Cardiac resynchronisation therapy optimisation strategies: systematic classification, detailed analysis, minimum standards and a roadmap for development and testing.

In this article an international group of CRT specialists presents a comprehensive classification system for present and future schemes for optimising CRT. This system is neutral to the measurement technology used, but focuses on little-discussed quantitative physiological requirements. We then present a rational roadmap for reliable cost-effective development and evaluation of schemes. A widely recommended approach for AV optimisation is to visually select the ideal pattern of transmitral Doppler flow. Alternatively, one could measure a variable (such as Doppler velocity time integral) and "pick the highest". More complex would be to make measurements across a range of settings and "fit a curve". In this report we provide clinicians with a critical approach to address any recommendations presented to them, as they may be many, indistinct and conflicting. We present a neutral scientific analysis of each scheme, and equip the reader with simple tools for critical evaluation. Optimisation protocols should deliver: (a) singularity, with only one region of optimality rather than several; (b) blinded test-retest reproducibility; (c) plausibility; (d) concordance between independent methods; and (e) transparency, with all steps open to scrutiny. This simple information is still not available for many optimisation schemes. Clinicians developing the habit of asking about each property in turn will find it easier to win now down the broad range of protocols currently promoted. Expectation of a sophisticated enquiry from the clinical community will encourage optimisation protocol-designers to focus on testing early (and cheaply) the basic properties that are vital for any chance of long term efficacy.

Acute hemodynamic benefits of biventricular and single-site systemic ventricular pacing in patients with a systemic right ventricle.

BACKGROUND: Patients treated by atrial redirection surgery (Senning or Mustard procedure) for transposition of the great arteries (TGA) have an important risk for heart failure caused by dysfunction of the systemic right ventricle. Conventional nonsystemic ventricular pacing (non-systVP) may even further increase this risk. OBJECTIVE: We investigated the effects of endocardial non-systVP, biventricular pacing (BiVP), and single-site systemic ventricular pacing (systVP) on systolic cardiac pump function in patients with TGA and status post atrial redirection surgery (SenningMustardTGA). METHODS: During clinically indicated catheterization in 9 patients with SenningMustardTGA, endocardial ventricular stimulation (overdrive DDD mode; 80-90 beats/min) was applied with temporary pacing leads at the nonsystemic and the systemic ventricle. Acute changes in the maximal rate of pressure rise (dP/dtmax) and systolic pressure of the systemic ventricle, as induced by non-systVP, systVP, and BiVP compared to reference, were assessed with a pressure wire within the systemic ventricle. Reference was AAI pacing with a similar heart rate (n = 7) or non-systVP at a lower heart rate than that during stimulation at experimental sites (85 beats/min vs 90 beats/min; n = 2). RESULTS: Systemic dP/dtmax and systolic ventricular pressure were significantly higher during systVP (+15.6% and +5.1%, respectively) and BiVP (+14.3% and +4.9%, respectively, compared with non-systVP). In 6 of 7 patients, systemic dP/dtmax was higher during BiVP and systVP than during AAI pacing. CONCLUSIONS: In a population of patients with SenningMustardTGA, acute hemodynamic effects of endocardial systVP and BiVP were significantly and equally better than those of non-systVP. In some patients, systVP and BiVP might even be better than ventricular activation by the intrinsic conduction system.

Permanent cardiac pacing in children: choosing the optimal pacing site: a multicenter study.

BACKGROUND: We evaluated the effects of the site of ventricular pacing on left ventricular (LV) synchrony and function in children requiring permanent pacing. METHODS AND RESULTS: One hundred seventy-eight children (aged <18 years) from 21 centers with atrioventricular block and a structurally normal heart undergoing permanent pacing were studied cross-sectionally. Median age at evaluation was 11.2 (interquartile range, 6.3-15.0) years. Median pacing duration was 5.4 (interquartile range, 3.1-8.8) years. Pacing sites were the free wall of the right ventricular (RV) outflow tract (n=8), lateral RV (n=44), RV apex (n=61), RV septum (n=29), LV apex (n=12), LV midlateral wall (n=17), and LV base (n=7). LV synchrony, pump function, and contraction efficiency were significantly affected by pacing site and were superior in children paced at the LV apex/LV midlateral wall. LV dyssynchrony correlated inversely with LV ejection fraction (R=0.80, P=0.031). Pacing from the RV outflow tract/lateral RV predicted significantly decreased LV function (LV ejection fraction <45%; odds ratio, 10.72; confidence interval, 2.07-55.60; P=0.005), whereas LV apex/LV midlateral wall pacing was associated with preserved LV function (LV ejection fraction ≥55%; odds ratio, 8.26; confidence interval, 1.46-47.62; P=0.018). Presence of maternal autoantibodies, gender, age at implantation, duration of pacing, DDD mode, and QRS duration had no significant impact on LV ejection fraction. CONCLUSIONS: The site of ventricular pacing has a major impact on LV mechanical synchrony, efficiency, and pump function in children who require lifelong pacing. Of the sites studied, LV apex/LV midlateral wall pacing has the greatest potential to prevent pacing-induced reduction of cardiac pump function.

