ABSTRACT
Background
Left ventricular ejection fraction (LVEF) has not demonstrated reliability in predicting ventricular arrhythmias or appropriate implantable cardioverter defibrillator (ICD) therapy (AICDt).
Objective
To evaluate the association between left ventricular global longitudinal strain (GLS) and AICDt.
Methods
One hundred seventy‐eight consecutive patients who received ICD implants for primary prevention of sudden cardiac death from 1/16/2015 to 1/26/2022 were followed until 1st appropriate ICD therapy (AICDt) for a ventricular arrhythmia, death, or loss to follow‐up. AICDt were physician adjudicated. Covariates included demographic variables (age, sex), clinical risk factors (LVEF, cardiac resynchronization therapy, coronary artery disease, anti‐arrhythmic drug use, QRS duration), and variables from the DO‐IT model (nonsustained ventricular tachycardia, atrial fibrillation, glomerular filtration rate, peripheral vascular disease, direct oral anticoagulant use, digoxin use, aldosterone antagonist use, and angiotensin converting enzyme inhibitor/angiotensin II receptor blocker use). Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI95) of GLS per 5% decrease (absolute value) for AICDt.
Results
Over a mean (standard deviation) follow up period of 5.09 (2.11) years, 44 of the 178 patients (79.77% male, 63.89 (12.89) years of age) in the final cohort experienced AICDt. In patients with coronary artery disease, GLS per 5% decrease (absolute value) was associated with AICDt independent of demographic variables (HR 2.16, CI95 1.09–4.27), clinical risk factors (HR 2.54, CI95 1.16–5.59), and variables from the DO‐IT model (HR 3.28, CI95 1.46–7.36).
Conclusion
Reduced GLS (absolute value) is an independent risk factor for AICDt in patients with coronary artery disease.
Reduced (absolute value) left ventricular global longitudinal strain is independently associated with an increased risk of appropriate therapies from primary prevention implantable cardioverter defibrillators.
1. Introduction
Left ventricular ejection fraction (LVEF) is the primary variable used to select candidates for primary prevention implantable cardioverter defibrillators (ICDs). Unfortunately, analysis of LVEF has not demonstrated reliability in predicting ventricular arrhythmias or appropriate ICD therapy (AICDt) [1, 2]. Echocardiographic strain imaging by speckle tracking has shown promise as a sensitive modality to evaluate cardiac function in a variety of disease processes [3, 4, 5]. The present study aimed to evaluate the association between global longitudinal strain (GLS) and AICDt in patients with primary prevention ICDs.
2. Methods
2.1. Study Population
We included 274 consecutive patients with at least 3 years of follow‐up data who received ICD implants for primary prevention of sudden cardiac death at a large tertiary care medical center from 1/16/2015 to 1/26/2022. Patients were followed until 1st appropriate ICD therapy (AICDt) for a ventricular arrhythmia, death, or loss to follow‐up. Patients were excluded if they had suboptimal 2D transthoracic echocardiogram (TTE) quality prohibiting accurate speckle tracking (n = 95), resulting in a primary cohort of 178 patients.
2.2. Global Longitudinal Strain
Echocardiograms completed 6 months or less before the date of ICD implantation were retrospectively analyzed with speckle tracking using a third‐party software (TomTec; Unterschlessheim, Germany). Global longitudinal strain (GLS) calculation was automated using standard apical two, three, and four chamber views. For the purposes of this study, the absolute value of GLS was utilized.
2.3. Appropriate ICD Therapies for Ventricular Arrhythmias
ICD interrogation reports from the medical record were reviewed. AICDt were physician adjudicated and defined as any anti‐tachycardia pacing or defibrillation for a ventricular arrhythmia including monomorphic ventricular tachycardia, polymorphic ventricular tachycardia, and ventricular fibrillation.
2.4. Covariates
Covariates included demographic variables, clinical risk factors for AICDt, and variables from the DO‐IT model, a previously validated AICDt risk prediction tool [6]. The demographic variables were age and sex. The clinical risk factors were LVEF, cardiac resynchronization therapy (CRT), anti‐arrhythmic drug use (AAD), coronary artery disease (CAD), and QRS duration. The variables from the DO‐IT model were the presence of nonsustained ventricular tachycardia (NSVT), atrial fibrillation (AF), glomerular filtration rate (GFR), peripheral vascular disease (PVD), direct oral anticoagulant use (DOAC), digoxin use, aldosterone antagonist use, diuretic use, and angiotensin converting enzyme inhibitor use or angiotensin II receptor blocker (ACE/ARB) use. Covariates were physician adjudicated based on review of the patient's electronic medical record and established clinical diagnoses at the time of ICD implantation. CAD was defined as the presence of a > 70% occlusion in at least 1 coronary vessel. AAD included flecainide, propafenone, quinidine, sotalol, dofetilide, amiodarone, mexiletine, or multaq. PVD included peripheral arterial disease and stroke.
