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Clinical characteristics and survival of patients with chronic heart failure and prolonged QRS duration
International Journal of Cardiology 86 (2002) 225–231 www.elsevier.com / locate / ijcard
Clinical characteristics and survival of patients with chronic heart failure and prolonged QRS duration Paul R. Kalra a , Rakesh Sharma a , Waqar Shamim a , Wolfram Doehner a,b , Roland Wensel a,b , Aidan P. Bolger a , Sabine Genth-Zotz a , Mariantonietta Cicoira a , Andrew J.S. Coats a , a,b , Stefan D. Anker * a
b
Clinical Cardiology, National Heart and Lung Institute, Dovehouse Street, London SW3 6 LY, UK ¨ Centrum for Molecular Medicine, Berlin, Germany Department of Cardiology, Charite´ , Campus Berlin-Buch at Max Delbruck Received 23 April 2002; accepted 20 May 2002
Abstract Background: Abnormal prolongation of QRS duration is a common finding in patients with chronic heart failure, and is associated with an impaired prognosis. The optimum QRS duration for separating chronic heart failure patients with respect to prognosis has not been determined. Whilst resynchronisation of ventricular conduction may benefit patients with QRS.150 ms, this has yet to be determined for patients with moderate QRS prolongation. Methods: We evaluated 155 patients with chronic heart failure (New York Heart Association class 2.660.8, mean6S.D.). The mean follow-up period was 8386748 days. Patients were sub-grouped according to QRS duration: ,120 ms (normal QRS, n582), 120–150 ms (moderate prolongation, n544) and .150 ms (severe prolongation, n529). Results: The optimal QRS duration for stratifying patients for 2-year event free survival was 120 ms (receiver operating characteristic analysis: area under curve 0.73; 95% CI 0.64–0.81). Moderate prolongation of QRS duration was associated with a worse New York Heart Association class, peak oxygen consumption and left ventricular ejection fraction when compared to patients with normal QRS duration (all P,0.05). Patients with moderate prolongation of QRS duration had similar impairment of New York Heart Association class and peak oxygen consumption as compared with patients with QRS duration .150 ms (all P.0.05). Conclusions: The optimum QRS duration for stratifying patients for medium to long-term event-free survival was 120 ms. Heart failure patients with moderate QRS prolongation share similar impairment of exercise capacity and functional class to those with severe prolongation. 2002 Elsevier Science Ireland Ltd. All rights reserved.
1. Introduction With an ageing population and improved survival post myocardial infarction the prevalence of heart failure has continued to increase; it is now the leading cause of hospitalisation in the Western World [1,2]. Despite the introduction of new drug therapies, chronic heart failure is still associated with a high *Corresponding author. Tel.: 144-2073-518-513; fax: 144-2073-518733. E-mail address: [email protected] (S.D. Anker).
mortality and morbidity, with many patients continuing to suffer unremitting symptoms and poor quality of life [3]. It is important to readily identify patients with a particularly poor prognosis in order to enable the implementation of novel therapies to improve this dismal outlook. Previous studies have demonstrated that prolongation of QRS duration determined from the resting electrocardiogram is associated with an impaired prognosis in patients with chronic heart failure [4,5]. To date, the optimum QRS duration for stratifying patients with respect to prognosis has not been
0167-5273 / 02 / $ – see front matter 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 02 )00270-X
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determined. Recent interest has focused on the potential benefits of resynchronisation of ventricular conduction with biventricular pacing. In patients with advanced, symptomatic heart failure and QRS duration .150 ms (chosen empirically), biventricular pacing improved both exercise tolerance and quality of life [6]. Whether it is of benefit in patients with QRS duration below 150 ms is not yet clear. Up to 40% of patients with chronic heart failure have evidence of prolongation of QRS duration ($120 ms) [4,7] and therefore large numbers of patients may be potential candidates for biventricular pacing. Few data are currently available regarding the clinical characteristics of chronic heart failure patients with moderate QRS prolongation. The aim of this study was to determine the cut-off for QRS duration that provides optimal separation of chronic heart failure patients into those with a relatively benign or poor prognosis, respectively. We also sought to compare heart failure patients with moderate prolongation of QRS duration (i.e. 120–150 ms) with those with severe QRS prolongation (i.e., .150 ms) and normal QRS duration (i.e., ,120 ms) in terms of clinical severity.
2. Methods We investigated 155 patients with chronic heart failure of varying degrees of severity (New York Heart Association class I–IV, mean6S.D. 2.660.8) secondary to left ventricular systolic impairment. All patients were attending the heart failure clinic of the Royal Brompton Hospital and were recruited as part of our metabolic study programme (Table 1). The diagnosis of heart failure was based on symptoms, examination and appropriate investigations (chest Xray, echocardiogram, radionucleotide ventriculography). During follow up, death or heart transplantation were classified as a significant event. Patient deaths were confirmed by the National Registry. All patients were in sinus rhythm, without permanent pacemaker, and were taking conventional heart failure therapy. Patients with uninterpretable or poor quality electrocardiographic tracings were excluded. All patients underwent standard 12-lead resting electrocardiography, recorded on a Hewlett-Packard Xli Page Writer (calibration 0.1 mV/ mm, paper speed
Table 1 Clinical characteristics of 155 patients with chronic heart failure All CHF patients Age (years) Sex (M / F) Creatinine (mmol / l) Uric acid (mmol / l) NYHA class QRS duration (ms) LVEF (%) (n5133) Peak VO 2 (ml / kg per min) (n5149) VE /VCO 2 slope
61611 133 / 22 121642 4916160 2.660.8 124634 2369 16.264.6 38.3611.9
LVEF, left ventricular ejection fraction; NYHA, New York Heart Association class; VCO 2 , carbon dioxide production; VE , minute ventilation; VO 2 , oxygen consumption (mean6S.D.).