Late recovery of atrioventricular conduction after postsurgical chronic atrioventricular block is not exceptional.

OBJECTIVE: Postsurgical atrioventricular block may complicate surgery for congenital heart defects and is generally considered permanent when persisting longer than 14 days after surgery. In this study, we evaluate the occurrence of spontaneous late recovery of atrioventricular conduction in postsurgical chronic atrioventricular block and discuss its clinical implications. METHODS: We retrospectively reviewed all cardiac surgical procedures on cardiopulmonary bypass between January 1993 and November 2010 in subjects younger than 18 years. Patients with postsurgical advanced second- or third-degree atrioventricular block persisting longer than 14 days after surgery were included. RESULTS: Of a total of 2850 cardiac surgical procedures on cardiopulmonary bypass, 59 (2.1%) were immediately complicated by chronic postsurgical atrioventricular block of advanced second (n = 4) or third degree (n = 55). In another 6 patients (0.2%), late occurrence of chronic advanced second- (n = 3) or third-degree (n = 3) atrioventricular block, without signs of any etiology other than previous surgery, was seen 0.4 to 10 years after surgery (median, 5.7 years). Late (>2 weeks) regression to either completely normal atrioventricular conduction or asymptomatic first-degree atrioventricular block occurred 3 weeks to 7 years (median, 3.1 years) after surgery in 7 (12%) patients with immediate postsurgical chronic atrioventricular block. CONCLUSIONS: Complete recovery of atrioventricular conduction or regression to asymptomatic first-degree atrioventricular block occurred in 12% of patients with postsurgical chronic second- or third-degree atrioventricular block. To prevent unnecessary adverse side effects of chronic ventricular pacing and to prolong battery longevity, ventricular pacing should be minimized in patients with recovered normal atrioventricular conduction.

The role of echocardiography in the assessment of right ventricular systolic function in patients with transposition of the great arteries and atrial redirection.

BACKGROUND: Although dysfunction of the systemic right ventricle (RV) in patients with complete transposition of the great arteries (TGA) after atrial redirection by Mustard or Senning procedures is well recognized, there are few data on systemic RV geometry and function. Echocardiography is a widely available imaging technique that is particularly suitable for clinical follow-up because of its non-invasive nature, low cost and lack of ionizing radiation. AIM: To examine the feasibility and variability of transthoracic echocardiography variables in the assessment of the systemic RV. METHODS: Multivariable transthoracic echocardiographic analysis, including assessment of global function variables (RV ejection fraction [RVEF; Simpson's method], RV fractional shortening [RVFS] and dP/dt), longitudinal function variables (tricuspid annular plane systolic excursion [TAPSE], peak systolic velocity at the junction of the RV free wall and the tricuspid annulus, assessed with pulsed tissue Doppler imaging [S' TDI]), tricuspid regurgitation and asynchrony, was performed in 35 consecutive patients with TGA after atrial redirection. Functional variables were compared with magnetic resonance imaging (MRI). Inter- and intraobserver echocardiographic analysis variability was assessed in ten randomly selected cases. RESULTS: Global and longitudinal function variables were not correlated with RVEF calculated by MRI, except for S' TDI, which was weakly correlated (P = 0.02, r = 0.37). Asynchrony assessment was feasible in all patients. Inter- and intraobserver echocardiographic analysis variability was high for RVEF, RVFS and dP/dt (> 10%), and low for TAPSE and S' TDI (5%). CONCLUSION: Owing to geometric changes, presumed contractility pattern shift and retrosternal position, conventional echocardiographic variables are not relevant for RV function assessment. Assessment of asynchrony and tricuspid regurgitation is easily feasible in routine practice and highly reproducible. Echocardiography does not permit complete assessment of the systemic RV after atrial redirection but is fully complementary with MRI and should not be abandoned. Future improvements in transducers and dedicated software should permit major improvements in the near future.

