Pacing-induced dyssynchrony during early reperfusion reduces infarct size.

OBJECTIVES: Considering the recent discovery of postconditioning, we investigated whether intermittent dyssynchrony immediately upon reperfusion induces cardioprotection as well. BACKGROUND: Intermittent dyssynchrony, induced by ventricular pacing, preconditions myocardium. METHODS: Isolated ejecting rabbit hearts were subjected to 30-min coronary occlusion and 2-h reperfusion. Control, left ventricular (LV) pacing preconditioning (LVPpreC) (3 x 5-min LV pacing), and LV pacing postconditioning (LVPpostC) (10 x 30-s LV pacing during early reperfusion) groups were studied. Mechanical effects of LV pacing were determined using local pressure-length loops (sonomicrometry), whereas effects on myocardial lactate release and coronary flow were assessed from coronary effluent and fluorescent microspheres, respectively. Anesthetized pigs underwent 60-min coronary occlusion and 3-h reperfusion in control and right ventricular (RV) pacing postconditioning groups (RVPpostC) (10 x 30-s RV pacing during early reperfusion). In all hearts, area at risk and infarct size were determined with blue dye and triphenyltetrazolium chloride staining, respectively. RESULTS: Infarct size, normalized to area at risk, was 47.0 +/- 12.3% in control rabbit hearts, but significantly smaller in LVPpreC (17.8 +/- 6.4%) and LVPpostC hearts (17.9 +/- 4.4%). Left ventricular pacing significantly altered regional mechanical work, but did not affect coronary flow or lactate release. In pigs, infarct size was significantly smaller in RVPpostC (9.8 +/- 3.0%) than in control (20.6 +/- 2.2%) animals. CONCLUSIONS: Intermittent dyssynchrony during early reperfusion reduces infarct size in 2 different animal models. Dyssynchrony-induced postconditioning cannot be attributed to graded reperfusion but may be induced by modulation of local myocardial workload. Dyssynchrony-induced postconditioning opens new possibilities for cardioprotection in the clinical setting.

Tailoring cardiac resynchronization therapy using interventricular asynchrony. Validation of a simple model.

This study explores the use of interventricular asynchrony (interVA) for optimizing cardiac resynchronization therapy (CRT), an idea emerging from a simple pathway model of conduction in the ventricles. Measurements were performed in six dogs with chronic left bundle branch block (LBBB) and in 29 patients of the Pacing Therapies for Congestive Heart Failure (PATH-CHF)-I study. In the dogs, intraventricular asynchrony (intraVA) was determined using left ventricular (LV) endocardial activation maps. In dogs and patients, the maximum rate of rise of LV pressure (LV dP/dt(max)) and the pulse pressure (PP) and interVA [time delay between upslope of LV and right ventricular (RV) pressure curves] were measured during LV, RV, and biventricular (BiV) pacing with various atrioventricular (AV) delays. Measurements in the canine hearts supported the pathway model in that optimal resynchronization occurred at approximately 50% reduction of intraVA and at an interVA value halfway that during LBBB and LV pacing. In patients with significant hemodynamic response during pacing (n = 22), intrinsic interVA and interVA at peak improvement (interVA(p)) varied widely between patients (from -83 to -15 ms and from -42 to +31 ms, respectively). However, the model predicted individual interVA(p) accurately (SD of +/-6 ms and +/-12 ms for LV dP/dt(max) and PP, respectively). At equal interVA, LV and BiV pacing produced equal hemodynamic response, but in 11 of 22 responders, BiV pacing reduced interVA insufficiently to reach the maximum hemodynamic response. LV pacing at short AV delay proved to result in better hemodynamics than predicted by the model, indicating that additional factors determine hemodynamics during LV preexcitation. Guided by a simple pathway model, interVA measurements accurately predict optimal hemodynamic performance in individual CRT patients.

Area of left ventricular regional conduction delay and preserved myocardium predict responses to cardiac resynchronization therapy.

