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Predictors of Death and Occurrence of Appropriate Implantable Defibrillator Therapies in Patients With Ischemic Cardiomyopathy
Predictors of Death and Occurrence of Appropriate Implantable Defibrillator Therapies in Patients With Ischemic Cardiomyopathy Arnold C.T. Ng, MBBSa,†, Matteo Bertini, MDa,†, C. Jan Willem Borleffs, MDa, Victoria Delgado, MDa, Eric Boersma, PhDb, Sebastiaan R.D. Piers, MSa, Joep Thijssen, MDa, Gaetano Nucifora, MDa, Miriam Shanks, MDa, See Hooi Ewe, MBBSa, Mauro Biffi, MDc, Nico R.L. van de Veire, MD, PhDa, Dominic Y. Leung, MBBS, PhDd, Martin J. Schalij, MD, PhDa, and Jeroen J. Bax, MD, PhDa,* Most patients with chronic ischemia and an implantable cardiac defibrillator (ICD) for primary prevention do not experience therapies for ventricular arrhythmias on follow-up. The present study aimed to identify independent clinical, electrocardiographic, and echocardiographic predictors of death and occurrence of ICD therapy in patients with chronic ischemic cardiomyopathy and ICD for primary prevention. A total of 424 patients with chronic ischemic cardiomyopathy, ejection fraction <35%, and New York Heart Association (NYHA) class >II were recruited. All patients underwent echocardiography before ICD insertion. Primary outcome was all-cause mortality; secondary outcome was occurrence of appropriate ICD therapy on follow-up. Primary and secondary outcomes occurred in 84 and 95 patients, respectively. Patients who died were more likely to have diabetes (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.00 to 2.79, p ⴝ 0.049), higher NYHA class (HR 1.96, 95% CI 1.15 to 3.33, p ⴝ 0.013), lower peri-infarct strain on echocardiogram (HR 1.25, 95% CI 1.07 to 1.46, p ⴝ 0.005), and lower glomerular filtration rate (HR 1.01, 95% CI 1.00 to 1.03, p ⴝ 0.022). Only peri-infarct strain (HR 1.22, 95% CI 1.09 to 1.36, p <0.001) predicted the occurrence of ICD therapy on follow-up. In conclusion, in chronic ischemic patients with an ICD for primary prevention, the presence of diabetes, renal dysfunction, higher NYHA class, and impaired peri-infarct zone function were predictors of all-cause mortality. In contrast, only impaired peri-infarct zone function determined the occurrence of appropriate ICD therapy on follow-up. © 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;106:1566 –1573) Despite a decrease in the rate of death from cardiovascular diseases over recent decades, annual mortality rate remains high in patients with previous myocardial infarction and left ventricular (LV) dysfunction.1 A significant proportion of all deaths in patients with chronic ischemic cardiomyopathy is due to pump failure and sudden cardiac death due to malignant ventricular arrhythmias arising from the peri-infarct zone.2,3 Although prophylactic implantable cardiac defibrillator (ICD) therapy has been shown to improve survival, prognostic markers for increased risk of death after insertion of ICD are unclear. Based on current guideline selection criteria, up to 35% of all patients underwent appropriate ICD therapies for ventricular arrhythmias by 3-year follow-up.4 Thus, insights into the mechanisms
a
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands; bErasmus Medical Center, Thoraxcenter Rotterdam, Rotterdam, The Netherlands; cDepartment of Cardiology, University of Bologna, Bologna, Italy; and dDepartment of Cardiology, University of New South Wales, Sydney, New South Wales, Australia. Manuscript received July 5, 2010; revised manuscript received and accepted July 21, 2010. *Corresponding author: Tel: 31-71-526-2020; fax: 31-71-526-6809. E-mail address: [email protected] (J.J. Bax). † Dr Ng and Dr Bertini contributed equally and should be considered joint first authors.
0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.07.029
underlying lethal postinfarct arrhythmias are of major importance and a better risk stratification tool is needed to identify “higher-risk” patients.5 Recent studies have demonstrated the ability of contrast-enhanced cardiac magnetic resonance to quantify the extent and function of the myocardium in the peri-infarct zone to predict mortality and occurrence of ventricular arrhythmias on follow-up.6 – 8 With advances in echocardiographic deformation imaging techniques such as 2-dimensional speckle tracking, similar site-specific quantifications of regional myocardial function in the infarct, peri-infarct, and remote zones can be rapidly performed semiautomatically. Therefore, the aim of the present prospective, single-blinded, observational study was to identify independent clinical, electrocardiographic (ECG), and echocardiographic determinants of mortality and occurrence of appropriate ICD therapy for ventricular arrhythmias in patients with chronic ischemic cardiomyopathy who received an ICD for primary prevention. Methods Patients with chronic ischemic cardiomyopathy were eligible for inclusion in the study if they had previous myocardial infarction ⬎40 days previously, New York Heart Association (NYHA) heart failure functional class ⱖII with optimal medical therapy, and LV ejection fraction ⱕ35%. All patients were referred for ICD implantation for primary www.ajconline.org
Coronary Artery Disease/Predictors of Death and ICD Therapies
prevention as recommended by American College of Cardiology and American Heart Association guidelines.9 Exclusion criteria included atrial fibrillation, history of surgical ventricular reconstruction, or electrophysiologic ventricular tachycardia ablation. All patients underwent an extensive baseline history and physical examination, 12-lead electrocardiography, and transthoracic echocardiography before ICD implantation. Baseline clinical variables recorded included NYHA functional class, cardiac risk factors, medications, and glomerular filtration rates (GFRs) calculated by the Modification of Diet in Renal Disease formula as recommended by the National Kidney Foundation, Kidney Disease Outcomes Quality Initiative Guidelines.10 Baseline ECG variables recorded included heart rate, PR interval, QRS duration, and corrected QT interval calculated by the Bazett formula (corrected QT interval ⫽ QT interval/[RR interval]½). Baseline echocardiographic variables recorded included LV volumes, ejection fraction, wall motion score index, and myocardial strain in the infarct, peri-infarct, and remote zones. All baseline clinical and ECG variables were collected by independent observers blinded to echocardiographic results. Similarly, all echocardiographic analyses were performed by separate independent observers blinded to clinical and ECG results. To ensure blinding, clinical/ECG and echocardiographic databases were kept in separate password-protected computers until merging for final data analyses. All patients were prospectively followed after ICD implantation for occurrence of death and appropriate ICD therapies due to ventricular tachycardia/fibrillation treated with antitachycardia pacing or shocks. From the various clinical, ECG, and echocardiographic variables recorded, independent determinants of all-cause mortality and occurrence of appropriate ICD therapies for ventricular tachycardia/fibrillation were identified. Transthoracic echocardiography was performed with patients at rest in the left lateral decubitus position and with a commercially available ultrasound transducer and equipment (M4S probe, Vivid 7, GE-Vingmed, Horten, Norway). All transthoracic echocardiographies were performed before ICD insertions and all images were digitally stored on hard disks for off-line analysis (EchoPAC 7.0.0, GE-Vingmed). A complete 2-dimensional, color, pulse-wave, and continuous-wave Doppler echocardiographic examination was performed.11,12 LV end-diastolic volume index and endsystolic volume index were calculated using the Simpson biplane method of disks and corrected for body surface area.13 LV ejection fraction was calculated and expressed as a percentage. In the present study, global and segmental longitudinal LV myocardial functions were determined by 2-dimensional speckle tracking strain analyses. To quantify global and segmental LV longitudinal strains, 2-dimensional speckle tracking analyses were performed on standard routine gray-scale images of apical 2-, 3-, and 4-chamber views. During analysis, the endocardial border was manually traced at end-systole and the region-of-interest width adjusted to include the entire myocardium. The software then automatically tracks the myocardium and accepts segments of good tracking quality and rejects poorly tracked segments, and allows the observer to manually over-ride its
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Figure 1. Graphic representation of a 17-segment polar map model that was automatically generated by 2-dimensional speckle tracking echocardiography. Three left ventricular segments (apical lateral, midlateral, and midposterior) were classified as infarct segments as defined by a segmental longitudinal strain ⬎⫺5%. The peri-infarct segments were the basal posterior, basal lateral, midinferior, mild anterior, apical inferior, apical anterior, and apical cap; remote segments were all other segments not defined as infarct or peri-infarct segments. ANT ⫽ anterior wall; ANT_SEPT ⫽ antero-septal wall; INF ⫽ inferior wall; LAT ⫽ lateral wall; POST ⫽ posterior wall; SEPT ⫽ septal wall.
decisions based on visual assessments of tracking quality. Results of LV longitudinal strain analysis were automatically displayed as a 17-segment polar map model with 17 segmental/regional strain values and a mean global strain value for the entire left ventricle. A previous study had demonstrated a segmental longitudinal strain value ⬎⫺4.5% as the optimal cut-off value to identify transmural scar tissue on contrast-enhancement cardiac magnetic resonance.14 Because EchoPAC displays only segmental strain values rounded to whole numbers in the polar map and to increase clinical utility, the optimal longitudinal strain cutoff value to define transmural scar was rounded to the nearest whole number of ⫺5%. Using the 17-segment model, an infarct segment was defined as a longitudinal strain value ⬎⫺5%. A peri-infarct segment was defined as immediately adjacent to an infarct segment. A remote segment was defined as any segment that was not an infarct or peri-infarct segment. Mean longitudinal strains of the infarct, peri-infarct, and remote zones were then manually averaged (Figure 1). Previous work has reported intra- and interobserver variabilities for longitudinal strain analysis in our laboratory as mean absolute differences ⫾1 SD of 1.2 ⫾ 0.5% and 0.9 ⫾ 1.0%, respectively.15 All deaths were also classified as sudden cardiac death, nonsudden cardiac death, and noncardiac death. Sudden cardiac death was defined as occurring within minutes after onset of acute symptoms, resulting from a documented cardiac arrhythmia, or was not witnessed and occurring unexpectedly without recognizable causes.
