REVIEWS Strategies to improve cardiac resynchronization therapy Kevin Vernooy, Caroline J. M. van Deursen, Marc Strik and Frits W. Prinzen Abstract | Cardiac resynchronization therapy (CRT) emerged 2 decades ago as a useful form of device therapy for heart failure associated with abnormal ventricular conduction, indicated by a wide QRS complex. In this Review, we present insights into how to achieve the greatest benefits with this pacemaker therapy. Outcomes from CRT can be improved by appropriate patient selection, careful positioning of right and left ventricular pacing electrodes, and optimal timing of electrode stimulation. Left bundle branch block (LBBB), which can be detected on an electrocardiogram, is the predominant substrate for CRT, and patients with this conduction abnormality yield the most benefit. However, other features, such as QRS morphology, mechanical dyssynchrony, myocardial scarring, and the aetiology of heart failure, might also determine the benefit of CRT. No single left ventricular pacing site suits all patients, but a late-activated site, during either the intrinsic LBBB rhythm or right ventricular pacing, should be selected. Positioning the lead inside a scarred region substantially impairs outcomes. Optimization of stimulation intervals improves cardiac pump function in the short term, but CRT procedures must become easier and more reliable, perhaps with the use of electrocardiographic measures, to improve long-term outcomes. Vernooy, K. et al. Nat. Rev. Cardiol. 11, 481–493 (2014); published online 20 May 2014; doi:10.1038/nrcardio.2014.67
Introduction
Department of Cardiology, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, Netherlands (K.V., M.S.). Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, Netherlands (C.J.M.v.D., F.W.P.). Correspondence to: F.W.P. frits.prinzen@ maastrichtuniversity.nl
Approximately one-quarter of all patients with heart failure are characterized as having abnormal ventricular electrical activation (dyssynchrony), which has become recognized as a distinct form of heart failure. The first application of cardiac resynchronization therapy (CRT) in the early 1990s was performed without preclinical research,1 but its success in the clinical setting led to extensive laboratory testing, which substantially expanded our understanding of the mechanisms of action and revealed possible new avenues for treatment.2–6 CRT consists of left ventricular (LV) and right ventricular (RV) stimulation (pacing) that is synchronized with atrial activation. Pacing is achieved with a pacemaker or an implantable cardioverter–defibrillator (ICD) with simultaneous biventricular pacing capacity. Abnormal atrioventricular and interventricular conduction abnormalities, and thereby cardiac pump function, can be substantially improved (Figure 1). CRT is one of the most-successful therapies for heart failure to have emerged in the past few decades. Initially, small studies showed that CRT could immediately improve systolic LV function and efficiency of the heart.7–9 Subsequent randomized clinical trials showed that CRT substantially reduced hospitalization for, and mortality from, heart failure.10–12 CRT was introduced Competing interests K.V. has received research grants from Medtronic. F.W.P. has received research grants from Biological Delivery Systems (Johnson & Johnson), EBR Systems, Medtronic, MSD, and Proteus Biomedical; and is an advisor to St. Jude Medical. The other authors declare no competing interests.
to treat patients with severe symptoms of heart failure,13 but has also proven effective for the treatment of patients with early symptoms of heart failure (NYHA class II; Box 1).14–16 Hundreds of thousands of devices have now been implanted worldwide.17 The success of CRT is determined by three groups of factors: selection of patients, positioning of the pacing leads, and tuning of the atrioventricular and interventricular intervals. In this Review, we discuss these determinants (including differentiation between the evidence from randomized clinical trials and single-centre studies) and possible future directions on the basis of experimental findings. Notably, no study has yet shown that the three main determinants have an additive effect on CRT response. Instead, if a determining feature in one group is particularly strong (such as distinct left bundle branch block [LBBB] morphology on the electrocardiogram), close attention to features in the other two groups of determinants seems to be less critical.