25 mm / s). The QRS duration was measured manually from the chest lead V2 with electronic callipers. The final value was determined from the average of three measurements. Serum creatinine and uric acid were measured in all patients. Maximal exercise testing was performed in 149 (96%) patients according to the modified Bruce protocol as previously described [8]. In summary, patients breathed air through a mouthpiece with a nose clip in place. A respiratory mass spectrometer (Amis, Innovision, Denmark) was used to monitor oxygen consumption and carbon dioxide production on-line on a breath-by-breath basis.
2.1. Statistical analysis All results are presented as mean6S.D. Data were analysed using Stat View 4.5 (Abacus Concepts, Berkeley, CA, USA). Differences between groups were assessed using ANOVA and Fisher’s post hoc test was applied as appropriate. Simple regression analysis was performed. The receiver-operating characteristic (ROC) curve for QRS duration was drawn and the area under the curve calculated (MedCalc 5.0, MedCalc, Belgium). The cut off level that resulted in the highest product of sensitivity and specificity was considered the optimum level for predicting outcome. Cox proportional hazards analysis was performed using baseline values to assess the association between QRS duration and outcome. The hazard ratio (RR) and 95% confidence interval (CI) as well as significance levels for x 2 (likelihood ratio test) were calculated and a Kaplan–Meier cumulative
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survival plot was constructed. A P value of ,0.05 was considered statistically significant.
3. Results
3.1. QRS duration and mortality Of the 155 patients, who were followed-up for a mean of 8386748 days (range 4–2531 days), 62 patients died or underwent heart transplantation after 4–2160 days (mean 4826514). The mean follow-up period of the remaining 93 patients was 10756787 days. Receiver–operating characteristic curves were plotted for QRS duration. At 2 years, the optimal QRS duration for separating patients into those with a relatively benign prognosis versus those with an adverse prognosis (increased risk of death or heart transplantation) was 120 ms (area under the curve 0.73; 95% CI 0.64–0.81) (Fig. 1a). Receiver–operating characteristic curves were also calculated for 6 months, and 1, 3 and 5 years; the optimal QRS duration for separating patients by event-free survival was 129 (area under the curve 0.74; 95% CI 0.66– 0.81), 134 (area under the curve 0.71; 95% CI 0.63– 0.79), 120 (area under the curve 0.68; 95% CI 0.58– 0.77) and 118 (area under the curve 0.61; 95% CI 0.49–0.71) ms, respectively (curves not shown). In view of the fact that the optimum QRS duration for stratifying patients for medium to long-term event-free survival was 120 ms, this value was used as a cut-off to perform Kaplan–Meier survival analysis (Fig. 1b). Heart failure patients with a QRS duration of $120 ms had a relative risk of death or heart transplantation of 3.2 (95% CI 1.9–5.7) as compared to patients with QRS duration ,120 ms. The cumulative event-free survival of patients at 2 years was 46.9% (95% CI 34.7–59.1) for patients with QRS$120 ms and 83.7% (95% CI 74.5–92.9) for patients with QRS,120 ms, respectively (P, 0.0001). Having established 120 ms as the optimum QRS duration for stratifying chronic heart failure patients by prognosis, we proceeded to compare the clinical characteristics of patients below and above this cutoff.
Fig. 1. (a) Receiver–operating characteristic curves for 2-year event-free survival for QRS duration in patients with chronic heart failure. (b) Kaplan–Meier survival plot for 155 patients with chronic heart failure: patients sub-grouped according to QRS duration.
3.2. Clinical characteristics of CHF patients subgrouped according to QRS duration ( Table 2 and Fig. 2) Subjects were subsequently sub-grouped into three categories according to QRS duration: ,120 ms (group A, normal QRS, 99611 ms, n582), 120–150 ms (group B, moderate prolongation, 13369 ms, n544) and .150 ms (group C, severe prolongation, 181620 ms, n529). Compared to patients with normal QRS duration (group A), patients in group B had significant impairment in both left ventricular ejection fraction (15% reduction) and peak oxygen consumption (16% reduction). In addition, they had a steeper (15%) VE /VCO 2 slope and were in a higher New York Heart Association class (Fig. 2). In contrast, patients in group B had similar limita-
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Table 2 Clinical characteristics of 155 patients with chronic heart failure sub-grouped according to QRS duration
Age (years) Creatinine (mmol / l) Uric acid (mmol / l) NYHA class QRS duration (ms) LVEF (%) (n) Peak Vo 2 (ml / kg per min) (n) VE /VCO 2 slope
Normal QRS (Group A) (,120 ms, n582)
Moderate QRS prolongation (Group B) (120–150 ms, n544)
Severe QRS prolongation (Group C) (.150 ms, n529)
59612 113635 4686148 2.460.8 99611 2669 (66) 17.764.4 (77) 35.9610.6
61611 119634 ‡ 4996154 3.061.0* 13369 2269* uu (40) 14.964.5** (43) 41.2613.2*
6467 144658** 5416193 2.760.7 181620 18610** (27) 14.364.3** (29) 41.2612.3 §
NYHA, New York Heart Association class; LVEF, left ventricular ejection fraction; VO 2 , oxygen consumption; VE , minute ventilation; VCO 2 , carbon dioxide production (mean6S.D.). *P,0.05 compared to group A; **P,0.001 compared to group A; ‡ P,0.05 compared to group C; § P50.06 compared to group A; i P50.053 compared to group C.
