Doctor of Philosophy

dissertationDespite a century of research and practice, the clinical accuracy of the electrocardiogram (ECG) to detect and localize myocardial ischemia remains less than satisfactory. Myocardial ischemia occurs when the heart does not receive adequate oxygen-rich blood to keep up with its metabolic requirements, and severe ischemia can lead to myocardial infarction and life-threatening arrhythmias. Early and accurate detection is an essential component of managing this condition. Ischemia is known to be a dynamic condition that reflects a changing imbalance between blood supply and metabolic demand so that it is natural that examination under physical stress conditions or exercise testing (ET) is in widespread clinical use. However, ET is characterized by poor sensitivity (68%) and specificity (77%), limiting its diagnostic usefulness and providing the motivation to address some gaps in our understanding of myocardial ischemia and its ECG signature. This dissertation is composed of three studies. The aim of the first study was to evaluate the conventionally held mechanisms for nontransmural ischemia using intramural electrodes to measure three-dimensional potential distributions in the ventricles of animals exposed to acute ischemia. We demonstrated that contrary to accepted dogma, the electrocar- diographic response of acute myocardial ischemia originated throughout the ventricular wall, i.e., in the subendocardium, midmyocardium, or the subepicardium, under various conditions. Our goal in the second study was to evaluate whether acute myocardial ischemia follows a similar pattern of spatial and temporal evolution as seen in myocardial infarction. Our findings show that the spatial and temporal evolution of acute ischemia is characterized by multiple distinct regions that expand in all three directions, with maximal expansion in the circumferential direction, especially in the early stages of ischemic development. Furthermore, with increased stress, these regions continue to expand and eventually merge into one another, and in the extreme become transmural. The progression of myocardial infarction, by contrast, was very quickly transmural in extent and formed a cohesive block of affected tissues. The aim of the third study was to evaluate the sensitivity of epicardial electrical markers of acute ischemia relative to direct evidence of ischemia derived from intramural electro- grams. The key finding from this study is that the epicardial T-wave is a more sensitive index of acute ischemia than epicardial ST segment changes, especially in the early stages of acute ischemia development

Diagnosis and Prognosis of Cardiac Syndrome X

Teule, G.J.J. [Promotor]Raymakers, P.G.H.M. [Copromotor

Myocardial first-pass perfusion cardiovascular magnetic resonance: history, theory, and current state of the art

In less than two decades, first-pass perfusion cardiovascular magnetic resonance (CMR) has undergone a wide range of changes with the development and availability of improved hardware, software, and contrast agents, in concert with a better understanding of the mechanisms of contrast enhancement. The following review provides a perspective of the historical development of first-pass CMR, the developments in pulse sequence design and contrast agents, the relevant animal models used in early preclinical studies, the mechanism of artifacts, the differences between 1.5T and 3T scanning, and the relevant clinical applications and protocols. This comprehensive overview includes a summary of the past clinical performance of first-pass perfusion CMR and current clinical applications using state-of-the-art methodologies

Intracoronary electrocardiogram as a direct measure of myocardial ischemia

The electrocardiogram is a valuable diagnostic method providing insight into pathologies of the heart, especially rhythm disorders or insufficient myocardial blood supply (myocardial ischemia). The commonly used surface ECG is, however, limited in detecting short-lasting myocardial ischemia, in particular in the territory of the left circumflex coronary artery supplying the postero-lateral wall of the left ventricle. Conversely, an ECG recorded in close vicinity to the myocardium, i.e., within a coronary artery (intracoronary ECG, icECG) has been thought to overcome these limitations. Since its first implementation during cardiac catheterization in 1985, icECG has shown ample evidence for its diagnostic value given the higher sensitivity for myocardial ischemia detection when compared to the surface ECG. In addition, icECG has been demonstrated to be a direct measure of myocardial ischemia in real-time, thus, providing valuable information during percutaneous coronary diagnostics and interventions. However, a lack of analysing systems to obtain and quantify icECG in real-time discourages routine use. The goals of this MD-PhD thesis are two-fold: First, to determine the diagnostic accuracy of icECG ST-segment shift during pharmacologic inotropic stress in comparison to established indices for coronary lesion severity assessment using quantitative angiographic percent diameter stenosis as reference (Project I). Second, to determine the optimal icECG parameter for myocardial ischemia detection and quantification (Project II and III). In essence, this thesis demonstrates that the icECG is an easy available diagnostic method providing highly accurate information on the amount of myocardial ischemia in real-time. Quantitative assessment of acute, transmural myocardial ischemia by icECG is most accurately performed by measuring ST-segment shift at the J-point, while the quantitative assessment during physical exercise, respectively its pharmacologic simulation, is most accurately performed by measuring ST-segment shift 60ms after the J-point

