Jan Janousek

Cardiac resynchronisation therapy in paediatric and congenital heart disease: differential effects in various anatomical and functional substrates

Background: Cardiac resynchronisation therapy (CRT) is increasingly used in children in a variety of anatomical and pathophysiological conditions, but published data are scarce. Objective: To record current practice and results of CRT in paediatric and congenital heart disease. Design: Retrospective multicentre European survey. Setting: Paediatric cardiology and cardiac surgery centres. Patients: One hundred and nine patients aged 0.24–73.8 (median 16.9) years with structural congenital heart disease (nu200a=u200a87), congenital atrioventricular block (nu200a=u200a12) and dilated cardiomyopathy (nu200a=u200a10) with systemic left (nu200a=u200a69), right (nu200a=u200a36) or single (nu200a=u200a4) ventricular dysfunction and ventricular dyssynchrony during sinus rhythm (nu200a=u200a25) or associated with pacing (nu200a=u200a84). Interventions: CRT for a median period of 7.5 months (concurrent cardiac surgery in 16/109). Main outcome measures: Functional improvement and echocardiographic change in systemic ventricular function. Results: The z score of the systemic ventricular end-diastolic dimension decreased by median 1.1 (p<0.001). Ejection fraction (EF) or fractional area of change increased by a mean (SD) of 11.5 (14.3)% (p<0.001) and New York Heart Association (NYHA) class improved by median 1.0 grade (p<0.001). Non-response to CRT (18.5%) was multivariably predicted by the presence of primary dilated cardiomyopathy (pu200a=u200a0.002) and poor NYHA class (pu200a=u200a0.003). Presence of a systemic left ventricle was the strongest multivariable predictor of improvement in EF/fractional area of change (p<0.001). Results were independent of the number of patients treated in each contributing centre. Conclusion: Heart failure associated with ventricular pacing is the largest indication for CRT in paediatric and congenital heart disease. CRT efficacy varies widely with the underlying anatomical and pathophysiological substrate.

Cyclic Mechanical Stretch Induces Cardiomyocyte Orientation and Polarization of the Gap Junction Protein Connexin43

Rationale: Cyclic mechanical stretch (CMS) is an important physiological and pathological factor in the heart. Objective: We examined whether CMS can affect localization of gap junctions with regard to the cell axis. Methods and Results: Neonatal rat cardiomyocytes were cultured (7 days) on flexible 6-well plates. Thereafter, cells were kept static or stimulated with CMS (1 Hz; 0, 10, 20% elongation) for 0, 24, or 48 hours (with or without 10 &mgr;mol/L PD98059, 5 &mgr;mol/L BIM I (bisindolylmaleimide I), 2 &mgr;mol/L H8 [N-(2-methlyamino-ethyl)-5-isoquinoline-sulfonamid], or 0.1 &mgr;mol/L angiotensin II. Additionally, cells were exposed to 24 hours of CMS followed by 24 hours of static recovery. CMS (24 hour, 10%) induced elongation of the cardiomyocytes and orientation 79±8° toward the stretch direction. Moreover, the distribution of connexin (Cx)43 together with N-cadherin changed, so that both proteins were accentuated at the cell poles, whereas in nonstretched cells, they were distributed around the cell without preferential localization. Additional angiotensin II reduced polar Cx43 accentuation. The CMS-induced changes in Cx43 were reversible within 24 hours after end of stretch, and could be completely prevented by the MEK1/2 inhibitor PD98059 but not by BIM I or H8. Moreover, stretch resulted in Cx43 protein and Cx43-mRNA upregulation and in a significant upregulation of the phosphorylated forms of ERK1/2, glycogen synthase kinase 3&bgr; and AKT. Furthermore, CMS resulted in a significant increase of the transcription factors activator protein 1 and CREB (cAMP response element–binding protein) in the nucleus. Conclusions: CMS results in self-organization of cardiomyocytes leading to elongated cells orientated transverse to the stretch axis, enhanced Cx43 expression and Cx43 accentuation at the cell poles. The Cx43-changes seem to depend on the ERK1/2 signaling cascade.

Predictors of left ventricular remodelling and failure in right ventricular pacing in the young.

