Cardiac resynchronization therapy (CRT) is a device-based treatment for patients with heart failure and reduced ejection fraction (HFrEF) who exhibit intraventricular conduction delays, such as left bundle branch block (LBBB), utilizing biventricular pacing to restore synchronous contraction of the heart's ventricles and enhance overall cardiac output.[1][2][3] First conceptualized in the early 1990s, CRT received U.S. Food and Drug Administration approval in 2001 following landmark clinical trials demonstrating its efficacy.[4]This therapy is particularly indicated for individuals with moderate to severe symptomatic heart failure (New York Heart Association [NYHA] class II-IV), left ventricular ejection fraction (LVEF) ≤35%, and prolonged QRS duration greater than 130-150 ms on optimal medical therapy, including those with or without an indication for an implantable cardioverter-defibrillator (ICD).[1][2][3] CRT devices, which can be pacemakers (CRT-P) or combined with defibrillators (CRT-D), are implanted surgically.[1][3]Clinical benefits of CRT include improved quality of life, enhanced exercise capacity, reduced heart failure hospitalizations, and increased survival rates, with evidence from the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure supporting its class I recommendation for appropriately selected patients.[1][2][5] However, potential risks encompass infection (up to 3.3%), lead dislodgement (2.9-10%), pneumothorax (0.66%), bleeding, and device malfunction, necessitating careful patient selection to exclude those with mild symptoms, diastolic heart failure, active infections, or comorbidities like advanced cancer that may limit benefits.[1][3] Efficacy is highest in patients with LBBB morphology and QRS durations over 149 ms, where CRT can reverse ventricular remodeling and mitigate mitral regurgitation, though response rates vary and ongoing optimization of device programming is often required post-implantation.[1][2]
Introduction and Background
Definition and Purpose
Cardiac resynchronization therapy (CRT) is a pacemaker-based intervention designed to deliver simultaneous or near-simultaneous electrical impulses to the right and left ventricles, thereby restoring coordinated ventricular contraction in patients exhibiting ventricular dyssynchrony.[1] This therapy addresses the inefficient pumping caused by asynchronous contractions, particularly in cases of left bundle branch block or other conduction abnormalities that delay left ventricular activation.[6]The primary purpose of CRT is to enhance cardiac output, alleviate heart failure symptoms, and mitigate adverse ventricular remodeling in individuals with reduced ejection fraction and conduction delays.[2] By optimizing the timing of ventricular depolarization, CRT improves mechanical efficiency and reduces the energy expenditure associated with dyssynchronous heartbeats.[6]At its core, CRT involves a battery-powered pulse generator implanted subcutaneously, connected to multiple leads: typically one in the right ventricle, another in the left ventricle accessed via the coronary sinus, and often a third in the right atrium for atrioventricular synchrony.[1] Devices are categorized as CRT-P, which provides pacing functions only, or CRT-D, which incorporates defibrillator capabilities to manage life-threatening arrhythmias alongside resynchronization.[2]CRT targets patients with systolic heart failure characterized by a left ventricular ejection fraction (LVEF) of ≤35% and prolonged QRS duration on electrocardiogram, indicating significant conduction delay.[1] This population generally includes those with moderate to severe symptoms despite optimized medical therapy, focusing on restoring synchrony to support overall cardiac function.[2]
History
The concept of cardiac resynchronization therapy (CRT) emerged in the late 1980s and early 1990s, driven by recognition of ventricular dyssynchrony as a key contributor to heart failure progression and initial animal studies showing hemodynamic improvements from biventricular pacing.[7] At the 7th World Symposium on Cardiac Pacing in 1983, de Teresa and colleagues first described CRT principles in four patients with heart block and dyssynchrony, marking an early clinical exploration.[8] By the early 1990s, small pilot studies tested dual-chamber pacing for symptomatic relief in heart failure, but it was the late 1990s when targeted biventricular pacing experiments demonstrated potential to correct left ventricular dyssynchrony in patients with prolonged QRS durations.[9]Key clinical milestones accelerated CRT's development in the early 2000s. The MUSTIC trial, published in 2001, was the first large randomized study, enrolling 67 patients with severe heart failure and showing significant gains in quality of life, 6-minute walk distance, and peak oxygen consumption after 12 weeks of biventricular pacing compared to atrial pacing alone.[10] That same year, the U.S. Food and Drug Administration (FDA) approved the first CRT pacemaker, Medtronic's InSync device on August 28, 2001, for patients with moderate-to-severe heart failure, enabling commercial transvenous implantation.[11] The CARE-HF trial in 2005 provided stronger evidence, randomizing 813 patients to CRT or medical therapy and reporting a 37% relative reduction in the primary endpoint of death or hospitalization for heart failure over 29 months, with sustained mortality benefits in long-term follow-up.During the 2000s, CRT transitioned from experimental to guideline-directed therapy, with early integration into implantable cardioverter-defibrillators (CRT-D) following FDA approval of the first such device on June 26, 2002, allowing simultaneous arrhythmia management and resynchronization for high-risk heart failure patients.[12] Trials like MADIT-CRT (2009) and RAFT (2011) broadened applications to asymptomatic or mildly symptomatic cases with left bundle branch block, reducing heart failure events by 41% and 25%, respectively.[4] Post-2020 advancements have included conduction system pacing techniques, such as His-bundle and left bundle branch area pacing, as physiological alternatives to traditional biventricular CRT, particularly for non-responders, with studies showing comparable or superior resynchronization rates and lower complication risks. In 2025, the Heart Rhythm Society issued a Clinical Consensus Statement on conduction system pacing, reinforcing its application in CRT for improved outcomes in select patients.[13][14]By 2025, CRT adoption has grown substantially, influenced by the 2022 AHA/ACC/HFSA guidelines, which upgraded recommendations to class I for patients with ejection fraction ≤35%, QRS ≥150 ms, and left bundle branch block on optimal medical therapy, emphasizing earlier intervention.[5] Worldwide, approximately 190,000 CRT devices are implanted annually as of 2023, due to refined patient selection and technological refinements.[15]
