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Project

Atrial septal defect: evaluation of the therapeutic approach in Belgium through a national database of congenital heart disease.

Atrial septal defect (ASD) represents approximately 10% of all congenital heart diseases (CHD) and is the third most common form of congenital heart defects.  The incidence of CHD in Belgium is 1%, with ASD accounting for 25% of the cases. (Data from the database of CHD UZ Leuven.)  A substantial shunt through the defect from the left to the rightatrium, causing a progressive volume overload of the right heart and pulmonary circulation, may lead to an initially reversible and later irreversible increase in pulmonary vascular resistance (PVR): the origin of pulmonary arterial hypertension (PAH).  This volume and pressure overload of the right heart may lead to heart failure and/or arrhythmias.  Finally, as PVR exceeds systemic resistance, the shunt is reversed (right-to-left shunt) leading to systemic arterial desaturation (and therelated consequences: polyglobulia, hyperuricemia, decreased renal function and abnormal coagulation): the Eisenmenger syndrome (ES).[1] Survival of patients with unrepaired ASDs is thought to be shortened and repair can avoid right ventricular (RV) failure, PAH, thrombo-embolic events and atrial dysrrhythmias. [2]  So, when the defect is discovered early, an ASD is usually closed in childhood, unless the defect is considered not to be clinically significant (< 5mm diameter and no RV volume overload). [3] However, even small ASDs might trigger the development of PAH. Although in some cases surgery remains the only option, percutaneous closure is now considered to be first line-treatment for secundum ASD, as it has similar success rates, lower complication rates and shorter length of hospital stay. [4,5]  Several reports stressed the importance of the implementation of national registries in order to optimize patient care by developing an efficient organizational structure, evidence based treatment protocols, and by assessing research and new treatment modalities.[6,7]  To obtain more structured national data and to create a forum for inter-universitary and inter-academic cooperation regarding adult CHD in Belgium, a national registry of Eisenmenger patients was initiated, which has recently been extended to ASD patients as well. Current guidelines recommend closure of the atrial shunt when substantial (pulmonary to systemic flow > 1,5/1), or for those shunts associated with RV volume overload, in the absence of severe PAH. [8]  Patients considered to have irreversible severe PAH are considered ineligible for shunt closure because of the risk of RV decompensation.  However, Balint et al. reported that transcatheter closure in patients with secundum ASD and moderate or severe PAH can be performed in selected subjects and is associated with good outcomes. [9]  Still, little is known Until which PVR or until what grade of PAH is an ASD still safely repairable? Some authors suspect the existence of masked PAH in patients with ASD.  These are patients with normal right heart pressures at rest, with a pathological increase during exercise.  Theres data supporting the notion that exercise-induced PAH is a mild and clinically relevant phase of the PAH spectrum.  If so, screening and early intervention may prevent progression of pulmonary vascular remodeling. [10]  Oelberg et al. showed that adults with ASD have reduced exercise performance which may be associated with an abnormal increase in pulmonary artery pressure during exercise.[11]  Whats the prevalence of masked PAH in corrected and non-corrected ASD patients?   Although an ASD seems an easilh a corrected ASD have a poorer prognosis than patients in a control group, especially in the presence of PAH, which confers an eightfold increased probability of functional limitations. In the Euroheart survey, PAH was present in 12% of patients with a closed ASD. [12]  Disease-targeting therapy to reduce PAH, such as prostanoids, endothelin receptor antagonists (ERAs) and phosphodiesterase (PDE) inhibitors, has already been used successfully as treatment for patients with PAH, including patients with ES.[13,14] Most studies until now only included patients with severe PAH, while light to moderate PAH is also related to functionality and outcome.