Chapter 7 Ischemic Heart Disease
Most coronary artery disease is caused by obstruction in the coronary arteries from atherosclerosis and coronary thrombosis. In the United States nearly 1.5 million people have an acute myocardial infarction annually, a cause of about a quarter of all deaths. The Centers for Disease Control estimates that nine million people in the United States have angina. Ischemic heart disease consists of those diseases in which blood flow to the myocardium is inadequate to supply normal oxygenation requirements. Signs of coronary artery disease are stable and unstable angina pectoris, acute myocardial infarction, and the complications of inadequate coronary flow, such as arrhythmias, congestive heart failure, ventricular aneurysms, mitral regurgitation, and emboli from left ventricular thrombus.
The initial plain chest film in patients undergoing acute myocardial infarction is obtained to search for signs of left ventricular failure and to screen for some of the complications of infarction. Nearly half the patients admitted to a coronary care unit have radiologic signs of pulmonary venous hypertension within the first 24 hours after an acute myocardial infarction. Even though many films are taken with portable technique in the supine position, the signs of pulmonary edema have a rather good correlation with the pulmonary capillary wedge pressure. The usual caveat, that low lung volumes can mimic signs of pulmonary edema, is appropriate. Indistinct hilar structures represent early engorgement of the vasculature and dilatation of the rich mediastinal lymphatics. You will occasionally see dilatation of upper lobe vessels even on supine films before the reticular pattern of interstitial edema develops. The width of the vascular pedicle above and adjacent to the aortic arch is frequently a good indicator of the intravascular volume. Increase in the size of the azygos vein and superior vena cava on serial films suggest an increase in intravascular blood volume and the need for treatment of left ventricular failure.
At times the assessment of pulmonary edema on the chest film does not correlate with the pulmonary capillary wedge pressure. Many variables may be involved, including low lung volumes, supine position, layered pleural effusions, and pneumonia. The amount of pulmonary edema seen on the chest film reflects a different hemodynamic parameter from that recorded by the pulmonary artery catheter. The pulmonary capillary wedge pressure is the instantaneous left ventricular end-diastolic pressure. Conversely, the chest film reflects changes in lung water over periods of several hours to a couple of days. If the patient has had several episodes of “flash” pulmonary edema during the last few hours, which was subsequently treated and reversed, the lungs still have excess water that has not been carried off by the lymphatic system and other drainage pathways. The therapeutic lag in the chest film findings indicates that the chest film is an average or integral of the lung water status over many hours, whereas the pulmonary artery catheter reflects current left atrial pressure, not the status of the intravascular volume.
Initially, most patients undergoing myocardial infarction have a normal heart size. The assessment of an enlarged heart on a supine portable chest film is rather inaccurate and usually not necessary for clinical management. Severe cardiomegaly generally indicates long-standing coronary artery disease with previous infarction or with a major complication (Fig. 7-1).
In addition to chronic left ventricular failure, left ventricular enlargement may also be the result of a true or false aneurysm, chronic mitral regurgitation, or rarely cardiac rupture. Heart enlargement is not a feature of acute mitral regurgitation or rupture of the interventricular septum because the left ventricle needs several hours to several days to dilate enough to be visible on the chest film. The most frequent site of a true left ventricular aneurysm is in the anterolateral and apical wall. Although left ventricular aneurysms may involve any wall segment, aneurysms in the posterolateral wall are frequently false aneurysms. A false left ventricular aneurysm exists when the left ventricle ruptures into a site of previous pericardial adhesions so that the rupture is contained by the pericardium. An increase in size of the left ventricular aneurysm on serial studies is suggestive of a false aneurysm and warrants urgent, definitive evaluation. Calcification of the anterolateral and apical region of the left ventricle usually takes several years after the myocardial infarction that produced the scarring (Fig. 7-2).
FIGURE 7-2 Computed tomography scan of calcified left ventricular apex. The linear calcification at the left ventricular apex is in an old infarct. The polypoid component represents a calcified thrombus. The patient recently had a coronary bypass operation so that anterior mediastinal and pericardial drains, a small pericardial effusion, and bilateral effusions are present.
