Author + information
- Received February 4, 2009
- Revision received June 1, 2009
- Accepted June 11, 2009
- Published online August 25, 2009.
- Larisa G. Tereshchenko, MD, PhD⁎,†,⁎ (, )
- Mitchell N. Faddis, MD, PhD†,
- Barry J. Fetics, MS⁎,
- Karl E. Zelik, MS‡,§,
- Igor R. Efimov, PhD‡ and
- Ronald D. Berger, MD, PhD⁎
- ↵⁎Reprint requests and correspondence:
Dr. Larisa G. Tereshchenko, Carnegie 592, 600 North Wolfe Street, Baltimore, Maryland 21287
Objectives This study aimed to identify an early marker of functional impairment after an implantable cardioverter-defibrillator (ICD) shock as a predictor of heart failure progression.
Background The ICD population has substantial risk of death due to progressive pump failure.
Methods Near-field (NF) bipolar right ventricular (RV) electrograms (EGMs) during induced ventricular fibrillation (VF) and 10 s after rescue ICD shock were analyzed in 310 patients (mean age 59 ± 14.5 years, 219 men [71%]) with structural heart disease, New York Heart Association functional class I to III, and implanted with a single- or dual-chamber Medtronic (Minneapolis, Minnesota) ICD for primary (245 patients, 79%) or secondary prevention of sudden cardiac arrest. A local injury current (LIC) on NF RV EGM was defined as a deviation of EGM potential ≥1 mV or ≥15% of the preceding R-wave peak-to-peak amplitude.
Results During mean follow-up of 29.3 ± 15.0 months, the combined end point of death or hospitalization due to congestive heart failure (CHF) exacerbation was documented in 40 patients (12.9%, or 5.3% per person-year of follow-up). LIC was observed in 106 patients. In multivariate risk analysis, after adjustment for baseline prognostic factors (ejection fraction, history of atrial fibrillation, diabetes mellitus) and appropriate ICD shocks during follow-up, patients with observed LIC after induced VF rescue ICD shock at ICD implantation were more likely to die or to be hospitalized (hazard ratio: 2.69; 95% confidence interval: 1.41 to 5.14; p = 0.003).
Conclusions Transient LIC on bipolar NF RV EGM after induced VF rescue ICD shock is associated with increased risk of CHF progression, future hospitalizations due to CHF exacerbation, and subsequent heart failure death.
Implantable cardioverter-defibrillators (ICDs) improve survival of patients who are at risk for sudden cardiac arrest (SCA) (1–4). However, long-term follow-up of ICD patients with congestive heart failure (CHF) has shown that both appropriate (5–7) and inappropriate (5,8) ICD shocks are associated with increased risk of death, predominantly from progressive heart failure. Thoughtful medical management of heart failure and programming of ICD therapies in this patient cohort might improve the prognosis, but no early markers of heart failure progression available at the time of ICD implantation are known.
Extensive data indicate that defibrillation shocks are accompanied by transient adverse effects. These adverse effects include: 1) transient ectopy, tachycardia, or induction of ventricular fibrillation (VF) (9,10); 2) complete heart block and increased pacing thresholds (10,11); 3) atrial and ventricular mechanical dysfunction (stunning) (12–15); 4) significant elevation of troponin I serum level (16); and 5) decrease of the myocardial lactate extraction rate by mitochondria (17). Whether transient signs of myocardial injury after an ICD shock could predict future progression of CHF remains unclear.
Changes of electrocardiogram (ECG) and intracardiac electrograms (EGMs) during ICD implantation procedures were observed previously. Transient ST-segment elevation on surface ECG after induced VF rescue ICD shock was described in 19% of patients (18), but its prognostic significance was not studied. Other investigators have shown that a current of injury on intracardiac EGM within 10 min of lead fixation serves as a marker of adequate active lead fixation during an ICD or pacemaker implantation procedure (19,20). The prognostic significance of transient local injury current (LIC) on near-field (NF) right ventricular (RV) EGM after induced VF rescue ICD shock is unknown. We hypothesized that LIC on bipolar NF RV EGM after induced VF rescue ICD shock predicts future CHF progression in patients with New York Heart Association (NYHA) functional class I to III CHF.
The study protocol was approved by the Johns Hopkins University and the Washington University Human Studies Committees, and all patients gave written informed consent before entering the study.
This is prospective observational study. Male and female patients older than 18 years with structural heart disease and NYHA functional class I to III CHF were eligible for the study if they had a Medtronic (Minneapolis, Minnesota) transvenous single- or dual-chamber ICD device with dedicated bipolar ICD lead implanted for primary or secondary prevention of SCA within 1 week before enrollment. Exclusion criteria were indications for cardiac resynchronization therapy defibrillator and NYHA functional class IV, contraindications for defibrillation threshold testing (DFT), pregnancy, inherited channelopathies, and concomitant conditions other than cardiac diseases that were associated with a high likelihood of death during 1 year after enrollment.