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Table 1 Baseline characteristics of patients Variable
Age (years) Median Interquartile range Men Body mass index (kg/m2) Median Interquartile range Body surface area (m2) Median Interquartile range New York Heart Association heart failure class II III and IV Hypertension Hyperlipidemia Diabetes mellitus Current smoker Family history ischemic heart disease Systolic blood pressure (mm Hg) Median Interquartile range Diastolic blood pressure (mm Hg) Median Interquartile range Medication at baseline Antiplatelets Anticoagulants  Blocker Angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker Calcium channel blocker Sotalol Amiodarone Diuretic Nitrate Statin Device implanted at study entry Implantable cardiac defibrillator plus cardiac resynchronization therapy Implantable cardiac defibrillator alone
Total Population (n ⫽ 424)
Primary Outcome
Secondary Outcome
Died (n ⫽ 84)
Alive (n ⫽ 340)
p Value
ICD Therapy (n ⫽ 95)
No ICD Therapy (n ⫽ 329)
p Value
68.5 60.6–75.3 88.4%
70.8 63.6–76.4 91.7%
68.1 59.9–74.7 87.6%
0.046
69.0 63.0–75.6 88.4%
68.1 60.2–75.0 88.4%
0.33
26.0 24.1–28.7
25.7 23.1–29.0
26.0 24.4–28.7
0.14
27.6 24.7–29.7
25.5 24.0–28.4
0.002
1.99 1.84–2.11
1.95 1.80–2.07
1.99 1.85–2.12
0.17
2.02 1.93–2.14
1.98 1.83–2.10
0.019
32.3% 67.7% 32.8% 69.7% 27.7% 21.4% 38.3%
21.4% 78.6% 34.5% 69.7% 40.7% 22.1% 42.3%
35.0% 65.0% 32.4% 69.7% 24.6% 21.3% 37.3%
32.6% 67.4% 36.8% 64.9% 20.4% 27.2% 43.7%
32.2% 67.8% 31.6% 71.2% 29.8% 19.7% 36.7%
120 110–140
115 103–130
123 110–140
0.006
123 108–140
120 110–138
0.84
73 65–81
70 64–80
75 65–83
0.026
75 69–83
71 65–80
0.09
48.3% 60.7% 65.9% 85.5%
39.3% 66.7% 64.3% 81.0%
50.6% 59.2% 66.3% 86.7%
0.083 0.26 0.83 0.24
42.1% 66.3% 64.2% 87.4%
50.2% 59.0% 66.4% 85.0%
0.21 0.25 0.79 0.68
9.2% 9.2% 16.8% 83.2% 25.8% 81.5%
9.5% 7.1% 22.6% 88.1% 32.1% 76.2%
9.2% 9.8% 15.4% 82.0% 24.3% 82.8%
10.5% 11.6% 14.7% 85.3% 28.4% 82.1%
8.9% 8.6% 17.4% 82.6% 25.1% 81.3%
0.77 0.49 0.64 0.64 0.60 0.99
61.6%
70.2%
59.4%
62.1%
61.4%
⬎0.99
38.4%
29.8%
40.6%
37.9%
38.6%
0.40
⬎0.99
0.024
ICD therapies were classified as appropriate when they occurred in response to ventricular tachycardia or ventricular fibrillation that was treated with antitachycardia pacing or shocks. These were documented from the ICD device interrogation printouts and confirmed by independent clinical cardiologists blinded to results from the present study. Time to appropriate ICD therapies were recorded from the ICD device interrogation printouts. The primary outcome was death from any cause. The secondary outcome was occurrence of appropriate, successful ICD therapy for ventricular tachycardia/fibrillation. All continuous variables were not of Gaussian distribution as tested by the Kolmogorov-Smirnov test and were therefore presented as median and interquartile range. Categorical variables were presented as frequencies and percentages and were compared using chi-square test with Yates correction. Mann-Whitney U test was used to com-
0.80 ⬎0.99 0.005 ⬎0.99 0.49
⬎0.99 0.60 0.16 0.24 0.18 0.21 0.089
⬎0.99
0.41 0.38 0.10 0.17 0.29
pare 2 groups of unpaired continuous variables. Cumulative event rates from time of ICD insertion were calculated using the Kaplan-Meier method and all patients were right censored.16 All patients who underwent an appropriate ICD therapy (secondary end point) and who subsequently died were also captured in the secondary end point. Log-rank tests for time-to-event data with respect to the primary and secondary outcomes were used for statistical comparison between 2 patient groups dichotomized based on median peri-infarct strain value. Multivariate Cox proportional-hazards models were constructed to identify independent clinical, ECG, and echocardiographic determinants of the primary (all-cause mortality) and secondary (occurrence of appropriate ICD therapies for ventricular tachycardia/ fibrillation) outcomes with significant univariate variables (p ⬍0.05) entered as covariates using the stepwise backward likelihood ratio selection method.17 ICD versus ICD
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Table 2 Baseline investigations of patients Variable
Hemoglobin (g/dl) Median Interquartile range Serum sodium (mmol/L) Median Interquartile range Estimated glomerular filtration rate (ml/min/1.73 m2) Median Interquartile range Electrocardiogram at baseline Heart rate (beats/min) Median Interquartile range PR interval (ms) Median Interquartile range QRS duration (ms) Median Interquartile range Corrected QT interval (ms) Median Interquartile range Echocardiogram at baseline Wall motion score index Median Interquartile range Left ventricular ejection fraction (%) Median Interquartile range Left ventricular end-diastolic volume index (ml/m2) Median Interquartile range Left ventricular end-systolic volume index (ml/m2) Median Interquartile range Global left ventricular longitudinal strain (%) Median Interquartile range Infarct zone longitudinal strain (%) Median Interquartile range Peri-infarct zone longitudinal strain (%) Median Interquartile range Remote zone longitudinal strain (%) Median Interquartile range
Total Population (n ⫽ 424)
Primary Outcome
Secondary Outcome
Died (n ⫽ 84)
Alive (n ⫽ 340)
p Value
ICD Therapy (n ⫽ 95)
No ICD Therapy (n ⫽ 329)
p Value
13.8 12.3–14.7
13.9 12.1–14.7
13.7 12.4–14.7
0.44
13.9 12.4–14.8
13.7 12.3–14.7
0.84
141 138–142
140 138–142
141 138–142
0.61
141 138–142
140 138–142
0.84
67.1 51.9–82.1
57.1 42.9–67.9
70.3 54.5–84.6
⬍0.001
67.2 50.8–78.5
67.0 52.1–83.3
0.29
70 61–81
72 63–84
69 60–80
0.058
73 63–83
69 60–80
0.021
178 156–200
184 160–216
176 156–196
0.083
178 157–194
178 156–200
0.67
131 106–162
144 118–170
128 104–160
0.016
136 116–166
130 105–161
0.099
450 425–472
451 434–478
448 424–472
0.12
450 423–475
450 426–472
0.87
1.84 1.56–2.19
1.97 1.63–2.19
1.81 1.56–2.13
0.078
1.88 1.69–2.25
1.81 1.56–2.19
0.20
27.0 21.0–32.0
26.0 18.0–31.0
27.5 21.0–32.0
0.21
26.0 20.0–30.0
27.0 21.0–32.9
0.091
94.1 73.8–115.8
97.1 70.6–126.5
93.4 74.3–112.9
0.60
98.3 78.3–126.1
92.3 72.5–111.3
0.081
68.7 52.0–87.9
69.3 50.0–100.1
68.7 52.0–84.2
0.46
73.9 56.7–96.5
68.1 51.0–83.1
0.042
⫺8.6 ⫺6.0 to ⫺10.5
⫺7.3 ⫺5.2 to ⫺9.5
⫺8.8 ⫺6.3 to ⫺10.7
0.001
⫺7.8 ⫺5.7 to ⫺10.1
⫺8.7 ⫺6.2 to ⫺10.6
0.073
⫺0.9 0.8 to ⫺2.8
⫺1.3 0.4 to ⫺3.3
⫺0.8 1.0 to ⫺2.7
0.051
⫺0.9 0.7 to ⫺2.9
⫺0.9 1.0 to ⫺2.8
0.65
⫺9.89 ⫺8.8 to ⫺11.3
⫺9.3 ⫺8.3 to ⫺10.5
⫺10.0 ⫺8.8 to ⫺11.7
0.001
⫺9.4 ⫺8.4 to ⫺10.7
⫺10.0 ⫺8.9 to ⫺11.6
0.003
⫺12.8 ⫺10.7 to ⫺15.3
⫺12.0 ⫺10.0 to ⫺14.1
⫺13.0 ⫺10.9 to ⫺15.5
0.041
⫺12.6 ⫺10.9 to ⫺15.0
⫺12.8 ⫺10.7 to ⫺15.4
0.57
with cardiac resynchronization therapy was also forced into the Cox proportional-hazards models as a factor to determine if there was a difference in all-cause mortality and occurrence of appropriate ICD therapies between the 2 groups. Cox proportional-hazards models were then used to estimate hazard ratios (HRs) and 95% confidence intervals
(CIs) for those independent variables. To avoid multicollinearity between univariate predictors, a correlation coefficient ⬍0.7 (corresponding to a tolerance ⬎0.5) was set. A 2-tailed p value ⬍0.05 was considered statistically significant. All statistical analyses were performed using SPSS 16 for Windows (SPSS, Inc., Chicago, Illinois).
