VLOGA VISOKOLOČLJIVOSTNIH ELEKTROKARDIOGRAFSKIH PARAMETROV PRI ZDRAVLJENJU SRČNEGA POPUŠČANJA Z ATRIO-BIVENTRIKULARNO ELEKTROSTIMULACIJO SRCA

Cvijić, Marta (author), Zupan, Igor (mentor)

Izhodišča: Atrio - biventikularna elektrostimulacija srca oz. resinhronizacijsko zdravljenje (CRT; angl. cardiac resynchronization therapy) je uveljavljena metoda zdravljenja bolnikov z napredovalim srčnim popuščanjem. Po zadnjih priporočilih evropskega kardiološkega združenja so za ta način zdravljenja primerni bolniki, ki so ob optimalnemu zdravljenju z zdravili v funkcijskem razredu NYHA II- IV, imajo močno oslabljen iztisni delež levega prekata (LVEF; angl. left ventricular ejection fraction ≤ 35%) in širino kompleksa QRS ≥ 120 ms. Kljub dokaj jasnim kriterijem je še vedno približno 30% bolnikov, ki se na takšen način zdravljenja ne odzovejo. V zadnjih letih se delež bolnikov, ki se ugodno odzivajo na CRT ni bistveno povečal. CRT je prvenstveno električna stimulacija srca, ki povzroči najprej usklajeno električno aktivacijo levega prekata (LV), le-to pa posledično vodi v usklajeno mehansko aktivacijo LV. Zato ni presenetljivo, da imajo pomembno vlogo v razumevanju uspešnosti zdravljenja s CRT elektrokardiografski parametri, ki označujejo motnje prevajanja in električno dissinhronijo. O vplivu CRT na EKG parametre prekatne repolarizacije ni veliko podatkov. Nekateri podatki kažejo na povečanje heterogenosti repolarizacije in možnosti prekatnih motenj ritma, medtem ko nekatere druge raziskave dokazujejo zmanjšanje heterogenosti repolarizacije po CRT. Zdravljenje s CRT vpliva tako na proces reverzne električne remodelacije kot tudi na mehansko remodelacijo srca. Soodvisnost doseganja električne in mehanske remodelacije ter časovni okvir električne remodelacije še niso v celoti raziskani. Z doktorsko dizertacijo želimo ovrednotiti pomen različnih EKG parametrov pri zdravljenju srčnega popuščanja s CRT ter opredeliti časovno povezavo med električno in mehansko remodelacijo po CRT. Metode: Preiskovano skupino so sestavljali bolniki s srčnim popuščanjem, ki smo jim v Univerzitetnem kliničnem centru Ljubljana vstavili napravo za biventrikularno elektrostimulacijo, in so izpolnjevali trenutno veljavne kriterije za zdravljenje s CRT. Pred vstavitvijo in ob kontrolah (1, 3, 6, 9 in 12 mesecev po vstavitvi) so imeli bolniki opravljeno ultrazvočno preiskavo srca in posnetek standardnega 12-kanalnega EKG in 20-minutnega visoko ločljivostnega Holter EKG. Ob kontrolah smo za čas snemanja EKG začasno prenastavili CRT na nastavitve, ki so omogočale posnetek v lasnem sinusnem ritmu oz. nestimuliran EKG posnetek. Elekrično remodelacijo (ER) smo opredelili kot zmanjšanje nativnega trajanja kompleksa QRS ≥ 10 ms. Določili smo tudi relativno skrajšanje kompleksa QRS (( QRS po vstavitvi- QRS pred vstavitvijo)/( QRS pred vstavitvijo)), ki smo ga izrazili v odstotkih. Parametre prekatne repolarizacije smo določili iz 20-minutnega visokoločljivostnega Holter EKG posnetka; analizirali smo variabilnost amplitude vala T (TAV), interval QTa (QT apeks), interval QTe (QT konec), disperzijo omenjenih intervalov, interval od apeksa do konca trajanja vala T (TpTe) in razmerje TpTe/QT. Opredelili smo pojavnost prekatnih motenj ritma; in sicer vse prekatne tahikardije, ki so bile prekinjene z aktivacijo ICD in vse epizode prekatne fibrilacije. Po vstavitvi smo beležili srčno-žilno umrljivost, hospitalizacijo zaradi poslabšanja srčnega popuščanja in potrebo po presaditvi srca (skupni opazovani dogodek). Rezultati: I.Povezava med elektrokardiografskimi parametri iz 12-kanalnega EKG in odzivom na zdravljenje Analizirali smo 101 bolnika (starost 63.2 ± 10.9 let, 66 (65.2%) moških, 37 bolnikov (36.6%) z ishemično kardiomiopatijo, 77 bolnikov (76.2%) v funkcijskem razredu NYHA III) z vstavljenim CRT. Eno leto po vstavitvi smo pri 32 bolnikih (31.7%) ugotovili nadpovprečno dober odgovor na zdravljenje (angl. super-response; relativno zmanjšanje končnega sistoličnega volumna LV (LVESV) ≥ 30%). Med skupino z nadpovprečnim odgovorom na zdravljenje in preostalimi bolniki ni bilo pomembnih razlik v EKG parametrih pred vstavitvijo CRT. Trajanje stimuliranega kompleksa QRS neposredno po vstavitvi CRT pa je bila v skupini z nadpovprečnim odgovorom na zdravljenje pomembno krajše (148 ± 22 ms vs. 162 ± 28 ms; P = 0.010). Pomembno skrajšanje trajanja kompleksa QRS smo beležili v skupini z nadpovprečnim odgovorom na zdravljenje (skupina z nadpovprečnim odgovorom na zdravljenje: iz 167 ± 26 ms na 148 ± 22 ms; P = 0.010 vs. skupina brez nadpovprečnega odgovora na zdravljenje: iz 165 ± 27 ms na 162 ± 28 ms; P = 0.536). Tudi relativno skrajšanje kompleksa QRS je bilo v skupini z nadpovprečnim odzivom na zdravljenje bistveno večje (12.1% (6.8-22.2) vs. 1.7% ([-11.9] do 11.8); P = 0.005). V mulitvariantni analizi, je ob upoštevanju funkcijskega razreda NYHA, levokračnega bloka in normalne srčne osi, relativno skrajšanje kompleksa QRS ostal edini neodvisni parameter povezan z nadpovprečnim odgovorom na zdravljenje s CRT. II. Vpliv resinhronizacijskega zdravljenja na parametre prekatne repolarizacije in povezava z prekatnimi motnjami ritma V analizo smo vključili 64 bolnikov (starost 63.9 ± 10.9 let, 47 (73%) moških, 23 bolnikov (36%) z ishemično kardiomiopatijo). Pri 33 bolnikih (51.6%) smo ugotovili pozitiven odgovor na zdravljenje (izboljšanje LVESV ≥ 15%). V prvem letu po vstavitvi so se parametri prekatne repolarizacije pomembno spremenili. Pomembno spremembo smo beležili pri intervalu QTec (P < 0.001), TpTe (P < 0.001), razmerju TpTe/QT (P < 0.001) in disperziji intervala QTe (P < 0.014), medtem ko pri TAV in intervalu QTa pomembne spremembe nismo beležili. V prvih mesecih po vstavitvi CRT smo pri vseh parametrih repolarizacije beležili povečanje heterogenosti repolarizacije, ki pa se je nato znižala tekom nadaljnjega opazovanja. Bolniki z odgovorom na zdravljenje in bolniki, pri katerih nismo beležili odgovora na zdravljenje s CRT, so imeli pomembno različne spremembe parametrov repolarizacije v opazovanem obdobju. Pri bolnikih z odzivom na zdravljenje smo sicer beležili povečanje heterogenosti repolarizacije v