tion of exercise and functional capacity, together with VE /VCO 2 slope to those in group C. Serum creatinine was lower (17%) in patients in group B, and a trend towards better left ventricular function was seen when this group was compared to those patients in group C.
3.3. Relationship of QRS duration to other variables Weak correlations were found between QRS duration and other clinical characteristics, already validated as important prognostic indicators in chronic heart failure: peak oxygen consumption (P,0.0001,
Fig. 2. Comparison of left ventricular ejection fraction, New York Heart Association class, peak oxygen consumption and VE /VCO 2 slope in patients with chronic heart failure grouped according to QRS duration. Patients with abnormal prolongation of QRS duration demonstrate impaired left ventricular function and exercise capacity when compared to patients with normal QRS duration. In contrast, patients with moderate (120–150 ms) and severe (.150 ms) prolongation of QRS duration appear to share similar clinical characteristics. LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; VCO 2 , carbon dioxide production; VE , minute ventilation; VO 2 , oxygen consumption.
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R50.34), left ventricular ejection fraction (P50.001, R50.32), serum creatinine (P,0.001, R50.28), New York Heart Association class (P,0.05, R50.21), age (P,0.05, R50.19), VE /VCO 2 slope (P,0.05, R50.19) and serum uric acid (P,0.05, R50.17).
4. Discussion The present study has shown for the first time that the optimal QRS duration for stratifying chronic heart failure patients for medium to long-term (2 and 3 years) event-free survival is 120 ms. Patients with a QRS duration of $120 ms have a relative risk of death or heart transplantation of 3.2 as compared to patients with QRS duration ,120 ms. Several investigative methods and clinical characteristics have been validated as important prognostic indicators in chronic heart failure. These include peak oxygen consumption and VE /VCO 2 slope [9], left ventricular ejection fraction [10], raised inflammatory cytokines [11], catecholamines [12], the erythrocyte sedimentation rate [13], and metabolic abnormalities such as elevated serum uric acid [14] and the development of cachexia [15]. This study, together with previous ones [4,5,16,17], has confirmed that analysis of the resting electrocardiogram may also be of help; this is particularly useful since it is an inexpensive test that is readily available both in primary and secondary care. The majority of previous studies compared patients with QRS duration ,120 ms with patients with QRS duration $120 ms [16,17]. The decision to choose a cut-off of 120 ms was presumably based on data derived from studies in healthy individuals. Whilst in earlier publications the upper limit of QRS duration in healthy adult males was deemed to be 100 ms [18], it is now generally accepted that an upper limit of 120 ms is more appropriate [19]. This value has been obtained from studies involving large numbers of healthy subjects, such as that by Selvester et al. [20]. They evaluated the electrocardiograms of over 1200 healthy white males and concluded that a QRS duration $120 ms was probably abnormal. However, in patients recovering from a myocardial infarction borderline QRS prolongation (90–110 ms) has recently been shown to predict increased mortality,
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emphasising the need to formally establish the optimum cut-off in specific disease states [21]. Since patients with chronic heart failure are known to have a poor prognosis [3], we have presented data for 2-year survival. The finding that cumulative event-free survival in patients with QRS duration $120 ms at this time point was less than 50% supports this decision. The optimum QRS duration for predicting long-term (5-year) survival was actually very similar at 118 ms. We have also shown that patients with chronic heart failure and moderately prolonged QRS duration (120–150 ms) have reduced exercise and functional capacity, together with left ventricular ejection fraction when compared to chronic heart failure patients with normal QRS duration. In contrast, patients with moderate prolongation of QRS duration are in similar NYHA class to patients with a QRS.150 ms and display a comparable reduction in peak oxygen consumption and increase in VE /VCO 2 slope. Abnormal prolongation of QRS duration may adversely contribute to the haemodynamic abnormalities and debilitating symptoms seen in patients with chronic heart failure as a result of ventricular asynchrony and exacerbating functional mitral regurgitation [22–24]. Ventricular resynchronization, with simultaneous stimulation of the right and left ventricles via transvenous pacing leads, represents a promising new therapeutic option for such patients with symptomatic, advanced heart failure. Several small studies have shown that ventricular electromechanical resynchronization can acutely improve left ventricular systolic function and reduce the severity of functional mitral regurgitation in this group of patients [25,26]. In light of these findings larger clinical trials have been initiated in an attempt to evaluate the longer-term effect of ventricular resynchronization on haemodynamic parameters, functional status and mortality (reviewed by Barold [27]). The Multisite Stimulation in Cardiomyopathy (MUSTIC) trial evaluated biventricular pacing in patients with symptomatic heart failure (New York Heart Association class III, LVEF,35%) and a QRS.150 ms (174620 ms) [6]. Biventricular pacing was associated with significantly improved exercise tolerance and quality of life. The Multicenter Insynch Randomized Clinical Evaluation (MIRACLE) trial
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confirmed that ventricular resynchronisation improved quality of life, functional class and LVEF, together with reducing ventricular size in chronic heart failure patients in New York Heart Association class III or IV [28]. Whilst it was stipulated that at enrolment patients should have QRS duration $130 ms, the mean QRS duration of recruited patients was substantially higher at 165 ms. Data are currently lacking as to whether patients with symptomatic heart failure and moderate prolongation of QRS duration gain similar symptomatic benefit to patients with QRS.150 ms. In this study we have shown that these groups of patients demonstrate similar limitation of functional capacity and severity of heart failure, together with a substantially impaired prognosis. We therefore believe that more patients with chronic heart failure and QRS duration 120–150 ms merit inclusion in trials evaluating the benefits of biventricular pacing.
