Electrocardiography and Doppler Echocardiography for Risk

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Provided by Elsevier - Publisher Connector Journal of the American College of Cardiology Vol. 45, No. 7, 2005 © 2005 by the American College of Cardiology Foundation ISSN 0735-1097/05/$30.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2004.12.064 Electrocardiography and Doppler Echocardiography for Risk Stratiﬁcation in Patients With Chronic Heart Failure Incremental Prognostic Value of QRS Duration and a Restrictive Mitral Filling Pattern Christian Bruch, MD,* Michael Gotzmann,* Jörg Stypmann, MD,* Frauke Wenzelburger, MD,† Markus Rothenburger, MD,† Matthias Grude, MD,* Hans H. Scheld, MD, FESC, FETCS,† Lars Eckardt, MD,‡ Günter Breithardt, MD, FESC, FACC,* Thomas Wichter, MD, FESC* Münster, Germany

OBJECTIVES This prospective study tested whether Doppler echocardiographic variables add incremental value to QRS duration in determining the prognosis of patients with chronic heart failure (CHF) and systolic dysfunction. BACKGROUND Diastolic dysfunction frequently is observed in patients with CHF, but its prognostic impact relative to that of QRS duration is unknown. METHODS A total of 193 patients with CHF and an ejection fraction Ͻ45% were enrolled prospectively. Echo measurements included left ventricular dimensions/volumes, ejection fraction, mitral early/late diastolic velocity ratio, deceleration time, and tissue Doppler mitral annular velocities. The mitral filling pattern was classified as either restrictive (RFP) or nonrestrictive. A cardiac event (cardiac death or urgent cardiac transplantation) was defined as combined study end point. RESULTS During a follow-up of 385 Ϯ 270 days, 24 patients suffered an event (cardiac death, n ϭ 21; urgent transplantation, n ϭ 3). The RFP, QRS duration, left ventricular systolic diameter, and mitral annular early diastolic velocity were independent predictors of an event. In patients with QRS duration Ͼ144 ms, the outcome was markedly poorer in the presence of RFPs as compared with their absence. Similarly, despite a QRS duration Յ144 ms, the outcome was worse in the presence of a RFP. A risk-stratification model based on the three strongest independent predictors separated groups into those with good prognosis and those with high, intermediate, and low event-free survival rates. CONCLUSIONS In subjects with CHF and systolic dysfunction, transmitral flow patterns add incremental value to QRS duration in determining the prognosis. (J Am Coll Cardiol 2005;45:1072–5) © 2005 by the American College of Cardiology Foundation

Despite advances in the medical management of patients Inclusion criteria were a history of CHF according to with chronic heart failure (CHF), morbidity and mortality Framingham criteria (4), left ventricular ejection fraction remain high (1). The prolongation of the QRS interval has (LVEF) Ͻ45%, and clinical stability after at least two been identified as an independent predictor of adverse months on standard medical therapy. Patients with congen- outcome (2). However, in patients with CHF, echo- ital heart disease (n ϭ 4), malignancy (n ϭ 2), severe Doppler indices of diastolic filling also provide prognostic valvular disease (n ϭ 6), atrial fibrillation (n ϭ 28), or under information, and a restrictive filling pattern (RFP) is indic- permanent pacemaker stimulation (n ϭ 27) were excluded. ative of a poor prognosis (3). This prospective study tested Follow-up information was obtained during routine ambu- whether Doppler echocardiographic variables add incre- latory visits but also by telephone contact with patients or mental value to QRS duration in determining the prognosis their physicians. All patients gave their informed consent of patients with CHF and systolic dysfunction. before study entry. Electrocardiography (ECG) analysis. QRS duration was METHODS measured in a 12-lead ECG using leads V3 to V6 (interob- Study patients. Two hundred seventy-one patients were server and intraobserver correlations for QRS duration: 0.97 recruited consecutively from our outpatient CHF clinic, and 0.98, respectively). which is jointly run by the Departments of Cardiology/ Echocardiography. All patients underwent a standard Angiology and Cardiothoracic Surgery in our institution. echo examination, including the assessment of transmitral peak early and late diastolic velocities (E, A) and decelera- From the Departments of *Cardiology and Angiology, †Thoracic and Cardiovas- tion time (DT). A RFP was defined by an E/A ratio Ͼ2, a cular Surgery, and ‡Electrophysiology, University Hospital of Münster, Münster, DT Ͻ150 ms, and a mitral annular E= velocity Ͻ8 cm/s (5). Germany Manuscript received October 30, 2004; revised manuscript received December 8, Tissue Doppler imaging (TDI)-derived peak systolic (S=), 2004, accepted December 21, 2004. early (E=), and late (A=) diastolic velocities were derived JACC Vol. 45, No. 7, 2005 Bruch et al. 1073 April 5, 2005:1072–5 ECG and Doppler Echo for Risk Stratification in Heart Failure