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Results Of the 444 patients enrolled in the study, adequate echocardiographic analyses were feasible in 424 patients (95.5%) and constituted the final study population. Median age was 68.5 years (interquartile range 60.6 to 75.3), and 375 patients were men (88.4%). All patients received an ICD for primary prevention. ICD combined with cardiac resynchronization therapy was implanted in 261 patients (61.6%). All patients underwent complete coronary revascularization before ICD implantation. All baseline clinical, ECG, and echocardiographic variables are presented in Tables 1 and 2. Most patients (67.7%) were in NYHA functional class III or IV. Median QRS duration was 131 ms (interquartile range 106 to 162) and median LV ejection fraction was 27.0% (interquartile range 21.0 to 32.0). Median follow-up duration for the entire study population was 24.2 months (interquartile range 14.6 to 42.0). In total 84 patients (19.8%) died during the study duration and median time to death was 15.1 months (interquartile range 7.7 to 28.1). Causes of death were sudden cardiac death in 12%, nonsudden cardiac death in 63%, and noncardiac death in 25%. Of patients who died, 77% did not undergo any appropriate ICD therapies from the time of ICD implantation to time of death. In total 95 patients (22.4%) underwent appropriate, successful ICD therapy due to ventricular tachycardia/fibrillation during the study duration. Of these patients, the first episode of ventricular arrhythmia was terminated by antitachycardia pacing alone in 56 patients (58.9%), whereas 39 patients (41.1%) received antitachycardia pacing followed by shock or shock alone. Median time to first occurrence of appropriate, successful ICD was 10.5 months (interquartile range 5.4 to 24.9). Only 20.0% of patients with previous appropriate, successful ICD therapy subsequently died during the study duration. Similarly, 20% of these were classified as sudden cardiac death, 60% were classified as cardiac death, and 20% were classified as noncardiac death. Differences in baseline clinical, ECG, and echocardiographic variables between patients who died and patients who survived are presented in Tables 1 and 2. Patients who died were more likely to be older (p ⫽ 0.046), diabetic (p ⫽ 0.005), in a higher NYHA functional class (p ⫽ 0.024), have lower systolic (p ⫽ 0.006) and diastolic (p ⫽ 0.026) blood pressures, and a lower GFR (p ⬍0.001). In addition, they had a wider QRS duration (p ⫽ 0.016). Moreover, they had greater impairment of global longitudinal strain (p ⫽ 0.001), peri-infarct zone longitudinal strain (p ⫽ 0.001), and remote zone longitudinal strain (p ⫽ 0.041). There were no significant differences in rates of cardiac resynchronization therapy, use of cardiac medications, LV volumes, or LV ejection fraction. When the patient population was dichotomized based on median peri-infarct zone longitudinal strain, a cumulative 6%, 11%, and 13% of patients with less impaired periinfarct zone longitudinal strain died by 1-, 2-, and 3-year follow-ups, respectively. In contrast, a respective 8%, 15%, and 19% of patients with more impaired peri-infarct zone
Figure 2. Kaplan-Meier estimates of (A) primary and (B) secondary outcomes. (A) Probability of primary outcome (all-cause mortality) differed significantly between the 2 groups dichotomized based on the median peri-infarct zone longitudinal strain value of 9.9% (chi-square 4.0). (B) Probability of secondary outcome (occurrence of appropriate, successful implantable cardiac defibrillator therapy for ventricular tachycardia/fibrillation) between the 2 groups dichotomized based on median peri-infarct zone longitudinal strain value (chi-square 7.1).
longitudinal strain died during the same period (p ⫽ 0.046, log-rank test; Figure 2). To identify independent predictors of death on followup, significant univariate predictors listed in Tables 1 and 2 with a p value ⬍0.05 (age, NYHA class, diabetes, systolic blood pressure, GFR, QRS duration, global LV longitudinal strain, peri-infarct zone longitudinal strain, and remote zone longitudinal strain) were entered into the Cox proportionalhazard model as covariates. ICD versus ICD with cardiac resynchronization therapy was also forced into the Cox proportional-hazards models as a factor to determine if there
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Figure 3. (Left) A patient with previous anterior myocardial infarction and a left ventricular ejection fraction of 33%. Mean infarct, peri-infarct, and remote zone longitudinal strains were 0.2%, ⫺13.7%, and ⫺19.2%, respectively. The patient did not develop any events after a follow-up duration of 32 months. (Right) A patient with previous inferior myocardial infarction and a left ventricular ejection fraction of 35%. Mean infarct, peri-infarct, and remote zone longitudinal strains were 0.5%, ⫺8.8%, and ⫺12.6%, respectively. The patient had the first episode of appropriate implantable cardiac defibrillator therapy at 9 months after implantable cardiac defibrillator insertion. Abbreviations as in Figure 1.
was a difference in all-cause mortality between the 2 groups. On multivariate analysis, presence of diabetes (hazard ratio [HR] 1.67, 95% CI 1.00 to 2.79, p ⫽ 0.049), higher NYHA functional class (HR 1.96, 95% CI 1.15 to 3.33, p ⫽ 0.013), every 1% absolute worsening of peri-infarct zone longitudinal strain (HR 1.25, 95% CI 1.07 to 1.46, p ⫽ 0.005), and every 10-ml/min/1.73 m2 decrease in GFR (HR 1.15, 95% CI 1.02 to 1.31, p ⫽ 0.022) were independently associated with an increased all-cause mortality on followup. There was no difference in all-cause mortality between ICD and ICD with cardiac resynchronization therapy after adjusting for differences in baseline characteristics. Therefore, considering that the peri-infarct zone longitudinal strain in the present study was ⫺6% to ⫺17%, the odds that a patient with a peri-infarct zone strain value of ⫺6% dying was approximately 11.5 times that of a patient with a periinfarct zone strain value of ⫺17%. Differences in baseline clinical, ECG, and echocardiographic variables between patients who underwent appropriate, successful ICD therapies for ventricular tachycardia/ fibrillation and those who did not are presented in Tables 1 and 2. Patients with appropriate ICD therapies were more likely to have a higher body mass index (p ⫽ 0.002), higher heart rate (p ⫽ 0.021), larger LV end-systolic volume index (p ⫽ 0.042), and greater impairment of peri-infarct zone longitudinal strain (p ⫽ 0.003). Similarly, when the patient population was dichotomized based on median peri-infarct zone longitudinal strain, a cumulative 8%, 11%, and 14% of patients with less impaired peri-infarct zone longitudinal strain underwent appropriate ICD therapies due to ventricular tachycardia/fibrillation by 1-, 2-, and 3-year follow-ups, respectively. In contrast, a respective 15%, 21%, and 25% of patients with more impaired peri-infarct zone longitudinal strain underwent appropriate ICD therapy during the same period (p ⫽ 0.008, log-rank test; (Figure 2).