[15] Whether it is useful to treat light to moderatePAH after correction of an ASD, in order to have a positive effect on functionality and outcome still needs to be evaluated. [4] If an ASDhasnt been closed, because of the assumption of a too highly elevated PVR, a conservative, non-medical, watchful-waiting approach is usually the treatment of choice. Consequently theres progressive disease and evolution of some patients to a typical ES. This leads to the question: Isit useful to associate selective pulmonary vasodilators in the case of a non-correctable ASD to slow down the increase in PVR and the related clinical complications? To determine surrogate endpoints to answer thesequestions, more insight in baseline characteristics of this patient population is needed. Recent data about clinical evaluation, the role of biochemical parameters, the value of echocardiography, and ergospirometry are scarce in this particular population; in this way, registries might help to identify measurable outcome variables.[16]      General hypothesis, specific aims    1. Evaluation of the usability of the national database of adult CHD, combined withthe epidemiologic description of Eisenmenger patients in Belgium. 2. Epidemiological description all ASD patients registered in Belgium, combined with identification of determinants of outcome, defined as clinical events (cardiac death, development of arrhythmias or PAH, short and long term complications). 3. Evaluation of clinical parameters, echocardiography, bicycle exercise testing, stress echocardiography and biochemical variables in patients with ASD in order to (1) identify reliable endpoints for interventional studies and (2) estimate the prevalence (and determinants) of masked PAH. 4. Evaluation of the effect of selective pulmonary vasodilators in patients with mild to moderate PAH after ASD repair. 5. To evaluate if it is beneficial to treat patients with unrepaired ASD with selective pulmonary vasodilators in order to slow down the increasein PVR and PAH and the related clinical complications. 6. Re-evaluationof Eisenmenger patients in Belgium after 3 years to evaluate determinants of outcome.  Methodology   Patients selection. Patients will be selected through the national registry of adult CHD, developed and maintained by an independent data manager (Alabus Ag, Switzerland).  To be part of the registry, all patients have given signed informed consent. A second informed consent will be obtained in order to participate in one of the prospective studies. These studies will be performed in accordance to the ethical principles as described in the Declaration of Helsinki and after review of the study protocol by the hospitals ethics committee. Study protocol (1) The first two (and sixth) studies have an epidemiological and retrospective design, describing the Eisenmenger and ASD population using the national database on CHD.  Clinical events defined as death of any cause, development of PAH or arrhythmias, hospitalization due to PAH complications and deterioration defined bypredetermined criteria will be considered as the main outcome parameterand evaluated through associative statistical analysis. 2) The third study has a prospective design comparing ASD patients with age and gender matched controls evaluating baseline characteristics of this patient population (clinical signs, echocardiography, bicycle exercise testing, stress echocardiography and biochemical parameters).  This study is necessary, because there is still no evidence in the literature which surrogate endpoints for outcome that can be used in patients with mild to moderate PAH.  (3) The fourth and fifth studies are prospective, randomized, placebo-controlled to evaluate  the effect of specificPAH treatment on surrogate endpoints (determined in the previous study and preferably considering myocardial performance and functional capacity) on residual PAH after ASD repair and on PAH in patients not eligible for ASD repair. This patient population will be more likely to be in NYHA I/II. Hoeper et al. concluded that placebo-controlled for shorter periods of time are still justified in this patient population from an ethical and scientific point of view. As the studies will be too short to determine the effect of vascular remodeling on life expectancy surrogate endpoints will help to evaluate the possible positive effect. Medical treatment with ERAs, PDE inhibitors and prostacyclin analogs has shown to besafe and effective in PAH. Endpoints (1) Endpoints in the retrospective, descriptive studies: Clinical events defined as death of any cause, development of PAH or arrhythmias, hospitalization due to PAH complications and deterioration defined by predetermined criteria will be described.