Large right ventricular fibroma in a 6-month-old infant.

This report describes the case of a 6-month-old girl with a large cardiac fibroma in the right ventricle. Ventricular tachycardia associated with the fibroma was successfully treated with amiodarone. At the age of 3 years, surgical resection was indicated because of right ventricular outflow tract obstruction caused by progression of the tumor. The fibroma was successfully resected, and further follow-up evaluation was uneventful.

Effects of nonsystemic ventricular pacing in patients with transposition of the great arteries and atrial redirection.

INTRODUCTION: Ventricular pacing may add additional risk for right ventricular (RV) dysfunction in patients with transposition of the great arteries (TGA) and atrial redirection. The aim of our study was to evaluate the effects of long-term nonsystemic ventricular pacing on cardiac function, dyssynchrony, and clinical performance in patients with systemic RV. METHODS AND RESULTS: Forty-six adults with TGA and atrial redirection, of whom 11 were permanently paced at the nonsystemic ventricle, underwent assessment of clinical status and exercise stress testing, as well as echocardiography to assess parameters of RV function and dyssynchrony. In paced patients, median NYHA functional class was II, which was significantly higher than in nonpaced patients (median class I; P = 0.002). Maximum performance and peak oxygen consumption on exercise testing were significantly lower in paced patients when compared with nonpaced patients (100 ± 30 vs 120 ± 32 W and 22 ± 6 vs 27 ± 7 mLO(2)/kg/min, respectively; P < 0.05 for both). On echocardiography, RV shortening fraction (27 ± 11 vs 33 ± 10%), RV ejection fraction (39 ± 7 vs 44 ± 10%) and RV dP/dt(max) (891 ± 470 vs 1,024 ± 318 mmHg/s) were significantly lower (P < 0.05 for all) in paced versus nonpaced patients. Inter- and intraventricular dyssynchrony was most pronounced in the paced group (99 ± 10 vs 25 ± 9 ms and 70 ± 29 vs 21 ± 15 ms, respectively; P < 0.001 for both). CONCLUSIONS: Long-term pacing of the nonsystemic ventricle in patients with atrial switch for TGA was associated with significantly impaired functional status, exercise capacity, and systemic ventricular function.

Impact of the permanent ventricular pacing site on left ventricular function in children: a retrospective multicentre survey.

BACKGROUND: Chronic right ventricular (RV) pacing is associated with deleterious effects on cardiac function. OBJECTIVE: In an observational multicentre study in children with isolated atrioventricular (AV) block receiving chronic ventricular pacing, the importance of the ventricular pacing site on left ventricular (LV) function was investigated. METHODS: Demographics, maternal autoantibody status and echocardiographic measurements on LV end-diastolic and end-systolic dimensions and volumes at age <18 years were retrospectively collected from patients undergoing chronic ventricular pacing (>1 year) for isolated AV block. LV fractional shortening (LVFS) and, if possible LV ejection fraction (LVEF) were calculated. Linear regression analyses were adjusted for patient characteristics. RESULTS: From 27 centres, 297 children were included, in whom pacing was applied at the RV epicardium (RVepi, n = 147), RV endocardium (RVendo, n = 113) or LV epicardium (LVepi, n = 37). LVFS was significantly affected by pacing site (p = 0.001), and not by maternal autoantibody status (p = 0.266). LVFS in LVepi (39 ± 5%) was significantly higher than in RVendo (33 ± 7%, p < 0.001) and RVepi (35 ± 8%, p = 0.001; no significant difference between RV-paced groups, p = 0.275). Subnormal LVFS (LVFS < 28%) was seen in 16/113 (14%) RVendo-paced and 21/147 (14%) RVepi-paced children, while LVFS was normal (LVFS ≥ 28%) in all LVepi-paced children (p = 0.049). These results are supported by the findings for LVEF (n = 122): LVEF was <50% in 17/69 (25%) RVendo- and in 10/35 (29%) RVepi-paced patients, while LVEF was ≥ 50% in 17/18 (94%) LVepi-paced patients. CONCLUSION: In children with isolated AV block, permanent ventricular pacing site is an important determinant of LV function, with LVFS being significantly higher with LV pacing than with RV pacing.

