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Am J Physiol Heart Circ Physiol 290: H79-H86, 2006. First published August 19, 2005; doi:10.1152/ajpheart.00648.2005
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TRANSLATIONAL PHYSIOLOGY

Increased ventricular repolarization heterogeneity in patients with ventricular arrhythmia vulnerability and cardiomyopathy: a human in vivo study

Vijay S. Chauhan, Eugene Downar, Kumaraswamy Nanthakumar, John D. Parker, Heather J. Ross, Wilson Chan, and Peter Picton

Division of Cardiology, University Health Network and Mount Sinai Hospital, Toronto, Canada

Submitted 15 June 2005 ; accepted in final form 15 August 2005


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Increased repolarization heterogeneity can provide the substrate for reentrant ventricular arrhythmias in animal models of cardiomyopathy. We hypothesized that ventricular repolarization heterogeneity is also greater in patients with cardiomyopathy and ventricular arrhythmia vulnerability (inducible ventricular tachycardia or positive microvolt T wave alternans, VT/TWA) compared with a similar patient population without ventricular arrhythmia vulnerability (no VT/TWA). Endocardial and epicardial repolarization heterogeneity was measured in patients with (n = 12) and without (n = 10) VT/TWA by using transvenous 26-electrode catheters placed along the anteroseptal right ventricular endocardium and left ventricular epicardium. Local activation times (AT), activation-recovery intervals (ARI), and repolarization times (RT) were measured from unipolar electrograms. Endocardial RT dispersion along the apicobasal ventricle was greater (P < 0.005) in patients with VT/TWA than in those without VT/TWA because of greater ARI dispersion (P < 0.005). AT dispersion was similar between the two groups. Epicardial RT dispersion along the apicobasal ventricle was greater (P < 0.05) in patients with VT/TWA than in those without VT/TWA because of greater ARI dispersion (P < 0.05). AT dispersion was similar between the two groups. A plot of AT as a function of ARI revealed an inverse linear relationship for no VT/TWA such that progressively later activation was associated with progressively shorter ARI. The AT-ARI relationship was nonlinear in VT/TWA. In conclusion, patients with cardiomyopathy and VT/TWA have greater endocardial and epicardial repolarization heterogeneity than those without VT/TWA without associated conduction slowing. The steep repolarization gradients in VT/TWA may provide the substrate for functional conduction block and reentrant ventricular arrhythmias.

action potential; dispersion; ventricular tachycardia; reentry; T wave alternans

VENTRICULAR ARRHYTHMIAS, particularly ventricular tachycardia (VT), are a major cause of sudden cardiac death (2). In explanted human hearts with ischemic cardiomyopathy, zones of slow conduction arising from strands of surviving myocardium (9) constitute an important determinant of reentrant VT, and these observations have been confirmed in human intraoperative mapping studies (10). In animal infarct models, reentrant VT also is associated with regions of functional conduction block due to large dispersions in refractory periods over short anatomic distances (15, 28). Similarly, animal models of nonischemic cardiomyopathy that develop ventricular arrhythmias have increased endocardial and transmural repolarization heterogeneity (1, 23). In particular, longer action potential durations (APDs) in the midmyocardium compared with the subepicardium provide the substrate for functional conduction block and reentry (1). These animal studies provide compelling evidence that repolarization heterogeneity is a prerequisite for reentrant ventricular arrhythmias in both ischemic and nonischemic cardiomyopathy (18).

Among patients with cardiomyopathy, it is unclear whether in vivo repolarization heterogeneity is increased in those with VT versus no clinical history of VT. A limited number of clinical studies have shown greater endocardial repolarization heterogeneity in conscious patients with structural heart disease compared with normal controls, but the reports are conflicting due to low spatial resolution, which limits detection of steep repolarization gradients within localized regions of diseased myocardium (22, 35, 37). Prior intraoperative studies in patients with cardiomyopathy have permitted assessment of epicardial repolarization gradients (12), but these studies are confounded by anesthetic agents (29) and epicardial cooling (8) that can alter the kinetics of repolarizing currents.

