Advanced mapping techniques in contemporary management of ventricular arrhythmias:unmasking the arrhythmic substrate

Both prophylactic ICD implantation and catheter ablation have important therapeutic implications in contemporary management of patients with lifetreatening rhythm disorders after myocardial infarction, originating from an arhrythmic substrate from a scarred area. According to the longterm results of the DAPA trial, prophylactic implantation of an implantable cardioverter defibrillator in patients with an acute myocardial infarction undergoing percutanous coronary intervention, reduced the risk for death in certain high-risk patients. This study underlined that we need to be careful extrapolating evidence of aging literature on a contemporary population. Other development of novel technologies in the field of catheter ablation, also asks for development of our view on the intended use of these strategies. Especially for specific cardiac diseases due to genetic mutations (Brugada syndrome and PLN mutants), there is not a one-size fits all manner for catheter based ablation and a disease-specific approach is mandatory for successful treatment. This thesis has shown that electro-anatomic mapping may be of significant value for a more complete definition and understanding of the arrhythmic substrate

Improving Clinical Risk Stratification at Diagnosis in Primary Prostate Cancer: A Prognostic Modelling Study.

INTRODUCTION: Over 80% of the nearly 1 million men diagnosed with prostate cancer annually worldwide present with localised or locally advanced non-metastatic disease. Risk stratification is the cornerstone for clinical decision making and treatment selection for these men. The most widely applied stratification systems use presenting prostate-specific antigen (PSA) concentration, biopsy Gleason grade, and clinical stage to classify patients as low, intermediate, or high risk. There is, however, significant heterogeneity in outcomes within these standard groupings. The International Society of Urological Pathology (ISUP) has recently adopted a prognosis-based pathological classification that has yet to be included within a risk stratification system. Here we developed and tested a new stratification system based on the number of individual risk factors and incorporating the new ISUP prognostic score. METHODS AND FINDINGS: Diagnostic clinicopathological data from 10,139 men with non-metastatic prostate cancer were available for this study from the Public Health England National Cancer Registration Service Eastern Office. This cohort was divided into a training set (n = 6,026; 1,557 total deaths, with 462 from prostate cancer) and a testing set (n = 4,113; 1,053 total deaths, with 327 from prostate cancer). The median follow-up was 6.9 y, and the primary outcome measure was prostate-cancer-specific mortality (PCSM). An external validation cohort (n = 1,706) was also used. Patients were first categorised as low, intermediate, or high risk using the current three-stratum stratification system endorsed by the National Institute for Health and Care Excellence (NICE) guidelines. The variables used to define the groups (PSA concentration, Gleason grading, and clinical stage) were then used to sub-stratify within each risk category by testing the individual and then combined number of risk factors. In addition, we incorporated the new ISUP prognostic score as a discriminator. Using this approach, a new five-stratum risk stratification system was produced, and its prognostic power was compared against the current system, with PCSM as the outcome. The results were analysed using a Cox hazards model, the log-rank test, Kaplan-Meier curves, competing-risks regression, and concordance indices. In the training set, the new risk stratification system identified distinct subgroups with different risks of PCSM in pair-wise comparison (p < 0.0001). Specifically, the new classification identified a very low-risk group (Group 1), a subgroup of intermediate-risk cancers with a low PCSM risk (Group 2, hazard ratio [HR] 1.62 [95% CI 0.96-2.75]), and a subgroup of intermediate-risk cancers with an increased PCSM risk (Group 3, HR 3.35 [95% CI 2.04-5.49]) (p < 0.0001). High-risk cancers were also sub-classified by the new system into subgroups with lower and higher PCSM risk: Group 4 (HR 5.03 [95% CI 3.25-7.80]) and Group 5 (HR 17.28 [95% CI 11.2-26.67]) (p < 0.0001), respectively. These results were recapitulated in the testing set and remained robust after inclusion of competing risks. In comparison to the current risk stratification system, the new system demonstrated improved prognostic performance, with a concordance index of 0.75 (95% CI 0.72-0.77) versus 0.69 (95% CI 0.66-0.71) (p < 0.0001). In an external cohort, the new system achieved a concordance index of 0.79 (95% CI 0.75-0.84) for predicting PCSM versus 0.66 (95% CI 0.63-0.69) (p < 0.0001) for the current NICE risk stratification system. The main limitations of the study were that it was registry based and that follow-up was relatively short. CONCLUSIONS: A novel and simple five-stratum risk stratification system outperforms the standard three-stratum risk stratification system in predicting the risk of PCSM at diagnosis in men with primary non-metastatic prostate cancer, even when accounting for competing risks. This model also allows delineation of new clinically relevant subgroups of men who might potentially receive more appropriate therapy for their disease. Future research will seek to validate our results in external datasets and will explore the value of including additional variables in the system in order in improve prognostic performance.This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pmed.100206