Pathophysiology and Rationale
Cardiac Dyssynchrony
Cardiac dyssynchrony refers to the uncoordinated contraction of the cardiac ventricles, resulting in suboptimal mechanical efficiency during systole.[16] It encompasses electrical dyssynchrony, characterized by delayed conduction leading to a prolonged QRS duration exceeding 120 ms on surface electrocardiogram (ECG), and mechanical dyssynchrony, which manifests as asynchronous regional wall motion.[16] The primary types include interventricular dyssynchrony, involving delayed activation between the left and right ventricles, and intraventricular dyssynchrony, marked by regional delays within the left ventricle (LV), such as between septal and lateral walls.[17] This pattern is most commonly observed in patients with left bundle branch block (LBBB), where altered conduction pathways disrupt the normal sequence of ventricular depolarization.[18]The condition often arises from conduction abnormalities, including LBBB or right ventricular pacing, which induce asynchronous electrical activation.[19] These disruptions are frequently exacerbated in the context of ischemic or non-ischemic cardiomyopathy, where underlying myocardial pathology amplifies the mechanical discordance.[20]Assessment of cardiac dyssynchrony relies on multiple imaging modalities. On ECG, it is primarily evaluated using QRS duration as a surrogate marker, calculated as the time interval from the onset of the Q wave to the end of the S wave in the lead showing the widest complex:\text{QRS}_d = \text{time from Q wave onset to S wave end in the widest lead}A QRS duration greater than 120–150 ms indicates significant electrical dyssynchrony, particularly in LBBB morphology.[21]Echocardiography provides direct visualization of mechanical dyssynchrony through signs such as septal flash—an early inward septal motion followed by rebound—and apical rocking, an abnormal apical motion due to opposing wall displacements.[22] Cardiac magnetic resonance imaging (MRI) can also quantify dyssynchrony by assessing regional strain and timing differences, offering superior tissue characterization in complex cases.[23]The hemodynamic consequences of dyssynchrony include inefficient ventricular pumping, as asynchronous contractions reduce stroke volume and cardiac output.[24] It also promotes increased mitral regurgitation through altered papillary muscle timing and annular distortion, further impairing forward flow.[25] Over time, these effects drive progressive adverse ventricular remodeling, characterized by dilation and fibrosis, independent of other heart failure risk factors.[26] This dyssynchrony contributes to the worsening progression of heart failure by amplifying systolic dysfunction and morbidity.[26]
Role in Heart Failure
Cardiac dyssynchrony plays a central role in the progression of heart failure with reduced ejection fraction (HFrEF) by inducing asynchronous ventricular contraction, which impairs overall cardiac efficiency. This discoordinate activation leads to suboptimal timing of regional contractions, resulting in inefficient blood ejection and a substantial reduction in stroke volume, alongside an increase in end-systolic volume due to prolonged contraction in late-activated regions.[27][24] In non-ischemic HFrEF, this mechanical inefficiency further promotes regional stress, contributing to myocardial fibrosis and scarring through altered stretch and perfusion patterns in delayed segments.[27][28] Atrioventricular dyssynchrony, often due to prolonged PR intervals, can compound these effects by impairing diastolic filling and overall hemodynamics.[29]Dyssynchrony is particularly prevalent in moderate to advanced HFrEF, affecting approximately 20-30% of patients with New York Heart Association (NYHA) class II-IV symptoms, where it exacerbates systolic dysfunction and correlates with left ventricular ejection fraction (LVEF) below 35% and QRS duration exceeding 130 ms.[30] These features contribute significantly to heart failure hospitalizations, with dyssynchronous patients experiencing higher rates of acute decompensation due to worsened pump function compared to those with isolated systolic impairment.[31][32]Observational studies demonstrate that dyssynchrony independently predicts adverse outcomes, distinguishing it from other heart failure etiologies like pure systolic dysfunction by correlating with elevated mortality risks—for instance, annual mortality rates of up to approximately 20% in untreated advanced cases with marked electrical delay.[33][34] In cohorts with LVEF <35% and prolonged QRS, dyssynchrony amplifies prognostic worsening, with higher all-cause mortality and event rates observed versus synchronized counterparts.[35][36]The rationale for cardiac resynchronization therapy (CRT) in this context lies in its ability to address this reversible dyssynchronous component, restoring coordinated contraction in a manner complementary to pharmacotherapy, which primarily targets neurohormonal activation but cannot correct electrical-mechanical mismatches.[27][24] By specifically mitigating the hemodynamic penalties of dyssynchrony, CRT interrupts the vicious cycle of remodeling and decompensation unique to this subgroup of heart failure.[37]
Indications and Patient Selection
Clinical Criteria