Clinical and experimental aspects of functional and flow reserve of the myocardium

Basic research over the past 50 years has provided the clinician with important concepts for understanding human coronary physiology. One such tool is the determination of coronary blood flow reserve. Defined as the ratio of maximal to resting coronary flow, flow reserve may be helpful in assessing the need for revascularization in selected patients (1), as well as providing insight into pathophysiological states involving small arterial vessels (2-4). Many methodologies have been developed for measuring myocardial blood flow in patients, however most are limited by poor spatial resolution, the need for prolonged sampling periods or inherent inaccuracies with the measurements (5). Two invasive techniques have recently shown promise in the determination of coronary flow reserve in patients. Ultrasonic Doppler catheters have become small and steerable and can accurately assess changes in coronary blood flow velocities following infusions of vasodilators such as papaverine and adenosine. The technique has gained widespread acceptance for use in the catheterization laboratory, particularly to evaluate the success of interventions such as percutaneous trans luminal coronary angioplasty ( 6). Another invasive modality combines videodensitometry and digital subtraction angiography. This method uses a measurement of contrast density at two different vessel locations to determine the transit time and together with vascular volume can provide measurements of coronary blood flow (7). Both of these techniques are safe and show good results when validated against other accepted techniques. The major disadvantage however is that neither absolute blood flow nor transmural flow distributions can be measured. Positron emission tomography (PET) is non-invasive, and thus does not theoretically alter baseline flows such as might occur with an intracoronary catheter. Positron emitting tracers such as H20 15 are administered either intravenously or as inhaled C02 15 and are rapidly extracted by the myocardium. With the use of high resolution, rapid tomographic scanners, one can measure time activity curves in the left ventricular chamber and the myocardial regions of interest. Using tracer kinetic principles, total and regional myocardial blood flows can be accurately quantitated. The results correlate well with flow measurements obtained from radiolabeled microspheres in dogs, over a wide range of flows (8). Because of the short half-lifes of the tracers, sequential measurements can be made to evaluate multiple interventions

Mechanical assist in cardiac arrest: Optimising circulatory support. Experimental studies.