UNLABELLED: Cardiac resynchronization therapy. BACKGROUND: A significant proportion of patients with dilated cardiomyopathy and left bundle branch block (LBBB) do not respond to cardiac resynchronization therapy (CRT). The purpose of this study was to investigate whether the electromechanical properties of the myocardium would predict acute hemodynamic improvement during left ventricular (LV) pacing. METHODS AND RESULTS: We studied 10 patients with idiopathic dilated cardiomyopathy and LBBB (ejection fraction (EF): 27%+/-7%; QRS duration: 166+/-16 msec) using three-dimensional electromechanical endocardial mapping technique to assess endocardial activation time (Endo-AT), unipolar voltage, and local linear shortening during sinus rhythm. LV stimulation was performed in VDD mode at five different sites and three atrioventricular delays within the coronary sinus. LV+dP/dtmax changes from baseline were measured during LV stimulation at each site (%DeltadP/dtmax). There was no significant relationship between maximum %DeltadP/dtmax during LV stimulation at the best coronary sinus site and LV EF, baseline LV+dP/dtmax, total LV Endo-AT, baseline QRS duration nor changes in QRS duration during LV pacing. However, the maximum %DeltadP/dtmax was significantly positively correlated with percentage area of late Endo-AT (r=0.97, P<0.001) and preserved LV myocardium (r=0.81, P=0.005), respectively. Patients with >20% of LV area with late Endo-AT and >30% of preserved LV myocardium had five times better acute hemodynamic response with LV stimulation. Multivariate analysis showed that only percentage area of late Endo-AT was independently correlated with %DeltadP/dtmax (P<0.05). CONCLUSION: The presence of a larger amount of LV area with late Endo-AT and preserved LV myocardium measured by electromechanical mapping could identify patients who have better acute improvement in systolic performance during LV stimulation.

Comparison of stimulation sites within left ventricular veins on the acute hemodynamic effects of cardiac resynchronization therapy.

OBJECTIVES: The purpose of this study was to study the acute hemodynamic effect of left ventricular (LV) stimulation sites within a coronary vein. BACKGROUND: Access to LV stimulation sites for resynchronization therapy is achieved using specialized lead systems navigated through a coronary vein. The effects of stimulation in different coronary veins have been evaluated previously, but less is known about stimulation sites within a coronary vein. METHODS: Twenty-four patients (New York Heart Association functional class II-IV, age 59 +/- 10 years, ejection fraction 21 +/- 7%, QRS 166 +/- 30 ms) were enrolled in the study. A novel over-the-wire lead system was used to access an anterior or lateral coronary vein. At each lead location, a randomized stimulation protocol was executed. Hemodynamic responses were evaluated using LV dP/dtmax. RESULTS: The mean time to cannulate the coronary sinus and position the LV lead was 19 +/- 30 minutes and 17 +/- 18 minutes, respectively. Data from stimulation at two sites within a coronary vein were obtained in 19 patients (anterior vein 11; lateral vein 8). Of these patients, 14 (anterior vein 9; lateral vein 5) showed large improvement in dP/dtmax (22%-25% in anterior vein, 37%-40% in lateral vein). Overall, there were no group differences in hemodynamic effects among different stimulation sites within a coronary vein, although significant variability among sites was observed in individuals. CONCLUSIONS: Resynchronization therapy through a coronary vein improves acute hemodynamic function of heart failure patients with LV conduction disorder. There were no significant differences between basal and apical pacing sites for this group.

Short-term effects of right-left heart sequential cardiac resynchronization in patients with heart failure, chronic atrial fibrillation, and atrioventricular nodal block.

