Inhibition of Thrombin in Cardiac Surgery : experiments in a porcine model

Cardiac surgery involving cardiopulmonary bypass (CPB) induces activation of inflammation and coagulation systems and is associated with ischemia-reperfusion injury (I/R injury)in various organs including the myocardium, lungs, and intestine. I/R injury is manifested as organ dysfunction. Thrombin, the key enzyme of coagulation , plays a cenral role also in inflammation and contributes to regulation of apoptosis as well. The general aim of this thesis was to evaluate the potential of thrombin inhibition in reducing the adverse effects of I/R injury in myocardium, lungs, and intestine associated with the use of CPB and cardiac surgery. Forty five pigs were used for the studies. Two randomized blinded studies were performed. Animals underwent 75 min of normothermic CPB, 60 min of aortic clamping, and 120 min of reperfusion period. Twenty animals received iv. recombinant hirudin, a selective and effective inbitor of thrombin, or placebo. In a similar setting, twenty animals received an iv-bolus (250 IU/kg) of antithrombin (AT) or placebo. An additional group of 5 animals received 500 IU/kg in an open label setting to test dose response. Generation of thrombin (TAT), coagulation status (ACT), and hemodynamics were measured. Intramucosal pH and pCO2 were measured from the luminal surface of ileum using tonometry simultaneusly with arterial gas analysis. In addition, myocardial, lung, and intestinal biopsies were taken to quantitate leukocyte infiltration (MPO), for histological evaluation, and detection of apoptosis (TUNEL, caspase 3). In conclusion, our data suggest that r-hirudin may be an effective inhibitor of reperfusion induced thrombin generation in addition to being a direct inhibitor of preformed thrombin. Overall, the results suggest that inhibition of thrombin, beyond what is needed for efficient anticoagulation by heparin, has beneficial effects on myocardial I/R injury and hemodynamics during cardiac surgery and CPB. We showed that infusion of the thrombin inhibitor r-hirudin during reperfusion was associated with attenuated post ischemia left ventricular dysfunction and decreased systemic vascular resistance. Consequently microvascular flow was improved during ischemia-reperfusion injury. Improved recovery of myocardium during the post-ischemic reperfusion period was associated with significantly less cardiomyocyte apoptosis and with a trend in anti-inflammatory effects. Thus, inhibition of reperfusion induced thrombin may offer beneficial effects by mechanisms other than direct anticoagulant effects. AT, in doses with a significant anticoagulant effect, did not alleviate myocardial I/R injury in terms of myocardial recovery, histological inflammatory changes or post-ischemic troponin T release. Instead, AT attenuated reperfusion induced increase in pulmonary pressure after CPB. Taken the clinical significance of postoperative pulmonary hemodynamics in patients undergoing cardiopulmonary bypass, the potential positive regulatory role of AT and clinical implications needs to be studied further. Inflammatory response in the gut wall proved to be poorly associated with perturbed mucosal perfusion and the animals with the least neutrophil tissue sequestration and I/R related histological alterations tended to have the most progressive mucosal hypoperfusion. Thus, mechanisms of low-flow reperfusion injury during CPB can differ from the mechanisms seen in total ischemia reperfusion injury.Sydänkeuhkoneen käyttö ja kirurginen vamma käynnistävät elimistössä voimakkaan tulehdus- ja