|
|
|
Tex Heart Inst J. 2006; 33(1): 3–8.
QTc Interval Prolongation Predicts Postoperative
Mortality in Heart Failure Patients Undergoing Surgical
Revascularization
Bojan Vrtovec, MD, PhD, Aria P. Yazdanbakhsh, MD,
Tatjana Pintar, MD, Charles D. Collard, MD, Igor D. Gregoric, MD, and
Branislav Radovancevic, MD
The Departments of Cardiopulmonary Transplantation
(Drs. Gregoric, Radovancevic, Vrtovec, and Yazdanbakhsh) and
Cardiovascular Anesthesiology (Drs. Collard and Pintar), Texas Heart
Institute at St. Luke's Episcopal Hospital, Houston, Texas 77030
|
|
Abstract
QTc interval prolongation is associated with increased mortality rates
in patients with advanced heart failure. We investigated the predictive
value of prolonged QTc interval in 567 patients with heart failure who
were undergoing coronary artery bypass graft surgery. The patients were in
New York Heart Association class III or IV, with left ventricular ejection
fractions of 0.40 or less. Before surgery, the QT interval duration was
measured in leads II and V4 of the standard electrocardiogram
and corrected by use of the Bazett formula. The QTc interval was prolonged
(>440 msec) in 243 patients (43%) and normal in 324 (57%). The 2 study
groups ---prolonged QTc versus normal QTc ---did not differ in terms of
age (62 [plus minus] 11 years vs 64 [plus minus] 10 years, P
=0.65), sex (80% male vs 76% male, P =0.31), ejection fraction
(0.29 [plus minus] 0.08 vs 0.29 [plus minus] 0.09, P =0.72),
hypertension (82% vs 78%, P =0.34), or diabetes (11% vs 7%,
P =0.10).
Within 1 month after coronary artery bypass grafting, 22 of 243
patients (9.1%) in the prolonged QTc group died, compared with 5 of 324 in
the normal QTc group (1.5%) (P =0.0001). QTc interval
prolongation was the only independent predictor of postoperative mortality
on multivariate analysis (P =0.002). We conclude that patients
with heart failure and preoperative QTc interval prolongation have
increased mortality rates after coronary artery bypass grafting.
Key words:
Coronary
disease/surgery, electrocardiography, heart failure, long QT syndrome,
mortality, myocardial revascularization, prognosis, risk factors,
treatment outcome |
The prevalence of patients with advanced heart failure due to ischemic
heart disease is steadily increasing.1 Recently, a number of
medical and invasive strategies have been proposed to improve survival in
this group of patients. The use of [beta]-blockers, defibrillators, and
biventricular pacing has been shown to be of considerable benefit in such
patients.2 Yet, in many, the disease still progresses to
advanced stages that are associated with profound hemodynamic distress and
high mortality rates. For these patients, the only widely available
definitive treatment is cardiac transplantation. However, the survival
benefit of transplantation is evident only in patients who are in the most
severe stages of heart failure, and the shortage of available donor organs
further limits the use of this treatment.3 Although the use of
left ventricular assist devices is an alternative for selected patients
with advanced ischemic heart failure, coronary artery bypass grafting
(CABG) remains the most frequently performed surgical procedure in this
group of patients.4 Surgical revascularization in patients with
severe left ventricular dysfunction has historically carried high
perioperative mortality and morbidity rates; however, advances in surgical
technique and myocardial protection have improved the safety of CABG in
selected patients with ischemic cardiomyopathy.5 Because many
patients with advanced ischemic heart failure could potentially benefit
from CABG and because a number of alternative treatments are available, it
is important to carefully select the patients in whom CABG would be most
beneficial. Despite the risk-stratification parameters proposed so
far,6 the selection criteria for CABG in patients with advanced
ischemic heart failure remain poorly defined.
QTc interval prolongation has been shown to predict mortality in
medically treated patients with advanced heart failur7 and in
patients with coronary artery disease.8 We therefore sought to
evaluate the predictive value of preoperative QTc interval duration in
patients with ischemic heart failure who were undergoing CABG.
|
|
Patients and
Methods
Patients.