Molecular Classification of Bladder Cancer

Decisions in the treatment of bladder cancer today are based on clinical and pathological risk variables such as tumor stage and tumor grade. The importance of these conventional risk variables is well documented since more than 10 years, and they are used routinely in the clinics. Over the last ten years, cancer research has seen a gradual transition towards personalized medicine, i.e. the exploitation of specific molecular properties in the treatment of tumors. The starting point for personalized medicine is a taxonomy of the tumor type, where genome, transcriptome, and/or proteome data is used to define molecular subtypes that make sense from biological and clinical viewpoints. The overall aim of the work presented in this thesis is to define the major gene expression subtypes of bladder tumors. The gene expression based subtypes should be viewed as a framework which can be refined either by the integration of genomic, epigenetic, or proteomic data or by the analysis of larger patient cohorts so that the subtypes can be described in greater detail. An exhaustive tumor classification should be based on biological similarity between tumors, and not only group together tumors with similar clinical risk profile. This will increase the probability that the taxonomy is relevant in the evaluation of novel therapies that function by altering pathways or transcriptional programs. In paper 1 we define the two major subtypes of bladder cancer, termed molecular subtype 1 and 2 (MS1 and MS2). In paper 2, MS1 and MS2 are subdivided into five major subtypes named Urobasal A, Urobasal B, Genomically Unstable, SCC-like, and Infiltrated, named after their dominating molecular characteristics. The subtypes were identified in an unsupervised manner and were identified also in external data sets, showing their general applicability. Secondary to the aim of tumor classification is the evaluation of the potential prognostic value of the described subtypes. To allow for clinical comparisons, tumor classification should be possible using immunohistochemistry (IHC) on archived material. In paper 3 we make use of the same set of tumors as in paper 2 and device a simplified classifier based on IHC and histology. This classifier identifies the five subtypes with the exception of Urobasal B which could not be reliably distinguished from the related Urobasal A subtype. The molecular pathological classifier defined in paper 3 thus has room for improvement and will need to evolve as the true molecular subtypes are refined. Up to this point we have shown that the subtypes differ in prognosis, but we could not determine whether this was independent of differences observed in stage and grade. In paper 4 we use an independent population based cohort of T1 tumors to retrospectively estimate the prognostic value of the molecular subtypes. The IHC/histology classifier defined in paper 3 is applied, and the molecular subtypes are compared to a current clinical risk stratification model in multivariate analyses. The results show that the subtypes contain as much prognostic information as the current clinical model, and that the best risk stratification is achieved by combining the subtypes with clinical data and an estimate of CD3+ lymphocyte infiltration

Association of the high-sensitive cardiac troponin T levels and long-term mortality in patients with acute aortic dissection type A

Introduction: Acute aortic dissection type A is a life-threatening cardiovascular emergency necessitating rapid diagnosis and treatment. We sought a new prognostic tool with cardiac biomarkers and simple inflammatory factors. Methods: from 2003 to 2014, 50 patients with documented acute aortic dissection type A were entered to this study. These patients were followed up until December 2020; within median follow up of 93.6 months. The patients were evaluated on the association of the baseline characteristics, first laboratory investigation, echocardiographic findings, surgical approach, and long-term mortality. Results: Total number of mortality during the follow up was 29 (58%) patients, which was significantly higher in medical group (89.4% vs 38.7%, P value=0.001). Multivariable analysis showed only an increase in hs-cTnT levels was suggested as a predictor of mortality (95% CI: 1.06–1.38; HR=1.21; P=0.005), so that for every 100 units increase, patients were 21% more likely to have mortality in long term. Also, performing surgical treatment for aortic dissection was determined as the independent predictor of surviving, so that death was 74.6% less than those who received medical treatment (95% CI: 0.13–0.58; HR=0.27; P=0.001). Conclusion: hs-cTnT is a potential predictor of mortality in patients with acute aortic dissection type A