Chronic ventricular pacing in children: toward prevention of pacing-induced heart disease.

In children with congenital or acquired complete atrioventricular (AV) block, ventricular pacing is indicated to increase heart rate. Ventricular pacing is highly beneficial in these patients, but an important side effect is that it induces abnormal electrical activation patterns. Traditionally, ventricular pacemaker leads are positioned at the right ventricle (RV). The dyssynchronous pattern of ventricular activation due to RV pacing is associated with an acute and chronic impairment of left ventricular (LV) function, structural remodeling of the LV, and increased risk of heart failure. Since the degree of pacing-induced dyssynchrony varies between the different pacing sites, 'optimal-site pacing' should aim at the prevention of mechanical dyssynchrony. Especially in children, generally paced from a very early age and having a perspective of life-long pacing, the preservation of cardiac function during chronic ventricular pacing should take high priority. In the perspective of the (patho)physiology of ventricular pacing and the importance of the sequence of activation, this paper provides an overview of the current knowledge regarding possible alternative sites for chronic ventricular pacing. Furthermore, clinical implications and practical concerns of the various pacing sites are discussed. The review concludes with recommendations for optimal-site pacing in children.

When is an optimization not an optimization? Evaluation of clinical implications of information content (signal-to-noise ratio) in optimization of cardiac resynchronization therapy, and how to measure and maximize it.

Impact of variability in the measured parameter is rarely considered in designing clinical protocols for optimization of atrioventricular (AV) or interventricular (VV) delay of cardiac resynchronization therapy (CRT). In this article, we approach this question quantitatively using mathematical simulation in which the true optimum is known and examine practical implications using some real measurements. We calculated the performance of any optimization process that selects the pacing setting which maximizes an underlying signal, such as flow or pressure, in the presence of overlying random variability (noise). If signal and noise are of equal size, for a 5-choice optimization (60, 100, 140, 180, 220 ms), replicate AV delay optima are rarely identical but rather scattered with a standard deviation of 45 ms. This scatter was overwhelmingly determined (ρ = -0.975, P < 0.001) by Information Content, [Formula: see text], an expression of signal-to-noise ratio. Averaging multiple replicates improves information content. In real clinical data, at resting, heart rate information content is often only 0.2-0.3; elevated pacing rates can raise information content above 0.5. Low information content (e.g. <0.5) causes gross overestimation of optimization-induced increment in VTI, high false-positive appearance of change in optimum between visits and very wide confidence intervals of individual patient optimum. AV and VV optimization by selecting the setting showing maximum cardiac function can only be accurate if information content is high. Simple steps to reduce noise such as averaging multiple replicates, or to increase signal such as increasing heart rate, can improve information content, and therefore viability, of any optimization process.

Comparison of a non-invasive arterial pulse contour technique and echo Doppler aorta velocity-time integral on stroke volume changes in optimization of cardiac resynchronization therapy.

AIMS: We investigated the accuracy and feasibility of a non-invasive arterial pulse contour technique for continuous measurement of stroke volume (SV) in optimization of atrioventricular (AV) delay in cardiac resynchronization therapy (CRT), by comparing SV changes assessed by Nexfin CO-Trek® (Nexfin) and echo Doppler aortic velocity-time integral (VTIao). Furthermore, we investigated whether AV-delay optimization increases the effect of CRT when compared with a default AV delay (120 ms). METHODS AND RESULTS: In 23 CRT patients, biventricular pacing (BiVP) was applied at various AV delays, while recording 10 beats preceding BiVP (baseline) and the first 10 BiVP beats, for both methods in parallel. Agreement between Nexfin and VTIao measurements was evaluated (Bland-Altman) on beat-to-beat changes in SV, as well as on effects of BiVP (averaged over 8 beats) at various AV delays. Individual optimal AV delays, for Nexfin (AVopt-n) and VTIao (AVopt-ao), were derived from the second-order polynomial fitted to the effect measurements of 20 patients. In 252 episodes assessed, the difference between measurements (= Nexfin - VTIao) was -0.6 ± 8.1% for beat-to-beat SV changes and -1.3 ± 7.3% for effects of BiVP. Optimal AV delays for Nexfin were well related to AVopt-ao (R(2) = 0.69). The effect (%) of BiVP at the optimal AV delay was significantly larger than at the default AV delay: median difference (range) being +6.3% (0.1-14.4%; P < 0.001) for VTIao and +4.7% (0.0-14.0%; P < 0.001) for Nexfin. CONCLUSION: Individual AV optimization increases the effect of CRT. Nexfin is a promising tool in individual CRT optimization, as Nexfin agrees with VTIao on measuring beat-to-beat SV changes and on assessing relative effects of BiVP on SV at various AV delays.

