Synchronizing Beats: From Theory to Advances and Insight in Cardiac Resynchronization Therapy

Abstract

Cardiac resynchronization therapy (CRT) is an established treatment for select patients with systolic heart failure, left ventricular conduction delay, and dyssynchronous contraction. Landmark trials have shown CRT’s benefits on symptoms, exercise capacity, reverse remodeling, hospitalization rates, and mortality. However, limitations exist including sub-optimal patient selection, procedural complexity, high non-responder rates, and device-related adverse effects. This review summarizes the evolution, physiology, clinical trial evidence, patient selection, delivery, and optimization of CRT. Key areas covered include guidelines for CRT use, invasive and noninvasive imaging to improve outcomes, alternative pacing sites to enhance response, and advances in lead technology and implantation techniques. Gaps in current knowledge are highlighted along with future directions for research to refine CRT utilization and improve real-world clinical outcomes. With further studies to address remaining questions, CRT is poised to become an even more effective therapy for heart failure patients with dyssynchronous cardiomyopathy.

1. Introduction

Cardiac resynchronization therapy (CRT) is preferred as a therapeutic approach for individuals presenting with left bundle branch block coupled with symptomatic systolic heart failure, regardless of optimal medical therapy. Guidelines on cardiac resynchronization therapy and cardiac pacing emphasize the importance of CRT in heart failure patients with specific criteria, such as left ventricular ejection fraction (LVEF) ≤ 35%, sinus rhythm, and typical left bundle branch block with QRS duration ≥150 ms [1]. Advancements in CRT have led to the exploration of alternative pacing sites, the development of newer device-based algorithms, and strategies when traditional CRT is not feasible or effective. Strategies targeting “multi-points” have shown superiority over classic CRT [2]. Additionally, conduction system pacing has arisen as a promising technique [3]. Furthermore, the development of leadless CRT devices has been a significant advancement in this therapy. These devices eliminate the need for traditional leads and are implanted directly into the heart, providing synchronized pacing without the complications associated with lead placement [4]. Successful CRT requires appropriate patient selection, left ventricular lead positioning, and post-implant management. Active research is ongoing to determine how these factors can be optimized to maximize the benefits of CRT [5].

2. Definition of CRT

Cardiac resynchronization therapy or biventricular pacing is a specialized type of pacemaker therapy that provides simultaneous electrical activation of the LV and RV used in patients with LV systolic dysfunction and dyssynchronous ventricular activation [6].

3. Evolution of cardiac resynchronization therapy

3.1 The stepwise evolution of cardiac resynchronization therapy

In 1925, Wiggers conducted canine experiments demonstrating that abnormal electrical activation of the ventricular myocardium led to reduced left ventricular pressure generation (dP/dt) and prolonged isometric contraction. He hypothesized these negative effects of “dyssynchrony” were influenced by the timing of myocardial activation relative to Purkinje fiber excitation. This pioneering work established the mechanistic foundation for cardiac resynchronization [7].

In the 1980s, imaging modalities like radionuclide ventriculography enabled researchers to quantify dyssynchrony’s effects on regional cardiac mechanics in humans. Studies by Grines et al. revealed conduction abnormalities like left bundle branch block (LBBB) reduced septal contribution to ventricular ejection and shortened left ventricular filling time, diminishing overall cardiac efficiency (Figure 1) [8, 9].

Figure 1.

Typical examples of 3D electrical activation in canine hearts during normal conduction (left) and after creation of left bundle branch block (right). Plotted activation times were derived from ≈110 epicardial and endocardial contact electrodes and referenced to the onset of the Q wave. Electrocardiographic tracings are shown, together with RV and LV pressures signals which are normalized to peak values to reveal timing [8].

Building on these mechanistic insights, several research groups began exploring whether purposefully pacing different ventricular regions could resynchronize contraction and improve cardiac output:

• Initially described by Befeler et al. in 1978, temporary biventricular pacing was evaluated to treat arrhythmias [10].

• In 1983, Teresa et al. reported improved hemodynamic outcomes in AV block patients with AV sequential pacing [11].

• In 1987, Mower patented “biventricular pacing” for heart failure using RV and LV leads [12]. His design included two electrodes: one in the RV and another around the LV free wall, connected in series and programmed to pace after a predetermined AV interval.

• In 1993, Bakker’s group tested a dual-chamber pacemaker with a Y adapter on 12 patients with HF and found that biventricular pacing improved functional capacity and left ventricular function [13].

• The pacing system with four chambers, pioneered by Cazeau et al., was observed to increase cardiac output and reduce pulmonary capillary pressure [14].

• Leclercq and team, in 1995, showed that CRT pacing (CRT-P) was more effective than AAI pacing for increasing the cardiac index and reducing pulmonary capillary wedge pressure, demonstrating the benefits of CRT in managing HF [15].

• Auricchio and colleagues found that varying the AV delay for individual patients could optimize the LV dP/dt max and aortic pulse pressure, indicating that CRT response can vary from patient to patient. This understanding led to a focus on personalizing CRT settings for each patient, taking into account factors like QRS duration and morphology, which are now part of the ongoing discussion about AV optimization in CRT [16].

4. Mechanisms of dyssynchrony

4.1 Dyssynchrony and remodeling

Dyssynchrony refers to timing differences in electrical or mechanical activation in the ventricles. It is caused by factors like right ventricular pacing and left bundle branch block (LBBB) [17]. Mechanical dyssynchrony causes inefficient contraction, increasing wall stress over time. This can lead to maladaptive remodeling like hypertrophy and fibrosis [18]. Molecular changes can also impair function in non-dyssynchronous regions [19]. Remodeling causes left ventricular dilation, reduced systolic/diastolic performance, and heart failure symptoms [19].

Chronic RV pacing ≥20–40% or LBBB can induce cardiomyopathy in some patients due to dyssynchrony-mediated remodeling [20]. Measuring mechanical dyssynchrony is important for:

• Detailed assessment beyond electrical dyssynchrony

• Understanding myocyte contraction

• Predicting cardiac resynchronization therapy (CRT) response

• Clinical decision-making in heart failure patients

The mechanisms involved in LBBB dyssynchrony include:

• Delayed LV relaxation and altered diastolic filling [17, 20]

• RV filling precedes LV filling [17]

• Altered LV intracavitary flow patterns [21]

• Impact on global myocardial wall stress during diastole

5. Physiology of biventricular pacing

5.1 Enhanced cardiac physiology through biventricular pacing

Following the implantation of a biventricular pacemaker, cardiac resynchronization therapy (CRT) greatly diminishes cardiac mechanical dyssynchrony, leading to immediate and long-term improvements in heart function and structure. As a result of synchronized ventricular contractions, cardiac output increases immediately. As time progresses, CRT fosters a process of reverse remodeling, evidenced by a reduced left ventricular (LV) size and enhanced LV function (Figure 2). These changes are akin to those produced by well-established medications for treating heart failure [22, 23]. These changes are associated with decreased heart failure symptoms and mortality rates (Figure 3) [24].

Figure 2.

Change in left ventricular ejection fraction after cardiac resynchronization therapy (CRT) in patients with different functional heart failure classes. Compared with before CRT (blue bars), left ventricular ejection fraction increased significantly in all studies after 3–6 months (red bars) and even more during longer follow-up (green bars). The larger bars on the right indicate data from a study comparing right ventricular (RV) and biventricular (BiV) pacing in pacemaker-dependent patients with mild HF symptoms. The lines indicate the individual response [22].

Figure 3.

Kaplan-Meier estimates of the probability of survival free of heart failure. There was a significant difference in the estimate of survival free of heart failure between the group that received cardiac-resynchronization therapy plus an implantable cardioverter-defibrillator (CRT-ICD) and the group that received an ICD only (unadjusted p < 0.001 by the log-rank test) [24].

Additionally, CRT can reduce mitral valve dilatation, lessening mitral regurgitation in heart failure patients [25]. On a cellular level, CRT enhances calcium-induced sarcomere contraction and increases beta-adrenergic receptor density, which improves heart muscle contractility and responsiveness [26]. It also boosts energy metabolism by upregulating mitochondrial enzyme activity [27]. However, these benefits are contingent on continued CRT, as discontinuation leads to the loss of therapeutic gains.