Ideally, repolarization gradients should be measured with higher spatial resolution in diseased myocardial segments under physiological conditions. Under these recording conditions, we hypothesized that epicardial and endocardial repolarization heterogeneity in patients with cardiomyopathy and ventricular arrhythmia vulnerability would be greater than in a similar patient population without ventricular arrhythmia vulnerability. To test this hypothesis, we measured repolarization heterogeneity in conscious patients, using transvenous multielectrode catheters placed along the apicobasal epicardial and endocardial surface of the anteroseptal ventricles where wall motion abnormalities were evident.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Patient population. Between 2002 and 2004, consecutive patients with cardiomyopathy and a left ventricular ejection fraction (LVEF) ≤40% were enrolled. Left ventricular function was evaluated by gated-blood pool nuclear imaging (MUGA) within 3 mo of enrollment, and all patients were required to have wall motion abnormalities involving the anterior wall, septum, or apex. The exclusion criteria comprised clinical evidence of heart failure, myocardial infarction or unstable angina within the past 3 mo, uncontrolled arterial hypertension, serum potassium or magnesium abnormalities, history of sustained ventricular arrhythmias, amiodarone therapy within the past 3 mo, and left ventricular thrombus. All patients underwent clinical risk stratification to assess suitability for prophylactic defibrillator implantation. Risk stratification was performed with programmed electrical stimulation to assess for VT inducibility in all patients before 2004. In 2004, all patients underwent risk stratification with microvolt T wave alternans (TWA) assessment instead of programmed electrical stimulation because of a change in institutional clinical practice patterns. The study was approved by the Research Ethics Boards of University Health Network and Mount Sinai Hospital, and all patients gave written informed consent.

Programmed electrical stimulation and microvolt T wave alternans. Programmed electrical stimulation or evaluation of microvolt TWA were performed in the nonsedated, postabsorptive state. {beta}-Blockers were held for five half-lives. Programmed stimulation was performed to assess for inducible VT by using a quadripolar catheter (Bard) positioned in the right ventricle (RV) from the femoral vein. Stimulus pulses from a biostimulator (Bloom) were delivered at twice diastolic threshold at 2-ms pulse width. Programmed stimulation consisted of up to three ventricular extrastimuli following two separate driving trains (S1) of eight beats at a cycle length of 600 and 400 ms. The coupling interval of each extrastimulus was decremented by 10 ms until ventricular refractoriness was achieved or a coupling interval of 200 ms was reached. Inducible VT was defined as sustained VT (>30 s) induced with up to three extrastimuli or sustained polymorphic VT/ventricular fibrillation (VF) with up to two extrastimuli. Microvolt TWA was assessed using the Heartwave System (Cambridge Heart) during right atrial pacing at a cycle length of 550 ms for 5 min. Right atrial pacing was achieved with a quadripolar catheter (Bard) introduced from the femoral vein. The definition of positive, negative, and indeterminate microvolt TWA, as previously described, was used (4).

Ventricular arrhythmia vulnerability was defined as inducible sustained VT with programmed ventricular stimulation or positive microvolt TWA, because both have been shown to predict ventricular arrhythmias and arrhythmic death (5, 6, 14, 17, 24, 27). Accordingly, patients were divided into two groups, namely, 1) no VT/TWA (ventricular arrhythmia nonvulnerable): no inducible VT or negative microvolt TWA, and 2) VT/TWA (ventricular arrhythmia vulnerable): inducible VT or positive microvolt TWA. Patients with inducible VF with three extrastimuli or indeterminate microvolt TWA were excluded, because these findings do not clearly identify a patient at high risk of ventricular arrhythmias or arrhythmic death.

Intracardiac recordings. The research protocol was performed 30 min after programmed electrical stimulation or assessment of microvolt TWA. Intracardiac repolarization gradients were measured between the apex and base of the LV epicardium and the RV endocardium. LV epicardial recordings were made using a 16-electrode catheter (Pathfinder; Cardima) consisting of eight electrode pairs (2-mm interelectrode spacing). Each electrode pair was separated by a distance of 6 mm. The catheter was introduced into the coronary sinus with the use of a guide sheath (Shuttle; Cook) and was advanced down the great cardiac vein to the cardiac apex, thereby lying along the anteroseptal LV epicardium. RV endocardial recordings were made using a 10-electrode catheter (Livewire; Daig) consisting of five electrode pairs (2-mm interelectrode spacing). Each electrode pair was separated by a distance of 5 mm. The catheter was positioned along the anteroseptal RV endocardium in close proximity to the 16-electrode catheter (Fig. 1). To maintain heart rate during recordings, the right atrium was paced with a quadripolar catheter (Bard) at 80% of the sinus cycle length. After 3 min of constant atrial pacing, simultaneous 12-lead ECG and unipolar intracardiac electrograms were recorded at a sampling frequency of 1,000 Hz on a Prucka workstation (GE Medical Systems). The unipolar electrograms were recorded from each epicardial and endocardial electrode at variable gain and filtered at a 0.05- to 500-Hz band pass.