We retrospectively
reviewed data on all patients referred to our institution for CABG from 1
January 2001 to 1 June 2002. From this group, we selected patients who had
a reduced left ventricular ejection fraction (LVEF) on preoperative heart
catheterization and who had been in New York Heart Association (NYHA)
class III or IV for at least 2 months before referral and evaluation at
our institution. Patients with pacemakers or implantable
cardioverter-defibrillators and patients taking type-III antiarrhyth-mic
medications were excluded.
QTc Interval Measurement.
Within the
24-hour period before surgery, resting, 12-lead electrocardiograms (ECGs)
were recorded at a paper speed of 25 mm/sec on a Marquette Resting ECG
recorder (Marquette Electronics Inc.; Milwaukee, Wis). Two independent
observers who were blinded to the clinical and survival data determined QT
interval duration. In accordance with the latest recommendations for
clinical QT interval measurement,9 QT interval duration was
recorded for 3 consecutive beats through leads II and V4. Using
calipers on printed ECGs, each QT interval was measured from the beginning
of the QRS complex to the visual return of the T wave to the isoelectric
line. When the T wave was interrupted by the U wave, the end of the T wave
was defined as the nadir between the T and the U wave. Patients with ECG
evidence of arrhythmias or pacemaker rhythms were excluded. Heart rate was
corrected using the Bazett formula, and QTc interval duration was defined
as the mean duration of all QTc intervals measured. Prolonged QTc was
defined as a QTc interval greater than 440 msec.
Cardiac Catheterization and CABG
Techniques. In all patients, cardiac catheterization was performed
within the 48 hours before surgery. Coronary angiography was performed
using standard techniques. Stenotic lesions were graded subjectively by
visual consensus of at least 2 experienced observers on an ordinal scale
of 0, 25%, 50%, 75%, 95%, or 100%. The extent of coronary artery disease
was characterized by the traditional 1-, 2-, or 3-vessel disease
classification. Biplane views were obtained during all ventriculography
procedures. Angiographic LVEF and regional wall motion were determined by
centerline regional wall motion analysis.10 In the presence of
excessive ventricular ectopy or catheter-induced mitral regurgitation,
ventriculography was repeated until technically adequate. All
ventriculography data were interpreted by at least 2 experienced
observers.
All patients underwent isolated CABG surgery in accordance with the
standard guidelines for surgical myocardial
revascularization.11
Follow-Up and Endpoints.
Patients
were followed up for 1 month after CABG. The primary endpoint was death
due to these cardiac causes: sudden cardiac death and pump failure. Sudden
cardiac death was defined as either a witnessed cardiac arrest or death
within 1 hour after the onset of acute symptoms, or an unexpected death in
a patient known to have been well within the previous 24
hours.12 Pump-failure death was defined as death resulting from
multiorgan failure due to the progression of heart failure.
Statistical Analysis.
Continuous
variables are expressed as mean [plus minus] SD. Differences between
survivors and patients who died during the postoperative period were
analyzed using 1-way analysis of variance (ANOVA). Comparisons of
categorical variables were made using a [chi]2 test. Univariate
and multivariate stepwise Cox proportional hazard regression analyses were
performed to identify independent predictors of postoperative mortality.
The P value for entering and staying in the model was set at
0.05. The Kaplan-Meier method was used to analyze and compare survival
rates in the prolonged and normal QTc groups. A P value less than
0.05 was considered significant.
|
|
Results
Patient Characteristics.
Of 1,112
patients eligible for the study, 201 were excluded because their LVEFs
were more than 0.40, and 250 were excluded because they were not in NYHA
functional class III or IV. Of the remaining 661 patients, 57 (9%) were
excluded because they were being treated with type-III antiarrhythmic
drugs, and 37 (6%) were excluded because they exhibited ECG abnormalities
such as atrial fibrillation (n=25) and pacemaker rhythm (n=12).
QTc Interval and Outcome.
Of the
remaining 567 patients, 27 (5%) died during the 1-month postoperative
period. Death was sudden in 3 cases (11%) and due to pump failure in 24
(89%). The preoperative QTc interval duration was significantly longer in
patients who died during the early postoperative period than it was in
survivors (476 [plus minus] 45 msec vs 434 [plus minus] 50 msec,
respectively; P 0.001).
In our study, the intraobserver relative error of QTc measurements was
2.4%. Using 440 msec as the cutoff value, the QTc interval was prolonged
in 243 patients (43%) and normal in 324 (57%). The 2 study groups did not
differ in any other clinical or laboratory preoperative characteristics
(Table I).
