1. 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.

2. 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

3. 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

4. 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.

5. 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

6. 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

7. 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

8. 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*

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).

10. 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).

11. 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).

12. Results-5
Incidence of Heart Failure in Patients with and without Baseline Electrocardiographic Left Ventricular Hypertrophy.
No. at risk
No ECG LVH , , , ,
+LVH by SL
+LVH by CVDP
+LVH by SL and CVDP

13. Results-6
Incidence of Cardiovascular Death According to Serial Measures of Electrocardiographic Left Ventricular Hypertrophy.
No. at risk
No ECG LVH ,
+LVH by SL
+LVH by CVDP
+LVH by SL and CVDP

14. 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.

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

16. Thank You!