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  		Fig. 1. Representative fluoroscopic images of intracardiac recording catheters. A: left anterior oblique. B: right anterior oblique. The 16-electrode catheter is positioned along the anteroseptal left ventricular (LV) epicardium (EPI). Electrode 1 is at the apex, and electrode 16 is at the base. The 10-electrode catheter lies along the anteroseptal right ventricular (RV) endocardium (ENDO) in close proximity to the 16-electrode catheter. Electrode 1 is at the apex and electrode 10 is at the base.

 
Intracardiac repolarization heterogeneity. The unipolar recordings were exported for off-line analysis and low-pass filtered at 50 Hz to improve signal quality (11). The local activation-recovery interval (ARI) was determined automatically for each unipolar electrogram by using custom software written in Labview (National Instruments). ARI represents the difference between local activation and recovery (16, 20), and it has been used to estimate APD in human cardiomyopathy (31). Local activation was defined as the minimum temporal derivative of voltage (dV/dt) of the unipolar QRS complex. Local recovery was defined as the maximum dV/dt of the unipolar T wave. Local activation and recovery were manually overread by an investigator (W. Chan) blinded to the patient's clinical profile. Local activation time (AT) corresponded to the interval from the onset of the earliest QRS on the 12-lead ECG to local activation on the unipolar electrogram. Local repolarization time (RT) was derived from the sum of local AT and ARI. The ARI, AT, and RT of 10 consecutive unipolar electrograms were averaged to define the ARI, AT, and RT of the corresponding recording electrode. Whole ARI, AT, and RT dispersion were determined separately for the RV endocardium and the LV epicardium and defined as the difference between maximum and minimum ARI, AT, and RT, respectively. In addition to computing repolarization heterogeneity along the whole apicobasal ventricular wall, we performed further analysis based on adjacent ventricular sites. The greatest difference in RT between adjacent ventricular sites was determined separately for the RV endocardium and LV epicardium. At these sites, the ARI and AT were computed. Adjacent RT dispersion was expressed in milliseconds per millimeter, taking into account the distance between adjacent recording electrodes. The primary end point of the study was repolarization heterogeneity as measured by RT dispersion.

Statistical analysis. Values are expressed as means ± SE. Comparison of continuous variables between groups was made using the unpaired t-test. For nonparametric data, comparison of continuous variables between groups was made using the Mann-Whitney U-test. The relationship between ARI and AT was assessed using simple linear regression analysis. Categorical variables were compared between groups by using the {chi}2 test or Fisher's exact test, where appropriate. Multiple comparisons were corrected using the Bonferroni method. A P value < 0.05 was considered statistically significant. Statistical analysis was performed using Systat (version 10; SPSS, Chicago, IL).


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Patient population. The study population included 10 patients with no inducible VT or negative TWA (no VT/TWA group) and 12 patients with inducible VT or positive TWA (VT/TWA group). Patient characteristics are presented in Table 1. The groups were similar with respect to age, gender, LVEF, and etiology of cardiomyopathy. There was no difference in QRS duration (116 ± 10 vs. 111 ± 3 ms, P = not significant, NS) or QTc interval (433 ± 11 vs. 412 ± 5 ms, P = NS) between VT/TWA and no VT/TWA. All patients had anterior, septal, or apical wall motion abnormalities, and the severity of wall motion abnormalities was similar between the two groups (Table 2).


