Introduction Current guidelines recommend cardiac resynchronisation therapy (CRT) in patients with severe symptomatic heart failure, depressed left ventricular (LV) systolic function and a wide QRS complex (≥120 ms). However, patients with heart failure having a narrow QRS complex might also benefit from CRT.
Design setting patients interventions During the Predictors of Response to Cardiac Resynchronisation Therapy (PROSPECT) trial, 41 patients were enrolled in a ‘narrow’ QRS sub-study. These patients had a QRS complex <130 ms, but documented evidence of mechanical dyssynchrony by any of seven pre-defined echocardiographic measures.
Results After 6 months of CRT, 26 (63.4%) patients showed improvement according to the Clinical Composite Score, 4 (9.8%) remained unchanged and 11 (26.8%) worsened. In patients with paired data, the 6-min walking distance increased from 334±118 m to 382±128 m, (p=0.003) and quality-of-life score improved from 44.2±19.7 to 26.8±20.2 (p<0.0001). Furthermore, there was a significant decrease in LV end-systolic diameter (from 59±9 to 55±12 mm, p=0.002) and in LV end-diastolic diameter (from 67±9 to 63±11 mm, p=0.007).
Conclusion The results suggest that CRT may have a beneficial effect in heart failure patients with a narrow QRS complex and mechanical dyssynchrony as assessed by echocardiography. The majority of patients improved on clinical symptoms, and there was an evident reduction in LV diameters. Larger studies are needed to clearly define selection criteria for CRT in patients with a narrow QRS complex.
- cardiac remodelling
Statistics from Altmetric.com
Cardiac resynchronisation therapy (CRT) is an established treatment option for patients with severe symptomatic heart failure, depressed left ventricular (LV) systolic function and presence of cardiac dyssynchrony, defined as a wide QRS complex (≥120 ms).1 The beneficial effects of CRT on heart failure symptoms, LV systolic function and prognosis in these selected patients have been widely demonstrated.2–4 However, only 30% of patients with heart failure demonstrate QRS prolongation and many are therefore not considered candidates to CRT.5 6 Furthermore, it has been shown that patients with depressed LV systolic function but a narrow QRS complex can also exhibit LV mechanical dyssynchrony, as assessed by echocardiography.7–9
In addition, previous single and multicentre studies in patients with a narrow QRS complexes and mechanical dyssynchrony have suggested beneficial effects of CRT in these patients.9–12 However, the results of the first randomised trial of CRT in these patients were ambiguous, and thus the full potential of CRT in patients with a narrow QRS complex remains currently unresolved.13
Predictors of response to cardiac resynchronisation therapy (PROSPECT) was the first large-scale, multicentre clinical trial that evaluated the performance of several echocardiographic measures of mechanical ventricular dyssynchrony to predict response to CRT.14 Response to CRT was defined as either improvement in clinical composite score, or a reduction in LV end-systolic volume (LVESV) at 6 months follow-up. Outside the USA, the protocol allowed inclusion of patients with a QRS complex <130 ms in a prospectively defined sub-study. In total, 41 patients were included, which have not been included in the main study cohort (a protocol-defined exclusion).14
This study reports the results of CRT on clinical symptoms as well as LV dimensions and LV function in these patients with a ‘narrow QRS’.
In this sub-study of the PROSPECT trial,14 patients with heart failure having a narrow QRS complex (<130 ms) were evaluated. Patients were included according to the following criteria: left ventricular ejection fraction (LVEF) ≤35%, NYHA class III or IV, and QRS duration <130 ms with documented evidence of mechanical dyssynchrony by any of the seven pre-defined echocardiographic measures (table 1). All patients were treated, unless contraindicated, with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (for at least 1 month before enrolment) and a β-blocker (started at least 3 months before and unchanged for at least 1 month).
Patients were enrolled in 15 centres in Europe and 1 centre in Hong Kong between March 2004 and November 2005. Patients underwent extensive evaluation before CRT implantation (baseline), at the time of implantation, immediately after implantation, and at 1, 3 and 6 months follow-up. This study complied with the Declaration of Helsinki and was approved by the Ethical Committee of each participating centre. All patients gave their consent to participate.