Ventricular tachycardia (VT)/VF was induced with a shock-on T-wave protocol. Stored intracardiac EGMs recorded during DFT (induced tachyarrhythmia and 10 s post-ICD shock) were extracted from the ICD memory 7 days after procedure, converted into digital format using proprietary Medtronic software, and further analyzed using custom Matlab (The MathWorks, Inc., Natick, Massachusetts) software application. Control recordings of NF RV EGM at rest simultaneously with 1-lead (lead II) surface ECG were obtained via Medtronic programmer 2090 using the NI USB-9215A portable data acquisition system (National Instruments, Austin, Texas) 7 days after the procedure.
Programming of the ICD device was based on the attending electrophysiologist's clinical evaluation. Patients were followed-up in the Washington University Arrhythmia Clinic and via the Internet-based CareLink (Medtronic, Inc., Minneapolis, Minnesota) remote monitoring system. All ICD interrogation data were adjudicated by an ICD end point committee (attending electrophysiologist and 2 of the investigators [L.G.T. and R.D.B.]). ICD shocks occurring for VT or VF were classified as appropriate.
Measurement of LIC on the bipolar NF RV EGM after induced VF rescue ICD shock
Endocardial NF RV EGM was recorded as the difference of potentials between the tip and the ring of the dedicated bipolar ICD lead implanted in the RV apex. The LIC was characterized as the magnitude of elevated or depressed potential immediately after the major fast EGM deflection (Fig. 1),measured from the baseline (the isoelectric portion before the major EGM deflection) to its highest point in millivolts. Peak-to-peak amplitude of major fast EGM deflection (R-wave) was measured to assess relative LIC on average representative beat. Significant LIC was defined as a deviation of EGM potential ≥1 mV or ≥15% of preceding R-wave peak-to-peak amplitude. Digital EGM (bandpass filter 2 to 100 Hz) was magnified and measured after separate calibration of each recording (1 mV equal to 30 to 40 pixels, Screen Calipers 4.0, Iconico, Inc., New York, New York). The first 2 s after shock were excluded. LIC was measured on every sinus beat and averaged. Ventricular-paced beats, distorted beats of undetermined origin, and ectopic beats were excluded.
Either of 2 major CHF events—death or hospitalization due to CHF exacerbation, whichever came first—served as the primary end point. We use the term “CHF event” to refer to this combined end point throughout the report. Cases of death with clear confirmed noncardiovascular cause were censored at the time of the last office visit. Time to event was measured from the day of ICD implantation.
Results are presented as mean ± SD for normally distributed variables, and as median and interquartile range for skewed distributions. Continuous variables were compared using the independent samples ttest if normally distributed and the Wilcoxon rank sum test if skewed. The Pearson chi-square test was used to compare categorical variables. A p value of <0.05 was considered significant. Kaplan-Meier survival analysis was used to compute mean and median survival time. The log-rank (Mantel-Cox) statistic was computed to test the equality of survival distributions. Cox multivariate regression model was used for adjustment by known predictors of CHF progression. Appropriate ICD shock for VT/VF at follow-up was treated as a time-dependent covariate. SPSS version 17.0.0 (SPSS Inc., Chicago, Illinois) and STATA version 10 (StataCorp LP, College Station, Texas) software packages were used for calculations.
The study population consisted of 310 patients (mean age 59.0 ± 14.5 years, 219 [71%] men) who underwent ICD implantation for primary (n = 245, 79%) or secondary (n = 65, 21%) prevention of SCA. Ischemic cardiomyopathy with myocardial infarction history was diagnosed in 187 (60.3%) patients and nonischemic cardiomyopathy in 123 (39.7%) patients. A single-chamber ICD was implanted in 175 (56.5%) patients, and dual-chamber ICD in 135 (43.5%) patients. A new dedicated bipolar transvenous ICD lead was implanted in 264 (85.1%) patients, and an ICD generator change procedure was performed in 46 (14.9%) patients who had had an ICD lead implanted more than 1 year ago. Only the first induced VT/VF and EGM after the first rescue ICD shock was analyzed.
Bipolar NF RV EGM changes after induced VF rescue ICD shock
Significant LIC after induced rescue ICD shock was found in 106 (34.2%) patients. The baseline characteristics of the patients are summarized in Table 1,and ICD shock characteristics are summarized in Table 2.Figure 2shows examples of EGM changes after induced VF rescue ICD shock. Control EGMs obtained 7 days after the procedure confirmed that observed changes were temporary and demonstrated isoelectric potential.