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  		Table 1. Patient characteristics

 

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  		Table 2. Left ventricular wall motion abnormalities

 
RV endocardial repolarization heterogeneity. Unipolar electrograms were recorded during atrial pacing at similar cycle lengths for VT/TWA and no VT/TWA patients (708 ± 40 vs. 673 ± 32 ms, P = NS). Mean AT, ARI, and RT values measured from the 10 recording electrodes are presented in Table 3, and no differences were apparent between VT/TWA and no VT/TWA patients. RV endocardial repolarization time increased from apex to base in 59% of patients, whereas the remainder manifested repolarization gradients in the opposite direction. Whole RT dispersion was greater in patients with VT/TWA compared with those without VT/TWA (73 ± 15 vs. 17 ± 3 ms, P < 0.005). Greater whole ARI dispersion in VT/TWA patients accounted for this observation, in that whole AT dispersion was similar between the groups (Fig. 2). Adjacent endocardial RT dispersion was greater in VT/TWA compared with no VT/TWA (12 ± 2 vs. 2.5 ± 0.4 ms/mm, P < 0.005), and this was due to larger adjacent ARI dispersion. Adjacent AT dispersion was similar between the two groups (Fig. 3). In the majority of VT/TWA patients, the maximum adjacent RT dispersion occurred at the apex (67%, n = 8).


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  		Table 3. Mean AT, ARI, and RT

 


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  		Fig. 2. Bar graphs showing whole activation-recovery intervals (ARI), activation time (AT), and repolarization time (RT) dispersion (measured from all recording electrodes) for the epicardium and endocardium in cardiomyopathic patients without ventricular arrhythmia vulnerability (inducible ventricular tachycardia or positive microvolt T wave alternans: no VT/TWA) and with VT/TWA. Whole endocardial ARI and RT dispersion were greater in VT/TWA than no VT/TWA. Whole endocardial AT dispersion was similar between the two groups. *P < 0.005 vs. no VT/TWA.

 


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  		Fig. 3. Bar graphs showing adjacent ARI, AT and RT dispersion (maximum difference between adjacent electrodes) for the epicardium and endocardium in no VT/TWA and VT/TWA groups. Adjacent endocardial ARI and RT dispersion were greater in VT/TWA than no VT/TWA. Adjacent epicardial ARI and RT dispersion were greater in VT/TWA than no VT/TWA. *P < 0.005 vs. no VT/TWA. {dagger}P < 0.05 vs. no VT/TWA.

 
To examine the relationship between AT and ARI, we plotted the ARI as a function of AT for each patient. Linear regression analysis showed a strong inverse linear relationship between AT and ARI in the patients without VT/TWA (r = –0.65 ± 0.08) such that progressively later activation was associated with shorter ARI. The mean slope of the regression line was –0.7 ± 0.1. In contrast, a weaker linear relationship was present in the patients with VT/TWA (r = –0.35 ± 0.13, P < 0.05 vs. no VT/TWA). Representative data showing RV endocardial unipolar electrograms, apicobasal repolarization gradients, and the AT-ARI relationship in a patient without VT/TWA and a patient with VT/TWA are shown in Fig. 4, A and B, respectively.



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  		Fig. 4. A: representative unipolar electrograms (left) from the endocardium of a patient with no VT/TWA. For each electrogram, the dotted line corresponds to the onset of the earliest surface QRS complex (not shown); the number in parentheses indicates the electrode number (from apex to base), which is followed by the AT and ARI. A plot of AT vs. ARI (top right) shows a strong inverse linear relationship (r = –0.92, P < 0.0005) with a slope of –1.4. RT and ARI are plotted (bottom right) as a function of electrode number from apex to base. Electrodes 1 and 2, 3 and 4, 5 and 6, 7 and 8, and 9 and 10 are electrode pairs (2-mm interelectrode distance) with 5-mm spacing between electrode pairs. RT dispersion and ARI dispersion are 9 and 18 ms, respectively. The maximum RT gradient measured 0.4 ms/mm between electrodes 6 and 7 (5-mm interelectrode distance) at the midsegment. B: representative unipolar electrograms (left) from the endocardium of a patient with VT/TWA. The AT vs. ARI plot (top right) shows a weaker inverse linear relationship (r = –0.56, P = NS) than in A. RT dispersion (102 ms) and ARI dispersion (88 ms) (bottom right) are both greater than in A, and a steeper RT gradient (11 ms/mm) is evident between electrodes 2 and 3 (2-mm interelectrode distance) at the apex.