prvih mesecih, a se je le-ta nato pomembno znižala. Medtem ko so se pri bolnikih brez odgovora na zdravljenje, parametri repolarizacije pomembno podaljševali tekom celotnega opazovanega obdobja. Obe skupini bolnikov sta imeli primerljive vrednosti parametrov repolarizacije pred vstavitvijo CRT. Pomembna razlika v parametrih repolarizacije med skupinama se je nato pokazala po 6 mesecih biventrikularne stimulacije. V prvem letu po implantaciji smo pri 10 bolnikih (15.6%) beležili prekatne motnje ritma. Več kot polovica teh bolnikov (60%) je imela motnje ritma v prvem mesecu po vstavitvi CRT. Porazdelitev motenj ritma z največjo pojavnostjo v prvem mesecu je ustrezala najvišjim vrednostim heterogenosti repolarizacije v istem obdobju. III. Časovni potek in povezava med električno in mehansko remodelacijo po resinhronizacijskem zdravljenju V raziskavo smo vključili 62 bolnikov (starost 65.7 ± 10.3 let, 50 (81%) moških). V prvem letu po vstavitvi smo beležili pomembo spremembo trajanja nativnega kompleksa QRS (P = 0.003). En mesec po vstavitvi CRT smo beležili pomembno skrajšanje nativnega kompleksa QRS (185 ms [175-194] vs. 180 ms [170-194]; P < 0.001), ki je nato vztrajalo v nadaljnjem opazovanem obdobju. Medtem ko smo mehansko remodelacijo LV, z zmanjšanjem volumna in izboljšanjem LVEF, beležili tekom celega leta po vstavitvi CRT (P < 0.001). Statistično pomembne strukturne spremembe so bile sicer opazne šele 3 mesece po vstavitvi CRT (EDV: 231 ml (191-280) vs. 200 ml (167-267), P < 0.05; ESV: 167 ml (137-206) vs. 140 ml (112-196), P < 0.05; EF: 27% (24-31) vs. 31% (24-38), P < 0.05). V skupini bolnikov z ER, je bilo izrazito skrajšanje trajanja kompleksa QRS beleženo v 1 mesecu po vstavitvi (pred vstavitvijo vs. 1 mesec po vstavitvi: 190 ms [179-196] vs. 180 ms [173-186]; P < 0.001), medtem ko pri bolnikih brez ER, pomembne spremembe trajanje kompleksa QRS nismo beležili. V prvem mesecu po vstavitvi je bila relativna sprememba ESV pri obeh skupinah, z in brez ER, primerljiva. V nadaljnjem opazovanem obdobju smo samo pri bolnikih z ER beležili pomembno reverzno remodelacijo LV. Mediani čas spremljanja bolnikov je bil 27 mesecev (18–37); v tem obdobju smo skupni opazovani dogodek beležili pri 15 bolnikih (24.2%). Bolniki z ER so imeli boljše preživetje do skupnega opazovanega dogodka kot bolniki brez ER (log-rank P = 0.028). Zaključki: Določeni parametri iz 12-kanalnega EKG zapisa so povezani z boljšim odzivom na zdravljenje po CRT. Absolutno trajanje stimuliranega kompleksa QRS in relativno skrajšanje trajanja kompleksa QRS neposredno po vstavitvi so povezani z nadpovprečnim odgovorom na zdravljenje s CRT. V prvem letu po vstavitvi CRT beležimo dinamične spremembe parametrov repolarizacije. Najvišje vrednosti heterogenosti repolarizacije v prvem mesecu po vstavitvi ustrezajo največji pojavnosti prekatnih motenj ritma v istem obdobju. Po vstavitvi CRT je ER dosežena preden so beležene pomembne volumetrične spremembe LV. Bolniki z doseženo ER po vstavitvi CRT imajo boljši klinični izid zdravljenja v primerjavi z bolnik brez ER.

