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Heart failure
Cardiac resynchronisation therapy: current indications, management and basic troubleshooting
  1. Praveen Rao,
  2. Mitchell Faddis
  1. Division of Cardiology, Washington University School of Medicine, St. Louis, Missouri, USA
  1. Correspondence to Dr Mitchell Faddis, Director of Clinical Cardiac Electrophysiology, Professor of Medicine, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA; faddism{at}wustl.edu

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Learning objectives

  • To understand the pathophysiology of left ventricular (LV) electrical dyssynchrony contributing to cardiomyopathy and congestive heart failure symptoms.

  • To be familiar with the seminal clinical trials that have established the impact of cardiac resynchronisation therapy (CRT) on the natural history of chronic systolic heart failure.

  • To be able to select patients that are good candidates to receive CRT.

Introduction

Cardiac resynchronisation therapy (CRT) is an established treatment for heart failure patients with left ventricular dysfunction complicated by left ventricular (LV) conduction delay. In patients who are candidates for CRT, the LV stroke volume is diminished both by cardiomyopathy and by a dyssynchronous contraction pattern caused by conduction delay (figure 1). Left bundle branch block (LBBB) is the category of LV conduction delay in cardiomyopathy patients where CRT is most effective as a therapy. Although other patterns of LV conduction delay may also respond to CRT, the pathophysiology of dyssynchrony tied to LV conduction delay is best understood by examination of the constellation of cardiomyopathy and LBBB. By stimulation of opposing sides of the left ventricle (figure 1), a more synchronised contraction can be achieved, and the LV stroke volume can be augmented to achieve clinically meaningful improvements in heart failure outcomes. Beyond the acute haemodynamic effects of CRT that improve heart failure symptoms, long-term beneficial changes at the myocardial cellular and transcriptional level lead to LV reverse remodelling and a direct impact on the natural history of systolic heart failure. Because of this, CRT is now routinely used in patients whose heart failure symptoms are mild to avoid progression of their cardiomyopathy and heart failure symptoms. Despite two decades for evolution of CRT implantation techniques and technology, CRT has been plagued with a non-response rate in the range of 30% that has varied little over time. Recent developments, particularly with multisite LV stimulation and LV endocardial pacing, appear to reduce the non-response rate and provide a more universal response to CRT.

Figure 1

LBBB creates LV electrical dyssynchrony with delayed activation of the lateral LV wall (purple and blue) compared with the RV and interventricular septum (red and pink) as shown on the left-hand figure. The figure on the right shows that with CRT, electrical synchronisation of the LV lateral wall and septum, shaded yellow, is achieved with stimulation from the coronary sinus (CS) pacing lead in a lateral branch. CRT, cardiac resynchronisation therapy; LBBB, left bundle branch block; LV, left ventricular; RV, right ventricular.

Pathophysiology of LV conduction delay

LBBB is present in about 30% of patients with cardiomyopathy and is associated with worse outcomes among heart failure patients.1 2 LBBB produces a pattern of early activation of the LV septum and late activation of the LV basal lateral wall3 producing a characteristic dyssynchronous LV contraction with contraction of the LV septum early in systole followed much later by contraction of the basal lateral LV wall. This portion of the LV is still in systolic motion when diastole begins.4 Early in systole, the LV septum contracts against a chamber that is unpressurised. The relaxed lateral wall bulges out in response to septal contraction. At the end of the QRS, the LV lateral wall contraction pushes against a relaxing LV septum. The result of this failure in contraction sequencing is that mechanical energy is wasted by ‘internal work’ as one LV wall alternately pushes on the other.5 Another consequence of dyssynchrony is in loss of economy in the cardiac cycle. Delayed pressurisation of the LV expands the isovolumic contraction time, and late activation of the lateral wall prolongs the isovolumic relaxation time. The resultant loss of LV filling time and LV ejection time further compromises myocardial performance.6

