JACC March 3, 2004 ABSTRACTS - Cardiac Function and Heart Failure 215A Cardiac Function and Heart Failure elderly (225±41 ms) than in younger patients (208±31 msec) (p<0.001). Increased atrial refractory period and age > 70 years were independent factors of decreased AF inducibil- ity. Conclusion : AF inducibility is paradoxically decreased in elderly patients. The AF induction is facilitated by the presence of a short atrial refractory period in patients younger than 70 years and programmed atrial stimulation should be interpreted cau- tiously in these patients. In the opposite, the increase of atrial refractory period could pro- tect the patients older than 70 years against AF induction. ORAL CONTRIBUTIONS 839 Hypertrophic Cardiomyopathy: Basic and Clinical II Tuesday, March 09, 2004, 10:30 a.m.-Noon Morial Convention Center, Room 210 10:30 a.m. 839-1 The Long-Term Effect of Surgical Myectomy on Survival in Patients With Obstructive Hypertrophic Cardiomyopathy Steve R. Ommen , Iacopo Olivotto, Martin S. Maron, Sandro Betocchi, Franco Cecchi, Michael J. Ackerman, Bernard J. Gersh, Joseph A. Dearani, Hartzell V. Schaff, Rick A. Nishimura, Barry J. Maron, Mayo Clinic, Rochester, MN Background: Surgical septal myectomy is the definitive treatment for relief of drug-refrac- tory symptoms in hypertrophic cardiomyopathy (HCM). Recent data document reduced survival when left ventricular outflow (LVOT) obstruction is present. However, the poten- tial effects of myectomy on long-term survival are unresolved. Methods: Overall mortality was assessed in 1337 HCM pts evaluated between 1983- 2001: (1) 289 consecutive pts underwent isolated surgical myectomy at Mayo Clinic for advanced symptoms attributable to LVOT obstruction; (2) 228 other pts with LVOT obstruction were managed without surgery; (3) 820 pts had nonobstructive HCM. Sur- vival after myectomy was compared to age and sex matched general population, nonop- erated obstructive pts, and nonobstructive pts. Results: Patients were 45 ± 20 years old, 58% were males, LV wall thickness was 22 ± 6 mm, the average resting gradient was 68 ± 37mmHg among the pts with LVOT obstruc- tion. Including 4 operative deaths (procedural mortality, 1.4%), survival after myectomy at 1, 5, and 10 years was 98%, 96%, and 83%, respectively. This survival did not differ sta- tistically from the age and sex matched general population, nor the pts with nonobstruc- tive HCM (98%, 95%, 88%). Myectomy pts had more favorable survival than nonoperated obstructive pts (90%, 80%, and 67%, log-rank p <0.0001). Multivariate Cox modelling with all relevant co-variates showed that myectomy (hazard ratio 0.20, p<0.0001) was independently associated with more favorable long-term survival. Conclusion: Surgical septal myectomy performed for the relief of LVOT obstruction and severe drug-refractory symptoms is associated with long-term survival equivalent to that of an age and sex matched general population. Although these data are retrospective and nonrandomized, they strongly suggest that myectomy reduces the excess mortality risk associated with the presence of LVOT obstruction. 10:45 a.m. 839-2 Mechanism of Systolic Anterior Motion and Regurgitation Post Septal Ablation in Hypertrophic Cardiomyopathy Francesca Nesta , Danita M. Yoerger, Michael H. Picard, Michael A. Fifer, Igor F. Palacios, Gus J. Vlahakes, Robert A. Levine, Judy Hung, Massachusetts General Hospital, Boston, MA Background: Systolic anterior motion of the mitral valve (SAM) in hypertrophic cardi- omyopathy (HCM) is secondary to both outflow tract narrowing and primary structural abnormalities of the mitral apparatus: the papillary muscles (PM) and leaflets are shifted anteriorly into the LV outflow path, causing SAM with regurgitation (MR). Clinical obser- vations suggest that relief of obstruction by septal ablation (SAb) does not always cause resolution of SAM and MR. We tested the hypothesis that persistent SAM relates to mal- position of the mitral apparatus, and that this finding can predict persistence of SAM. Methods: We reviewed echoes of 30 patients with HCM before and 3 months post SAb. We assessed anterior leaflet malposition by the antero-posterior projection of the coapta- tion point onto the mitral annular diameter (A/D ratio) in early systole. MR was assessed by proximal jet in the LAX view. Results: Most patients (22/30=73%) had SAM at 3 months despite successful SAb (gradient reduction > 50%), and had more anterior mal- position and less MR reduction than those without SAM: A/D 0.44 vs 0.57, MR proximal jet reduction by 7% vs 51%, p < 0.0001. Anterior malposition was also present prior to SAb, with A/D < 0.4 being predictive of SAM post SAb (p<0.007). Conclusions: SAM and its related MR are not always eliminated by SAb. MV malposition is a strong determi- nant and predictor of SAM and MR reduction post SAb and may represent a new thera- peutic target during ablation procedures. 