Likewise, significant univariate predictors listed in Tables 1 and 2 with a p value ⬍0.05 (body mass index, heart rate, LV end-systolic volume index, and peri-infarct zone longitudinal strain) were entered into the Cox proportionalhazard model as covariates to identify independent determinants of occurrence of appropriate, successful ICD therapy for ventricular tachycardia/fibrillation. ICD versus ICD with cardiac resynchronization therapy was also forced into the Cox proportional-hazards models as a factor to determine if there was a difference in the occurrence of appropriate ICD therapies between the 2 groups. On multivariate analysis, only every 1% absolute worsening of peri-infarct zone longitudinal strain (HR 1.22, 95% CI 1.09 to 1.36, p ⬍0.001) was independently associated with an increased risk of having appropriate ICD therapy on follow-up. There was no difference in occurrence of appropriate ICD therapies for ventricular arrhythmias between ICD and ICD with cardiac resynchronization therapy after adjusting for differences in baseline characteristics. Similarly, considering that the peri-infarct zone longitudinal strain was ⫺6% to ⫺17% in the present study, the odds that a patient with a periinfarct zone strain value of ⫺6% having an appropriate ICD therapy for ventricular arrhythmia on follow-up was approximately 8.6 times that of a patient with a peri-infarct zone strain value of ⫺17%. Figure 3 shows examples of 2 patients who did and did not have appropriate ICD therapies on follow-up. Discussion The present study demonstrated that in patients with ischemic cardiomyopathy who received ICD for primary prevention, the independent determinants of all-cause mortality were diabetes, renal function, NYHA functional class, and peri-infarct strain. In contrast, peri-infarct strain was the
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only determinant of occurrence of appropriate ICD therapies for ventricular arrhythmias during follow-up. Multicenter studies such as the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) have shown that mortality rate in patients with heart failure is high despite optimal medical therapy.1 Determining the prognosis in heart failure is complex and numerous independent predictors of adverse outcomes have been reported.18,19 Often, simple clinical and laboratory parameters such as advanced age, hypotension, prolonged QRS duration, and hyponatremia are strong adverse prognosticators. For example, subanalysis of the MADIT II showed that advanced age, higher NYHA functional class, prolonged QRS duration, impaired renal function, and presence of atrial fibrillation were associated with an increased all-cause mortality on follow-up.18,19 In the present study, patients with atrial fibrillation were excluded because the variable RR interval prevents generation of the 17-segment polar map for segmental longitudinal strain quantification. However, NYHA functional class and impaired renal function were similarly independently associated with an increased all-cause mortality risk. In addition, diabetes was identified as an independent risk factor. Diabetes mellitus is often rated as an equivalent of coronary artery disease, and diabetic patients have a high risk for cardiovascular morbidity and mortality. The risk of death is 2 to 3 times higher in diabetic patients compared to nondiabetics, and there is a strong association between diabetes and heart failure.20,21 Previous studies have demonstrated that patients with diabetes, ischemic heart disease, and heart failure have a dismal prognosis.22 In diabetic patients, there is often concomitant presence of hyperglycemia, obesity, metabolic syndrome, dyslipidemia, hypertension, and renal dysfunction. The resulting synergistic interplay among these factors leads to subsequent myocardial hypertrophy, autonomic neuropathy, accelerated atherosclerosis, ischemia, and eventual myocardial dysfunction with replacement fibrosis, thus contributing to an increased cardiovascular morbidity and mortality.23 The present study also compared patients who received an ICD to those who received an ICD and cardiac resynchronization therapy and found similar survival between the 2 groups. This result was similar to the Cardiac-Resynchronization Therapy for the Prevention of Heart-Failure Events (MADIT-CRT) by the MADIT-CRT trial investigators.24 The combination of ICD and cardiac resynchronization therapy was significantly associated with a lower primary end point (defined as all-cause mortality and heart failure) compared to ICD alone. However, subgroup analysis demonstrated that the primary end point was primarily driven by a decrease in nonfatal heart failure, whereas there was no difference in all-cause mortality between the 2 groups.24 Echocardiographic assessment of LV function is usually the first diagnostic imaging test performed for heart failure. Although LV volumes and LV ejection fraction are long known to be strong predictors of mortality after myocardial infarction25 and a decreased LV ejection fraction is an eligibility criterion for ICD implantation, they have a progressive decrease in discriminatory value over time for identifying patients with chronic ischemic cardiomyopathy who would benefit most from this expensive and invasive
ICD treatment strategy.26 Therefore, alternative noninvasive imaging strategies may help to refine risk assessment before and after insertions of ICD and maximize the benefit–risk ratio and cost-effectiveness of ICD therapy. Yan et al7 studied 144 patients after myocardial infarction with contrast-enhanced cardiac magnetic resonance and demonstrated that extent of peri-infarct zone independently predicted all-cause (HR 1.42, p ⫽ 0.005) and cardiovascular (HR 1.49, p ⫽ 0.01) mortalities. Similarly, the present study demonstrated greater impairments of baseline global and regional myocardial strains in the infarct, peri-infarct, and remote zones in patients who died. Multivariate analysis showed superior predictive value of peri-infarct strain over that of infarct and remote zones, highlighting the prognostic value of characterizing peri-infarct zone myocardial function. As such, the present study demonstrated that the odds that a patient with a peri-infarct zone strain value of ⫺6% dying was approximately 11.5 times that of a patient with a peri-infarct zone strain value of ⫺17%. In the present study, the presence of ischemia contributing to an impaired peri-infarct strain cannot be excluded and may well contribute to an increased risk of having appropriate ICD therapy on follow-up. However, although specific tests for myocardial ischemia were not reported, all patients were referred by their primary care physicians to undergo appropriate coronary revascularization before ICD implantation as part of the study protocol and routine clinical practice. Furthermore, cardiac stress imaging tests have ⬍100% sensitivity and specificity for detection of myocardial ischemia.27 Therefore, the treatment strategy in the present study protocol is representative of current standard clinical practice. Current guidelines recommend ICD as a class I indication for patients with chronic ischemic cardiomyopathy, LV ejection fraction ⱕ35%, and NYHA functional class ⱖII on optimal medical therapy.9 Identification of diabetes, renal dysfunction, and impaired peri-infarct strain as adverse prognostic markers helps to further risk-stratify patients with chronic ischemic cardiomyopathy who had undergone ICD for primary prevention. In addition, the study provided mechanistic insight into the role of peri-infarct strain in determining the risk for death and occurrence of appropriate ICD therapy on follow-up. Future studies are needed to determine if interventions targeting these adverse risk factors can alter prognosis in this patient population. Furthermore, the role of peri-infarct strain in identifying “at-risk” patients may be explored in future studies on electrophysiologic ventricular tachycardia ablation and for patients with LV ejection fraction ⬎35% and thus not eligible for primary ICD prevention based on current guidelines. 1. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML. The Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877– 883. 2. de Luna AB, Coumel P, Leclercq JF. Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 157 cases. Am Heart J 1989;117:151–159. 3. Eckardt L, Haverkamp W, Johna R, Bocker D, Deng MC, Breithardt G, Borggrefe M. Arrhythmias in heart failure: current concepts of mechanisms and therapy. J Cardiovasc Electrophysiol 2000;11:106 – 117.
Coronary Artery Disease/Predictors of Death and ICD Therapies 4. Moss AJ, Greenberg H, Case RB, Zareba W, Hall WJ, Brown MW, Daubert JP, McNitt S, Andrews ML, Elkin AD, for the Multicenter Automatic Defibrillator Implantation Trial–II (MADIT-II) Research Group. Long-term clinical course of patients after termination of ventricular tachyarrhythmia by an implanted defibrillator. Circulation 2004;110:3760 –3765. 5. Myerburg RJ, Reddy V, Castellanos A. Indications for implantable cardioverter-defibrillators based on evidence and judgment. J Am Coll Cardiol 2009;54:747–763. 6. Fernandes VR, Wu KC, Rosen BD, Schmidt A, Lardo AC, Osman N, Halperin HR, Tomaselli G, Berger R, Bluemke DA, Marban E, Lima JAC. Enhanced infarct border Zone function and altered mechanical activation predict inducibility of monomorphic ventricular tachycardia in patients with ischemic cardiomyopathy. Radiology 2007;245:712– 719. 7. Yan AT, Shayne AJ, Brown KA, Gupta SN, Chan CW, Luu TM, Di Carli MF, Reynolds HG, Stevenson WG, Kwong RY. Characterization of the peri-infarct Zone by contrast-enhanced cardiac magnetic resonance imaging is a powerful predictor of post-myocardial infarction mortality. Circulation 2006;114:32–39. 8. Roes SD, Borleffs CJW, van der Geest RJ, Westenberg JJM, Marsan NA, Kaandorp TAM, Reiber JHC, Zeppenfeld K, Lamb HJ, De Roos A, Schalij MJ, Bax JJ. Infarct tissue heterogeneity assessed with contrast-enhanced MRI predicts spontaneous ventricular arrhythmia in patients with ischemic cardiomyopathy and implantable cardioverterdefibrillator. Circ Cardiovasc Imaging 2009;2:183–190. 9. Epstein AE, DiMarco JP, Ellenbogen KA, Mark Estes NA III, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. J Am Coll Cardiol 2008;51:2085–2105. 10. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis 2002;39(suppl):S1–S266. 11. Nishimura R, Miller FJ, Callahan M, Benassi R, Seward J, Tajik A. Doppler echocardiography: theory, instrumentation technique and application. Mayo Clin Proc 1985;60:321–343. 12. Tajik A, Seward J, Hagler D, Mair D, Lie J. Two dimensional realtime ultrasonic imaging of the heart and great vessels: technique, image orientation, structure identification and validation. Mayo Clin Proc 1978;53:271–303. 13. Mosteller RD. Simplified calculation of body-surface area. N Engl J Med 1987;317:1098. 14. Roes SD, Mollema SA, Lamb HJ, van der Wall EE, De Roos A, Bax JJ. Validation of echocardiographic two-dimensional speckle tracking longitudinal strain imaging for viability assessment in patients with