hyytymisjärjestelmän aktivaation. Avosydänleikkauksissa sydän pysäytetään ja sen verenkierto estetään toimenpiteen ajaksi. Lisäksi sydänkehkokoneen käytön aikainen poikkeava verenkierto voi johtaa muidenkin elinten kuten suolen ja keuhkojen toimintahäiriöön. Erityisesti elinten verenkierron palautumisvaiheeseen, ns. reperfuusiovaiheesen, liittyy paikallinen nopea tulehdus- ja hyytymismekanismin monimutkainen ja osin yhteensidottu aktivoituminen, jossa trombiinilla näyttäisi olevan keskeinen asema. Trombiinilla tiedetään olevan myös apoptoosia aktivoivia ominaisuuksia. Tämän tutkimussarjan yleistavoitteena oli selvittää voidaanko sydänkirurgiaan ja sydänkeuhkokoneen käyttöön liittyvässä iskemia-reperfuusiotilanteessa sydänlihaksen, keuhkojen ja suoliston toipumista edistää eri mekanismeilla toimivilla trombiinin estäjillä. Sisällyttämällä koeasetelmaan kaksi eri mekanismilla toimivaa trombiininestäjää (hirudiini, antitrombiini) ja mittaamalla samanaikaisesti sekä hyytymismekanismin aktivaatiota että inflammatorista vastetta pyrittiin erittelemään välittyykö mahdollinen toipumista edistävä mekanismi puhtaasti trombiinin eston kautta ja onko antitrombiinin trombiinin estosta erillisellä anti-inflammatorisella vaikutuksella merkitystä. Kyseessä oli avosydänkirurginen koeasetelma sialla, jossa eläin kytkettiin sydänkeuhkokoneeseen. Satunnaistetusti ja sokotetusti 15 min ennen yhden tunnin sydänlihasiskemian loppua sian verenkiertoon annettiin tutkimuslääkettä tai placeboa. Sydämen hemodynaamista toipumista seurattiin kahden tunnin ajan ja samalla mitattiin sekä hyytymisaktivaatiota trombiinin muodostuksen tasolla että inflammatorista vastetta verinäytteistä ja sydän- ja suolibiopsioista. Kahden tunnin reperfuusiovaiheen jälkeen sydänlihaksesta, keuhkoista ja suolesta otettiin koepalat histologista tarkastelua ja apoptoosin määrittämistä varten. Lisäksi suoliston verenkiertoa mitattiin epäsuorasti ohutsuoleen asetetun tonometria katetrin avulla perfuusion aikana ja sen jälkeen. Yhteenvetona osatöiden tuloksista todettiin, että hirudiini estää sekä reperfuusion aikaista trombiinin muodostusta että jo muodostunutta trombiinia, jolla on edullisia vaikutuksia sydänlihaksen toipumiseen iskeemisestä stressistä, systeemiverenkierron vastukseen ja suoliston mikroverenkiertoon. Sydänlihaksen koepaloista mikroskoopilla tehdyssä analyysissä mikrotromboosia ei todettu mutta sydänlihaksen parempaan toipumiseen liittyi hirudiinia saaneilla eläimillä tulehdussolujen vähäisempi määrä ja apoptoosia esiintyi merkittävästi vähemmän kuin kontrolleilla. Johtopäätöksenä oli, että reperfuusion aikaisen trombiinin muodostuksen estolla näyttäsi olevan muitakin edullisia vaikutuksia sydänlihaksen toipumisessa kuin hyytymisjärjestelmän aktivaation esto. Antitrombiinin veren hyytymistä estävä vaikutus tuli selvästi esille mutta antitrombiini ei vähentänyt reperfuusion aikaista trombiinin muodostusta. Antitrombiini ei estänyt sydänlihaksen histologista vauriota ja vaikutus minuuttivolyymiin ja isku-tilavuuteen oli vain lyhytaikaista ja ohimenevää. Sen sijaan antitrombiini näytti merkittävästi estävän reperfuusiovaiheen keuhkovaltimopaineen ja –vastuksen nousua. Suolen seinämän tulehduksellinen vaste ei assosioitunut suolen limakalvon huonontuneeseen verenkiertoon vaan päinvastoin. Tämä löydös oli vastoin aiempia kokeellisilla suolen verenkierron kokonaan estetyillä malleilla tehtyjä havaintoja. Tulos viittaa siihen, että sydänkeuhkokoneen aiheuttama verenkierron low-flow tilanteen reperfuusiovaurion mekanismit ja sen seuraukset suolen seinämässä poikkeavat totaalin iskemia-reperfuusio vaurion mekanismeista