a prognostic index to classify patients into different risk Abbreviations and Acronyms groups. A p value of Ͻ0.05 was considered significant. A ϭ peak late diastolic mitral filling velocity A= ϭ peak late diastolic mitral annular velocity CHF ϭ chronic heart failure RESULTS DT ϭ deceleration time E ϭ peak early diastolic mitral filling velocity During a follow-up of 385 Ϯ 270 days, 24 patients suffered E= ϭ peak early diastolic mitral annular velocity ϭ ϭ an event (cardiac death, n 21; urgent cardiac transplan- ECG electrocardiography ϭ LVEF ϭ left ventricular ejection fraction tation, n 3) and thus reached the study end point. Eleven RFP ϭ restrictive filling pattern patients were censored (elective cardiac transplantation, n ϭ S= ϭ peak systolic mitral annular velocity 9; death from noncardiac cause, n ϭ 2). TDI ϭ tissue Doppler imaging Patients with or without event did not differ significantly with respect to the etiology of CHF, but QRS duration was significantly longer in patients with an event (Table 1). In such from the septal and lateral mitral annulus and averaged for patients, LVEF and DT were reduced, and RFP was more each patient (6). Interobserver and intraobserver correla- frequent (Table 2). The independent predictors of an event tions for conventional echo measurements and TDI vari- identified by the multivariate Cox analysis are listed in Table 3. ables reached 0.94 and 0.98, respectively. Survival analysis. In patients with a QRS duration Ͼ144 Outcome measurements and statistical analysis. Death ms, the event-free survival was significantly lower than in from a cardiac cause or urgent cardiac transplantation was patients with a QRS duration Յ144 ms (event-free survival considered as the combined study end point. Numerical rate of 69% vs. 90%, p ϭ 0.0021) (Fig. 1). In patients with a values are expressed as mean Ϯ SD. Continuous variables QRS duration Ͼ144 ms, the presence of a RFP indicated a were compared between groups using an unpaired t test (for poor prognosis (event-free survival rate 51% vs. 79% in those normally distributed variables) or Mann-Whitney U test with a non-RFP, p ϭ 0.023) (Fig. 2A). Likewise, in patients (for non-normally distributed variables). The chi-square test with a QRS duration Յ144 ms, a RFP indicated a less- was used to compare categoric variables. Clinical, ECG, and favorable outcome than that in patients without RFP (event- echo variables were evaluated for the combined study end free survival rate rate 59% vs. 97%, p Ͻ 0.0001) (Fig. 2B). point in a univariate Cox proportional hazard model. All Construction of a noninvasive risk score. The noninva- variables with a significant association were entered in a sive predictive model was based on the three strongest multivariate Cox model to identify independent predictors independent predictors, i.e., presence of a RFP, QRS of outcome. Receiver operating characteristic curves were duration Ͼ144 ms, and left ventricular systolic diameter generated to define cut-off values for independent predic- index Ͼ2.75 cm/m2. Very low-, low-, intermediate-, and tors. Event-free survival was analyzed by the Kaplan-Meier high-risk groups were identified by the absence of any risk method, and survival curves were compared by the log-rank factor or the presence of one, two, or three risk factors with test. Independent predictors identified by the multivariate an event-free survival of 100%, 91%, 64%, and 41%, Cox proportional hazard survival model were used to derive respectively (Fig. 3).