Cardiac resynchronization therapy (CRT) candidacy is determined by evidence-based criteria emphasizing patients with symptomatic heart failure and electrical dyssynchrony who remain inadequately managed despite optimal medical therapy. Core indications include New York Heart Association (NYHA) functional class II-IV symptoms, left ventricular ejection fraction (LVEF) ≤35%, and prolonged QRS duration on electrocardiogram, particularly in sinus rhythm. Specifically, a Class I recommendation applies to patients with left bundle branch block (LBBB) and QRS duration ≥150 ms (Class IIa for QRS 120-149 ms), while a Class IIa recommendation is given for non-LBBB morphology with QRS ≥150 ms.[38][5]Patients must have failed optimized guideline-directed medical therapy (GDMT), including beta-blockers, renin-angiotensin-aldosterone system inhibitors, and sodium-glucose cotransporter-2 inhibitors, typically for at least 3 months unless contraindicated. CRT is applicable to both ischemic and non-ischemic etiologies of heart failure, though non-ischemic cardiomyopathy often shows greater reverse remodeling response. Reversible causes of heart failure, such as acute ischemia or uncontrolled hypertension, must be excluded prior to implantation to ensure chronicity of the condition. In patients with atrial fibrillation, CRT may be considered (Class IIa) if atrioventricular node ablation can achieve ≥40% biventricular pacing.[5][38][39]Response predictors enhance patient selection to maximize benefits. Electrical dyssynchrony assessed by QRS morphology and duration remains the primary criterion per current guidelines; while historical echocardiographic markers of mechanical dyssynchrony (e.g., septal-to-posterior wall motion delay) showed correlations with outcomes, they are not recommended for routine selection due to limited reproducibility and trial evidence. Comorbidities like advanced renal dysfunction (e.g., estimated glomerular filtration rate <30 mL/min/1.73 m²) may diminish candidacy due to higher procedural risks and lower response rates.[5][40]In clinical trials, CRT recipients are typically aged 60-80 years, reflecting the peak incidence of advanced heart failure, with a 60-70% male predominance due to higher rates of ischemic disease in men. These demographics underscore the need for equitable access, as women often exhibit superior response profiles despite underrepresentation in studies.[41][42]
Guidelines and Contraindications
Cardiac resynchronization therapy (CRT) is guided by major international recommendations from organizations such as the American Heart Association (AHA), American College of Cardiology (ACC), Heart Failure Society of America (HFSA), and European Society of Cardiology (ESC), which outline evidence-based criteria for patient selection to maximize benefits in heart failure management. The 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure provides a Class I recommendation (strong evidence, benefit >>> risk) for CRT in patients with left ventricular ejection fraction (LVEF) ≤35%, New York Heart Association (NYHA) class II, III, or ambulatory IV symptoms, left bundle branch block (LBBB) morphology, and QRS duration ≥150 ms on guideline-directed medical therapy (GDMT).[5] Similarly, the 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy recommend CRT as Class I for symptomatic heart failure (NYHA II-III) with LVEF ≤35%, LBBB, and QRS ≥150 ms despite optimal medical therapy, with Class IIa considerations for QRS 120-149 ms in LBBB or non-LBBB with QRS ≥150 ms in NYHA III-IV. The 2025 ACC/AHA Appropriate Use Criteria (AUC) for implantable cardioverter-defibrillators, CRT, and pacing update these frameworks by integrating conduction system pacing (e.g., His bundle or left bundle branch area pacing) scenarios, rating traditional biventricular CRT as appropriate (score 7-9) for LVEF ≤35% with LBBB and QRS ≥150 ms across NYHA II-III/ambulatory IV, while noting emerging roles for physiologic pacing alternatives in select cases.[43]Guideline recommendations are stratified by class to reflect the strength of evidence and clinical applicability: Class I indicates procedures that are effective, with benefit far outweighing risk; Class IIa suggests reasonable use with moderate benefit over risk; Class IIb implies possible benefit but with greater uncertainty; and Class III denotes no benefit or potential harm, where CRT is not recommended.[5] For instance, CRT is Class III (no benefit) for QRS <120 ms regardless of morphology, based on trials like RE-THIN-Q and ECHO-CRT showing lack of efficacy.[5] The choice between CRT with pacemaker (CRT-P) and CRT with defibrillator (CRT-D) depends on the need for secondary prevention of sudden cardiac death, with CRT-D preferred in patients with LVEF ≤30-35% and ischemic cardiomyopathy (Class I), while CRT-P suffices for non-ischemic cases without ventricular arrhythmias (Class IIa).[43]
Limited benefit; consider alternatives like conduction system pacing[43]
LVEF ≤35%, NYHA II, LBBB, QRS 120-149 ms, sinus rhythm
4-6 (May be appropriate)
7-9 (Appropriate if ICD indicated)
Expected survival >1 year; GDMT optimized[5]
LVEF 36-50%, AV block, NYHA II-IV
7-9 (Appropriate)
4-6 (May be appropriate)
For pacing indication; BLOCK-HF trial support[5]
Absolute contraindications to CRT include conditions where implantation poses excessive risk or offers no meaningful benefit, such as limited life expectancy (<1 year due to non-cardiac causes) or active systemic infection.[1] Relative contraindications encompass uncontrolled atrial fibrillation (without rate or rhythm control, as it impairs resynchronization efficacy), narrow QRS (<130 ms, per Class III recommendations), and recent myocardial infarction (within 40 days, due to unstable substrate).[5][1] The 2025 AUC further cautions against CRT in advanced chronic kidney disease (eGFR <30 mL/min/1.73 m² or dialysis-dependent), rating it as may be appropriate (score 4-5) owing to heightened procedural risks and diminished long-term gains.[43]Post-2023 updates, including the 2024 ACC Expert Consensus Decision Pathway on heart failure treatment, emphasize CRT's role in facilitating GDMT optimization, particularly in early heart failure stages where device therapy can stabilize patients to tolerate full doses of medications like SGLT2 inhibitors and ARNI.[44] The 2021 ESC guidelines highlight multipoint pacing as a Class IIa option for non-responders to standard biventricular CRT, aiming to enhance resynchronization in challenging anatomies.
