Plymen, CM; (2014) The right ventricle in Adult Congenital Heart Disease. Doctoral thesis , UCL (University College London).

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Abstract

Heart failure (HF) and sudden cardiac death (SCD) in congenital heart disease (CHD) is prevalent and can relate to abnormal right ventricular (RV) physiology and abnormalities of QRS duration, and QRS, JT and QT dispersion (d). Characterising disease and identifying factors that may predict adverse outcome in those with either a subpulmonary or subsystemic RV, as well as investigating potential avenues to ameliorate abnormal RV physiology is necessary to improve outcomes in this young population. I undertook several studies during the course of this Thesis to examine and further understand these two separate physiological substrates: In the first I studied the effect of isolated percutaneous (PPVI) pulmonary valve implantation on surface ECG parameters. PPVI represents a pure model of RV mechanical and electrophysiological changes post replacement as compared to surgical replacement: Ninety nine PPVI procedures in patients with CHD (aged 23.1±10 yrs) were studied pre, post and 1-year following PPVI with serial ECG’s and echocardiography/ magnetic resonance imaging (CMR). 43% had pulmonary stenosis, 27% pulmonary regurgitation (PR) and 29% mixed lesions. In those with predominantly PR (n=26), QRS duration decreased significantly (135±27 to 128±29ms; p=0.007). However, in the total cohort no significant change in QRS duration at 1 year was observed (137±29 to 134±29ms). QTc, QRSd, QTd and JTd all significantly reduced at 1 yr (p≤0.001). RV EDV correlated with pre-procedure QRS duration (r=0.34; p<0.002) but there was no correlation after PPVI. This is the first study to report electrical remodelling following isolated PPVI and it confirms that reductions in QRS duration occur post PPVI in PR, as reported for equivalent surgical cohorts. Further, increased homogeneity of repolarisation, in combination with improved conduction, may reduce arrhythmic events in congenital cardiac patients with pulmonary valvular disease. My second study sought to create an epicardial electroanatomic map of the RV and then apply post-operative targeted single and dual site RV temporary pacing with measurement of haemodynamic parameters. I wished to determine the potential role of cardiac resynchronization therapy (CRT) in the setting of RV dysfunction as little is known regarding the potential benefits of CRT in this setting. Sixteen adults (age=32±8 yrs, 6M; 10F) with right bundle branch block (RBBB) and repaired tetralogy of Fallot (ToF; n=8) or corrected congenital pulmonary stenosis (n=8) undergoing surgical pulmonary valve replacement (PVR) for PR underwent intra-operative epicardial RV mapping and haemodynamic assessment of random pacing configurations including site of latest RV activation. I found that the commonest site of latest activation was the RV free wall & dual chamber (DDD) pacing here, alone or combined with RV apical pacing, resulted in significant increases in cardiac output (CO) vs AAI pacing (p<0.01 all measures). DDD RV alternative site pacing significantly improved CO by 16 % vs AAI, and 8.5% versus DDD RV apical pacing (p=0.02). Single site RV pacing targeted to the region of latest activation in patients with RBBB undergoing PVR thus induces acute improvements in haemodynamics and implies that targeted pacing in such patients has therapeutic potential both post-operatively and in the long term. QRS duration is a strong predictor of survival in acquired left ventricular dysfunction, but equivalent data in those with a systemic RV is lacking. My next studies investigated not only the relationship between ECG parameters, arrhythmia burden and outcome in adults with transposition of the great arteries (TGA) late after atrial switch repair, but also the interrelationships between various HF markers in this cohort. Adults with Senning or Mustard palliation of TGA under follow up at a dedicated congenital HF clinic and 13 similar adults who suffered a cardiac death were included for study. Patients were subdivided by arrhythmic history, surgical intervention and death. Assessment included symptom assessment, venous blood sampling for circulating N-terminal pro brain natriuretic peptide (NT-proBNP) levels, measurement of surface ECG and CMR for the assessment of RV systolic function and determination of indexed RV volumes. I found that QRS duration (p=0.0003) and QTc interval (p=0.0009) increase significantly with changing arrhythmia subtype, and that both QRS and QTc were independently associated with increased risk of death: for 1ms increase in QRS HR 15 [95% CI 3.3-68.6] and for QTc HR 10.7 [95% CI 2.3-49] (p<0.0001 for both). QRS >104ms and QTc >406ms had a sensitivity/specificity for predicting death of 96%/66% and 96%/56% respectively. Two year mortality was 36% when QRS<104ms and 88% when >104ms (p<0.0001 for difference). Further, compared to those with uncomplicated surgery, patients with complex surgical history had higher NT-proBNP levels (55±26 vs 20±35pmol/L; P=0.002) and longer QRS duration (116±28ms vs 89±11ms; P=0.0004) whilst showing no difference in NYHA class and RV function. There was a significant relationship between diastolic and systolic RV volumes and both NT-proBNP levels (r=0.43, P=0.01; r=0.53, P=0.001 respectively) and QRS duration (r=0.47, P=0.004; r=0.53, P=0.001 respectively). These findings suggest that QRS width and corrected QTc interval on surface ECG are associated with increased risk of death in adults late after atrial switch repair of TGA. Given that a QRS of only 104ms defines a high risk population, careful examination of the ECG is desirable in all patients and therapy to reduce risk attempted. Further, together with these simple surface ECG parameters, circulating NT-proBNP levels constitute safe, cost effective and widely available surrogate markers of systemic RV function and provide additional information on heart failure status. Both measures hold promise as prognostic markers and their association with long-term outcome should be determined. Lastly, I examined the mechanisms of late RV failure and studied their relationship to subjective quality of life assessment as this are poorly characterised. Equilibrium Contrast CMR imaging was used to quantify extracellular volume (ECV) in the septum and RV free wall of adults presenting to a specialist clinic late after atrial redirection surgery for TGA. These were compared to age and sex matched healthy volunteers. Patients were also assessed with a standardised CMR protocol, NT-proBNP and surface ECG measurement, and cardiopulmonary exercise (CPEX) testing. Patients also completed a Minnesota Living With Heart Failure Questionnaire (MLHFQ) self assessment. I determined that mean septal ECV was significantly higher in patients than controls (0.254±0.036, vs 0.230±0.032; p=0.03). NT-proBNP positively related to septal ECV (p=0.04; r=0.55) but chronotropic index (CI) during CPEX testing negatively related to ECV (p=0.04; r=-0.58). No relationship was seen with other CMR or CPEX parameters. Median MLHFQ score was 6(2-19), median NT-pro BNP 24 (16-43) and mean peak VO2 24±7mL/kg/min. There was a significant positive correlation between MLHFQ score and NT-proBNP (p=0.001, r=0.34) and a significant negative correlation with peak VO2 (p=0.001, r=0.49. ). Septal interstitial expansion is seen in adults late after atrial redirection surgery for TGA. It correlates well with NT-proBNP and CI and may have a role in the development of RV systolic impairment. The MLHFQ correlates highly with NT-proBNP and exercise capacity in patients with systemic RV impairment. The ability of the MLHFQ in predicting HF events and prognosis in adults with CHD needs further evaluation.

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