An acute consequence of dyssynchrony caused by LV conduction delay is that the latest LV wall becomes overstretched by earlier contracting wall segments, and a disproportionate share of LV pressurisation is shifted to this late activating wall. The chronic effects of myocyte overstretching and increased wall tension in the late activated wall are manifold. Myocardial energy consumption is increased,7 and there is a regional redistribution of myocardial blood flow to match the increase in regional increased work of the late activating wall.8 Sarcomere ultrastructure is disrupted.9 10 Myocyte survival is reduced.11 Expression of ion channels, calcium sensitivity of contraction force, calcium handling and mitochondrial energetics are all decreased in maladaptive ways by chronic wall tension overloading.7 12 13 In an animal model of dyssynchronous heart failure, each of these chronic changes reverses with initiation of CRT.7 9–13 In the clinical realm, CRT remains unique among inotropic therapies in that cardiac function is enhanced, but myocardial energy expenditure is reduced among patient with heart failure and LBBB.14

Clinical trials

Beginning with the initial, small clinical trials of CRT,15 16 consistent clinical and LV functional improvements have been documented in prospective clinical trials of CRT in heart failure patients with LV conduction delay manifest by QRS prolongation on the 12-lead electrocardiogram. Although adherence to a current standard of care for heart failure medical therapy including spironolactone, beta blocker therapy and vasodilators was not uniform among the early trials, most CRT trials met those standards. All of the seminal trials followed a randomised prospective design. The trials can be grouped by severity of heart failure and the QRS duration in the enrolled patients. The initial large, prospective trials focused on patients who remained highly symptomatic with New York Heart Association (NYHA) heart failure symptoms in the class 3 and 4 range despite optimal medical therapy with QRS durations >120 ms. In that group of clinical trials, Miracle,17 Companion18 and Care-HF19 demonstrated clinical improvements in patients on a stable heart failure medical regimen. In addition to clinical improvements, both Companion and Care-HF demonstrated a significant reduction in a combined end point of death or cardiovascular hospitalisation associated with CRT (Care-HF: 39% reduction; Companion: CRT-pacemaker (CRT-P) 34% reduction and CRT-defibrillator (CRT-D) 40% reduction). In other words, both Companion and Care-HF provided the first clear evidence of a direct effect of CRT on the natural history of severe heart failure in the presence of an evidenced-based multidrug medical regimen for heart failure.

A second group of clinical trials looked at the effect of CRT in patients with milder degrees of heart failure and LV conduction delay manifest as a QRS interval >120 ms. That group of clinical trial includes Contak-CD,20 Miracle ICD,21 Reverse,22 Raft23 and Madit-CRT.24 The two largest and most recent trials in the group, Raft and Madit-CRT, showed a significant reduction (25% reduction in Raft and 34% reduction in Madit-CRT) in the primary outcome composite measure of death or heart failure event (hospital admission in Raft and heart failure requiring intravenous diuretic in Madit-CRT). The follow-up period of these two trials was considerably longer (40 months in Raft and 29 months in Madit-CRT) than the earlier trials that had found non-significant changes in their primary outcome measures in a similar patient cohort after just 6 months (Contak-CD and Miracle ICD) or 12 months (Reverse) of follow-up.

A third group of clinical trials examined the effects of CRT in patients with a narrow QRS. In RethinQ25 and Echo-CRT,26 echocardiographic measures of LV dyssynchrony, were used to select a patient group that might benefit from CRT. The RethinQ trial and the smaller Lesser Earth27 showed a non-significant change in exercise capacity with CRT in patients with heart failure and a narrow QRS. Echo-CRT was a larger trial with power to measure a change in the primary endpoint of death or heart failure admission. Echo-CRT was stopped due to a non-significant change in the primary endpoint and an excess of deaths in the CRT arm. These trials demonstrated that CRT is not a good surrogate for a functioning conduction system in heart failure patients and that the potential to worsen outcomes with CRT in this patient group seems likely.