The intrinsic QRS duration was determined within 30 days prior to implantation. Before CRT implantation, the clinical status was assessed including NYHA functional class, quality-of-life score (using the Minnesota Living with Heart Failure questionnaire), and the 6-min walk test. These evaluations were also performed at each scheduled follow-up visit.
Echocardiography was performed within 30 days prior to implantation, after device implantation and at 6 months follow-up. Left ventricular dimensions (LV end-diastolic diameter (LVEDD) and LV end-systolic diameter (LVESD)) were measured from M-mode recordings obtained at the parasternal long-axis views. Left ventricular end-diastolic volume (LVEDV) and LVESV were measured at the apical 2-chamber and 4-chamber views, and LVEF was calculated using the biplane Simpson's method.22 Severity of mitral regurgitation was graded semi-quantitatively from colour-flow Doppler images at the parasternal long-axis and the apical 4-chamber view and expressed as the ratio of regurgitant jet area to the left atrial area.23 For evaluation of global LV systolic and diastolic function, the myocardial performance index (MPI) was calculated as described previously.24 Time between cessation and onset of the mitral inflow and the LV ejection time were measured at the pulsed-wave Doppler recordings of the mitral inflow and the LV outflow.24
Mechanical dyssynchrony was assessed with the following measures (table 1): left ventricular filling ratio,15 left ventricular pre-ejection interval,15 intraventricular dyssynchrony left lateral wall contraction,15 septal-to-posterior wall motion delay,16 standard deviation of time from QRS to peak systolic velocity for 12 segments,17 18 septal to lateral delay19 and finally, delayed longitudinal contraction.20 21
Finally, atrioventricular (A-V) optimisation was performed using the Ritter's method.25 The sonographer collecting echo data at follow-up was blinded to patient's clinical response to CRT.
All echocardiographic recordings were analysed in the core laboratories: the Emory University-Crawford Long Hospital (Atlanta, USA) processed all studies from Hong Kong; the Policlinico San Matteo (Pavia, Italy) analysed all European standard two-dimensional measurements. Analysis of European tissue Doppler imaging measurements was divided between Pavia and Hammersmith (London, UK) depending on the availability of equipment. The echocardiographic core labs were blinded to patient's clinical response to CRT.
CRT device implantation
Any Medtronic market-released CRT device, with or without implantable cardioverter defibrillator functionality could be used. Implantation of the CRT system followed standard procedures.2
All patients with a successful CRT implantation underwent A-V optimisation within 7 days using the Ritter's method to maximise diastolic filling.25 Devices with programmable V-V timing remained programmed to nominal biventricular pacing.
Follow-up after 6 months CRT
Clinical changes after CRT were evaluated using the heart failure clinical composite score (CCS).26 The CCS describes the clinical status of the patient at 6 months, regardless of vital status, and includes both objective and subjective clinical measures.
A patient's CCS was classified as one of the following:
Worsened: the patient died or was hospitalised for or associated with worsening heart failure, demonstrated worsening in NYHA class at last observation carried forward, had moderate or marked worsening of patient's global assessment score at last observation carried forward, or permanently discontinued CRT because of or associated with worsening heart failure.
Improved: the patient had not worsened as defined above and demonstrated improvement in NYHA class at last observation carried forward or had moderate or marked improvement in patient's global assessment score at last observation carried forward.
Unchanged: the patient had neither improved nor worsened.
An independent endpoint committee (see appendix) adjudicated all hospitalisations and CRT discontinuations for heart failure relatedness. A positive clinical change after CRT was defined as a designation of improved. Other clinical measures included: change in NYHA functional class, change in distance covered in the 6-min hall walk test and change in quality-of-life score.
Echocardiographic changes after CRT were assessed using changes in LV diameters and volumes (LVESD, LVEDD, LVESV and LVEDV), LVEF and MPI at 6 months follow-up, as compared with baseline (paired measurements).