with chronic heart failure the optimum QRS duration for stratifying medium and long-term event-free survival is 120 ms. In addition, patients with chronic heart failure and moderate prolongation of QRS duration share similar impairment of exercise capacity and functional class with patients who have severe QRS prolongation (.150 ms). Therefore all chronic heart failure patients with abnormal QRS duration require careful evaluation. Recent studies have shown that biventricular pacing can improve functional capacity and quality of life in heart failure patients with QRS duration in excess of 150 ms and this represents a novel therapeutic strategy in symptomatic patients resistant to conventional medication. Whether this mode of therapy would be of benefit for patients with a moderate prolongation of QRS duration (120–150 ms) is not known and requires further evaluation in prospective clinical trials.
4.1. Study limitations
Acknowledgements
This current study provides a description of the clinical characteristics of a cohort of chronic heart failure patients with varying degrees of QRS prolongation, recruited for metabolic assessment as part of an ongoing study programme. Although it shows that patients with a moderate prolongation of QRS duration share many characteristics with patients (QRS.150 ms) in whom biventricular pacing has been shown to alleviate symptoms, it does not attempt to identify a lower QRS threshold at which this intervention might be considered. This clearly requires meticulous assessment in the form of a prospective, randomized, double-blind, controlled study. We performed manual assessment of QRS duration from the resting electrocardiogram. Although we appreciate that this is subject to potential errors, we also feel that this is justifiable since it is the method utilised in routine clinical practice and commonly in the assessment of patients for suitability for entry into clinical trials.
PRK, APB and the Department of Clinical Cardiology are supported by the British Heart Foundation. PRK was previously supported by Wessex Heartbeat and the Waring Trust. RS is supported by the Robert Luff Foundation. AJS Coats is supported by the Viscount Royston Trust. S.D. Anker is supported ¨ with a postgraduate fellowship of the Max Delbruck Centrum for Molecular Medicine, Berlin, Germany.
5. Conclusions We have shown for the first time that in patients
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P.R. Kalra et al. / International Journal of Cardiology 86 (2002) 225–231 [7] Aaronson KD, Schwartz JS, Chen TM, Wong KL, Goin JE, Mancini DM. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 1997;95:2660–7. [8] Anker SD, Swan JW, Volterrani M et al. The influence of muscle mass, strength, fatigability and blood flow on exercise capacity in cachectic and non-cachectic patients with chronic heart failure. Eur Heart J 1997;18:259–69. [9] Ponikowski P, Francis DP, Piepoli MF et al. Enhanced ventilatory response to exercise in patients with chronic heart failure and preserved exercise tolerance: marker of abnormal cardiorespiratory reflex control and predictor of poor prognosis. Circulation 2001;103:967–72. [10] Cohn JN, Johnson GR, Shabetai R et al. Ejection fraction, peak exercise oxygen consumption, cardiothoracic ratio, ventricular arrhythmias, and plasma norepinephrine as determinants of prognosis in heart failure. The V-HeFT VA Cooperative Studies Group. Circulation 1993;87:VI5–16. [11] Rauchhaus M, Doehner W, Francis DP et al. Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation 2000;102:3060–7. [12] Cohn JN, Levine TB, Olivari MT et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. New Engl J Med 1984;311:819–23. [13] Sharma R, Rauchhaus M, Ponikowski PP et al. The relationship of the erythrocyte sedimentation rate to inflammatory cytokines and survival in patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors. J Am Coll Cardiol 2000;36:523– 8. [14] Anker SD, Rauchhaus M, Doehner W et al. Uric acid and survival in chronic heart failure: validation and first attempts at metabolic, functional and haemodynamic staging. Eur Heart J (Abstract) 2000;21:1631. [15] Anker SD, Ponikowski P, Varney S et al. Wasting as independent risk factor for mortality in chronic heart failure. Lancet 1997;349:1050– 3. [16] Unverferth DV, Magorien RD, Moeschberger ML, Baker PB, Fetters JK, Leier CV. Factors influencing the one-year mortality of dilated cardiomyopathy. Am J Cardiol 1984;54:147–52.
