Cardiac resynchronization therapy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief:: Bhaskar Purushottam, M.D. [2]

Cardiac resynchronization therapy (CRT) is an evidence based device treatment for congestive heart failure. CRT is indicated in those patients with symptomatic congestive heart failure despite optimal medical therapy who have a reduced left ventricular ejection fraction(an LVEF ≤ 35%), and a wide QRS (≥ 0.12 sec). It involves timed atrioventricular and biventricular pacing, which can improve left ventricular function, heart failure symptoms and may be associated with a reduction in mortality.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Sara Zand, M.D.[2] Bhaskar Purushottam, M.D. [3], Hardik Patel, M.D.

Cardiac resynchronization therapy (CRT) with or without an implantable cardiac defibrillator (ICD) is indicated in patients who have an LVEF less than or equal to 35%, left bundle branch block (LBBB) with a QRS duration greater than or equal to 0.15 seconds, and normal sinus rhythm, for the treatment of NYHA functional Class III or ambulatory Class IV heart failure symptoms in patients whose medical therapy has been optimized.

Abbreviations: AF: Atrial fibrillation; A-V: Atrio-ventricular; CRT: Cardiac resynchronization therapy ; HFrEF: Heart failure with reduced ejection fraction; ICD: Implantable cardioverter-defibrillato; LBBB:Left bundle branch block; LVEF: Left ventricular ejection fraction; NYHA:New York Heart Association; RV: = Right ventricular

^[1]

• CRT reduces morbidity and mortality.^[2]
• CRT improves cardiac function, and enhances quality of life.
• Several characteristics predictors of improvement in morbidity and mortality including the extent of reverse remodelling as the most important mechanisms of action of CRT.
• Patients with HFrEF and ischemic etiology have less improvement in LV function due to myocardial scar tissue, which is less likely to undergo favorable remodelling.
• Women may be more likely to respond to CRT than men, possibly due to smaller body and heart size.^[2]
• QRS duration predicts CRT response.^[3]
• QRS morphology is related to a beneficial response to CRT.
• Patients with left bundle branch block (LBBB) morphology are more likely to respond favorably to CRT, whereas there is less certainty about patients with non-LBBB morphology.
• Patients with LBBB morphology often have wider QRS durations, and there is a current debate about whether QRS durations or QRS morphology is the

the main predictor of a beneficial response to CRT.^[4]

• there is little evidence to suggest that QRS morphology or etiology of disease influence the effect of CRT on morbidity or mortality.
• Implantation of CRT is not recommended if QRS duration is <130 ms.
• If a patient is selected to receive an ICD and is in sinus rhythm, with a LBBB, CRT-D should be considered if the QRS is between 130 and 149 ms and is recommended if QRS is ≥ 150 ms.
• When LVEF is reduced, RV pacing may exacerbate cardiac dyssynchrony.
• This can be prevented by CRT, which might improve patient outcomes.
• CRT rather than RV pacing is recommended for patients with HFrEF regardless of NYHA class who have an indication for ventricular pacing in order to reduce morbidity, although no clear effect on mortality was observed.
• In patients with HFrEF who have received a conventional pacemaker or an ICD and subsequently develop worsening HF with a high proportion of RV pacing, CRT implantation is recommended.^[5]
• CRT is superior to RV pacing in patients undergoing atrioventricular (AV) node ablation in AF patients.^[6]
• In patients with AF, CRT-D compared with ICD, was not benefit and less than half of patients had >90% biventricular capture.
• CRT in patients with AF may be an option in selected patient with QRS≥ 150 ms, high biventricular pacing.^[7]
• When biventricular capture is <98%, it reflects a loss of resynchronization and poor prognosis in CRT.
• Patients with extensive myocardial scar will have less improvement in LV function with CRT.
• Pacing thresholds are higher in scarred myocardium and, if possible, lead placement should avoid such regions.
• Although patients with extensive scarring have an intrinsically worse prognosis, there is little evidence that they obtain less prognostic benefit from CRT.
• Optimization of AV intervals or interventricular delay intervals (VV intervals) after implantation by using echo– or electrocardiographic criteria or BP response may be considered for patients who have had no response to CRT.^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief:: Bhaskar Purushottam, M.D. [2] Synonyms and Keywords: CRT

CRT is contraindicated in patients who are asymptomatic or who have a limited life expectancy.

• Patients who are asymptomatic with a reduced LVEF who have no other indications for pacing.
• Patients who have a limited life expectancy due to a non-cardiac condition.
• Patients who have a limited functional capacity due to a chronic non-cardiac condition.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief:: Bhaskar Purushottam, M.D. [2]

Left ventricular systolic dysfunction is associated with electromechanical dyssynchrony which may be in the form of atrioventricular, interventricular, intraventricular and intramural delay. The impaired electromechanical coupling in turn diminishes the left ventricular systolic function.