6. Major clinical trials

6.1 The core clinical trials

The MUSTIC and PATH-HF studies evaluated the safety and efficacy of CRT in 2001. MUSTIC randomized 67 HF patients to receive CRT for 3 months or no CRT, showing improvements in walking distance, quality of life, and peak oxygen uptake (VO2) [28]. PATH-HF demonstrated enhanced walking distance and peak VO2 after 12 months of biventricular pacing, along with evidence of left ventricular reverse remodeling [29]. The MIRACLE study, a double-blind trial, randomized 453 HF patients to receive CRT-P or no pacing, observing improvements across various metrics, including left ventricular reverse remodeling, at the 6-month mark [24]. Throughout the 2000s, clinical trials highlighted the advantages of therapy with implantable cardioverter defibrillator (ICD) in patients with impaired left ventricular function. Primary prevention trials showed significant improvements in survival rates with ICDs [30]. The MIRACLE-ICD research, which investigated the impact of supplementing ICD with CRT (CRT-Defibrillation [CRT-D]), determined that CRT-D enhances life quality and the NYHA functional classification. However, the investigation did not extend to walking distance, but it indicated a positive clinical effect without any safety concerns [31]. As the first trial to compare CRT-P and CRT-D with optimal pharmacological therapy (OPT), the COMPANION trial found that CRT-P and CRT-D showed a 20% reduction in mortality or hospitalization, but CRT-D showed the lowest total mortality, demonstrating the benefit of combining CRT and ICD (Figure 4) [32, 33].

Figure 4.

Hospital admission rate per patient is shown by treatment arm [32].

According to the CARE-HF study, CRT-P reduced cardiovascular hospitalizations, mortality, and quality of life among patients with left ventricular ejection fraction (LVEF) and mitral regurgitation who underwent OPT with or without CRT-P [28]. Despite the therapeutic advantages, the response to CRT varies, with a non-responder rate of 20–40% [34]. Significant clinical trials have refined the understanding and application of CRT. REVERSE (Resynchronization reverses Remodeling in Systolic left ventricular dysfunction) found that CRT induced reverse remodeling in patients with mild heart failure symptoms and left ventricular dysfunction, suggesting benefits from early intervention [35]. MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy) demonstrated that CRT reduced hospitalizations due to heart failure in patients with a wide QRS complex and mild symptoms. It emphasized the preventive potential of CRT in halting the progression of heart failure [24].

RAFT (Resynchronization for Ambulatory Heart Failure Trial) included patients with more severe symptoms (NYHA class II–III) and showed a significant mortality reduction for those receiving CRT, confirming the life-saving impact of the therapy in a population with advanced heart failure (Figure 5) [36]. Recent trials have also advised against CRT use in patients with narrow QRS complexes and mechanical dyssynchrony, as these patients did not benefit and may even experience harm [23, 37].

Figure 5.

Kaplan-Meier estimates of death or hospitalization for heart failure (composite primary outcome) and death from any cause. Panel A shows the probability of the primary outcome among patients who were receiving optimal medical therapy along with cardiac-resynchronization therapy (CRT) plus an implantable cardioverter-defibrillator (ICD), as compared with those receiving an ICD alone. The probability of event-free survival at 5 years was 0.576 in the ICD-CRT group and 0.487 in the ICD group. Panel B shows the probability of death from any cause in each group, with a probability of survival at 5 years of 0.714 in the ICD-CRT group and 0.654 in the ICD group [36].

7. Special considerations

7.1 Atrial fibrillation and cardiac resynchronization therapy

A large proportion of trial participants with atrial fibrillation (AF) or heart failure (HF) are excluded from cardiac resynchronization therapy (CRT) trials [38, 39]. A meta-analysis comparing 1164 AF patients with a total of 797 patients with sinus rhythm revealed that AF patients exhibited greater enhancements in ejection fraction. However, AF patients experienced lesser improvements in functional outcomes compared to those in sinus rhythm. Remarkably, in both groups, there was no apparent difference in mortality rates [40].

• CRT devices are programmed to pace only when the heart rate is below a certain threshold, a feature that may present challenges in individuals with atrial fibrillation (AF) characterized by rapid ventricular response. This limitation has the potential to diminish the efficacy of pacing interventions in such patients.

• To ensure CRT delivers maximum benefit, it is essential to control the rate of ventricular contraction by managing AV nodal conduction (Figure 6) [41].

• AV nodal conduction can be slowed using medications like beta-blockers, calcium channel blockers, or digoxin.

• In cases where medication is insufficient, catheter ablation of the AV node can induce complete AV block, allowing the CRT device to pace the heart 100% of the time [42].

Figure 6.

Survival decreases with reducing biventricular (BiV) pacing in an observational analysis of 36,935 patients with cardiac resynchronization therapy defibrillators. (A) Survival analysis by biventricular pacing percentage. (B) Survival analysis by biventricular pacing percentage and by the presence of significant atrial fibrillation (AFib), defined as average daily burden 0.5% [41].

7.2 Pacing indications and heart failure (HF) risk in bradycardia

The risk of heart failure (HF) is higher for patients with bradycardia who require pacing, regardless of their systolic function status. Conventional pacing typically involves placing a ventricular lead at the right ventricular apex (RVA). However, this can cause left bundle branch block (LBBB) and negatively affect the left ventricular (LV) remodeling and function [43]. To mitigate the risk of HF in these patients, new pacing strategies have been introduced:

• Minimizing right ventricular pacing: Specific pacing algorithms can reduce the amount of RVA pacing [44].

• Alternative pacing sites: Septal pacing is considered an option to prevent the dyssynchrony associated with RVA pacing [45].

• Biventricular pacing (CRT): Biventricular pacing is another alternative, and studies have shown its benefits. In the PAVE study, CRT showed superiority over RVA pacing in maintaining ejection fraction (EF) and exercise capacity over 6 months [29]. The APAF study also demonstrated that CRT significantly reduced death from HF, hospitalization due to HF, or worsening HF compared to RVA pacing [46].

• BLOCK HF trial: This trial indicated that CRT is more effective than RV pacing in patients with an LVEF ≤50% and who are expected to pace frequently, reducing mortality, HF-related urgent care visits, and LV dysfunction (Figure 7) [47].

• In the PACE study, biventricular pacing was shown to prevent adverse LV remodeling and decreased EF at both 12 and 24 months in patients with normal systolic function. However, the long-term significance of these results is not fully known, and CRTs may carry greater risks of complications [48]. However, the BIOPACE trial compared BiV pacing with RV pacing in 1810 patients with AVB over 5.6 years. The study found no significant difference in death or heart failure hospitalization between the two groups, despite a slight non-significant trend favoring BiV pacing (HR 0.87; p = 0.08). This trend persisted across different LVEF levels but remained statistically insignificant [49].

Figure 7.

Freedom from a primary-outcome event [47].

7.3 Outcomes of CRT-P versus CRT-D

The COMPANION trial in 2004 showed CRT-D reduced all-cause mortality more than CRT-P (36% vs. non-significant trend of 9% reduction), suggesting the superiority of CRT-D [33]. However, the CARE-HF trial in 2005 found CRT-P reduced total mortality compared to medical therapy alone after 29 months of follow-up [29]. A large European registry study of over 1700 patients found CRT-D was superior to CRT-P in reducing mortality over 2 years of follow-up [50]. However, the excess mortality seen with CRT-P was due to non-SCD causes, suggesting a residual risk of SCD was not higher with CRT-P [50]. A nationwide study in England of over 50,000 CRT implantations from 2009 to 2017 reported lower total mortality with CRT-D than CRT-P over a median 2.7 years of follow-up [50].

The risk of SCD is governed by the underlying cardiomyopathy type and timing of CRT implantation. A study analyzing over 15,000 CRT procedures found mortality was lower for non-ischemic cardiomyopathy and when implanted earlier in the disease course [51]. Factors to consider in choosing CRT-D vs. CRT-P include the residual risk of SCD despite CRT (still around 2.7% per year according to recent trials), as well as individual patient characteristics and comorbidities influencing risks of SCD vs. non-SCD death.