Implantation Procedure
Device Types
Cardiac resynchronization therapy (CRT) devices are implantable systems designed to deliver biventricular pacing to restore synchronous ventricular contraction in patients with heart failure and dyssynchrony. The primary types include CRT pacemakers (CRT-P) and CRT defibrillators (CRT-D), which differ in their capabilities, size, and indications based on patient arrhythmia risk.[3][1]CRT-P devices provide resynchronization through pacing alone, without defibrillation capability, making them suitable for heart failure patients who require synchronization but have low risk of life-threatening ventricular arrhythmias. These devices feature a smaller pulse generator, typically with a volume of 20-40 cc, powered by lithium-based batteries that offer a projected longevity of 7-12 years depending on pacing demands and device model. The pulse generator includes algorithms for optimizing atrioventricular (AV) and interventricular (VV) delays to enhance resynchronization efficiency.[3][29][45]In contrast, CRT-D devices integrate resynchronization pacing with implantable cardioverter-defibrillator (ICD) functionality to detect and terminate ventricular tachycardia or fibrillation via shocks or antitachycardia pacing. These are indicated for primary prevention in patients with ischemic heart failure and reduced ejection fraction (≤35%), particularly those with prior ventricular arrhythmias or high sudden cardiac death risk. CRT-D pulse generators are larger, typically 40-70 cc, to accommodate high-voltage capacitors for shock delivery, and their battery life is shorter, generally 5-8 years, due to the additional energy demands. Like CRT-P, they incorporate AV/VV optimization algorithms within the pulse generator.[3][46][29]Device selection is guided by clinical guidelines, prioritizing CRT-D for patients with elevated arrhythmia risk, such as those with New York Heart Association class II-IV symptoms, left bundle branch block, and QRS duration ≥150 ms, while CRT-P suffices for lower-risk profiles. Emerging options include leadless CRT systems, such as ultrasound-based endocardial pacing (e.g., WiSE-CRT), which received FDA approval in April 2025 and is available in limited release as of late 2025 but remains non-standard and reserved for cases where conventional implantation fails; investigational hybrid approaches combining subcutaneous or extravascular ICDs with pacing for CRT, developed since the early 2020s, aim to reduce lead-related complications but are not yet widely available. Additionally, as of 2025, devices supporting left bundle branch area pacing (LBBAP) integrated with CRT, such as BIOTRONIK's Acticor/Rivacor Sky CRT-D, offer alternatives for improved implantation success and stability in select patients.[46][29][47][48][49][50]
Lead Placement
In cardiac resynchronization therapy (CRT), the right ventricular (RV) lead is typically positioned at the RV apex or along the interventricular septum via transvenous access through the subclavian or axillary vein, where it serves to sense and pace the RV myocardium.[38] This placement achieves high procedural success rates exceeding 95%, with active fixation mechanisms enhancing stability and reducing dislodgement risks, particularly when septal positioning is selected to promote more physiological activation patterns.[38] Fluoroscopic guidance in multiple projections ensures precise positioning while minimizing complications such as perforation, which occurs in 0.6-5.2% of cases and is higher with apical placement (odds ratio 3.37).[38]The left ventricular (LV) lead is advanced retrogradely through the coronary sinus (CS) ostium into a posterolateral or lateral cardiac vein tributary, targeting the region of latest mechanical or electrical activation to optimize resynchronization.[51] Quadripolar leads are preferred for this placement due to their ability to allow multipolar pacing configurations, which help avoid phrenic nerve stimulation affecting 5-10% of implants and facilitate adjustments for suboptimal initial positioning.[38] Success rates for CS cannulation and LV lead deployment range from 90-95%, though challenges such as CS dissection (0.7-2.1% incidence) or venous tortuosity contribute to a 10-15% failure rate, often necessitating alternative approaches like His bundle pacing.[38][52]An atrial lead is optionally placed in the right atrial appendage for patients in sinus rhythm to maintain atrioventricular (AV) synchrony, accessed transvenously via the cephalic or axillary vein with active or passive fixation.[51] This positioning yields success rates above 95-98%, with the cephalic vein approach reducing complications compared to subclavian access, though lateral wall placement carries a higher risk of phrenic nerve capture.[38] These leads connect to biventricular pacemakers or implantable cardioverter-defibrillators to deliver synchronized pacing.[51]Fluoroscopy remains the standard imaging modality for real-time guidance during lead placement, enabling multi-angle visualization to confirm electrode contact and electrical thresholds.[38] Pre-procedural computed tomography (CT) angiography is increasingly utilized for detailed coronary venous mapping, with AI-enhanced algorithms introduced since 2023 improving segmentation accuracy and predicting optimal LV lead sites by integrating anatomical and scar data from prior imaging.[53][54] This targeted approach enhances procedural efficiency and response rates in complex anatomies.[55]
Surgical Technique
The implantation of a cardiac resynchronization therapy (CRT) device is a minimally invasive procedure performed in an electrophysiology or catheterization laboratory under continuous fluoroscopic guidance to ensure precise lead positioning.[1] Patients undergo preoperative preparation, including fasting for at least 6 hours, evaluation of coagulation status, and adjustment of anticoagulants such as withholding rivaroxaban for 24-48 hours to minimize bleeding risks.[56] Antibiotic prophylaxis with intravenous cefazolin (typically 2 g) is administered 30-60 minutes prior to incision to prevent device-related infections.[56] Local anesthesia, using 2% lidocaine, is applied at the venous access and device pocket sites, supplemented by conscious sedation with agents like midazolam (1-6 mg) or fentanyl (25-100 μg) to maintain patient comfort without general anesthesia.[57][56]Venous access is established using a sheath (9-11 Fr depending on device type) inserted into the cephalic, axillary, or subclavian vein, with the axillary approach preferred under fluoroscopic guidance at the confluence of the second and third ribs to reduce complications such as pneumothorax (incidence approximately 0.66%).[1][56] A venogram with 10-15 mL of contrast may be performed if access is challenging, confirming vein patency.