Beneficial effects of biventricular pacing in chronically right ventricular paced patients with mild cardiomyopathy.

AIMS: To investigate whether cardiac resynchronization therapy (CRT) by means of biventricular (BiV) pacing can improve left ventricular (LV) function, remodelling and clinical status in chronically right ventricular (RV) paced patients with mild cardiomyopathy. METHODS AND RESULTS: Thirty-six chronically (10 +/- 7 years) RV paced patients with left ventricular ejection fraction (LVEF) < 40% or LVEDD > 55 mm, without an established indication for CRT, were subjected to 6 months RV and BiV pacing in a patient-blinded, randomized crossover design. Treatment-effects of BiV pacing were evaluated for LV function, LV remodelling and clinical status. As compared with RV pacing, BiV pacing significantly improved LV function (LVEF 46 +/- 12 vs. 39 +/- 12% and LVFS 24 +/- 7 vs. 21 +/- 7%) and reduced LV end-diastolic and end-systolic diameters and volumes (LVEDD 56 +/- 8 vs. 59 +/- 8 mm, LVESD 43 +/- 8 vs. 47 +/- 9 mm, LVEDV 132 +/- 65 vs.144 +/- 62 mL and LVESV 77 +/- 56 vs. 92 +/- 55 mL, respectively). In 19 patients (53%) response to BiV pacing was clinically relevant, defined as LVESV reduction >15%. BiV pacing also significantly improved NYHA classification. CONCLUSION: BiV pacing following chronic RV pacing may improve LV function and reverse LV remodelling in patients with relatively mild LV dysfunction or remodelling. Hence, upgrade to BiV pacing might be considered in chronically RV paced patients with mild cardiomyopathy.

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.

Chronic left ventricular pacing preserves left ventricular function in children.

Chronic right ventricular (RV) pacing can induce structural and functional cardiac deterioration. Because animal studies showed a benefit of left ventricular (LV) over RV pacing, this study compared the effects of chronic RV and LV pacing in children. Retrospectively, echocardiographic data were evaluated from 18 healthy children (control subjects) and from children undergoing chronic epicardial RV pacing (7 RVP) or LV pacing (7 LVP). Assessment included LV end-diastolic wall thickness (LVEDWT) and end-systolic wall thickness (LVESWT) as well as LV end-diastolic diameter (LVEDD) and end-systolic diameter (LVESD). The shortening fraction and eccentricity index (LV diameter/2xLV wall thickness) were calculated as measures of LV function and eccentricity, respectively. Duration of QRS and septal posterior wall motion delay (SPWMD) were used as measures of electrical and mechanical dyssynchrony, respectively. A p value less than 0.05 determined significance. As the findings showed, LVEDD, LVESD, LVEDWT, and LVESWT were not significantly different between the groups. The shortening fraction was significantly lower in the RVP (21.7%+/-6.0%) than in the LVP (32.2%+/-5.2%) or control (29.3%+/-4.3%) children. The systolic LV eccentricity index was significantly larger in the RVP (1.8+/-0.2) than in the LVP (1.4+/-0.1) or control (1.4+/-0.2) children. The SPWMD was significantly larger in the RVP (338+/-20 ms) than in the LVP (-16+/-14 ms) or control (-5+/-35 ms) group, whereas QRS duration was similarly longer in the RVP (157+/-10 ms) and LVP (158+/-22 ms) groups compared than in the control group (69+/-7 ms). The authors conclude that LV function in children is preserved by chronic pacing at the LV lateral wall.