8. Patient selection

8.1 Clinical indications and patient selection criteria for CRT

Patients with reduced LVEF and prolonged QRS duration with HF in sinus rhythm should consider CRT; HF in AF patients might also be considered. However, ensuring biventricular capture or return to sinus rhythm is important. Not all HF patients are suitable for CRT—they must meet specific criteria. The main selection criteria are sinus rhythm, LVEF ≤35%, LBBB, QRS ≥150 ms, NYHA class III/IV, on maximal medical therapy. Other criteria that might be considered include AF, LVEF 35–50%, non-LBBB, QRS 130–149 ms, and NYHA class II. CRT is not recommended for QRS <130 ms without an indication of RV pacing (Tables 1 and 2) [1, 52, 54].

CRT is strongly recommended	Maybe used
Sinus rhythm	AF
LVEF ≤ 35	LVEF >35 to <50
LBBB QRS morphology	Non-LBBB QRS morphology
QRS complex duration ≥ 150 ms	QRS duration of 130–149 ms
NYHA functional class III or IV	NYHA Class II
Ischemic or nonischemic cardiomyopathy
Maximal pharmacological therapy for heart failure
Not recommended: QRS duration < 130 ms without an indication for RV pacing.

Table 1.

Patient selection for cardiac resynchronization therapy implantation [52].

	Best candidate	Worst candidate
QRS duration	>150 ms	<120 ms
QRS morphology	LBBB	Nin-LBBB
Scar and dyssynchrony	(−)	(+)
Etiology	CAD (−)	CAD (+)
Gender	Female	Male
Atrial fibrillation	(−)	(+)
CKD	(−)	(+)

Table 2.

Patient selection for cardiac resynchronization therapy implantation [53].

CAD, coronary artery disease; CKD, chronic kidney disease; CRT, cardiac resynchronization therapy; LBBB, left bundle branch block.

8.2 Current guidelines for CRT

The 2021 ESC/EHRA guidelines and 2022 ACC/AHA/HFSA guidelines strongly recommend CRT for symptomatic HF patients in sinus rhythm with LVEF ≤35%, QRS ≥150 ms, and LBBB. The ESC guidelines emphasize CRT for patients requiring RV pacing, while the ACC/AHA/HFSA guidelines assign this a Class IIa recommendation (Tables 3 and 4) [52, 55]. For non-LBBB with QRS >150 ms or LBBB with QRS 120–149 ms, CRT should be considered. The ACC/AHA/HFSA guidelines do not recommend CRT for QRS <120 ms, while the ESC guidelines use a cutoff of <130 ms [55].

COR	Recommendations
	LBB QRS morphology
1	CRT is recommended for symptomatic patients with HF in SR with LVEF ≤35%, QRS duration ≥150 ms, and LBBB QRS morphology despite OMT, in order to improve symptoms and reduce morbidity and mortality.
2A	CRT should be considered for symptomatic patients with HF in SR with LVEF ≤35%, QRS duration 130,149 ms, and LBBB QRS morphology despite OMT, in order to improve symptoms and reduce morbidity and mortality.
	Non-LBBB QRS morphology
2A	CRT should be considered for symptomatic patients with HF in SR with LVEF ≤35%, QRS duration ≥150 ms, and non-LBBB QRS morphology despite OMT, in order to improve symptoms.
2B	CRT should be considered for symptomatic patients with HF in SR with LVEF ≤35%, QRS duration 130,149 ms, and non-LBBB QRS morphology despite OMT, in order to improve symptoms and reduce morbidity and mortality.
	QRS duration
3	CRT is not indicated in patients with HF and QRS duration <130 ms without an indication for RV pacing.
	In patients with HF with permanent AF who are candidates for CRT:
2A	CRT should be considered for patients with HF and LVEF ≤35% in NYHA III or IV despite OMT if they are in AF and have intrinsic QRS ≥130 ms, provided a strategy to ensure biventricular capture is in place, in order to improve symptoms and reduce morbidity and mortality.
2A	AVJ ablation should be added in the case of incomplete biventricular pacing (<90–95%) due to conducted AF.
	In patients with symptomatic AF and uncontrolled heart rate are candidates for AVJ ablation (irrespective QRS duration).
1	CRT is recommended in patients with HFrEF.
2A	CRT rather than standard RV pacing should be considered in patients with HFmrEF.
2A	RV pacing should be considered in patients with HFpEF.
2B	CRT may be considered in patients with HFpEF.
2A	Patients who have received a conventional pacemaker or an ICD who subsequently develop symptomatic HF with LVEF ≤35% despite OMT, and who have a significant proportion of PV pacing, should be considered for upgrade to CRT.
	Recommendation for patients with heart failure and atrioventricular block
1	CRT rather than RC pacing is recommended for patients with HFrEF (<40%) regardless of NYHA class who have an indication for ventricular pacing and high-degree AVB in order to reduce morbidity. This includes patients with AF.
	Recommendations for using His bundle pacing
2A	CRT candidates in whom coronary sinus lead implantation is unsuccessful, HBP should be considered as a treatment option along with other techniques such as surgical epicardial lead.
2A	HBP with ventricular backup lead may be considered in patients whom a “pace-and-ablate” strategy for rapidly conducted superventricular arrhythmia is indicated, particularly when the intrinsic QRS is narrow first up.

CLASS (STRENGTH) OF RECOMMENDATION
CLASS 1 (STRONG)	Benefit > > > Risk
Suggested phrases for writing recommendations:
Is recommended
Is indicated/useful/effective/beneficial
Should be performed/administered/other
Comparative-Effectiveness Phrases†:
Treatment/strategy A is recommended/indicated in preference to treatment B
Treatment A should be chosen over treatment B
CLASS 2a (MODERATE)	Benefit > > Risk
Suggested phrases for writing recommendations:
Is reasonable
Can be useful/effective/beneficial
Comparative-Effectiveness Phrases†:
Treatment/strategy A is probably recommended/indicated in preference to treatment B
It is reasonable to choose treatment A over treatment B
CLASS 2b (WEAK)	Benefit ≥ Risk
Suggested phrases for writing recommendations:
May/might be reasonable
May/might be considered
Usefulness/effectiveness is unknown/unclear/uncertain or not well-established
CLASS 3: No Benefit (MODERATE)
(Generally, LOE A or B use only)	Benefit = Risk
Suggested phrases for writing recommendations:
Is not recommended
Is not indicated/useful/effective/beneficial
Should not be performed/administered/other
Class 3: Harm (STRONG)	Risk > Benefit
Suggested phrases for writing recommendations:
Potentially harmful
Causes harm
Associated with excess morbidity/mortality
Should not be performed/administered/other

Table 3.

Recommendation of 2021 ESC guidelines on cardiac pacing and CRT [52].

COR	Recommendations
1	For patients who have LVEF <35% sinus rhythm, left bundle branch block (LBBB) with a QRS duration ≥150 ms, and NYHA class II, III, or ambulatory IV symptoms on GDMT, CRT is indicated to reduce total mortality, reduce hospitalizations, and improve symptoms and QOL.; For patients who have LVEF ≤35%, sinus rhythm, LBBB with a QRS duration of ≥150 ms, and NYHA class II, and III, or ambulatory IV symptoms on GDMT, CRT implantation provides high economic value.
2A	For patients who have LVEF ≤35%, sinus rhythm, a non-LBBB pattern with a QRS duration ≥150 ms, and NYHA class II, III, or ambulatory class IV symptoms on GDMT, CRT can be useful to reduce total mortality, reduce hospitalizations, and improve symptoms and QOL.
2A	In patients with high-degree or complete heart block and LVEF of 36–50%, CRT is reasonable to reduce total mortality, reduce hospitalizations, and improve symptoms and QOL.
2A	For patients who have LVEF ≤35%, sinus rhythm, LBBB with QRS duration 120–149 ms, and NYHA class II, III, or ambulatory IV symptoms on GDMT, CRT can be useful to reduce total mortality, reduce hospitalizations, and improve symptoms and QOL.
2A	In patients with AF and LVEF ≤35% on GDMT, CRT can be useful to reduce total mortality improve symptoms and QOL, and increase LVEF, if: (a) the patient requires ventricular pacing or otherwise meets CRT criteria (b) atrioventricular nodal ablation or pharmacological rate control will allow near 100% ventricular pacing with CRT.
2A	For patients on GDMT who have LVEF ≤35% and are undergoing placement of a new or replacement device implantation with anticipated requirement for significant (>40%) ventricular pacing, CRT can be useful to reduce total mortality, reduce hospitalizations, and improve symptoms and QOL.
2B	For patients who have LVEF ≤35%, sinus rhythm, a non-LBBB with QRS duration of 120–149 ms, and NYHA class III or ambulatory class IV on GDMT, CRT can be useful to reduce total mortality, reduce hospitalizations, and improve symptoms and QOL.
2B	For patients who have LVEF ≤30%, ischemic cause of HF, sinus rhythm, LBBB with QRS duration ≥150 ms, and NYHA class I symptoms on GDMT, CRT may be considered to reduce hospitalizations and improve symptoms and QOL.
3	In patients with QRS duration <120 ms, CRT is not recommended.
3	For patients with NYHA I or II symptoms and non-LBBB pattern with QRS duration <150 ms, CRT is not recommended.
3	For patients comorbidities or frailty limit survival with good functional capacity to <1 year, ICD and cardiac resynchronization therapy with defibrillation (CRT-D) are not indicated.

