Cardiac Resynchronization Therapy

Cardiac resynchronization therapy (CRT), also known as biventricular pacing or multisite ventricular pacing, involves simultaneous pacing of the right ventricle (RV) and the left ventricle (LV). In addition to a conventional RV endocardial lead (with or without a right atrial [RA] lead), CRT involves an additional coronary sinus (CS) lead placed for LV pacing. (See Permanent Pacemaker Insertion.)

CRT has made a dramatic impact on the treatment of most patients with heart failure (HF) and an abnormal QRS duration. It was introduced in the 1990s and revolutionized therapy for many patients with persistent symptoms of systolic HF. The basic goal of CRT is to restore LV synchrony in patients with dilated cardiomyopathy and a widened QRS, which is predominantly a result of left bundle branch block, thereby improving mechanical functioning of the LV. (Ie, The aim of CRT is to restore mechanical synchrony by electrically activating the heart in a synchronized manner.) This involves placement of a CS lead for LV pacing, in addition to placement of a conventional RV endocardial lead, with or without a (right atrial) lead.

There is strong evidence from randomized controlled trials showing that CRT combined with optimal medical therapy improves HF symptoms, LV ejection fraction (LVEF), and quality of life (QOL), while decreasing HF hospitalizations and reducing mortality. ^[2]

The QRS complex on a surface 12-lead electrocardiogram (ECG) represents ventricular depolarization. The QRS duration (QRSd) is the most readily available marker of ventricular dyssynchrony. A prolonged QRS has been shown to be a marker for atrioventricular, interventricular, and intraleft ventricular dyssynchronies. ^[3] The net result of these disturbances in timing of cardiac contraction is decreased pump function. The American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Rhythm Society (HRS) and Heart Failure Society of America (HFSA) guidelines recommend use of cardiac resynchronization therapy for a QRS duration longer than 120 ms on the 12-lead ECG as a marker of ventricular dyssynchrony. ^{[4, 5]}

Randomized clinical trials have confirmed the effectiveness of cardiac resynchronization therapy (CRT) for the following purposes:

• Improving cardiac hemodynamics and symptoms ^{[6, 7]}

• Preventing hospitalization

• Improving mortality ^[8]  (relative to conventional therapy) in patients with advanced heart failure (HF) symptoms and severe left ventricular (LV) dysfunction

Evidence suggests that CRT may even be beneficial in patients with mildly symptomatic HF (New York Heart Association [NYHA] class II). ^{[8, 9, 10]}  A study of 659 patients with HF who underwent successful CRT found the procedure safe to use in patients with clinically significant mitral regurgitation (MR). ^[11] At 12-month follow-up, patients with more than mild MR had comparable results to patients with mild or no MR. Most of the benefits appear to be associated with the presence of left bundle branch block (LBBB) on electrocardiography (ECG). ^[11]  The longer the QRS duration (QRSd) (particularly >150 msec), the more beneficial CRT is likely to be. ^[12]

In light of this and other accumulating evidence, the American College of Cardiology (ACC), American Heart Association (AHA), and Heart Rhythm Society (HRS) modified the class I indication for CRT to include not only patients with NYHA class III and IV symptoms but also those with NYHA class II symptoms and LBBB with a QRSd that is at least 150 ms. ^[5]

Results from a retrospective study that evaluated long-term outcomes in patients with ambulatory NYHA class III and IV HF who underwent CRT over a 4-year period (2003-2007) indicate that, despite inferior outcomes for those with ambulatory NYHA class IV heart relative to those with NYHA class III symptoms, the survival of patients in both groups are parallel over extended follow-up (mean follow-up, 5.0 ± 2.5 y). ^[13]  Ambulatory NYHA class IV status was an independent factor for poor long-term outcomes, with a 40% survival free of LV assist device (LVAD) or heart transplantation at 5 years.

The ACC/AHA/HRS guidelines for CRT ^{[4, 5]}

Class I (“Indicated”)

CRT is indicated for the following:

• (With or without an implantable cardioverter-defibrillator [ICD]) Patients with sinus rhythm, an LVEF of 35% or less, a QRSd of 120 ms or longer, and an NYHA functional class III or ambulatory IV HF symptoms despite optimal medical therapy ^[4]
• Patients with sinus rhythm, an LVEF of 35% or less, LBBB with a QRSd of at least 150 ms, and NYHA class II, III, or ambulatory IV symptoms despite optimal medical therapy ^[5]

Class IIa (“Reasonable”)

CRT can be useful for patients who have the following conditions ^[5] :

