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In contemporary clinical cardiology practice, echocardiography plays a leading role in the diagnosis and management guidance of various forms of myocardial remodelling. Furthermore, it is the most commonly used diagnostic technique in the elucidation of the underlying substrates and pathophysiologic mechanisms of heart failure as a consequence of ventricular remodelling. Due to its widespread availability, non-invasiveness, userfriendliness and relatively low cost, echocardiography is still irreplaceable by other cardiac imaging methods which should rather be seen as complementary diagnostic tools. This thesis sought to study several types of ventricular remodelling and their consequences on regional and global myocardial function, employing different echocardiographic tools and dedicated signal and image analysis algorithms in the detection of ventricular dysfunction. Recent echocardiographic techniques based on Myocardial Velocity Imaging have provided the possibility of a more detailed and integrated insight to cardiac (dys-) function. Based on novel understandings, we first gave an original integrated overview on ‘cardiac function’, distinguishing intrinsic myocyte function (often referred to as contractility) and ventricular pump function as well as the main components of function, namely force development and deformation. Additionally, the boundary conditions in which the heart functions, which determine the interactions between these components were defined as: a) wall properties such as tissue composition/elasticity, fibre structure and global geometry, and b) interaction between the heart and peripheral circulation, mostly described as (pressure & volume) loading conditions. Furthermore, Doppler echocardiography data were analyzed in a study addressing flow remodelling as a consequence of cellular and force remodelling in ischaemically remodelled hearts. A dedicated automated quantification of the CW outflow Doppler traces was used to define specific trace parameters indicative of myocardial dysfunction. It was shown that decreased overall contractility results in a more symmetrical outflow velocity profile, which would suggest that the global development of contractile force has been remodelled to cope with the decreased output resulting from decreased contractility. Similar automatic quantification of the aortic instantaneous peak velocities was further employed in patients with hypertrophic remodelling due to aortic stenosis. This study has shown that the values of trace asymmetry before surgery are predictive of the change in EF 112 pre- and postoperatively: all of the patients with markedly symmetric preoperative instantaneous peak velocities showed stagnation or deterioration of EF postoperatively. Furthermore, the study has proven that the symmetry of the shape of the instantaneous peak velocities is a more reliable predictor of functional improvement after the valve replacement procedure as compared to mean aortic gradient and aortic valve area which are widely used in preoperative assessment of patients with aortic stenosis. An intraoperative Doppler myocardial imaging study was performed along with standard echocardiography in an analysis of electrical remodelling in patients with LBBB during the CRT implantation procedure. In addition to confirming the septal flash as a mechanical consequence of the underlying electrical problem and a valid marker of intraventricular dyssynchrony, an acute contractility recruitment, resolution of the septal flash as well as reverse remodelling immediately following CRT device activation was shown in these patients. As opposed to remodelling induced by changes in loading conditions, evidence of hypertrophy and hypercontractility without an additional change in afterload resulting in increased cardiac output and inducing additional signs of vascular remodelling was demonstrated in patients with early stage acromegaly. Finally, a comprehensive view on the changing role of echocardiography in the diagnosis of hypertrophic myopathies is presented. Previous knowledge as well as regional deformation data (including deformation pattern analysis) are combined to provide an indicator toward the disease underlying hypertrophic ventricular remodelling: in hypertensive heart disease LVH is predominantly localized in the basal septal region showing reduced systolic strain values with post-systolic shortening; systemic diseases such as Fabry’s disease often affect a specific region - the basal (infero)lateral segment in which post-systolic deformation is often present. Hypertrophic cardiomyopathy is associated with regions of local fibre disarray, in which no myocardial deformation is present at all, while in the surrounding segments (often showing similar thickness) deformation is reduced, but almost normal as compared to undiseased hearts. The absence of deformation is mostly associated with the thickest segments. Amyloidosis seems to provide an exception in which the impairment of systolic function affects the myocardium globally – it is presented with global LVH and diffuse, severe reduction of longitudinal strain, while the radial strain is still preserved, but of low values., U suvremenoj kardiologiji ehokardiografija ima vodeću ulogu u dijagnostici i odabiru postupaka u raznim oblicima remodeliranja miokarda. Nadalje, to je najčešće primjenjivana metoda u rasvjetljavanju temeljnih supstrata i patofizioloških mehanizama zatajenja srca kao posljedice remodeliranja klijetki. Zahvaljujući širokoj dostupnosti, neinvazivnosti, lakoći primjene i relativno malenoj cijeni, ehokardiografija je i dalje nezamjenjiva u odnosu na druge metode oslikavanja u kardiologiji, koje bi valjalo prihvatiti kao komplementarne dijagnostičke metode. Cilj je ove disertacije istražiti nekoliko oblika remodeliranja klijetki i njihovih posljedica na regionalnu i globalnu funkciju