Om disputationen
Usama Boles, Institutionen för folkhälsa och klinisk medicin, försvarar torsdag 21 november kl. 9.00 sin avhandling Nya kunskaper inom kranskärlsektasi. Faktultetsopponent Corrado Tamburino, universitetet i Catania, Italien. Huvudhandledare Michael Henein. Plats: Major Groove, målpunkt J0.
Usama Boles har examen från universitetet i Kairo, Egypten. Cairo Strax därefter avslutade han en magisterexamen i kardiologi vid Trinity College i Dublin, Irland, där han publicerade forskning om ventrikulär aktiveringstid i tidig hypertoni med diastolisk dysfunktion. Doktorandstudierna vid Umeå universitet har haft fokus på ett relativt sällsynt tillstånd i kranskärl. Dessutom har Usama Boles författat några kapitel i arytmiböcker, många andra publikationer inom hjärtarytmi och enheter.
Usama Boles beskrivning av avhandlingen (engelska)
Coronary artery ectasia (CAE) is a rather uncommon disease that is in focus of the doctoral thesis of Usama Boles in cardiology at the Department of publich health and clinical medicine that he will defend 21 november.
Coronary artery ectasia (CAE) is defined as a diffuse dilatation of the epicardial coronary arteries exceeding 1.5 folds the diameter of the normal adjacent arterial segment and/ or the remaining non-dilated part of the same artery.
The disease prevalence varies according to many factors such as the anatomical appearance; aneurysm i.e. localized vs. long dilated segment, presence of congenital or systemic inflammatory disorder (e.g. Kawasaki, Takayasu disease, polycystic kidney disease and Ehlers-Danlos syndrome) and common association with heavy atherosclerosis and remodelling failure of the coronary intimal wall. Due to the abundant literature on CAE, we dedicated our project to non-atherosclerotic CAE that has a relatively diffuse nature (i.e. more than 20 mm in length). Our research revealed the underlying systemic pro inflammatory response. The atherosclerotic pathogenesis of the pure form of the disease was not proven and hence we detected a quite different long term outcome in this rare disease. CAE doesn't appear to have a benign nature, however, in the acute settings a short term major cardiac events (MACE) are relatively similar to non ectatic coronaries. We suggested the management of acute presentations in acute coronary syndrome should be the same despite of higher conventional inflammatory markers.
Coronary ectasia is a rare disease, commonly attributed to the existence of heavy atherosclerosis and the common association emphasised that concept. Other literatures revealed that the non-atherosclerotic form of CAE (also called as Isolated CAE) is rarer and may have non-benign outcome.
The clinical implications of the presence of the disease and its association with atherosclerosis was not clear and is much debated. Hence, the purpose of this research was to shed light on the pathogenesis of the disease which should lead to better understanding of the clinical nature of CAE. We studied pure (isolated) forms of CAE with, at maximum, minimal atherosclerosis or have no evidence of it.
In the first paper; we studied the untargeted lipid profiling in CAE using metabolomics analysis that was performed in Umea Metabolomics centre. We extracted the metabolites of CAE (from serum samples) and compared the outcome with age and gender matched controls. The metabolites were identified by Mass Feature Extraction (MFE) and then aligned and matched using Mass profile Professional TM . Overall 65 metabolites were different between CAE and Control groups, however, only 27 metabolites were identified. Phosphatidylcholines (PC) and Sphyngomyeline (SM) metabolites were disturbed in CAE patients. PC species carry fatty acids and act as intermediates to atherosclerosis enhancement. PC levels were lower in CAE than normals, while were previously proved higher in atherosclerosis and CAD. SM species are also significantly lower in CAE. SM are carried out into the arterial wall on atherogenic lipoproteins and stimulates lipoprotein aggregations and macrophages foam cell formations. SM higher levels predict the presence of atherosclerosis; however, CAE has lower levels. This new methodology added more power to believe that CAE is not an atherosclerosis process.
