Unfortunately, atherosclerotic involvement of the coronary arteries is an exceptionally common phenomenon. In a recent study of young individuals, from teenage to 35 years, who had succumbed to motor vehicle accidents and underwent post‐mortem, the vast majority already had subclinical atheromatous coronary plaques.27
Knowing that the disease is relatively endemic in the Western world, and expected to become the dominant cause of death and disability worldwide by 2020,28
it is a challenge to define a threshold which partitions to having or not having CAD.
If a patient presents with angina, has a functional test that shows ischaemia, and then undergoes a coronary angiogram which shows critical stenosis of
70% narrowing of one or more epicardial arteries, then an indisputable diagnosis of CAD can be made. But a large proportion of patients who present with CAD do not have symptoms of angina, and only surface because they have had a routine stress test which is abnormal. If intravascular ultrasound is used, most patients who undergo coronary angiography will be found to have at least some or even substantial plaque accumulation in the arterial wall but without any encroachment of the arterial lumen by the corresponding angiogram.29
This occurs because, during the early phases of atherosclerotic development, there is extensive arterial remodelling with lipid pool accumulation in the arterial wall while fully preserving normal luminal dimension. By strict anatomical definition, this could be classified as CAD with even quantification of the plaque volume burden. But this is complicated because it may be occult, and not associated with any symptoms of angina or abnormalities of functional testing for ischaemia. Furthermore, the coronary angiogram is an incomplete assessment which only shows the accumulation of plaque that results in narrowing of the arterial lumen. A substantial proportion of patients have irregularities of their angiographic borders which correspond to some plaque accumulation. Complicating this matter further, there is often a grey zone—a patient with atypical symptoms, an abnormal stress test, and a 50–60% subcritical narrowing. Should this patient be classified as having CAD? And should the patient with “silent” ischaemia who has a tight narrowing be considered a case? These are just some of the vagaries in the definition of CAD at any given time of assessment.
The complexity increases fully when one considers the multiple longitudinal angiographic studies that show that, in a
6‐month time period, an individual can progress from having slight (<30%) narrowing to critical >70% stenosis.30
This can result from a plaque fissure, erosion or rupture event and typically occurs superimposed at a site of only minimal luminal encroachment. Thus, it is important to acknowledge that the assessment of a “case” is only relevant to the actual time in which the study was performed, and that this is a dynamic phenomenon. Safeguards are therefore needed to pre‐empt the potential recategorisation of a control to a case.
Patients who present for a coronary angiogram represent a bias of ascertainment. It is important to acknowledge that much of the disease is occult with lack of definition by coronary angiography because symptoms may be non‐specific or non‐existent.
The phenotype of myocardial infarction, one of the manifestations of CAD, is more restrictive and has thus far proven more useful in terms of identifying susceptibility genes. But it, too, leaves us with a skewed group of patients. For patients to have presented with the triad of (1) symptoms of protracted chest pain or associated, unequivocal signs of ischaemia, (2) classic electrocardiographic ST segment elevation changes, and (3) enzymatic confirmation of myocardial necrosis, a diagnosis of myocardial infarction is straightforward. However, this is not at all representative. A significant minority of patients with myocardial infarction present with sudden cardiac death and never reach the hospital, leading to a survival bias. As patients are systematically excluded from any genetic study, translating myocardial infarction genetic investigation to an initial non‐fatal presentation phenotype. An even larger proportion of patients have an acute coronary syndrome without ST segment elevation myocardial infarction, but instead have a normal ECG, or non‐specific ECG abnormalities, including ST segment depression, or T wave changes, or both. There are important differences between ST segment elevation myocardial infarction, which involves occlusive coronary thrombus and more extensive myocardial necrosis, and non‐ST segment elevation myocardial infarction, which typically occurs with mural, non‐occlusive thrombosis, may result from more extensive collateral flow, and results in less necrosis. The difference in clinical and angiographic profiles may be accompanied by differences in genetic predisposition. Thus, it would be helpful to know the specific type of myocardial infarction in any given cohort or subgroup that is analysed.
The age of onset of myocardial infarction is an especially important determinant. The genome‐wide association studies of Shiffman et al25,26
showed that completely different gene variants were associated with myocardial infarction by defining the phenotype as a function of age.
The linkage study that focused on the youngest myocardial infarction cohort seemed to have the most yields in terms of significant loci of interest.8
Thus, specific age and type of myocardial infarction, and the fact that we have been dealing only with initial, non‐fatal myocardial infarction are all important considerations to acknowledge. Finally, it is important to note that myocardial infarction represents a very small fraction of the individuals who have the CAD phenotype, and it is likely that there are specific susceptibility genes that play a role in both phenotypes and only one of these processes. There are vast pathophysiological differences between the chronic accumulation of arterial plaque as compared with a sudden plaque rupture event with attendant thrombosis. Box 1 provides considerations for a set of criteria.
Box 1 Considerations for phenotype categorisations (the following criteria were adjudicated by a panel of independent investigators)
- Cases for coronary artery disease
Angiographic stenosis of 70% in a major epicardial artery
Family history of coronary artery disease
No history of smoking
Normal low density cholesterol and high density cholesterol, normal C reactive protein.
- Cases for myocardial infarction
Normal coronary arteries by selective coronary angiography or multidetector CT (<10% narrowing)
No family history of coronary artery disease
No history of cerebrovascular or peripheral artery disease
Age much much greater than cases by 10–20 years.