Leonard M. Rademakers

Left ventricular endocardial pacing improves resynchronization therapy in canine left bundle-branch hearts.

Background—We investigated the benefits of the more physiological activation achieved by left ventricular (LV) endocardial pacing (ENDO) as compared with conventional epicardial (EPI) LV pacing in cardiac resynchronization therapy. Methods and Results—In 8 anesthetized dogs with experimental left bundle-branch block, pacing leads were positioned in the right atrium, right ventricle, and at 8 paired (EPI and ENDO) LV sites. Systolic LV pump function was assessed as LVdP/dtmax and stroke work and diastolic function as LVdP/dtmin. Electrical activation and dispersion of repolarization were determined from 122 epicardial and endocardial electrodes and from analysis of the surface ECG. Overall, ENDO-biventricular (BiV) pacing more than doubled the degree of electrical resynchronization and increased the benefit on LVdP/dtmax and stroke work by 90% and 50%, respectively, as compared with EPI-BiV pacing. During single-site LV pacing, the range of AV intervals with a >10% increase in LV resynchronization (79±31 versus 32±24 ms, P<0.05) and LVdP/dtmax (92±29 versus 63±39 ms) was significantly longer for ENDO than for EPI pacing. EPI-BiV but not ENDO-BiV pacing created a significant (40±21 ms) transmural dispersion of repolarization. Conclusions—Data from this acute animal study indicate that the use of an endocardial LV pacing electrode may increase the efficacy of resynchronization therapy as compared with conventional epicardial resynchronization therapy.

LV Endocardial Pacing Improves Resynchronization Therapy in Canine LBBB Hearts

Background—We investigated the benefits of the more physiological activation achieved by left ventricular (LV) endocardial pacing (ENDO) as compared with conventional epicardial (EPI) LV pacing in cardiac resynchronization therapy. Methods and Results—In 8 anesthetized dogs with experimental left bundle-branch block, pacing leads were positioned in the right atrium, right ventricle, and at 8 paired (EPI and ENDO) LV sites. Systolic LV pump function was assessed as LVdP/dtmax and stroke work and diastolic function as LVdP/dtmin. Electrical activation and dispersion of repolarization were determined from 122 epicardial and endocardial electrodes and from analysis of the surface ECG. Overall, ENDO-biventricular (BiV) pacing more than doubled the degree of electrical resynchronization and increased the benefit on LVdP/dtmax and stroke work by 90% and 50%, respectively, as compared with EPI-BiV pacing. During single-site LV pacing, the range of AV intervals with a >10% increase in LV resynchronization (79±31 versus 32±24 ms, P<0.05) and LVdP/dtmax (92±29 versus 63±39 ms) was significantly longer for ENDO than for EPI pacing. EPI-BiV but not ENDO-BiV pacing created a significant (40±21 ms) transmural dispersion of repolarization. Conclusions—Data from this acute animal study indicate that the use of an endocardial LV pacing electrode may increase the efficacy of resynchronization therapy as compared with conventional epicardial resynchronization therapy.

Endocardial Left Ventricular Pacing Improves Cardiac Resynchronization Therapy in Chronic Asynchronous Infarction and Heart Failure Models

Background— Studies in canine hearts with acute left bundle branch block (LBBB) showed that endocardial left ventricular (LV) pacing improves the efficacy of cardiac resynchronization therapy (CRT) compared with conventional epicardial LV pacing. The present study explores the efficacy of endocardial CRT in more compromised hearts and the mechanisms of such beneficial effects. Methods and Results— Measurements were performed in 22 dogs, 9 with acute LBBB, 7 with chronic LBBB combined with infarction (embolization; LBBB plus myocardial infarction, and concentric remodeling), and 6 with chronic LBBB and heart failure (rapid pacing, LBBB+HF, and eccentric remodeling). A head-to-head comparison was performed of the effects of endocardial and epicardial LV pacing at 8 sites. LV activation times were measured using ≈100 endocardial and epicardial electrodes and noncontact mapping. Pump function was assessed from right ventricular and LV pressures. Endocardial CRT resulted in better electric resynchronization than epicardial CRT in all models, although the benefit was larger in concentrically remodeled LBBB plus myocardial infarction than in eccentrically remodeled LBBB+HF hearts (19% versus 10%). In LBBB and LBBB+HF animals, endocardial conduction was ≈50% faster than epicardial conduction; in all models, transmural impulse conduction was ≈25% faster when pacing from the endocardium than from the epicardium. Hemodynamic effects were congruent with electric effects. Conclusions— Endocardial CRT improves electric synchrony of activation and LV pump function compared with conventional epicardial CRT in compromised canine LBBB hearts. This benefit can be explained by a shorter path length along the endocardium and by faster circumferential and transmural impulse conduction during endocardial LV pacing.