(2) Surrogate endpoints in the prospective, randomized, placebo-controlled studies. (a) Echocardiography Echocardiography is the most widely available imaging test. Disease severity and effect of treatment can be evaluated non-invasively, not only to assess the magnitude of the pathophysiologic adaptations of the heartand pulmonary circulation, but also to detect changes in cardiac structure and function associated with medicaltreatment. Classical two-dimensional, M-Mode and Doppler echocardiography allows us to evaluate (1) RV dysfunction measured by Doppler Tei index of myocardial performance, (2) right and left ventricular dimensions, (3) elevated right atrial pressure as measured by hepatic vein congestion or right atrial area/volume and (4) decreased LV preload, which can bemeasured at baseline and after treatment. M-mode echocardiographic measurements of amplitude of the movement of tricuspid and mitral annulus correlate with right and left ventricular ejection fraction respectively.[17] Tissue Doppler imaging (TDI) might help to assess myocardial velocity (as index of underlying systolic and diastolic function), but might beinfluenced by different loading conditions.[18] Strain, strain rate andspeckle tracking are newer imaging modalities, currently investigated in several studies.  Strain rate describes the rate of change in length calculated as the difference between two velocities normalized to the distance between them.  Strain is the percentage change in lengthduring relaxation/contraction.  These measures are thought to be less load dependent indices of contractile function.[19]  Speckle tracking is an alternative method for quantification of systolic function.  It doesnt have the limitation of angle dependence that TDI-derived strain measurements have. Bicycle stress echocardiography may be helpful to increase the sensitivity of detecting abnormal hemodynamics and for following up the effect of treatment.  This makes it possible toidentify patients with masked PAH by measuring pulmonary pressures during exercise.[20,21] The equipment and expertise needed to conduct echocardiography (including strain/strain-rate, speckle tracking and stress echocardiography) is available in the Laboratory for echocardiography UZ Leuven under supervision of Prof. Dr. Voigt. Echocardiography and off-line analyses would be performed by myself under supervision of Prof. Dr. Voigt.   (b) Cardiopulmonary exercise testing (CPET). Despite RV volume overloading, many patients with ASD do not complain of limited exercise capacity, while assessment with CPET shows a significantly impaired exercise capacity.[22,23]  Measurement of ventilation andpulmonary gas exchange during exercise testing provides an accurate andnon-invasive evaluation of functional capacity and might provide additional information to understand symptoms and underlying pathophysiology.  Several parameters have already been shown of value in the evaluation of patients with idiopathic pulmonary hypertension (iPAH).  Patients with PPH have an inability to adequately increase pulmonary (and therefore systemic) blood flow during exercise resulting in a failure to meet the exercise 02 requirement.  This can be evaluated through peak oxygen consumption (peak vO2), peak O2 pulse and anaerobic threshold.[24,25]  The ventilatory equivalent for CO2 (i.e. the ratio of minute ventilation to carbon dioxide output) is increased in patients with primary pulmonary hypertension and might be a useful parameter to evaluate the efficacy of a drug in improving lung perfusion, even in the short term.[26] CPET can be used to detect a right-to-left shunt during exercise.[27] The equipment and expertise that is needed to efficiently conduct CPET is available in the laboratory for exercise testing UZ Leuven (Prof. Vanhees).  CPET would be performed by an observatory experienced in CPET, analysis of the data will be done by myself.   (c) Biochemistry Patients with patent ASD have significantly elevated brain natriuretic peptide (BNP) levels, which may be an early marker of right ventricular systolic function impairment.  