<p>Kvantifisering av hjertets muskelfunksjon med tøyning og tøyningshastighet målt med ultralyd for vurdering av koronar sykdom.</p><p>Automatisert metode versus manuell ved akutt hjerteinfarkt og ultralyd stress test.</p><p>Vanligvis måles hjertets muskelfunksjon med ultralyd, en mye brukt metode for å diagnostisere hjertesykdommer. Vurderingen av muskelfunksjonen baserer seg i dag på en subjektiv visuell gradering av bevegelsen av hjertemuskelen, og dette krever erfaring. En ny automatisert diagnostisk ultralydsmetode basert på måling av hastigheten i hjertemuskelen gir et kvantitativt mål på muskelens tøyning og sammentrekning. Den nye metoden gir ny og mer detaljert informasjon om hjertets funksjon og om pasientens prognose enn vanlig ultralydsvurdering.</p><p>Den nye metoden er mer presis ved oppfølgning etter hjerteinfarkt. Et hjerteinfarkt gir nedsatt bevegelse av muskelen og måles med den nye metoden som nedsatt hastighet som muskelen forkortes med. Små forandringer i den skadde hjertemuskelen, ikke alltid synlige for øyet, kan mer nøyaktig følges over tid med den nye metoden. Utbredelsen av hjerteinfarktet kan også vurderes mer nøyaktig.</p><p>Det samme gjelder når angina vurderes under belastning. Når en pasient ikke kan sykle eller gå på tredemølle brukes en medisinsk belastningstest. Ved å belaste hjertet med et medikament som øker hjertemuskelens arbeid samtidig med en ultralydundersøkelse, kan vi oppdage redusert blodforsyningsreserve i hjertet. Stresstesten hjelper til med å vurdere om en trang blodåre bør åpnes etter et hjerteinfarkt, og til å vurdere pasienters risiko for hjertekomplikasjoner før en større operasjon. Den nye metoden gir i tillegg mer informasjon om den langsiktige prognosen sammenlignet med den gamle metoden. Vi har funnet at den nye ultralydsmetoden er mer presis (gir større diagnostisk treffsikkerhet i diagnostikk av koronarsykdom) sammenlignet med den gamle.</p><p>Måling av sammentrekningshastigheter i hjertemuskelen ble utviklet og testet på Institutt for sirkulasjon og bildediagnostikk ved NTNU av Andreas Heimdal og Asbjørn Støylen i 1998. Metoden trengte teknisk videreutvikling og testing i et større pasientmateriale. Metoden har ikke fått stor utbredelse på sykehusene pga støyfylte kurver og tidskrevende analyser, men med denne automatiserte metoden blir brukervennligheten større som muliggjør klinisk bruk.</p> / Paper I and II preprinted with kind permission of Elsevier, sciencedirect.com

<p>In patients with unstable coronary artery disease, this study evaluated the degree of inflammation and coagulation activity, relations to myocardial cell damage, prognosis, and influences of randomisation to 72 h infusion with three different doses of inogatran, a direct thrombin inhibitor (n=904), or unfractionated heparin (n=305). </p><p>Anticoagulant treatment effects were evaluated with aPT time. In inogatran treated patients with aPT times ≥ 44 s (median), the 7-days event rate - death, myocardial infarction or refractory angina – was 11.6 %, compared to 6.6 % with aPT times < 44 s (p=0.01). Higher aPT times was related to improved outcome during heparin treatment.</p><p>Markers of inflammation, i.e. fibrinogen and C-reactive protein (CRP), and coagulation, i.e. prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), soluble fibrin (SF) and D-dimer were analysed in serial samples (n=320). High fibrinogen, F1+2 and D-dimer levels persisted at 30 days. Patients with myocardial damage, detected by elevated troponin, had higher levels of all markers except TAT.</p><p>Ischemic events occurred at 30 days in 17 % of patients with high (pre-treatment top tertile) and 8.5 % of patients with lower fibrinogen levels (p=0.03), while high CRP levels only were related to increased mortality. At 30 days, patients with high compared to low pre-treatment levels of TAT or SF had 40 % lower event rate. Patients with early decreased compared to raised F1+2 or TAT levels during treatment had 50 % lower 30-days event rate (p<0.05). </p><p>Conclusions: The aPT time is an inappropriate indicator of antithrombotic efficacy. The raise in fibrinogen in the acute phase is sustained, and indicates risk of thrombosis and new ischemic events. The pronounced CRP elevation is transient, but associated with increased mortality. Higher coagulation activity may identify patients with a thrombotic condition as the major cause of instability, who are best responders to anticoagulant therapy. However, reactivation of coagulation activity with raised risk of ischemic events is a concern at cessation of treatment.</p>