11:00 a.m. 839-3 Frequency, Spectrum, and Phenotype of Hypertrophic Cardiomyopathy Patients With Multiple Sarcomeric Mutations Sara L. Van Driest , Steve R. Ommen, Melissa L. Will, Vlad C. Vasile, Susan Chung, A. Jamil Tajik, Bernard J. Gersh, Michael J. Ackerman, Mayo Clinic, Rochester, MN Background: Hypertrophic cardiomyopathy (HCM) is caused by pathogenic mutations involving 8 genes that encode critical proteins comprising the sarcomere. Here, we deter- mine the frequency, spectrum, and phenotype associated with complex genetic status (i.e. > 1 sarcomeric mutation) in a cohort of unrelated patients (pts) evaluated at a tertiary outpatient HCM clinic. Methods: DNA was obtained from 389 unrelated HCM pts and analyzed for mutations in myosin binding protein C encoded by MYBPC3, β -myosin heavy chain (MYH7), regula- tory and essential light chains (MYL2 and MYL3), troponin T (TNNT2), troponin I (TNNI3), α -tropomyosin (TPM1), and actin (ACTC) using polymerase chain reaction, denaturing high performance liquid chromatography, and DNA sequencing. Clinical data were extracted from pt records blinded to pt genotype. Results: Of the 389 HCM pts, 151 (38.8%) harbored at least one putative pathogenic mutation. Eleven pts (2.8% of total and 7.2% of genotyped subset) had 2 putative sarco- meric mutations: compound MYBPC3 in 2 pts, MYBPC3 and MYH7 (3), MYBPC3 and TNNT2 (2), MYBPC3 and TNNI3 (1), MYBPC3 and TPM1 (1), compound MYH7 (1), and MYH7 and TNNT2 (1). When compared to pts with single sarcomeric mutations, or no sarcomeric mutations, pts with multiple mutations were younger at diagnosis (21.7 ± 11 years vs 36.4 ± 17 vs 45.1 ± 19, p <0.005, had greater hypertrophy (maximum left ven- tricular wall thickness = 24.6 ± 12 mm vs 22.8 ± 6 vs 20.7 ± 6, p <0.05), and more fre- quently received an ICD (36% vs 24% vs 10%, p = 0.0002). However, those with multiple mutations were not more likely to have had a surgical myectomy than those with a single mutation or no identifiable sarcomeric mutation. Conclusion: This study represents a comprehensive mutational analysis searching for multiple genetic defects in a large HCM cohort from a single tertiary referral center. Com- plex genetic status was found in nearly 3% of HCM pts. On average, pts with multiple sar- comeric mutations were diagnosed 20 years earlier and displayed the greatest degree of hypertrophy. The possibility of multiple mutations involving the sarcomere adds further complexity to the development and implementation of clinical molecular genetic testing for HCM. 11:15 a.m. 839-4 Treatment With Antioxidant N-Acetylcysteine Reverses Interstitial Fibrosis in a Mouse Model of Human Hypertrophic Cardiomyopathy Mutation Natalia Tsybouleva, Tripti Halder, Rajnikant Patel, Silvia Lutucuta, Gilberto De Freitas, Masakuni Ishiyama, Blase Carabello, Ali J. Marian , Baylor College of Medicine, Houston, TX The genetic basis of human hypertrophic cardiomyopathy (HCM) is known but the patho- genesis of its phenotypes is unknown. We have generated transgenic mice by cardiac- restricted expressing mutant cardiac troponin T (cTnT)-Q92 protein, known to cause HCM in humans; which exhibits enhanced systolic function, interstitial fibrosis (IF) and myocyte disarray. Since oxidative stress is implicated in the pathogenesis of fibrosis, we tested whether treatment with anti-oxidant N-acetyl cysteine (NAC) could reverse or attenuate IF in the cTnT-Q92 mice. We performed a placebo-controlled study and ran- domized 24 mice to placebo or NAC (1g/Kg/d) and include 12 non-transgenic (NTG) mice as controls. We performed echocardiography prior to and after 16 weeks of therapy fol- lowed by histological and molecular characterization. Transgenic mice had higher left ventricular (LV) ejection fraction and smaller LV end systolic diameter and smaller heart weight/body weight (HW/BW) as compared to NTG mice at the baseline. No significant differences in the body weight, male/female ratio, mean age, and heart rates were present among the three groups. Treatment with NAC reduced concentrations of alondi- aldehyde and 4-hydroxy-2(E)-nonenal, indices of oxidative stress, in the left ventricular tissue (NTG: 3.0 ± 0.6; Placebo: 3.5 ± 0.4; NAC: 2.3 ± 0.3, p=0.01). Similarly, collagen volume fraction (CVF) was normalized (NTG: 3.4% ± 0.9; Placebo: 7.8 ± 1.7; NAC: 3.8 ±