Left Ventricular Septal and Left Ventricular Apical Pacing Chronically Maintain Cardiac Contractile Coordination, Pump Function and Efficiency

Background—Conventional right ventricular (RV) apex pacing can lead to adverse clinical outcome associated with asynchronous activation and reduced left ventricular (LV) pump function. We investigated to what extent alternate RV (septum) and LV (septum, apex) pacing sites improve LV electric activation, mechanics, hemodynamic performance, and efficiency over 4 months of pacing. Methods and Results—After AV nodal ablation, mongrel dogs were randomized to receive 16 weeks of VDD pacing at the RV apex, RV septum, LV apex, or LV septum (transventricular septal approach). Electric activation maps (combined epicardial contact and endocardial noncontact) showed that RV apical and RV septal pacing induced significantly greater electric desynchronization than LV apical and LV septal pacing. RV apex and RV septal pacing also significantly increased mechanical dyssynchrony, discoordination (MRI tagging) and blood flow redistribution (microspheres) and reduced LV contractility, relaxation, and myocardial efficiency (stroke work/myocardial oxygen consumption). In contrast, LV apical and LV septal pacing did not significantly alter these parameters as compared with the values during intrinsic conduction. At 16 weeks, acute intrasubject comparison showed that single-site LV apical and LV septal pacing generally resulted in similar or better contractility, relaxation, and efficiency as compared with acute biventricular pacing. Conclusions—Acute and chronic LV apical and LV septal pacing maintain regional cardiac mechanics, contractility, relaxation, and efficiency near native levels, whereas RV apical or RV septal pacing diminish these variables. Acute LV apical and LV septal pacing tend to maintain or improve contractility and efficiency compared with biventricular pacing.

Myocardial Infarction Does Not Preclude Electrical and Hemodynamic Benefits of Cardiac Resynchronization Therapy in Dyssynchronous Canine Hearts

Background—Several studies suggest that patients with ischemic cardiomyopathy benefit less from cardiac resynchronization therapy. In a novel animal model of dyssynchronous ischemic cardiomyopathy, we investigated the extent to which the presence of infarction influences the short-term efficacy of cardiac resynchronization therapy. Methods and Results—Experiments were performed in canine hearts with left bundle branch block (LBBB, n=19) and chronic myocardial infarction, created by embolization of the left anterior descending or left circumflex arteries followed by LBBB (LBBB+left anterior descending infarction [LADi; n=11] and LBBB+left circumflex infarction [LCXi; n=7], respectively). Pacing leads were positioned in the right atrium and right ventricle and at 8 sites on the left ventricular (LV) free wall. LV pump function was measured using the conductance catheter technique, and synchrony of electrical activation was measured using epicardial mapping and ECG. Average and maximal improvement in electric resynchronization and LV pump function by right ventricular+LV pacing was similar in the 3 groups; however, the site of optimal electrical and mechanical benefit was LV apical in LBBB hearts, LV midlateral in LBBB+LCXi hearts and LV basal-lateral in LBBB+LADi hearts. The best site of pacing was not the site of latest electrical activation but that providing the largest shortening of the QRS complex. During single-site LV pacing the range of atrioventricular delays yielding ≥70% of maximal hemodynamic effect was approximately 50% smaller in infarcted than noninfarcted LBBB hearts (P<0.05). Conclusions—Cardiac resynchronization therapy can improve resynchronization and LV pump function to a similar degree in infarcted and noninfarcted hearts. Optimal lead positioning and timing of LV stimulation, however, require more attention in the infarcted hearts.