Both papillary muscle rupture and rupture of the interventricular septum produce nearly identical findings on the chest radiograph. Both complications typically have moderate interstitial pulmonary edema with mild enlargement of the pulmonary arteries. There is a mild increase in heart size with signs of enlargement of all four cardiac chambers.
Pericardial effusion is common after acute myocardial infarction and is seen in about 25% of patients with echocardiography. This small amount of fluid is not visible on chest films but can be inferred if pleural effusions are visible. A large amount of pericardial fluid may result from either hemorrhagic pericarditis or cardiac tamponade as a result of ventricular rupture. Dressler syndrome usually occurs 2 to 10 weeks after infarction and is manifest on the chest film as pleural effusions, areas of patchy airspace disease, and a large cardiac silhouette.
The majority of patients with asymptomatic ischemia or mild angina should be treated medically. However, for physically active middle-aged individuals with moderate ischemia or objective evidence by both treadmill testing and ambulatory monitoring of significant myocardial ischemia, revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) surgery may be considered and may reduce their risk of serious or fatal cardiac events.
Many patients with moderate or severe stable angina or unstable angina do not respond adequately to medical therapy. PCI or CABG surgery may even improve their left ventricular systolic function. Coronary angiography is used mainly to identify atherosclerotic coronary stenosis, and less often, congenital anomalies and manifestations of other diseases. Each coronary artery is opacified so that its origin, course, and termination are visualized at least in two orthogonal projections. The orthogonal projections are necessary because atherosclerotic stenoses tend to be eccentric; a minor plaque in one projection may appear as a major stenosis in the opposite oblique view (Fig. 7-3).
FIGURE 7-3 Necessity for multiple projections. Coronary angiography must be performed in two orthogonal projections because the atherosclerotic lesion is eccentric. In A, the lumen projects a 77% stenosis, whereas in B, only a 5% stenosis is seen.
The analysis of a coronary arteriogram for coronary artery disease consists of four tasks. First, the extent and location of stenoses must be determined. Second, the severity of each stenosis is graded so that a clinical decision can be made regarding both treatment and prognosis. Third, the morphology of the atherosclerotic plaque is graded. Fourth, the size of the vessel distal to the stenosis is evaluated to see if it is a suitable recipient for a bypass graft or stent placement at the stenosis.
Coronary atherosclerosis begins as lipid deposition in the arterial wall, which appears grossly as a raised, fatty streak. As the lesion progresses, a fibrous cap develops over the endothelial lipid deposit. Disruption of an atherosclerotic plaque results in fissuring and intraluminal thrombosis (Fig. 7-4). The thrombus may lead to intermittent vessel occlusion and unstable angina. Large ulcers at the site of the plaque can cause formation of a fixed thrombus and a chronic occlusion resulting in acute myocardial infarction. Severe stenoses tend to progress to total occlusion about three times more frequently than less severe lesions.
FIGURE 7-4 Unstable angina. Right coronary angiogram showed a proximal ruptured plaque (solid arrow) associated with an endoluminal defect (open arrow) consistent with a thrombus, just distal to the stenosis. The midposterior descending artery is occluded by a distal emboli (arrowhead).
In patients with unstable angina, most coronary stenoses are only of moderate degree. It is the mild to moderate coronary stenosis that commonly precedes most coronary occlusions in patients with unstable angina. Angiography during acute myocardial infarction usually shows a thrombus in the infarct-related artery. After thrombolysis, many of these patients have an underlying lesion with less than 70% stenosis. Those stenoses that later progress usually have eccentric shapes with overhanging edges and are thought to represent plaque disruption. Therefore, the state of the atherosclerotic plaque—whether it is covered with a fibrin cap or has deep fissures that may lead to thrombus—is an important angiographic observation.