Today, invasive coronary angiography is still the gold standard to perform the diagnosis of coronary artery disease. But it is an invasive procedure that carries non negligible morbidity (1.5%) and mortality (0.15%), and results in high costs. Less invasive and more cost-effective techniques are highly desirable. Over the past 15 years, substantial advances have been made in non-invasive cardiac imaging. In the first part of this work, we prospectively evaluated the diagnostic accuracy of 40-slice multidetector CT (MDCT) to detect coronary artery disease prior to cardiac valve surgery in 82 patients. On a per-patient basis, MDCT correctly identified 14/15 patients with (sensitivity 93%) and 60/67 patients without coronary disease (specificity 90%). Performing invasive angiography only in case of abnormal CT might have avoided invasive angiography in 60/82 (73%) patients without coronary disease. Thus, MDCT could be potentially useful in the preoperative evaluation of such patients, allowing to avoid systematic cardiac catheterization in a large number of patients. Magnetic resonance coronary angiography (MRCA) has also emerged as a promising alternative due to the lack of ionizing radiation and absence of iodinated contrast injection. Therefore, we compared diagnostic accuracy of whole-heart MRCA and MDCT, against QCA, to identify >50% stenosis basis in 77 patients. WH-MRCA acquisition failed in a high number of patients. This was caused by an unstable breathing pattern or drift of the diaphragm position. Because of higher success rate, MDCT had higher diagnostic accuracy than WH-MRCA to detect coronary stenosis. Thus MDCT is superior to WH-MRCA, however WH-MRCA can perform as well as CT in interpretable segments with adequate image quality. In the second part of this work, to evaluate whether MDCT and cardiac magnetic resonance (cMR) might allow simultaneous assessment of aortic valve area (AVA), we compared measurements of AVA by MDCT to cMR, transesophageal and transthoracic echocardiography. AVA by MDCT and cMR correlated highly with AVA by other techniques. In our study, we compared 3 planimetric approaches to AVA calculated by the continuity equation using TTE. We did observe excellent correlations between planimetric and continuity equation-derived AVA, but all 3 planimetric measures were found to overestimate continuity equation AVA. A potential explanation for this observation could be that we measure different aortic valve orifices. Indeed planimetric techniques measure the true dimensions of the anatomical orifice, whereas the continuity equation measures the "effective" orifice area. The ability of MDCT and cMR to accurately assess aortic valve area at the time of non-invasive coronary imaging, places these techniques in a strong position for the comprehensive assessment of such patients. However, despite these good results, it must nonetheless be emphasized that to be acceptable in daily clinical practice, a strategy in which invasive coronary angiography would not be performed systematically but rather selectively in only a subset of patients, requires a perfect sensitivity for disease detection in individual patients. Unfortunately, the present work shows that MDCT and WH-MRCA have not yet reached such a level of accuracy. Finally, these tests are not a substitute for other imaging techniques in all cardiovascular conditions. Unlike an echocardiogram machine, the MRI and MDCT scanners cannot be brought to the bedside of an acutely ill patient.

In patients with unstable coronary artery disease, this study evaluated the degree of inflammation and coagulation activity, relations to myocardial cell damage, prognosis, and influences of randomisation to 72 h infusion with three different doses of inogatran, a direct thrombin inhibitor (n=904), or unfractionated heparin (n=305). Anticoagulant treatment effects were evaluated with aPT time. In inogatran treated patients with aPT times ≥ 44 s (median), the 7-days event rate - death, myocardial infarction or refractory angina – was 11.6 %, compared to 6.6 % with aPT times &lt; 44 s (p=0.01). Higher aPT times was related to improved outcome during heparin treatment. Markers of inflammation, i.e. fibrinogen and C-reactive protein (CRP), and coagulation, i.e. prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), soluble fibrin (SF) and D-dimer were analysed in serial samples (n=320). High fibrinogen, F1+2 and D-dimer levels persisted at 30 days. Patients with myocardial damage, detected by elevated troponin, had higher levels of all markers except TAT. Ischemic events occurred at 30 days in 17 % of patients with high (pre-treatment top tertile) and 8.5 % of patients with lower fibrinogen levels (p=0.03), while high CRP levels only were related to increased mortality. At 30 days, patients with high compared to low pre-treatment levels of TAT or SF had 40 % lower event rate. Patients with early decreased compared to raised F1+2 or TAT levels during treatment had 50 % lower 30-days event rate (p&lt;0.05). Conclusions: The aPT time is an inappropriate indicator of antithrombotic efficacy. The raise in fibrinogen in the acute phase is sustained, and indicates risk of thrombosis and new ischemic events. The pronounced CRP elevation is transient, but associated with increased mortality. Higher coagulation activity may identify patients with a thrombotic condition as the major cause of instability, who are best responders to anticoagulant therapy. However, reactivation of coagulation activity with raised risk of ischemic events is a concern at cessation of treatment.