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chronic ischemic left ventricular dysfunction and comparison with contrast-enhanced magnetic resonance imaging. Am J Cardiol 2009;104:312–317. Ng ACT, Delgado V, Bertini M, van der Meer RW, Rijzewijk LJ, Shanks M, Nucifora G, Smit JWA, Diamant M, Romijn JA, De Roos A, Leung DY, Lamb HJ, Bax JJ. Findings from left ventricular strain and strain rate imaging in asymptomatic patients with type 2 diabetes mellitus. Am J Cardiol 2009;104:1398 –1401. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457– 481. Cox D. Regression models and life-tables. J R Stat Soc 1972;34:187– 220. Zareba W, Piotrowicz K, McNitt S, Moss AJ. Implantable cardioverter-defibrillator efficacy in patients with heart failure and left ventricular dysfunction (from the MADIT II population). Am J Cardiol 2005;95:1487–1491. Goldenberg I, Vyas AK, Hall WJ, Moss AJ, Wang H, He H, Zareba W, McNitt S, Andrews ML. Risk stratification for primary implantation of a cardioverter-defibrillator in patients with ischemic left ventricular dysfunction. J Am Coll Cardiol 2008;51:288 –296. Laakso M. Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes 1999;48:937–942. Thrainsdottir IS, Aspelund T, Thorgeirsson G, Gudnason V, Hardarson T, Malmberg K, Sigurdsson G, Ryden L. The association between glucose abnormalities and heart failure in the population-Based Reykjavik Study. Diabetes Care 2005;28:612– 616. de Groote P, Lamblin N, Mouquet F, Plichon D, McFadden E, Van Belle E, Bauters C. Impact of diabetes mellitus on long-term survival in patients with congestive heart failure. Eur Heart J 2004;25:656 – 662. Boudina S, Abel ED. Diabetic cardiomyopathy Revisited. Circulation 2007;115:3213–3223. Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, Estes NAM, Foster E, Greenberg H, Higgins SL, Pfeffer MA, Solomon SD, Wilber D, Zareba W. The MADIT-CRT Trial Investigators. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009;361:1329 –1338. White HD, Norris RM, Brown MA, Brandt PW, Whitlock RM, Wild CJ. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 1987; 76:44 –51. Solomon SD, Zelenkofske S, McMurray JJV, Finn PV, Velazquez E, Ertl G, Harsanyi A, Rouleau JL, Maggioni A, Kober L, White H, Van de Werf F, Pieper K, Califf RM, Pfeffer MA. The Valsartan in Acute Myocardial Infarction Trial (VALIANT) Investigators. Sudden death in patients with myocardial infarction and left ventricular dysfunction, heart failure, or both. N Engl J Med 2005;352:2581–2588. Schinkel AFL, Bax JJ, Geleijnse ML, Boersma E, Elhendy A, Roelandt JRTC, Poldermans D. Noninvasive evaluation of ischaemic heart disease: myocardial perfusion imaging or stress echocardiography? Eur Heart J 2003;24:789 – 800.
a
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands; bErasmus Medical Center, Thoraxcenter Rotterdam, Rotterdam, The Netherlands; cDepartment of Cardiology, University of Bologna, Bologna, Italy; and dDepartment of Cardiology, University of New South Wales, Sydney, New South Wales, Australia. Manuscript received July 5, 2010; revised manuscript received and accepted July 21, 2010. *Corresponding author: Tel: 31-71-526-2020; fax: 31-71-526-6809. E-mail address: [email protected] (J.J. Bax). † Dr Ng and Dr Bertini contributed equally and should be considered joint first authors.
0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2010.07.029
underlying lethal postinfarct arrhythmias are of major importance and a better risk stratification tool is needed to identify “higher-risk” patients.5 Recent studies have demonstrated the ability of contrast-enhanced cardiac magnetic resonance to quantify the extent and function of the myocardium in the peri-infarct zone to predict mortality and occurrence of ventricular arrhythmias on follow-up.6 – 8 With advances in echocardiographic deformation imaging techniques such as 2-dimensional speckle tracking, similar site-specific quantifications of regional myocardial function in the infarct, peri-infarct, and remote zones can be rapidly performed semiautomatically. Therefore, the aim of the present prospective, single-blinded, observational study was to identify independent clinical, electrocardiographic (ECG), and echocardiographic determinants of mortality and occurrence of appropriate ICD therapy for ventricular arrhythmias in patients with chronic ischemic cardiomyopathy who received an ICD for primary prevention. Methods Patients with chronic ischemic cardiomyopathy were eligible for inclusion in the study if they had previous myocardial infarction ⬎40 days previously, New York Heart Association (NYHA) heart failure functional class ⱖII with optimal medical therapy, and LV ejection fraction ⱕ35%. All patients were referred for ICD implantation for primary www.ajconline.org
Coronary Artery Disease/Predictors of Death and ICD Therapies
prevention as recommended by American College of Cardiology and American Heart Association guidelines.9 Exclusion criteria included atrial fibrillation, history of surgical ventricular reconstruction, or electrophysiologic ventricular tachycardia ablation. All patients underwent an extensive baseline history and physical examination, 12-lead electrocardiography, and transthoracic echocardiography before ICD implantation. Baseline clinical variables recorded included NYHA functional class, cardiac risk factors, medications, and glomerular filtration rates (GFRs) calculated by the Modification of Diet in Renal Disease formula as recommended by the National Kidney Foundation, Kidney Disease Outcomes Quality Initiative Guidelines.10 Baseline ECG variables recorded included heart rate, PR interval, QRS duration, and corrected QT interval calculated by the Bazett formula (corrected QT interval ⫽ QT interval/[RR interval]½). Baseline echocardiographic variables recorded included LV volumes, ejection fraction, wall motion score index, and myocardial strain in the infarct, peri-infarct, and remote zones. All baseline clinical and ECG variables were collected by independent observers blinded to echocardiographic results. Similarly, all echocardiographic analyses were performed by separate independent observers blinded to clinical and ECG results. To ensure blinding, clinical/ECG and echocardiographic databases were kept in separate password-protected computers until merging for final data analyses. All patients were prospectively followed after ICD implantation for occurrence of death and appropriate ICD therapies due to ventricular tachycardia/fibrillation treated with antitachycardia pacing or shocks. From the various clinical, ECG, and echocardiographic variables recorded, independent determinants of all-cause mortality and occurrence of appropriate ICD therapies for ventricular tachycardia/fibrillation were identified. Transthoracic echocardiography was performed with patients at rest in the left lateral decubitus position and with a commercially available ultrasound transducer and equipment (M4S probe, Vivid 7, GE-Vingmed, Horten, Norway). All transthoracic echocardiographies were performed before ICD insertions and all images were digitally stored on hard disks for off-line analysis (EchoPAC 7.0.0, GE-Vingmed). A complete 2-dimensional, color, pulse-wave, and continuous-wave Doppler echocardiographic examination was performed.11,12 LV end-diastolic volume index and endsystolic volume index were calculated using the Simpson biplane method of disks and corrected for body surface area.13 LV ejection fraction was calculated and expressed as a percentage. In the present study, global and segmental longitudinal LV myocardial functions were determined by 2-dimensional speckle tracking strain analyses. To quantify global and segmental LV longitudinal strains, 2-dimensional speckle tracking analyses were performed on standard routine gray-scale images of apical 2-, 3-, and 4-chamber views. During analysis, the endocardial border was manually traced at end-systole and the region-of-interest width adjusted to include the entire myocardium. The software then automatically tracks the myocardium and accepts segments of good tracking quality and rejects poorly tracked segments, and allows the observer to manually over-ride its
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Figure 1. Graphic representation of a 17-segment polar map model that was automatically generated by 2-dimensional speckle tracking echocardiography. Three left ventricular segments (apical lateral, midlateral, and midposterior) were classified as infarct segments as defined by a segmental longitudinal strain ⬎⫺5%. The peri-infarct segments were the basal posterior, basal lateral, midinferior, mild anterior, apical inferior, apical anterior, and apical cap; remote segments were all other segments not defined as infarct or peri-infarct segments. ANT ⫽ anterior wall; ANT_SEPT ⫽ antero-septal wall; INF ⫽ inferior wall; LAT ⫽ lateral wall; POST ⫽ posterior wall; SEPT ⫽ septal wall.
decisions based on visual assessments of tracking quality. Results of LV longitudinal strain analysis were automatically displayed as a 17-segment polar map model with 17 segmental/regional strain values and a mean global strain value for the entire left ventricle. A previous study had demonstrated a segmental longitudinal strain value ⬎⫺4.5% as the optimal cut-off value to identify transmural scar tissue on contrast-enhancement cardiac magnetic resonance.14 Because EchoPAC displays only segmental strain values rounded to whole numbers in the polar map and to increase clinical utility, the optimal longitudinal strain cutoff value to define transmural scar was rounded to the nearest whole number of ⫺5%. Using the 17-segment model, an infarct segment was defined as a longitudinal strain value ⬎⫺5%. A peri-infarct segment was defined as immediately adjacent to an infarct segment. A remote segment was defined as any segment that was not an infarct or peri-infarct segment. Mean longitudinal strains of the infarct, peri-infarct, and remote zones were then manually averaged (Figure 1). Previous work has reported intra- and interobserver variabilities for longitudinal strain analysis in our laboratory as mean absolute differences ⫾1 SD of 1.2 ⫾ 0.5% and 0.9 ⫾ 1.0%, respectively.15 All deaths were also classified as sudden cardiac death, nonsudden cardiac death, and noncardiac death. Sudden cardiac death was defined as occurring within minutes after onset of acute symptoms, resulting from a documented cardiac arrhythmia, or was not witnessed and occurring unexpectedly without recognizable causes.