At 1 month after CABG, the cardiac mortality rate was significantly
higher in the prolonged QTc group (22/243 [9.1%]) than in the normal QTc
group (5/324 [1.5%]) (P =0.0001). The same was true for the
pump-failure mortality rate (20/243 [8.2%] vs 4/324 [1.2%], respectively;
P =0.0001). The sudden-death mortality rate, however, was not
significantly different between the 2 study groups (2/243 [0.8%] vs 1/324
[0.3%], respectively; P =0.40) (Fig. 1).
Univariate and Multivariate Predictors of
Outcome. The results of the univariate analysis of potential
predictors of outcome are presented in Table II. Parameters reaching or
approaching statistical significance in the univariate analysis were
included in a multivariate Cox proportional-hazards regression model of
cardiac mortality at 1 month (Table III). Both QTc interval prolongation
(>440 msec) and severely depressed LVEF ([less-than-or-equal]0.25) were
found to be univariate predictors of outcome after CABG surgery. However,
QTc interval prolongation was the only independent predictor of 1-month
postoperative mortality on multivariate analysis.
Kaplan-Meier Survival
Estimation. Survival as evaluated by Kaplan-Meier analysis was 6
times higher in the normal QTc group than in the prolonged QTc group
(P =0.0001) (Fig. 2).
|
|
Discussion
The results of our study indicate that a prolonged QTc interval
(>440 msec) is an adverse prognostic sign in patients with ischemic
heart failure undergoing isolated CABG. Preoperative QTc interval
prolongation correlates with increased cardiac and pump-failure mortality
rates within 1 month after the operation.
QTc Interval Prolongation in Ischemic
Heart Failure. QTc interval on the surface ECG reflects the time
between the initial fast depolarization of the left ventricle and its
subsequent repolarization. Duration of the QTc interval is highly
dependent on T wave morphology, which is determined by the differences in
the time course of repolarization of 3 predominant ventricular myocardial
cell types (endocardial, epicardial, and M cells).13 In the
presence of cardiac disease, ventricular repolarization heterogeneity is
increased, leading to QTc interval prolongation.14 It appears
that QTc interval duration in heart failure is independent of left
ventricular loading conditions;15 however, the duration is
affected by various noncardiac stimuli and especially by inflammation and
changes in autonomic nervous tone, both of which are present in advanced
heart failure.16 Although this may limit the value of QTc
interval in the analysis of the electrophysiological properties of
ventricular myocardium,17 it offers the possibility of
evaluating the combined impact of different disease processes on heart
failure. Therefore, QTc prolongation in patients with heart failure
appears to be more than merely a manifestation of ventricular
repolarization instability; it also appears to be a marker of disease
severity.
In our study, QTc interval prolongation was present in 43% of patients,
in agreement with the prevalence of prolonged QTc interval in other
studies of patients with heart failure.7,18 The preoperative
QTc interval prolongation observed in our study should be viewed as a
parameter affected by the severity of heart failure.
QTc Interval Duration and Outcome after
CABG. In this study population, a prolonged QTc interval was an
independent predictor of 1-month mortality after CABG. The most common
cause of death was multiorgan failure caused by progressive worsening of
heart failure; sudden cardiac death was rare. The relatively low rate of
sudden cardiac death may be due, in part, to the study design, which
excluded patients with ECG abnormalities and implantable
cardioverter-defibrillators. Previously, in a cohort of heart failure
patients awaiting cardiac transplantation, QTc interval prolongation was
inversely correlated with peak exercise oxygen consumption and directly
associated with increased mortality.15 Furthermore, in patients
with heart failure who have brain natriuretic peptide levels greater than
400 pg/mL, QTc interval prolongation appears to be an adverse prognostic
sign that predicts both pump failure and sudden cardiac death.7
Worsening of heart failure is one of the most common causes of death
and readmission to the hospital after CABG.19 This suggests
that CABG may not be an appropriate treatment option for certain heart
failure patients, particularly those with advanced disease. Accordingly,
we and others20 have found severely depressed preoperative LVEF
to be an indicator of adverse outcomes after CABG. No studies have
addressed the predictive value of QTc interval in this setting.