Death, CHF hospitalizations, and appropriate ICD shocks
During a mean follow-up of 29.3 ± 15.0 months, the combined end point of death or hospitalization due to CHF exacerbation was documented in 40 patients (12.9%, or 5.3% per person-year of follow-up). Appropriate ICD shocks were observed in 78 patients (25.2%, or 10.3% per person-year of follow-up); of these patients, 3 patients died median 113 days after appropriate ICD shocks, and 3 patients underwent successful heart transplantation. CHF events were twice as frequent among patients with appropriate ICD shocks (n = 16, 20.5%) compared with patients without sustained arrhythmia (n = 24 of 232, 10.3%; p = 0.020). ICD shock preceded CHF event by median 132 days (interquartile range 6 to 627 days).
Risk of CHF progression associated with LIC at ICD implantation
LIC (−) patients had a higher CHF event-free survival rate during follow-up (88.1% vs. 71.1%, p = 0.015) (Fig. 3A).Cox proportional hazard ratio (HR) for the newly implanted ICD lead subgroup was higher (HR: 3.29, 95% confidence interval [CI]: 1.54 to 7.06, p = 0.002) than for all patients (HR: 2.61, 95% CI: 1.37 to 4.99, p = 0.004). Figure 3B shows Kaplan-Meier curves when the analysis was confined to patients with newly implanted leads. This effect was not significant for the chronic ICD lead subgroup (HR: 0.78, 95% CI: 0.09 to 6.67, p = 0.820). Multivariate Cox model that included LIC, time-dependent appropriate ICD shocks at follow-up, new/chronic lead factor, and interaction between LIC and the lead factor confirmed effect modification (p < 0.0001).
In patients with LIC, subsequent sustained VT/VF events with appropriate ICD shocks predicted CHF progression (Fig. 4A)(event-free survival 40% vs. 80%, p < 0.006), whereas in patients without LIC, subsequent VT/VF was not predictive (Fig. 4B) (event-free survival 87% vs. 88%, p = 0.683). Multivariate Cox regression model that included LIC, time-dependent appropriate ICD shocks, and interaction between LIC and ICD shocks confirmed significant effect modification (p = 0.001).
After adjustment for baseline factors (age, race, left ventricular ejection fraction [LVEF], NYHA functional class, history of diabetes mellitus, atrial fibrillation or flutter, renal failure, hypertension, use of digoxin and aldosterone antagonists) and time-dependent appropriate ICD shocks during follow-up, LIC signified a highly increased risk of subsequent CHF events. Each Cox model included LIC, time-dependent appropriate ICD shocks during follow-up, NYHA functional class, and other covariates tested one by one as listed in Table 3.LIC was a significant predictor in all tested Cox models with HR from 2.2 to 2.6 (p < 0.01). HRs of time-dependent appropriate ICD shock at follow-up ranged from 2.5 to 7.1. Time-dependent appropriate ICD shock at follow-up was not a significant predictor in the models that included cycle length of VF and renal failure. NYHA functional class HRs ranged from 2.7 to 3.1 and were significant in all models (p < 0.001).
To our knowledge, this is the first description of LIC on bipolar NF RV EGM after ICD shock. Our results demonstrate for the first time that transient myocardial injury after induced VF rescue ICD shock manifesting as LIC on bipolar NF RV EGM is associated with increased risk of CHF progression, future hospitalizations due to CHF exacerbation, and heart pump failure death. LIC after induced VF rescue ICD shock was a predictor of adverse CHF outcomes after adjustment by traditional risk factors, including appropriate ICD shocks and LVEF or NYHA functional class, and provided additional prognostic information.
We propose a “triple-hit” hypothesis to explain the genesis of LIC on the NF RV EGM: 1) cardiac myocytes are fragile due to an underlying condition that leads to progressive CHF; 2) mechanical injury occurs due to lead placement; and 3) a rescue ICD shock elicits LIC, especially if the first 2 “hits” are present.
CHF progression in ICD patients
High risk of death due to pump failure in ICD patient populations without or after appropriate ICD therapies remains an important health care problem. Several clinical factors elucidated to be prognostic for CHF progression in ICD patients in previous studies are appropriate and inappropriate ICD shocks (5), renal failure (21), NYHA functional class, and LVEF (22). Our study is the first to show that the LIC phenomenon after induced VF rescue ICD shock carries an independent high risk, if observed in newly implanted ICD leads.