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[17] Koga Y, Wada T, Toshima H, Akazawa K, Nose Y. Prognostic significance of electrocardiographic findings in patients with dilated cardiomyopathy. Heart Vessels 1993;8:37–41. [18] Friedman H. In: Diagnostic electrocardiography and vectorcardiography, 3rd ed., New York: McGraw-Hill, 1985. [19] Braunwald E, Zipes DP, Libby P. In: Heart disease: a textbook of cardiovascular medicine, 6th ed, Philadelphia, PA: WB Saunders, 2001, p. 92. [20] Selvester RH, Velasquez DW, Elko PP, Cady LD. Intraventricular conduction defect (IVCD), real or fancied, QRS duration in 1,254 normal adult white males by a multilead automated algorithm. J Electrocardiol 1990;23(Suppl.):118–22. [21] Pudil R, Feinberg MS, Hod H, Boyko V, Mandelzweig L, Behar S. The prognostic significance of intermediate QRS prolongation in acute myocardial infarction. Int J Cardiol 2001;78:233–9. [22] Xiao HB, Brecker SJ, Gibson DG. Effects of abnormal activation on the time course of left ventricular pressure pulse in dilated cardiomyopathy. Br Heart J 1992;68:403–7. [23] Grines LC, Bashore TM, Boudoulas H, Olson S, Shafer P, Wooley CF. Functional abnormalities in isolated left bundle branch block. The effect of interventricular asynchrony. Circulation 1989;79:845– 53. [24] Erlebacher JA, Barbarash S. Intraventricular conduction delay and functional mitral regurgitation. Am J Cardiol 2001;88:83–6. [25] Etienne Y, Mansourati J, Touiza A et al. Evaluation of left ventricular function and mitral regurgitation during left ventricularbased pacing in patients with heart failure. Eur J Heart Fail 2001;3:441–7. [26] Nelson GS, Berger RD, Fetics BJ et al. Left ventricular or biventricular pacing improves cardiac function at diminished energy cost in patients with dilated cardiomyopathy and left bundle branch block. Circulation 2000;102:3053–9. [27] Barold SS. What is cardiac resynchronization therapy? Am J Med 2001;111:224–32. [28] Louis A, Cleland JG, Crabbe S et al. Clinical Trials Update: CAPRICORN, COPERNICUS, MIRACLE, STAF, RITZ-2, RECOVER and RENAISSANCE and cachexia and cholesterol in heart failure. Highlights of the Scientific Sessions of the American College of Cardiology, 2001. Eur J Heart Fail 2001;3:381–7.
Clinical characteristics and survival of patients with chronic heart failure and prolonged QRS duration Paul R. Kalra a , Rakesh Sharma a , Waqar Shamim a , Wolfram Doehner a,b , Roland Wensel a,b , Aidan P. Bolger a , Sabine Genth-Zotz a , Mariantonietta Cicoira a , Andrew J.S. Coats a , a,b , Stefan D. Anker * a
b
Clinical Cardiology, National Heart and Lung Institute, Dovehouse Street, London SW3 6 LY, UK ¨ Centrum for Molecular Medicine, Berlin, Germany Department of Cardiology, Charite´ , Campus Berlin-Buch at Max Delbruck Received 23 April 2002; accepted 20 May 2002
Abstract Background: Abnormal prolongation of QRS duration is a common finding in patients with chronic heart failure, and is associated with an impaired prognosis. The optimum QRS duration for separating chronic heart failure patients with respect to prognosis has not been determined. Whilst resynchronisation of ventricular conduction may benefit patients with QRS.150 ms, this has yet to be determined for patients with moderate QRS prolongation. Methods: We evaluated 155 patients with chronic heart failure (New York Heart Association class 2.660.8, mean6S.D.). The mean follow-up period was 8386748 days. Patients were sub-grouped according to QRS duration: ,120 ms (normal QRS, n582), 120–150 ms (moderate prolongation, n544) and .150 ms (severe prolongation, n529). Results: The optimal QRS duration for stratifying patients for 2-year event free survival was 120 ms (receiver operating characteristic analysis: area under curve 0.73; 95% CI 0.64–0.81). Moderate prolongation of QRS duration was associated with a worse New York Heart Association class, peak oxygen consumption and left ventricular ejection fraction when compared to patients with normal QRS duration (all P,0.05). Patients with moderate prolongation of QRS duration had similar impairment of New York Heart Association class and peak oxygen consumption as compared with patients with QRS duration .150 ms (all P.0.05). Conclusions: The optimum QRS duration for stratifying patients for medium to long-term event-free survival was 120 ms. Heart failure patients with moderate QRS prolongation share similar impairment of exercise capacity and functional class to those with severe prolongation. 2002 Elsevier Science Ireland Ltd. All rights reserved.