Current imaging techniques for ischemic heart disease are used increasingly to differentiate viable from nonviable myocardium in patients with coronary artery disease and left ventricular dysfunction. Acute coronary occlusion generally results in reduced regional myocardial contraction. An acute reduction of blood flow of 80% below a control value in a coronary artery causes akinesis in that segment of the left ventricle, whereas a 95% reduction causes dyskinesis. Akinesis of a segment of the left ventricle, however, does not reliably distinguish viable myocardium from scar.
Myocardial hibernation is a related state in which left ventricular wall motion abnormalities from chronic ischemia return to normal after relief of the ischemia by angioplasty or grafting. The myocardium remains viable during chronic ischemia even though the wall motion is decreased.
These two conditions of reversible left ventricular dysfunction are important to recognize because vigorous treatment of the thrombus or spasm in myocardial stunning and relief of the obstruction in myocardial hibernation may reverse the impaired ventricular performance and potentially salvage the jeopardized myocardium. Stress echocardiography is the modality of choice to assess left ventricular wall motion abnormalities. Stress cardiac magnetic resonance imaging (CMRI) has demonstrated better sensitivity and specificity, but is less available. Furthermore, CMRI is capable of providing useful information about left ventricular viability (Fig. 7-5).
FIGURE 7-5 Gadolinium-enhanced cardiac magnetic resonance imaging in short axis. A, First pass of contrast. The myocardium of the left ventricle should be homogeneously enhanced. In the anteroseptal myocardium, there is a defect in enhancement (arrows), demonstrating impaired perfusion. B, Late phase. The gadolinium is enhancing the same anteroseptal myocardium, delineating a myocardial infarction in the left anterior descending territory.
(Courtesy Dr. Ricardo Cury and Dr. Cesar Cattani, Beneficiancia Portuguesa Hospital, São Paolo, Brazil.)
Most coronary stenoses occur in the proximal portion of both arteries. The distribution of lesions is rather uniform in the three major arteries. The distribution of coronary stenoses with greater than 50% stenosis is: right coronary artery, 37%; left circumflex artery, 28%; left anterior descending artery, 33%; and left main artery, 3%.
In the right coronary artery, most severe stenoses develop in its proximal half, although there are occasional severe plaques at the bifurcation of the posterior descending and posterior left ventricular arteries (Fig. 7-6). The right ventricular marginal branch frequently has a severe stenosis at its origin.
FIGURE 7-6 Right coronary stenoses. A, In lateral projection, there is a 90% stenosis of the proximal right coronary artery (arrow), just before a second large marginal branch. B, Right coronary angiogram. A midright irregular stenosis (arrow) is depicted. C, Right coronary angiogram showing diffuse atherosclerotic disease with a distal right stenosis (solid arrow) and an ostial/proximal stenosis of the posterior descending (PD) artery (open arrow). D, In the lateral projection, there is a severe ostial right coronary artery stenosis (solid arrow), associated with two proximal and one mid stenosis (open arrows). An ulcer is demonstrated just before the origin of the posterior descending artery (arrowhead). M, right ventricular marginal artery; PLV, posterolateral left ventricular artery.
The left main coronary artery should not taper. It is usually narrowed either at its ostium or at the bifurcation of the left anterior descending and circumflex arteries. Occasionally, the entire main arterial segment may be uniformly narrowed but usually one of its ends is more severely involved. Detection of plaques in this segment is particularly important because severe lesions are associated with an increased mortality during cardiac catheterization (Fig. 7-7).
FIGURE 7-7 Left main coronary artery stenosis (arrows). Cranially angled left anterior oblique views show a discrete (A) and diffuse (B) stenosis. C, In the right anterior oblique view the left main artery is smaller than the left anterior descending artery, a sign of diffuse atherosclerosis. D, diagonal artery; L, left anterior descending artery.
Left main equivalent disease describes the combination of stenoses that would cause a decrease in blood supply similar to that caused by a single stenosis in the left main coronary artery. This concept is applied so that a stenosis at the origin of both the left anterior descending and left circumflex arteries is not a left main equivalent. Either of these stenoses may become more severe but may follow a separate time course. Occlusion of one of these would not result in as large an area of myocardium becoming ischemic as would a single event in the left main coronary artery.