• Language: Slovenian
• Keywords: atrio-biventrikularana elektrostimulacija, ECG, repolarizacija, QRS kompleks, remodelacija
• Work type: Doctoral dissertation
• Organization: MF - Faculty of Medicine
• Year: 2018
• PID: 20.500.12556/RUL-101601
• COBISS.SI-ID: 3914004
• Publication date in RUL: 21.06.2018

Secondary language

• Language: English
• Title: THE ROLE OF HIGH-RESOLUTION ELECTROCARDIOGRAPHIC PARAMETERS IN TREATMENT OF HEART FAILURE WITH ATRIO-BIVENTRICULAR PACING

Abstract

Background: Cardiac resynchronization therapy (CRT) has emerged as an effective treatment strategy for patients with advanced heart failure (New York Heart Association classes II–IV heart failure, left ventricular ejection fraction (LVEF) ≤ 35%, and a QRS duration ≥ 120 ms). Approximately 30% of patients do not respond favourably to CRT. In recent years, the proportion of patients who respond favourably to CRT did not increase significantly. CRT is merely electrical therapy that improves left ventricular (LV) mechanical dyssynchrony by changing the sequence of electrical activation and restoring electrical synchrony. Therefore, ECG parameters of conduction anomalies and electrical dyssynchrony play an evolving and important role in understanding the mechanism of CRT response. Little is known about the effect of CRT on ventricular repolarization parameters. There are some data about the increase repolarization heterogeneity after CRT and potentially its proarrhytmic effect. On the other hand, some studies found amelioration of repolarization heterogeneity after CRT. However, interdependence between electrical and mechanical remodelling and time course of electrical remodelling have not been fully investigated. The present thesis evaluated the value of different ECG parameters in heart failure patients treated with CRT and clarified the time course and relationship between electrical and mechanical reverse remodelling after CRT. Methods: The study population was selected from heart failure patients treated with CRT according to contemporary guidelines in University medical centre Ljubljana. All patients included in the study had transthoracic two-dimensional echocardiography performed at baseline and at follow-up visits (1, 3, 6, 9 and 12 months after implantation). Resting supine 12-lead ECGs and 20-minutes high-resolution Holter ECG were recorded before and after CRT implantation. At follow-ups, CRT was temporarily reprogrammed to VVI 40 bpm to allow native conduction. An absolute decrease in native pre-implant QRS duration ≥ 10 ms was defined as significant electrical remodelling (ER). Relative change in QRS duration was defined as the difference between post-implant QRS duration and baseline QRS duration divided by baseline QRS duration expressed in percent. All ventricular repolarization parameters (T-wave amplitude variability [TAV], QTa interval [QT apex], QTe interval [QT end], dispersion of QT, Tpeak to Tend interval [TpTe], and TpTe /QT ratio) were assessed from high-resolution 20-minutes ECG recordings. Ventricular tachyarrhythmia episodes (VTs) were classified as sustained ventricular tachycardia with appropriate ICD therapy or ventricular fibrillation. Heart failure hospitalization, cardiovascular death and cardiac transplantation were used as a combined end point to observe clinical outcome. Results: I. The association of electrocardiographic parameters from 12-leads ECG and response to CRT The study population consisted of 101 patients with a mean age of 63.2 ± 10.9 years (66 (65.2%) males, 37 (36.6%) ischaemic aetiology, 77 patients (76.2%) in NYHA class III). After 12 months of biventricular pacing, 32 patients (31.7%) fulfilled the echocardiographic criteria of super-response (a relative reduction in LVESV ≥ 30%). There were no statistically significant differences in baseline ECG parameters when super-responder group was compared with non-super-responder group. Post-implant paced QRS duration was shorter in super-responder group (148 ± 22 ms vs. 162 ± 28 ms; P = 0.010). Additionally, only in super-responders significant QRS reduction was observed after implantation (super-responders: from 167 ± 26 ms to 148 ± 22 ms; P=0.010 vs. non-super-responders: from 165 ± 27 ms to 162 ± 28 ms; P = 0.536). Relative shortening of QRS complex was significantly higher in super-responders (12.1% (6.8-22.2) vs. 1.7% ([-11.9] to 11.8); P = 0.005). Only relative QRS shortening remained independently related to super-response to CRT in multivariable