13-year single-center experience with the treatment of acute type B aortic dissection

Background. Acute type B aortic dissection (TBAD) is catastrophic event associated with significant mortality and lifelong morbidity. The optimal treatment strategy of TBAD is still controversial. Methods. This analysis includes patients treated for TBAD at the Helsinki University Hospital, Finland in 2007-2019. The endpoints were early and late mortality, and intervention of the aorta. Results. There were 205 consecutive TBAD patients, 59 complicated and 146 uncomplicated patients (mean age of 66 +/- 14, females 27.8%). In-hospital and 30-day mortality rates were higher in complicated patients compared with uncomplicated patients with a statistically significant difference (p = 0.035 and p = 0.015, respectively). After a mean follow-up of 4.9 +/- 3.8 years, 36 (25.0%) and 22 (37.9%) TBAD -related adverse events occurred in the uncomplicated and complicated groups, respectively (p = 0.066). Freedom from composite outcome was 83 +/- 3% and 69 +/- 6% at 1 year, 75 +/- 4% and 63 +/- 7% at 5 years, 70 +/- 5% and 59 +/- 7% at 10 years in the uncomplicated group and in the complicated group, respectively (p = 0.052). There were 25 (39.1%) TBAD-related deaths in the overall series and prior aortic aneurysm was the only risk factor for adverse aortic-related events in multivariate analysis (HR 3.46, 95% CI 1.72-6.96, p < 0.001). Conclusion. TBAD is associated with a significant risk of early and late adverse events. Such a risk tends to be lower among patients with uncomplicated dissection, still one fourth of them experience TBAD-related event. Recognition of risk factors in the uncomplicated group who may benefit from early aortic repair would be beneficial.Peer reviewe

Torakoabdominaalisten aortta-aneurysmien hoito Suomessa vuonna 2020

Torakoabdominaalisten aortta-aneurysmien ja munuaisvaltimoiden yläpuolelle ulottuvien pararenaalisten vatsa-aortta-aneurysmien hoito on keskitetty Suomessa yliopistosairaaloihin. Näiden valtimonpullistumien hoito on vaativaa, koska munuaisvaltimot ja suolilievevaltimot lähtevät aortan aneurysmaattisesta segmentistä. Aneurysman hoidossa näiden sivuhaarojen verenkierto täytyy rekonstruoida joko avoleikkauksen yhteydessä aorttaproteesista lähtevillä sivuhaaroilla tai suonensisäisessä hoidossa endovaskulaarisilla tekniikoilla. Avoleikkaus on vakiintunut hoitomuoto, johon kuitenkin liittyy merkittävä kuoleman ja vakavien komplikaatioiden riski. Avoleikkauksen ja suonensisäisen hoidon yhdistelmä eli hybridileikkaus on tavanomaista avoleikkausta kevyempi vaihtoehto, mutta silti suuri ja riskialtis toimenpide. Monimutkaisen endovaskulaarisen hoidon tulokset isoissa keskuksissa ovat nykyään vertailukelpoisia tai parempia avoleikkaukseen verrattuna, vaikka endovaskulaaritekniikalla hoidetut potilaat ovat usein iäkkäämpiä ja sairaampia. Endovaskulaarisesta hoitomuodosta on tullut merkittävä pararenaalisten ja torakoabdominaalisten aortta-aneurysmien avoleikkauksen vaihtoehto potilaille, joiden verisuonianatomia soveltuu suonensisäiseen toimenpiteeseen