 
LV epicardial repolarization heterogeneity. Mean AT, ARI, and RT values measured from the 16 recording electrodes are presented in Table 3, and there were no differences between patients with VT/TWA and without VT/TWA. LV epicardial repolarization time increased from apex to base in 63% of patients, whereas the remainder manifested repolarization gradients in the opposite direction. There was no difference in whole RT dispersion between patients with VT/TWA and without VT/TWA (66 ± 15 vs. 51 ± 8 ms, P = 0.55). Whole ARI dispersion and AT dispersion also were similar between the two groups. Whole epicardial RT dispersion in both groups was comparable to the large endocardial RT dispersion in patients with VT/TWA (Fig. 2). Adjacent epicardial RT dispersion was greater in VT/TWA compared with no VT/TWA (10 ± 2 vs. 2.6 ± 0.4 ms/mm, P < 0.05), and this was due to larger adjacent ARI dispersion. Adjacent AT dispersion was similar between the two groups (Fig. 3). In half of the VT/TWA patients, the maximum adjacent RT dispersion occurred at the apex.

Linear regression analysis of LV epicardial ARI as a function of AT showed a strong linear relationship in patients without VT/TWA (r = –0.66 ± 0.14). The mean slope of the regression line was –1.3 ± 0.2. No linear relationship between AT and ARI was observed in VT/TWA (r = 0.1 ± 0.2, P < 0.05 vs. no VT/TWA). Representative data showing LV epicardial unipolar electrograms, apicobasal repolarization gradients, and the ARI-AT relationship in a patient without VT/TWA and a patient with VT/TWA are shown in Fig. 5, A and B, respectively.



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  		Fig. 5. A: representative unipolar electrograms (left) from the epicardium of a patient with no VT/TWA. Electrogram annotation is the same as in Fig. 4. The plot of AT vs. ARI (top right) shows a strong inverse linear relationship (r = 0.98, P < 0.0005) with a slope of –1.4. The RT and ARI are plotted (bottom right) as a function of electrode number from apex to base. Electrodes 1 and 2, 3 and 4, 5 and 6, 7 and 8, 9 and 10, 11 and 12, 13 and 14, and 15 and 16 are electrode pairs (2-mm interelectrode distance) with 6-mm spacing between electrode pairs. RT dispersion and ARI dispersion are 12 and 33 ms, respectively, and the maximum RT gradient measured 1 ms/mm between electrodes 6 and 7 (6-mm interelectrode distance) at the apex. B: representative unipolar electrograms (left) from the epicardium of a patient with VT/TWA. The AT vs. ARI plot (top right) shows no linear relationship (r = 0.01, P = NS). RT dispersion (40 ms) and ARI dispersion (37 ms) (bottom right) are both greater than in A, and a steeper RT gradient (12 ms/mm) is evident between electrodes 3 and 4 (2-mm interelectrode distance) at the apex.

 
Ischemic vs. nonischemic cardiomyopathy repolarization heterogeneity. Repolarization heterogeneity was compared between patients with ischemic (n = 16) and nonischemic cardiomyopathy (n = 6). The groups were similar with respect to age (58 ± 3 vs. 57 ± 4 yr, P = NS), LVEF (30 ± 2 vs. 27 ± 4%, P = NS), and prevalence of VT/TWA (56 vs. 50%, P = NS). All patients with nonischemic cardiomyopathy underwent TWA evaluation instead of programmed stimulation where the sensitivity for VT induction is low. There was a trend toward greater whole and adjacent RV endocardial RT dispersion in ischemic cardiomyopathy compared with nonischemic cardiomyopathy (57 ± 13 vs. 24 ± 8 ms; 9 ± 2 vs. 5 ± 1 ms/mm, P = 0.07). LV epicardial RT dispersion was not significantly different between patients with ischemic and nonischemic cardiomyopathy (56 ± 9 vs. 72 ± 10 ms; 7 ± 2 vs. 5 ± 1 ms/mm, P = NS). To evaluate the effect of ventricular function on repolarization heterogeneity, we correlated LVEF with whole and adjacent RT dispersion. There was no significant linear relationship between LVEF and RT dispersion involving the RV endocardium [r = –0.43 (whole), r = –0.36 (adjacent)] or LV epicardium [r = –0.11 (whole), r = –0.25 (adjacent)].