Schoen et al. showed that NT-proBNP is a parameter which correlates to RV dilatation, pulmonary pressure and the amount of interatrial shunting in volume load of the right heart caused by an underlying ASD.  Their role in the assessment of treatment strategies however is still unclear. [28-30]   (d) SF 36 questionnaire The 36 item short form health survey (SF 36) is a commonly used and validated tool to assess health perception in patients with congenital heart disease. [31]   Milestones and timing of the PhD project   (a) First paper (cfr first aim): December 2008, (b) Second paper (cfr second aim): July 2009, (c)Third paper (cfr third aim): July 2010, (d) Fourth paper (cfr fourth aim):  March 2012, (e) Fifth paper (cfr fifth aim): March 2012, (e) Sixth paper (cfr sixth aim): August 2012   Synopsis/conclusion.  PAH treatment in patients with an ASD hasnt been studied until now, because they present mostly with less severe symptoms.  Little is known which endpoints could be used in interventional studies.  Prospective studies to describe baseline characteristics of this patientpopulation are necessary to select useful and reliable endpoints. Using these (surrogate) endpoints randomized, placebo-controlled studies make it possible to address several unanswered research questions in this patient population in order to optimize patient care.   References        1                      Sommer RJ HZ, Rhodes JF: Pathophysiology of congenital heart disease in the adult: Part i: Shunt lesions. Circulation 2008;117:1090-1099.      2                      Konstantinides S GA, Olschewski M, Görnandt L, Roskamm H, Spillner G, Just H, Kasper W.: A comparisonof surgical and medical therapy for atrial septal defect in adults. N Engl J Med 1995;333:469-473.      3                      Warnes CA WR, Bashore TM, ChildJS et al: ACC/AHA 2008 guidelines for the management of adults with congenital heart disease J Am CollCardiol 2008;52:e1-121.      4                      Sharp A MI: Secundum atrial septal defects: Time to close them all? Heart 2008;94:1120-1122.      5                      Du ZD HZ, Kleinmann CS, Silvermandd NH, Larntz K for the Amplatzer Investigators.: Comparison between trancatheter and surgical closure of secundum atrial septal defect in children andadults.  Results of a multicenter nonrandomized trial. J Am Coll Cardiol 2002;39:1836-1844.     6                      Party RotBCSW: Grown-up congenital heart (guch) disease: Current needs and provision of service for adolescents and adults with congenital heart disease in the uk. Heart 2002;88:i1-i14.      7                      Engelfriet P TJ, Kaemmerer H, Gatzoulis MA, Boersma E,Oechslin E, Thaulow E, Popelova J, Moons P, Meijboom F, Daliento L, Hirsch R, Laforest V, Thilen U, Mulder B.: Adherence to clinical guidelinesin the clinical care for adults with congenital heart disease: The euroheart survey on adult congenital heart disease. Eur Heart J 2006;27:737-745.      8                      Attie F RM, Granados N, Zabal C, Buendia A, CalderonJ.: Surgical treatment for secundum atrial septal defects in patients > 40 years old.  A randomized clinical trial. J Am Coll Cardiol2001;38:2035-2042.      9                      Balint OH SA, Haberer K, Tobe L, McLaughlin P, Siu SC, Horlick E, Granton J, Silversides CK.: Outcomes in patients with pulmonary hypertension undergoing percutaneous atrial septal defect closure. Heart 2008;94:1189-1193.      10                    Tolle JJ WA, Van Horn TL, Pappagianopoulos PP, Systrom DM: Exercise-induced pulmonary arterial hypertension. Circulation 2008;118:283-2189.      11                    Oelberg DA MF, Kreisman H, Wolkove N, Langleben D, Small D.: Evaluation of right ventricular systolic pressure during incremental exercise by doppler echocardiography in adults with atrial septal defects. Chest 1998;113:1459-1465.      12                    Engelfriet PMF, Boersma E, Tijssen J, Mulder B.: Repaired and open atrial septal defects type ii in adulthood: An epidemiological study of a large europeancohort. Int J Cardiol 2008;126:379-385.      13                    Rubin LJ BD, Barst RJ, GalieN, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G.: Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896-903.      