miokarda, primjenom različitih ehokardiografskih metoda i specifičnih algoritama analize signala i slike u otkrivanju disfunkcije srca. Novije ehokardiografske tehnike temeljene na oslikavanju miokardnih brzina gibanja (Myocardial Velocity Imaging) omogućuju podrobniji i integrirani pogled u (dis)funkciju srca. Na temelju novijih spoznaja, na početku disertacije prikazan je originalni, integrirani pregled „srčane funkcije“, razlikujući intrinzičnu funkciju miocita (obično nazivanu kontraktilitetom) i crpnu funkciju klijetki, kao i glavne sastojnice srčane funkcije, to jest razvoj sile i deformaciju., Uvjeti u kojima srce radi, koji određuju odnos između navedenih sastavnica, definirani su kao: a) svojstva stijenke poput građe/elastičnosti tkiva, strukture vlakna i globalne geometrije, te b) interakcija srca i periferne cirkulacije koja se većinom opisuje kao stanje punjenja (tlačno i volumno opterećenje). U ispitivanju remodeliranja protoka kao posljedici staničnog remodeliranja i remodeliranja sile u ishemijski remodeliranom srcu, obrađivali smo podatke Dopplerske ehokardiografije. Posebna automatska kvantifikacija Dopplerskih zapisa istiska lijeve klijetke primijenjena je u definiranju specifičnih svojstava krivulje, koja ukazuju na disfunkciju miokarda. Dokazali smo da smanjenje ukupne kontraktilnosti uzrokuje simetričniji oblik krivulje istiska lijeve klijetke, što sugerira remodeliranje globalne kontraktilne sile, kako bi se prilagodila smanjenju istiska zbog smanjene kontraktilnosti. Slična automatska kvantifikacija trenutnih vršnih brzina protoka kroz aortni zalistak primijenjena je i u bolesnika s hipertrofijskim remodeliranjem klijetki u aortnoj stenozi. Ovo istraživanje pokazalo je da predoperativne vrijednosti asimetrije Dopplerskog zapisa predskazuju poslijeoperacijsku promjenu ejekcijske frakcije: u svih bolesnika sa značajno simetričnim predoperativnim vršnim brzinama kroz aortni zalistak dokazali smo pogoršanje ili 114 istovjetnu ejekcijsku frakciju nakon operacije. Nadalje, ovo je istraživanje dokazalo da je simetričnost vršnih brzina pouzdaniji predskazatelj funkcijskog oporavka nakon zamjene aortnog zalistka, u usporedbi sa srednjim transaortnim gradijentom i površinom aortnog ušća koji se često koriste u predoperativnoj evaluaciji bolesnika s aortnom stenozom. U analizi električnog remodeliranja u bolesnika s blokom lijeve grane, provedeno je, uz standardnu ehokardiografiju, intraoperacijsko ispitivanje miokardnog Dopplera tijekom postupka ugradnje resinkronizacijskog elektrostimulatora. Uz potvrdu flash - septuma kao mehaničke posljedice temeljnog električnog problema te valjanog pokazatelja intraventrikulske disinkronije, u ovoj skupini bolesnika dokazano je i akutno poboljšanje kontraktilnosti, nestanak flash - septuma kao i povratno remodeliranje lijeve klijetke neposredno nakon uključivanja resinkronizacijskog elektrostimulatora. Za razliku od remodeliranja uzrokovanog promjenom uvjeta punjenja, u skupini bolesnika s akromegalijom dokazali smo hipertrofiju i hiperkontraktilnost lijeve klijetke uz posljedično povećanje minutnog volumena srca te razvoj znakova vaskularnog remodeliranja, bez dodatnih promjena u tlačnom opterećenju srca. Disertacija završava širim prikazom izmijenjene uloge ehokardiografije u dijagnozi hipertrofijskih bolesti miokarda. Prethodna saznanja kao i podatci o regionalnoj deformaciji (uključujući analizu uzoraka deformacije) povezani su u svrhu prepoznavanja bolesti koja je u podlozi hipertrofijskom remodeliranju klijetki: u hipertenzivnoj bolesti srca hipertrofija je većinom lokalizirana u bazalnom interventrikulskom septumu uz smanjenje vrijednosti sistoličkog strain-a te nastanak post-sistoličkog izduljenja. Sistemske bolesti poput Fabryjeve bolesti često zahvaćaju određenu regiju srca – bazalni (infero)lateralni segment u kojem je često prisutno post-sistoličko zadebljanje. Hipertrofijska kardiomiopatija je povezana s ograničenim područjima poremećene arhitekture srčanih vlakana, u kojima je deformacija u potpunosti odsutna, dok je u okolnim segmentima (često slične debljine stijenke) deformacija smanjena, no gotovo normalna. Odsutnost deformacije obično je povezana s najzadebljanijim segmentima. Čini se da amiloidoza predstavlja iznimku u kojoj smanjenje sistoličke funkcije globalno zahvaća miokard - nalazi se globalna hipertrofija lijeve klijetke te difuzno, teško oštećenje logitudinalnog straina dok je radijalni strain još očuvan, ali malenih vrijednosti.

Major histocompatibility class I chain-related gene A (MICA) mismatching and development of anti-MICA antibodies after heart transplantation

We agree that appreciable heterogeneity in cardiac structure exists among patients in the echocardiographic substudies of PARAGON-HF, TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist), and I- PRESERVE (Irbesartan in Heart Failure With Preserved Ejection Fraction). Specifically, left ventricular (LV) mass was similar between PARAGON- HF and I-PRESERVE but appreciably lower than in TOPCAT (Americas region), whereas left atrial (LA) size was similar between PARAGON-HF and I-PRESERVE but appreciably higher than TOPCAT (Americas region). Indeed, LA enlargement was observed in >80% of PARAGON-HF patients in the echocardiographic study. Although one interpretation of this variability may be to question the certainty of the HFpEF diagnosis among these studies, 96% of patients in the PARAGON-HF echocardiography substudy met the 2016 European Society of Cardiology heart failure guideline echocardiographic criteria for HFpEF, and >75% met the diagnostic criteria for HFpEF recently proposed by the European Society of Cardiology Heart Failure Association. More importantly, E/e′, estimated pulmonary arterial pressure, and incidence of HF-specific clinical events were similarly elevated in all 3 studies, strongly suggesting that these morphological differences instead reflect the inherent heterogeneity of this syndrome.