Kvantifisering av hjertets muskelfunksjon med tøyning og tøyningshastighet målt med ultralyd for vurdering av koronar sykdom. Automatisert metode versus manuell ved akutt hjerteinfarkt og ultralyd stress test. Vanligvis måles hjertets muskelfunksjon med ultralyd, en mye brukt metode for å diagnostisere hjertesykdommer. Vurderingen av muskelfunksjonen baserer seg i dag på en subjektiv visuell gradering av bevegelsen av hjertemuskelen, og dette krever erfaring. En ny automatisert diagnostisk ultralydsmetode basert på måling av hastigheten i hjertemuskelen gir et kvantitativt mål på muskelens tøyning og sammentrekning. Den nye metoden gir ny og mer detaljert informasjon om hjertets funksjon og om pasientens prognose enn vanlig ultralydsvurdering. Den nye metoden er mer presis ved oppfølgning etter hjerteinfarkt. Et hjerteinfarkt gir nedsatt bevegelse av muskelen og måles med den nye metoden som nedsatt hastighet som muskelen forkortes med. Små forandringer i den skadde hjertemuskelen, ikke alltid synlige for øyet, kan mer nøyaktig følges over tid med den nye metoden. Utbredelsen av hjerteinfarktet kan også vurderes mer nøyaktig. Det samme gjelder når angina vurderes under belastning. Når en pasient ikke kan sykle eller gå på tredemølle brukes en medisinsk belastningstest. Ved å belaste hjertet med et medikament som øker hjertemuskelens arbeid samtidig med en ultralydundersøkelse, kan vi oppdage redusert blodforsyningsreserve i hjertet. Stresstesten hjelper til med å vurdere om en trang blodåre bør åpnes etter et hjerteinfarkt, og til å vurdere pasienters risiko for hjertekomplikasjoner før en større operasjon. Den nye metoden gir i tillegg mer informasjon om den langsiktige prognosen sammenlignet med den gamle metoden. Vi har funnet at den nye ultralydsmetoden er mer presis (gir større diagnostisk treffsikkerhet i diagnostikk av koronarsykdom) sammenlignet med den gamle. Måling av sammentrekningshastigheter i hjertemuskelen ble utviklet og testet på Institutt for sirkulasjon og bildediagnostikk ved NTNU av Andreas Heimdal og Asbjørn Støylen i 1998. Metoden trengte teknisk videreutvikling og testing i et større pasientmateriale. Metoden har ikke fått stor utbredelse på sykehusene pga støyfylte kurver og tidskrevende analyser, men med denne automatiserte metoden blir brukervennligheten større som muliggjør klinisk bruk. / Paper I and II preprinted with kind permission of Elsevier, sciencedirect.com

Angiogenic cell therapy is currently being developed as a treatment for coronary artery disease (CAD); however, endothelial dysfunction (ED), commonly found in patients with CAD, impairs the ability for revascularization to occur. We hypothesized that culture on a collagen matrix will improve survival and function of circulating progenitor cells (CPCs) isolated from a mouse model of ED. Overall, ED decreased the expression of endothelial markers in CPCs and impaired their function, compared to normal mice. Culture of CPCs from ED mice on collagen was able to increase cell marker expression, and improve migration and adhesion potential, compared to CPCs on fibronectin. Nitric oxide production was reduced for CPCs on collagen for the ED group; however, CPCs on collagen had better viability under conditions of serum deprivation and hypoxia, compared to fibronectin. This study suggests that a collagen matrix may improve the function of therapeutic CPCs that have been exposed to ED.

Numerous studies in North America, Europe and Australia have linked depression to increased risk of morbidity and mortality in coronary artery disease (CAD). Although the co-morbidity of depression and CAD is well documented in the western world, little work on the subject has been carried out in Asia. Differing depression presentations in Asia necessitate the use of culture-specific depression rating scales. This study sought to determine whether the correlation between CAD and depression documented in western countries also exists in an Asian nation: Thailand. It was hypothesized that rates of depressive symptoms were higher in Thai inpatients with either unstable angina or recent myocardial infarction than in Thai inpatients with non-cardiac (orthopedic) complications. A 15-question culturally-appropriate self-rating depression inventory was administered to 56 Thai inpatients33 cardiac and 23 orthopedicat two public and one private hospital in Bangkok. Subjects were asked to rate each of the fifteen items on a scale from 0-3 based on how they felt during the past week. Higher scores correlated with greater depressive symptoms. Five cardiac and two orthopedic patients were excluded from the final analysis because of past medical history of major depressive disorder. Of the remaining 49 patients, questionnaire scores ranged from 1 to 23, with a mean depression score of 9.00 (S.E.M.=.84). Cardiac patients showed significantly greater depressive symptoms than their orthopedic counterparts at one public and one private hospital: Ramathibodi Hospital (P=.01) and Bangkok General Hospital (P=.005), respectively. For cardiology patients, the three highest scoring items were early insomnia (Mean = 1.39), late insomnia (Mean = 1.25) and loss of appetite (Mean = 1.04). For orthopedic patients, the three highest scoring items were work inhibition (Mean = 1.05), anxiety (Mean = .86), and early insomnia (Mean = .86). On post-hoc analysis, it was shown that patients in hospital units with air-conditioning showed significantly fewer depressive symptoms than patients without air-conditioning (P=.003), where the daily temperature often reached 115[degrees]F. Rates of depressive symptoms did not differ in accordance with education level (P=.15), gender (P=.49) or age (P=.29). In conclusion, this study provides some evidence that Thai inpatients hospitalized for severe CAD have greater depressive experience than their orthopedic counterparts. This finding supports our hypothesis that depression and CAD are linked in Thailand as they are in western countries.

