Axel Schmermund

Analyse des natürlichen Verlaufs der Koronargefäßverkalkung und Identifizierung ihrer Determinanten

ZusammenfassungDie Heinz Nixdorf Recall Studie ist eine seit dem Jahr 2000 laufende bevölkerungsbasierte Studie zur verbesserten Vorhersage kardiovaskulärer Ereignisse durch Einbeziehung moderner bildgebender und nichtbildgebender Verfahren. Ein Schwerpunkt liegt in der Evaluation der prognostischen Bedeutung der koronaren Kalzifizierung („coronary artery calcium“ [CAC]).Die derzeitig verwendeten Algorithmen zur Risikostratifikation beschreiben das tatsächliche Risiko auf dem Boden einer kleinen Zahl etablierter Risikofaktoren oft nur ungenau. Mit Hilfe der nichtinvasiven Quantifizierung der CAC-Progression könnte die individuelle Arteriosklerosedynamik durch chronisch rezidivierende, oft subklinisch verlaufende Plaquerupturen erkannt werden, lange bevor mit dem plötzlichen Herztod oder einem Myokardinfarkt ein unumkehrbares klinisches Ereignis in der gleichen pathogenetischen Kaskade eintritt. Während der unabhängige prognostische Nutzen der CAC-Messung bei asymptomatischen Personen mit intermediärem Risiko weitgehend etabliert ist, konnten bisherige Studien noch keinen sicheren Nachweis für einen unabhängigen prognostischen Wert der seriellen CAC-Score-Messung erbringen. Neben der Klärung dieser Frage kann in der Heinz Nixdorf Recall Studie auch der Einfluss der etablierten und neuen Risikofaktoren, z. B. metabolisches Syndrom, psychosoziale Risikofaktoren, Umweltfaktoren oder genetische Einflussgrößen, auf die CAC-Progression und spätere Ereignisse bewertet werden. Ferner wird der Zusammenhang der CAC-Progression mit der Inzidenz von Herzinsuffizienz oder Aortenklappen- und Aortenkalzifikationen erarbeitet.Seit April 2006 kommen die Teilnehmer 5 Jahre nach der Basiserhebung nun erneut in das Studienzentrum, um den Gesundheitsstatus und die Entwicklung des kardiovaskulären Risikoprofils zu bestimmen. Basierend auf aktuellen Studienergebnissen und neuen einschlägigen Studien aus internationalen Arbeitsgruppen, wurde kürzlich die erneute CAC-Quantifizierung im Rahmen der Heinz Nixdorf Recall Studie ermöglicht. Die Zielsetzung der Studie konnte daher um wesentliche Aspekte erweitert werden: 1. die Analyse des natürlichen Verlaufs der Progression koronare Kalzifikationen und 2. die Identifizierung ihrer Determinanten. Die Rationale für die serielle Messung koronarer Kalzifikationen wird in dieser Arbeit erörtert.Die Heinz Nixdorf Recall Studie wird einen wesentlichen Beitrag zur Bewertung neuer Methoden in der Risikostratifikation leisten. Die Ergebnisse werden voraussichtlich erhebliche Konsequenzen für die Implementierung neuer Methoden in die kardiovaskuläre Risikostratifikation haben.AbstractThe Heinz Nixdorf Recall Study, which was inaugurated in 2000, is an ongoing population-based study to evaluate the prediction of cardiovascular events by integrating new imaging and nonimaging modalities in risk assessment. A focus is the additional prognostic value of coronary artery calcification (CAC).Currently used risk stratification algorithms often describe the individuals risk based on few established risk factors only inaccurately. Using noninvawursive quantification of CAC progression, the natural history of atherosclerosis with its repetitive, frequently subclinical plaque ruptures, may detect an unstable course of the disease long before the disease irreversibly manifests in sudden death or myocardial infarction. While the independent additional prognostic value of CAC quantification has been shown in asymptomatic patients at intermediate risk, only few studies provided evidence for an independent prognostic value of serial CAC measurements. In the Heinz Nixdorf Recall Study, the impact of established and new risk factors, e.g., the metabolic syndrome, psychosocial and environmental risk factors, or genetic variables, can be assessed. Further, the association of CAC progression with the incidence of other cardiovascular diseases such as heart failure or aortic or aortic valve calcification can be described.Since April 2006, the participants of the study return to the study center 5 years after baseline recruitment to assess health status and to determine the risk factor profile. Based on recently published data, serial CAC measurements have been granted allowing for (1) characterization of the natural history of CAC progression, and (2) identification of its determinants. The rationale of serial CAC quantification is discussed in this article.The Heinz Nixdorf Recall Study will contribute to the appraisal of new imaging modalities in risk stratification.