2.5. Statistical Analysis
The relationship between GLS and AICDt was explored using unadjusted cumulative incidence curves accounting for the competing risk of death. Categories of GLS (absolute value) were based on previously proposed cut‐off values (< 8% for severe reduction, ≥ 8% and < 12.5% for moderate reduction, and ≥ 12.5% for mild to normal) [7]. Cox proportional hazards models were used to calculate Hazard Ratios (HRs) and 95% confidence intervals (CI95) of GLS (per 5% decrease in absolute value) for AICDt. Model A (demographics) adjusted for age and sex. Model B (clinical risk factors) adjusted for AAD, CRT, CAD, QRS duration, and LVEF. Model C (DO‐IT model variables) adjusted for NSVT, AF, GFR, PVD, ACE/ARB, digoxin, aldosterone antagonist, diuretic use and DOAC. Stratified analysis by presence or absence of CAD was conducted. Statistics were completed in RStudio (Version 2023.06.01 + 421).
3. Results
In our final cohort of 178 patients, there were 82 people with CAD, 4 patients with hypertrophic cardiomyopathy, 5 patients with cardiac sarcoidosis, 87 patients with idiopathic nonischemic cardiomyopathy, 1 patient with congenital heart disease, 4 patients with chemotherapy induced cardiomyopathy, and 3 patients with muscular dystrophy. There were 8 patients with CAD who also had a NICM. Six had an idiopathic NICM, 1 had congenital heart disease, and 1 had muscular dystrophy. Over a mean (standard deviation) follow up period of 5.09 (2.11) years, 44 of the 178 patients (79.77% male, 63.89 (12.89) years of age) in the final cohort experienced AICDt. There were no statistically significant differences in covariates between those who did and did not receive AICDt with the exception of LVEF and GFR (Table 1). ICDs were implanted in accordance with American Heart Association/American College of Cardiology/Heart Rhythm Society practice guidelines [8]. For 171 patients, ICDs were implanted for persistent LVEF≤ 35% despite 3 months of maximally tolerated medical therapy or if patients presented with a pacing indication and LVEF≤ 35%. For the remaining 7 patients, ICDs were implanted for the presence of HCM with high risk features (4 patients) or sarcoidosis with high risk features and/or having a pacing indication (3 patients). ICDs were programmed according to operator preference. The mean (standard deviation) detection rate for the slowest ventricular arrhythmia treatment zone was 192.12 (14.73), 191.41 (19.13), and 192.36 (13.10) for the entire cohort, those who received ICD shocks, and those who did not receive ICD shocks, respectively. There was no statically significant difference in slowest ventricular arrhythmia treatment zone between those who received shocks and those who did not (p = 0.76).
TABLE 1.
Baseline characteristics.
| AICDt (n = 44) | No AICDt (n = 134) | p | |
|---|---|---|---|
| Age | 62.70 (11.37) | 64.29 (13.37) | 0.44 |
| Sex | 39 (88.64) | 103 (76.87) | 0.09 |
| GLS, % (absolute value) | 8.61 (3.80) | 9.81 (3.89) | 0.08 |
| LVEF, % | 27.48 (7.59) | 30.37 (8.90) | 0.04 |
| CRT | 25 (56.81) | 63 (47.01) | 0.26 |
| AAD | 2 (4.55) | 17 (12.67) | 0.17 |
| CAD | 24 (54.55) | 58 (43.28) | 0.19 |
| QRS duration | 136.0 (35.50) | 134.97 (35.35) | 0.87 |
| AF | 10 (22.73) | 34 (25.37) | 0.72 |
| GFR | 58.27 (7.02) | 54.93 (10.62) | 0.02 |
| PVD | 4 (9.09) | 13 (9.70) | 1.0 |
| NSVT | 2 (4.55) | 5 (3.73) | 1.0 |
| DOAC | 2 (4.55) | 18 (13.43) | 0.17 |
| Diuretic | 25 (56.82) | 88 (65.67) | 0.29 |
| Digoxin | 2 (4.55) | 11 (8.21) | 0.52 |
| Aldosterone Antagonist | 11 (25) | 41 (30.60) | 0.48 |
| ACE/ARB | 40 (90.91) | 109 (81.34) | 0.16 |
Note: Data presented as n (%) for categorical variables and mean (standard deviation) for continuous variables. p‐values reported for comparison with Welch two sample T‐test for continuous variables and Pearson's Chi‐squared test or Fisher's exact test for categorical variables.
Abbreviations: AAD, anti‐arrhythmic drug use; ACE, angiotensin converting enzyme inhibitor; AF, atrial fibrillation; AICDt, appropriate implantable cardioverter defibrillator therapies; ARB, angiotensin II receptor blocker; CAD, coronary artery disease; CRT, cardiac resynchronization therapy; DOAC, direct oral anticoagulant; GFR, glomerular filtration rate; GLS, left ventricular global longitudinal strain; LVEF, left ventricular ejection fraction; NSVT, nonsustained ventricular tachycardia; PVD, peripheral vascular disease.