Endpoint parameters are compared between baseline and 6 months using a paired Wilcoxon signed-rank test including all patients with paired data. Baseline characteristics are compared between the PROSPECT narrow QRS and wide QRS cohorts using a two-sample t test for continuous variables and a Fisher's exact test for categorical variables.
Data are presented as mean±SD for continuous variables and as counts and percentages for categorical variables. Reported baseline statistics include all patients with available data, comparative endpoint statistics are based on patients with paired data.
All analyses were done with the use of SAS software (version 9.1, SAS Institute Inc). A p value <0.05 was considered significant.
Forty-one patients (29 male; mean age, 64±13 years) with a narrow QRS complex (<130 ms) and mechanical dyssynchrony were successfully implanted with a CRT device. The LV lead location was lateral in 11 (27%) patients, postero-lateral in 18 (44%) patients, antero-lateral in 6 (15%) patients and posterior in 3 (7%) patients. In the remaining three (7%) patients, the LV lead was inserted in the mid-cardiac vein or the anterior vein. A total of 34 patients were enrolled in Europe and 7 in Hong Kong. A flow-chart of patient enrolment is presented in figure 1.
Compared with the prolonged QRS patients enrolled in the PROSPECT trial, baseline clinical and echocardiographic characteristics of the narrow QRS population were generally similar, although patients in the current study were younger (table 2). Also, MPI was slightly better in the patients with a narrow QRS complex. By protocol design, patients in the present study had a shorter QRS duration and less frequently left bundle branch block configuration.
Clinical changes at 6 months follow-up
After 6 months of CRT, 26 (63.4%) patients Improved, 4 (9.8%) remained Unchanged and 11 (26.8%) Worsened (figure 2), according to the CCS. Two patients (4.9%) died before the 6 months follow-up.
In the remaining patients, all other clinical measures improved significantly (figure 3A–C). Mean NYHA functional class improved from 3.0±0.2 to 2.2±0.7 (p<0.0001, figure 3A). Of note, 31 patients out of the initial 41 (76%) demonstrated an improvement ≥1 NYHA class. Furthermore, paired analysis demonstrated that the 6-min walking distance increased from 334±118 m to 382±128 m (p=0.003, figure 3B) and finally, the Minnesota living with heart failure quality-of-life score improved from 44.2±19.7 to 26.8±20.2 (p<0.0001, figure 3C).
Echocardiographic changes at 6 months follow-up
In the patients with paired echocardiographic measurements, there was a significant decrease in LVESD (from 59±9 mm to 55±12 mm, p=0.002, figure 3D) and in LVEDD (from 67±9 mm to 63±11 mm, p=0.007) at 6 months follow-up. No significant changes in LVESV (from 182±76 ml to 173±81 ml, p=0.13, figure 3E) or LVEDV (from 252±90 ml to 244±92 ml, p=0.42) were observed at 6 months follow-up. There was a slight, but nonsignificant increase in LVEF (from 29±7% to 31±11%, p=0.14). Finally, the MPI improved significantly at 6 months follow-up (from 0.78±0.25 to 0.59±0.30, p<0.001, figure 3F).
The main findings in the current study are that in heart failure patients with narrow QRS complexes and echocardiographic evidence of mechanical dyssynchrony, 6 months of CRT leads to clinical improvement and significant reduction in LV diameter (LVEDD, LVESD), as well as an improvement in MPI.