model adjusting for NYHA class, normal axis and LBBB with mid-QRS notching. II. The effect of cardiac resynchronization therapy on ventricular repolarization parameters and their relation to ventricular tachyarrhythmias Sixty-four patients (mean age of 63.9 ± 10.9 years, 47 (73%) males, 23 (36%) ischaemic cardiomyopathy) were enrolled in the analysis. Response to CRT, predefined as a relative reduction in LVESV ≥ 15%, was observed in 33 patients (51.6%). There were significant changes in repolarization parameters of native conduction over 12 months after CRT implantation. Significant changes over time was observed in QTec (P < 0.001), TpTe (P < 0.001), TpTe/QT ratio (P < 0.001) and dispersion of QTe (P < 0.014), whereas TAV values and QTa intervals were unchanged over first year after CRT. All repolarization parameters showed a similar pattern of changes with the increased repolarization heterogeneity in first months after CRT implantation, which then declined over time. Significant differences in repolarization parameters were observed between patients with and those without echocardiographic response to CRT. In responder group, despite significant prolongation in the first months, decline of repolarization parameters were noted during further follow-ups. On the other hand, in non-responder group progressive increase of repolarization parameters at follow-ups compared with pre-implant value were observed. Responder and non-responder group had similar pre-implant value of all repolarization parameters. Significant difference between groups in repolarization parameters was detected after 6 months of biventricular pacing. Appropriate device therapy was observed in 10 patients (15.6%) within 1 year after CRT implantation. More than half of the patients (60%) had VTs within the first month after CRT implantation. Distribution of VTs with the highest occurrence in the first month corresponded with the highest repolarization heterogeneity in the same period. III. Time course and relationship between electrical and mechanical reverse remodelling after CRT The study population included 62 patients (50 (81%) males, with mean age of 65.7 ± 10.3 years). There were significant changes in native QRS duration during 12 months after implantation (P = 0.003). Significant shortening of QRS duration was already observed at 1 month after CRT (pre-implant vs. 1 month: 185ms (175-194) vs. 180ms (170-186); P < 0.05), which persisted during further follow-ups. On the other hand, progressive LV structural remodelling was observed during 12 months with continuous reductions in LV volumes and improvement of LVEF (P < 0.001, for all). However, significant echocardiographic changes were observed only after 3 months of CRT (EDV: 231 ml (191-280) vs. 200 ml (167-267), P < 0.05; ESV: 167 ml (137-206) vs. 140 ml (112-196), P < 0.05; EF: 27% (24-31) vs. 31% (24-38), P < 0.05). In patients with ER, the reductions in QRS duration were already pronounced after one month of CRT (pre-implant vs. 1 month: 190 ms [179-196] vs. 180 ms [173-186]; P < 0.001) and persisted over follow-up. There were no changes in QRS duration during follow-ups in patients without ER. One month after implantation, relative changes in ESV were similar in both groups. At later follow-ups, patients with ER demonstrated progressive reverse LV remodelling compared with patients without ER. During a median follow-up of 27 months (18–37 months), the combined end point was observed in 15 (24.2%) patients. Compared with patients without ER, a superior survival free from combined end point was observed among patients with ER (chi-squared = 4.85, log-rank P = 0.028). Conclusion: Some baseline ECG parameters from 12-leads ECG recording are associated with increased degree of echocardiographic response after CRT. Absolute post-implant QRS duration and acute relative shortening of QRS duration after initiation of CRT were correlated with super-response. However, there were dynamic changes of repolarization parameters of native conduction during 12 months after CRT. Increase repolarization heterogeneity in the first month after CRT corresponded with the high rate of VTs in the same periods. Additionally, electrical remodelling of native conduction is achieved before mechanical remodelling. Patients with electrical remodelling had better clinical outcome compared with patients without electrical remodelling.

• Keywords: cardiac resynchronization therapy, ECG, repolarization, QRS, remodelling