• An LVEF up to 35%, sinus rhythm, LBBB with a QRSd of 120-149 ms, and NYHA class II, III, or ambulatory IV symptoms on guideline-directed medical therapy (GDMT)
• An LVEF up to 35%, sinus rhythm, a non-LBBB pattern with a QRSd of at least 150 ms, and NYHA class III/ambulatory class IV symptoms on GDMT
• Atrial fibrillation and an LVEF up to 35% on GDMT if a) the patient requires ventricular pacing or otherwise meets CRT criteria and b) atrioventricular (AV) nodal ablation or pharmacologic rate control will allow near 100% ventricular pacing with CRT
• On GDMT, with an LVEF up to 35% and undergoing new or replacement device placement with anticipated requirement for significant (>40%) ventricular pacing

Class IIb (“May be considered”)

CRT may be considered for patients who have the following ^[5] :

• An LVEF up to 30%, an ischemic HF etiology, sinus rhythm, LBBB with a QRSd of at least 150 ms, and an NYHA class I symptoms on GDMT
• An LVEF up to 35%, sinus rhythm, a non-LBBB pattern with a QRSd of 120-149 ms, and an NYHA class III/ambulatory class IV on GDMT
• An LVEF up to 35%, sinus rhythm, a non-LBBB pattern with a QRSd of at least 150 ms, and NYHA class II symptoms on GDMT

In patients with other forms of conduction disturbance (eg, right bundle branch block [RBBB] or right ventricular [RV] pacing), cardiac resynchronization therapy (CRT) is of questionable utility and therefore cannot be recommended at this time.

American College of Cardiology (ACC), American Heart Association (AHA), and Heart Rhythm Society (HRS) guidelines

Class III ("No benefit")

• CRT is not recommended for patients with NYHA class I or II symptoms and non-LBBB pattern with a QRSd less than 150 ms.
• CRT is not indicated for patients whose comorbidities and/or frailty limit survival with good functional capacity to less than 1 year.

Multiple sheaths are available for obtaining access to the coronary sinus (CS). The various delivery systems differ with regard to shape and especially with regard to size. For example, one delivery system allows the delivery of a 6F pacing lead via the inner catheter, whereas other systems allow delivery of only 4F leads.

Selection of the pacing leads should be dictated predominantly by the anatomy of the branch and the ease of deliverability. Bipolar leads are used in most cases, with unipolar leads reserved for patients with extremely small branches (ie, branches that are too small to accommodate a 4F bipolar lead). In Europe, multipolar leads with four separate pacing electrodes are available; these have been associated with improved implantation success. ^[14]

Left ventricular (LV) pacing leads are typically secured either with active fixation using tines or with passive fixation using the multiple curves of the lead to fit it tightly in the target vein. An active-fixation unipolar lead is available whose tines can be extended from the body of the lead (proximal to the pacing port) and retracted if repositioning is necessary.

Leads from different manufacturers have not only different fixation curves but also different pacing electrode spacing. Wider pacing electrode placement improves lead capture and electronic repositioning (ie, changing the pacing vector), but it also increases the risk for diaphragmatic capture.

Pacemakers

A pacemaker is an electronic device, approximately the size of a pocket watch, that senses intrinsic heart rhythms and provides electrical stimulation when indicated. Cardiac pacing can be either temporary or permanent.

Permanent pacing is most commonly accomplished through transvenous placement of leads to the endocardium (ie, right atrium [RA] or right ventricle [RV]) or epicardium (ie, to the LV surface via the CS), which are subsequently connected to a pacing generator placed subcutaneously in the infraclavicular region.

Permanent pacemakers are implantable devices that sense intrinsic cardiac electric potentials and, if these are too infrequent or absent, transmit electrical impulses to the heart to stimulate myocardial contraction. A specialized type of pacemaker therapy, cardiac resynchronization therapy (CRT) with biventricular pacing, with or without an implantable cardioverter-defibrillator (ICD), has been used as adjunctive therapy in patients with heart failure.

For more information, see the article Pacemakers and Implantable Cardioverter-Defibrillators.

Implantable Defibrillators

The ICD is first-line treatment and prophylaxis in patients at risk for ventricular tachycardia (VT) or ventricular fibrillation (VF). Available devices offer tiered therapy with programmable antitachycardia pacing schemes, as well as low-energy and high-energy shocks in multiple tachycardia zones.

Dual-chamber, rate-responsive bradycardia pacing is available in all ICDs, and sophisticated discrimination algorithms minimize shocks for atrial fibrillation, sinus tachycardia, and other non–life-threatening supraventricular tachyarrhythmias. Diagnostic functions, including stored electrograms, allow for verification of shock appropriateness.