A final group of two clinical trials, BlockHF28 and BioPace,29 examined the role of CRT to prevent progression to heart failure in patients who required ventricular pacing for atrioventricular node (AV) block. In BlockHF, patients were recruited with mild LV dysfunction defined as an LV ejection fraction (EF) of <50%  who required ventricular pacing randomised to right ventricle (RV) only pacing or CRT. BlockHF examined a primary endpoint of death, heart failure event requiring intravenous therapy or a 15% decline in the LVEDVI. A significant 26% decline in the primary endpoint was observed with an average follow-up period of 37 months. The larger BioPace trial results have been presented, but not published. The trial recruited patients with AV block without an LV dysfunction requirement who required ventricular pacing randomised to CRT or RV only pacing. A non-significant difference in the primary endpoint of death or heart failure admission was observed between CRT and RV pacing groups over 5.6 years of follow-up. The trials suggest that CRT may be useful to prevent progressive LV dysfunction and symptomatic heart failure in patients that require ventricular pacing due to AV nodal block in the presence of LV dysfunction.

None of the large clinical trials of CRT in the presence of LV dysfunction and heart failure have had adequate statistical power to measure a change in survival with CRT. A series of meta analyses have been performed to measure the impact of CRT on mortality in patients with heart failure.30–32 Each has shown improvement in survival with CRT. The most recent analysis using a network meta-analysis methodology showed an incremental benefit of CRT-D over CRT-P in patients with cardiomyopathy, LV conduction delay and heart failure.

Patient selection and 2013 ESC guidelines

Careful patient selection of who receives CRT is a critical part of maximising benefit while minimising risk. Many of the non-responders to CRT are due to extending the therapy beyond guideline-driven indications. The 2013 ESC Guidelines on Cardiac Pacing and Cardiac Resynchronization Therapy33 largely base indications for CRT on NYHA functional class, ejection fraction and QRS morphology and width (figure 2).

Figure 2

Indications for cardiac resynchronisation therapy in patients in sinus rhythm. Based on the 2013 ESC Guidelines on Cardiac Pacing and Cardiac Resynchronisation Therapy.33 CRT, cardiac resynchronisation therapy; IV, intravenous; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association. 

The 2012 ACCF/AHA/HRS Focused Update Incorporated into the 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities is very similar to the ESC guidelines for CRT implantation. However, these 2012 ACCF/AHA/HRS guidelines give a class IIa recommendation for an anticipated high burden of ventricular pacing (>40%) as indicated by the Block-HF trial. In addition, they give a class IIb recommendation for patients with NYHA class I symptoms, left ventricular ejection fraction (LVEF) ≤30%, ischaemic cardiomyopathy, with an LBBB with QRS ≥150 ms.

Non-responders and basic troubleshooting

An incomplete understanding exists of the relationship between correction of electrical dyssynchrony by CRT and the magnitude of improvements in mechanical function that result. Up to 20% of patients can normalise their LVEF with CRT as ‘super responders’.34 However, many of the patients who undergo CRT implant do not benefit to the same degree. This is likely due in many cases to extension of CRT to patients beyond evidence-based indications such as those with a narrow QRS. Even among patients who have guideline-directed CRT implantation, >30% do not receive much benefit.33 35 Figure 3 summarises factors that impact CRT response involving patient selection, implant technique and postprocedure management.

Figure 3

CRT response optimisation involves addressing factors prior to implant, during implant and during follow-up. CRT, cardiac resynchronisation therapy; CS, coronary sinus; RV, right ventricle.

Since there is a clear mortality benefit with CRT in the appropriate patient, investigations have focused on the identification of patient characteristics that accurately predict CRT response. The definition of a positive CRT response can differ between physicians and patients but should be reasonable and evidence based. Improvements of at least 15% in left ventricular end diastolic volume (LVEDV), left ventricular end diastolic volume (LVEDV) or stroke volume, or improvement in 6 min walk distance of at least 25% are commonly used to define response to CRT.