CLASS (STRENGTH) OF RECOMMENDATION
CLASS 1 (STRONG)	Benefit > > > Risk
Suggested phrases for writing recommendations:
Is recommended
Is indicated/useful/effective/beneficial
Should be performed/administered/other
Comparative-Effectiveness Phrases†:
Treatment/strategy A is recommended/indicated in preference to treatment B
Treatment A should be chosen over treatment B
CLASS 2a (MODERATE)	Benefit > > Risk
Suggested phrases for writing recommendations:
Is reasonable
Can be useful/effective/beneficial
Comparative-Effectiveness Phrases†:
Treatment/strategy A is probably recommended/indicated in preference to treatment B
It is reasonable to choose treatment A over treatment B
CLASS 2b (WEAK)	Benefit ≥ Risk
Suggested phrases for writing recommendations:
May/might be reasonable
May/might be considered
Usefulness/effectiveness is unknown/unclear/uncertain or not well-established
CLASS 3: No Benefit (MODERATE)
(Generally, LOE A or B use only)	Benefit = Risk
Suggested phrases for writing recommendations:
Is not recommended
Is not indicated/useful/effective/beneficial
Should not be performed/administered/other
Class 3: Harm (STRONG)	Risk > Benefit
Suggested phrases for writing recommendations:
Potentially harmful
Causes harm
Associated with excess morbidity/mortality
Should not be performed/administered/other

Table 4.

2022 AHA/ACC/HFSA guidelines for the management of heart failure [55].

8.3 QRS criteria in CRT

The definition of left bundle branch block (LBBB) varies across medical guidelines and studies, affecting how patients are classified and recommended for cardiac resynchronization therapy (CRT). This inconsistency may lead to improper inclusion or exclusion of patients [56, 57]. Some researchers have proposed redefining LBBB criteria by considering gender differences in ventricular wall thickness and requiring septal activation patterns on ECG [57]. Complications also arise in patients with LBBB after myocardial infarction [58]. Studies show that strict ECG criteria, like QS or rS in V1, mid-QRS notching, and absence of Q in lateral leads, are associated with better CRT outcomes (Tables 5 and 6) [59].

	Responders (n = 75)	Non-responders (n = 27)	p-Value
PR interval	162.2 ± 23.0	182.2 ± 32.3	0.02
QRS duration	172.4 ± 21.9	170.7 ± 24.2	n.s.
LBBB morphology	77.3%	66.7%	n.s.
R amplitude in V1	1.1 ± 0.4	1.3 ± 0.5	0.04
S amplitude in V1	14.2 ± 5.9	14.5 ± 6.8	n.s.
R amplitude in V6	6.6 ± 5.0	3.6 ± 2.9	0.01
S amplitude in V6	4.1 ± 3.9	7.3 ± 6.6	0.01
R6/S6	4.6 ± 5.4	1.7 ± 2.5	0.02
(S1 + R6) − (S6 + R1)	15.7 ± 10.8	9.5 ± 8.8	0.02
Paced QRS duration	127.5 ± 26.3	137.0 ± 23.2	0.08

Table 5.

Electrocardiographic variable in responder and non-responder group [59].

Predictors of CRT response	Predictors of CRT non-response
True LBBB
QRS duration ≥130 ms in women and ≥140 ms in men Mid-QRS notching and/or slurring in two contiguous leads in V1–2 or I-aVL, V5–V6 Absence of q waves in the lateral leads Absence of R wave in V1 (≥1 mm) 45 ms ≤ between the peak of the R to the nadir of the S wave in V1
Non-true LBBB and non-LBBB
QRS duration ≥150 ms Mid-QRS notching or/and slurring in one lateral lead Masquerading bundle branch block ID in lead V6 > 60 ms QR-max index >120 ms	More than two notches on the R wave or the nadir of the S wave. <32.5 ms to the beginning of the QRS fragmentation from the QRS onset and a longer fractionation duration Lead one ratio < 12
All QRS morphologies
ID in lead I ≥ 110 ms ID in lead aVL ≥ 130 ms ID/QRS duration >0.69 in lead I [ID in lead I-ID in lead V1] >90 ms [aVLID-aVFID]/QRSd >25% [V5ID-V1ID]/QRSd >25% Large R/S in V6 (absence of deep S wave)	QRS duration <130 ms

Table 6.

Useful electrocardiographic signs to support the prediction of favorable response to cardiac resynchronization therapy [59].

According to trials such as MADIT-CRT and RAFT, patients with left bundle branch block (LBBB) benefit more from CRT than those with right bundle branch block (RBBB) or intraventricular conduction delay (IVCD) [30, 60]. While CRT trials historically used QRS ≥ 150 ms, evidence now supports QRS > 120–130 ms, especially in sicker patients. However, guidelines still advise CRT for QRS ≥ 150 ms or ≥ 130 ms + LBBB based on trials like MADIT-CRT, REVERSE, and RAFT (Figure 8) [28, 60, 61]. A meta-analysis shows CRT is effective for QRS ≥ 150 ms but not <150 ms [61]. Clinicians can be optimistic about CRT response for QRS ≥ 150 ms, particularly non-LBBB patients. More data are needed for Class I patients.

Figure 8.

Central Illustration relation between QRS duration and the response and outcome of cardiac resynchronization therapy. (Left) Taken from a meta-analysis of individual patient data from landmark cardiac resynchronization therapy (CRT) trials showing hazard ratios (y-axis and solid purple line) 95% confidence interval (CI) (blue shading) for effects on total mortality of CRT versus control patients, with QRS duration plotted on the x-axis using spline smoothing. The intersection between the solid purple line and the vertical dashed line at a hazard ratio of 1.0 (no effect) denotes the QRS duration above which there is a high certainty of response. (Right) Data from a subanalysis of the REVERSE study showing the proportion of patients with an improved clinical response (CRT in solid gold line and control in dashed gold line) and the absolute change in left ventricular end-systolic volume index (LVESVi) at 12 months (CRT in solid blue line and control patients in dashed blue line) [59].

8.4 CRT and narrow QRS complex

CRT has undergone assessment for patients exhibiting a QRS duration <120 ms, resulting in different outcomes. While initial investigations conducted at single centers proposed symptomatic improvements in this population subset following CRT, findings from extensive trials have contradicted these findings.

Particularly, the LESSER-EARTH trial (Evaluation of Resynchronization Therapy for Heart Failure) and the EchoCRT (Echocardiography-Guided Cardiac Resynchronization Therapy) study, both multicenter, randomized, controlled trials, failed to indicate a mortality advantage with the incorporation of CRT to an Implantable Cardioverter Defibrillator (ICD) among this patient cohort [62, 63].

In the LESSER-EARTH trial, CRT did not improve clinical outcomes or lead to left ventricular (LV) reverse remodeling. There was even an indication that CRT could potentially be harmful [62, 63]. The EchoCRT trial focused on patients with a QRS duration of 130 ms or less, Left Ventricular Ejection Fraction (LVEF) of 35% or less, and mechanical dyssynchrony. In this investigation, participants underwent implantation of CRT-Defibrillator (CRT-D) devices and were subsequently randomly allocated to either activate or deactivate the CRT function. The trial was prematurely terminated due to futility, as there was noted to be a rise in mortality rates in patients receiving CRT-D (Figure 9) [63]. These findings suggest that extending CRT to patients with shorter QRS durations may not provide the expected benefits and could even be detrimental, challenging the rationale for using CRT in this subset of heart failure patients.