Late Outcome after Surgery for Type-A Aortic Dissection

The aim of this study was to evaluate all-cause mortality and aortic reoperations after surgery for Stanford type A aortic dissection (TAAD). We evaluated the late outcome of patients who underwent surgery for acute TAAD from January 2005 to December 2017 at the Helsinki University Hospital, Finland. We studied 309 patients (DeBakey type I TAAD: 89.3%) who underwent repair of TAAD. Aortic root repair was performed in 94 patients (30.4%), hemiarch repair in 264 patients (85.4%) and partial/total aortic arch repair in 32 patients (10.4%). Hospital mortality was 13.6%. At 10 years, all-cause mortality was 34.9%, and the cumulative incidence of aortic reoperation or late aortic-related death was 15.6%, of any aortic reoperation 14.6%, reoperation on the aortic root 6.6%, on the aortic arch, descending thoracic and/or abdominal aorta 8.7%, on the descending thoracic and/or abdominal aorta 6.4%, and on the abdominal aorta 3.8%. At 10 years, cumulative incidence of reoperation on the distal aorta was higher in patients with a diameter of the descending thoracic aorta >= 35 mm at primary surgery (cumulative incidence in the overall series: 13.2% vs. 4.0%, SHR 3.993, 95%CI 1.316-12.120; DeBakey type I aortic dissection: 13.6% vs. 4.5%, SHR 3.610, 95%CI 1.193-10.913; patients with dissected descending thoracic aorta: 15.8% vs. 5.9%, SHR 3.211, 95%CI 1.067-9.664). In conclusion, surgical repair of TAAD limited to the aortic segments involved by the intimal tear was associated with favorable survival and a low rate of aortic reoperations. However, patients with enlarged descending thoracic aorta at primary surgery had higher risk of late reoperation. Half of the distal aortic reinterventions were performed on the abdominal aorta

Impact of national holidays and weekends on incidence of acute type A aortic dissection repair

Publisher Copyright: © 2022, The Author(s).Previous studies have demonstrated that environmental and temporal factors may affect the incidence of acute type A aortic dissection (ATAAD). Here, we aimed to investigate the hypothesis that national holidays and weekends influence the incidence of surgery for ATAAD. For the period 1st of January 2005 until 31st of December 2019, we investigated a hypothesised effect of (country-specific) national holidays and weekends on the frequency of 2995 surgical repairs for ATAAD at 10 Nordic cities included in the Nordic Consortium for Acute Type A Aortic Dissection (NORCAAD) collaboration. Compared to other days, the number of ATAAD repairs were 29% (RR 0.71; 95% CI 0.54–0.94) lower on national holidays and 26% (RR 0.74; 95% CI 0.68–0.82) lower on weekends. As day of week patterns of symptom duration were assessed and the primary analyses were adjusted for period of year, our findings suggest that the reduced surgical incidence on national holidays and weekends does not seem to correspond to seasonal effects or surgery being delayed and performed on regular working days.Peer reviewe

Epitranscriptomics of Ischemic Heart Disease—The IHD-EPITRAN Study Design and Objectives

Epitranscriptomic modifications in RNA can dramatically alter the way our genetic code is deciphered. Cells utilize these modifications not only to maintain physiological processes, but also to respond to extracellular cues and various stressors. Most often, adenosine residues in RNA are targeted, and result in modifications including methylation and deamination. Such modified residues as N-6-methyl-adenosine (m6A) and inosine, respectively, have been associated with cardiovascular diseases, and contribute to disease pathologies. The Ischemic Heart Disease Epitranscriptomics and Biomarkers (IHD-EPITRAN) study aims to provide a more comprehensive understanding to their nature and role in cardiovascular pathology. The study hypothesis is that pathological features of IHD are mirrored in the blood epitranscriptome. The IHD-EPITRAN study focuses on m6A and A-to-I modifications of RNA. Patients are recruited from four cohorts: (I) patients with IHD and myocardial infarction undergoing urgent revascularization; (II) patients with stable IHD undergoing coronary artery bypass grafting; (III) controls without coronary obstructions undergoing valve replacement due to aortic stenosis and (IV) controls with healthy coronaries verified by computed tomography. The abundance and distribution of m6A and A-to-I modifications in blood RNA are charted by quantitative and qualitative methods. Selected other modified nucleosides as well as IHD candidate protein and metabolic biomarkers are measured for reference. The results of the IHD-EPITRAN study can be expected to enable identification of epitranscriptomic IHD biomarker candidates and potential drug targets