In the present study, heart failure patients who exhibited QTc interval
prolongation had a 6-fold higher mortality rate after CABG than did
patients who exhibited a normal QTc interval. Because QTc interval has
been shown to be prolonged after CABG,21 this procedure may not
be of benefit to patients with ischemic heart failure and preoperative QTc
interval prolongation. On the other hand, QTc duration has been shown to
decrease significantly after implantation of a left ventricular assist
device, which suggests a beneficial effect of left ventricular mechanical
support.22 Therefore, in selected patients with advanced heart
failure and QTc interval prolongation, earlier left ventricular assist
device implantation may be warranted instead of a high-risk CABG
procedure.
Study Limitations.
Our study and its
results have several limitations. First, the study excluded 2 large
subgroups of heart failure patients: patients in whom heart failure
progression was associated with atrial arrhythmias or with the need for
permanent pacing, and those who were taking type-III antiarrhythmic
medications or had implantable cardioverter-defibrillators. Therefore, our
results cannot be directly applied to all patients with advanced heart
failure. Second, we did not attempt to analyze QT interval dispersion in
our study. Even though QT dispersion has been proposed as a risk marker in
patients with advanced heart failure, the reproducibility of QT dispersion
measurements has been poor.23 We did, however, minimize
intraobserver variability in our study by using only leads II and
V4 to determine QT interval length. Finally, the postoperative
follow-up of our patients was relatively short, which could account for
the low mortality rates observed in our study.
|
|
Conclusions
QTc intervals greater than 440 msec are associated with adverse
outcomes in ischemic heart failure patients undergoing CABG. Although the
mechanism underlying QTc prolongation is not fully understood, it appears
that QTc prolongation may be a good adjunct in risk stratification of
patients with advanced heart failure who are being considered for surgical
revascularization. Further studies are needed to determine its
pathophysiologic significance and to determine whether it can be used with
other markers as part of a multivariate risk stratification protocol for
therapeutic decision-making in patients with advanced heart failure.
|
|
Footnotes
|
|
References
1.
Levy D, Kenchaiah S, Larson MG, Benjamin EJ, Kupka MJ,
Ho KK, et al. Long-term trends in the incidence of and survival with heart
failure. N Engl J Med 2002;347:1397 --402. [PubMed] [Free Full Text].
2.
Jessup M, Brozena S. Heart failure. N Engl J Med 2003;
348:2007 --18. [PubMed] [Full Text].
3.
Deng MC, De Meester JM, Smits JM, Heinecke J, Scheld
HH. Effect of receiving a heart transplant: analysis of a national cohort
entered on to a waiting list, stratified by heart failure severity.
Comparative Outcome and Clinical Profiles in Transplantation (COCPIT)
Study Group. BMJ 2000; 321:540 --5. [ Free Full text in PMC].
4.
Ascione R, Narayan P, Rogers CA, Lim KH, Capoun R,
Angelini GD. Early and midterm clinical outcome in patients with severe
left ventricular dysfunction undergoing coronary artery surgery. Ann
Thorac Surg 2003;76:793 --9. [PubMed] [Full Text].
5.
Trachiotis GD, Weintraub WS, Johnston TS, Jones EL,
Guyton RA, Craver JM. Coronary artery bypass grafting in patients with
advanced left ventricular dysfunction. Ann Thorac Surg 1998;66:1632 --9.
[PubMed] [Full Text].
6.
Gardner SC, Grunwald GK, Rumsfeld JS, Mackenzie T, Gao
D, Perlin JB, et al. Risk factors for intermediate-term survival after
coronary artery bypass grafting. Ann Thorac Surg 2001;72:2033 --7. [PubMed].
7.
Vrtovec B, Delgado R, Zewail A, Thomas CD, Richartz BM,
Radovancevic B. Prolonged QTc interval and high B-type natriuretic peptide
levels together predict mortality in patients with advanced heart failure.
Circulation 2003;107: 1764 --9. [PubMed] [Free Full Text].
8.
Elming H, Brendorp B, Kober L, Sahebzadah N,
Torp-Petersen C. QTc interval in the assessment of cardiac risk. Card
Electrophysiol Rev 2002;6:289 --94. [PubMed] [Full Text].
9.
Toivonen L. More light on QT interval measurement.
Heart 2002;87:193 --4. [PubMed]
[Free Full Text].
10.