Figure 9.

Echo-CRT trial cardiac-resynchronization therapy in heart failure with a narrow QRS complex Kaplan-Meier estimates for primary-outcome events. Panel A shows the Kaplan-Meier curves for the primary composite outcome of death from any cause or hospitalization for heart failure. Panel B shows the Kaplan-Meier curves for death from any cause [63].

9. Predictors of response

9.1 Non-responders to cardiac resynchronization therapy

Approximately 33% of patients do not show a hemodynamic improvement following the therapy (Figure 10). The relevance of measuring individual responses to CRT is questioned, as this is not a common practice in other medical interventions that aim for an average treatment effect, acknowledging that some patients will not benefit regardless [64]. Non-response rates for heart failure drugs like enalapril, bisoprolol, and spironolactone are high, suggesting that lack of response might be influenced by genetic factors. However, the challenge remains to identify a reliable surrogate marker for prognostic response to CRT. LV reverse remodeling is suggested as one such surrogate because of its predictive value for cardiovascular mortality. Yet, it is not perfect as it does not predict symptomatic improvement and could lead to misclassification of non-responders.

Figure 10.

30% of CRT patients are non-responders.

Other potential surrogate markers like peak VO2 and natriuretic peptides have their limitations, with the former weakly predicting mortality and the latter being too variable to be useful in clinical practice. Factors known to reduce the response to CRT include increased scar burden, certain scar locations, extreme mechanical dyssynchrony, and comorbidities like severe right ventricular dysfunction, pulmonary hypertension, renal failure, and valvular disease (Figure 11) [65]. However, without studies comparing these factors to control patients on optimal therapy, their impact on CRT effectiveness is not clear. Preventing the deterioration of a patient’s condition could be considered a response to CRT, though this effect has not been quantified in research. Gender and the cause of heart failure are noted to influence CRT outcomes, with women and those with nonischemic HF etiology generally experiencing better results from CRT [66].

Figure 11.

Factors associated with sub-optimal CRT response [65].

9.2 Electrocardiographic parameters as predictors of response to CRT

While no single ECG parameter could predict CRT response on its own, yet specific parameters did demonstrate a difference between responders and non-responders. In particular, an increased amplitude of the R wave in lead V6, an elevated R/S ratio in the same lead, and the derived figure (S1 + R6) − (S6 + R1) may suggest a greater likelihood of response in both LBBB and non-LBBB patients [67].

ECG variables: (S1 + R6) − (S6 + R1): This computed variable involves the summation of the S wave in lead V1 and the R wave in lead V6, subtracted from the sum of the S wave in lead V6 and the R wave in lead V1. The significant difference in this variable between responders and non-responders suggests that the spatial and temporal characteristics of ventricular depolarization, as reflected on the ECG, might correlate with the mechanical synchrony achieved through CRT [68].

R6/S6 ratio: The ratio of the R wave to the S wave amplitude in lead V6 provides an index of the electrical activity in the lateral wall of the left ventricle. A higher R6/S6 ratio in responders may indicate a more favorable left ventricular electrical substrate for CRT [69].

Height of R wave in V6: The R wave amplitude in the V6 lead represents the electrical forces directed toward the lateral wall of the left ventricle. A higher amplitude might correlate with less scarring and better contractile reserve in the lateral wall, which could translate into a better response to CRT [70].

LBBB vs. Non-LBBB Patients: Patients with LBBB typically have a more dyssynchronous contraction pattern, and CRT aims to correct this dyssynchrony. Therefore, parameters that reflect the extent of dyssynchrony in LBBB patients may be more predictive of CRT response in this group compared to non-LBBB patients (Figure 12) [67, 71].

Figure 12.

LBBB responder and non LBBB responder.

9.3 The role of imaging

9.3.1 Imaging for patient selection

9.3.1.1 Echocardiography

• Early investigations indicated that echocardiographic assessments of mechanical dyssynchrony were indicative of the outcome of cardiac resynchronization therapy (CRT) [72]. Nevertheless, recent trials have observed that echocardiographic evaluations of dyssynchrony lacked consistent reliability in predicting CRT response. Clinical recommendations have subsequently shifted away from employing echocardiographic dyssynchrony as a criterion for patient selection for cardiac resynchronization therapy (CRT) [1, 73]

9.3.1.2 Cardiac magnetic resonance (CMR) and dyssynchrony

• CMR, especially myocardial tagging, offers a sophisticated method for assessing myocardial motion [74].

• Despite some measures of dyssynchrony via CMR showing promise in predicting CRT outcomes, they lack external validation.

• Complicating its use in predicting CRT response, mechanical dyssynchrony is influenced by various factors beyond conduction disturbances, including myocardial perfusion, viability, and passive motion [1].

9.3.1.3 Imaging to guide left ventricular (LV) pacing

• While dyssynchrony imaging may not be ideal for selecting patients, it has the potential to optimize LV lead placement [75].

• The TARGET and STARTER trials indicated that echocardiography could help improve CRT outcomes by targeting late-activated myocardial segments [75].

• CT imaging of coronary veins and CMR to avoid pacing in scarred areas are other strategies [1].

• Emerging techniques include electroanatomic and ECG body surface mapping, as well as image fusion and computational modeling to assist in LV lead positioning [76].

9.3.1.4 Scar burden

• A higher scar burden has been associated with a lower response rate to CRT in CMR and nuclear imaging studies [76].

• However, a specific cutoff for scar burden that predicts CRT response has not been established or validated [1].

• The assessment of scar burden and its clinical implications in CRT continues to be a research focus.

10. Optimizing outcomes

10.1 Enhancing CRT outcomes by targeting the LV pacing site

10.1.1 Current CRT implantation technique

• The transvenous technique for CRT, established in 1994, remains standard practice [77].

• A posterolateral LV lead placement with good pacing parameters and no diaphragmatic stimulation is the typical goal [77].

• Studies yield conflicting results; some suggest lead position on the LV free wall is not crucial, while others find non-apical positions more favorable [78].

10.1.2 Variability in patient response

• Even with appropriate fluoroscopic positioning, patient responses to CRT are variable [29]. Fluoroscopic imaging does not account for myocardial factors that affect pacing efficacy [78].

10.1.3 Targeting late-activated segments

• Recent approaches focus on implanting LV leads in segments of the heart that activate late to improve CRT response (Figure 13) [79, 80].

• The STARTER trial (Echocardiography-guided left ventricular lead placement for cardiac resynchronization therapy) found this method reduced death or HF hospitalization but achieved only 30% accuracy in targeting late-activated segments (Figure 14) [81].

• Scarring was not considered in these results, raising questions about the influence of myocardial scarring on outcomes [50].

Figure 13.

Examples of QLV measurements. The calipers are aligned with the onset of QRS and peak of the left ventricular electrogram. The QLV was calculated as 90 ms for the patient in (A) and 165 ms for the patient in (B) [79].

Figure 14.

Kaplan-Meier plots of the results of the primary end point of freedom from heart failure hospitalization or death after cardiac resynchronization therapy (CRT), including all randomized patients with intention-to-treat analysis. Patients randomized to echocardiographic guided left ventricular (LV) lead positioning strategy had a significantly more favorable clinical outcome in comparison to routinely treated patients [81].

10.1.4 Influence of myocardial scarring

• Pacing in scarred myocardium correlates with a poorer response to CRT [82].

• The degree of scarring intensifies the negative impact on CRT efficacy [82].

• CMR-guided pacing to avoid scarred tissue seems beneficial, but further validation is needed [82].

10.1.5 Enhancing the response by multipolar LV leads

Multipoint pacing (MPP) in cardiac resynchronization therapy (CRT) has revealed improving clinical outcomes and reversing left ventricular (LV) remodeling associated with heart failure [83]. In a randomized, multicenter study conducted in the Middle East, patients implanted with CRT-D devices were randomized to receive either biventricular pacing (BiV) or MPP therapy. According to the study, a higher proportion of MPP patients had a reduction in end-systolic volume (ESV) of 15% or more and improved NYHA functional class than those with BiV (Figure 15) [84].

Figure 15.

End-systolic volume (ESV) response distribution (top), detailed ESV response distribution (middle), and end-systolic volume + ejection fraction (ESV + EF) response distribution (bottom) for biventricular (BiV) and multipoint pacing (MPP) patients [84].