BACKGROUND: Single-site ventricular pacing in patients with heart failure, atrial fibrillation, and severe atrioventricular (AV) nodal block risks the generation of discoordinate contraction. Whether altering the site of stimulation can offset this detrimental effect and what role sequential right ventricular-left ventricular (RV-LV) stimulation might play in such patients remain unknown. METHODS AND RESULTS: Nine subjects with heart failure (ejection fraction, 14% to 30%), atrial fibrillation, and AV block were studied by pressure-volume analysis. Ventricular stimulation was applied to the RV (apex and outflow tract), LV free wall, and biventricular (BiV) at 80 and 120 bpm. BiV improved systolic function more than either site alone (dP/dt(max), 810+/-83, 924+/-98, 983+/-102 mm Hg/s for RV, LV, BiV, respectively; P<0.05), although LV pacing was significantly better than RV pacing. However, only BiV improved diastolic function (isovolumic relaxation) over RV or LV alone. Similar results were obtained for both heart rates. RV pacing site did not alter the BiV effect, and concomitant stimulation of both RV sites did not improve function over each alone. Finally, varying RV-LV delay revealed optimal responses with simultaneous pacing. CONCLUSIONS: Simultaneous BiV pacing acutely enhances both systolic and diastolic function over single-site RV or LV pacing in congestive heart failure patients with atrial fibrillation and advanced AV block. Sequential RV-LV stimulation offers minimal benefit on average and should perhaps be considered only in targeted subsets such as nonresponding patients.

Biventricular mechanical asynchrony predicts hemodynamic effect of uni- and biventricular pacing.

We tested whether biventricular resynchronization explains contractile function changes with univentricular and biventricular pacing in heart failure patients with varying magnitudes of baseline biventricular asynchrony. Thirty patients (New York Hospital Association class > or = III, QRS duration > or =120 ms) were tested. Contractile function was measured by left ventricular maximum first derivative of pressure over time (dP/dtmax). Biventricular mechanical asynchrony was quantified by the normalized pressure-pressure (NPP) loop area formed by the cross-plot of right and left intraventricular pressure curves from each cardiac cycle. Any ventricular pacing increased dP/dtmax if it decreased baseline NPP loop area and almost always worsened dP/dtmax and asynchrony when baseline NPP loop area <0.3. The quantitative relationship between dP/dtmax and NPP loop area change depended on ventricular pacing site and timing relative to intrinsic activation. For similar NPP loop decreases, dP/dtmax increased 16% more with left and biventricular pacing compared with right ventricular pacing. In conclusion, right, left, or biventricular pacing can improve contractile function only in patients having sufficient baseline biventricular asynchrony. However, biventricular resynchronization is only one of the improvement mechanisms.

The promise of resynchronization therapy. Who (and how many) will benefit?

It has been estimated that about 320,000 to 400,000 patients in the USA alone are possible candidates to cardiac resynchronization therapy according to the recently published AHA/ACC/NASPE guidelines for pacing and the results of the COMPANION trial. The selection of the most suitable candidate for CRT/CRTD is a crucial issue, but still a matter of debate. A large variety of clinical, invasive and non-invasive criteria have been proposed for appropriately selecting candidates for CRT. However, in all the studies the parameters have been retrospectively identified and none has reported their results in the form of a multivariate regression model. We have now well characterized the patients in sinus rhythm who most likely benefit from this non-pharmacological approach. The fact that the COMPANION trial was able to single out a specific subgroup of heart failure patients that can be treated better than what was very short time ago best medical therapy validates the large body of research that investigators worldwide have created about this therapy. Finally, the concept that any patients that require ventricular pacing, who have heart failure class II/III or IV may benefit from receiving biventricular rather than right ventricular pacing as much as the other patients with more classical indication for CRT is still open to discussion and needs to be tested in a randomized multicenter trial.

Systolic improvement and mechanical resynchronization does not require electrical synchrony in the dilated failing heart with left bundle-branch block.

BACKGROUND: Biventricular (BiV) and left ventricular (LV) pacing similarly augment systolic function in left bundle-branch block (LBBB)-failing hearts despite different electrical activation. We tested whether electrical synchrony is required to achieve mechanical synchronization and functional benefit from pacing. METHODS AND RESULTS: Epicardial mapping, tagged MRI, and hemodynamics were obtained in dogs with LBBB-failing hearts during right atrial, LV, and BiV stimulation. BiV and LV both significantly improved chamber hemodynamics (eg, 25% increase in dP/dt(max) and aortic pulse pressure) compared with atrial pacing-LBBB, and this improvement correlated with mechanical resynchronization. Electrical dispersion, however, decreased 13% with BiV but increased 23% with LV pacing (P<0.01). CONCLUSION: Improved mechanical synchrony and function do not require electrical synchrony. Mechanical coordination plays the dominant role in global systolic improvement with either pacing approach.