Aims To identify risk factors for left ventricular (LV) dysfunction in right ventricular (RV) pacing in the young. Methods and results Left ventricular function was evaluated in 82 paediatric patients with either non-surgical (n = 41) or surgical (n= 41) complete atrioventricular block who have been 100% RV paced for a mean period of 7.4 years. Left ventricular shortening fraction (SF) decreased from a median (range) of 39 (24–62)% prior to implantation to 32 (8–49)% at last follow-up (P < 0.05). Prevalence of a combination of LV dilatation (LV end-diastolic diameter >+2z-values) and dysfunction (SF < 0.26) was found to increase from 1.3% prior to pacemaker implantation to 13.4% (11/82 patients) at last follow-up (P = 0.01). Ten of these 11 patients had progressive LV remodelling and 8 of 11 were symptomatic. The only significant risk factor for the development of LV dilatation and dysfunction was the presence of epicardial RV free wall pacing (OR = 14.3, P < 0.001). Other pre-implantation demographic, diagnostic, and haemodynamic factors including block aetiology, pacing variables, and pacing duration did not show independent significance. Conclusion Right ventricular pacing leads to pathologic LV remodelling in a significant proportion of paediatric patients. The major independent risk factor is the presence of epicardial RV free wall pacing, which should be avoided whenever possible.

Adverse effects of Wolff-Parkinson-White syndrome with right septal or posteroseptal accessory pathways on cardiac function

AIMSnWolff-Parkinson-White syndrome with right septal or posteroseptal accessory pathways causes eccentric septal mechanical activation and may provoke left ventricular (LV) dyssynchrony and dysfunction. The aim of the study was to evaluate the effect of radiofrequency catheter ablation (RFA) of the accessory pathways on LV function.nnnMETHODS AND RESULTSnRetrospectively, transthoracic echocardiography and electrocardiogram recordings were analysed in 34 patients (age: 14.2 +/- 2.5 years) with right septal or posteroseptal accessory pathways prior and after (median: 1 day) successful RFA. Results prior to RFA, LV ejection fraction was decreased (<55%) in 19/34 patients (56%). After RFA, QRS duration was normalized (129 +/- 23 vs. 90 +/- 11, P < 0.0001), LV function improved (ejection fraction: 50 +/- 10 vs. 56 +/- 4%, P = 0.0005) and septal-to-posterior wall motion delay as a global measure for LV dyssynchrony decreased (110 +/- 94 vs. 66 +/- 53, P = 0.012). Longitudinal two-dimensional strain evaluated in five patients demonstrated a decrease of left intraventricular mechanical delay from 292 +/- 125 to 118 +/- 37 ms after RFA.nnnCONCLUSIONnWolff-Parkinson-White syndrome with right septal or posteroseptal accessory pathways may cause LV dyssynchrony and jeopardize global LV function. Radiofrequency catheter ablation resulted in normalized QRS duration, mechanical resynchronization, and improved LV function. Even in the absence of arrhythmias, RFA of right septal or posteroseptal pathways may be considered in patients with significantly decreased LV function.

Cardiac Resynchronization Therapy in Pediatric and Congenital Heart Disease

Cardiac resynchronization therapy (CRT) is an emerging option for treating dyssynchrony‐associated heart failure in patients with pediatric or congenital heart disease. CRT has proved beneficial for both the acute manipulation of cardiac output after surgery for congenital heart defects and for the management of chronic systemic ventricular failure. Although there are no prospective and randomized trial data, retrospective series show that CRT is similarly effective for managing dyssynchrony‐associated heart failure in this younger population as it is for treating adults with ischemic and idiopathic dilated cardiomyopathy. The heterogeneity of anatomical and functional substrates in which CRT shows efficacy calls for further studies defining the usefulness of CRT in specific subgroups of patients.