For more information, see the articles Pacemakers and Implantable Cardioverter-Defibrillators and Cardioverter-Defibrillator Implantation.

Cardiac resynchronization therapy (CRT) has been solidly established as an important advanced heart failure (HF) therapy to reduce all-cause mortality, death resulting from progressive HF, and symptoms of HF, as well as to improve left ventricular (LV) function. ^{[6, 7, 8, 9, 10, 15]}

Predictors of response to CRT with an implantable cardioverter-defibrillator (ICD) appear to include a native left bundle branch block (LBBB), nonischemic cardiomyopathy, and femal sex. ^[16]  Factors contributing to nonresponse to CRT may include patient selection, inadequate delivery and supoptimal lead position. ^[17]

The Multisite Stimulation in Cardiomyopathy (MUSTIC) trial was one of the first trials to demonstrate significant clinical improvement with CRT. ^[18]  The investigators included patients with New York Heart Association (NYHA) functional class III HF with an LV ejection fraction (LVEF) of 35% or less, an LV end-diastolic diameter greater than 60 mm, and a QRS duration (QRSd) longer than 150 ms to compare exercise tolerance and quality of life (QOL) during active biventricular pacing for 3 months and during backup right-ventricular (RV)-only pacing for another 3 months. The results showed a statistically significant improvement in 6-minute walking distance (the primary end point), as well as an improved QOL and peak oxygen consumption. ^[18]

The MUSTIC trial was followed by the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) study, in which 453 patients in sinus rhythm with NYHA class III or IV HF, an LVEF of 35% or less, and a QRSd longer than 130 ms were randomly assigned to CRT versus control. ^[19]  The patients had significant improvements in 6-minute walking distance, NYHA functional class, and QOL score, as well as the number of hospitalizations secondary to HF. ^[19] The ensuing MIRACLE Implantable Cardiac Defibrillator (MIRACLE ICD) trial, the first randomized trial to evaluate the effectiveness of CRT with an ICD, showed that after 6 months, there was a statistically significant improvement in the QOL score, peak oxygen consumption, and functional capacity. ^[7] The results also demonstrated that CRT does not interfere with cardioverter-defibrillator function.

The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial was the largest and arguably the most important trial to show CRT in combination with optimal pharmacologic therapy, with and without ICD, could significantly reduce mortality and hospitalization in patients with HF. ^[6] The study comprised 1520 patients with an NYHA class III or IV HF, an LVEF of 35% or less, and a QRSd of 120 ms or longer. Unlike previous trials, COMPANION evaluated a primary composite end point of time to hospitalization or death from any cause.

Similarly, the Cardiac Resynchronization in Heart Failure (CARE-HF) trial had similar results, proving significant reductions in all-cause mortality and hospitalization for major cardiovascular events at 29 months in patients with CRT (pacing only) over optimal medical therapy. ^[15]  It was the first trial to definitively show that CRT (pacing only), even in the absence of ICD therapy, had a mortality benefit.

Three relatively newer landmark studies—REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE), ^[10] Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT), ^[9]  and Resynchronization for Ambulatory Heart Failure Trial (RAFT) ^[8] —investigated the effectiveness of CRT in HF patients with a wide QRS complex and mild HF symptoms (NYHA class I-II). Patients were randomized to CRT plus ICD ("CRT-ON") and CRT alone ("CRT-OFF"). REVERSE showed significant reverse remodeling, MADIT-CRT showed less hospitalization, and RAFT showed significant reduction in mortality in the CRT arm. The CRT benefit shown in these studies is consistent with those from older studies performed in patients with more severe HF symptoms.

A 2018 substudy report of the MADIT-CRT trial indicated that in CRT-treated HF patients, left atrial abnormality on electrocardiography (ECG) appeared to be an ECG indicator of poor long-term outcome in those with LBBB. ^[20]  The investigators suggested that the P-wave terminal force in lead V₁ (PTF-V₁) (in which a PTF-V₁ of 0.04 mm/s or longer was considered abnormal) provided additional prognostic information in the context of CRT, thereby potentiating the role of ECG in stratifying risk in HF patients. ^[20]

Preliminary data indicate that not only do elderly patients (≥75 years) undergo CRT with ICD less often than younger patients, ^[21] but the elderly do not appear to derive a survival benefit with the addition of an ICD. ^[22]

Updated guidelines on cardiac pacing and cardiac resynchronization therapy (CRT) were published in August 2021 by the European Society of Cardiology (ESC) and European Heart Rhythm Association (EHRA) in Europace. ^{[23, 24]} Emphasis has been placed on patient-centered care, shared decision making, and appropriate workup/testing prior to pacemaker implantation.