It is known that neurohumoral and cytokine activations contribute to the inflammatory and oxidative characteristics of CHF patients (23). We speculate that these pathways that have been activated for the long term in at-risk CHF patients result in a dramatic response to induced VF rescue ICD shock. Since patients without subsequent CHF were less likely to exhibit LIC, susceptibility for heart failure progression appears to be the “first hit” prerequisite for the LIC phenomenon we observed, and allows the appearance of LIC to serve as a marker of CHF risk.
Local mechanical myocardial injury and injury current on bipolar intracardiac EGM
Transient LIC presenting on NF RV EGM during the acute placement of an ICD or pacemaker lead is well known. Several groups of investigators linked characteristics of LIC at the time of an active-fixation lead placement with subsequent adequate lead fixation (19,20) and with lead perforation (24). Transvenous insertion of endocardial leads for permanent pacing (25) or use with an ICD (26) is accompanied by acute injury, followed by a sequence of cardiac histopathological changes starting with acute inflammation and leading eventually to the formation of a fibrous connective tissue scar (27,28). Maximum ventricular lead diameter, number of implanted leads (25), and CRT device left ventricular lead placement (29) were independent predictors of peak cardiac troponin I levels in patients undergoing conventional pacemaker/ICD implantation. Less frequently observed LIC in patients with chronic leads is a finding that suggests recent local mechanical injury is usually required as the “second hit” for LIC to occur. Future study is needed to determine the optimal prognostic time window from lead fixation to VT/VF induction.
Transient myocardial injury after ICD shock
According to the excitation theory of defibrillation, electrical shocks depolarize the membranes of most cardiac cells, resulting in resynchronization of electrical activity of the heart. If shock-induced changes in transmembrane potential are excessively large, they can cause transient cell membrane damage due to electroporation (30–32). Other potential causes of myocardial injury after an ICD shock include free radical formation (33,34) and conformation changes of the membrane ion channels (35). We speculate that enhanced LIC on bipolar NF RV EGM after an ICD shock in patients prone to subsequent CHF progression is produced by local voltage gradients, resulting from potential differences between electroporated myocardial cells and normal cells. In our study, LIC was observed after ICD shock, but not in subsequent control EGMs, thus supporting the importance of the shock and possibly the induced arrhythmia) for the “third hit.”
Our results show that appropriate ICD shock predicts future CHF exacerbation and death only in patients with significant LIC after rescue ICD shock. Conversely, patients without LIC and subsequent appropriate ICD shocks during follow-up had the same favorable course as patients without ICD shocks. This important clinical finding suggests that ICD shock does not cause, but rather unveils, risk of progressive CHF.
Our observations were limited by the 10-s post-shock EGM recording storage. We were unable to determine a final recovery time point and duration of EGM changes. EGM after ICD lead fixation but before induced VT/VF was not available for analysis.
Specific filter settings on bipolar NF RV EGM may preclude analysis of other manufacturers' EGMs. The small number of end point events limited multivariate Cox regression analysis.
The small number of chronic leads in this study prompts further investigation of LIC after ICD shock in chronic leads to determine its predictive value for subsequent CHF exacerbation.
In this study, we did not test the effect of ICD shock alone, without preceding induced arrhythmia, on the genesis of LIC. Theoretically, this could have been assessed at device implantation through the use of a protocol for upper limit of vulnerability testing (36,37), instead of that used to determine DFT.
The observed LIC phenomenon predicts progression of CHF in ICD patients with appropriate ICD shocks, and with otherwise stable NYHA functional class I to III CHF. Early awareness of the high risk of CHF exacerbation and thoughtful medical management may improve CHF prognosis in ICD patients.
The authors thank Jane Chen, Timothy Smith, Marye Gleva, and Bruce Lindsay for providing medical care for study participants, and Judy Osborn for help with collection of follow-up data.
This study was supported by Medtronic, Inc., as an Investigator-Initiated Research Project (awarded to Drs. Berger and Tereshchenko). Dr. Faddis has served as a consultant for Boston Scientific Corp., Stereofaxis, Inc., and St. Jude Medical, Inc. Dr. Efimov has been a stockholder and Scientific Advisory Board Chair with CARDIALEN, and has received National Institutes of Health grants HL67322, HL074283, and HL082729.
- Abbreviations and Acronyms
- congestive heart failure
- confidence interval
- defibrillation threshold testing
- hazard ratio
- implantable cardioverter-defibrillator
- local injury current
- left ventricular ejection fraction
- near field
- New York Heart Association
- right ventricle/ventricular
- sudden cardiac arrest
- ventricular fibrillation
- ventricular tachycardia
- Received February 4, 2009.
- Revision received June 1, 2009.
- Accepted June 11, 2009.
- American College of Cardiology Foundation
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