Left ventricular resynchronization therapy in a canine model of left bundle branch block.

Positive responses to left (LV) and biventricular (BV) stimulation observed in heart failure patients with left bundle branch block (LBBB) suggest a possible mechanism of LV resynchronization. An anesthetized canine LBBB model was developed using radio frequency ablation. Before and after ablation, LV pressure derivative over time (dP/dt) and aortic pulse pressure (PP) were assessed during normal sinus rhythm with right ventricle (RV), LV, or BV stimulation combined with four atrioventricular delays in six dogs. In three more dogs, M-mode echocardiograms of septal and LV posterior wall motion were obtained before and after LBBB and during LV stimulation. LBBB caused QRS widening and hemodynamics deterioration. Before ablation, stimulation alone worsened LV dP/dt and PP. After ablation, LV and BV stimulation maximally increased LV dP/dt by 16% and PP by 7% (P < 0.001), whereas little improvement was observed during RV stimulation. M-mode echocardiogram showed that LBBB resulted in a paradoxical septal wall motion that was corrected by LV stimulation. In conclusion, LV and BV stimulation improved cardiac function in a canine LBBB model via resynchronization of LV excitation and contraction.

Cardiac resynchronization therapy restores optimal atrioventricular mechanical timing in heart failure patients with ventricular conduction delay.

We characterized the relationship between systolic ventricular function and left ventricular (LV) end-diastolic pressure (LVEDP) in patients with heart failure (HF) and baseline asynchrony during ventricular stimulation. The role of preload in the systolic performance improvement that can be obtained in HF patients with LV stimulation is uncertain.We measured the maximum rate of increase of LV pressure, LVEDP, aortic pulse pressure (PP) and the atrioventricular mechanical latency (AVL) between left atrial systole and LV pressure onset in 39 patients with HF. Two subgroups were identified: "responder" if PP improved, or "nonresponder."Maximum hemodynamic improvement occurred at an atrioventricular (AV) delay that did not decrease LVEDP. Left ventricular and biventricular (BV) stimulation increased systolic hemodynamics significantly, despite no significant increase in LVEDP. All parameters decreased when the LVEDP was decreased by shorter AV delay. Left ventricular and BV stimulation provided better hemodynamics than right ventricular (RV) stimulation. For the nonresponder subgroup, systolic hemodynamics only worsened during AV delay shortening. For the responder subgroup, optimum PP was achieved when AVL was near zero. Restoration of optimal left atrial-ventricular mechanical timing partly contributes to the hemodynamic improvements observed in this patient subgroup. However, preload alone cannot explain the differences seen between RV and BV stimulation and the contradictory PP decreases even at maximal preload in the nonresponder subgroup. These results may be explained by a site-dependent mechanism such as the degree of ventricular synchrony. Caution should be taken in these patients when optimizing AV delays using echocardiography techniques that focus on LV inflow.

Effect of cardiac resynchronization therapy on ventricular remodeling.

Cardiac resynchronization therapy (CRT) is a new non-pharmacological option for patients with advanced heart failure and ventricular conduction delay. Four randomized prospective studies have provided evidence that CRT increases exercise capacity, improves functional class and quality of life. There is also increasing evidence that CRT may trigger an inverse remodeling process leading to reduction of ventricular diameter and eventually of the atrial size. The pathophysiological mechanism throughout CRT may promote inverse remodeling is: (1) reduction of systolic and diastolic mitral regurgitation; (2) reduction of sympathetic/parasympathetic imbalance as well as reduction of neurohumoral activation due to increased systolic blood pressure and improved filling time; (3) reduction of regional wall stress. The structural changes taking place during CRT are directly related to continuous pacing, because lack of pacing immediately shows the new onset of remodeling. The duration of the reported changes of ventricular diameter is still unknown, and it is also unknown whether such reverse remodeling process of the ventricle and of the atria will lead to a reduction of cardiac death and incidence of ventricular arrhythmias.