Preimplant

A major reason patients may not receive significant benefit from CRT is improper patient selection. For example, patients with end-stage heart failure who are inotrope dependent or with numerous other comorbidities that limit their functional status and lifespan will likely see limited benefit from CRT.36 Current indications for CRT patient selection are summarised in figure 4. Patients who respond best to CRT are female, patients with a non-ischaemic cardiomyopathy and LBBB with a wide QRS (figure 5). In addition, managing expectations about the potential benefits of CRT using evidence-based definitions is important.

Figure 4

Patient selection for CRT implantation. CRT, cardiac resynchronisation therapy; IV, intravenous; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.

Figure 5

Clinical factors affecting response to cardiac resynchronisation therapy. Based on the 2013 ESC Guidelines on Cardiac Pacing and Cardiac Resynchronization Therapy.33 CRT, cardiac resynchronisation therapy; LBBB, left bundle branch block.

Many centres perform imaging studies to define areas of mechanical dyssynchrony prior to the procedure, but this practice has yielded conflicting results. Recent studies using cardiac MRI to identify areas of scar and late mechanical activation and concordant LV lead placement suggest benefit in terms of LV reverse remodelling, cardiac mortality and heart failure hospitalisations.37 If a patient is initially selected using guideline-directed indications, then performing additional preimplant imaging to optimise lead positioning during the procedure is reasonable. The utility of this method is often practically limited by the regional distribution of coronary venous branches that are present however. Although there are many potential benefits to CRT, it is also important to recognise potential complications with placement of an additional lead. The Replace registry demonstrated a significantly higher periprocedural complication rate from additional leads and more complex procedures such as addition of a CS lead for CRT.38 These risks are justifiable in appropriate selected patients after a thorough discussion of the potential risks versus the expected benefits of CRT.

Procedural technique

Variability in coronary venous anatomy can have important implications for optimal placement of a CS lead. A detailed study of 620 cadaveric specimens showed the midlateral LV wall could be accessed via the left posterior vein in 92% of cases, a lateral branch of the anterior interventricular vein in 86% of cases and the middle cardiac vein in 20% of cases.39 Over 90% of the hearts had at least two of these three possible options. The left phrenic nerve also coursed over the midlateral wall in 45% of the hearts. Hence, using a multielectrode lead can reduce stimulation of the left phrenic nerve while still maintaining good anatomic lead positioning. Quadripolar leads have been shown to be useful to reduce phrenic nerve stimulation, reduce the need for reoperation and possibly reduce overall mortality in patients who receive quadripolar leads relative to bipolar leads.40

Due to this anatomic variability, a CS venogram is often helpful in identifying both available options for lead placement and potential limitations from an acute takeoff, short branch or vessel tortuosity (figure 6A–D). These factors influence decisions about CS lead size, shape and length, in addition to the need for more complex procedural techniques such as retrograde snaring or venoplasty.

Figure 6
Figure 6

6A and 6B: balloon occlusive venogram of coronary sinus anatomy in RAO fluoroscopic view, demonstrating several lateral branches as potential options for lead placement. Figure 6B shows quadripolar lead placement in right anterior oblique (RAO) view. Figure 6C and 6D: balloon occlusive venogram of coronary sinus anatomy in left anterior oblique (LAO) fluoroscopic view, demonstrating lateral branches as potential options for lead placement. Figure 6D shows quadripolar lead placement in LAO view.

Although it is often assumed that the mid-lateral LV wall is good for lead placement, the ideal location varies between patients due to differences in the site of maximal mechanical or electrical delay. Studies have shown that targeting LV lead placement to the site of latest mechanical delay can enhance CRT outcomes.41 42 Once the lead is introduced in the coronary venous system, one can determine the site of latest electrical activation by measuring the QLV.43 This marker of regional activation delay is defined by the time interval from the first QRS deflection on a surface ECG to local intrinsic activation at the LV stimulation site. A QLV of at least 95 ms suggests improvement in LV reverse remodelling and quality of life metrics. Varying lead location, pacing vectors and RV–LV timing offsets can influence the biventricular-paced QRS morphology and achievement of the narrowest QRS.

Postimplant

Postprocedure follow-up is a critical part of CRT management. This involves addressing device level factors and includes assessment of broader cardiac and non-cardiac conditions that can limit LV reverse remodelling, quality of life and symptomatic benefit.