Table 1. Clinical Characteristics of Study Patients Total Patients With Event Patients Without Event p Value (169 ؍ n) (24 ؍ n) (193 ؍ n) Age (yrs) 58 Ϯ 11 64 Ϯ 11 57 Ϯ 11 0.01 Male/female (%) 76/24 87/13 75/25 0.164 BSA (m2) 1.9 Ϯ 0.2 1.9 Ϯ 0.2 1.9 Ϯ 0.2 0.427 ILVD/non-ILVD (%) 63/37 71/29 63/37 0.439 NYHA class 2.6 Ϯ 0.5 2.9 Ϯ 0.4 2.6 Ϯ 0.5 0.027 DM, n (%) 28 (15) 9 (38) 19 (11) Ͻ0.001 ICD, n (%) 81 (42) 6 (25) 75 (46) 0.111 QRS duration (ms) 137 Ϯ 37 159 Ϯ 38 133 Ϯ 36 0.002 LBBB (%) 66 (34) 12 (50) 54 (32) Ͻ0.001 Medication (%) ACE-I or ARB 96 100 95 0.264 Diuretics 87 96 86 0.169 Digoxin 61 67 60 0.51 Beta-blockers 87 71 89 0.016 Nitrates 27 29 26 0.777

Mann-Whitney U test was used for comparison of continuous variables owing to their non-normal distribution. ACE-I ϭ angiotensin-converting enzyme inhibitor; ARB ϭ angiotensin receptor blocker; BSA ϭ body surface area; DM ϭ diabetes mellitus; ICD ϭ implantable cardioverter-deﬁbrillator; ILVD ϭ ischemic left ventricular dysfunction; LBBB ϭ left bundle branch block; NYHA ϭ New York Heart Association. 1074 Bruch et al. JACC Vol. 45, No. 7, 2005 ECG and Doppler Echo for Risk Stratiﬁcation in Heart Failure April 5, 2005:1072–5

Table 2. Echocardiographic Characteristics of Study Patients Total Patients With Event Patients Without Event p Value (169 ؍ n) (24 ؍ n) (193 ؍ n) LAD (cm) 4.9 Ϯ 0.8 5.3 Ϯ 0.7 4.8 Ϯ 0.8 0.009 LVDDI (cm/m2) 3.5 Ϯ 0.5 3.7 Ϯ 0.5 3.5 Ϯ 0.5 0.141 LVSDI (cm/m2) 2.8 Ϯ 0.5 3.1 Ϯ 0.5 2.8 Ϯ 0.5 0.032 LVDVI (ml/m2) 116 Ϯ 46 133 Ϯ 51 113 Ϯ 45 0.056 LVSVI (ml/m2) 81 Ϯ 39 96 Ϯ 42 79 Ϯ 38 0.043 LVEF (%) 31 Ϯ 10 27 Ϯ 10 31 Ϯ 10 0.030 FS (%) 20 Ϯ 717Ϯ 520Ϯ 8 0.056 PW Doppler Mitral E/A ratio 1.58 Ϯ 1.02 2.19 Ϯ 1.12 1.49 Ϯ 0.96 0.003 DT 187 Ϯ 78 141 Ϯ 49 194 Ϯ 79 Ͻ0.001 RFP, n (%) 49 (25) 15 (63) 34 (20) Ͻ0.001 Tissue Doppler S= (cm/s) 4.85 Ϯ 1.18 4.3 Ϯ 0.88 4.93 Ϯ 1.19 0.022 E= (cm/s) 6.08 Ϯ 1.73 5.26 Ϯ 1.14 6.19 Ϯ 1.77 0.007 A= (cm/s) 6.62 Ϯ 2.28 5.22 Ϯ 1.68 6.81 Ϯ 2.29 0.002 E/E= ratio 12.9 Ϯ 6.4 15.5 Ϯ 5.1 12.5 Ϯ 6.4 0.004

