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Left ventricular performance during single chamber atrial, dual chamber and biventricular pacing

Andi Eie Albertsen

Background:
Each year almost 3000 patients receive a cardiac pacemaker in Denmark. Patients with sick sinus syndrome are well treated with a single pacemaker lead inserted in the right atrium (AAI(R)-pacing). However, electrical conduction disturbance between the atria and the ventricles (AV-block) is the most common cause of implanting a pacemaker and these patients need ventricular pacing most of the time. Thus, patients with AV-block receive DDD(R)-pacing through two pacing leads inserted into the right atrium and ventricle, respectively. Yet, experimental and clinical studies have indicated that DDD(R)-pacing can be harmful to some patients because dyssynchronous contraction of the left ventricular (LV) walls may compromise myocardial performance and lead to heart failure.
 A new pacemaker type has been developed to treat patients with congestive heart failure. These pacemakers are connected to leads in the right atrium and ventricle. In addition a third lead is inserted transvenously through the coronary sinus to the lateral wall of the LV making it feasible to pace both ventricles at the same time. This modus, biventricular (BIV)-pacing results in reduction of LV dyssynchrony. Patients presently considered to be eligible for BIV-pacing have predominant heart failure and low ejection fraction (EF). Randomized trials have shown improvement in heart failure symptoms and reduced mortality during BIV-pacing in such patients.


Main hypotheses of the Ph.D. studies:
- DDD(R)-pacing increases LV dyssynchrony and reduces LVEF as compared to AAI(R)-pacing in patients with sick sinus syndrome. (Study 1)
- DDD(R)-pacing increases LV dyssynchrony and reduces LVEF as compared to
BIV-pacing in patients with high grade AV-block. (Study 2)
Methods: Tissue-Doppler modalities were used for detection and analysis of the extension of myocardium with delayed longitudinal contraction (DLC) representing dyssynchrony. Three-dimensional echocardiography was used to measure LVEF. Data at baseline and after 12 months of pacing were reported as mean ± SD if distributed normally, otherwise as median with first and third quartile in brackets.

Material and results:
In study 1, 50 consecutive patients with sick sinus syndrome were randomized to either AAI(R)- or DDD(R)-pacing. Dyssynchrony increased significantly in the DDD(R)-group from baseline before pacemaker implantation (1.3±1.4 segments with DLC per patient) to the 12 months follow-up (2.1±1.5 segments with DLC per patient; p<0.05). No change was observed in the AAI(R)-group (1.6±2.1 vs. 1.3±1.9 segments with DLC per patient, NS). LVEF decreased significantly in the DDD(R)-group from baseline (63.6(60.8-69.9)%) to the 12 months follow-up (58.3(56.1-65.7)%, p<0.05), while no change was observed in the AAI(R)-group (61.3(58.9-67.9)% at baseline vs. 62.5(56.8-67.4)% at the 12 months follow-up, NS). A modest increase of p-NTproBNP was observed in the DDD(R)-group (78±85 pmol/l to 86±125 pmol/l, NS), whereas a significantly decrease was found in the AAI(R)-group (120±178 pmol/l to 57±79 pmol/l, baseline and 12 months follow-up, respectively; p<0.05).
In study 2, 50 patients with high grade AV-block were randomized to either DDD(R)- or BIV-pacing. Dyssynchrony was more prominent in the DDD(R)-group than in the BIV-group already at the baseline recording obtained within 12 hours of pacemaker implantation (2.2±2.2 vs. 1.4±1.3 segments with DLC per patient, NS) and the difference became significant at the 12 months follow-up (1.8±1.9 vs. 0.8±0.9 segments with DLC per patient, p<0.05). In the DDD(R)-group LVEF decreased significantly from 59.7(57.4-61.4)% at baseline to 57.2(52.1-60.6)% at the 12 months follow-up (p<0.05). LVEF remained unchanged in the BIV-group (58.9(47.1-61.7)% at baseline vs. 60.1(55.2-63.3)% after 12 months (NS)). The p-NTproBNP was unchanged in the DDD(R)-group during follow-up (122±178 pmol/l vs. 91±166 pmol/l, NS) but decreased significantly in the BIV-group (from 198±505 pmol/l to 86±95 pmol/l after 12 months, p<0.05).
 In a third study (Study 3), inter- and intra-operator variability of 3-dimensional echocardiography was studied in 14 randomly selected patients. Both the inter-operator (mean difference 1.0±3.5%) and intra-operator variability study (mean difference 0.0±3.4%) showed excellent concordance for determination of LVEF.
 In Study 4 the intra-observer and intra-operator variability of DLC was expressed as: 1) the variability of the number of segments with DLC per patient and 2) the agreement of presence or absence of DLC in each and all of the 16 LV-segments. The mean difference of the number of segments with DLC per patient in the intra-operator analysis (0.6 ±1.1) and the intra-observer analysis (-0.3 ±0.9) seemed to be satisfactory. For the consideration of each individual segment the overall agreement was 86.6% (95% confidence interval: 82-91) for intra-operator and 90.2% (95% confidence interval: 84-96) for intra-observer variability.
 Study 5 showed that pacemaker implantation did not seem to affect measurement of p-NT-proBNP.

Conclusions:
The present Ph.D.-study evaluated the impact of conventional DDD(R)-pacing on LV function as compared to 1) AAI(R)-pacing in patients with sick sinus syndrome (Study 1) and 2) to BIV-pacing in patients with AV-block (Study 2). Both AAI(R)- and BIV-pacing were superior to DDD(R)-pacing regarding presence of regional LV dyssynchrony and overall LV performance. It was also documented that 3-dimensional echocardiography was a reproducible technique for quantification of LVEF, the primary end-point of Study 1 and 2. DLC variability seemed in the present studies to be satisfactory to quantify LV dyssynchrony. The level of p-NTproBNP is known to reflect the degree of heart failure. In Study 1 and 2 the superiority of AAI(R)- and BIV-pacing as compared to DDD(R)-pacing was supported by the significant reduction of p-NTproBNP in the AAI(R)- and BIV-group after 12 months. Pacemaker insertion in it self did not seem to affect p-NT-proBNP.
 The finding of dyssynchrony during RV-pacing in Study 1 supports experimental studies in animals. Study 2 is the first to show that patients with high grade AV-block may benefit from BIV-pacemakers. The study supports a long-term perspective of offering BIV-pacemakers to patients with AV-block eligible for pacemaker treatment, but large-scale trials with clinical endpoints are needed before a general recommendation can be proposed.