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The major findings in this study are that patients with cardiomyopathy and inducible VT or positive microvolt T wave alternans have greater RV endocardial and LV epicardial repolarization heterogeneity along the anteroseptal ventricle compared with similar patients without inducible VT or negative microvolt T wave alternans. Increased repolarization heterogeneity is due to greater ARI dispersion rather than AT dispersion and associated with nonlinearity in the AT vs. ARI relationship. This is the first study to our knowledge that has characterized endocardial and epicardial repolarization heterogeneity in vivo in human subjects under physiological conditions. The localized recordings in the anteroseptal ventricle, where wall motion abnormalities suggested myocardial disease, revealed a primary abnormality in repolarization unrelated to conduction delay in cardiomyopathic patients susceptible to ventricular arrhythmias.

There is a consistent body of evidence from animal studies of heart disease that increased repolarization heterogeneity promotes reentrant ventricular arrhythmias. Steep gradients in APD >10 ms/mm can create functional conduction block that presages reentry (1, 15, 18, 19, 28). Our patients with VT/TWA had endocardial and epicardial repolarization gradients approaching 10 ms/mm, which could provide the substrate for functional conduction block in response to a premature ventricular beat, thereby initiating reentry. These steep gradients predominated in the apex, which tended to be more akinetic in the VT/TWA group, suggesting that more extensive apical myocardial disease may provide the necessary electroanatomic substrate (21). The presence of ischemic substrate did not influence repolarization gradients, which were similar between patients with ischemic and nonischemic cardiomyopathy. These observations are congruent with animal models of ischemic and nonischemic cardiomyopathy in which increased repolarization heterogeneity has been recorded associated with the induction of reentrant ventricular arrhythmias.

In our study, repolarization heterogeneity was measured across the apicobasal ventricle as well as between adjacent recording electrodes (2- to 6-mm interelectrode distance). Whereas epicardial RT dispersion across the apicobasal ventricle was similar between VT/TWA and no VT/TWA groups, RT dispersion between adjacent electrodes was greater in the latter group. Many patients with no VT/TWA exhibited a steady increase in epicardial repolarization time from apex to base, resulting in large whole RT dispersion but minimal adjacent RT dispersion. This observation emphasizes the clinical relevance of sampling localized regions of diseased myocardium to evaluate arrhythmogenic substrate (12). In our study, LVEF did not correlate with either localized or apicobasal LV epicardial repolarization heterogeneity. Thus global measures of ventricular function may be insensitive to the localized myocardial segments, particularly scar that may have increased repolarization heterogeneity. More extensive LV scar has been shown to predict recurrent ventricular arrhythmias independent of LVEF (34), and this may be due to increased repolarization heterogeneity across localized scar. Compared with LVEF, T wave alternans, as an index of repolarization heterogeneity, is significantly better in predicting death and sustained ventricular arrhythmias in patients with ischemic and nonischemic cardiomyopathy (3).

Repolarization time and repolarization heterogeneity are dependent on both AT and APD (12). In the absence of significant differences in AT dispersion, conduction slowing did not account for the greater RT dispersion in our patients with VT/TWA. Instead, the RT dispersion was caused by large gradients in APD. An inverse linear relationship between AT and APD, with a slope approximating unity, was observed in our patients without VT/TWA, which permits uniform repolarization such that early and late activated regions recover more or less simultaneously. Previous studies involving patients with cardiomyopathy (38) and preserved ventricular function (8, 12) without ventricular arrhythmias also have shown an inverse linear relationship between the APD and AT. In contrast, there was no linear relationship between APD and AT in the VT/TWA patients, which may contribute to nonuniform recovery. Nonlinearity of the APD-AT relationship also has been reported in patients with ventricular hypertrophy from aortic stenosis, although this was not correlated with VT inducibility (8). We speculate that electrotonic interactions that normally link AT with APD are impaired in VT/TWA (13, 32). Thus insufficient shortening of APD in diseased myocardial segments that activate late may contribute to the increased repolarization heterogeneity.

