Date Published: February 27, 2007
Publisher: Public Library of Science
Author(s): Raffaele Bugiardini, Lina Badimon, Peter Collins, Raimund Erbel, Kim Fox, Christian Hamm, Fausto Pinto, Annika Rosengren, Christodoulos Stefanadis, Lars Wallentin, Frans Van de Werf
Abstract: The authors discuss how to stratify risk in patients with chest pain and a normal coronary angiogram.
Partial Text: Chest pain may be associated with coronary arteries that appear “normal.” Normal is defined here as no visible disease or luminal irregularities (less than 50%) as judged visually at coronary angiography. Normal angiography in patients with chest pain is five times more common in women than in men . Among patients with chest pain and normal angiography, an unknown number are suffering from cardiac pain of ischemic origin. Uncertainty is often difficult to allay, for medical attendants as well as for patients, resulting in perpetuation of symptoms, difficulties in management, and establishment of risk of subsequent coronary events . In this article, we discuss how to stratify risk in patients with chest pain and a normal coronary angiogram. We based our article on a literature review, using the key words “angina with normal angiography,” “angina with normal coronary arteries,” “non-obstructive coronary disease,” or “chest pain of non-cardiac origin,” plus “[a]etiology,” “pathophysiology,” “diagnosis,” “classification,” “prognosis,” or “therapy.” A longer, more detailed version of this paper is found in the supplementary file S1.
Over the past ten years, many terms have been proposed to label patients suffering chest pain due to myocardial ischemia despite normal coronary angiography, including syndrome X , microvascular angina , and non-atherosclerotic myocardial ischemia . The term syndrome X refers only to patients showing ST-segment depression on an exercise electrocardiogram (ECG) with completely smooth coronary arteries at angiography. More recently it has come to be used also for the metabolic syndrome, comprising hypertension, insulin resistance, elevated triglycerides, low levels of high-density-lipoproteins, and obesity. The term microvascular angina may have outlived its usefulness, because patients with chest pain and normal angiography often exhibit a disorder not only of the coronary microcirculation, but also of the entire coronary artery and peripheral circulation [6,7].
The idea that some forms of ischemic heart disease may be caused by abnormalities of the microcirculatory vessels is not new. This idea was proposed 16 years ago as a cause of angina pectoris . Although the importance of microcirculation for the regulation of coronary blood flow has become clearer, pathophysiological explanations of the disease process are still poorly understood.
The prognosis of patients with chest pain and normal or near normal coronary arteries at angiography is not as benign as reported by preliminary cohort studies. Many such patients are at an increased risk of myocardial infarction and cardiac death. In fact, 2% of patients—men and women—with unstable angina and non-ST-segment elevation (and normal or near normal coronary arteries at angiography) die within one year of their admission .
Coronary vascular dysfunction due to abnormal endothelium-dependent coronary vasodilatation is predictive of adverse outcomes [7,8,19–21]. Conversely, impaired endothelial-independent vasodilatation predicts favorable outcomes . The reason for this discrepancy is not known. One might hypothesize that a blunted response to exogenous nitric oxide donors (coronary endothelial-independent vasodilatation) might simply reflect the presence of atherosclerosis, leading to increased stiffness of the vessel wall . Conversely, endothelial dysfunction and atherosclerosis, although causally related, are distinct problems and may exist separately. Coronary endothelial vasoreactivity may indeed represent an index that combines information about the underlying atherosclerotic process and the overall stress imposed by risk factors on the arterial wall.
Nearly 4 million cardiac catheterizations are performed annually in United States hospitals alone, with one in ten discharges having undergone coronary arteriography . More than 20% of patients aged 45–79 years admitted to hospital receive diagnostic cardiac catheterization . More than 50% of women who are referred for cardiac catheterization because of chest pain show non-obstructive coronary lesions or smooth coronary arteries. . Most of these patients have no diagnosis of angina at the time of discharge.
There are currently no critical pathways specifically developed for patients with chest pain and normal angiograms. So far, physicians apply (in varying proportions) pathophysiologic reasoning, personal clinical experience, and published research in the development of their own clinical approaches. Treatment objectives include symptom relief and risk factor identification and management with the objective of reducing progression in the underlying disease process with enhancement of event-free survival.
We recommend the development of large-scale prospective collaborative clinical trials as well as retrospective analyses of already completed trials, in which the results of angiography may be available in at least a portion of patients. Large numbers of patients will need to be studied, since relatively low-risk patients will be included. These studies require considerable communication among all parties: researchers, physicians, hospital administrators, patient groups, and policy planners. This communication can only be realized by close collaboration between important scientific institutions playing a prominent role in research funding and program development. A call to action for risk assessment strategies in this area is warranted.