Dyssynchronous heart failure Dyssynchronous electrical activation in the heart immediately causes major contraction abnormalities (Figure 2), as has been shown in animals and humans during RV pacing, and in animals after induction of LBBB. 2,18–20 Local contraction patterns become out of phase, which causes local strain abnormalities. These changes lead to considerable differences in myocardial workload between regions, with the highest workload in the latest-activated regions.18,20,21 Consequently, the efficiency of cardiac pump function is approximately
NATURE REVIEWS | CARDIOLOGY
VOLUME 11 | AUGUST 2014 | 481 © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ Cardiac resynchronization therapy (CRT) is widely used to improve cardiac pump function and prolong life in patients with heart failure, but 30–50% do not respond to treatment ■■ Appropriate selection of patients, careful positioning of pacing leads, and optimization of resynchronization settings can notably improve response to CRT ■■ Patients with left bundle branch block (LBBB), a QRS duration >150 ms, or both, benefit most from CRT; whether mechanical dyssynchrony provides additional useful diagnostic information is disputed ■■ Optimal left ventricular lead positions vary considerably between individuals, but scarred regions should be avoided, and selection of a late-activated region is particularly important in patients with non-LBBB morphology ■■ The greatest benefit from CRT might come from the optimal placement of one left ventricular pacing lead, rather than the combined effects of pacing at multiple sites ■■ Optimization of atrioventricular and interventricular intervals increases acute haemodynamic response, but the lack of an accurate method to measure synchronization has hampered assessment of long-term effects
a
During CRT
Before CRT
Activation Early
*
*
Pump function 20% Efficiency 20% Late After CRT
Before CRT 5
–5 Septum –10 –15
Systole
–20 MVC AVO
18
16
Septum 0
14 12 10 11.75 8 6 4 3.25
2
1.25
0
Strain (%)
Lateral wall
Contribution to systolic shortening (%)
Strain (%)
0
5
18
Contribution to systolic shortening (%)
b
–5 –10
Lateral wall
–15
Systole
–20 MVC AVO
AVC MVO
16 14 12 10 15.10 8 6 4 2 0
0.60 1.05
AVC MVO
Cardiac cycle
Cardiac cycle Shortening during systole
Rebound stretch
Stretch during systole
Figure 1 | Sequences of electrical activation and strain curves before and after CRT in a dog with left branch bundle block. a | 3D representations of electrical activation indicate regions with early (red) or late (blue) activation. Before pacing, the electrical activation progresses slowly from the right to the left ventricle, but resynchronization is seen after biventricular pacing (asterisks). b | Myocardial strain curves (shortening indicated by negative values). Before CRT, the different strain curves in the septum and lateral wall indicate poor coordination of contraction, quantified by the sum of early systolic stretch (green) and rebound stretch (blue). After CRT, the contributions of early systolic stretch and rebound stretch to total systolic deformation are substantially reduced, which indicates improved coordination between the various regions. Abbreviations: AVC, atrial valve closing; AVO, atrial valve opening; CRT, cardiac resynchronization therapy; MVC, mitral valve closing; MVO, mitral valve opening. Panel b reprinted from De Boeck, B. W. et al. Septal rebound stretch reflects the functional substrate to cardiac resynchronization therapy and predicts volumetric and neurohormonal response. Eur. J. Heart Fail. 11 (9), 863–871 (2009), with permission from John Wiley and Sons.
482 | AUGUST 2014 | VOLUME 11
30% lower in people with dyssynchronous hearts than in those with synchronous hearts.20 The regional differences in myocardial workload seem to be an important factor in myocardial maladaptations, which further worsen cardiac function during prolonged abnormal activation. These maladaptations consist of complex molecular and cellular remodelling, including regional differences in the expression of calcium channels3 and loss of the transverse tubule system.22,23 These remodelling processes impair pump function and might lead to arrhythmia (Figure 2).24
Outcomes from CRT Upon starting CRT, electrical and mechanical variables change on a beat-to-beat basis.7,8,25–30 Pump function is rapidly improved by correction of the early contraction of the septum,31 which results in uniform distribution of myocardial workload and blood flow and, therefore, increased myocardial efficiency.20,21 Experimental and clinical studies have shown that these acute effects are followed by a gradual increase in ejection fraction and reduction in LV volume, even in the absence of heart failure in animal models.32,33 Animal studies have demonstrated at least partial reversal at the molecular and cellular levels of the contractile and electrical remodelling that was initiated by LBBB.3,22,34 In observational and controlled clinical studies, improve ments achieved with CRT seem to continue over a period of years.12,35,36 In addition to the short-term and long-term haemo dynamic improvements gained with CRT, reversal of pathological remodelling in failing hearts might be possible. Nevertheless, whether acute haemodynamic and long-term clinical effects of CRT are coupled to each other remains uncertain.37,38 Although large studies of CRT suggest consistent beneficial effects across groups of patients, results