Left ventricular systolic dysfunction is often accompanied by impaired electromechanical coupling, which may further diminish the left ventricular systolic function. The types of electromechanical dyssynchrony are atrioventricular, interventricular, intraventricular and intramural delay^[1]. Atrioventricular dyssynchrony results in a late diastolic ventriculoatrial gradient and so called “pre-systolic” mitral regurgitation. Interventricular dyssynchrony is the time delay between the contraction of the left and right ventricles and this is calculated by measuring the difference in the time of onset of systolic flow in the aortic and pulmonic valve. A time difference greater than or equal to 40 milliseconds is indicative of interventricular dyssynchrony. There are several echocardiographic techniques to measure intraventricular dyssynchrony, which include M mode echocardiography, tissue Doppler imaging, tissue strain, strain rate analysis and speckle tracking echocardiography. Intramural dyssynchrony is the dyssynchrony within the myocardial wall and it has been measured using speckle tracking echocardiography^[2]. However, the most common abnormalities are prolonged atrio-ventricular and ventricular conduction, which causes regional mechanical delay within the left ventricle.

This mechanical delay is responsible for ventricular dyssynchrony, which can result in the following hemodynamic abnormalities^[3]:

1. Reduced left ventricular systolic function, decreased dP/dT and cardiac output
2. Delayed contraction of lateral and posterior left ventriclular wall with abnormal septal motion
3. Increased myocardial energy expenditure
4. Adverse remodeling with increased left ventricular dilatation left ventricular end systolic volume
5. Functional mitral regurgitation
6. Delayed mitral valve opening
7. Reduced left ventricular filling time with increased left atrial pressures
8. Distorted mitral valve annulus
9. Delayed aortic valve opening and closure with reduced systolic ejection time

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief:: Bhaskar Purushottam, M.D. [2]

CRT requires implantation of atrial and right ventricular leads, as well as a third lead in the coronary sinus and the lateral or posterior branch to stimulate the left ventricle.

CRT involves a procedure similar to that of a pacemaker placement. In addition to that of the routine implantation of the atrial and right ventricular lead, a third lead is introduced into the coronary sinus and the lateral or posterior branch is accessed for stimulation of the left ventricle. Previously, an epicardial left ventricular lead was implanted after a limited lateral throacotomy. Such epicardial lead implantation is associated with high capture thresholds, suboptimal position for resynchronization, a far more invasive procedure, risk of general anaesthesia and standard complications associated with thoracotomy. However, this approach may be used if the coronary sinus or the appropriate branch cannot be accessed due to anatomical variations, vein stenosis, coronary sinus injury, tortuosity of the coronary sinus and distortion of the ostium.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief:: Bhaskar Purushottam, M.D. [2]

Approximately 30% of patients undergoing CRT will not sustain clinical or functional improvements for a wide variety of reasons.

30% of the CRT recipients are considered “non-responders”. A patient is considered a “non-responder” if there is no significant clinical or functional improvement following CRT. There are multiple explanations as to why some patients are non-responders.

1. Not all patients with QRS duration greater than or equal to 0.12 seconds have mechanical dyssynchrony. Unfortunately, the PROSPECT^[1] trial which set out to examine the various echocardiographic parameters to predict CRT response was not successful. Some of the major limitations in the study were the technical difficulties in obtaining the dyssynchrony parameters and the discrepancies among the different centers.
2. The leads may have been placed in regions of the left ventricle which are not dyssynchronous
3. The leads may have been placed in regions with fibrosis or viable myocardium.
4. Anterior left ventricular lead placement has been associated with worsening hemodynamics.
5. Non-responsiveness can occur due to high left ventricular capture thresholds
6. Lead dislodgement
7. Long atrioventricular delay
8. Atrial tachyarrhythmias with rapid ventricular response
9. Frequent premature ventricular contractions.
10. Lack of optimal atrioventricular and ventricular to ventricular (i.e., right ventricle to left ventricle) timing can result in non-responsiveness.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief:: Bhaskar Purushottam, M.D. [2]

Bleeding, infection and lead dislodgement are not uncommon complications of cardiac resynchronization therapy.

1. Bleeding and Hematomas: The incidence in clinical trials is 2.4%; in routine clinical practice, the actual incidence of pocket hematomas is probably higher as the trials only reported those hematomas, which needed surgical intervention. It is important to note that early re-intervention of pocket hematomas is associated with a 15-fold increase in infection^[1].
2. Infection
3. Lead dislodgement. (CRT trials demonstrated a rate verying from 2.9% to 10.6%; the MIRACLE-ICD^[2] study demonstrated a higher occurence of lead dislodgement with left ventricular lead than right atrial and right ventricular leads-6.8%, 15 and 0.6% respectively).

1. Pneumothorax (0.9% in CRT trials, Medicare registry^[3] reported 1.2%),
2. Myocardial injury
3. Coronary sinus dissection (1.3%) or perforation (1.3%)(complication rate related to coronary veins has been reported in 2%)
4. Pericardial tamponade.
5. Pocket erosion
6. Lead fracture
7. Inappropriate phrenic nerve stimulation: Given the proximity of the posterior wall of the left ventricle to the phrenic nerve, there remains the risk of inappropriate phrenic nerve stimulation.

For CRT patients, the average in-hospital mortality is 0.3% and the 30 day mortality is 0.7%. Reynolds et al.^[3] showed a 1.1% in-hospital mortality in 30,984 Medicare patients undergoing CRT. This disparity in the in-hospital mortality rates can be explained by the strict inclusion criteria of the trials, where the selected patients are healthier than the unselected patients in clinical practice.^[4]

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