In paper two, we examined the systemic immune-inflammatory response in CAE. Extended cytokines profile including IL-10, IL-12, IL-23, IL-13, IL-2, IL-4, IL-6, IL-8, IFN-γ, IL-1β and TNF- α in CAE patients and compared them with a control group. CAE patients had raised systemic levels of INF-γ, TNF-α, IL-1β, IL-6, and IL-8 and lower IL-2 and IL-4 than controls. A similar pattern was found when CAE systemic levels were compared with the CAD group. These findings likely reflect a state of increased inflammatory response through macrophage activation with resulting cytokine release. Leukocytes, and their differential subgroups, as a key player in the inflammatory process, were higher in pure CAE. The lower level of IL-2 and IL-4 suggest perturbed TH pathways. This profile of cytokines disturbance may suggest enhanced systemic pro-inflammatory response in CAE. CAE cytokine milieu differs from atherosclerosis, indicating a different pathophysiology despite common conclusions of a chronic but exaggerated inflammation process.
In paper three, we investigated the conventional inflammatory response in CAE patients in acute cardiac presentations requiring urgent coronary angiogram and intervention. The clinical outcome over 2 years' period was investigated and correlated with the conventional cardiovascular risk factors. The cohort size was 3321 patients presented with acute coronary syndrome (ACS) in two UK centres. The prevalence of CAE among those patients was 2.7 % and most interestingly the conventional CV risk factors were not different between CAE and CAD. Anatomically, right coronary and left circumflex were significantly and commonly involved with CAE. Conventional inflammatory markers like WCC, neutrophils and Neutrophil/ Lymphocytes (N/L) ratio were higher in CAE patients but significantly lower in diffuse form of CAE (i.e. diffuse defined as more than one segment involved in one or more of the three epicardial coronary arteries). The treatment options between medical therapy, coronary intervention or surgical option were not affected by the inflammation profile in both groups and hence we concluded that despite of the significantly higher markers in CAE group yet the treatment options and short term major acute cardiac events over the subsequent 2 years were not different. This conclusion of equivocal prognosis recommended no altered management should be applied in CAE patients present with ACS. This project has emphasised the role of standard clinical management in CAE patients in acute settings despite of the different disease pathophysiology from pure atherosclerosis.
Paper Four investigated the long term clinical outcome in CADE patients, without atherosclerosis (or very low burden). We reviewed the clinical presentations, cardiac admissions and CV mortalities over and average of ten years, in 41 patients with pure or minimal atherosclerosis (i.e. < 20 % luminal narrowing, or just coronary irregularities) versus non ectatic coronaries with minimal CAD. All CV risk factors, acute major cardiac events "MACE" and mortality were carefully collected. Overall CV related mortality were higher in CAE group. Apart from smoking (that was significantly higher in CAE patients) other CV factors failed to predict mortality or hospital re admissions with MACE during follow up. CAE prognosis seemed more serious than minimal CAD on long term outcome. Smoking was a strong association while dyslipidaemia had only a trend toward worse prognosis. Theses findings were suggested before but yet smoking was documented only in atherosclerotic CAE and was also followed for a shorter period.
While CAE is a known problem, we provided further insight on the true form of non-atherosclerotic ectasia. We provided unique tools for the investigation to the pathophysiology of the disease that was clearly successful to separate the disease from atherosclerosis. This is to add more power to the existent literature in identifying CAE as a unique disease with some association with atherosclerosis. Clear forms of CAE are not part of atherosclerotic process and that is why not all atherosclerotic CAD have ectatic changes and vice versa. Moreover, when CAE patients has acute presentations, the disease is related to more agressive inflammatory response, yet the later failed to demonstrate worse prognosis. From the clinical perspective, the outcome and treatment of acute CAE patients should follow the same guidelines and standard as atherosclerotic, non ectatic, coronaries. Prognosis over a short period was the same.
However, when CAE is identified on diagnostic angiograms, the long-term outcome and CV mortality were higher. This indicates the need for meticulous follow up of such patients. Smoking, in particular, is a predictor for worse long term outcome among CAE patients. Overall, this thesis has a clear message that, CAE nature and pathogenesis is different from atherosclerosis despite of the common association. CAE carries worse prognosis at the long term but not as such in short term follow up after acute cardiac presentations.
We reviewed 16,464 angiograms performed between 2003 and 2011, from Umeå Heart Centre of Umeå University Hospital, Sweden and Letterkenny University hospital, Ireland. CAE inclusion criteria of coronary artery diameter > 1.5 that of the original calibre of the artery or adjacent artery diameter, and is not localized (i.e. > 20mm long and/or includes more than one-third of the artery length) were used, no structural abnormalities of previous intervention. Mixed CAE having only minimal coronary disease (≤ 20% luminal stenosis). Follow up data for complete charts were available in 41/66 patients. Serum samples were collected and processed accordingly for lipidomic and Cytokines projects.