An example of a left main equivalent lesion would be a severe left anterior descending artery stenosis when an occluded right coronary artery is supplied by collaterals from the left anterior descending artery. Here one lesion controls the blood supply to the bulk of the heart. A similar example would be a stenosis in a long left anterior descending artery that extends completely around the apex in place of the usual posterior descending artery. Here also a significant percentage of myocardium is affected by a single stenosis.
Clinically, loss of 40% of the left ventricular myocardium produces cardiogenic shock. A left main or left main equivalent coronary stenosis usually affects this much of the myocardium. If collateral vessels supply an adequate perfusion to an occluded vessel, other combinations of coronary stenoses may produce a situation in which one lesion controls the blood supply to a major portion of the left ventricle.
In the left anterior descending artery, stenoses before or after the first large septal branch may have different clinical implications. Patients with chronic stable angina who have a severe stenosis before the first septal branch have a statistically higher mortality when compared with patients who have a stenosis distal to this branch (Fig. 7-8). The first septal branch can supply nearly half of the interventricular septum and a contractile portion of the ventricle and is closely related to the conduction system. A stenosis before the first septal branch also frequently involves a large diagonal branch that supplies a portion of the lateral wall. This correlation does not hold in unstable angina pectoris, where there is no association between severe plaques before and after the first septal branch.
FIGURE 7-8 Left anterior descending artery stenoses (arrows). A, Left coronary angiogram showing an 80% proximal left anterior descending artery (LAD) stenosis before the first septal branch (S). B, A tapering 90% stenosis in the middle segment of the left anterior descending artery distal to the septal branch. LCX, left circumflex artery; LM, left main coronary artery.
The angiographic appearance of coronary atherosclerosis ranges from a single focal plaque to multiple diffuse stenoses with eccentric and ulcerated margins. Isolated stenoses are usually discrete irregularities in the vessel wall, rarely more than 10 mm long. Multiple focal stenoses may be present in series with one another. Diffuse atherosclerosis is occasionally difficult to recognize because no normal-sized vessel is adjacent to the narrowing for comparison.
Atherosclerotic plaques tend to have eccentric and sharp edges that help distinguish them from spasm, which is usually smooth and fusiform. Thrombus within the artery may be distinguished from plaques if contrast medium flows on both sides of the lucency (Fig. 7-9). Occlusive thrombi may be impossible to distinguish from a fibrosed artery, but sharp, slanting edges are more typical of thrombus.
FIGURE 7-9 Coronary thrombus (arrows). A, In the left anterior oblique view the right coronary artery is occluded by a thrombus. Contrast medium tracks on both sides of the filling defect. B, Thrombus (filling defect) has formed on the downstream side of a severe left anterior descending artery (LAD) stenosis. The blood flow through the left anterior descending artery and its branches is impaired compared to the filling of the left circumflex artery (LCX). The angiogram is a caudal right anterior oblique projection.
Plaque morphology can be analyzed by location, shape, and severity (Box 7-1). Each lesion is resolved into length, calcification, involvement of major branches, presence of adjacent thrombus, tortuosity of the involved segment, and eccentricity of the plaque edges.
Box 7-1 Descriptors of coronary stenoses
Both clinical and angiographic studies have confirmed that angiographic morphology is correlated with unstable coronary syndromes. Simple plaques with a smooth fibrous covering, smooth borders, and an hourglass configuration are associated with stable angina. Complex lesions with plaque rupture, intraplaque hemorrhage, and irregular borders in eccentric stenoses are associated with unstable angina and myocardial infarction (Fig. 7-10).
FIGURE 7-10 Simple and complex stenoses (arrows). A, The left anterior descending artery (LAD) has a proximal smooth 95% stenosis in the cranial right oblique view. B, The right coronary artery has two complex stenoses, one after the first marginal branch (M1), which is ulcerated (arrow), and one irregular, after the second marginal branch (M2·; arrowhead). LCX, left circumflex artery; LM, left main coronary artery; M, marginal branch.
