Prognostic Implications of Left Ventricular Mass and Geometry Following Myocardial Infarction: the VALsartan In Acute myocardial iNfarcTion (VALIANT) Echocardiographic Study Anil Verma, MDNo relationships to disclose Jalal Ghali, MDResearch funding from Novartis pharmaceuticals Alessandra Meris, MDNo relationships to disclose J. Malcolm O. Arnold, MDResearch funding from Novartis Pharmaceuticals Mikhail Bourgoun, MD,No relationships to disclose Eric Velazquez, MD Consulting fees/Honoraria, significant –Novartis Lars Kober, MDNo relationships to disclose Marc A. Pfeffer, MD, PhDResearch grant, consulting fees/Honoraria- Novartis Scott D. Solomon, MDResearch grant, speaker’s bureau, consulting fees/Honoraria- Novartis

Prognostic Implications of Left Ventricular Mass and Geometry Following Myocardial Infarction: the VALsartan In Acute myocardial iNfarcTion (VALIANT) Echocardiographic Study Anil Verma, MD, Jalal Ghali, MD, Alessandra Meris, MD, J. Malcolm O. Arnold, MD, Mikhail Bourgoun, MD, Eric Velazquez, MD, Lars Kober, MD, Marc A. Pfeffer, MD, PhD, Scott D. Solomon, MD Brigham and Women’s Hospital, Wayne State University, University Hospital, LHSC, Duke Clinical Research Institute, Duke University Medical Center, Rigshospitalet, University of Copenhagen

BACKGROUND  Left ventricular hypertrophy (LVH) and alterations in LV geometry have been associated with increased mortality and other cardiovascular (CV) events  Patients with concentric LVH (increased relative wall thickness [RWT] and LV mass index [LVMi]), have been shown to have the highest incidence of adverse CV events, including death  There are limited data on the association of LV mass and geometry to prognosis in high risk individuals following myocardial infarction

OBJECTIVE To explore the prognostic value of echocardiographically determined LV mass and geometry in the specific setting of high risk MI

14,703 METHODS double-blind active-controlled ♦ median duration: 24.7 months ♦ event-driven Valsartan and Captopril Valsartan 610 (Echo cohort) 603 (available for analysis)

 The ASE-recommended formula for estimation of LV mass from 2D linear LV measurements LV mass = 0.8 x {1.04[(LVIDd + PWTd + SWTd) 3 - (LVIDd) 3 ]} g  LV mass was indexed to body surface area RWT = 2 x PWTd/LVIDd METHODS Devereux RB, Alonso DR, Lutas EM, et al. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986;57:450–8 LVIDd PWTd SWTd

Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification. J Am Soc Echo Dec;18(12): METHODS Concentric Remodeling N=110 (18%) Concentric Hypertrophy N=76 (13%) Normal Geometry N=305 (51%) Eccentric Hypertrophy N=112 (19%) ≤0.42>0.42 ≤ 95 (♀)> 95 (♀) ≤ 115 (♂)> 115 (♂) Left Ventricular Mass Index (gm/m 2 ) Relative Wall Thickness Concentric Remodeling N=110 (18%) Concentric Hypertrophy N=76 (13%) Normal Geometry N=305 (51%) Eccentric Hypertrophy N=112 (19%)

Distribution of Baseline LV-Mass index in VALIANT Percent of patients LV-Mass index gm/m 2 Mean LVMi 98.8 ± 28.4

Baseline characteristics stratified by LV Geometry Characteristics Normal geometry Concentric remodeling Eccentric hypertrophy Concentric hypertrophy P value Age, yr 60.8 ± ± ± 11.5*70.2 ± 9.8*<0.001 Female sex, % <0.001 Medical history, % MI Hypertension Diabetes mellitus Heart failure < <0.001 SBP ± ± ± ± eGFR, ml/min/1.73 m ± ± ± 18.1*61.7 ± 21.1*<0.001 β-blockers Aspirin Statin *p value <0.001 vs. patients with normal LV geometry; Plus-minus values are means ± SD

Baseline Echo Characteristics Stratified by LV Geometry Normal geometry Concentric remodeling Eccentric hypertrophy Concentric hypertrophyP value LVMi, gm/m ± ± ±23.4*132.4±23.9*<0.001 RWT0.35 ± ± 0.05*0.35 ± ± 0.05*<0.001 EDVi, ml/m ± ± ±18.1*62.6±15.0<0.001 ESVi, ml/m ± ±7.1†45.0±14.1*38.9±11.8<0.001 LV-EF, %39.5 ± ± ± 6.4†38.3±6.0<0.001 LAVi, ml/m ± ± ± 9.7*28.3± 8.2*<0.001 RV-FAC, %42.5 ± ± ± 5.3‡41.5± 3.9<0.001 *p value <0.001; ‡p value <0.01; †p value <0.05 vs. patients with normal LV geometry Plus-minus values are means ±SD, *p value <0.001; ‡p value <0.01; †p value <0.05 vs. patients with normal geometry

Unadjusted Kaplan Meier Curves for All Cause Mortality Cumulative incidence Days Normal Concentric Remodeling Eccentric Hypertrophy Concentric Hypertrophy

Days Cumulative incidence Unadjusted Kaplan Meier curves for Death or Heart Failure Normal Concentric Remodeling Eccentric Hypertrophy Concentric Hypertrophy

Unadjusted Kaplan Meier Curves for Cardiovascular Composite Cumulative Incidence Days Normal Concentric Remodeling Eccentric Hypertrophy Concentric Hypertrophy

Death CV Composite CV Death Death/HF ( ) 1.20 ( ) 1.19 ( ) 1.22 ( ) Adjusted hazard ratios (95%, CI) for adverse outcomes for every 10 gm/m 2 increase in baseline LV Mass index and for every 0.1 unit increase in baseline RWT 10 gm/m 2 increase in baseline LVMi Death CV Composite CV Death Death/HF ( ) 1.70 ( ) 1.80 ( ) 1.70 ( ) 0.1 unit increase in baseline RWT HR adjusted for age, PTCA for index-MI, afib complicating MI, diabetes, hypertension, prior MI, Killip class, history of CHF, new LBB, history of angina, LVEF, eGFR and COPD

Crude incidence rates/100-person years of adverse CV outcomes stratified by LV geometric patterns CV DeathReinfarction HFStrokeSDCV composite Incidence Rate/100-person years Normal Concentric remodeling Eccentric hypertrophy Concentric hypertrophy * * * * † † * p<0.001 † p<0.01

LIMITATIONS  2D Echo is limited in its accuracy for measuring LV mass since all methods assume a uniform thickness of the LV, which is not the case in areas of chronic infarction or with geometric deformity of the LV cavity  We did not assess for changes in LV mass and its geometrical patterns and its potential influence on CV risk  Finally, our results are predominantly applicable to the high risk post MI patients and generalizability to the broader group of post MI patients may be limited

CONCLUSIONS  Echo determined LV geometry and baseline LV mass are important independent predictors of increased morbidity and mortality following MI  Concentric LVH carries the greatest risk of adverse CV events including death  Increase in baseline RWT and the presence of concentric remodeling in the absence of increased LV mass was associated with an increased risk of subsequent CV complications  Our findings suggest that routine assessment of LV mass and RWT could be utilized to better risk- stratify patients following myocardial infarction