Clinical Implications of Electrocardiographic Left Ventricular Strain and Hypertrophy in Asymptomatic Aortic Stenosis: The SEAS study Anders M. Greve, MD1; Kurt Boman, MD, PhD2; Christa Gohlke-Baerwolf, MD3; Antero Y. Kesäniemi, MD4; Christoph A. Nienaber, MD5; Simon Ray, MD, MD6; Kenneth E. Egstrup, MD7; Anne B. Rossebø, MD8; Richard B. Devereux, MD9; Lars Køber, MD1; Ronnie Willenheimer, MD, PhD10; Kristian Wachtell, MD, PhD1,11 1Department of Medicine B, The Heart Center, Rigshospitalet, Copenhagen, Denmark; 2Skelleftå Lasarett and Umeå University, Skelleftå, Sweden; 3Herz-Zentrum Bad Krozingen, Bad Krozingen, Germany; 4Institute of Clinical Medicine, Department of Internal Medicine and Biocenter Oulu, University of Oulu and Clinical Research Center, Oulu University Hospital, Oulu, Finland;5Department of Cardiology and Angiology, University Hospital Rostock, Rostock School of Medicine, Rostock, Germany; 6Department of Cardiology, North West Heart Centre, University Hospitals of South Manchester, Manchester, United Kingdom; 7Medicinsk Afdeling, OUH Svendborg Sygehus, Denmark; 8Department of Cardiology Oslo University Hospital, Ullevål, Oslo, Norway; 9Weill Cornell Medical College, New York, NY; 10Heart Health Group and Lund University Hospital, Malmö, Sweden; 11Gentofte University Hospital, Copenhagen, Denmark.

Background-1 Any echocardiographic degree of asymptomatic aortic stenosis (AS) is not significantly associated with increased risk of all-cause mortality. Pellikka et al. Circulation 2005

Background-2 Specific characteristics such as severe stenosis and/or reduced left ventricular performance may identify patients with higher risk of decompensation Otto CM. JACC 2006 Pellikka P et al. Circulation 2005

Objectives To examine: If simple electrocardiographic measures of left ventricular (LV) hypertrophy (LVH) and strain are predictive of poor prognosis in asymptomatic patients with mild-to-moderate AS.

Methods-1 The SEAS study included 1,873 asymptomatic patients with mild-to-moderate AS (peak jet ≥2.5 and ≤4.0 m/sec) and normal left ventricular systolic function. Randomization to simvastatin/ezetimibe combination vs. placebo: mean follow-up 4.3 years. No significant effect of cholesterol-lowering therapy on AS progression or AS related outcomes. Rossebø AB et al. Am J Cardiol 2008 Rossebø AB et al. NEJM 2008

Methods-2 Baseline and annual in-study electro- and echocardiograms read blinded at corelab reading centers. Electrocardiographic LVH: Sokolow-Lyon voltage criterion; RV5-6+SV1 ≥35 mV Cornell voltage-duration criteria; (RaVL+SV3+[6 mV in women]) × QRS-duration ≥2440 mVmsec Electrocardiographic strain: T-wave inversion in leads V4-6 Cramariuc D et al. JACC imaging 2009 Greve AM et al. Am J Cardiol 2011

Methods-3 Endpoints adjudicated by endpoint committee -prespecified endpoint manual prepared by the SEAS Steering Committee. Heart failure defined as date of hospitalization for heart failure (excluding prior AVR, heart failure and/or known heart disease, aside from AS). Data analyzed by t-tests for normally distributed continuous variables. Chi-square for categorical data. Survival analyses by Cox-based competing risk regression. Rossebø AB et al. Am J Cardiol 2008