Differential effects of the site of permanent epicardial pacing on left ventricular synchrony and function in the young: implications for lead placement

AIMSnTo analyse left ventricular (LV) synchrony and function with respect to the epicardial pacing site in the young.nnnMETHODS AND RESULTSnLeft ventricular function and synchrony (M-mode, speckle tracking) were evaluated during mid-term follow-up in 32 children with complete non-surgical (n = 15) or surgical (n = 17) atrioventricular block (structural heart disease in 21/32) paced from LV apex (n = 19), right ventricular (RV) apex (n = 7), and RV free wall (n = 6), respectively. Data are in the following order: LV apical, RV apical, and RV free wall pacing. Septal to posterior wall motion delay (SPWMD) = median 0, 69, and 136 ms (P < 0.001), septal to lateral mechanical delay = 54 +/- 29, 73 +/- 24, and 129 +/- 70 ms (P = 0.001), apical to basal mechanical delay = 96 +/- 37, 106 +/- 50, and 79 +/- 18 ms (P NS), and LV ejection fraction (LVEF) = 57 +/- 9, 49 +/- 12, and 33 +/- 10% (P < 0.001), respectively. Left ventricular ejection fraction correlated negatively with SPWMD (R(2) = 0.454, P < 0.001) and septal to lateral mechanical delay (R(2) = 0.320, P < 0.001) but not with apical to basal mechanical delay. Right ventricular free wall pacing (P = 0.014) and SPWMD (P = 0.044) were negative multivariable predictors of LVEF.nnnCONCLUSIONnCompared with other sites, LV apical pacing preserves septal to lateral LV synchrony and systolic function and may be the preferred epicardial pacing site in the young.

Normal limits for heart rate as established using 24-hour ambulatory electrocardiography in children and adolescents.

BACKGROUNDnTo the best of our knowledge, normal limits of heart rate with respect to gender, and as established using 24-hour ambulatory Holter electrocardiography, have yet to be published for the entire age range of children and adolescents.nnnOBJECTIVESnTo establish the normal limits for heart rate in newborns, infants, children, and adolescents of both genders.nnnPATIENTS AND METHODSnWe obtained 24-hour Holter recordings from 616 healthy subjects aged from birth to 20 years with structurally normal hearts. The subjects were not receiving medication, and had not been submitted to prior cardiac intervention. Off-line analysis was performed with Mars 8000 scanners, analysing 5 consecutive RR intervals by the software available for automatic calculation of heart rate. All subjects were in sinus rhythm. Best-fit non-linear regressions were applied to correlate age and gender with minimum and mean heart rate, as well as with maximal RR-interval, and to calculate the 5th, 25th, 75th and 95th percentiles.nnnRESULTSnWe observed significant gender-dependent differences in heart rate for persons aged 10 years and older, with the males exhibiting lower minimal and mean heart rates, and higher RR-intervals, than the females. Correlation of heart rate with age and gender could be established with sufficient accuracy using non-linear regression (p less than 0.0001): Minimum heart rate (male: R(2)=0.778, female: R(2) = 0.664) and mean heart rate (male: R(2) = 0.820, female: R(2) = 0.736) decreased with age, while the maximal RR-interval prolonged (male: R(2) = 0.562, female: R(2) = 0.486). Age and gender-related graphs of centiles were constructed.nnnCONCLUSIONSnHeart rate, as documented using Holter recodings, can be correlated with age and gender, permitting establishments of normal gender-specific limits for children and adolescents.

Coagulation profile and liver function in 102 patients after total cavopulmonary connection at mid term follow up

Objective: To examine coagulation factors and liver function test abnormalities in patients after total cavopulmonary connection (TCPC). Design: Cross sectional study comprising clinical and echocardiographic evaluation, and biochemical and coagulation profile screening. Setting: Tertiary referral centre. Methods: 102 patients aged 4–24 years (median 10 years) at one to eight years (median five years) after TCPC were examined. All patients were maintained on a low dose of aspirin. 96% of patients were in a good clinical condition (New York Heart Association class I or II). No intracardiac thrombi were detected on echocardiography and ventricular function was good in 91% of patients. Results: Total bilirubin was increased in 27% and γ glutamyltransferase in 54% of patients. Serum total protein, albumin, and prealbumin were normal in almost in all patients. Compared with the control group, patients after TCPC had significantly lower fibrinogen, factor V, factor VII, and protein C concentrations, prolonged international normalised ratio, and increased antithrombin III concentration. Factor V concentration was abnormally decreased in 35%, factor VII in 16%, and protein C in 28% of patients. Antithrombin III was increased in 23% of patients. Factor VII, factor V, protein C, and antithrombin III correlated significantly with serum prealbumin. There was also a significant correlation between procoagulant factor VII and both anticoagulant protein C and antithrombin III. Conclusions: Almost half of patients after TCPC had laboratory signs of mild cholestasis. Decreased liver synthesis of procoagulant and anticoagulant factors was observed but overall coagulation homeostasis appeared to be in balance in this selected group of patients with a good clinical outcome.