Non-Invasive Measurement of Coronary Atherosclerosis

In order to understand plaque formation and plaque composition it is necessary to have a knowledge of the normal histology. In general, arteries contain three concentric layers: the intima, media and adventitia (Fig. 4.1.1). The intima consists of a single layer of endothelial cells with only a small amount of underlying connective tissue. The intima is separated from the media by a thick layer of elastic fibers called the intern elastic lamina. The media is mostly composed of smooth muscle cells. Approximately the inner half of the smooth muscle cell layer receives its nutrients from the lumen via diffusion. The outer half, however, needs nourishment from blood vessels themselves, called the vasa vasorum, which course into the media from the adventitia. Between the media and the adventitia lies the external elastic lamina. The adventitia consists of connective tissue, nerve fibers and the vasa vasorum. nOpen image in new window n nFig. 4.1.1. nMicrograph showing a normal muscular artery with a single layer thick intima (I), the media (M, arrows mark the borders) and adventitia (A)

Coronary Calcium Scanning

It is increasingly recognized that only by preventing ischemic heart disease can morbidity and mortality associated with cardiovascular diseases be substantially reduced. There are two main preventive strategies: one that focuses on community-wide measures (“population approach”) and one that focuses on high-risk individuals (“high-risk approach”) (1). Certainly, both approaches have strengths and limitations, and should work best if applied in a complementary fashion. Although clear goals can be set for community-wide measures (such as promoting healthy diet, increasing physical activity, and marginalizing smoking), strategies for successful implementation depend on political, cultural, and economic surroundings. Trials in Central and Western Europe have failed to fulfil the expectations (2,3). By contrast, the high-risk approach has been demonstrated to be effective regarding both lifestyle and pharmacological interventions (1). The problem with this approach is the need to reliably identify high-risk subjects.

Detection and Quantification of Coronary Calcium With Electron Beam CT

Electron beam computed tomography (EBCT) employs well-known computed tomography technology. However, in distinction to other CT machines, no mechanical parts are moved. Whereas in usual CT machines, the distance between cathode and anode is very short, it measures approx 9 ft in EBCT. The electron beam, which produces the X-rays by striking the anode, is steered over this distance by an electromagnetic deflection system. The latest generation of EBCT machines (e−Speed™, GE Imatron) achieves an image acquisition time of only 30 ms, which is sufficient to freeze the motion of the heart.

Clinical Implications of Assessing Coronary Calcification

There are three major areas where EBCT scanning for coronary calcium is likely to prove of significant clinical value. These areas are discussed in detail below.

Coronary Calcium as an Indicator of Coronary Artery Disease

Due to biological factors (mainly arterial remodeling) and the methodological limitations of a contour method, coronary angiography may underestimate both the extent and the severity of atherosclerosis (TopoL and Nissen 1995). But, angiography remains the clinical standard method for defining coronary anatomy in patients. Angiography and electron beam computed tomography (EBCT) evaluate two facets of atherosclerotic plaque disease, that is, luminal narrowing and calcified plaque itself. This was emphasized by a recent study in 49 patients with normal or near-normal angiograms, of whom 28 (57%) had quantifiable coronary calcium (Schmermund et al. 1998b). Coronary calcium in these patients was usually observed in the form of “spotty” calcium as defined by Kajinami et al. (1997). Some coronary segments with spotty calcium showed an increased lumen caliber, probably due to exaggerated compensatory remodeling. Accordingly, atherosclerotic plaque formation in these patients did not entail luminal narrowing, but rather even resulted in a seemingly paradoxical increased lumen in some cases. While other noninvasive tests focus on the physiological consequences of coronary obstruction, EBCT represents anatomic disease itself (Fig. 4.5.1) (ERBEL 1996). Indeed, early stages of atherosclerotic plaque formation that may oftentimes go undetected by angiography are reliably visualized by EBCT (Schmermund et al. 1998b; Baumgart et al. 1997).

What is the current role of electron beam computed tomography in coronary imaging

Electron beam computed tomography (EBCT) has emerged as a powerful means to examine and quantitate cardiovascular anatomy, function, and flow in patients presenting with a variety of diseases of the heart, coronary arteries, pericardium and great vessels. This brief discussion is focused on the developing use of EBCT to image the coronary arteries. There are currently two main areas of interest, i.e., the quantification of coronary calcium by EBCT and the use of peripheral contrast injections for coronary luminal opacification (intravenous EBCT coronary angiography). The amount of coronary calcium as determined by EBCT has been shown to be representative of coronary atherosclerotic plaque burden and thus offers a non-invasive approach to the delineation of coronary artery disease. In several thousands patients followed over one through 5 years, quantities of coronary calcium have been demonstrated to predict cardiovascular events and related mortality. Individuals with large amounts of coronary calcium have a high likelihood of at least one obstructive coronary lesion, require strict measures regarding modifiable risk factors, and may additionally be considered for further evaluations of potential myocardial ischemia. Intravenous EBCT coronary angiography has been performed by several independent groups of investigators and has yielded highly reproducible results. The proximal segments of the major coronary arteries are reliably visualized. High negative predictive values suggest that this technique may be of value for ruling out significant disease in patients undergoing clinical evaluation for obstructive versus non-obstructive coronary artery disease. As is true for any cardiac imaging modality, EBCT should be analyzed in the context of the patient’s history and symptoms.