Results-1 LVH by SL LVH by CVDP EKG strain Variable (n=260) (n=220) + LVH by Sokolow-Lyon - 30.7% 31.2% + LVH by CVDP 26.2% 24.7% + ECG strain 41.8% 46.4% Peak aortic jet velocity (m/sec) 3.2 ± 0.6* 3.2 ± 0.5* Aortic valve area index (cm2/m2) 0.61 ± 0.20 0.59 ± 0.20 0.57 ± 0.19* Mean aortic gradient (mmHg) 24.7 ± 9.6* 24.0 ± 8.3* 25.0 ± 9.3* Mild aortic stenosis 43.1%* 42.3%* 38.2%* LV mass indexed by BSA (g/m²) 109.8 ± 33.2* 116.4 ± 36.7* 113.3 ± 34.8* LV ejection fraction (%) 64.2 ± 9.2* 62.3 ± 9.1* 63.6 ± 8.9*

Results-2 Baseline EKG Strain and Rate of Heart Failure Serial Measures of EKG Strain and Rate of Heart Failure Unadjusted HR; 3.7 (1.8 – 7.6), p<0.001 Adjusted HR*; 2.4 (1.0 – 6.0), p=0.05 Unadjusted HR; 6.4 (2.9 – 14.1), p<0.001 Adjusted HR*; 4.5 (1.8 – 11.3), p=0.002 * Adjusted for age, gender, echocardiographic peak aortic jet velocity, left ventricular ejection fraction and left ventricular mass, cholesterol levels, systolic- and diastolic blood pressure, estimated glomerular filtration rate, study drug, digoxin and body mass index, respectively baseline and serial values (based on annual reexamination).

Results-3 Baseline EKG LVH by SL and Rate of Heart Failure Serial Measures of EKG LVH by SL and Rate of Heart Failure Unadjusted HR; 4.1 (2.1 – 8.0), p<0.001 Adjusted HR*; 4.0 (1.8 – 9.3), p=0.001 Unadjusted HR; 4.0 (2.1 – 7.9), p<0.001 Adjusted HR*; 3.5 (1.6 – 7.7), p=0.002 * Adjusted for age, gender, echocardiographic peak aortic jet velocity, left ventricular ejection fraction and left ventricular mass, cholesterol levels, systolic- and diastolic blood pressure, estimated glomerular filtration rate, study drug and body mass index, respectively baseline and serial values (based on annual reexamination).

Results-4 Baseline EKG LVH by CVDP and Rate of Heart Failure Serial Measures of EKG LVH by CVDP and Rate of Heart Failure Unadjusted HR; 4.2 (2.1 – 8.2), p<0.001 Adjusted HR*; 1.8 (0.8 – 4.2), p=0.18 Unadjusted HR; 6.7 (3.4 – 13.0), p<0.001 Adjusted HR*; 3.7 (1.6 – 8.6), p=0.002 * Adjusted for age, gender, echocardiographic peak aortic jet velocity, left ventricular ejection fraction and left ventricular mass, cholesterol levels, systolic- and diastolic blood pressure, estimated glomerular filtration rate, study drug and body mass index, respectively baseline and serial values (based on annual reexamination).

Results-5 Incidence of Heart Failure in Patients with and without Baseline Electrocardiographic Left Ventricular Hypertrophy. No. at risk No ECG LVH 1,092 1,080 1,055 1,028 996 +LVH by SL 189 188 183 177 172 +LVH by CVDP 151 147 142 134 125 +LVH by SL and CVDP 67 63 69 58 55

Results-6 Incidence of Cardiovascular Death According to Serial Measures of Electrocardiographic Left Ventricular Hypertrophy. No. at risk No ECG LVH 1,092 990 943 173 761 +LVH by SL 189 177 166 32 132 +LVH by CVDP 151 155 173 28 164 +LVH by SL and CVDP 67 70 67 16 61

Discussion In asymptomatic mild-to-moderate AS with preserved LVEF, additional electrocardiographic strain and LVH was despite similar AS severity associated with poor prognosis. Possible mechanisms: Electrocardiographic repolarization abnormalities are associated with adverse impact of AS on LV structure and function. Increased myocyte volume may lead to abnormal repolarization.

Conclusion Low-cost and widely available measures of electrocardiographic LVH and strain may assist the clinician in identifying asymptomatic AS patients with poor prognosis.

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