Moreover, a systematic review and meta-analysis comparing multipoint pacing (MPP) to traditional biventricular (BiV) pacing revealed that MPP correlated with a heightened occurrence of patients experiencing functional improvement and elevated delta left ventricular (LV) dP/dtmax, suggesting enhanced hemodynamic parameters. Despite no notable variance between MPP and BiV in terms of hospitalization for heart failure, LV end-systolic volume, and all-cause mortality, MPP was associated with significantly lower projected battery longevity. These findings suggest that MPP has the potential to improve functional class and acute hemodynamic parameters in patients with heart failure, yet additional investigation is needed to understand the long-term advantages and optimize programming strategies for MPP [83]. Multipolar LV leads also offer the possibility of avoiding diaphragmatic stimulation and selecting from multiple pacing vectors [76]. This technology might enable specific targeting of viable and late-activated myocardium [76]. Although promising, more evidence is required to confirm whether multipolar leads enhance CRT outcomes [76]. Preference for multipolar leads is increasing, potentially making them the new standard [76].

10.2 Device optimization to enhance CRT response

Device optimization in cardiac therapy is crucial to improve left ventricular (LV) function, which is affected by atrioventricular (AV) delays. While echocardiography has traditionally been employed for identifying optimal AV delays, its time-consuming nature has led to its decline in busy medical settings. Instead, operators often use a trial-and-error approach to find the best device settings, which is not methodologically robust. Furthermore, echocardiographic optimization, despite being a gold standard, has not been proven to enhance outcomes and may be no more effective than using standard device settings [85].

Automatic, device-based AV and VV (ventriculo-ventricular) optimization offer practical benefits over manual methods. However, studies have shown mixed results. The FREEDOM study revealed that the QuickOpt algorithm was less effective than echocardiographic optimization [85]. Similarly, the Smart-AV study found that the Smart-AV algorithm did not result in LV reverse remodeling when compared to standard settings [76]. Adaptive CRT, which uses an algorithm for automatic selection of pacing mode and AV/VV optimization, was shown to be comparable to echocardiographic optimization in the Adaptive CRT study (Figure 16) [53, 85]. Nonetheless, it remains uncertain if these benefits are due to the optimization of AV/VV intervals or the pacing mode itself [76].

Figure 16.

End-improved survival with dynamic optimization of CRT pacing using adaptive CRT algorithm: analysis of real world patient data [53].

10.3 Possible solutions for non-responders

10.3.1 Alternative pacing

Lead-based endocardial LV pacing and conduction system pacing like His bundle pacing (HBP) and left bundle branch area pacing (LBBAP) can improve outcomes for non-responders to standard biventricular pacing. HBP activates the physiological conduction system but has limitations like difficult implantation, high pacing thresholds, and early battery depletion [86].

10.3.2 His-bundle pacing

His bundle pacing restores physiological activation of the ventricles. It has shown feasibility and efficacy for managing arrhythmias and heart failure [87, 88, 89, 90, 91]. However, it has drawbacks such as challenging implantation, unstable pacing thresholds, the risk of crosstalk, and failure to achieve cardiac resynchronization in some patients. Limitations include prolonged procedures, high thresholds, early battery depletion, and lead dislodgement (Figure 17) [92, 93, 94].

Figure 17.

Forms of His bundle pacing. (A) During selective His bundle (HB) capture, ventricular activation occurs directly over the His-Purkinje system. There is an isoelectric line between the pacing stimulus and the QRS which is identical to the native QRS. (B) In nonselective HB pacing there is fusion capture of HB and adjacent myocardial tissue resulting in the presence of pseudo-delta wave. Although paced QRS duration is slightly increased (by the H-QRS interval), the overall electrical axis of the paced QRS is concordant with the electrical axis of the intrinsic QRS [92].

10.3.3 Left bundle branch area pacing

In the evolving landscape of cardiac resynchronization therapy (CRT), left bundle branch area pacing (LBBAP) has emerged as a promising alternative to traditional approaches. While HBP has shown promise in CRT, it is not without its challenges. The presence of potential blockages along the conduction system can hinder the effectiveness of HBP. To overcome these obstacles, researchers have proposed stimulating the conduction system distal to the His bundle, specifically targeting the left bundle branch. This distal approach aims to bypass areas of blockage and achieve a more profound and targeted form of cardiac resynchronization (Figure 18).

Figure 18.

Left bundle area pacing in left bundle branch block patients targets zones [86].

LBBAP has gained attention as a practical, safe, and promising option in the realm of CRT. Its versatility extends beyond patients who have experienced unsuccessful Biventricular Pacing (BVP)-CRT implantation or are non-responders. LBBAP is also being considered as a primary choice for addressing intraventricular conduction delay [95]. The technique involves pacing either the main trunk of the left bundle branch or its anterior/posterior fascicles, with a preference for the main trunk in cases of the left bundle branch block. In cases lacking conduction abnormalities, especially those with a narrow QRS, left bundle branch area pacing (LBBAP) provides a distinct advantage. Through retrograde activation of the right bundle branch, LBBAP can promptly stimulate the right ventricle with minimal delay. This approach aids in preserving interventricular synchrony and potentially achieving physiological ventricular synchrony. As a result, LBBAP is proving to be a suitable pacing strategy, especially in the context of pure anti-bradycardia pacing without intraventricular conduction abnormalities [96, 97].

Recent studies have shed light on the comparative effectiveness of LBBAP in relation to other pacing strategies. The left bundle branch pacing vs. left ventricular septal pacing vs. Biventricular Pacing for Cardiac Resynchronization Therapy trial demonstrated superior clinical outcomes with LBBAP compared to LVSP and BIVP for CRT patients [53]. Achieving left bundle branch capture appeared to be a crucial factor in the success of LBBAP, while LVSP and BIVP showed no significant differences. This prospective, multicenter study involving 415 patients undergoing CRT further solidified the position of LBBAP as the preferred pacing strategy based on the research findings [98].

Left bundle branch area pacing represents a promising frontier in the field of cardiac resynchronization therapy and is regarded as an excellent choice for BVP-CRT for patients with left ventricular dysfunction and conduction abnormalities. Further research is crucial to affirm the potential significance of these pacing techniques and to deepen our understanding of their similarities and differences [53, 97].

10.3.4 Left bundle branch area pacing procedural protocol

The goal of conduction system pacing is to produce a more physiologic ventricular activation sequence that resembles normal ventricular activation during sinus rhythm. This goal can be achieved either by capturing the HIS bundle directly at the base of the interventricular septum (IVS) or by capturing the left bundle, which is located more distally on the IVS. Of the two techniques, left bundle branch area pacing (LBBAP) has emerged as the most attractive of the two techniques given higher sensing amplitude, lower capture threshold and greater degree of stability, and low number of lead revisions [99, 100]. Thus, only LBBAP technique will be discussed in this section.

From its inception, LBBAP has been performed almost exclusively using lumen-less pacing leads (LLL-LBBAP), mainly the SelectSecure 3830 (Medtronic Inc., Minneapolis, USA). Alternatively, standard-stylet-driven pacing leads (SDL-LBBAP) have been reported to be both safe and practical [101]. Although the lead and helix designs differ, the implantation technique is similar for both leads. Both techniques use a delivery sheath to deliver the lead at a more perpendicular angle to the IVS to allow for lead migration into the septum, as indicated in Figure 19. In patients presenting with left bundle branch block (LBBB), backup ventricular pacing is highly recommended, given the possibility of transient complete AV block due to mechanical pressure on the HIS bundle.

Figure 19.

Lumen-less and style-driven leads used in LBBAP and corresponding delivery sheaths.

10.3.4.1 LBBAP implantation steps

10.3.4.1.1 Identification of the initial site of implantation on the septum

The sheath and dilator are advanced to the RV over a guidewire, this is best achieved in right anterior oblique (25-degree) view. Once the delivery system is in the RV, the dilator and wire are withdrawn, and the lead is advanced to the tip of the sheath. The Ideal location for lead fixation is 1–1.5 cm apical to the HIS location in the RV septum. This can be achieved by connecting electronic clips to the lead in a unipolar fashion and sensing HIS bundle depolarization to determine the starting point in the RV. Alternatively, pacing from the lead tip and observing the paced morphology, can help locate the optimal site for lead fixation. The ideal pacing morphology as shown in Figure 20 includes the following:

• W pattern in V1, with a hump or notch on the later half preferably

• R wave is taller in lead II than III

• aVR and aVL discordance in the first 40 ms

Figure 20.