at an individual level are variable. In the literature, most attention is given to nonresponders to CRT, who account for 20–30% of patients in studies in which soft clinical end points (such as NYHA functional class and quality of life) are used, and 30–50% in those in which echocardio graphic indices are used.17 CRT benefits measured using soft end points are generally more pronounced for patients with severe heart failure, whereas benefits in the echocardiographic surrogate end points are usually more pronounced for patients with mild heart failure.39 The category of nonresponders also includes those who experience adverse effects, because the condition of some patients seems to worsen with CRT.40 Given that CRT requires long-term implantation of multiple leads, and the device has considerable associated costs to the health-care system, the best possible application of this therapy is evidently desirable. Outcomes also differ between groups of responders. In a subgroup analysis of the MADIT‑CRT trial,41 approximately 25% of patients had an increased LV ejection fraction (from 30% to 47%) and a 40% reduction in end-diastolic LV cavity volume. These values are substantially higher than the usual 5–10% increase
www.nature.com/nrcardio © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Patient selection
Box 1 | ESC guidelines for CRT159 CRT is indicated (class I) ■■ Sinus rhythm, LBBB with a QRS duration >150 ms, and NYHA class II, III, and ambulatory IV (evidence level A) ■■ Sinus rhythm, LBBB with a QRS duration 120–150 ms, and NYHA class II, III, and ambulatory IV (evidence level B) ■■ Conventional pacemaker, high percentage right ventricular pacing, and NYHA class III and ambulatory IV (evidence level B) CRT should be considered (class IIa) ■■ Sinus rhythm, non-LBBB with a QRS duration >150 ms, and NYHA class II, III, and ambulatory IV (evidence level B) ■■ Chronic atrial fibrillation, a QRS duration ≥120 ms, NYHA class III and ambulatory IV, and near to 100% biventricular pacing guaranteed or concomitant atrioventricular junction ablation (evidence level B) ■■ Chronic atrial fibrillation with uncontrolled heart rate in candidates for atrioventricular junction ablation (evidence level B) ■■ Conventional pacemaker indication and expected high percentage of ventricular pacing (evidence level B) CRT can be considered (class IIb) ■■ Sinus rhythm, non-LBBB with a QRS duration 120–150 ms, and NYHA class II, III, and ambulatory IV (evidence level B) CRT is not recommended (class III) ■■ Sinus rhythm, QRS duration 150 ms before treatment and a high cumulative percentage of RV pacing after treatment are strong predictors of CRT response. In patients with a QRS duration of 120–150 ms before treatment, an additional indicator of a good response is required, for example LBBB morphology of the QRS complex. The evidence for LBBB being the predominant substrate for CRT is very strong. In randomized, controlled trials, such as MADIT‑CRT16 and RAFT,43 benefits with CRT were achieved almost exclusively in patients with LBBB. Con versely, right bundle branch block and intraventricular conduction disturbances generally predict no effect or even a negative response to CRT,43 except for possibly in patients with these features and a QRS duration >150 ms, perhaps because of delayed LV activation.44,45 Patients with right bundle branch block, intraventricular conduction disturbances, and a QRS duration of 120–150 ms have only a class IIa indication for CRT, and treatment is contraindicated if the QRS duration is
Introduction
Department of Cardiology, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, Netherlands (K.V., M.S.). Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, Netherlands (C.J.M.v.D., F.W.P.). Correspondence to: F.W.P. frits.prinzen@ maastrichtuniversity.nl
Approximately one-quarter of all patients with heart failure are characterized as having abnormal ventricular electrical activation (dyssynchrony), which has become recognized as a distinct form of heart failure. The first application of cardiac resynchronization therapy (CRT) in the early 1990s was performed without preclinical research,1 but its success in the clinical setting led to extensive laboratory testing, which substantially expanded our understanding of the mechanisms of action and revealed possible new avenues for treatment.2–6 CRT consists of left ventricular (LV) and right ventricular (RV) stimulation (pacing) that is synchronized with atrial activation. Pacing is achieved with a pacemaker or an implantable cardioverter–defibrillator (ICD) with simultaneous biventricular pacing capacity. Abnormal atrioventricular and interventricular conduction abnormalities, and thereby cardiac pump function, can be substantially improved (Figure 1). CRT is one of the most-successful therapies for heart failure to have emerged in the past few decades. Initially, small studies showed that CRT could immediately improve systolic LV function and efficiency of the heart.7–9 Subsequent randomized clinical trials showed that CRT substantially reduced hospitalization for, and mortality from, heart failure.10–12 CRT was introduced Competing interests K.V. has received research grants from Medtronic. F.W.P. has received research grants from Biological Delivery Systems (Johnson & Johnson), EBR Systems, Medtronic, MSD, and Proteus Biomedical; and is an advisor to St. Jude Medical. The other authors declare no competing interests.