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Table 1 Baseline characteristics of patients Variable
Age (years) Median Interquartile range Men Body mass index (kg/m2) Median Interquartile range Body surface area (m2) Median Interquartile range New York Heart Association heart failure class II III and IV Hypertension Hyperlipidemia Diabetes mellitus Current smoker Family history ischemic heart disease Systolic blood pressure (mm Hg) Median Interquartile range Diastolic blood pressure (mm Hg) Median Interquartile range Medication at baseline Antiplatelets Anticoagulants  Blocker Angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker Calcium channel blocker Sotalol Amiodarone Diuretic Nitrate Statin Device implanted at study entry Implantable cardiac defibrillator plus cardiac resynchronization therapy Implantable cardiac defibrillator alone
Total Population (n ⫽ 424)
Primary Outcome
Secondary Outcome
Died (n ⫽ 84)
Alive (n ⫽ 340)
p Value
ICD Therapy (n ⫽ 95)
No ICD Therapy (n ⫽ 329)
p Value
68.5 60.6–75.3 88.4%
70.8 63.6–76.4 91.7%
68.1 59.9–74.7 87.6%
0.046
69.0 63.0–75.6 88.4%
68.1 60.2–75.0 88.4%
0.33
26.0 24.1–28.7
25.7 23.1–29.0
26.0 24.4–28.7
0.14
27.6 24.7–29.7
25.5 24.0–28.4
0.002
1.99 1.84–2.11
1.95 1.80–2.07
1.99 1.85–2.12
0.17
2.02 1.93–2.14
1.98 1.83–2.10
0.019
32.3% 67.7% 32.8% 69.7% 27.7% 21.4% 38.3%
21.4% 78.6% 34.5% 69.7% 40.7% 22.1% 42.3%
35.0% 65.0% 32.4% 69.7% 24.6% 21.3% 37.3%
32.6% 67.4% 36.8% 64.9% 20.4% 27.2% 43.7%
32.2% 67.8% 31.6% 71.2% 29.8% 19.7% 36.7%
120 110–140
115 103–130
123 110–140
0.006
123 108–140
120 110–138
0.84
73 65–81
70 64–80
75 65–83
0.026
75 69–83
71 65–80
0.09
48.3% 60.7% 65.9% 85.5%
39.3% 66.7% 64.3% 81.0%
50.6% 59.2% 66.3% 86.7%
0.083 0.26 0.83 0.24
42.1% 66.3% 64.2% 87.4%
50.2% 59.0% 66.4% 85.0%
0.21 0.25 0.79 0.68
9.2% 9.2% 16.8% 83.2% 25.8% 81.5%
9.5% 7.1% 22.6% 88.1% 32.1% 76.2%
9.2% 9.8% 15.4% 82.0% 24.3% 82.8%
10.5% 11.6% 14.7% 85.3% 28.4% 82.1%
8.9% 8.6% 17.4% 82.6% 25.1% 81.3%
0.77 0.49 0.64 0.64 0.60 0.99
61.6%
70.2%
59.4%
62.1%
61.4%
⬎0.99
38.4%
29.8%
40.6%
37.9%
38.6%
0.40
⬎0.99
0.024
ICD therapies were classified as appropriate when they occurred in response to ventricular tachycardia or ventricular fibrillation that was treated with antitachycardia pacing or shocks. These were documented from the ICD device interrogation printouts and confirmed by independent clinical cardiologists blinded to results from the present study. Time to appropriate ICD therapies were recorded from the ICD device interrogation printouts. The primary outcome was death from any cause. The secondary outcome was occurrence of appropriate, successful ICD therapy for ventricular tachycardia/fibrillation. All continuous variables were not of Gaussian distribution as tested by the Kolmogorov-Smirnov test and were therefore presented as median and interquartile range. Categorical variables were presented as frequencies and percentages and were compared using chi-square test with Yates correction. Mann-Whitney U test was used to com-
0.80 ⬎0.99 0.005 ⬎0.99 0.49
⬎0.99 0.60 0.16 0.24 0.18 0.21 0.089
⬎0.99
0.41 0.38 0.10 0.17 0.29
pare 2 groups of unpaired continuous variables. Cumulative event rates from time of ICD insertion were calculated using the Kaplan-Meier method and all patients were right censored.16 All patients who underwent an appropriate ICD therapy (secondary end point) and who subsequently died were also captured in the secondary end point. Log-rank tests for time-to-event data with respect to the primary and secondary outcomes were used for statistical comparison between 2 patient groups dichotomized based on median peri-infarct strain value. Multivariate Cox proportional-hazards models were constructed to identify independent clinical, ECG, and echocardiographic determinants of the primary (all-cause mortality) and secondary (occurrence of appropriate ICD therapies for ventricular tachycardia/ fibrillation) outcomes with significant univariate variables (p ⬍0.05) entered as covariates using the stepwise backward likelihood ratio selection method.17 ICD versus ICD
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Table 2 Baseline investigations of patients Variable
Hemoglobin (g/dl) Median Interquartile range Serum sodium (mmol/L) Median Interquartile range Estimated glomerular filtration rate (ml/min/1.73 m2) Median Interquartile range Electrocardiogram at baseline Heart rate (beats/min) Median Interquartile range PR interval (ms) Median Interquartile range QRS duration (ms) Median Interquartile range Corrected QT interval (ms) Median Interquartile range Echocardiogram at baseline Wall motion score index Median Interquartile range Left ventricular ejection fraction (%) Median Interquartile range Left ventricular end-diastolic volume index (ml/m2) Median Interquartile range Left ventricular end-systolic volume index (ml/m2) Median Interquartile range Global left ventricular longitudinal strain (%) Median Interquartile range Infarct zone longitudinal strain (%) Median Interquartile range Peri-infarct zone longitudinal strain (%) Median Interquartile range Remote zone longitudinal strain (%) Median Interquartile range
Total Population (n ⫽ 424)
Primary Outcome
Secondary Outcome
Died (n ⫽ 84)
Alive (n ⫽ 340)
p Value
ICD Therapy (n ⫽ 95)
No ICD Therapy (n ⫽ 329)
p Value
13.8 12.3–14.7
13.9 12.1–14.7
13.7 12.4–14.7
0.44
13.9 12.4–14.8
13.7 12.3–14.7
0.84
141 138–142
140 138–142
141 138–142
0.61
141 138–142
140 138–142
0.84
67.1 51.9–82.1
57.1 42.9–67.9
70.3 54.5–84.6
⬍0.001
67.2 50.8–78.5
67.0 52.1–83.3
0.29
70 61–81
72 63–84
69 60–80
0.058
73 63–83
69 60–80
0.021
178 156–200
184 160–216
176 156–196
0.083
178 157–194
178 156–200
0.67
131 106–162
144 118–170
128 104–160
0.016
136 116–166
130 105–161
0.099
450 425–472
451 434–478
448 424–472
0.12
450 423–475
450 426–472
0.87
1.84 1.56–2.19
1.97 1.63–2.19
1.81 1.56–2.13
0.078
1.88 1.69–2.25
1.81 1.56–2.19
0.20
27.0 21.0–32.0
26.0 18.0–31.0
27.5 21.0–32.0
0.21
26.0 20.0–30.0
27.0 21.0–32.9
0.091
94.1 73.8–115.8
97.1 70.6–126.5
93.4 74.3–112.9
0.60
98.3 78.3–126.1
92.3 72.5–111.3
0.081
68.7 52.0–87.9
69.3 50.0–100.1
68.7 52.0–84.2
0.46
73.9 56.7–96.5
68.1 51.0–83.1
0.042
⫺8.6 ⫺6.0 to ⫺10.5
⫺7.3 ⫺5.2 to ⫺9.5
⫺8.8 ⫺6.3 to ⫺10.7
0.001
⫺7.8 ⫺5.7 to ⫺10.1
⫺8.7 ⫺6.2 to ⫺10.6
0.073
⫺0.9 0.8 to ⫺2.8
⫺1.3 0.4 to ⫺3.3
⫺0.8 1.0 to ⫺2.7
0.051
⫺0.9 0.7 to ⫺2.9
⫺0.9 1.0 to ⫺2.8
0.65
⫺9.89 ⫺8.8 to ⫺11.3
⫺9.3 ⫺8.3 to ⫺10.5
⫺10.0 ⫺8.8 to ⫺11.7
0.001
⫺9.4 ⫺8.4 to ⫺10.7
⫺10.0 ⫺8.9 to ⫺11.6
0.003
⫺12.8 ⫺10.7 to ⫺15.3
⫺12.0 ⫺10.0 to ⫺14.1
⫺13.0 ⫺10.9 to ⫺15.5
0.041
⫺12.6 ⫺10.9 to ⫺15.0
⫺12.8 ⫺10.7 to ⫺15.4
0.57
with cardiac resynchronization therapy was also forced into the Cox proportional-hazards models as a factor to determine if there was a difference in all-cause mortality and occurrence of appropriate ICD therapies between the 2 groups. Cox proportional-hazards models were then used to estimate hazard ratios (HRs) and 95% confidence intervals
(CIs) for those independent variables. To avoid multicollinearity between univariate predictors, a correlation coefficient ⬍0.7 (corresponding to a tolerance ⬎0.5) was set. A 2-tailed p value ⬍0.05 was considered statistically significant. All statistical analyses were performed using SPSS 16 for Windows (SPSS, Inc., Chicago, Illinois).