Cardiac resynchronisation and the use of mechanical dyssynchrony
Presently, cardiac resynchronisation therapy is considered a class I indication in patients with heart failure in NYHA functional class III or IV, with a depressed LVEF (≤35%) and a QRS duration >120 ms.1 Nonetheless, approximately 30% of patients do not demonstrate clinical improvement after CRT. In an effort to optimise patient selection and outcome after CRT, many studies have used echocardiographic measures of mechanical dyssynchrony to better identify potential responders to CRT.15 16 18 20 27 These studies were performed under the assumption that correction of mechanical dyssynchrony is the key mechanism in improving cardiac function and clinical outcome in heart failure patients treated with CRT. Accordingly, numerous echocardiographic markers of baseline mechanical dyssynchrony have been reported to identify patients with a favourable response to CRT.15 16 18 20 27 PROSPECT was the first large multicentre clinical trial to evaluate these echocardiographic measures to predict response to CRT.14
More recently, improvements in the success of CRT have been related to positioning the LV pacing lead at the site of latest mechanical activation, as assessed with echocardiography.28 29 Ansalone et al investigated 31 patients with nonischemic cardiomyopathy and indicated that patients with the LV lead positioned in the region of latest mechanical activation (identified with tissue Doppler imaging) had the most benefit from CRT.28
Another study by Ypenburg et al assessed LV dyssynchrony and the site of latest mechanical activation with novel speckle tracking two-dimensional radial strain in a large cohort of 257 ischaemic and nonischemic heart failure patients undergoing CRT.29 The LV lead position was determined from the chest x ray obtained after CRT implantation. At 6 months follow-up, LVESV decreased from 189±83 ml to 134±71 ml (p<0.001) in patients with the LV lead positioned at the site of latest mechanical activation, whereas in the group with the LV lead placed outside the area of latest mechanical activation, no significant changes in LVESV were observed (172±61 ml to 162±63 ml, p=NS). More importantly, the 2-year mortality rate in patients with a concordance between the LV lead position and the site of latest mechanical activation was 15% (23 patients) as compared with 21% (19 patients) in patients with a discordance between the LV lead position and the site of latest mechanical activation (p<0.05).
The abovementioned results suggest an important interplay between the LV lead position and the site of latest mechanical activation, resulting in both higher response rate (LV reverse remodelling) and superior long-term survival. However, no studies on the relation between the LV lead position and the site of latest mechanical activation in patients with a narrow QRS complex have been performed to date. Therefore it seems premature to extrapolate these favourable results to a ‘narrow’ QRS population.
Mechanical dyssynchrony and CRT in patients with ‘narrow’
In the past decade, several studies have observed mechanical dyssynchrony in patients with heart failure having a depressed LVEF and narrow QRS complex (<130 ms).7–9 The hypothesis that CRT might result in clinical improvement in patients with heart failure having narrow QRS has recently been explored by a number of investigators. Turner et al reported acute haemodynamic improvement in heart failure patients with a normal QRS duration (≤120 ms) when treated with LV pacing.30 Temporary pacing leads were placed in the right atrium and at the LV free wall in 20 patients with a depressed LVEF (mean, 31%; range, 15%–40%). Left ventricular pacing was applied with the longest A-V delay that ensured ventricular capture. The authors reported an acute increase in cardiac output, predominantly in patients with pulmonary wedge pressure >15 mmHg at baseline.
Achilli et al were the first to investigate the longer-term effects of CRT in patients with heart failure having a narrow QRS complex and evidence of mechanical dyssynchrony.11 The authors studied clinical and functional changes after CRT in 14 patients with ‘narrow’ QRS (≤120 ms) and compared these changes with 38 patients having ‘wide’ QRS. At 6 months follow-up, patients in the narrow QRS group did not only show improvement in NYHA functional class (from 3.3±0.5 to 1.7±0.6, p<0.001) and 6-min walking distance (from 276±89 m to 370±70 m, p<0.001), but also demonstrated a marked reduction in LV diameters (LVEDD from 72±9 mm to 66±9 mm and LVESD from 61±8 mm to 56±8 mm, p<0.05 for both). More importantly, there were no differences in changes from baseline to follow-up between the narrow and wide QRS groups, suggesting that patients with a narrow QRS complex had similar benefit from CRT as compared with patients having a wide QRS complex.