1. Introduction With an ageing population and improved survival post myocardial infarction the prevalence of heart failure has continued to increase; it is now the leading cause of hospitalisation in the Western World [1,2]. Despite the introduction of new drug therapies, chronic heart failure is still associated with a high *Corresponding author. Tel.: 144-2073-518-513; fax: 144-2073-518733. E-mail address: [email protected] (S.D. Anker).
mortality and morbidity, with many patients continuing to suffer unremitting symptoms and poor quality of life [3]. It is important to readily identify patients with a particularly poor prognosis in order to enable the implementation of novel therapies to improve this dismal outlook. Previous studies have demonstrated that prolongation of QRS duration determined from the resting electrocardiogram is associated with an impaired prognosis in patients with chronic heart failure [4,5]. To date, the optimum QRS duration for stratifying patients with respect to prognosis has not been
0167-5273 / 02 / $ – see front matter 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 02 )00270-X
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determined. Recent interest has focused on the potential benefits of resynchronisation of ventricular conduction with biventricular pacing. In patients with advanced, symptomatic heart failure and QRS duration .150 ms (chosen empirically), biventricular pacing improved both exercise tolerance and quality of life [6]. Whether it is of benefit in patients with QRS duration below 150 ms is not yet clear. Up to 40% of patients with chronic heart failure have evidence of prolongation of QRS duration ($120 ms) [4,7] and therefore large numbers of patients may be potential candidates for biventricular pacing. Few data are currently available regarding the clinical characteristics of chronic heart failure patients with moderate QRS prolongation. The aim of this study was to determine the cut-off for QRS duration that provides optimal separation of chronic heart failure patients into those with a relatively benign or poor prognosis, respectively. We also sought to compare heart failure patients with moderate prolongation of QRS duration (i.e. 120–150 ms) with those with severe QRS prolongation (i.e., .150 ms) and normal QRS duration (i.e., ,120 ms) in terms of clinical severity.
2. Methods We investigated 155 patients with chronic heart failure of varying degrees of severity (New York Heart Association class I–IV, mean6S.D. 2.660.8) secondary to left ventricular systolic impairment. All patients were attending the heart failure clinic of the Royal Brompton Hospital and were recruited as part of our metabolic study programme (Table 1). The diagnosis of heart failure was based on symptoms, examination and appropriate investigations (chest Xray, echocardiogram, radionucleotide ventriculography). During follow up, death or heart transplantation were classified as a significant event. Patient deaths were confirmed by the National Registry. All patients were in sinus rhythm, without permanent pacemaker, and were taking conventional heart failure therapy. Patients with uninterpretable or poor quality electrocardiographic tracings were excluded. All patients underwent standard 12-lead resting electrocardiography, recorded on a Hewlett-Packard Xli Page Writer (calibration 0.1 mV/ mm, paper speed
Table 1 Clinical characteristics of 155 patients with chronic heart failure All CHF patients Age (years) Sex (M / F) Creatinine (mmol / l) Uric acid (mmol / l) NYHA class QRS duration (ms) LVEF (%) (n5133) Peak VO 2 (ml / kg per min) (n5149) VE /VCO 2 slope
61611 133 / 22 121642 4916160 2.660.8 124634 2369 16.264.6 38.3611.9
LVEF, left ventricular ejection fraction; NYHA, New York Heart Association class; VCO 2 , carbon dioxide production; VE , minute ventilation; VO 2 , oxygen consumption (mean6S.D.).
25 mm / s). The QRS duration was measured manually from the chest lead V2 with electronic callipers. The final value was determined from the average of three measurements. Serum creatinine and uric acid were measured in all patients. Maximal exercise testing was performed in 149 (96%) patients according to the modified Bruce protocol as previously described [8]. In summary, patients breathed air through a mouthpiece with a nose clip in place. A respiratory mass spectrometer (Amis, Innovision, Denmark) was used to monitor oxygen consumption and carbon dioxide production on-line on a breath-by-breath basis.
2.1. Statistical analysis All results are presented as mean6S.D. Data were analysed using Stat View 4.5 (Abacus Concepts, Berkeley, CA, USA). Differences between groups were assessed using ANOVA and Fisher’s post hoc test was applied as appropriate. Simple regression analysis was performed. The receiver-operating characteristic (ROC) curve for QRS duration was drawn and the area under the curve calculated (MedCalc 5.0, MedCalc, Belgium). The cut off level that resulted in the highest product of sensitivity and specificity was considered the optimum level for predicting outcome. Cox proportional hazards analysis was performed using baseline values to assess the association between QRS duration and outcome. The hazard ratio (RR) and 95% confidence interval (CI) as well as significance levels for x 2 (likelihood ratio test) were calculated and a Kaplan–Meier cumulative
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survival plot was constructed. A P value of ,0.05 was considered statistically significant.
3. Results
3.1. QRS duration and mortality Of the 155 patients, who were followed-up for a mean of 8386748 days (range 4–2531 days), 62 patients died or underwent heart transplantation after 4–2160 days (mean 4826514). The mean follow-up period of the remaining 93 patients was 10756787 days. Receiver–operating characteristic curves were plotted for QRS duration. At 2 years, the optimal QRS duration for separating patients into those with a relatively benign prognosis versus those with an adverse prognosis (increased risk of death or heart transplantation) was 120 ms (area under the curve 0.73; 95% CI 0.64–0.81) (Fig. 1a). Receiver–operating characteristic curves were also calculated for 6 months, and 1, 3 and 5 years; the optimal QRS duration for separating patients by event-free survival was 129 (area under the curve 0.74; 95% CI 0.66– 0.81), 134 (area under the curve 0.71; 95% CI 0.63– 0.79), 120 (area under the curve 0.68; 95% CI 0.58– 0.77) and 118 (area under the curve 0.61; 95% CI 0.49–0.71) ms, respectively (curves not shown). In view of the fact that the optimum QRS duration for stratifying patients for medium to long-term event-free survival was 120 ms, this value was used as a cut-off to perform Kaplan–Meier survival analysis (Fig. 1b). Heart failure patients with a QRS duration of $120 ms had a relative risk of death or heart transplantation of 3.2 (95% CI 1.9–5.7) as compared to patients with QRS duration ,120 ms. The cumulative event-free survival of patients at 2 years was 46.9% (95% CI 34.7–59.1) for patients with QRS$120 ms and 83.7% (95% CI 74.5–92.9) for patients with QRS,120 ms, respectively (P, 0.0001). Having established 120 ms as the optimum QRS duration for stratifying chronic heart failure patients by prognosis, we proceeded to compare the clinical characteristics of patients below and above this cutoff.