14                    Galie N BM, Gatzoulis MA, Granton J, Bergr RMF, Lauer A, Chiossi E, Landzberg M and for the Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) Investigators.: Bosentan therapy in patients with eisenmenger syndrome: A multicenter, double-blind, randomized, placebo-controlled study. Circulation 2006;114:48-58.      15                    Galiè N RL, Hoeper M, Jansa P, Al-Hiti H, Meyer G, Chiossi E, Kusic-Pajic A, Simonneau G: Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (early study): A double-blind, randomised controlled trial. Lancet 2008;371:2093-2100.      16                    DavlourosPA NK, Webb G, Gatzoulis MA: The right ventricle in congenital heart disease. 2008 2008;92:i27-i38.      17                    Hanseus KC BG, Brodin LA, Pesonen E: Analysis of atrioventricular plane movements by doppler tissue imaging and m-mode in children with atrial septal defects before and after surgical and device closure. Pediatr Cardiol 2002;23:152-159.      18                    Pauliks LB CK-C,Chang D, Kirby SK, Logan L, DeGroff CG, Boucek MM, Valdez-Cruz LM: Regional myocardial velocities and isovolumic acceleration before and after device closure of atrial septal defects: A color tissue doppler study. Am Heart J 2005;150:294-301.      19                    Eyskens B GJ, Claus P, Boshoff D, Gewillig M, Mertens L: Ultrasonic strain rate and strain imaging of the right ventricle in children before and after percutaneous closure of an atrial septal defect. J Am Soc Echocardiogr 2006;19:994-1000.      20                    Oelberg DA MF,Kreisman H, Wolkove N, Langleben D, Small D: Evaluation of right ventricular systolic pressure during incremental exercise by doppler echocardiography in adults with atrial septal defect. Chest 1998;113:1459-1465.      21                    Grünig E JB, Mereles D, Barth U, Borst MM, Vogt IR, Fischer C, Olschewdski H, Kuecherer HF, Kübler W: Abnormal pulmonary artery pressure response in asymptomatic carriers of primary pulmonary hypertension gene. Circulation 2000;102:1145-1150.      22                    Diller G-P DK, Okonko D, Li W, Babu-Narayan SV, Broberg CS, Johansson B, Bouzas B, Mullen MJ, Poole-Wilson PA, Francis DP, Gatzoulis MA: Exercise intolerance in adult congenital heart disease: Comparative severity, correlates, and prognostic implication. Circulation 2005;112:828-835.      23                    Brochu M-C BJ-F, Dore A, Juneau M, De Guise P, Mercier L-A: Improvement in exercise capacity in asymptomatic andmildly symptomatic adults after atrial septal defect percutaneous closure. Circulation 2002;106:1821-1826.      24                    Palange P WS, Carlsen KH, Casaburi R, Gallagher CG, Gosselink R, O'Donnell DE, Puente-Maestu L, Schols AM, Singh AM, Whipp BJ: Recommendtaions on the use of exercise testing in clinical practice. Eur Respir J 2007;29:185-209.      25                    Sun X-G HJ, Oudiz RJ, Wasserman K: Exercise pathophysiology in patients with primary pulmonary hypertension. Circulation 2001;104:429-435.      26                    Ting H SX-G, Chuang M-L, Lewis DA, Hansen JE, Wasserman K: A noninvasive assessment of pulmonary perfusion abnormality in patients with primary pulmonary hypertension. Chest 2001;119:S24-S32.      27                    Sun X-G HJ, Oudiz RJ, Wasserman K: Gas exchange detection of exercise-induced right-to-left shunt in patients with primary pulmonary hypertension. Circulation 2002;105:54-60.      28                    Schoen SPZT, Kittner T, Braun MU, Fuhrmann J, Shmeisser A, Strasser RH: Nt-probnp correlates with right heart haemodynamic parameters and volumes in patients with atrial septal defects. Eur J Heart Fail 2007;9:660-666.      29                    Trojnarska O SA, Gwizdala A, Oko-Sarnowska Z, Katarzynski S, Siniawski A, Chmara E, Cieslinski A.: Evaluation of exercise capacity with cardiopulmonary exercise testing and type b natriuretic peptide concentrations in adult patients with patent atrial septal defect. Cardiology 2006;106:154-160.      30                    Yap LB AH, Mukerjee D, Coghlan JG, Timms PM: The natriuretic peptides and their role in disorders of right heart dysfunction and pulmonary hypertension. 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Date:1 Oct 2008 →  8 Oct 2012
Keywords:Cardiology
Disciplines:Physiology, Cardiac and vascular medicine, Respiratory medicine
Project type:PhD project