An unpaired t test was used for comparison of LAD and LVEF (normal distribution), a Mann-Whitney U test was used for comparison of all other continuous variables (non-normal distribution). A ϭ peak late diastolic mitral filling velocity; A= ϭ peak late diastolic mitral annular velocity; DT ϭ deceleration time; E ϭ peak early diastolic mitral filling velocity; E= ϭ peak early diastolic mitral annular velocity; FS ϭ fractional shortening; LAD ϭ left atrial diameter; LV ϭ left ventricular; LVDDI ϭ LV end-diastolic diameter index; LVDVI ϭ LV end-diastolic volume index; LVEF ϭ LV ejection fraction; LVSDI ϭ LV end-systolic volume index; LVSVI ϭ LV systolic volume index; PW ϭ pulsed-wave; RFP ϭ restrictive filling pattern; S= ϭ peak systolic mitral annular velocity. DISCUSSION Our findings indicate that a combination of predictive factors more accurately predicts the individual risk than a This study is the first to combine the prognostic impact of single parameter or cut-off value. In our risk model, in the the ECG and the echocardiogram, two methods that are presence of two or three risk factors, outcome was signifi- routinely used in the follow-up of patients with CHF. The cantly worse as compared with the presence of Յ1 risk main finding is that a RFP provides independent prognostic factor. In the absence of any risk factor, no patient suffered information that is incremental to QRS duration in patients a cardiac event during follow-up (Fig. 3). The variables with CHF. considered in our model are readily available in the daily Given the increasing number of individuals affected by clinical setting and are cost-effective, enabling serial CHF, risk stratification is of tremendous importance. In such follow-up examinations. Other markers, such as natriuretic patients, QRS prolongation is a known predictor of adverse peptides or TDI analysis of left ventricular asynchrony (8), outcome. Shamim et al. (2) found a mortality of 50% in CHF may have added further prognostic information but were patients with a QRS duration Ͼ140 ms as opposed to a not considered in the present analysis. mortality of 23% in the remaining patients. However, our For the TDI-derived mitral annular E= velocity, Wang et al. study and others show that although QRS prolongation has (9) recently reported an incremental predictive power for prognostic value, there is a substantial overlap of QRS duration cardiac mortality compared with standard clinical and echo between patients with or without event (Table 2). In this measurements. However, in their study, patients with various setting, the assessment of diastolic function added incremental prognostic information. In CHF patients with or without QRS prolongation, outcome was significantly worse in the presence of a RFP (Figs. 2A and 2B). These findings are in line with observations by Hansen et al. (7), who found an incremental value of a RFP to peak oxygen consumption in determining the prognosis in patients with CHF. Table 3. Multivariate Cox Proportional Hazard Analysis: Predictors of Cardiac Events Relative Risk Variable Chi-Square (95% CI) p Value RFP 19.93 6.62 (2.7–16.4) Ͻ0.0001 QRS duration Ͼ144 ms 10.96 4.26 (1.7–10.6) Ͻ0.0001 LVSDI Ͼ2.75 cm/m2 4.82 3.34 (1.1–10.3) 0.028 E= Ͻ5.5 cm/s 4.82 2.48 (1.0–6.0) 0.04 Figure 1. Kaplan-Meier survival curves in subgroups of patients according CI ϭ confidence interval; E= ϭ peak early diastolic mitral annular velocity; LVSDI ϭ to a QRS duration Ͻ144 ms and Ͼ144 ms. Comparison between groups left ventricular systolic diameter index; RFP ϭ restrictive filling pattern. by log-rank test yielded a significant difference (p ϭ 0.021). JACC Vol. 45, No. 7, 2005 Bruch et al. 1075 April 5, 2005:1072–5 ECG and Doppler Echo for Risk Stratification in Heart Failure

Figure 3. Risk model based on a restrictive ﬁlling pattern, QRS duration Ͼ144 ms, and left ventricular systolic diameter index Ͼ2.75 cm/m2. Notably, in subjects without any risk factor (RF) the event-free survival was 100%.

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