Cardiac function before and after treatment for various types of loading conditions and in myocardial restriction : A prospective study on pediatric patients with two- and three-dimensional echocardiography and measurement of serum natriuretic peptides

Background: The incidence of all forms of congenital heart defects is 0.75%. For patients with congenital heart defects, life-expectancy has improved with new treatment modalities. Structural heart defects may require surgical or catheter treatment which may be corrective or palliative. Even those with corrective therapy need regular follow-up due to residual lesions, late sequelae, and possible complications after interventions. Aims: The aim of this thesis was to evaluate cardiac function before and after treatment for volume overload of the right ventricle (RV) caused by atrial septal defect (ASD), volume overload of the left ventricle (LV) caused by patent ductus arteriosus (PDA), and pressure overload of the LV caused by coarctation of the aorta (CoA), and to evaluate cardiac function in patients with Mulibrey nanism. Methods: In Study I, of the 24 children with ASD, 7 underwent surgical correction and 17 percutaneous occlusion of ASD. Study II had 33 patients with PDA undergoing percutaneous occlusion. In Study III, 28 patients with CoA underwent either surgical correction or percutaneous balloon dilatation of CoA. Study IV comprised 26 children with Mulibrey nanism. A total of 76 healthy voluntary children were examined as a control group. In each study, controls were matched to patients. All patients and controls underwent clinical cardiovascular examinations, two-dimensional (2D) and three-dimensional (3D) echocardiographic examinations, and blood sampling for measurement of natriuretic peptides prior to the intervention and twice or three times thereafter. Control children were examined once by 2D and 3D echocardiography. M-mode echocardiography was performed from the parasternal long axis view directed by 2D echocardiography. The left atrium-to-aorta (LA/Ao) ratio was calculated as an index of LA size. The end-diastolic and end-systolic dimensions of LV as well as the end-diastolic thicknesses of the interventricular septum and LV posterior wall were measured. LV volumes, and the fractional shortening (FS) and ejection fraction (EF) as indices of contractility were then calculated, and the z scores of LV dimensions determined. Diastolic function of LV was estimated from the mitral inflow signal obtained by Doppler echocardiography. In three-dimensional echocardiography, time-volume curves were used to determine end-diastolic and end-systolic volumes, stroke volume, and EF. Diastolic and systolic function of LV was estimated from the calculated first derivatives of these curves. Results: (I): In all children with ASD, during the one-year follow-up, the z score of the RV end-diastolic diameter decreased and that of LV increased. However, dilatation of RV did not resolve entirely during the follow-up in either treatment group. In addition, the size of LV increased more slowly in the surgical subgroup but reached control levels in both groups. Concentrations of natriuretic peptides in patients treated percutaneously increased during the first month after ASD closure and normalized thereafter, but in patients treated surgically, they remained higher than in controls. (II): In the PDA group, at baseline, the end-diastolic diameter of LV measured over 2SD in 5 of 33 patients. The median N-terminal pro-brain natriuretic peptide (proBNP) concentration before closure measured 72 ng/l in the control group and 141 ng/l in the PDA group (P = 0.001) and 6 months after closure measured 78.5 ng/l (P = NS). Patients differed from control subjects in indices of LV diastolic and systolic function at baseline, but by the end of follow-up, all these differences had disappeared. Even in the subgroup of patients with normal-sized LV at baseline, the LV end-diastolic volume decreased significantly during follow-up. (III): Before repair, the size and wall thickness of LV were higher in patients with CoA than in controls. Systolic blood pressure measured a median 123 mm Hg in patients before repair (P < 0.001) and 103 mm Hg one year thereafter, and 101 mm Hg in controls. The diameter of the coarctation segment measured a median 3.0 mm at baseline, and 7.9 at the 12-month (P = 0.006) follow-up. Thicknesses of the interventricular septum and posterior wall of the LV decreased after repair but increased to the initial level one year thereafter. The velocity time integrals of mitral inflow increased, but no changes were evident in LV dimensions or contractility. During follow-up, serum levels of natriuretic peptides decreased correlating with diastolic and systolic indices of LV function in 2D and 3D echocardiography. (IV): In 2D echocardiography, the interventricular septum and LV posterior wall were thicker, and velocity time integrals of mitral inflow shorter in patients with Mulibrey nanism than in controls. In 3D echocardiography, LV end-diastolic volume measured a median 51.9 (range 33.3 to 73.4) ml/m² in patients and 59.7 (range 37.6 to 87.6) ml/m² in controls (P = 0.040), and serum levels of ANPN and proBNP a median 0.54 (range 0.04 to 4.7) nmol/l and 289 (range 18 to 9170) ng/l, in patients and 0.28 (range 0.09 to 0.72) nmol/l (P < 0.001) and 54 (range 26 to 139) ng/l (P < 0.001) in controls. They correlated with several indices of diastolic LV function. Conclusions (I): During the one-year follow-up after the ASD closure, RV size decreased but did not normalize in all patients. The size of the LV normalized after ASD closure but the increase in LV size was slower in patients treated surgically than in those treated with the percutaneous technique. Serum levels of ANPN and proBNP were elevated prior to ASD closure but decreased thereafter to control levels in patients treated with the percutaneous technique but not in those treated surgically. (II): Changes in LV volume and function caused by PDA disappeared by 6 months after percutaneous closure. Even the children with normal-sized LV benefited from the procedure. (III): After repair of CoA, the RV size and the velocity time integrals of mitral inflow increased, and serum levels of natriuretic peptides decreased. Patients need close follow-up, despite cessation of LV pressure overload, since LV hypertrophy persisted even in normotensive patients with normal growth of the coarctation segment. (IV): In children with Mulibrey nanism, the LV wall was hypertrophied, with myocardial restriction and impairment of LV function. Significant correlations appeared between indices of LV function, size of the left atrium, and levels of natriuretic peptides, indicating that measurement of serum levels of natriuretic peptides can be used in the clinical follow-up of this patient group despite its dependence on loading conditions.

