Cardiac dyssynchrony refers to abnormal timing of contractions within the heart, where different parts of the myocardium contract out of sync with each other.
Cardiac dissynchrony, contributes to the development and progression of heart failure (HF) through conduction abnormalities at disrupt, coordinated, cardiac contraction, particularly left bundle branch block (LBBB).
Electrical dyssynchrony — delayed or abnormal conduction (e.g., left bundle branch block, LBBB) causing the electrical signal to reach different regions at different times.
Mechanical dyssynchrony — the actual contraction timing mismatch, which can occur even without obvious electrical delay.
There are three subtypes:
Atrioventricular (AV) dyssynchrony — poor timing between atrial and ventricular contraction, reducing the atrial kick contribution to filling
Interventricular dyssynchrony — the right and left ventricles contracting out of phase with each other.
Intraventricular dyssynchrony — different walls of the same ventricle (usually the LV) contracting at different times; the most clinically significant form.
Pathophysiology
In LBBB-type dyssynchrony, the septum contracts early while the lateral LV wall contracts late.
This causes:
Septal dyskinesis (early inward, then outward rebound)
Reduced stroke volume and ejection fraction
Increased wall stress and myocardial oxygen demand
Functional mitral regurgitation from poor papillary muscle coordination
Over time: adverse LV remodeling and heart failure progression
Dyssynchrony is present in ~25–30% of patients with heart failure with reduced ejection fraction (HFrEF), particularly those with wide QRS (≥150 ms) and LBBB morphology.
It is independently associated with worse outcomes.
Assessment:
ECG: QRS duration and morphology (LBBB is the strongest surrogate)
Echocardiography: Tissue Doppler imaging (TDI), speckle-tracking strain, M-mode septal-to-posterior wall motion delay
Cardiac MRI: Feature tracking for mechanical dyssynchrony mapping
Nuclear imaging (phase analysis on SPECT)
Treatment
Cardiac resynchronization therapy (CRT) — biventricular pacing (or conduction system pacing) that simultaneously stimulates both ventricles, restoring coordinated contraction.
Strongest evidence in:
LVEF ≤35% QRS ≥150 ms with LBBB morphology Symptomatic HF (NYHA II–IV) on optimal medical therapy
CRT reduces hospitalizations, improves symptoms and quality of life, and reduces mortality in appropriate candidates. ~70% are responderswith measurable LV reverse remodeling.
His bundle pacing and left bundle branch area pacing (LBBAP) are emerging alternatives that restore more physiological conduction.
Normal Conduction and the Basis of Synchrony
In the normal heart, the electrical impulse propagates through the His-Purkinje system to achieve synchronous biventricular activation within approximately 40 ms.
This rapid, coordinated activation ensures optimal stroke volume and efficient cardiac output.
Cardiac dyssynchrony arises when this coordinated activation is disrupted, and it manifests at three levels:
Electrical vs. Mechanical Dyssynchrony
Electrical dyssynchrony is defined by QRS duration ≥120 ms and is present in approximately 20–30% of heart failure patients.
Mechanical dyssynchrony — differences in the timing of regional myocardial contraction — is present in 50–70% of patients with widened QRS/LBBB but also in 10–30% of HF patients with narrow QRS.
The relationship between the two is imperfect: approximately 30–40% of patients with wide QRS lack significant mechanical dyssynchrony, while some with narrow QRS have substantial mechanical dyssynchrony.
This discordance is modulated by calcium cycling, myofilament interactions, regional loading, and fibrosis.
LBBB is the most common and best-characterized cause of cardiac dyssynchrony, present in ~34% of chronic HF patients.
The acute mechanical consequences include:
Septal flash — rapid early inward septal motion during isovolumic contraction, followed by septal rebound stretch as the delayed lateral wall contracts.
Apical rocking — back-and-forth translational motion of the LV apex
Wasted myocardial work — energy consumed during segmental lengthening rather than shortening.
The global wasted work ratio rises from 0.09 ± 0.03 in healthy controls to 0.36 ± 0.16 in LBBB patients.
Reduced LV dP/dt, worsened mitral regurgitation from dyscoordinate papillary muscle activation, and paradoxical septal wall motion.
Critically, strain imaging has clarified that there are two distinct mechanisms of mechanical dyssynchrony: electrical conduction delay (e.g., LBBB), which is amenable to CRT, and contractile disparity from ischemia or scarring, which is not amenable to CRT.
This distinction is fundamental to patient selection.
LBBB can independently cause cardiomyopathy.
In a longitudinal cohort of 4,541 adults ≥65 years with structurally normal hearts, LBBB at baseline was associated with a cumulative HF incidence of 48% vs. 12.2% over median 14.6-year follow-up.