[57] A subcutaneous or submuscular pocket is created in the left prepectoral region for the pulse generator, with subpectoral placement favored for CRT-defibrillators to lower erosion risk; meticulous hemostasis is ensured using electrocautery.[56]Leads are inserted sequentially, starting with the right ventricular lead advanced through the tricuspid valve to the apex or septum, followed by the right atrial lead (if required) into the appendage, and finally the left ventricular lead via coronary sinus cannulation using specialized catheters or guidewires for ostium localization.[57][1] Fluoroscopy guides advancement, with coronary sinus venography (using balloon occlusion and contrast) to visualize posterolateral branches for optimal left ventricular lead deployment in the proximal or mid-segment.[57] Each lead undergoes intra-procedural testing: pacing capture thresholds are verified to be below 2 V at 0.5 ms pulse width, sensing amplitudes exceed 5 mV for R-waves, and absence of phrenic nerve or diaphragmatic stimulation is confirmed by adjusting vectors if needed.[29][57] Leads are secured to the pectoralis fascia, the sheath is split to avoid dislodgement, and the device is connected for initial programming to optimize atrioventricular and interventricular delays.[57] The incision is closed in layers with absorbable sutures, and a sterile dressing is applied.[1]The procedure typically lasts 1-3 hours, depending on complexity, and may allow for same-day discharge in uncomplicated cases with adequate post-procedure monitoring.[58] The standard transvenous endocardial approach via the coronary sinus is used in over 95% of cases; epicardial placement, involving limited thoracotomy, is reserved for the rare instances (about 5%) where transvenous access fails due to anatomical issues.[57] Emerging trends include robotic assistance to enhance precision in lead manipulation and reduce radiation exposure, as demonstrated in initial case reports of minimally invasive robotic CRT-defibrillator implants without sternotomy.[59]
Mechanism of Action
Electrical Resynchronization
Cardiac resynchronization therapy (CRT) achieves electrical resynchronization primarily through biventricular pacing, which coordinates the activation of the left and right ventricles to correct conduction delays associated with ventricular dyssynchrony. In patients with prolonged QRS duration, typically due to left bundle branch block, biventricular pacing restores synchronous ventricular activation by delivering simultaneous or sequentially timed impulses to both ventricles via leads in the right ventricle and a coronary sinus branch targeting the left ventricle. This intervention shortens the QRS duration by an average of 20-40 ms, as observed in clinical studies evaluating acute hemodynamic responses, thereby promoting more uniform electrical wavefront propagation across the myocardium.[60]Optimization of the atrioventricular (AV) delay is crucial to ensure effective atrial contribution to ventricular filling without allowing intrinsic conduction to interfere. Programmed AV delays of 80-120 ms are commonly targeted, balancing preload enhancement with prevention of fusion beats that could undermine resynchronization; this range has been validated in echocardiographic optimization protocols where shorter delays maximize left ventricular filling time. Pacing is typically delivered in DDD-biventricular (BiV) mode for patients in sinus rhythm, enabling atrial tracking and dual-chamber support while providing biventricular stimulation. Advanced algorithms, such as SmartDelay, automate adjustments by dynamically optimizing the AV delay and interventricular (VV) interval, often applying a left ventricular offset of 0-80 ms to fine-tune synchrony based on intrinsic conduction intervals.[61][62]Effective electrical resynchronization is quantified by the degree of QRS narrowing, calculated as \Delta QRS = QRS_{post} - QRS_{pre}, where QRS_{pre} is the baseline duration and QRS_{post} is the paced duration; a reduction of ≥20 ms correlates with improved outcomes.[63] This narrowing reflects reduced intraventricular conduction delays and has been associated with decreased dispersion of repolarization, as evidenced by lower rates of new-onset ventricular arrhythmias in implantable cardioverter-defibrillator interrogations following CRT activation. By minimizing heterogeneous repolarization times, CRT lowers the substrate for reentrant arrhythmias, enhancing electrical stability without increasing proarrhythmic risk in responsive patients.[64]
Mechanical and Hemodynamic Effects
Cardiac resynchronization therapy (CRT) reverses mechanical dyssynchrony, particularly septal dyssynchrony, by restoring coordinated contraction patterns in the left ventricle (LV).[65] This reversal is evident through echocardiographic measures such as septal flash and apical rocking, which diminish post-implantation, leading to improved interventricular and intraventricular synchrony.[66] Studies using speckle-tracking echocardiography demonstrate that CRT significantly enhances LV twist mechanics, with peak twist increasing immediately after pacing due to better electromechanical activation.[67] Similarly, radial and circumferential strain patterns normalize, reducing regional disparities in shortening and stretch, which contributes to overall mechanical efficiency.[68]Hemodynamically, CRT augments LV contractility and output by increasing the maximum rate of LV pressure rise (dP/dtmax) by approximately 18% at rest, reflecting enhanced systolic performance.[69]Stroke volume rises by 10-20% in responders, driven by optimized ejection without excessive metabolic demand.[70] Additionally, pulmonary capillarywedgepressure decreases substantially, from baseline levels around 16 mmHg to about 10 mmHg chronically, alleviating left-sided filling pressures and reducing pulmonary congestion.[71]A key long-term mechanical benefit of CRT is reverse remodeling, which halts and reverses LV dilation by decreasing end-systolic volume. This is quantified as the change in LV end-systatic volume (ΔLVESV), defined by the equation:\Delta \text{LVESV} = \text{LVESV}_\text{post} - \text{LVESV}_\text{pre}where a negative value indicates improvement, and a reduction of ≥15% at 6 months is a standard threshold for significant reverse remodeling associated with better outcomes.[72]The effects of CRT differ temporally, with acute hemodynamic improvements—such as immediate boosts in stroke volume and dP/dtmax—occurring within hours of activation due to resynchronized contraction.[68] Chronically, over 6-12 months, CRT promotes structural changes including fibrosis regression in the LV lateral wall, evidenced by reduced expression of fibrogenic markers like p38 MAPK and TNF-α, further supporting sustained mechanical recovery.[68]
Clinical Benefits and Outcomes
Short-term Improvements
