Cardiac Dyssynchrony and Heart Failure Development:Insight from a Pacing Model

Activation sequence abnormality in the left ventricle (LV) is considered harmful to the maintenance of orchestrated cardiac contraction, especially in patients with left bundle branch block and right ventricular (RV) pacing. The conduction disturbance creates both dyssynchronous contraction and relaxation of the LV that is harmful to LV global performance. Large clinical studies have demonstrated ventricular pacing is associated with increased atrial fibrillation and hospitalization for heart failure even with maintenance of atria-ventricular (AV) synchrony. Though only a proportion of patients develop heart failure after receiving RV apical pacing, several observational studies have reported detrimental effects of RV pacing on LV function and morphology.

Artificial right ventricle (RV) apical pacing creates LV desynchronization by initiating impulse from local myocardium and bypassing His-Purkinje system. The consequence of abnormal impulses conduction is LV septum contracts first and stretches the not-yet-activated remote LV lateral wall. The stretched LV lateral wall requires more energy to contract and stretch the other regions that are already activated. This abnormal stretching is a key mediator of the adverse tissue remodeling process.

RV apical pacing as a treatment modality for bradyarrhythmia has demonstrated to increase the incidence of heart failure hospitalization in many long-term clinical studies. The MOST trial demonstrated that the risks of heart failure development were proportional to cumulative ventricular pacing burden regardless of pacing mode. The recent study also reported traditional RV apical pacing resulted in a reduction in the LV ejection fraction and adverse LV remodeling in patient with pre-existing normal systolic function and these effects were prevented by biventricular pacing. These clinical findings implicate that ventricular desynchronization by RV apical pacing is associated with a higher incidence of heart failure development. But molecular evidence of RV pacing associated adverse effects based on a structurally normal heart model is still lacking.

To investigate the contribution of right ventricular (RV) apical pacing to the left ventricular (LV) negative remodeling, we measured the inter- and intra-ventricular mechanical dyssynchrony by echocardiography as well as plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) level in 116 consecutive patients of symptomatic bradyarrhythmias including sinus node dysfunction (SND) in 80 and atrioventricular block (AVB) in 36. DDDR pacemakers were implanted in 76 patients (SND, 40), and AAIR pacemakers in 40 (all SND). Clinical manifestations were retrospectively correlated.

After 3.5 years of chronic pacing, DDDR pacemaker patients demonstrated higher plasma NT-proBNP concentration (503±111 pg/ml) than AAIR patients (194±42 pg/ml, p=0.002) despite similar cardiovascular function in baseline. Multivariate regression analysis revealed that the only predictor of the highest quartile of plasma NT-proBNP, i.e.≧ 386 pg/ml, was the IVTD (per 10 msec, p= 0.01). Reprogramming to minimize ventricular pacing % in 8 patients of SND caused parallel reduction of plasma NT-proBNP.

Interventricular mechanical dyssynchrony, imposed mostly by RV apical pacing, could lead to abnormal heightening of plasma NT-proBNP concentration after chronic DDDR pacing in common pacemaker patients with normal baseline LV function.

To investigate contraction and hypertrophy-related protein expression changes and extracellular matrix (ECM) remodeling of the LV by desynchronization. We performed the animal study with atria-sensed RV apical pacing in dogs.

Six dogs underwent dual chamber pacemaker (DDD) implantation and AV nodal catheter ablation. The pacing group received atria-sensed RV apical pacing for 12 weeks. LV dyssynchrony was assessed with speckle tracking technique. Another 4 dogs was sham-operated for pacemaker implantation only and their pacemakers were kept as off status. After 12 weeks of atria-sensed obligatory RV pacing, LVs were separated into septum and lateral wall for analysis. Contraction-related protein, including sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) and phospholamban, and hypertrophy-related protein, including phospho-p38, phospho-ERK and phospho-JNK expression, zymographic activity, including matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitors of metalloproteinase-1 (TIMP-1), TIMP-3, collagen transcript expression, and histology were examined in opposite portions of the LV to identify possible ECM remodeling changes by RV apical pacing.

Both electrical and mechanical dyssynchrony were evident in RV paced dogs compared to sham-operated dogs. The late-activated LV lateral wall of paced dogs displayed a 23% reduction in the amount of sarcoplasmic reticulum Ca2+ ATPase, a 32% reduction in phospholamban levels, but a 3.6-fold increase in phospho-JNK expression, a 2.2-fold increase in phospho-p38, and 1.9-fold increase in phospho-ERK expression. There were no significant differences in the early-activated LV septum between paced and sham dogs.

For ECM analysis, compared with sham-operated dogs, increased interstitial fibrosis and fragmentation of myofibrils was found in the LV lateral wall in the pacing group (8.3 ± 1.5% in pacing group vs 3.9 ± 0.9% in sham group, P < 0.01);. Collagen type II mRNA showed a significant 2.10 ± 0.70 fold increase in the LV lateral wall in the pacing group (P < 0.01). While collagen type I mRNA was increased, the difference was not significant. Zymography demonstrated MMP-9 activity was enhanced in both the LV lateral wall and septum in the pacing group (1.88 ± 0.29 fold, P < 0.01 in the LV lateral wall and 1.45 ± 0.19 fold, P < 0.01 in the LV septum), but MMP-2 activity was enhanced in the LV lateral wall (1.58 ± 0.04 fold, P < 0.01). Immunfluorescence stain confirmed the activation of MMP-2 and MMP-9 in the LV lateral wall in the pacing group. Protein expression of TIMP-1 and TIMP-3 showed regional differences in the pacing group and both proteins were increased in the LV lateral wall (1.23 ± 0.16, P < 0.05 for TIMP-1 and 1.98 ± 0.27, P < 0.01 for TIMP-3).

Temporal dispersion of mechanical activation by RV apical pacing induced spatial dispersion of protein expression in the LV. LV dyssynchrony by RV apical pacing also elicits heterogeneous ECM remodeling in the LV. These findings assist in the elucidation of the pathophysiology of LV desynchronization.