Multiple myocardial infarctions result from extensive coronary disease and occur with greater frequency in persons with diabetes. You are more likely to find a decreased ejection fraction in patients with diabetes mellitus but patients with diabetes and those without do not differ significantly in number and extent of severe stenosis. Type II hyperlipoproteinemia is associated with extensive coronary calcifications and severe involvement of the distal distribution of the coronary arteries (Fig. 7-11). These patients may have an unusual edge in the left sinus of Valsalva at the ostium of the left coronary artery, which can make catheterization difficult. Patients with type IV hyperlipoproteinemia have a distribution of stenoses similar to that in patients with normal lipid findings.
There are many causes of coronary stenosis other than atherosclerosis. Frequently, the cause can only be determined by clinical correlation with a systemic disease (Box 7-2). Even then, in the adult age range, it is often impossible to exclude coexisting atherosclerosis. The clinical constellation of chest pain, a positive exercise test, and a normal coronary arteriogram is referred to as syndrome X. The cause of the syndrome is unknown, is not related to large vessel spasm, and may be related to abnormalities in precapillary vessels that are too small to be seen with coronary angiography. In contrast, myocardial infarction can occur with a normal coronary arteriogram. This event is rare and has been caused by thrombosis with recanalization, coronary spasm, cocaine abuse, viral myocarditis, chest trauma, and carbon monoxide intoxication.
What degree of arterial narrowing constitutes a severe stenosis? Many studies have correlated the degree of stenosis with the ultimate clinical or pathologic outcome. Severe stenoses correlate well with an impairment in the left ventriculogram. Early clinical studies by Likoff and Proudfit demonstrated a good association between arteriographic evidence of one-, two-, and three-vessel disease with the clinical signs and symptoms of ischemic heart disease. Comparison of arteriograms with postmortem examinations demonstrates a rough correlation with a 50% arterial reduction or 75% area reduction in a coronary artery associated with a transmural myocardial infarct. Because it is easier to measure the greatest percentage diameter reduction in a coronary artery from serial views, the diameter and not the area reduction is measured. The severity of the obstructive disease is assessed in each coronary artery segment by comparing the arterial diameter at a point of maximum lumen reduction with a proximal or distal “normal-appearing” artery. A coronary stenosis is graded as the highest percentage of stenosis seen in all projections.
Because atherosclerotic plaques tend to be eccentric, coronary angiography must be performed in two orthogonal projections so the maximal arterial narrowing can be identified (Fig. 7-12). This system has many limitations. The normal-appearing artery may itself be diffusely diseased. A similar percentage of stenosis in a smaller distal artery is ascribed the same physiologic consequence, even though flow through a larger proximal arterial segment must be quite different. In a large artery with a greater cross-sectional area, the amount of myocardium supplied by its coronary flow is proportionate to the smaller area supplied by a distal coronary artery. A similar degree of narrowing of a small distal coronary artery produces the same profusion deficit as does the same percentage of stenosis in a large or proximal artery. The length of a coronary stenosis is important but is difficult to subjectively evaluate as to severity of a lesion reducing distal flow. Given these limitations, a 50% or greater stenosis in a patient with ischemic heart disease is defined as a significant stenosis.
FIGURE 7-12 Necessity for multiple projections. The severe stenosis (arrow) is not clearly visible in the lateral view (A), but is nicely demonstrated in the mid left anterior descending artery (LAD) in the cranial right anterior oblique projection (B). D, diagonal branch; LCX, left circumflex artery; S, septal branch.
Coronary blood flow in humans is about 70 to 80 ml per minute per 100 g of myocardium for a cardiac output of 5 L/min. This flow can increase by a factor of three or four during vigorous exercise. The hydraulic factors that influence blood flow through a vessel are expressed in Poiseuille’s equation
where Q. is flow per unit time, r is radius, P is pressure, L is length, and μ is viscosity. This equation is strictly valued for nonpulsatile, streamline flow and a uniform viscosity. With some allowance for the transfer of this mathematical principle to a biologic system, the equation helps explain some of the determinants of coronary flow. Under normal conditions, all the variables in the equation are constant except for the radius of the vessel. However, a number of factors act on the major site of vascular resistance: the precapillary arteriole.