Cardiac resynchronization therapy (CRT) often leads to rapid symptom relief in eligible patients, with many experiencing improvements in heart failure symptoms within the first few months post-implantation. In clinical trials, approximately 70% of responders achieve at least a one-level improvement in New York Heart Association (NYHA) functional class, typically shifting from class III to II, reflecting reduced dyspnea and fatigue during daily activities.[73]Functional metrics further demonstrate these early gains. The 6-minute walk test (6MWT) distance commonly increases by 30 to 50 meters at 3 to 6 months, enabling better exercise tolerance and independence.[74]Quality of life, as measured by the Minnesota Living with Heart Failure Questionnaire (MLHFQ), typically improves by 10 to 15 points in the first 90 days, indicating substantial alleviation of physical and emotional burdens associated with heart failure.[74] Additionally, CRT reduces heart failure hospitalizations by about 30% to 40% within the first year, primarily through decreased acute decompensations.[74]A CRT responder is generally defined as a patient showing a ≥15% reduction in left ventricular end-systolic volume (LVESV) on echocardiography (with some studies using ≥10%) or a positive clinical composite score, encompassing survival without hospitalization, absence of worsening symptoms, and objective improvements like NYHA class or 6MWT. Response rates range from 60% to 70% in selected populations, highlighting CRT's efficacy in the majority of appropriately implanted patients.[75]Seminal trials provide robust evidence for these short-term effects. The Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT), involving patients with mild heart failure, demonstrated early reverse remodeling with a mean LVESV reduction of 22.5 mL at 12 months compared to implantable cardioverter-defibrillator therapy alone.[76] These improvements stem from the resynchronization of ventricular contraction, leading to enhanced cardiac output and reduced dyssynchrony-related stress.[76]
Long-term Survival and Quality of Life
Long-term studies have demonstrated that cardiac resynchronization therapy (CRT), particularly with defibrillator (CRT-D), provides substantial survival benefits in patients with heart failure and reduced ejection fraction. Over 5 years, CRT is associated with a 20-30% relative reduction in all-cause mortality compared to optimal medical therapy alone, as evidenced by hazard ratios ranging from 0.70 to 0.80 in major trials and meta-analyses.[77][78] When compared to implantable cardioverter-defibrillator (ICD) therapy alone, CRT-D yields an absolute risk reduction of 5-10% in mortality at extended follow-up, with Kaplan-Meier survival estimates showing differences of approximately 5% in cohorts like the RAFT trial extension.[79][78]Regarding morbidity, CRT significantly lowers the incidence of heart failure events beyond the initial post-implantation period. The COMPANION trial reported a 37% reduction in cardiac hospitalizations with CRT compared to medical therapy, a benefit that persists over multiple years with sustained reverse remodeling.[80] Longitudinal data indicate that left ventricular ejection fraction (LVEF) improvements are maintained, often reaching 40-45% in responders after 5 years, contributing to fewer decompensations and better hemodynamic stability.[81]Quality of life enhancements from CRT endure long-term, as measured by tools like the Minnesota Living with Heart Failure Questionnaire (MLHFQ), where patients experience persistent score improvements of 10-15 points at 5 years, reflecting reduced symptoms and enhanced daily functioning.[82] This translates to fewer rehospitalizations, with reductions of 30-40% in heart failure admissions per patient-year, leading to estimated cost savings of approximately $20,000 per patient annually through averted inpatient care.[83][84]
Complications and Risks
Procedural Risks
Procedural risks associated with cardiac resynchronization therapy (CRT) implantation primarily arise during lead placement and vascular access, with overall complication rates ranging from 4% to 27% depending on the study population and follow-up duration.[85] These risks are generally low but can lead to prolonged hospitalization or reintervention, emphasizing the need for experienced operators and careful patient monitoring.Lead-related complications are among the most frequent, including coronary sinus (CS) dissection, which occurs in approximately 0.7% of cases and may require procedural abandonment or alternative lead positioning in severe instances.[86]Left ventricular (LV) lead dislodgement affects 1.4% to 10.6% of patients shortly after implantation, often necessitating revision within the first year, with higher rates observed in passive fixation leads compared to active or quadripolar designs.[87][88]Pneumothorax, typically resulting from subclavian venipuncture, has an incidence of 0.5% to 2.2% and may resolve conservatively but occasionally requires chest tube insertion.[89]Vascular and access-site issues include pocket hematoma in 2% to 4.3% of procedures, which can increase infection risk and prolong recovery, and subclavian vein thrombosis in less than 1% (0.6%), often managed with anticoagulation without long-term sequelae.[90][85]Acute cardiac complications, such as right ventricular perforation, occur in about 0.9% of implants and are usually detected intraoperatively via fluoroscopy or echocardiography, allowing for prompt repositioning.[85] Transient atrioventricular (AV) block is uncommon during CRT implantation but can arise from mechanical irritation near the conduction system, resolving spontaneously in most cases without permanent pacing adjustment. Intracardiac echocardiography (ICE) aids in mitigating these risks by providing real-time visualization during CS cannulation and lead advancement, particularly in complex anatomies, reducing procedural time and fluoroscopy exposure.[91]Peri-procedural mortality remains low at less than 0.5% (0.3% in recent cohorts), primarily linked to perforation or hemodynamic instability, though rates increase with age, with elderly patients (over 70) facing heightened complication risks due to frailty and comorbidities.[85][92]
Long-term Complications