Mid-term follow up of thromboembolic complications in left ventricular endocardial cardiac resynchronization therapy.

BACKGROUND Endocardial left ventricular (LV) pacing for cardiac resynchronization therapy (CRT) has been proposed as an alternative to traditional LV transvenous epicardial pacing with equal or superior cardiac performance. The risks of cerebral thromboembolism and possible interference with mitral valve function moderate its clinical application. OBJECTIVE The purpose of this study was to investigate cerebral thromboembolic complications after LV endocardial lead placement. Mitral regurgitation (MR) was the secondary outcome measure. METHODS CRT candidates with a failed coronary sinus approach or nonresponders to conventional CRT underwent endocardial LV lead implantation (45 atrial transseptal, 6 transapical). Coumarin was prescribed with a targeted international normalized ratio between 3.5 and 4.5. Patient records were checked and general practitioners were contacted regarding cerebral thromboembolic complications. MR was evaluated by echocardiography at baseline and after 6 months. RESULTS In 7 patients, 6 ischemic strokes and 2 transient ischemic attacks occurred, corresponding to 6.1 thromboembolic events per 100 patient-years (95% confidence interval 3.4-15.8). One patient refused hospital admission; all other patients had a subtherapeutic anticoagulation level at the time of the event. No major bleeding complications occurred. There was no change in the grade of MR (grade 2, P = .727) after 6 months. CONCLUSION Endocardial LV lead placement in patients with advanced heart failure is associated with thromboembolic risk. However, all but 1 patient had a subtherapeutic level of anticoagulation. Endocardial LV lead placement is not associated with aggravation of MR.

Vectorcardiography as a Tool for Easy Optimization of Cardiac Resynchronization Therapy in Canine Left Bundle Branch Block Hearts

Background—In cardiac resynchronization therapy (CRT), optimization of left ventricular (LV) stimulation timing is often time consuming. We hypothesized that the QRS vector in the vectorcardiogram (VCG) reflects electric interventricular dyssynchrony, and that the QRS vector amplitude (VAQRS), halfway between that during left bundle branch block (LBBB) and LV pacing, reflects optimal resynchronization, and can be used for easy optimization of CRT. Methods and Results—In 24 canine hearts with LBBB (12 acute, 6 with heart failure, and 6 with myocardial infarction), the LV was paced over a wide range of atrioventricular (AV) delays. Surface ECGs were recorded from the limb leads, and VAQRS was calculated in the frontal plane. Mechanical interventricular dyssynchrony (MIVD) was determined as the time delay between upslopes of LV and right ventricular pressure curves, and systolic function was assessed as LV dP/dtmax. VAQRS and MIVD were highly correlated (r=0.94). The VAQRS halfway between that during LV pacing with short AV delay and intrinsic LBBB activation accurately predicted the optimal AV delay for LV pacing (1 ms; 95% CI, –5 to 8ms). Increase in LV dP/dtmax at the VCG predicted AV delay was only slightly lower than the highest observed [INCREMENT]LV dP/dtmax (–2.7%; 95% CI, –3.6 to –1.8%). Inability to reach the halfway value of VAQRS during simultaneous biventricular pacing (53% of cases) was associated with suboptimal hemodynamic response, which could be corrected by sequential pacing. Conclusions—The VAQRS reflects electric interventricular dyssynchrony and accurately predicts optimal timing of LV stimulation in canine LBBB hearts. Therefore, VCG may be useful as a reliable and easy tool for individual optimization of CRT.

Pressure Ulcers and Prolonged Hospital Stay in Hip Fracture Patients Affected by Time-to-Surgery