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Results Of the 444 patients enrolled in the study, adequate echocardiographic analyses were feasible in 424 patients (95.5%) and constituted the final study population. Median age was 68.5 years (interquartile range 60.6 to 75.3), and 375 patients were men (88.4%). All patients received an ICD for primary prevention. ICD combined with cardiac resynchronization therapy was implanted in 261 patients (61.6%). All patients underwent complete coronary revascularization before ICD implantation. All baseline clinical, ECG, and echocardiographic variables are presented in Tables 1 and 2. Most patients (67.7%) were in NYHA functional class III or IV. Median QRS duration was 131 ms (interquartile range 106 to 162) and median LV ejection fraction was 27.0% (interquartile range 21.0 to 32.0). Median follow-up duration for the entire study population was 24.2 months (interquartile range 14.6 to 42.0). In total 84 patients (19.8%) died during the study duration and median time to death was 15.1 months (interquartile range 7.7 to 28.1). Causes of death were sudden cardiac death in 12%, nonsudden cardiac death in 63%, and noncardiac death in 25%. Of patients who died, 77% did not undergo any appropriate ICD therapies from the time of ICD implantation to time of death. In total 95 patients (22.4%) underwent appropriate, successful ICD therapy due to ventricular tachycardia/fibrillation during the study duration. Of these patients, the first episode of ventricular arrhythmia was terminated by antitachycardia pacing alone in 56 patients (58.9%), whereas 39 patients (41.1%) received antitachycardia pacing followed by shock or shock alone. Median time to first occurrence of appropriate, successful ICD was 10.5 months (interquartile range 5.4 to 24.9). Only 20.0% of patients with previous appropriate, successful ICD therapy subsequently died during the study duration. Similarly, 20% of these were classified as sudden cardiac death, 60% were classified as cardiac death, and 20% were classified as noncardiac death. Differences in baseline clinical, ECG, and echocardiographic variables between patients who died and patients who survived are presented in Tables 1 and 2. Patients who died were more likely to be older (p ⫽ 0.046), diabetic (p ⫽ 0.005), in a higher NYHA functional class (p ⫽ 0.024), have lower systolic (p ⫽ 0.006) and diastolic (p ⫽ 0.026) blood pressures, and a lower GFR (p ⬍0.001). In addition, they had a wider QRS duration (p ⫽ 0.016). Moreover, they had greater impairment of global longitudinal strain (p ⫽ 0.001), peri-infarct zone longitudinal strain (p ⫽ 0.001), and remote zone longitudinal strain (p ⫽ 0.041). There were no significant differences in rates of cardiac resynchronization therapy, use of cardiac medications, LV volumes, or LV ejection fraction. When the patient population was dichotomized based on median peri-infarct zone longitudinal strain, a cumulative 6%, 11%, and 13% of patients with less impaired periinfarct zone longitudinal strain died by 1-, 2-, and 3-year follow-ups, respectively. In contrast, a respective 8%, 15%, and 19% of patients with more impaired peri-infarct zone
Figure 2. Kaplan-Meier estimates of (A) primary and (B) secondary outcomes. (A) Probability of primary outcome (all-cause mortality) differed significantly between the 2 groups dichotomized based on the median peri-infarct zone longitudinal strain value of 9.9% (chi-square 4.0). (B) Probability of secondary outcome (occurrence of appropriate, successful implantable cardiac defibrillator therapy for ventricular tachycardia/fibrillation) between the 2 groups dichotomized based on median peri-infarct zone longitudinal strain value (chi-square 7.1).
longitudinal strain died during the same period (p ⫽ 0.046, log-rank test; Figure 2). To identify independent predictors of death on followup, significant univariate predictors listed in Tables 1 and 2 with a p value ⬍0.05 (age, NYHA class, diabetes, systolic blood pressure, GFR, QRS duration, global LV longitudinal strain, peri-infarct zone longitudinal strain, and remote zone longitudinal strain) were entered into the Cox proportionalhazard model as covariates. ICD versus ICD with cardiac resynchronization therapy was also forced into the Cox proportional-hazards models as a factor to determine if there
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Figure 3. (Left) A patient with previous anterior myocardial infarction and a left ventricular ejection fraction of 33%. Mean infarct, peri-infarct, and remote zone longitudinal strains were 0.2%, ⫺13.7%, and ⫺19.2%, respectively. The patient did not develop any events after a follow-up duration of 32 months. (Right) A patient with previous inferior myocardial infarction and a left ventricular ejection fraction of 35%. Mean infarct, peri-infarct, and remote zone longitudinal strains were 0.5%, ⫺8.8%, and ⫺12.6%, respectively. The patient had the first episode of appropriate implantable cardiac defibrillator therapy at 9 months after implantable cardiac defibrillator insertion. Abbreviations as in Figure 1.
was a difference in all-cause mortality between the 2 groups. On multivariate analysis, presence of diabetes (hazard ratio [HR] 1.67, 95% CI 1.00 to 2.79, p ⫽ 0.049), higher NYHA functional class (HR 1.96, 95% CI 1.15 to 3.33, p ⫽ 0.013), every 1% absolute worsening of peri-infarct zone longitudinal strain (HR 1.25, 95% CI 1.07 to 1.46, p ⫽ 0.005), and every 10-ml/min/1.73 m2 decrease in GFR (HR 1.15, 95% CI 1.02 to 1.31, p ⫽ 0.022) were independently associated with an increased all-cause mortality on followup. There was no difference in all-cause mortality between ICD and ICD with cardiac resynchronization therapy after adjusting for differences in baseline characteristics. Therefore, considering that the peri-infarct zone longitudinal strain in the present study was ⫺6% to ⫺17%, the odds that a patient with a peri-infarct zone strain value of ⫺6% dying was approximately 11.5 times that of a patient with a periinfarct zone strain value of ⫺17%. Differences in baseline clinical, ECG, and echocardiographic variables between patients who underwent appropriate, successful ICD therapies for ventricular tachycardia/ fibrillation and those who did not are presented in Tables 1 and 2. Patients with appropriate ICD therapies were more likely to have a higher body mass index (p ⫽ 0.002), higher heart rate (p ⫽ 0.021), larger LV end-systolic volume index (p ⫽ 0.042), and greater impairment of peri-infarct zone longitudinal strain (p ⫽ 0.003). Similarly, when the patient population was dichotomized based on median peri-infarct zone longitudinal strain, a cumulative 8%, 11%, and 14% of patients with less impaired peri-infarct zone longitudinal strain underwent appropriate ICD therapies due to ventricular tachycardia/fibrillation by 1-, 2-, and 3-year follow-ups, respectively. In contrast, a respective 15%, 21%, and 25% of patients with more impaired peri-infarct zone longitudinal strain underwent appropriate ICD therapy during the same period (p ⫽ 0.008, log-rank test; (Figure 2).