3.1. Association of Left Ventricular Global Longitudinal Strain With Appropriate ICD Therapies
In the primary cohort and those with CAD, the cumulative incidence of AICDt was the lowest (numerically) in those with GLS (absolute value) ≥ 12.5% (Figure 1). In the primary cohort, reduction in the absolute value of GLS (per 5% decrease in absolute value) was independently associated with AICDt in model C (HR 1.72, CI95 1.06–2.82), but not in models A or B. In patients with CAD, GLS (per 5% decrease in absolute value) was independently associated with AICDt in models A (HR 2.16, CI95 1.09–4.27), B (HR 2.54, CI95 1.16–5.59), and C (HR 3.28, CI95 1.46–7.36). In patients without CAD, GLS (per 5% decrease in absolute value) was not associated with AICDt in models A, B, or C (Table 2).
FIGURE 1.
Cumulative incidence of appropriate implantable cardioverter defibrillator therapies for categories of global longitudinal strain. Unadjusted cumulative incidence curves accounting for the competing risk of death are presented. The absolute value of GLS is reported. Data truncated at year 4 due to increased censoring. Panel A was created with the primary cohort. Panel B was created with patients who had coronary artery disease. Panel C was created with patients who did not have coronary artery disease.
TABLE 2.
Association between left ventricular global longitudinal strain and appropriate implantable cardioverter defibrillator therapy.
| Model A | Model B | Model C | ||||
|---|---|---|---|---|---|---|
| HR (CI95) a | p | HR (CI95) | p | HR (CI95) | p | |
| Primary Cohort (n = 178, 44 events) | 1.41 (0.92–2.18) | 0.12 | 1.18 (0.70–2.00) | 0.53 | 1.72 (1.06–2.82) | 0.03 |
| Patients with coronary artery disease (n = 82, 24 events) | 2.16 (1.09–4.27) | 0.03 | 2.54 (1.16–5.59) | 0.02 | 3.28 (1.46–7.36) | < 0.01 |
| Patients without coronary artery disease (n = 96, 20 events) | 0.99 (0.61–1.61) | 0.98 | 0.55 (0.25–1.20) | 0.13 | 1.25 (0.67–2.37) | 0.48 |
Note: Model A: Cox proportional hazards model including age, sex, left ventricular global longitudinal strain. Model B: Cox proportional hazards model including left ventricular ejection fraction, anti‐arrhythmic drug use, coronary artery disease, QRS duration, cardiac resynchronization therapy, and left ventricular global longitudinal strain. Coronary artery disease was removed for stratified analysis. Model C: Cox proportional hazards model including angiotensin converting enzyme inhibitor/angiotensin II receptor blocker use, nonsustained ventricular tachycardia, atrial fibrillation, glomerular filtration rate, peripheral vascular disease, diuretic use, aldosterone antagonist use, digoxin use, direct oral anticoagulant use, and left ventricular global longitudinal strain.
Abbreviations: CI95, 95% confidence interval; HR, Hazard ratio.
Hazard ratios of global longitudinal strain per 5% decrease (absolute value) for appropriate implantable cardioverter defibrillator therapy.
4. Discussion
In this retrospective cohort of patients receiving primary prevention ICDs, reduced GLS (absolute value) was independently associated with an increased risk of AICDt. This association was not observed in patients without CAD.
There are conflicting data on whether reduced GLS (absolute value) is an independent risk factor for ventricular arrhythmias or AICDt, highlighting the need for additional studies [9]. Unlike the present analysis, several prior studies utilized composite endpoints (including mortality and heart failure) and/or did not have continuous rhythm monitoring for identifying arrhythmias which may have influenced their results [9]. Importantly, our study demonstrates that the etiology of cardiomyopathy can influence the prognostic value of GLS. Longitudinally oriented myofibers are most prominent within the subendocardium and are therefore affected earliest by reductions in oxygen delivery. Therefore, GLS may be a more sensitive indicator of underlying ischemic heart disease [5]. In fact, GLS has been shown correlate with left ventricular bipolar voltage abnormalities in patients with ischemic cardiomyopathy undergoing ventricular tachycardia ablation [10]. If our findings are validated, future randomized trials evaluating prophylactic VT ablation may consider analyzing GLS for patient selection. Larger cohort studies will be needed to help clarify which subgroups of nonischemic cardiomyopathy can benefit from analysis of GLS for AICDt risk stratification. Future studies should also investigate whether GLS can be used to select patients for primary prevention ICDs independent of LVEF, particularly in patients with coronary artery disease.
The present analysis has limitations. It was a single center retrospective cohort with a relatively small sample size limiting generalizability of the results. As true for all observational studies, confounding by imperfectly measured or unmeasured factors could not be accounted for.
5. Conclusion
In conclusion, reduced left ventricular GLS is an independent risk factor for AICDt in patients with CAD, but not in people without CAD. Our findings will need validation in independent cohorts before analysis of GLS can be used to inform prevention strategies for AICDt or even sudden death.
Funding
The authors have nothing to report.
Ethics Statement
The study received approval from the Institution Review Board and Pennstate Health Milton S. Hershey Medical Center.
Conflicts of Interest
The authors declare no conflicts of interest.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.