Bleeker et al evaluated the effects of CRT in 33 prospectively selected patients with a narrow QRS complex who demonstrated significant LV dyssynchrony (Ts-(lateral-septal) ≥65 ms).10 At 6 months follow-up, patients improved in NYHA class (from 3.1±0.3 to 2.0±0.6, p<0.001) and showed a significant decrease in LV volumes (LVESV from 189±60 ml to 144±58 ml and LVEDV from 238±72 ml to 203±66 ml, p<0.001 for both). Other studies focussing on the potential favourable effects of CRT in patients with a narrow QRS complex and echocardiographic evidence of mechanical dyssynchrony have supported these findings.9 12
Cardiac resynchronisation therapy in narrow QRS: the RethinQ study
Based on the encouraging outcomes of these observational studies, a randomised, multicentre trial was conducted to determine the effect of CRT in heart failure patients with a narrow QRS complex. In the resynchronisation therapy in narrow QRS (RethinQ) study, 172 patients with a narrow QRS complex were randomised in a 1:1 fashion to a CRT ON group and a control group (CRT OFF).13 All patients had documented echocardiographic evidence of mechanical dyssynchrony, defined as either septal-to-posterior wall motion delay ≥130 ms or septal to LV free wall (lateral or posterior) delay ≥65 ms. The study failed to demonstrate a significant difference in the primary endpoint (increase in peak oxygen consumption ≥1.0 ml/kg of body weight per minute during exercise testing at 6 months) between the CRT and the control groups. Nonetheless, there was a significant difference in change in NHYA class (54% improved in the CRT group, as compared to 29% in the control group, p=0.006). This discrepancy between peak oxygen consumption and quality of life has been described previously. In an early study by Wilson et al, over 50% of potential heart transplant candidates with an LVEF <35% and a reduced peak oxygen consumption (mean, 13.3±2.7 ml/min per kilogram) exhibited only mild or moderate haemodynamic dysfunction during exercise testing.31 Another study by Mancini et al was able to identify peak oxygen consumption as a predictor of mortality in 114 patients with ambulatory heart failure screened for cardiac transplantation.32 However, patients were either granted or denied transplantation based on baseline peak oxygen consumption results. Since peak oxygen consumption influenced cardiac transplantation (and thereby survival), these results cannot be used to validate peak oxygen consumption as an independent predictor of mortality in heart failure. In addition, other studies have identified peak oxygen consumption as being unable to predict survival in patients with heart failure.33 34 Consequently, (changes in) peak oxygen consumption may not be the preferred method to assess response to CRT. Conversely, 6-min walking distance has been demonstrated to show a good relation with both heart failure symptoms and outcome after CRT.35 Finally, Castel et al recently demonstrated that 6-min walking distance is an independent predictor of mortality in patients undergoing CRT.36 In the current study, 6-min walking distance improved significantly, indicating benefit from CRT.
At this point, relative merits of CRT with regard to long-term clinical outcomes (worsening heart failure, survival) in narrow QRS patients remain unclear. The currently ongoing trial, EchoCRT (http://ClinicalTrials.gov identifier: NCT00683696) will further address this issue since it will include over 1200 patients with heart failure having a narrow QRS complex and randomise them to a CRT or control group.37 Main endpoints in this trial will be the reduction in all-cause mortality or first hospitalisation for worsening heart failure during a follow-up of at least 24 months.
Changes in LV diameters versus changes in LV volumes
In the current study, while end-diastolic and end-systolic LV diameters appear to decrease with CRT, there was no detectable change in LV volumes. If this discrepancy is the result of a variability of measurement in a small sample size, then no firm conclusions can be drawn as to the real effect of CRT in this population. However, given that both end-diastolic and end-systolic diameters are smaller at 6 months, and that diameter measurements have higher reproducibility than volume measurements, it is less likely that the findings are purely due to chance. Conversely, the higher variability for measurements of LV volumes may explain the lack of significant reduction in LVESV at 6 months follow-up. Of note, there was a small decrease in LVESV, but this did not reach statistical significance. Possibly, with only 36 patients with paired LVESV measurements, the study was not powered to detect this small decrease as significant. Nonetheless, if this discrepancy is due to a true physiologic effect of CRT, then the differential effect on the basal diameters and volume must be due to a more spherical LV shape at 6 months, which would be contrary to previous reports.17 38 One possibility for this discrepancy is that in this population, changes in LV diameter may occur before changes in volume are detected. The much larger prospective study, EchoCRT, should shed more light on this issue.
