1. Restrictive Physiology is a Major Predictor of Poor Outcomes in Children with Hypertrophic Cardiomyopathy Shiraz A Maskatia MD, Jamie A Decker MD, Joseph A Spinner BA, Jeffrey J Kim MD, Jack F Price MD, John L Jefferies MD, William J Dreyer MD, E O’Brian Smith PhD, Joseph W Rossano MD, Susan W Denfield MD

2. Background Hypertrophic cardiomyopathy (HCM) is associated with an increased risk of sudden and heart failure deaths in children 1,2 Previously identified risk factors for death or heart transplant (HT) in children include abnormal BP response to exercise and left ventricular hypertrophy 2 A subgroup of patients with restrictive physiology (RP) with worse outcomes has been described, but data in children is limited 3,4 1. Nugent et al Circulation 2005 2. Decker et al J Am Coll Cardiol 2009 3. Colan et al Circulation 2007 4. Webber et al Circulation (S2) 2008

3. Hypothesis The presence of restrictive physiology is a major predictor of hospitalization, death or transplant in children with HCM

4. Methods Retrospective review of patients followed for HCM at Texas Children’s Hospital Inclusion criteria: – Age < 18 years at the time of diagnosis – Follow up time ≥ 1 year – Echocardiogram (echo) evidence of HCM without secondary cause Outcomes analysis included Poisson and Cox regression

5. Methods RP on echo defined as > 1 echo with one of the following: – Left atrial enlargement without left ventricular dilation – Mitral inflow E/A ratio ≥ 3 – Mitral E/E’ ratio ≥ 10 RP on catheterization (cath) defined as: – Systolic pulmonary artery pressure ≥ 35 mmHg – Left or right ventricular end diastolic pressure ≥ 15 mmHg – Pulmonary vascular resistance index ≥ 4 woods units

6. Results 444 patients with HCM treated at our institution from 1/1/1985 to 1/1/2010 119 patients met inclusion criteria RP by echo was present in 49 (41%) patients – Left atrial enlargement was present in 43 (88%) patients – E/E’ ratio ≥ 10 present in 27 (55%) patients – E/A ratio ≥ 3 present in 9 (18%) patients

7. 17 (14%) patients underwent cath – RP by cath present in 11 (65%) patients – Of the 11 patients with RP by cath, 10 (91%) had RP by echo No evidence of RP present in 69 (58%) patients One patient had RP by cath, and not by echo Results

8. Patient Characteristics All patients (n=119) Non- restrictive (n=69) Restrictive by Echo (n=49) Restrictive by Cath (n=11) Age at diagnosis (years)10.2 ± 5.511.2 ± 5.59.2 ± 5.39.4 ± 5.5 Male (%)86 (72%)51 (74%)29 (59%)4 (36%) Symptoms at presentation (%)31 (26%)16 (23%)12 (24%)7 (64%) FH of HCM (%)47 (40%)22 (32%)22 (45%)6 (55%) Ventricular arrhythmias (%)9 (7.6%)2 (3%)7 (14%)1 (9%) IVS (z-score)5.7 ± 4.84.8 ± 4.76.8 ± 4.74.5 ± 2.6 Abn BP response (%)35 (29%)13 (19%)19 (39%)3 (27%)

9. Results Patients with RP by echo – higher ventricular septal z-scores (p=0.03) – more likely to have ventricular arrhythmias (p=0.02 OR=5.6 CI=1.1-28.2) – more likely to have an abnormal blood pressure response to exercise (p=0.01 OR=3.9 CI=1.4-11.4) Patients with RP by cath had higher left ventricular free wall z-scores (p=0.03)

10. 7 patients died; 6 (86%) had RP 3 pts underwent HT; all 3 had RP Aborted sudden cardiac death (aSCD) occurred in 9 pts; 6 (67%) had RP RP by echo or cath had a positive predictive value of 17% and a negative predictive value of 98% for death or HT Results

11. Risk FactorHazard Ratio (95% Conf Int)P-value Hospitalization Restrictive by Echo3.5 (1.3-9.3) 0.01 Restrictive by Cath11.5 (3.0-43.5) <0.01 Restrictive on presentation 7.4 (1.4-38.5) 0.02 Female 4.8 (2.1-10.8) <0.01 Age at presentation (years) 1.1 (1.1-1.2) 0.05 Symptoms at presentation 1.7 (0.77-3.8) 0.19 Abnormal BP response 2.1 (0.73-5.9) 0.17 Septal wall thickness z-score 1.02 (0.94-1.1) 0.63 Death or Aborted Sudden Cardiac Death Restrictive by Echo3.8 (1.2-11.9) 0.02 Restrictive by Cath4.7 (1.1-22.7) 0.05 Restrictive on presentation 9.0 (1.1-76.9) 0.05 Female 1.5 (0.54-4.4) 0.43 Age at presentation (years) 1.02 (0.93-1.1) 0.70 Symptoms at presentation 6.5 (1.9-22.7) <0.01 Septal wall thickness z-score 1.03 (0.89-1.2) 0.67 Death or Heart Transplant Restrictive by Echo5.7 (1.05-31) 0.04 Restrictive by Cath89 (4.9-1000) <0.01 Restrictive on presentation 22 (1.05-500) 0.04 Female 1.33 (0.32-5.6) 0.69 Age at presentation (years) 0.93 (0.80-1.1) 0.37 Symptoms at presentation 8.0 (1.66-38) <0.01 Septal wall thickness z-score 0.98 (0.82-1.15) 0.98

14. Limitations Retrospective analysis Determination of left atrial volume was subjective Only 14% of patients in the study underwent cath – may result in selection bias.

15. Conclusions Children with hypertrophic cardiomyopathy without restrictive physiology have a good prognosis Children with hypertrophic cardiomyopathy and restrictive physiology accounted for the majority of poor outcomes Patients with evidence of restrictive physiology on echocardiogram and symptoms should undergo further hemodynamic assessment by cardiac catheterization