Cardiac Magnetic Resonance as Risk Stratification Tool in Non-Ischemic Dilated Cardiomyopathy Referred for Implantable Cardioverter Defibrillator Therapy—State of Art and Perspectives

Non-ischemic dilated cardiomyopathy (DCM) is a disease characterized by left ventricular dilation and systolic dysfunction. Patients with DCM are at higher risk for ventricular arrhythmias and sudden cardiac death (SCD). According to current international guidelines, left ventricular ejection fraction (LVEF) <= 35% represents the main indication for prophylactic implantable cardioverter defibrillator (ICD) implantation in patients with DCM. However, LVEF lacks sensitivity and specificity as a risk marker for SCD. It has been seen that the majority of patients with DCM do not actually benefit from the ICD implantation and, on the contrary, that many patients at risk of SCD are not identified as they have preserved or mildly depressed LVEF. Therefore, the use of LVEF as unique decision parameter does not maximize the benefit of ICD therapy. Multiple risk factors used in combination could likely predict SCD risk better than any single risk parameter. Several predictors have been proposed including genetic variants, electric indexes, and volumetric parameters of LV. Cardiac magnetic resonance (CMR) can improve risk stratification thanks to tissue characterization sequences such as LGE sequence, parametric mapping, and feature tracking. This review evaluates the role of CMR as a risk stratification tool in DCM patients referred for ICD

Multi-omic characterisation of Barrett’s oesophagus reveals a molecular continuum in the progression to oesophageal adenocarcinoma

Barrett’s oesophagus (BE) is the main risk factor for the development of oesophageal adenocarcinoma (OAC) yet only 0.4%/year of non-dysplastic (ND) BE cases progress to cancer (Bhat et al., 2011). In this thesis I present the first comprehensive, multi-omics study comparing indolent, non-progressors with those who progressed to a range of dysplasia grades. BE is highly heterogeneous with regards to mutational load, copy-number aberrations (CNAs) and structural variants (SVs). Mutational signatures are laid down early and persist regardless of progression status. Hence, Cosmic signature 17 (T:A>G:C in a CTT context), the hallmark of OAC, is visible in indolent, ND samples. TP53 mutation, GATA6 amplification, ERBB2 amplification, APC mutation and whole genome doubling are confined to cases that have progressed with TP53 being by far the most prevalent. In contrast CDKN2A alteration occurs early in around 50% of indolent cases. SV analysis reveals a dominance of translocations from the early ND grade. Spatial analysis of multiple samples from across BE segments shows that the total mutation burden, total CNAs and total numbers of SVs to be surprisingly constant. However, clonality analysis highlights the complexity of BE, with some cases arising from a clear ancestral clone while others having minimal sharing of variants and showing heterogeneity in terms of driver events. Transcriptomic analysis reveals a clear but gradual differential gene expression between ND and dysplastic biopsies. We demonstrate a loss of the intestinal metaplasia phenotype with progression and downregulation of the HNF4A pathway, a transcription factor with roles in intestinal development. In progression there is an upregulation of genes in the ERK/MAPK pathway. In summary, BE is a heterogeneous disease that shows a continuum of abnormalities in the progression towards cancer. We hypothesise that it is the accumulation of events that tip the balance to progression, rather than a stepwise model through the phenotypic dysplasia grades. Selected features could help to differentiate indolent from high risk disease and further work is being performed to identify scoring systems and biomarkers to apply in the clinical setting

Cardiogenic shock; focus on ventilatory strategies, the elderly, and biomarker-based risk stratification