Target pacing morphology at the RV septum to indicate an adequate site for lead fixation.

Once an adequate unipolar pacing morphology is observed, contrast injection of the sheath is helpful to assess the apposition of the sheath to the septum, this is usually performed in the lateral anterior oblique view (20–25 degrees). A satisfactory contrast injection should show near perpendicular alignment on the interventricular septum. This location should be stored as a reference to assess lead placement into the septum.

10.3.4.1.2 Lead deployment and advancement into the septum

Lead advancement into the septum requires clockwise rotation of the lead with forward pressure while monitoring lead migration into the septum on fluoroscopy. The lead can be observed to rotate during forward displacement. Approximately 6–8 mm into the septum, lead impedance as well as pacing morphology should be evaluated.

Pacing morphology following initial rotation should be assessed, as the lead migrates into the septum the notch in V1 will start to move later in the QRS, ultimately, the notch will reach the end of the QRS and an R′ will be observed. Although this is usually observed during LBBAP, it is not a universal finding and adequate final locations can only show a notch in V1 in the later half with terminal negative electrical force. Once the lead helix reaches the LV sub-endocardium, a sudden reduction in the QRS duration typically occurs, along with a decrease in the left ventricular activation time (LVAT), indicating successful capture of the LV conduction system. LVAT is defined as the interval from pacing stimulation to the appearance of R waves in leads V4–V6 (Figure 21A).

Figure 21.

(A) Progression of unipolar pacing morphology during lead fixation into the ventricular septum. (B) Sheath contrast injection showing extent of septal lead migration.

Initial impedance is expected to be relatively high during penetration. As the lead migrates into the septum, lead impedance will start to gradually decrease, signaling deep penetration into the septum and proximity to the left ventricular endocardium. Generally, unipolar lead impedance should be >500 Ohms. Sheath contrast injection can help determine lead implantation depth into the septum, as well as identify inadvertent septal perforation (Figure 21B).

10.3.4.1.3 Determining final lead position

The final lead position should show a pacing morphology that reflects a terminal R′ in V1 and LVAT of less than 90 ms, this usually is accompanied by a narrow QRS of less than 120 ms. When the left ventricular conduction system is captured with the lead helix, a low pacing threshold (<1.5 V/0.5 ms) is usually observed. Observing fixations beats which are premature ventricular depolarizations (VPD) with RBBB morphology with left axis deviation signifies mechanical stimulation of the left posterior fascicle, this finding indicates proximity to LV endocardium, and further migration into the septum should be avoided [102]. Left bundle potentials can be recorded once the lead helix is in proximity to the LV endocardium. Once the final location is reached, bipolar pacing should be performed, and pacing impedance and bipolar capture threshold determined. Following sheath removal, adequate lead slack should be ensured to prevent lead dislodgement or migration, and a 12-lead ECG is recommended to document pacing morphology immediately following implantation (Figure 22).

Figure 22.

(A) Final lead location in a patient who underwent CRT-D placement with a left bundle branch area pacing following failed CS cannulation due to lack of acceptable CS branches. (B) ECG showing LBBAP with narrow QRS of 88 ms and LVAT of 72 ms.

10.3.4.1.4 Septal perforation and septal artery injury

Septal lead perforation into the LV cavity can occur due to excessive lead rotation and migration into the septum. This is indicated by a marked decrease in pacing impedance that corresponds with sudden increase in unipolar capture threshold. Fluoroscopy usually shows deep penetration of the lead from the site of initial implantation. Sheath contrast injection can show contrast escape into the LV cavity. If septal perforation occurs, withdrawal of the lead into the RV is usually possible without major consequences as the lead track into the septum is sealed by septal muscle rebound and rarely leaves residual connection between the right and left ventricle. The lead should be removed from the sheath and examined for any retained muscle tissues as this will hinder lead re-implantation.

Septal perforator artery injury can occur during LBBAP lead implantation, this can be minimized by placing the lead inferiorly and posteriorly on the septum to avoid the large septal branches usually observed in the anterior septum. Contrast injection into the delivery sheath can delineate septal vascular injury [103].

10.3.5 Endocardial left ventricular (LV) pacing

Endocardial pacing seems to produce more efficient resynchronization than epicardial pacing. It allows pacing from a variety of LV sites without restrictions from coronary sinus anatomy [104]. Potential advantages of endocardial LV pacing include optimizing the pacing site to target the latest activation area based on evidence from trials like TARGET, which showed echo-guided targeting had superior response compared to empirical placement [1]. Studies show endocardial pacing accesses fast-conducting tissue or Purkinje fibers for faster LV activation than epicardial pacing and may reduce arrhythmogenic effects by restoring physiological activation/repolarization patterns [105].

Lead-based endocardial LV pacing was used in the ALSYNC trial of 132 patients, which reported 55% had reverse remodeling and 59% symptomatic improvement at 6 months [106]. However, it is limited by thromboembolic risk requiring anticoagulation. The WiSE-CRT leadless system avoids these risks. The SELECT-LV trial of 35 patients showed a high 97.1% procedural success and 84.8% clinical response at 6 months [107]. An international WiSE-CRT registry of 90 patients demonstrated good procedural success at 94.4% and 69.8% clinical response at 6 months Figures 23 and 24 [98, 104, 108]. Endocardial LV pacing warrants further research into leadless delivery systems as a promising option for CRT non-responders.

Figure 23.

(A) Primary composite outcome. (B) Heart failure (HF)-related hospitalization. Left bundle branch pacing vs. left ventricular septal pacing vs. biventricular pacing for cardiac resynchronization therapy [98].

Figure 24.

Endocardial LV pacing—components of the WiSE-CRT system [104].

11. Procedural techniques

11.1 Pre-implant patient evaluation

Before cardiac resynchronization therapy (CRT) implantation, a comprehensive patient evaluation is crucial. The European Society of Cardiology and the European Heart Rhythm Association have provided guidelines for this process [109]. The assessment should include a detailed medical history, physical examination, vital signs, and laboratory tests to ensure that patients have stable heart failure (HF) while on guideline-directed medical therapy (GDMT) [109].

Echocardiography plays a vital role in measuring left ventricular ejection fraction (LVEF) and assessing cardiac size and function. Additionally, a 12-lead electrocardiogram (ECG) is necessary to evaluate QRS duration and morphology [109]. For patients at high risk of thromboembolism receiving warfarin, maintaining treatment at a lower dose while monitoring the international normalized ratio (INR 2–3) is recommended, with postoperative heparin being discouraged [109].

Prophylactic treatment with antibiotics that target staphylococcal bacteria is recommended [109]. Also, performance of quality life (QOL) functionality assessments to assess the anticipated response to cardiac resynchronization therapy (CRT) is advised [109]. Cardiac magnetic resonance imaging (cMRI) and computed tomography angiography (CTA) can both reflect valuable insights into myocardial viability and venous anatomy, respectively.

Identifying and managing atrial fibrillation or frequent premature ventricular contractions (PVCs) that may hinder continuous CRT therapy delivery is essential [109]. For patients with a low to moderate risk of thromboembolism, changing the anticoagulant therapy dose before surgery is recommended to minimize bleeding risk [109]. CRT should be postponed in patients with HF, on inotrope medication, or with unstable ventricular arrhythmias [25]. Patients should not be excluded from cardiac resynchronization therapy based on echocardiographic dyssynchrony assessment [25].

If a patient is decompensated with HF, dependent on inotropes, or has unstable ventricular arrhythmias, CRT should be postponed until the medical condition improves [25]. The assessment of dyssynchrony in the echocardiogram should not be used to rule out patients for CRT [25].

11.2 Perioperative period

Close monitoring post-CRT implantation is essential due to potential changes in urine output and electrolyte balance, which may necessitate modifications to the prescribed drugs [110]. Temporarily withdrawing antiplatelet agents before implantation may decrease bleeding risk [111]. Perioperative antibiotic administration has been shown to significantly reduce infection rates [110].