Animal models demonstrate that isolated LBBB causes a 25% increase in LV end-diastolic volume, 23% decrease in LVEF, and asymmetric hypertrophy within 16 weeks.
The natural history in humans progresses from isolated LBBB → HFpEF → HFmrEF → HFrEF over 5–21 years.
At the cellular level, the maladaptive remodeling cascade/dyssynchronopathy involves gap junctional remodeling, T-tubule disruption with desynchronized intracellular Ca²⁺ release, and abnormal Ca²⁺ handling which identifies the primary culprit in prolonging electromechanical delay.
These adaptations are maladaptive, which explains why CRT continues to increase its therapeutic effect over time by reversing these processes.
RV apical pacing produces an LBBB-like activation pattern, inducing both interventricular and intraventricular dyssynchrony.
The MOST trial showed that ventricular pacing >40% of the time conferred a 2.6-fold increased risk of HF hospitalization.
This has driven interest in conduction system pacing as an alternative.
QRS duration and morphology remain the cornerstone for identifying electrical dyssynchrony and selecting CRT candidates.
CRT significantly reduces death or HF hospitalization in patients with QRS ≥150 ms but not in QRS <150 ms.
MADIT-CRT subgroup analysis showed CRT benefit only in LBBB and not in non-LBBB.
Strauss criteria for LBBB refine conventional definitions: QRS ≥140 ms in men / ≥130 ms in women, QS or rS in V1–V2, and mid-QRS notching or slurring in ≥2 contiguous lateral leads.
Patients meeting Strauss criteria respond more frequently to CRT-71% sensitivity, 64% specificity for CRT response.
Multiple echocardiographic techniques have been developed to assess mechanical dyssynchrony:
Tissue Doppler Imaging (TDI): Opposing wall delay ≥60–65 ms and the Yu Index (12-segment SD ≥33 ms) showed promising single-center results (sensitivity 76–96%, specificity 78–83%).
No single echocardiographic measure of dyssynchrony could reliably predict CRT response.
Cardiac Magnetic Resonance (CMR)
CMR’s unique strength is simultaneous assessment of dyssynchrony and myocardial scar.
Late gadolinium enhancement (LGE) for scar assessment is critical: total scar burden inversely predicts CRT response (median 3% in responders vs. 35% in non-responders), and scar at the LV lead position is associated with non-response.
Combined dyssynchrony + scar assessment consistently outperforms either alone.
Cardiac Resynchronization Therapy
The strongest recommendation (Class I) is for patients with LVEF ≤35%, sinus rhythm, LBBB with QRS ≥150 ms, and NYHA class II–ambulatory IV on guideline-directed medical therapy.
CRT is contraindicated (Class III) for QRS <120 ms.
Approximately 30–50% of CRT recipients are classified as non-responders.
Favorable predictors include LBBB morphology, non-ischemic cardiomyopathy, female sex, wider QRS, and sinus rhythm.
Adverse predictors include ischemic etiology, non-LBBB morphology, QRS <150 ms, atrial fibrillation, and myocardial scar at the LV lead site.
CRT-D vs. CRT-P:
No adequately powered head-to-head RCT has directly compared CRT-D vs. CRT-P.
Meta-analyses of observational data suggest CRT-D reduces all-cause mortality ~20% over CRT-P, but not in non-ischemic etiology or age >75 years.
CRT-D appears most beneficial in younger patients with ischemic etiology and severely reduced EF (<30%), while CRT-P may be sufficient in older patients with non-ischemic etiology.
Conduction System Pacing
Conduction system pacing (His bundle pacing or left bundle branch area pacing [LBBAP]) is emerging as an alternative to biventricular pacing.
A meta-analysis and 17 observational studies (4,327 patients) showed CSP was associated with lower all-cause mortality, and reduced HF hospitalization compared with biventricular pacing.
However, the LEFT-BUNDLE-CRT trial (]did not meet non-inferiority of LBBAP-CRT to BiVP-CRT, and large definitive RCTs are still needed.
The 2023 HRS guideline proposes CSP as a reasonable alternative, particularly when coronary sinus lead placement fails.
Cardiac dyssynchrony — whether electrical (QRS ≥120 ms) or mechanical (regional contraction timing differences) — drives a maladaptive remodeling cascade that progressively worsens heart failure.
LBBB is the prototypical substrate, capable of independently causing cardiomyopathy over years to decades.
Assessment relies primarily on ECG criteria (QRS duration and LBBB morphology) for CRT patient selection, as no echocardiographic dyssynchrony parameter has been validated in a large RCT to improve selection beyond ECG criteria.
CRT remains one of the most effective therapies in heart failure, with landmark trials demonstrating 25–36% mortality reductions in appropriately selected patients, and the field continues to evolve with conduction system pacing as a potential alternative delivery strategy.