Anxiety is a highly prevalent comorbidity in coronary artery disease (CAD) and confers increased risk of subsequent cardiac events and mortality. However, biological mechanisms of this relationship are not well understood. Ceramides are sphingolipids involved in inflammatory signaling and cell viability in the periphery and nervous system, and are implicated in pathophysiological mechanisms associated with anxiety. This study aimed to investigate relationships between plasma ceramide concentrations and anxiety symptomology as assessed by the Spielberger State-Trait Anxiety Inventory trait subscale (STAI-T) in CAD patients with linear regressions. High performance liquid chromatography coupled electrospray ionization tandem mass spectrometry was used to assay sphingolipid species. Plasma C22:0 ceramide (β=-0.232, p=0.018) concentrations and 8 other species of sphingolipids (SM18:0, SM20:1, C18:0, C20:0, C18:1, DHC22:0, LacC22:0, LacC24:1) were negatively correlated with STAI-T score when controlling for gender, BMI, and CES-D. Findings suggest specific sphingolipids to be potential markers for anxiety severity in CAD.

Anxiety is a highly prevalent comorbidity in coronary artery disease (CAD) and confers increased risk of subsequent cardiac events and mortality. However, biological mechanisms of this relationship are not well understood. Ceramides are sphingolipids involved in inflammatory signaling and cell viability in the periphery and nervous system, and are implicated in pathophysiological mechanisms associated with anxiety. This study aimed to investigate relationships between plasma ceramide concentrations and anxiety symptomology as assessed by the Spielberger State-Trait Anxiety Inventory trait subscale (STAI-T) in CAD patients with linear regressions. High performance liquid chromatography coupled electrospray ionization tandem mass spectrometry was used to assay sphingolipid species. Plasma C22:0 ceramide (β=-0.232, p=0.018) concentrations and 8 other species of sphingolipids (SM18:0, SM20:1, C18:0, C20:0, C18:1, DHC22:0, LacC22:0, LacC24:1) were negatively correlated with STAI-T score when controlling for gender, BMI, and CES-D. Findings suggest specific sphingolipids to be potential markers for anxiety severity in CAD.

Coronary magnetic resonance angiography (CMRA) is a potential diagnostic tool for coronary artery disease (CAD). Compared to the current gold standard, x-ray angiography, CMRA provides three-dimensional visualization of coronary vessel lumens without the use of catheters and ionizing radiation. CMRA, however, requires long acquisition times that span multiple heartbeats. Typically, to reduce cardiac motion artifacts, electrocardiogram (ECG) gating is used to synchronize data acquisition windows to diastasis periods. Gating errors may cause vessel blurring by unintentionally triggering the scanner to acquire image data during periods of significant cardiac motion. This is particularly problematic for CMRA because of the associated fine spatial resolution requirement for diagnosing CAD. This thesis presents and tests the novel idea of determining the timing of global epicardial diastasis periods from the motion of the basal ventricular septum. An experiment involving a small patient cohort undergoing elective diagnostic angiography revealed a significant correlation between the beat-to-beat diastasis periods of the ventricular septum and the coronary vasculature. This motivated the ii development and testing of the hypothesis that suggests sharper coronary artery images may be obtained by using cardiac gating windows determined by septal motion. A preliminary study involving a small volunteer cohort provided encouraging results, but also revealed limitations of using ultrasound to measure septal motion during a pre- scan prior to an MRA exam. This led to the major technical development of this thesis, which is a magnetic resonance imaging (MRI) method called the Septal Scout for monitoring septal motion at a very high temporal resolution. The technique was applied to a volunteer cohort which showed that cardiac gating windows as determined by the Septal Scout provided sharper coronary images compared with conventional ECG gating. The scientific knowledge and technical developments presented in this thesis are intended to improve CMRA as a non-invasive diagnostic tool of CAD. In the future, I intend to integrate the concepts presented here into a functioning MRI-based cardiac gating system. As well, I intend to validate the Septal Scout in a patient cohort study.