Likewise, significant univariate predictors listed in Tables 1 and 2 with a p value ⬍0.05 (body mass index, heart rate, LV end-systolic volume index, and peri-infarct zone longitudinal strain) were entered into the Cox proportionalhazard model as covariates to identify independent determinants of occurrence of appropriate, successful ICD therapy for ventricular tachycardia/fibrillation. ICD versus ICD with cardiac resynchronization therapy was also forced into the Cox proportional-hazards models as a factor to determine if there was a difference in the occurrence of appropriate ICD therapies between the 2 groups. On multivariate analysis, only every 1% absolute worsening of peri-infarct zone longitudinal strain (HR 1.22, 95% CI 1.09 to 1.36, p ⬍0.001) was independently associated with an increased risk of having appropriate ICD therapy on follow-up. There was no difference in occurrence of appropriate ICD therapies for ventricular arrhythmias between ICD and ICD with cardiac resynchronization therapy after adjusting for differences in baseline characteristics. Similarly, considering that the peri-infarct zone longitudinal strain was ⫺6% to ⫺17% in the present study, the odds that a patient with a periinfarct zone strain value of ⫺6% having an appropriate ICD therapy for ventricular arrhythmia on follow-up was approximately 8.6 times that of a patient with a peri-infarct zone strain value of ⫺17%. Figure 3 shows examples of 2 patients who did and did not have appropriate ICD therapies on follow-up. Discussion The present study demonstrated that in patients with ischemic cardiomyopathy who received ICD for primary prevention, the independent determinants of all-cause mortality were diabetes, renal function, NYHA functional class, and peri-infarct strain. In contrast, peri-infarct strain was the
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only determinant of occurrence of appropriate ICD therapies for ventricular arrhythmias during follow-up. Multicenter studies such as the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) have shown that mortality rate in patients with heart failure is high despite optimal medical therapy.1 Determining the prognosis in heart failure is complex and numerous independent predictors of adverse outcomes have been reported.18,19 Often, simple clinical and laboratory parameters such as advanced age, hypotension, prolonged QRS duration, and hyponatremia are strong adverse prognosticators. For example, subanalysis of the MADIT II showed that advanced age, higher NYHA functional class, prolonged QRS duration, impaired renal function, and presence of atrial fibrillation were associated with an increased all-cause mortality on follow-up.18,19 In the present study, patients with atrial fibrillation were excluded because the variable RR interval prevents generation of the 17-segment polar map for segmental longitudinal strain quantification. However, NYHA functional class and impaired renal function were similarly independently associated with an increased all-cause mortality risk. In addition, diabetes was identified as an independent risk factor. Diabetes mellitus is often rated as an equivalent of coronary artery disease, and diabetic patients have a high risk for cardiovascular morbidity and mortality. The risk of death is 2 to 3 times higher in diabetic patients compared to nondiabetics, and there is a strong association between diabetes and heart failure.20,21 Previous studies have demonstrated that patients with diabetes, ischemic heart disease, and heart failure have a dismal prognosis.22 In diabetic patients, there is often concomitant presence of hyperglycemia, obesity, metabolic syndrome, dyslipidemia, hypertension, and renal dysfunction. The resulting synergistic interplay among these factors leads to subsequent myocardial hypertrophy, autonomic neuropathy, accelerated atherosclerosis, ischemia, and eventual myocardial dysfunction with replacement fibrosis, thus contributing to an increased cardiovascular morbidity and mortality.23 The present study also compared patients who received an ICD to those who received an ICD and cardiac resynchronization therapy and found similar survival between the 2 groups. This result was similar to the Cardiac-Resynchronization Therapy for the Prevention of Heart-Failure Events (MADIT-CRT) by the MADIT-CRT trial investigators.24 The combination of ICD and cardiac resynchronization therapy was significantly associated with a lower primary end point (defined as all-cause mortality and heart failure) compared to ICD alone. However, subgroup analysis demonstrated that the primary end point was primarily driven by a decrease in nonfatal heart failure, whereas there was no difference in all-cause mortality between the 2 groups.24 Echocardiographic assessment of LV function is usually the first diagnostic imaging test performed for heart failure. Although LV volumes and LV ejection fraction are long known to be strong predictors of mortality after myocardial infarction25 and a decreased LV ejection fraction is an eligibility criterion for ICD implantation, they have a progressive decrease in discriminatory value over time for identifying patients with chronic ischemic cardiomyopathy who would benefit most from this expensive and invasive
ICD treatment strategy.26 Therefore, alternative noninvasive imaging strategies may help to refine risk assessment before and after insertions of ICD and maximize the benefit–risk ratio and cost-effectiveness of ICD therapy. Yan et al7 studied 144 patients after myocardial infarction with contrast-enhanced cardiac magnetic resonance and demonstrated that extent of peri-infarct zone independently predicted all-cause (HR 1.42, p ⫽ 0.005) and cardiovascular (HR 1.49, p ⫽ 0.01) mortalities. Similarly, the present study demonstrated greater impairments of baseline global and regional myocardial strains in the infarct, peri-infarct, and remote zones in patients who died. Multivariate analysis showed superior predictive value of peri-infarct strain over that of infarct and remote zones, highlighting the prognostic value of characterizing peri-infarct zone myocardial function. As such, the present study demonstrated that the odds that a patient with a peri-infarct zone strain value of ⫺6% dying was approximately 11.5 times that of a patient with a peri-infarct zone strain value of ⫺17%. In the present study, the presence of ischemia contributing to an impaired peri-infarct strain cannot be excluded and may well contribute to an increased risk of having appropriate ICD therapy on follow-up. However, although specific tests for myocardial ischemia were not reported, all patients were referred by their primary care physicians to undergo appropriate coronary revascularization before ICD implantation as part of the study protocol and routine clinical practice. Furthermore, cardiac stress imaging tests have ⬍100% sensitivity and specificity for detection of myocardial ischemia.27 Therefore, the treatment strategy in the present study protocol is representative of current standard clinical practice. Current guidelines recommend ICD as a class I indication for patients with chronic ischemic cardiomyopathy, LV ejection fraction ⱕ35%, and NYHA functional class ⱖII on optimal medical therapy.9 Identification of diabetes, renal dysfunction, and impaired peri-infarct strain as adverse prognostic markers helps to further risk-stratify patients with chronic ischemic cardiomyopathy who had undergone ICD for primary prevention. In addition, the study provided mechanistic insight into the role of peri-infarct strain in determining the risk for death and occurrence of appropriate ICD therapy on follow-up. Future studies are needed to determine if interventions targeting these adverse risk factors can alter prognosis in this patient population. Furthermore, the role of peri-infarct strain in identifying “at-risk” patients may be explored in future studies on electrophysiologic ventricular tachycardia ablation and for patients with LV ejection fraction ⬎35% and thus not eligible for primary ICD prevention based on current guidelines. 1. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML. The Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877– 883. 2. de Luna AB, Coumel P, Leclercq JF. Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 157 cases. Am Heart J 1989;117:151–159. 3. Eckardt L, Haverkamp W, Johna R, Bocker D, Deng MC, Breithardt G, Borggrefe M. Arrhythmias in heart failure: current concepts of mechanisms and therapy. J Cardiovasc Electrophysiol 2000;11:106 – 117.
Coronary Artery Disease/Predictors of Death and ICD Therapies 4. Moss AJ, Greenberg H, Case RB, Zareba W, Hall WJ, Brown MW, Daubert JP, McNitt S, Andrews ML, Elkin AD, for the Multicenter Automatic Defibrillator Implantation Trial–II (MADIT-II) Research Group. Long-term clinical course of patients after termination of ventricular tachyarrhythmia by an implanted defibrillator. Circulation 2004;110:3760 –3765. 5. Myerburg RJ, Reddy V, Castellanos A. Indications for implantable cardioverter-defibrillators based on evidence and judgment. J Am Coll Cardiol 2009;54:747–763. 6. Fernandes VR, Wu KC, Rosen BD, Schmidt A, Lardo AC, Osman N, Halperin HR, Tomaselli G, Berger R, Bluemke DA, Marban E, Lima JAC. Enhanced infarct border Zone function and altered mechanical activation predict inducibility of monomorphic ventricular tachycardia in patients with ischemic cardiomyopathy. Radiology 2007;245:712– 719. 7. Yan AT, Shayne AJ, Brown KA, Gupta SN, Chan CW, Luu TM, Di Carli MF, Reynolds HG, Stevenson WG, Kwong RY. Characterization of the peri-infarct Zone by contrast-enhanced cardiac magnetic resonance imaging is a powerful predictor of post-myocardial infarction mortality. Circulation 2006;114:32–39. 8. Roes SD, Borleffs CJW, van der Geest RJ, Westenberg JJM, Marsan NA, Kaandorp TAM, Reiber JHC, Zeppenfeld K, Lamb HJ, De Roos A, Schalij MJ, Bax JJ. Infarct tissue heterogeneity assessed with contrast-enhanced MRI predicts spontaneous ventricular arrhythmia in patients with ischemic cardiomyopathy and implantable cardioverterdefibrillator. Circ Cardiovasc Imaging 2009;2:183–190. 9. Epstein AE, DiMarco JP, Ellenbogen KA, Mark Estes NA III, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. J Am Coll Cardiol 2008;51:2085–2105. 10. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis 2002;39(suppl):S1–S266. 11. Nishimura R, Miller FJ, Callahan M, Benassi R, Seward J, Tajik A. Doppler echocardiography: theory, instrumentation technique and application. Mayo Clin Proc 1985;60:321–343. 12. Tajik A, Seward J, Hagler D, Mair D, Lie J. Two dimensional realtime ultrasonic imaging of the heart and great vessels: technique, image orientation, structure identification and validation. Mayo Clin Proc 1978;53:271–303. 13. Mosteller RD. Simplified calculation of body-surface area. N Engl J Med 1987;317:1098. 14. Roes SD, Mollema SA, Lamb HJ, van der Wall EE, De Roos A, Bax JJ. Validation of echocardiographic two-dimensional speckle tracking longitudinal strain imaging for viability assessment in patients with
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