Long-term complications of cardiac resynchronization therapy (CRT) primarily involve device-related issues that manifest months to years after implantation, with infection, lead failure, phrenic nerve stimulation, and battery depletion being the most significant. These events can necessitate device revision or explantation, impacting patient outcomes and requiring ongoing management.Infections occur at a cumulative rate of approximately 1-2% over 2-3 years post-implantation, often presenting as pocket erosion or lead endocarditis.[93] Such infections typically require complete system explantation in about 70% of cases to achieve resolution, with conservative management carrying a high risk of recurrence.[94]Lead failure, including fractures and insulation breaches, affects roughly 0.5-2% of leads per year, with left ventricular (LV) leads exhibiting a higher risk due to their coronary venous placement and mechanical stresses.[95][96] Fractures account for a notable portion of these failures, often leading to pacing loss or inappropriate shocks, and may require lead extraction or replacement.Phrenic nerve stimulation arises in 10-20% of patients during LV pacing, particularly with mid-lateral or apical lead positions, causing diaphragmatic contraction and discomfort.[97][98] It is commonly managed through noninvasive vector reprogramming using multipolar leads to adjust pacing sites and avoid the phrenic nerve trajectory.[99]Battery depletion typically occurs after 5-10 years of service, with median longevity around 6 years for CRT-defibrillators due to high pacing demands.[100][101] Replacement procedures carry risks comparable to initial implantation, including infection or lead issues, while twiddler's syndrome—patient manipulation leading to lead dislodgement—remains rare overall (about 1%) but occurs more frequently (up to 15% in some frail cohorts) among elderly or cognitively impaired individuals.[102][103]
Technological Advancements
Traditional Biventricular Pacing
Traditional biventricular pacing, the cornerstone of cardiac resynchronization therapy (CRT), involves the simultaneous or near-simultaneous pacing of both ventricles to correct dyssynchronous contraction in patients with heart failure and conduction abnormalities. This approach typically employs a transvenous implantation technique where a right ventricular lead is placed in the right ventricle apex or septum, while the left ventricular lead is advanced through the coronary sinus (CS) ostium and positioned in a posterolateral or lateral tributary vein for endocardial pacing of the left ventricle.[1] The LV lead delivers single-point stimulation at the targeted site, aiming to optimize ventricular synchrony by aligning the activation sequence more closely with physiological norms.[1] This methodology has been refined over time to prioritize basal or mid-segmental positions in the CS tributaries to maximize hemodynamic benefits, avoiding apical placements that may lead to suboptimal resynchronization.[104]The efficacy of traditional biventricular pacing is well-established in selected patients, with response rates approximating 70% in ideal candidates who exhibit left bundle branch block, QRS duration greater than 150 ms, and preserved viability in the paced region.[1] Responders typically experience improvements in left ventricular ejection fraction, reduced heart failure hospitalizations, and enhanced quality of life, as demonstrated in landmark trials like CARE-HF and MADIT-CRT. However, limitations persist, with approximately 30% of patients classified as non-responders, often attributable to myocardial scar tissue that hinders effective pacing propagation or anatomical challenges such as CS tortuosity and unfavorable venous anatomy that complicate lead placement.[1] These factors underscore the importance of pre-implant imaging, such as cardiac MRI, to assess scar burden and vein accessibility.[105]Advancements in device technology have enhanced the reliability of traditional biventricular pacing, particularly through the adoption of quadripolar leads like the Medtronic Attain Performa series, which offer multiple pacing electrodes within a single vein to enable vector optimization and reduce phrenic nerve stimulation.[106] These leads allow for multi-site stimulation options along the CS tributary, improving capture thresholds and adaptability to individual anatomies.[107] Complementary algorithms, such as Medtronic's AdaptivCRT, provide automated AV and VV timing adjustments based on real-time ECG analysis, promoting consistent biventricular pacing percentages above 95% and further boosting response rates.[108]Since its formalization in the early 2000s, traditional biventricular pacing has formed the basis of major clinical guidelines, including the 2002 ACC/AHA/NASPE update that first recommended CRT for symptomatic heart failure patients with ventricular dyssynchrony.[109] It remains the predominant method, accounting for the vast majority of CRT implants as of recent data, reflecting its proven track record despite the emergence of alternative techniques.[110] Ongoing refinements continue to address implantation challenges, ensuring its role as the standard for achieving electrical and mechanical resynchronization.[1]
Emerging Techniques
Conduction system pacing (CSP) represents a physiological alternative to traditional biventricular pacing in cardiac resynchronization therapy (CRT), directly stimulating the heart's native conduction system to achieve more synchronous ventricular activation and address limitations such as suboptimal response rates in some patients.[111] CSP encompasses His-bundle pacing (HBP), which targets the His bundle for selective or non-selective pacing, and left bundle branch area pacing (LBBAP), which involves pacing the left bundle branch to correct left bundle branch block patterns more efficiently.[50] These techniques offer high implantation success rates exceeding 95%, with clinical response rates around 70-90% in experienced centers, particularly for patients with reduced ejection fraction and conduction delays.[112] Pacing thresholds are notably lower, typically 0.5-1 V at 0.5 ms, reducing energy consumption and battery drain compared to conventional methods.[113] The 2025 European Heart Rhythm Association (EHRA)/European Society of Cardiology (ESC) clinical consensus statement recommends CSP, especially LBBAP, for CRT non-responders to improve outcomes, as well as for patients with left ventricular ejection fraction ≤40% and atrioventricular block, positioning it as a preferred strategy in challenging cases.[111]Multipoint pacing (MPP) advances CRT by utilizing quadripolar leads to stimulate multiple sites on the left ventricle simultaneously, enhancing resynchronization in patients with heterogeneous scar tissue or suboptimal single-site pacing.[114] This approach targets two distinct left ventricular sites, optimizing activation wavefronts and promoting greater reverse remodeling. The MORE-CRT MPP randomized trial, with results published in 2023 and further analyzed in 2025, demonstrated that MPP converted approximately 30% of initial non-responders to responders within six months, with a 10-15% improvement in left ventricular remodeling metrics such as end-systolic volume reduction compared to single-point biventricular pacing.[115] Additionally, MPP was associated with a significant reduction in heart failure hospitalizations and all-cause mortality in non-responders, highlighting its role in refining CRT efficacy for broader patient applicability.