From a CRT perspective, maximising biventricular pacing is critical. In a large cohort of patients from a remote-monitoring network, achieving greater than 98.6% of time in biventricular pacing was associated with a mortality benefit over biventricular pacing less than 98.6% of the time.44 Factors that reduce biventricular pacing include AV delay programming, atrial arrhythmias and frequent PVCs. AV nodal ablation to definitively manage atrial arrhythmias that result in reduced biventricular pacing percentage is reasonable in selected cases. Optimising RV–LV timing postprocedurally can also be used to improve response to CRT in cases where LV pre-excitation is not apparent on the surface ECG with CRT.

Other important cardiac factors to address include anaemia, optimal heart failure medication therapy, angina treatment and RV dysfunction. Several extracardiac factors to address include pulmonary disease, sleep disorders, thyroid dysfunction, medication side effects, patient compliance and exercise training. Each of these can affect the perceived benefits after CRT implant.

Future directions

After two decades of investigation into indicators of CRT response, QRS duration remains an important predictor of response. In a meta-analysis of clinical trials of CRT, a QRS duration of greater than 140 ms was noted to be the cut-off below which a statistically significant impact of CRT on overall mortality was not observed.45 Unfortunately, QRS duration remains a poor discriminator to preclude non-response to CRT. A recent examination of radial strain imaging in patients with a QRS duration between 120 ms and 149 ms suggests that a novel metric of dyssynchrony, the systolic stretch index, has a potent predictive value in identifying patients with CRT response measured as freedom from heart failure or death.46 Panoramic imaging of LV activation at baseline or with CRT through ECGi imaging promises to provide a similar degree of patient-specific electrical mapping to predict and guide implantation of CRT.47

Multisite stimulation of the LV has been investigated as a means to improve response rates to CRT, presumably through overcoming limitations imposed by slow conduction and scar that limit rapid, concentric activation of the LV.48 New proprietary device algorithms such as MultiPoint Pacing (St. Jude Medical, St. Paul, Minnesota, USA) have been developed to pace from more than one CS electrode on a single quadripolar lead. Widespread use of quadripolar leads will facilitate multisite stimulation in patients who do not respond to single site CRT. Quadripolar lead designs are now available that maximise separation of the proximal and distal pole of the lead to augment the multisite pacing effect.

An alternative strategy for ventricular resynchronisation, in some patients, is His-bundle pacing that can capture activation of the distal conduction system in some patients with LBBB. His-bundle pacing has the advantage over CRT of myocardial stimulation at hundreds of sites through the distal conduction system. As experience and tools improve, His-bundle pacing could play an increasingly prominent role in strategic device selection. Finally, LV endocardial stimulation has been proposed and implemented in small studies of CRT where coronary sinus lead placement has failed.49 More recently, a comparison of multiple endocardial and epicardial LV stimulation sites in a series of patients with a poor response to CRT (online supplementary file 1) demonstrated superior haemodynamic responses to endocardial stimulation.50 

Supplementary file 1

Key points

  • Left bundle branch block (LBBB) produces dyssynchronous activation of the left ventricular (LV) septum and lateral wall that contributes directly to a reduction in cardiac output.

  • Cardiac resynchronisation therapy (CRT) treats LV dyssynchrony and produces a positive inotropic effect but lowers myocardial oxygen consumption.

  • Multiple randomised, prospective clinical trials have established that CRT has a direct effect on the natural history of chronic systolic heart failure associated with dyssynchrony through a reduction in mortality, lower hospitalisation rates and improvements in heart failure symptoms, LV structure and function.

  • The clinical response to CRT is dependent on multiple factors including patient selection, CRT implantation techniques and device programming.

  • Improvements in CRT response rates are noted with new developments including quadripolar leads, multisite LV stimulation and LV endocardial stimulation.

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References

Footnotes

  • Competing interests None declared.

  • Provenance and peer review Commissioned; externally peer reviewed.

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