessed outcome irrespective of genetic background. However, the large pro-portion of patients with no detectable sarcomere myofilament gene mutations,possibly including phenocopies, may confound our perception of the the natu-ral history of HCM due to sarcomeric myofilament mutations. We therefore in-vestigated the clinical features and outcome of 250 HCM patients followed 6±3years after genetic identification of such mutations. The impact of the implantablecardioverter-defibrillator (ICD), both in terms of appropriate intervention rates andadverse effects, was specifically assessed.Results: Overall, 16 pts (6%; incidence 1% per year) died of cardiovascularcauses, including progressive heart failure (n=7), SCD (n=5), ischemic stroke(n=1) and other non cardiac diseases (n=3). Of these, 9 (5%) occurred in thesubset of patents without ICD (group 1) including 3 sudden deaths; while 7 (11%)occurred among pts with ICD (group 2), of whom 3 had prior appropriate inter-ventions. Two of the deaths in group 2 were sudden, occurring despite the device:unfortunately, neither an autopsy nor an ICD interrogation was performed in thesepts, and the exact causes of death could not be ascertained. At final evaluation,6±3 years after genetic testing, 34 pts (14%) were in NYHA class III/IV and 25(10%) had overt LV systolic dysfunction (LVEF <50%). Survival in the two groupswas comparable (p=0.15) despite more severe clinical profile and greater preva-

Abstract 863 – Table 1

Phenotype Gene Frequency or mean ± standard deviation P-value

Gene-positive Gene-negative

Age at initial evaluation (years) Any sarcomere 43.4±14.2 49.2±15.5 <0.0005Multiple sarcomere 35.4±11.8 47.1±15 <0.0005

Family history of HCM Any sarcomere 44.4% 21.2% <0.0005MYBPC3 loss of function (LOF) 56.9% 28.9% <0.0005MYH7 52.5% 29% <0.0005

Right ventricular hypertrophy TNNI3 54.5% 22.6% 0.024Asymmetrical septal hypertrophy pattern Any sarcomere 87.8% 68.9% <0.0005Moderate-severe diastolic dysfunction SCN5A 46.7% 26.5% 0.020Left ventricular (LV) outflow tract gradient (mmHg) MYBPC3 splicing 57.3±50.9 33.1±40.6 0.014LV dilation PKP2 17.6% 3.4% 0.023Fractional shortening (%) TTN truncating 34.5±5.7% 39.6±8.8% 0.003Family history of sudden cardiac death (SCD) Any sarcomere 32.5% 17.1% <0.0005TPM1 71.4% 23.9% 0.014

MYBPC3 LOF 49.1% 20.8% <0.0005Syncope Multiple sarcomere 41.7% 15.4% 0.003Non-sustained ventricular tachycardia Multiple sarcomere/ associated 55.8% 38.7% 0.030SCD Any sarcomere 4.7% 1.0% 0.031

lence of end-stage in group 2. No difference in survival was observed based onthe affected gene. Among the 64 pts with ICD, only 7 (11%; 2 in primary and 5in secondary prevention) experienced appropriate shocks for VT of VF, with anoverall annual incidence of 2%. However, 16 pts (25% of the ICD subset, includ-ing 2 with appropriate shocks) experienced device-related complications such asinappropriate ICD interventions (n=10; including 4 with electric storms due to leadfracture), infections (n=4) and lead dislocation (n=6).Conclusions: In HCM patients due to sarcomere myofilament mutations, cardio-vascular mortality and sudden cardiac death was low even in the presence ofmultiple risk factors. End-stage progression appeared to be common, supportingthe hypothesis of long-term disease progression to heart failure. The ICD allowedfavourable survival rates in a subset of high risk HCM patients, at the cost ofconsiderable complication rates, even when no appropriate interventions wererecorded. Sudden cardiac death may occur even after ICD implantation.

865 | BEDSIDERisk factors in noncompaction cardiomyopathy - data from theGerman NCCM registry (ALKK)

B.J. Gerecke1, C. Stoellberger2, M. Gietzelt3, R. Haux3, R. Engberding1.1Hospital of Wolfsburg, Wolfsburg, Germany; 2Rudolfstiftung Hospital, Vienna,Austria; 3TU Braunschweig, Braunschweig, Germany

Objective: Isolated noncompaction cardiomyopathy (NCCM) is considered a pri-mary genetic cardiomyopathy. Smaller studies suggest that the prognosis of ptswith NCCM is determined by heart failure (HF) symptoms, different arrhythmias,and thrombembolic events, ranging from asymptomatic to life threatening events.To investigate possible risk factors in this disease we analysed the data of theGerman NCCM registry (ALKK), which is a registry in a real life clinical setting.Methods: By January 31th, 2013 the German NCCM registry had enrolled a totalof 269 pts with NCCM (180 male, age 18 to 88 years, mean age 53.8 yrs) witha mean follow up period of 28 mths. ECGs, echocardiographic and cardiac MRimages were reviewed. The pts were followed in 6 mths intervals for clinical eventsand symptoms. The incidence of severe HF symptoms (NYHA III/IV), malignantarrhythmias (VT/VF), embolic events and deaths were analysed in respect to thefactors: age, gender, LV systolic function, atrial fibrillation (AF), left bundle branchblock (LBBB) and the presence of late enhancement (LE) in the MR images.Results: Age and gender showed no significant influence on the clinical eventsof the pts, although there were more men included. The presence of a LBBB wassignificantly associated with symptoms of heart failure (Odds ratio (OR) 2.54,95%-confidence interval (CI) (1.42, 4.54)), malignant arrhythmias (OR 2.49, CI(1.23, 5.05)) and cardiac (OR 8.49, CI (2.52, 28.65)) and all cause (OR 4.17,CI (1.61, 10.79)) death. The presence of AF was correlated with a higher risk ofdeath for all-cause mortality (OR 4.66, CI (1.78, 12.19)) and for cardiac deaths(OR 5.86, CI (1.88, 18.32)). Severely depressed LV ejection fraction (EF) was asignificant risk factor for deaths (OR 6.78, CI (2.18, 21.04)), for cardiac deaths(OR 9.63, CI (2.09, 44.37)), for heart failure (OR 8.9, CI (5.05, 15.67)) and forVT/VF (OR 2.32, CI (1.18-4.55)). LE in MRI was rarely found in the pts of theregistry. There was no statistic significant correlation between the presence of LEand events. The analysed risk factors showed no correlations to embolic events.Summary: In the real life clinical setting of the German NCCM registry prognosiswas better than previously reported. Pts with NCCM and AF, LBBB, depressedLVEF (<35%) were at high risk for a significant clinical event.

866 | BEDSIDEHypertrophic cardiomyopathy. Long term outcomes of patientswith implantable cardioverter defibrillator in a single centre

N. Galizio, N. Martinenghi, A. Fernandez, A. Palazzo, J. Gonzalez, H. Casabe,H. Fraguas, F. Renedo, G. Carnero, L. Favaloro. University Hospital. FavaloroFoundation., Capital Federal, Argentina

Background: Sudden cardiac death (SCD) is a common mode of death in Hyper-trophic cardiomyopathy (HCM). Implantable cardioverter defibrillator (ICD) is themost effective therapy for prevention of SCD but it is not excempt of complications.

at Imperial C

ollege London L

ibrary on June 6, 2014http://eurheartj.oxfordjournals.org/

Dow

nloaded from