Background:Hip fractures are associated with high morbidity. Pressure ulcer formation after hip surgery is often related to delayed patient mobilization. The objectives of this study were to determine whether time-to-surgery affects development of pressure ulcers postoperatively and, thus, length of hospital stay.Patients and Methods:We performed a retrospective analysis of consecutive hip fracture patients, aged 60 years and above, who underwent surgery between 1995 and 2001. The primary outcome was in-hospital development of pressure ulcers. The secondary outcome measure was the overall length of hospital stay. Analyses were adjusted for relevant confounders.Results:Of the 722 patients enrolled, 488 patients (68%) received surgery at 12 h after admission. Approximately 30% (n = 214) developed pressure ulcers during admission, whilst 19% of patients operated within 12 h of admission developed pressure ulcers. Time-to-surgery was an independent predictor of both development of pressure ulcers (OR = 1.7, 95% confidence interval [CI] = 1.2–2.6; p = 0.008) and length of hospital stay (11.3 vs 13.3 days in the early and the late surgery group, respectively, p = 0.050). Furthermore, development of pressure ulcers was associated with prolonged postoperative hospital stay (19.5 vs 11.1 days for patients with and without pressure ulcers, respectively, p = 0.001)Interpretation:In hip fracture patients, time-to-surgery was an independent predictor of both postoperative pressure ulcer development and prolonged hospital stay. These data suggest that the implementation of an early surgery protocol following admission for hip fractures may reduce both the postoperative complications and overall hospital stay.

Intrapericardial delivery of amiodarone and sotalol: atrial transmural drug distribution and electrophysiological effects.

Amiodarone and sotalol are frequently used in the treatment of atrial fibrillation. However, oral and intravenous (IV) therapy with these drugs has suboptimal efficacy and is associated with serious extracardiac side effects. We hypothesized that intrapericardial (IPC) delivery produces antiarrhythmic effects at lower plasma drug concentrations than IV delivery. Goats (n = 27) were randomised into 5 groups receiving either IPC vehicle, amiodarone (IV or IPC) or dl-sotalol (IV or IPC). Epicardial and endocardial atrial effective refractory period and atrial response to burst pacing (rapid atrial response, RAR) were assessed before and after 3 hours of drug infusion at 2 mg·kg−1·h−1. IPC delivery produced steeply decreasing drug concentrations from epicardium to endocardium in both atria and ventricles. Plasma drug concentrations were significantly lower in IPC than in IV groups. IPC amiodarone and sotalol reduced epicardial RAR inducibility (−74% ± 20% and −66% ± 30%, respectively) compared with IV delivery (−11% ± 17% and −17% ± 28%, respectively; P < 0.05). Endocardial RAR inducibility was only reduced in the IPC amiodarone group (−70% ± 17%, P < 0.05). In conclusion, IPC delivery of amiodarone and sotalol increases atrial drug concentration and antiarrhythmic effects at reduced plasma drug concentrations. These potential benefits are particularly prominent for IPC delivered amiodarone.

Epicardial application of an amiodarone-releasing hydrogel to suppress atrial tachyarrhythmias.

BACKGROUND Amiodarone is currently the most effective antiarrhythmic drug for sinus rhythm maintenance. However, due to serious extracardiac adverse effects, prophylactic amiodarone therapy is only appropriate for patients at high risk for postoperative atrial fibrillation (AF). We hypothesized that epicardial application of an amiodarone-releasing hydrogel would produce therapeutic myocardial drug concentrations, while systemic levels would remain low. METHODS Goats were fitted with right atrial epicardial patch electrodes. A poly(ethylene glycol)-based hydrogel with amiodarone (1mg/kg bw) (n=10) or without drug (n=6) was applied to the right atrial epicardium. Atrial effective refractory period (AERP), conduction time and atrial response to burst pacing (rapid atrial response, RAR) were assessed up to 28days in awake goats. Myocardial, plasma and extracardiac tissue amiodarone concentrations were analysed by high-performance liquid chromatography. RESULTS The amiodarone-loaded hydrogel produced therapeutic drug concentrations in the right atrium up to 21days after application. In this period, AERP and conduction time were prolonged, while RAR inducibility was reduced (P<0.05) compared to animals treated with drug-free hydrogel. Mean amiodarone concentrations in the right atrium were 1 order of magnitude higher than in other heart chambers and 2 orders of magnitude higher than in extracardiac tissues. Plasma amiodarone levels remained below the detection limit (<10ng/mL) during the 28-day follow-up. CONCLUSIONS Epicardial application of an amiodarone-releasing hydrogel reduces atrial vulnerability to tachyarrhythmias up to 3weeks, while extracardiac drug levels remain low. Therefore, amiodarone-releasing hydrogel could be applied during cardiac surgery to prevent postoperative AF at minimal risk for extracardiac adverse side effects.