Sheehan FH, Bolson EL, Dodge HT, Mathey DG, Schofer J,
Woo HW. Advantages and applications of the centerline method for
characterizing regional ventricular function. Circulation 1986;74:293
--305. [PubMed].
11.
Eagle KA, Guyton RA, Davidoff R, Ewy GA, Fonger J,
Gardner TJ, et al. ACC/AHA guidelines for coronary artery bypass graft
surgery: executive summary and recommendations: A report of the American
College of Cardiology/ American Heart Association Task Force on Practice
Guidelines (Committee to revise the 1991 guidelines for coronary artery
bypass graft surgery). Circulation 1999;100:1464 --80. [PubMed] [Free Full Text].
12.
Stevenson WG, Stevenson LW, Middlekauff HR, Saxon LA.
Sudden death prevention in patients with advanced ventricular dysfunction.
Circulation 1993;88:2953 --61. [PubMed].
13.
Yan GX, Antzelevitch C. Cellular basis for the normal T
wave and the electrocardiographic manifestations of the long-QT syndrome.
Circulation 1998;98:1928 --36. [PubMed] [Free Full Text].
14.
Antzelevitch C, Shimizu W. Cellular mechanisms
underlying the long QT syndrome. Curr Opin Cardiol 2002;17:43 --51. [PubMed] [Full Text].
15.
Boccalandro F, Velasco A, Thomas C, Richards B,
Radovancevic B. Relations among heart failure severity, left ventricular
loading conditions, and repolarization length in advanced heart failure
secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol
2003;92:544 --7. [PubMed] [Full Text].
16.
Kjaer A, Hesse B. Heart failure and neuroendocrine
activation: diagnostic, prognostic and therapeutic perspectives. Clin
Physiol 2001;21:661 --72. [PubMed] [Full Text].
17.
Magnano AR, Holleran S, Ramakrishnan R, Reiffel JA,
Bloomfield DM. Autonomic nervous system influences on QT interval in
normal subjects. J Am Coll Cardiol 2002; 39:1820 --6. [PubMed] [Full Text].
18.
Brendorp B, Elming H, Jun L, Kober L, Malik M, Jensen
GB, et al. Qtc interval as a guide to select those patients with
congestive heart failure and reduced left ventricular systolic function
who will benefit from antiarrhythmic treatment with dofetilide.
Circulation 2001;103:1422 --7. [PubMed] [Free Full Text].
19.
Hannan EL, Racz MJ, Walford G, Ryan TJ, Isom OW,
Bennett E, Jones RH. Predictors of readmission for complications of
coronary artery bypass graft surgery. JAMA 2003; 290:773 --80. [PubMed] [Free Full Text].
20.
De Carlo M, Milano A, Borzoni G, Pratali S, Barzaghi C,
Tartarini G, et al. Predicting outcome after myocardial revascularization
in patients with left ventricular dysfunction. Cardiovasc Surg 1998;6:58
--66. [PubMed] [Full Text].
21.
Wranicz JK, Ruta J, Strzondala M, Kosmider M, Bolinska
H, Zaslonka J. QT interval duration in 24-hour Holter monitoring after
different interventional treatment of coronary artery disease in patients
after the myocardial infarction. Med Sci Monit 2000;6:100 --2. [PubMed] [Free Full Text].
22.
Harding JD, Piacentino V 3rd, Gaughan JP, Houser SR,
Margulies KB. Electrophysiological alterations after mechanical
circulatory support in patients with advanced cardiac failure. Circulation
2001;104:1241 --7. [PubMed] [Free Full Text].
23.
Malik M, Batchvarov VN. Measurement, interpretation and
clinical potential of QT dispersion. J Am Coll Cardiol 2000;36:1749 --66.
[PubMed] [Full
Text]. |
|
Figures and
Tables
 |
Fig. 1 Early
postoperative mortality in heart failure patients with normal versus
prolonged QTc intervals. |
 |
Fig. 2 Kaplan-Meier
survival curves in patients classified according to QTc interval
duration (prolonged vs normal) (P
=0.0001). |
 |
Table I. Preoperative
Characteristics of Patients with Prolonged (>440 msec) and Normal
QTc Intervals* |
|
Table II. Univariate
Analysis of Potential Predictors of Early Postoperative
Mortality |
|
Table III. Multivariate
Analysis of Potential Predictors of Early Postoperative
Mortality | |
|