New recommendations include those for pacing after syncope, pacing following transcatheter aortic valve implantation (TAVI), CRT for heart failure (HF) and for prevention of pacing-induced cardiomyopathy, and pacing in various infiltrative and inflammatory diseases of the heart, as well as in different cardiomyopathies. ^{[23, 24]} New sections include those on pacing the His bundle (HBP) and the left bundle branch (LBB), as well as on evaluation of suspected or documented bradycardia or conduction system disease.

Select Key Messages

Cardiac pacing

Cardiac pacing is indicated in patients with:

• Sinus node dysfunction (SND), including those with bradycardia–tachycardia type of SND, when symptoms are clearly attributed to bradyarrhythmia

• Sinus rhythm (SR) and permanent or paroxysmal third- or second-degree type 2 or high-degree atrioventricular block (AVB), irrespective of symptoms

Single-lead ventricular pacing is indicated in the setting of permanent atrial fibrillation (AF) and permanent or paroxysmal AVB.

In the setting of syncope and unexplained falls, determine the diagnosis using available diagnostic methods before considering pacemaker therapy.

Cardiac resynchronization therapy

CRT is recommended in patients with symptomatic HF and left ventricular (LV) ejection fraction (EF) ≤35% despite optimal medical therapy (OMT) who are in SR and have LBB block (LBBB) QRS morphology, when QRS duration is ≥150 ms. Consider CRT in these patients when QRS duration is 130–149 ms.

In the setting of non-LBBB QRS morphology, less convincing evidence exists for the benefit of CRT, especially with normal PR and QRS duration < 150 ms. CRT should not be used in patients with HF and QRS duration < 130 ms unless ventricular pacing is needed.

Consider CRT in those with permanent AF, symptomatic HF, LVEF ≤35%, and QRS ≥130 ms who remain in New York Heart Association (NYHA) class III or ambulatory IV despite OMT.

Consider AV junction (AVJ) ablation for those with AF and CRT when at least 90-95% effective biventricular pacing is not achievable.

For patients with high-degree AVB and an indication for cardiac pacing who have HF with reduced EF (HFrEF) (LVEF < 40%), the ESC/EHRA recommend CRT rather than right ventricular (RV) pacing.

His bundle pacing

HBP may:

• Result in normal or near-normal ventricular activation; it is an attractive alternative to RV pacing

• Be considered for select patients with AVB and LVEF >40%, who are anticipated to have >20% ventricular pacing

• Correct ventricular conduction in a subset of patients with LBBB; thus, it may be used in lieu of biventricular pacing for HBP-based CRT in select patients

In patients offered HBP, individual consideration should be given for implanting an RV lead used as “backup” for pacing. In patients treated with HBP, tailor the device programming to the specific requirements of HBP.

Consider implantation of a leadless pacemaker when no upper extremity venous access exists, when the risk of device pocket infection is particularly heightened, and in patients on hemodialysis.

TAVI, other surgeries, and perioperative considerations

Undergoing TAVI raises the risk of developing AVB. Base decisions regarding post-TAVI cardiac pacing on preexisting and new conduction disturbances. Consider ambulatory electrocardiographic (ECG) monitoring for 7-30 days or electrophysiologic studies (EPS) in post-TAVI patients who have new LBBB or progression of a preexisting conduction anomaly, but who do not yet have any indication for a pacemaker.

In patients undergoing surgery for endocarditis or tricuspid valve surgery who have or develop AVB under surgery, consider placing epicardial pacing leads during surgery.

To reduce the risk of complications:

• Administer preoperative antibiotics before cardiovascular implantable electronic device (CIED) procedures

• Chlorhexidine–alcohol should be preferred for skin antisepsis

• Attempt cephalic or axillary vein access as first choice

• Avoid heparin bridging in CIED procedures to minimize the risk of hematoma and pocket infection

• Consider use of an antibiotic-eluting envelope in CIED reintervention procedures to lower the infection risk

Radiation therapy can be offered to patients with a pacemaker or CRT—provided individualized treatment planning and risk stratification is done beforehand and the device is interrogated as recommended around the period of radiation therapy.

For more information, please go to Transvenous Cardiac Pacing and Transcutaneous Cardiac Pacing.

Go to 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: Developed by the Task Force on cardiac pacing and cardiac resynchronization therapy of the European Society of Cardiology (ESC) With the special contribution of the European Heart Rhythm Association (EHRA) for full details.