Cardiogenic shock (CS) is the most severe form of acute heart failure (HF) characterized by hypotension and systemic hypoperfusion caused by cardiac dysfunction. Prolonged hypotension provokes neurohumoral compensatory mechanisms and systemic inflammatory responses, leading to organ injury followed by multiorgan failure and poor prognosis. CS may be caused by various etiological factors, acute coronary syndromes (ACS) being the most common cause. In addition to prompt recognition of CS, the cause of shock should be treated urgently, as by means of immediate revascularization in the case of ACS-related CS. Although aggressive therapy options, such as mechanical circulatory devices and ventilatory support, may be used, this approach is demanding on the patient, carries risk for complications, and requires additional healthcare resources. Despite advanced therapy options, prognosis in CS is still very poor with a short-term mortality rate up to 40%. Appropriate risk assessment in the early stage of shock is crucial to identify patients most likely to benefit from intensive and costly treatment. The aim of this thesis was to assess the treatment of respiratory failure in CS, focusing on the use of different ventilatory strategies and their impact on outcome; to evaluate the contemporary clinical picture, prognosis, and risk assessment of elderly (≥ 75 years) CS patients; and to investigate prognostic properties of two novel biomarkers in the early phase of CS. The study population consisted of the multinational, observational, prospective CardShock study, which included 219 patients with both ACS and non-ACS etiologies. Study I evaluated the use of different ventilatory strategies in CS. Although most patients (63%) were treated with invasive mechanical ventilation (IMV), a fair number were successfully treated with non-invasive ventilation (NIV) (12%). The intensity of respiratory support required was dependent on the severity of shock; those treated with IMV suffered from more severe shock and had higher 90-day mortality compared with those treated with NIV (49% vs. 27%). However, after balancing the IMV and NIV groups with shock severity and clinical characteristics, the choice of ventilatory strategy itself did not influence the outcome. Study II assessed the key features of elderly (≥ 75 years) CS patients. The elderly constituted a quarter of the population. Despite similar etiology and treatment of shock, they had a higher in-hospital mortality rate compared with younger patients (46% vs. 33%). However, those elderly patients who survived to hospital discharge had a prognosis comparable to that of the younger. The two contemporary risk prediction scores, the CardShock risk score and the IABP-SHOCK II risk score, proved to be useful in the early risk stratification in the elderly patients as well. Furthermore, by incorporating the novel biomarkers into the scores, the risk prediction ability of the scores improved markedly. Study III evaluated concentrations of a novel biomarker, growth differentiation factor 15 (GDF-15), in CS. GDF-15 is a stress-responsive cytokine that is expressed under acute and chronic stressful conditions and it has shown prognostic potential in various diseases. In this study GDF-15 levels were already very high at the beginning of CS and associated with markers of hypoperfusion (high lactate, low pH) and various acute organ dysfunctions (heart, renal, liver) indicating severe circulatory failure. High and increasing levels of GDF-15 were associated with a worse outcome, while low and decreasing levels were indicative of better prognosis. Furthermore, GDF-15 improved the early risk stratification of CS beyond the clinical risk score. Study IV investigated the levels of soluble urokinase-type plasminogen activator receptor (suPAR) in the early stage of CS. suPAR is a novel biomarker secreted in response to inflammatory stimuli and thought to reflect the level of immunoactivation. suPAR has prognostic ability in many acute and chronic diseases, including cardiovascular diseases, cancer, and sepsis. In this study, suPAR levels were clearly elevated during the first days of CS. High levels were associated with both acute and chronic organ dysfunctions. suPAR had independent prognostic potential in CS and improved the risk stratification, especially in the patients with intermediate risk. In conclusion, NIV can be used safely in the treatment of respiratory failure in suitable CS patients. The choice of ventilation strategy did not appear to influence outcome. Elderly patients constitute a considerable portion of CS patients with high mortality. Contemporary risk scores are also useful for early risk prediction in this age group. High levels of the novel biomarkers GDF-15 and suPAR are indicative of severe circulatory failure and end-organ injury, suggesting poor prognosis. These biomarkers may be new prognostic tools in the risk assessment of CS.Sydänperäinen sokki on monitahoinen oireyhtymä, jossa sydämen akuutti toimintahäiriö aiheuttaa sen supistumiskyvyn merkittävän heikentymisen johtaen vaikeaan verenkiertovajaukseen, kudosten hapenpuutteeseen ja monielinvaurioon sekä lopulta hoitamattomana kuolemaan. Oireyhtymän