Outcome after Surgery for Iatrogenic Acute Type A Aortic Dissection

(1) Background: Acute Stanford type A aortic dissection (TAAD) may complicate the outcome of cardiovascular procedures. Data on the outcome after surgery for iatrogenic acute TAAD is scarce. (2) Methods: The European Registry of Type A Aortic Dissection (ERTAAD) is a multicenter, retrospective study including patients who underwent surgery for acute TAAD at 18 hospitals from eight European countries. The primary outcomes were in-hospital mortality and 5-year mortality. Twenty-seven secondary outcomes were evaluated. (3) Results: Out of 3902 consecutive patients who underwent surgery for acute TAAD, 103 (2.6%) had iatrogenic TAAD. Cardiac surgery (37.8%) and percutaneous coronary intervention (36.9%) were the most frequent causes leading to iatrogenic TAAD, followed by diagnostic coronary angiography (13.6%), transcatheter aortic valve replacement (10.7%) and peripheral endovascular procedure (1.0%). In hospital mortality was 20.5% after cardiac surgery, 31.6% after percutaneous coronary intervention, 42.9% after diagnostic coronary angiography, 45.5% after transcatheter aortic valve replacement and nihil after peripheral endovascular procedure (p = 0.092), with similar 5-year mortality between different subgroups of iatrogenic TAAD (p = 0.710). Among 102 propensity score matched pairs, in-hospital mortality was significantly higher among patients with iatrogenic TAAD (30.4% vs. 15.7%, p = 0.013) compared to those with spontaneous TAAD. This finding was likely related to higher risk of postoperative heart failure (35.3% vs. 10.8%, p < 0.0001) among iatrogenic TAAD patients. Five-year mortality was comparable between patients with iatrogenic and spontaneous TAAD (46.2% vs. 39.4%, p = 0.163). (4) Conclusions: Iatrogenic origin of acute TAAD is quite uncommon but carries a significantly increased risk of in-hospital mortality compared to spontaneous TAAD

Outcome after Surgery for Iatrogenic Acute Type A Aortic Dissection

(1) Background: Acute Stanford type A aortic dissection (TAAD) may complicate the outcome of cardiovascular procedures. Data on the outcome after surgery for iatrogenic acute TAAD is scarce. (2) Methods: The European Registry of Type A Aortic Dissection (ERTAAD) is a multicenter, retrospective study including patients who underwent surgery for acute TAAD at 18 hospitals from eight European countries. The primary outcomes were in-hospital mortality and 5-year mortality. Twenty-seven secondary outcomes were evaluated. (3) Results: Out of 3902 consecutive patients who underwent surgery for acute TAAD, 103 (2.6%) had iatrogenic TAAD. Cardiac surgery (37.8%) and percutaneous coronary intervention (36.9%) were the most frequent causes leading to iatrogenic TAAD, followed by diagnostic coronary angiography (13.6%), transcatheter aortic valve replacement (10.7%) and peripheral endovascular procedure (1.0%). In hospital mortality was 20.5% after cardiac surgery, 31.6% after percutaneous coronary intervention, 42.9% after diagnostic coronary angiography, 45.5% after transcatheter aortic valve replacement and nihil after peripheral endovascular procedure (p = 0.092), with similar 5-year mortality between different subgroups of iatrogenic TAAD (p = 0.710). Among 102 propensity score matched pairs, in-hospital mortality was significantly higher among patients with iatrogenic TAAD (30.4% vs. 15.7%, p = 0.013) compared to those with spontaneous TAAD. This finding was likely related to higher risk of postoperative heart failure (35.3% vs. 10.8%, p &lt; 0.0001) among iatrogenic TAAD patients. Five-year mortality was comparable between patients with iatrogenic and spontaneous TAAD (46.2% vs. 39.4%, p = 0.163). (4) Conclusions: Iatrogenic origin of acute TAAD is quite uncommon but carries a significantly increased risk of in-hospital mortality compared to spontaneous TAAD

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