to treat patients with severe symptoms of heart failure,13 but has also proven effective for the treatment of patients with early symptoms of heart failure (NYHA class II; Box 1).14–16 Hundreds of thousands of devices have now been implanted worldwide.17 The success of CRT is determined by three groups of factors: selection of patients, positioning of the pacing leads, and tuning of the atrioventricular and interventricular intervals. In this Review, we discuss these determinants (including differentiation between the evidence from randomized clinical trials and single-centre studies) and possible future directions on the basis of experimental findings. Notably, no study has yet shown that the three main determinants have an additive effect on CRT response. Instead, if a determining feature in one group is particularly strong (such as distinct left bundle branch block [LBBB] morphology on the electrocardiogram), close attention to features in the other two groups of determinants seems to be less critical.
Dyssynchronous heart failure Dyssynchronous electrical activation in the heart immediately causes major contraction abnormalities (Figure 2), as has been shown in animals and humans during RV pacing, and in animals after induction of LBBB. 2,18–20 Local contraction patterns become out of phase, which causes local strain abnormalities. These changes lead to considerable differences in myocardial workload between regions, with the highest workload in the latest-activated regions.18,20,21 Consequently, the efficiency of cardiac pump function is approximately
NATURE REVIEWS | CARDIOLOGY
VOLUME 11 | AUGUST 2014 | 481 © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ Cardiac resynchronization therapy (CRT) is widely used to improve cardiac pump function and prolong life in patients with heart failure, but 30–50% do not respond to treatment ■■ Appropriate selection of patients, careful positioning of pacing leads, and optimization of resynchronization settings can notably improve response to CRT ■■ Patients with left bundle branch block (LBBB), a QRS duration >150 ms, or both, benefit most from CRT; whether mechanical dyssynchrony provides additional useful diagnostic information is disputed ■■ Optimal left ventricular lead positions vary considerably between individuals, but scarred regions should be avoided, and selection of a late-activated region is particularly important in patients with non-LBBB morphology ■■ The greatest benefit from CRT might come from the optimal placement of one left ventricular pacing lead, rather than the combined effects of pacing at multiple sites ■■ Optimization of atrioventricular and interventricular intervals increases acute haemodynamic response, but the lack of an accurate method to measure synchronization has hampered assessment of long-term effects
a
During CRT
Before CRT
Activation Early
*
*
Pump function 20% Efficiency 20% Late After CRT
Before CRT 5
–5 Septum –10 –15
Systole
–20 MVC AVO
18
16
Septum 0
14 12 10 11.75 8 6 4 3.25
2
1.25
0
Strain (%)
Lateral wall
Contribution to systolic shortening (%)
Strain (%)
0
5
18
Contribution to systolic shortening (%)
b
–5 –10
Lateral wall
–15
Systole
–20 MVC AVO
AVC MVO
16 14 12 10 15.10 8 6 4 2 0
0.60 1.05
AVC MVO
Cardiac cycle
Cardiac cycle Shortening during systole
Rebound stretch
Stretch during systole
Figure 1 | Sequences of electrical activation and strain curves before and after CRT in a dog with left branch bundle block. a | 3D representations of electrical activation indicate regions with early (red) or late (blue) activation. Before pacing, the electrical activation progresses slowly from the right to the left ventricle, but resynchronization is seen after biventricular pacing (asterisks). b | Myocardial strain curves (shortening indicated by negative values). Before CRT, the different strain curves in the septum and lateral wall indicate poor coordination of contraction, quantified by the sum of early systolic stretch (green) and rebound stretch (blue). After CRT, the contributions of early systolic stretch and rebound stretch to total systolic deformation are substantially reduced, which indicates improved coordination between the various regions. Abbreviations: AVC, atrial valve closing; AVO, atrial valve opening; CRT, cardiac resynchronization therapy; MVC, mitral valve closing; MVO, mitral valve opening. Panel b reprinted from De Boeck, B. W. et al. Septal rebound stretch reflects the functional substrate to cardiac resynchronization therapy and predicts volumetric and neurohormonal response. Eur. J. Heart Fail. 11 (9), 863–871 (2009), with permission from John Wiley and Sons.