Sydämen toiminta synnynnäisissä sydänvioissa ennen ja jälkeen toimenpiteiden tilavuus- ja painekuormituksessa sekä restriktiivisessä sydänlihassairaudessa. Prospektiivinen seurantatutkimus, jossa käytetään kaksi- ja kolmiulotteista ultraääntä sekä mitataan natriureettisia peptiditasoja. Synnynnäisten sydänvikojen insidenssi on 0,75 %. Yleisin synnynnäinen sydänvika on kammioväliseinäreikä (20 % vioista). Seuraavina tulevat avoin valtimotiehyt (PDA, 14 %), eteisväliseinäaukko (ASD, 10 %), eteiskammioväliseinäaukko (AVSD, 7 %), ja aortan kaventuma eli koarktaatio (CoA 4 %). Osa sydänvioista ei vaadi hoitoa, osa voidaan hoitaa sydänkatetroinnissa tehtävällä, perkutaanisella, toimenpiteellä ja osa joudutaan korjaamaan sydänleikkauksella. Vielä on kuitenkin sydänvikoja, joihin on tarjolla vain palliatiivista hoitoa. Odotettavissa oleva elinikä synnynnäistä sydänvikaa sairastavilla lapsilla on pidentynyt parantuneiden hoitomahdollisuuksien ansiosta. Seurannassa on tärkeää arvioida mahdollisimman tarkasti sydämen toimintaa ja sen muutoksia lapsen kasvaessa. Synnynnäiset sydänviat kuormittavat sydäntä eri tavalla. ASD aiheuttaa sydämen oikean puolen tilavuuskuormituksen. PDA aiheuttaa oikovirtauksen aortan ja keuhkovaltimon välillä ja kuormittaa sydämen vasenta puolta. CoA aiheuttaa vasemman kammion painekuormituksen. Mulibrey nanismiin liittyy sydänlihaksen ja sydänpussin jäykistyminen. Tässä väitöskirjatutkimuksessa tutkittiin erilaisten kuormitusolosuhteiden vaikutusta sydämen toimintaan vertaamalla kaksi-(2D) ja kolmiulotteisella (3D) ultraäänitutkimuksella saatuja tuloksia ja natriureettisten peptidien seerumipitoisuuksia iän ja/tai kehon pinta-alan suhteen vakioitujen terveiden kontrollien tuloksiin ennen sydänvian perkutaanista tai kirurgista hoitoa ja 6-12 kuukauden seurannan aikana. Lisäksi vertailtiin terveiden verrokkien ja Mulibrey nanismia sairastavien lasten sydänlöydöksiä. Tutkimuksessa osoitettiin, että ASD:n sulun jälkeen vasemman kammion koko normaalistui, mutta operatiivisesti hoidetuilla hitaammin kuin katetrointitekniikalla suljetuilla. Tilavuuskuormituksen aiheuttama oikean kammion laajentuminen ei täysin korjaantunut vuoden seurannassa. Vähäinenkin PDA, joka aiheuttaa sivuäänen, saa aikaan mitattavia muutoksia sydämen toiminnassa. Muutokset häviävät katetrointitekniikalla tehdyn sulun jälkeen puolen vuoden seurannassa. CoA aiheuttaa vasemman kammion painekuormituksen. Hoidon jälkeenkin on tärkeätä jatkaa seurantaa hyvästä hoitotuloksesta huolimatta, sillä tutkimuksessamme osoitettiin vasemman kammion seinämien olevan paksummat kuin kontrolleilla vielä vuoden kuluttua hoitotoimenpiteestä. Osalla Mulibrey nanismia sairastavista lapsista oli todettavissa jäykän eli konstriktiivisen sydänpussin lisäksi restriktiivinen sydänlihassairaus. Kaikissa väitöskirjan osatöissä osoitettiin natriureettisten peptidien seerumikonsentraatioiden määritysten hyödyllisyys osana kliinistä seurantaa.