The magnitude of RV endocardial repolarization heterogeneity in our patients without VT/TWA was 17 ms, which corresponds with previous studies involving patients with cardiomyopathy as well as normal ventricular function (22, 37). RV endocardial repolarization gradients have not been previously defined in patients with cardiomyopathy and inducible VT, but Vassallo et al. (35) found gradients of 90 ms between 10 evenly spaced recording sites in the LV, which is similar to our observations along the anteroseptal RV (73 ms). In contrast, Franz et al. (12) recorded less repolarization heterogeneity (26 ms) between 5 and 10 LV endocardial sites in patients undergoing bypass surgery. However, these patients had preserved ventricular function and VT inducibility was not evaluated. LV epicardial repolarization heterogeneity was 66 and 51 ms in our VT/TWA and no VT/TWA patients, respectively. There are no reported in vivo LV epicardial repolarization heterogeneity measurements in humans for comparison with our study. In patients undergoing bypass surgery with preserved ventricular function, LV epicardial repolarization gradients of 41 (12) and 14 ms (8) have been documented between 5 and 10 recording sites, which is significantly less than in our cardiomyopathic patients. Although differences in ventricular function may account for the discrepancy, these intraoperative studies may underestimate in vivo epicardial repolarization gradients, because time constraints limit high-resolution mapping and epicardial cooling can influence repolarization time (8). In addition, anesthetic agents, such as pentobarbital sodium, have been shown to alter repolarization time by blocking the late sodium current (29).

The electrophysiological mechanism for the development of significant dispersion of repolarization in heart disease is not well understood. After myocardial infarction in animals, marked heterogeneity of repolarization is created by adjacent regions of scar, normal myocardium, and hypertrophied myocardium from structural remodeling (15, 33). Within the hypertrophied, remodeled myocardium, myocytes exhibit prolongation in APD and increased repolarization heterogeneity (26). Impaired intercellular coupling in heart disease can further increase repolarization heterogeneity by reducing electrotonic interactions between adjacent regions of myocardium with different APDs (36). In a canine model of pacing-induced heart failure, reduced connexin43 expression produced uncoupling between muscle layers, leading to marked dispersion of repolarization between the epicardium and midmyocardium (25). The role of the autonomic nervous system and altered sympathetic innervation is another putative mechanism. During intraoperative mapping in cardiac arrest survivors, Calkins et al. (7) found greater midmyocardial ventricular refractory periods in regions of sympathetic denervation as defined by PET imaging compared with adjacent innervated regions.

Study limitations. There are several limitations that need to be addressed. First, only the anteroseptal ventricular wall was sampled. It is possible that other regions had greater repolarization heterogeneity and provided the substrate for VT inducibility or TWA. Sampling the anteroseptal ventricle permitted simultaneous transvenous epicardial and endocardial recordings in patients, thereby avoiding arterial access and thromboembolic risk to the patient. Second, long-term follow up was not available to evaluate the relationship of increased repolarization heterogeneity to ventricular arrhythmias and sudden death; however, VT inducibility and TWA have been shown to predict these clinical end points. Third, ventricular arrhythmia vulnerability was assessed by either VT inducibility or TWA but not both. The study findings were confirmed in subset analysis in which patients with inducible VT had greater RT heterogeneity than those with noninducible VT. Similarly, RT heterogeneity was greater in patients with positive TWA vs. negative TWA (Table 4). Finally, repolarization heterogeneity was measured at different cycle lengths for each patient. Because repolarization heterogeneity diminishes at shorter cycle lengths (30), the atrial pacing cycle length was maximized for each patient, and it was similar between the two groups.


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  		Table 4. Subgroup repolarization heterogeneity

 

   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by Heart and Stroke Foundation of Canada Grant NA 4936 and Canadian Foundation for Innovation Grant 7498 (to V. Chauhan).


   ACKNOWLEDGMENTS
 
We thank S. Kelly RN and the nursing staff of the Clinical Cardiovascular Research Laboratory of Mount Sinai Hospital for help in the completion of these studies.


   FOOTNOTES
 

Address for reprint requests and other correspondence: V. S. Chauhan, PMCC 3-503, Toronto General Hospital, 150 Gerrard St. W., Toronto, ON, Canada M5G 2C4 (e-mail: vijay.chauhan{at}uhn.on.ca)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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