Simulation of congenital heart defects: a novel way of training in echocardiography

Background: Echocardiography is one of the most important diagnostic imaging modalities in paediatric cardiology. Owing to the large number of lesions, achieving expertise often requires years of training. Echocardiography is still taught using the apprenticeship model, which is time- and personnel consuming. Objectives: To extend the echocardiography simulator EchoCom to enable simulation of congenital heart lesions and validate it for training in paediatric echocardiography. Methods: The simulator consists of a life-size manikin, a dummy transducer with attached three-dimensional (3D) tracking system and a computer application. Transthoracic real-time (RT) 3D echocardiographic datasets were collected and embedded into the simulator. Two-dimensional images were calculated and resliced from these datasets according to the position of the tracking sensor. Ten RT 3D datasets of congenital heart lesions were selected for validation. Datasets were blinded and without additional information presented to 43 participants who were stratified according to their expertise (12 experts, 16 intermediates, 15 beginners). Participants were asked to list the relevant findings and make a diagnosis. Construct validation was tested comparing diagnostic performance for each group. Face and content validation were tested using a standardised questionnaire. Results: Participants judged the simulator as realistic and useful. The main drawback was the adult size of the manikin. The diagnostic performance of each group differed significantly proving construct validity. Conclusions: According to this validation the prototype simulator could make a significant contribution to training in the use of echocardiography in congenital heart disease.

Moderate versus deep hypothermia for the arterial switch operation — experience with 100 consecutive patients

OBJECTIVESnTo evaluate the impact of moderate versus deep perioperative hypothermia on postoperative morbidity in patients receiving the arterial switch operation (ASO).nnnMETHODSnOne hundred consecutive patients received the ASO from 9/98 to 4/06 using temperature-corrected full-flow moderate (M>24 degrees C, n=51) or deep hypothermic cardiopulmonary bypass (CPB) (D <20 degrees C, n=49). Complex TGA morphology was present in 33 patients (M: 27.4%, D: 38.8%, n.s.). Median age was 9 days (M) versus 10 days (D) and body weight was 3.5+/-0.7 kg (M) versus 3.6+/-0.9 kg (D) (both p=n.s.). Follow-up was 3.7+/-2.1 years.nnnRESULTSnLowest perioperative rectal temperature was 25.3+/-1.1 degrees C (M) versus 19.0+/-0.8 degrees C (D), p<0.001. Intraoperative blood transfusion (M: 231+/-47 ml, D: 252+/-112 ml, p=0.04) and postoperative lactate level (M: 3.2+/-1.3 mmol/l, D: 3.8+/-2.4 mmol/l, p=0.02) were lower under moderate hypothermia. One patient (D) suffered myocardial ischemia, required ECMO support and died. All other patients were safely weaned from CPB using dopamine (M: 3.0 microg/kg min, D: 3.4 microg/kg min, n.s.) and dobutamine (M: 5.6 microg/kg min, D: 6.7 microg/kg min, p=0.048). Secondary chest closure was performed in 41% (M) versus 59% (D) (p=0.04). Patients were extubated after 89 h (M) versus 126 h (D) (p=0.03). Under moderate hypothermia ICU stay (M: 8.4+/-4.7 days, D: 12.0+/-13.8 days, p=0.03) and hospital stay (M: 12.8+/-6.8 days, D: 20.7+/-15.5 days, p=0.001) were shorter. Five-year freedom from reoperation was 97.0% for simple and 85.2% for complex TGA with RVOT reconstruction in 4/6 patients.nnnCONCLUSIONSnThe ASO under full-flow moderate compared to deep hypothermia was advantageous regarding length of procedure and primary chest closure rate. Moderate hypothermia seemed to be beneficial for pulmonary recovery, length of chest tube drainage treatment and inotropic support. No worse early or long-term effects of moderate hypothermia were found.