patogeneesissä myös elimistön neurohumoraalisilla vasteilla sekä systeemisen tulehdusreaktion kehittymisellä on oma roolinsa. Mikä tahansa sydämen toimintaa heikentävä sairaus voi olla syynä sydänperäiseen sokkiin, useimmiten kyseessä on laaja sydäninfarkti. Hoidon kulmakivenä on sydämen toimintahäiriön aiheuttaneen syyn tunnistaminen ja välitön korjaaminen. Sokkiin liittyvää verenkierto- ja hengitysvajausta hoidetaan tarvittaessa mekaanisia tukilaitteita avuksi käyttäen tehohoito-olosuhteissa, mikä on kuitenkin potilaille raskasta, altistaa komplikaatioille ja vaatii runsaasti terveydenhuollon resursseja. Kehittyneistä hoitotoimenpiteistä huolimatta kuolleisuus sydänperäiseen sokkiin on edelleen korkea noin 40 %. Hoidossa oleellista on sokin tunnistaminen, raskaista hoidoista hyötyvien korkean riskin potilaiden tunnistaminen ja hoitotoimenpiteiden aloittaminen riittävän varhaisessa vaiheessa ennen peruuttamattomien pääte-elinvaurioiden syntymistä. Tämän väitöskirjan tavoitteena oli selvittää sokkiin liittyvän hengitysvajauksen hoitoa keskittyen eri hengitystukimuotojen käyttöön ja niiden mahdolliseen ennustevaikutukseen sekä tutkia iäkkäiden (≥ 75-vuotiaiden) sokkipotilaiden taudin kliinistä kuvaa ja selvittää ajankohtaisten riskipisteytysmallien käyttökelpoisuutta tämän ikäryhmän ennusteen arvioimisessa. Lisäksi tavoitteena oli arvioida kahden uuden biomarkkerin käyttökelpoisuutta sydänperäisen sokin ennustearviossa. Väitöskirjan tutkimusaineisto on peräisin 219 potilasta käsittävästä monikansallisesta, havainnoivasta CardShock –tutkimuksesta. Ensimmäisessä osatyössä tutkittiin sydänperäiseen sokkiin sairastuneiden potilaiden hengitysvajauksen hoitoa ja eri hengitystukimuotojen käyttöä keskittyen non-invasiiviseen (NIV) hengitystukihoitoon. Tutkimuksessa havaittiin, että sydänperäiseen sokkiin sairastuneiden hengitystuen tarve riippui sokin vaikeusasteesta. Suurin osa potilaista (63%) hoidettiin invasiivisella mekaanisella ventilaatiolla (IMV) keinoilmatien kera, mutta merkittävä osa (12%) pärjäsi pelkästään non-invasiivisella ventilaatiolla (NIV). IMV:lla hoidetut potilaat kärsivät vaikeammasta sokin taudinkuvasta ja heillä oli korkeampi 90 päivän kuolleisuus NIV:llä hoidettuihin verrattuna (49% vs. 27%). Hengitystukistrategian valinnalla ei kuitenkaan ollut vaikutusta ennusteeseen. Toisessa osatyössä selvitettiin iäkkäiden (≥ 75-vuotiaiden) sydänperäiseen sokkiin sairastuneiden potilaiden kliinistä taudinkuvaa, hoitoa ja ennustearviota. Neljäsosa potilaista oli yli 75-vuotiaita. Huolimatta sokin samankaltaisesta etiologiasta ja hoidosta iäkkäiden potilaiden sairaalakuolleisuus oli selvästi nuorempia korkeampi (46% vs. 33%). Toisaalta sokista selvinneiden iäkkäiden ennuste ei eronnut nuorempien ennusteesta. Tutkimuksen mukaan sydänperäiseen sokkiin sairastuneille kehitetyt riskipisteytysmallit toimivat hyvin myös iäkkäillä ja niiden ennustearviota voidaan parantaa yhdistämällä ne biomarkkereiden kanssa. Kolmannessa osatyössä tutkittiin biomerkkiaine GDF-15 pitoisuuksia sydänperäisen sokin alkuvaiheessa sekä niiden yhteyttä ennusteeseen. GDF-15-pitoisuuksien tiedetään nousevan elimistön erilaisissa akuuteissa sekä kroonisissa stressitilanteissa ja GDF-15 omaa ennustearvoa useissa eri sairauksissa. Tutkimuksessa havaittiin, että GDF-15–pitoisuudet olivat hyvin korkeita jo sokin ensivaiheessa. Korkeat pitoisuudet olivat yhteydessä kudosten riittämätöntä verenkiertoa kuvastaviin biomarkkereihin (korkea laktaatti ja matala pH) ja elintoimintahäiriöihin (sydän, maksa, munuaiset) sekä huonompaan ennusteeseen. Lisäksi todettiin, että nouseva GDF-15 –taso oli merkki huonosta ennusteesta, kun taas laskevat pitoisuudet kuvastivat parempaa ennustetta. Yhdistettynä kliiniseen riskipisteytysmalliin GDF-15 paransi sokkipotilaiden ennustearviota huomattavasti. Neljännessä osatyössä määritettiin biomerkkiaine suPAR:n pitoisuuksia sydänperäisen sokin alkuvaiheessa. SuPAR on biomerkkiaine, jonka pitoisuus nousee sekä akuuttien että kroonisten tulehduksellisten tilojen yhteydessä kuvastaen elimistön immunoaktivaatiota. Sen on todettu omaavan ennustearvoa useissa eri sairauksissa, kuten syövissä, sepsiksessä sekä sydän- ja verisuonisairauksissa. Tässä tutkimuksessa suPAR-tasot olivat selvästi koholla sydänperäiseen sokkiin sairastuneilla. Korkeat pitoisuudet olivat yhteydessä eri elintoimintahäiriöihin ja suurempaan kuolemanriskiin. Tutkimuksessa todettiin, että suPAR oli itsenäinen sydänperäisen sokin ennustetekijä ja yhdistettynä kliinisen riskipisteytysmallin kanssa se paransi erityisesti keskiriskin potilaiden ennustearviota. Yhteenvetona voidaan todeta, että sydänperäiseen sokkiin liittyvää hengitysvajausta voidaan hoitaa voidaan turvallisesti myös NIV:lla oikein valikoiduilla potilailla, eikä hengitysvajauksen hoitomuodolla ole merkitystä potilaan ennusteen kannalta. Iäkkäät muodostavat merkittävän osan sydänperäiseen sokkiin sairastuneista potilaista ja sokin ennustearvioon luodut kliiniset riskipisteytysmallit toimivat hyvin myös tässä ikäryhmässä. Tutkitut biomerkkiaineet, GDF-15 ja suPAR, kuvastavat sydänperäiseen sokkiin liittyvää vaikeaa verenkiertovajausta sekä siihen liittyviä elintoimintahäiriöitä ja voivat olla avuksi sokkipotilaiden ennustearviossa