Introduction: Mechanical circulatory support (MCS) may be useful in cardiac arrest (CA), both in- and out- of hospital. However, efficacy and survival benefit has been difficult to evaluate compared to standard cardiopulmonary resuscitation. In three experimental studies we aimed to assess different modes of MCS during CA in providing adequate organ perfusion and systemic circulation and identify predictors of sustainable post-CA heart function. Different theoretical assumptions were the background for analysis in the three study protocols performed as acute experiments in anaesthetized pigs: Paper I: A major limitation to the effectiveness of a LVAD alone during CA is the lack of left ventricular (LV) filling due to minimal pulmonary circulation. We therefore wanted to assess if the combination of a left- and right ventricular assist device (BIVAD/BiPella) was beneficial as circulatory support versus a LVAD alone. Paper II: ECMO has the potential to replace systemic circulation during CA. However, concerns have been voiced regarding retrograde flow-delivery and effect on the myocardium during circulatory collapse. Based on results from Paper I we optimized BiPella support aiming to improve and maintain acceptable coronary perfusion pressure, believing this could potentially rectify the poor outcome of BIVAD/BiPella in Paper I if successful. Thus, in Paper II we compared the efficacy of balanced biventricular circulatory assist with extracorporeal membrane oxygenation (ECMO). Paper III: Pressure build-up in the left ventricle during cardiac arrest may be detrimental during extracorporeal cardiopulmonary resuscitation (ECPR) as indicated in Paper II. Therefore, we wished to investigate if unloading (venting) the left ventricle using add-on LVAD could be of benefit. However, the ideal flow-contributions of each assist device when combining LVAD and ECMO during ECPR in is not known. We therefore wanted to compare ECMO with standard or reduced flow and add-on LVAD versus ECMO alone. Finally, we wished to assess the contribution of add-on LVAD regarding pulmonary flow. Materials and methods: The animal experiments were performed at the Vivarium, University of Bergen, and protocols were approved by the Norwegian Animal Research Authority or by the Norwegian Food Safety Authority. Paper I and II were performed with percutaneous techniques. The final experiment was an open chest model. All protocols followed a similar timeline: 1. Anaesthesia and instrumentation of the pig. 2. Baseline evaluation. 3. Induction of CA by application of a 9V DC battery to the myocardium. 4. Immediate initiation of mechanical circulatory support (MCS). 5. Three attempts of cardioversion at the end of the CA period. 6. If successful return of spontaneous circulation (ROSC) was achieved, unsupported observation (Paper II and Paper III). Comparisons between intervention groups: 1. Haemodynamics (during and after CA). 2. Organ tissue blood flow rate (organ perfusion) and device output as calculated from fluorescent microspheres. 3. Arterial blood gases and biomarkers. 4. ROSC. 5. Sustained cardiac function post-ROSC (Paper II and Paper III). In Paper I, twenty animals were randomized in two groups receiving circulatory support either by the Impella CP alone (LVAD) or in combination with the Impella RP (BIVAD/BiPella) during 30 minutes of CA. In Paper II, twenty pigs were randomized to receive MCS either by BiPella or by extracorporeal membrane oxygenation (ECMO) during 40 minutes of CA. If ROSC was successful, animals were observed for 60 minutes unsupported. In Paper III, twenty-four animals were randomized in three groups. Extracorporeal cardiopulmonary resuscitation (ECPR) in Group 1 was provided by ECMO with standard-flow and add-on Impella CP. In Group 2: ECMO with reduced flow combined with Impella CP. In Group 3, animals were supported by standard-flow ECMO alone. ECPR lasted for 60 minutes. If ROSC was successful, 180 minutes unsupported observation followed. Results: Paper I demonstrated that BIVAD/BiPella provides superior circulatory support and perfusion for peripheral organs (including the brain) related to higher LVAD output and increased central aortic pressure compared to LVAD alone. However, myocardial perfusion was related to the pressure difference between mean aortic pressure and mean left ventricular pressure during cardiac arrest. Myocardial perfusion was inferior with BiPella resulting in significantly fewer ROSC (5/10 vs 10/10, p = 0.033) despite significantly higher etCO2 (p = 0.029). Paper II showed that balancing RVAD and LVAD to ensure acceptable coronary perfusion pressure and concomitant LVAD output was feasible, also sustaining vital organ perfusion. However, ECMO provided a more optimal systemic circulatory support. Device output and mean aortic pressure were increased with subsequent improved peripheral tissue perfusion reflected by reduction of s-lactate. In animals where sufficient myocardial perfusion pressure (mean aortic pressure – mean LV pressure > 10-15 mmHg) could not be achieved, perfusion (ml/min/g) was reduced in the subendo- and midmyocardium, averaging 0.59 ± 0.05 vs. 0.31 ± 0.07, (p = 0.005) and 0.91 ± 0.06 vs 0.65 ± 0.15 (p = 0.085), but not in the subepicardium (1.02 ± 0.07 vs 0.86 ± 0.17, p = 0.30) irrespective of group. These subjects also had inferior post-ROSC cardiac function. Paper III showed that add-on LVAD improved haemodynamics compared with ECMO alone during refractory CA. Add-on LVAD could not substitute a reduced ECMO-flow. Three animals with reduced ECMO flow and adjunctive Impella support did not achieve ROSC. With ECMO alone, ROSC was obtained in all animals. However, 4/8 died post-ROSC due to development of cardiogenic shock. In the remaining 21 animals, 17 animals had sustained cardiac function at study termination 3 h after ROSC. Animals without sustained cardiac function (7/24) had reduced mAP (p < 0.001), CPP (p = 0.002) and mPAf (p = 0.004) during CA and ECPR. Conclusions: Paper I: Biventricular support during cardiac arrest was associated with high intraventricular pressure in the left ventricle resulting in decreased myocardial perfusion pressure, reduced myocardial tissue blood flow rate and subsequent reduction in ROSC. Paper II: Myocardial perfusion and sustained cardiac function were related to myocardial perfusion pressure during VF irrespective of MCS (ECMO and balanced biventricular support). Balanced biventricular support maintained lower intraventricular pressure compared to ECMO. Paper III: Add-on LVAD improved haemodynamics compared to ECMO alone. An add-on Impella could not substitute a reduction in ECMO flow. Increased mean aortic pressure, myocardial perfusion pressure and mean pulmonary artery flow were related to sustained cardiac function and ROSC.Doktorgradsavhandlin