Fig. 1. (a) Receiver–operating characteristic curves for 2-year event-free survival for QRS duration in patients with chronic heart failure. (b) Kaplan–Meier survival plot for 155 patients with chronic heart failure: patients sub-grouped according to QRS duration.
3.2. Clinical characteristics of CHF patients subgrouped according to QRS duration ( Table 2 and Fig. 2) Subjects were subsequently sub-grouped into three categories according to QRS duration: ,120 ms (group A, normal QRS, 99611 ms, n582), 120–150 ms (group B, moderate prolongation, 13369 ms, n544) and .150 ms (group C, severe prolongation, 181620 ms, n529). Compared to patients with normal QRS duration (group A), patients in group B had significant impairment in both left ventricular ejection fraction (15% reduction) and peak oxygen consumption (16% reduction). In addition, they had a steeper (15%) VE /VCO 2 slope and were in a higher New York Heart Association class (Fig. 2). In contrast, patients in group B had similar limita-
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Table 2 Clinical characteristics of 155 patients with chronic heart failure sub-grouped according to QRS duration
Age (years) Creatinine (mmol / l) Uric acid (mmol / l) NYHA class QRS duration (ms) LVEF (%) (n) Peak Vo 2 (ml / kg per min) (n) VE /VCO 2 slope
Normal QRS (Group A) (,120 ms, n582)
Moderate QRS prolongation (Group B) (120–150 ms, n544)
Severe QRS prolongation (Group C) (.150 ms, n529)
59612 113635 4686148 2.460.8 99611 2669 (66) 17.764.4 (77) 35.9610.6
61611 119634 ‡ 4996154 3.061.0* 13369 2269* uu (40) 14.964.5** (43) 41.2613.2*
6467 144658** 5416193 2.760.7 181620 18610** (27) 14.364.3** (29) 41.2612.3 §
NYHA, New York Heart Association class; LVEF, left ventricular ejection fraction; VO 2 , oxygen consumption; VE , minute ventilation; VCO 2 , carbon dioxide production (mean6S.D.). *P,0.05 compared to group A; **P,0.001 compared to group A; ‡ P,0.05 compared to group C; § P50.06 compared to group A; i P50.053 compared to group C.
tion of exercise and functional capacity, together with VE /VCO 2 slope to those in group C. Serum creatinine was lower (17%) in patients in group B, and a trend towards better left ventricular function was seen when this group was compared to those patients in group C.
3.3. Relationship of QRS duration to other variables Weak correlations were found between QRS duration and other clinical characteristics, already validated as important prognostic indicators in chronic heart failure: peak oxygen consumption (P,0.0001,
Fig. 2. Comparison of left ventricular ejection fraction, New York Heart Association class, peak oxygen consumption and VE /VCO 2 slope in patients with chronic heart failure grouped according to QRS duration. Patients with abnormal prolongation of QRS duration demonstrate impaired left ventricular function and exercise capacity when compared to patients with normal QRS duration. In contrast, patients with moderate (120–150 ms) and severe (.150 ms) prolongation of QRS duration appear to share similar clinical characteristics. LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; VCO 2 , carbon dioxide production; VE , minute ventilation; VO 2 , oxygen consumption.
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R50.34), left ventricular ejection fraction (P50.001, R50.32), serum creatinine (P,0.001, R50.28), New York Heart Association class (P,0.05, R50.21), age (P,0.05, R50.19), VE /VCO 2 slope (P,0.05, R50.19) and serum uric acid (P,0.05, R50.17).