Ductal carcinoma in situ and invasive breast cancer: diagnostic accuracy and prognosis

The studies in this thesis contribute to more accurate risk assessment and prognosis prediction for DCIS and to better response evaluation of IBC treatment.For the Ductal Carcinoma In Situ (DCIS) studies, unbiased cohorts were used within the international Grand Challenge PRECISION consortium, funded by Cancer Research UK and KWF Dutch Cancer Society. DCIS is graded as low-, intermediate-, or high-grade depending on how abnormal the DCIS-cells look like. However, we showed that pathologists often disagree on grade. To overcome this limitation, we found that almost all DCIS scored as non-high-grade by the majority of pathologists express the estrogen receptor (ER) and are negative for the growth factor receptor HER2, whereas high-grade DCIS is mixed in expression for ER and HER2. We also provided insights in the recurrence risks of DCIS after treatment. See also https://cancergrandchallenges.org/teams/precision.The studies on Invasive Breast Cancer (IBC) were performed on a hospital-based cohort. We found for example substantial variation in tumour response evaluation for HER2-positive IBC after pre-operative chemotherapy due to different guidelines used. For accurate outcome analysis, reducing such variation is mandatory. Therefore, we are working on reaching international consensus of response evaluation. The Netherlands Cancer Institute-Antoni van Leeuwenhoek Ziekenhuis The Netherlands Comprehensive organisation (IKNL)LUMC / Geneeskund

Aortopathy in patients with a bicuspid aortic valve : determining susceptibility for aortic complications

The prevalence of aortic dilation and related complications as rupture and dissection is higher in patients with a bicuspid aortic valve (BAV) as compared to patients with a tricuspid aortic valve (TAV), although not every individual carries this increased risk. It is therefore essential to identify those patients who are less susceptible for aortic wall pathology, as preventive ascending aortic surgery would not be necessary in this group. Since aortic diameter as a criterion for surgery is only decisive at population level, it would be very valuable to have tailored risk stratification at patient level. The purpose of this thesis was therefore to investigate the possibility to identify patients with BAV, without apparent dilation, with an increased susceptibility for future complications as aortic dilation and dissection. Furthermore the biological mechanism underlying aortic wall pathology in BAV was compared to a known genetically determined syndrome with an increased risk of aortopathy being Marfan syndrome.UBL - phd migration 201