[116]Leadless and hybrid CRT systems are emerging to minimize infection risks and improve patient comfort by eliminating transvenous leads, combining subcutaneous implantable cardioverter-defibrillators (S-ICDs) with endocardial left ventricular leads for targeted pacing. The WiSE CRT System, for instance, employs wirelessultrasound technology to deliver endocardial left ventricular pacing from a subcutaneous transmitter, achieving effective resynchronization in patients unsuitable for epicardial leads.[117] The SOLVE-CRT trial confirmed the safety and efficacy of this leadless approach, with low complication rates and sustained clinical benefits in heart failure patients.[118] AI-guided implant planning further enhances precision through automated cardiac imaging analysis for assessing myocardial viability and conduction patterns.[119]Looking ahead, gene therapy is being explored to address underlying molecular defects in heart failure, with early-phase trials evaluating adeno-associated virus-based vectors for sarcomere gene replacement showing promise in reversing cardiomyopathy phenotypes, though clinical integration remains investigational as of 2025.[120] CSP is gaining substantial traction, driven by its physiological advantages and guideline endorsements, as heart failure prevalence rises.[121]
Follow-up and Optimization
Device Programming
Device programming in cardiac resynchronization therapy (CRT) involves post-implant adjustments to device settings to optimize atrioventricular (AV) synchrony, interventricular synchrony, and overall hemodynamic performance, thereby enhancing the benefits of biventricular pacing.[122] Key parameters include the AV delay, typically programmed to 100-150 ms to allow sufficient time for atrial contraction to contribute to ventricular filling while ensuring complete ventricular capture, and the ventriculoventricular (VV) offset, often set with left ventricular (LV) pacing preceding right ventricular (RV) pacing by 10-40 ms to correct interventricular dyssynchrony.[123] These settings are individualized based on patient-specific conduction patterns to promote electrical and mechanical resynchronization.Optimization is guided by diagnostic testing to achieve maximal resynchronization, such as using 12-lead electrocardiography (ECG) to minimize QRS duration, which serves as a surrogate for electrical synchrony, or echocardiography to assess mechanical parameters like septal flash or aortic velocity-time integral.[122] Non-invasive hemodynamic assessments, including bioreactance-based monitoring of maximum rate of pressure change (dP/dt), provide real-time evaluation of cardiac output and contractility during programming, offering a practical alternative to invasive methods.[124]Modern CRT devices incorporate automated algorithms for dynamic programming to adapt to physiological changes. For instance, the QuickOpt algorithm (Abbott) uses intracardiac electrograms to rapidly optimize AV and VV delays, aiming for efficient resynchronization without manual intervention.[125] Similarly, AdaptiveCRT (Medtronic) employs fusion pacing strategies, switching between biventricular and LV-only modes based on intrinsic AV conduction every minute to maintain optimal synchrony and reduce the risk of pacing-induced complications.[107] The SyncAV algorithm (Abbott) further refines this by dynamically shortening AV delays to promote fusion with intrinsic conduction, often using offsets of 10-60 ms to narrow QRS duration by up to 24%.[122]Despite these advances, challenges persist, with approximately 20-40% of patients classified as non-responders who may require reprogramming within the first 3-6 months to address suboptimal pacing or evolving conduction.[126] Emerging artificial intelligence (AI)-assisted tools in remote monitoring of cardiac implantable devices have shown promise in reducing clinician workload through automated alert prioritization, with examples classifying up to 42.8% of transmissions as false positives while maintaining high sensitivity, potentially decreasing follow-up visits.[127]
Patient Monitoring
Patient monitoring in cardiac resynchronization therapy (CRT) involves a structured approach to ensure device efficacy, detect potential issues early, and optimize patient outcomes through regular assessments and remote surveillance. Routine follow-up typically includes in-clinic visits at 1, 3, and 6 months post-implantation, followed by annual evaluations thereafter, allowing for comprehensive device interrogation and clinical review.[128] These visits are supplemented by remote monitoring systems, such as Medtronic's CareLink Network, which enable patients to transmit device data from home transmitters or smartphone apps, providing alerts on battery status, lead integrity, and pacing parameters without requiring frequent office attendance.[129][130] Remote monitoring is recommended as a Class I intervention to reduce in-office visits, particularly for patients with mobility limitations, and should be initiated within 2 weeks of implantation for continuous data transmission.[38][130]Response to CRT is evaluated longitudinally to confirm therapeutic benefit and guide adjustments. Echocardiography is performed every 6-12 months to assess left ventricular end-systolic volume (LVESV) reduction, with a target of at least 15% decrease indicating positive reverse remodeling.[38][131] Symptom scores, such as New York Heart Association (NYHA) class improvements, are tracked alongside functional metrics like 6-minute walk distance.[38] Non-invasive device interrogations during follow-up measure the percentage of biventricular (BiV) pacing, aiming for greater than 90-95% to ensure optimal synchrony.[38]Issue detection relies on automated alerts from remote monitoring platforms to identify deviations such as atrial fibrillation episodes, elevated pacing thresholds, or reduced BiV pacing efficiency.[130] These systems facilitate early intervention, with continuous connectivity recommended to minimize delays in addressing actionable events like lead dysfunction or battery depletion.[130] Emerging trends as of 2025 include integration of wearable devices for real-time activity and heart rate data, enhancing holistic surveillance when combined with CRT telemetry.[132]For non-responders, defined as those with less than 15% LVESV reduction at 6 months, management involves optimizing guideline-directed medical therapy (GDMT) for heart failure, such as adjustments to beta-blockers or SGLT2 inhibitors.[5] In select cases, upgrading to conduction system pacing (CSP), such as left bundle branch area pacing, may be considered to improve synchrony and response rates.[133][134] This approach prioritizes individualized reassessment to sustain long-term benefits.