4. Discussion The present study has shown for the first time that the optimal QRS duration for stratifying chronic heart failure patients for medium to long-term (2 and 3 years) event-free survival is 120 ms. Patients with a QRS duration of $120 ms have a relative risk of death or heart transplantation of 3.2 as compared to patients with QRS duration ,120 ms. Several investigative methods and clinical characteristics have been validated as important prognostic indicators in chronic heart failure. These include peak oxygen consumption and VE /VCO 2 slope [9], left ventricular ejection fraction [10], raised inflammatory cytokines [11], catecholamines [12], the erythrocyte sedimentation rate [13], and metabolic abnormalities such as elevated serum uric acid [14] and the development of cachexia [15]. This study, together with previous ones [4,5,16,17], has confirmed that analysis of the resting electrocardiogram may also be of help; this is particularly useful since it is an inexpensive test that is readily available both in primary and secondary care. The majority of previous studies compared patients with QRS duration ,120 ms with patients with QRS duration $120 ms [16,17]. The decision to choose a cut-off of 120 ms was presumably based on data derived from studies in healthy individuals. Whilst in earlier publications the upper limit of QRS duration in healthy adult males was deemed to be 100 ms [18], it is now generally accepted that an upper limit of 120 ms is more appropriate [19]. This value has been obtained from studies involving large numbers of healthy subjects, such as that by Selvester et al. [20]. They evaluated the electrocardiograms of over 1200 healthy white males and concluded that a QRS duration $120 ms was probably abnormal. However, in patients recovering from a myocardial infarction borderline QRS prolongation (90–110 ms) has recently been shown to predict increased mortality,
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emphasising the need to formally establish the optimum cut-off in specific disease states [21]. Since patients with chronic heart failure are known to have a poor prognosis [3], we have presented data for 2-year survival. The finding that cumulative event-free survival in patients with QRS duration $120 ms at this time point was less than 50% supports this decision. The optimum QRS duration for predicting long-term (5-year) survival was actually very similar at 118 ms. We have also shown that patients with chronic heart failure and moderately prolonged QRS duration (120–150 ms) have reduced exercise and functional capacity, together with left ventricular ejection fraction when compared to chronic heart failure patients with normal QRS duration. In contrast, patients with moderate prolongation of QRS duration are in similar NYHA class to patients with a QRS.150 ms and display a comparable reduction in peak oxygen consumption and increase in VE /VCO 2 slope. Abnormal prolongation of QRS duration may adversely contribute to the haemodynamic abnormalities and debilitating symptoms seen in patients with chronic heart failure as a result of ventricular asynchrony and exacerbating functional mitral regurgitation [22–24]. Ventricular resynchronization, with simultaneous stimulation of the right and left ventricles via transvenous pacing leads, represents a promising new therapeutic option for such patients with symptomatic, advanced heart failure. Several small studies have shown that ventricular electromechanical resynchronization can acutely improve left ventricular systolic function and reduce the severity of functional mitral regurgitation in this group of patients [25,26]. In light of these findings larger clinical trials have been initiated in an attempt to evaluate the longer-term effect of ventricular resynchronization on haemodynamic parameters, functional status and mortality (reviewed by Barold [27]). The Multisite Stimulation in Cardiomyopathy (MUSTIC) trial evaluated biventricular pacing in patients with symptomatic heart failure (New York Heart Association class III, LVEF,35%) and a QRS.150 ms (174620 ms) [6]. Biventricular pacing was associated with significantly improved exercise tolerance and quality of life. The Multicenter Insynch Randomized Clinical Evaluation (MIRACLE) trial
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confirmed that ventricular resynchronisation improved quality of life, functional class and LVEF, together with reducing ventricular size in chronic heart failure patients in New York Heart Association class III or IV [28]. Whilst it was stipulated that at enrolment patients should have QRS duration $130 ms, the mean QRS duration of recruited patients was substantially higher at 165 ms. Data are currently lacking as to whether patients with symptomatic heart failure and moderate prolongation of QRS duration gain similar symptomatic benefit to patients with QRS.150 ms. In this study we have shown that these groups of patients demonstrate similar limitation of functional capacity and severity of heart failure, together with a substantially impaired prognosis. We therefore believe that more patients with chronic heart failure and QRS duration 120–150 ms merit inclusion in trials evaluating the benefits of biventricular pacing.
with chronic heart failure the optimum QRS duration for stratifying medium and long-term event-free survival is 120 ms. In addition, patients with chronic heart failure and moderate prolongation of QRS duration share similar impairment of exercise capacity and functional class with patients who have severe QRS prolongation (.150 ms). Therefore all chronic heart failure patients with abnormal QRS duration require careful evaluation. Recent studies have shown that biventricular pacing can improve functional capacity and quality of life in heart failure patients with QRS duration in excess of 150 ms and this represents a novel therapeutic strategy in symptomatic patients resistant to conventional medication. Whether this mode of therapy would be of benefit for patients with a moderate prolongation of QRS duration (120–150 ms) is not known and requires further evaluation in prospective clinical trials.
4.1. Study limitations
Acknowledgements
This current study provides a description of the clinical characteristics of a cohort of chronic heart failure patients with varying degrees of QRS prolongation, recruited for metabolic assessment as part of an ongoing study programme. Although it shows that patients with a moderate prolongation of QRS duration share many characteristics with patients (QRS.150 ms) in whom biventricular pacing has been shown to alleviate symptoms, it does not attempt to identify a lower QRS threshold at which this intervention might be considered. This clearly requires meticulous assessment in the form of a prospective, randomized, double-blind, controlled study. We performed manual assessment of QRS duration from the resting electrocardiogram. Although we appreciate that this is subject to potential errors, we also feel that this is justifiable since it is the method utilised in routine clinical practice and commonly in the assessment of patients for suitability for entry into clinical trials.
PRK, APB and the Department of Clinical Cardiology are supported by the British Heart Foundation. PRK was previously supported by Wessex Heartbeat and the Waring Trust. RS is supported by the Robert Luff Foundation. AJS Coats is supported by the Viscount Royston Trust. S.D. Anker is supported ¨ with a postgraduate fellowship of the Max Delbruck Centrum for Molecular Medicine, Berlin, Germany.
5. Conclusions We have shown for the first time that in patients
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