Main limitations of this study include its small sample size and uncontrolled design. As such, this study should be considered a pilot, hypothesis generating study, conducted in a multicentre setting. In addition, no long-term outcome data are available. More remodelling may take longer and can occur after the 6-month follow-up. Also, no data are available with regard to morbidity and mortality.
The following participated in the narrow QRS sub-study of PROSPECT:
Steering Committee – E. Chung (chair), W. Abraham, J. Bax, S. Ghio, C. Leclercq, A. Leon, J. Merlino, P. Nihoyannopoulos, J-P. Sun, L.Tavazzi, C-M.Yu;
Investigators – Austria – A.Ö. Krankenhaus der Elisabethinen, Linz, S. Winter; Belgium - Onze Lieve Vrouw Ziekenhuis, Aalst, P. Geelen; Denmark – KAS Gentofte, Hellerup, P. Sogaard; France – Institut Arnault Tzanck, Saint-Laurent du Var, P. Durand; Hospital La Timone, Marseille, G. Habib; Hong Kong, China - Prince of Wales Hospital, Hong Kong, CM Yu; Italy – Dipartimento di Scienze Cardiovascolari e Respiratorie Universita degli Studi di Roma ‘La Sapienza’, Rome, F. Fedele; Ospedale San Giovanni Calibita Fatebenefratelli, Rome, A. Puglisi; The Netherlands – Leiden University Medical Center, Leiden, J. Bax; Norway – Sorlandet Sykehus, Kristiansand, F.T. Gjestvang; Spain – Hospital Ramón y Cajal, Madrid, C. Moro Serrano; UK – Royal Brompton and Harefield Trust Hospital, Middlesex, M. Mason; King's College Hospital, Department of Cardiology, London, M. Monaghan; Leeds General Infirmary, Leeds, C. Pepper; Northwick Park Hospital, Middlesex, R. Senior; Hammersmith Hospital, P. Nihoyannopoulos;
Echo Review Committee – J. Gorcsan III (chair), M. St. John Sutton, J. de Sutter;
Echo Core Lab Measurement Authors – J. Bax, S. Ghio, J. Merlino, P. Nihoyannopoulos, D. Notobartolo, P. Søgaard, J.P. Sun;
Endpoint Adjudication Committee – A. Bank, D. Böcker, M. Klapholz, D. Lacroix, T. Lawo, M.Givertz, A. Pietersen.
Funding Medtronic Inc. provided funding for this study and manufactured the CRT system used in this research. Other Funders: NIH.
Competing interests John Gorcsan III: received grants from NIH award K24 HL04503-01, and from GE Healthcare, Medtronic, St Jude Medical and Biotronik.
Eugene S. Chung: received research support from Medtronic; consultant for Medtronic, Boston Scientific, St Jude Medical; speaker for Medtronic, Boston scientific.
William T. Abraham: consulting fees from Medtronic.
Christophe Leclercq: research grants from Medtronic, St. Jude Medical, Biotronik, Boston Scientific and Sorin Ela.
Mark J. Monaghan: research support from Medtronic, Philips, Siemens, GE Healthcare, TomTec; Speaker's bureau for Philips, Siemens.
Petros Nihoyannopoulos: research grant from Medtronic.
Cheuk-Man Yu: research grant from Medtronic, speaker for Medtronic, Boston Scientific, St Jude Medical, Philips and GE Healthcare.
Myriam Demas: employee of Medtronic.
Bart Gerritse: employee of Medtronic.
Jeroen J. Bax: received grants from Medtronic, Boston Scientific, BMS medical imaging, St. Jude Medical, Edwards Life sciences & GE Healthcare.
Ethics approval This study was conducted with the approval of the Ethical Committee of each participating centre.
Provenance and peer review Not commissioned; externally peer reviewed.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.