482 | AUGUST 2014 | VOLUME 11
30% lower in people with dyssynchronous hearts than in those with synchronous hearts.20 The regional differences in myocardial workload seem to be an important factor in myocardial maladaptations, which further worsen cardiac function during prolonged abnormal activation. These maladaptations consist of complex molecular and cellular remodelling, including regional differences in the expression of calcium channels3 and loss of the transverse tubule system.22,23 These remodelling processes impair pump function and might lead to arrhythmia (Figure 2).24
Outcomes from CRT Upon starting CRT, electrical and mechanical variables change on a beat-to-beat basis.7,8,25–30 Pump function is rapidly improved by correction of the early contraction of the septum,31 which results in uniform distribution of myocardial workload and blood flow and, therefore, increased myocardial efficiency.20,21 Experimental and clinical studies have shown that these acute effects are followed by a gradual increase in ejection fraction and reduction in LV volume, even in the absence of heart failure in animal models.32,33 Animal studies have demonstrated at least partial reversal at the molecular and cellular levels of the contractile and electrical remodelling that was initiated by LBBB.3,22,34 In observational and controlled clinical studies, improve ments achieved with CRT seem to continue over a period of years.12,35,36 In addition to the short-term and long-term haemo dynamic improvements gained with CRT, reversal of pathological remodelling in failing hearts might be possible. Nevertheless, whether acute haemodynamic and long-term clinical effects of CRT are coupled to each other remains uncertain.37,38 Although large studies of CRT suggest consistent beneficial effects across groups of patients, results at an individual level are variable. In the literature, most attention is given to nonresponders to CRT, who account for 20–30% of patients in studies in which soft clinical end points (such as NYHA functional class and quality of life) are used, and 30–50% in those in which echocardio graphic indices are used.17 CRT benefits measured using soft end points are generally more pronounced for patients with severe heart failure, whereas benefits in the echocardiographic surrogate end points are usually more pronounced for patients with mild heart failure.39 The category of nonresponders also includes those who experience adverse effects, because the condition of some patients seems to worsen with CRT.40 Given that CRT requires long-term implantation of multiple leads, and the device has considerable associated costs to the health-care system, the best possible application of this therapy is evidently desirable. Outcomes also differ between groups of responders. In a subgroup analysis of the MADIT‑CRT trial,41 approximately 25% of patients had an increased LV ejection fraction (from 30% to 47%) and a 40% reduction in end-diastolic LV cavity volume. These values are substantially higher than the usual 5–10% increase
www.nature.com/nrcardio © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Patient selection
Box 1 | ESC guidelines for CRT159 CRT is indicated (class I) ■■ Sinus rhythm, LBBB with a QRS duration >150 ms, and NYHA class II, III, and ambulatory IV (evidence level A) ■■ Sinus rhythm, LBBB with a QRS duration 120–150 ms, and NYHA class II, III, and ambulatory IV (evidence level B) ■■ Conventional pacemaker, high percentage right ventricular pacing, and NYHA class III and ambulatory IV (evidence level B) CRT should be considered (class IIa) ■■ Sinus rhythm, non-LBBB with a QRS duration >150 ms, and NYHA class II, III, and ambulatory IV (evidence level B) ■■ Chronic atrial fibrillation, a QRS duration ≥120 ms, NYHA class III and ambulatory IV, and near to 100% biventricular pacing guaranteed or concomitant atrioventricular junction ablation (evidence level B) ■■ Chronic atrial fibrillation with uncontrolled heart rate in candidates for atrioventricular junction ablation (evidence level B) ■■ Conventional pacemaker indication and expected high percentage of ventricular pacing (evidence level B) CRT can be considered (class IIb) ■■ Sinus rhythm, non-LBBB with a QRS duration 120–150 ms, and NYHA class II, III, and ambulatory IV (evidence level B) CRT is not recommended (class III) ■■ Sinus rhythm, QRS duration 150 ms before treatment and a high cumulative percentage of RV pacing after treatment are strong predictors of CRT response. In patients with a QRS duration of 120–150 ms before treatment, an additional indicator of a good response is required, for example LBBB morphology of the QRS complex. The evidence for LBBB being the predominant substrate for CRT is very strong. In randomized, controlled trials, such as MADIT‑CRT16 and RAFT,43 benefits with CRT were achieved almost exclusively in patients with LBBB. Con versely, right bundle branch block and intraventricular conduction disturbances generally predict no effect or even a negative response to CRT,43 except for possibly in patients with these features and a QRS duration >150 ms, perhaps because of delayed LV activation.44,45 Patients with right bundle branch block, intraventricular conduction disturbances, and a QRS duration of 120–150 ms have only a class IIa indication for CRT, and treatment is contraindicated if the QRS duration is