Despite technological advancements and improved surgical techniques, complications such as LV lead failure, hematomas, dissections, perforations, heart block, lead dislodgement, renal failure, and mortality can occur, with overall complication rates ranging from 4% to 28% (Figure 25) [110, 113].

Figure 25.

Rates of reported complications of cardiac resynchronization therapy in randomized controlled trials, registries, and administrative databases [112].

11.3 Targeting LV lead placement

Optimal LV lead placement and stability are critical for successful CRT outcomes [110, 114, 115]. Conventional lead implantation involves placing a single LV lead through the coronary sinus (CS) into a suitable vein, with the target vein selected based on anatomical considerations. Fluoroscopic guidance and operator experience are used for optimal site determination (Figure 26) [110, 114, 115]. However, this approach has limitations, including subjective assessment and potentially suboptimal positioning.

Figure 26.

CS venous tributaries and segments of the left ventricle [116].

Research has shown that apically positioned LV leads are associated with poorer clinical outcomes [110]. While the COMPANION and MADIT-CRT trials demonstrated comparable responses between lateral, anterior, or posterior locations, the REVERSE trial patients benefited from lateral positions [110]. Imaging techniques may assist in selecting specific LV pacing sites based on anticipated electromechanical optimization [110].

11.4 Techniques for CRT implantation

Techniques for CRT implantation as recommended by The European Society of Cardiology [109].

11.4.1 Pre-procedural considerations

• Patient assessment and imaging to understand venous anatomy.

• Selection of equipment based on the patient’s anatomical requirements.

11.4.2 Sedation and anesthesia

• Conscious sedation and local anesthesia are the norms.

• General anesthesia for special cases such as pediatric patients or those who cannot be sedated under normal circumstances.

11.4.3 Pacing leads placement sequence

1. Right ventricular (RV) lead: Establish baseline pacing.

2. Left ventricular (LV) lead: Critical for resynchronization, placed using the sheath in the CS branch.

3. Right atrial (RA) lead: Placed last to complete the setup.

11.4.4 LV lead positioning

• Obtaining a detailed phlebogram to visualize the CS anatomy.

• Selecting a target vein based on size, absence of stenosis, and location.

• Aim for proximal to mid-third of the LV to match areas of greatest dyssynchrony.

11.4.5 Branch cannulation techniques

• Customizing approaches to patient-specific anatomy, such as using specialized catheters or leads.

• Maneuvers for difficult angles including inner catheters or leads with special curves.

11.4.6 Lead stability and placement troubles

• Ensuring lead stability with designs meant for aggressive fixation or active fixation mechanisms.

• Stenting as a method to secure a lead position.

• Exploring alternative venous branches or sheath shapes for challenging anatomy.

• Post-implantation assessment including electronic repositioning and chest radiography [112].

11.4.7 Post-procedure management

• Monitoring complications such as diaphragmatic capture or threshold variations.

• Chest X-ray to confirm final lead placement and for future comparisons.

Potential need for reprogramming or repositioning leads electronically in case of issues [109].

11.5 Implantation tips and tricks

Difficult LV lead implantations in CRT can be attributed to various factors such as difficulty accessing the coronary venous system, anatomic variations, scar tissue, phrenic nerve stimulation, and lead instability. By utilizing new technologies, improved tools, and techniques, clinicians can overcome these challenges and improve the success rates of CRT implantations for heart failure patients [112].

Potential Causes of Difficult LV Lead Implantations and Solutions:

Failure to access the coronary venous system: Difficulty in accessing the coronary venous system is a common cause of implant failure. Improved technology, such as specific sheaths with primary and secondary curves, allows better support and cannulation of the coronary sinus (CS). Techniques like withdrawing the sheath with counterclockwise rotation and using contrast dye injections for better visualization can aid in accessing the CS [117].

Anatomic variations in the coronary venous system: Upon successful cannulation of the coronary sinus (CS), and obtaining a venogram, the CS anatomy is recognized. In case of failure, alternative imaging modalities like venous-phase coronary angiography, computed tomography (CT)-guided imaging, fiberoptic endoscopy, or intracardiac echocardiography can be used. Specially shaped sheaths and inner catheters can be used for lead delivery in challenging vessel segments [112].

Extensive scar tissue in the target region: Scar tissue can make lead implantation difficult. Techniques such as careful dissection of the scar tissue, use of guidewires or inner catheters for support, and consideration of alternative lead placement sites can help overcome this challenge [116].

Phrenic nerve stimulation: Phrenic nerve stimulation can occur during LV lead implantation, causing diaphragmatic contraction. Proper lead positioning, pacing adjustments, or using multipolar leads can help avoid or manage phrenic nerve stimulation [118].

LV lead instability: LV lead instability can lead to poor pacing outcomes. Techniques like using fixation screws, atraumatic leads, and active fixation leads can enhance lead stability and reduce the risk of dislodgement [112].

11.6 Delivery of CRT in the real world

Cardiac resynchronization therapy (CRT) has been shown to provide incremental survival benefits to optimal pharmacotherapy (OPT) in patients with advanced heart failure (HF), according to the IMPROVE HF study [119]. Moreover, recent evidence suggests CRT may slow disease progression even in mild HF cases. Despite these benefits, the adoption rate of CRT remains low [50]. HF significantly impacts both survival rates and quality of life, with non-CRT patients experiencing a mortality rate comparable to certain cancers, as indicated by the CARE-HF study. Yet, the treatment of HF with CRT has not reached the same level of comprehensive patient coverage as seen in oncology for those with both advanced and early-stage disease [120]. Additionally, CRT is not without its complications, which must be considered. One of the key barriers to effective CRT delivery is the separation between the fields of HF and electrophysiology. A multidisciplinary approach is crucial, requiring a shift in focus to ensure that patients are systematically identified and treated across specialties, including within general practice. Implementing computerized alerts for QRS duration and left ventricular (LV) function across both secondary and primary care levels could improve patient identification and treatment rates [121].

12. Conclusion and future directions

The journey of cardiac resynchronization therapy (CRT) from its nascent experimental stages to a well-established treatment for heart failure with reduced ejection fraction and ventricular dyssynchrony has been remarkable. CRT has undoubtedly changed the landscape of heart failure management, reducing symptoms, improving quality of life, and enhancing survival rates [122]. As evidenced by the CORE trials and other pivotal studies, CRT’s utility in reversing negative remodeling and promoting a more efficient cardiac function is clear.

However, the path ahead is paved with challenges and opportunities that beckon further exploration. Future directions for the advancement of CRT include:

Personalization of therapy: Ongoing research aims to refine patient selection criteria through genetic profiling, advanced imaging techniques, and biometric data analysis to predict CRT response more accurately. Personalizing therapy may involve adjusting device settings and pacing strategies for individual patient anatomy and physiology.

Technological innovation: The development of leadless and modular CRT devices offers a glimpse into a future with minimally invasive procedures and reduced complications. Advances in battery technology, device miniaturization, and biocompatibility are expected to further improve patient outcomes and comfort.

Algorithm enhancement: Device-based algorithms that adapt to physiological changes in real-time and dynamically manage pacing are under investigation. These algorithms may potentially cater to daily variations in patient activity and circadian rhythms.

Combination therapies: Research into the synergistic effects of combining CRT with other heart failure therapies, such as novel pharmacological agents or stem cell therapy, could provide a multipronged approach to treating the underlying pathology of heart dysfunction.

Conduction system pacing: The exploration of pacing techniques that more closely mimic the heart’s natural conduction system, such as His-bundle pacing or left bundle branch pacing, offers the promise of improved outcomes over traditional CRT.

Global accessibility: Efforts to increase the global accessibility of CRT, especially in low- and middle-income countries, are essential. This includes the development of cost-effective devices and training programs for local healthcare professionals.

Long-term studies: There is a need for long-term studies to understand the enduring impacts of CRT on chronic heart failure and to identify any late-emerging benefits or complications associated with therapy. In conclusion, while CRT has established itself as a cornerstone therapy for a subset of heart failure patients, the quest for optimization and innovation continues. Embracing a multidisciplinary approach that integrates advancements in technology, a deeper understanding of cardiac physiology, and individualized patient care is the key to unlocking the full potential of CRT in the future.

Thanks

To my parents, Alyah and Mohammed, my guiding stars in memory, whose love and wisdom resonate in every word.