The coronary system autoregulates its blood flow for transient variations in perfusion pressure. Abrupt increases in perfusion pressure (aortic pressure minus right atrial pressure) result in an equivalent increase in coronary blood flow, which gradually returns toward the initial value as vascular resistance changes. A similar response occurs when there is a quick decrease in perfusion pressure.
The blood flow through both left and right coronary arteries is influenced by the extravascular resistance supplied by the thick-walled left ventricle. In the left coronary artery, most blood flow is in diastole. In left ventricular hypertrophy, left coronary flow may even reverse. In contrast, right coronary blood flow is more constant and occurs quite equally during systole and during diastole. In diseases that increase left ventricular wall tension, resting coronary flow tends to be more phasic. Because left coronary flow occurs mainly during diastole, changes in heart rate can lead to critical alterations in myocardial blood supply. In tachycardia, the diastolic filling period is shortened, so blood flow occurs during a shorter time period. Enhancement of left ventricular contraction, as occurs with aortic stenosis or with sympathetic stimulation, similarly increases the time of the heart in systole and thereby reduces left coronary flow. The opposite effect would occur in a patient on propranolol in whom there is bradycardia and decreased afterload.
Resting coronary blood flow in a normal vascular bed does not decrease until the diameter of the stenosis is at least 80% of the adjacent normal vessel. As a stenosis is gradually increased, the distal vascular bed—mainly at the level of the precapillary arteriole—begins to dilate and thus reduces the vascular resistance. However, if the vasculature is already maximally dilated so that autoregulation is no longer present, coronary flow begins to decrease with a stenosis of 30% to 50%. This effect can be seen after pretreatment with a vasodilator but is also thought to occur in the presence of atherosclerosis. In this latter instance, the precapillary sphincters of the distal vascular bed may theoretically dilate slowly from the growth of proximal stenoses.
Coronary flow reserve is the maximal flow divided by the resting flow. The “50% significant stenosis” is then a rough approximation to this physiologic model. The maximal flow is that which occurs when the coronary vascular bed has undergone maximal vasodilatation. Fig. 7-13 shows the relation between coronary blood flow and a focal stenosis in an artery at rest and after maximal vasodilatation.
FIGURE 7-13 Hemodynamically significant stenosis—a stenosis that reduces flow in the distal artery. A, The model is an isolated coronary artery in which a plaque is growing progressively larger. B, At rest, when the coronary vasculature is moderately constricted, coronary flow is unchanged until an 80% stenosis is reached because of autoregulation of the vasculature, mainly at the precapillary sphincters. When the experiment is repeated with a vasodilating agent such as exercise, so that the flow is triple the previous resting value, then a 40% stenosis begins to cause a decrease in downstream flow.
If a significant stenosis is defined as that which causes coronary blood flow to decrease, a significant stenosis at rest is roughly 80% reduction in diameter. However, after maximal vasodilatation, a significant stenosis changes to 40%. The interpretation of these results indicates that stenoses greater than 80% cause a reduction in flow under all circumstances, whereas stenoses less than 40% are not significant even under conditions in which there is maximal vasodilatation. The border zone between 40% and 80% represents the limitation of this method. Unfortunately for clinical decision making, most stenoses fall in this middle zone.
Fractional flow reserve (FFR) is an invasive index of the functional severity of a stenosis determined from coronary pressure measurement during coronary catheterization. A 0.014-in pressure wire is advanced, after calibration, into the relevant coronary segment. It is positioned distally to the stenosis. Adenosine is administered intravenously to induce maximal hyperemia. FFR is calculated as the ratio of mean hyperemic distal coronary pressure measured by the pressure wire to mean aortic pressure measured through the guiding catheter. In patients with coronary stenosis of moderate severity, FFR appears to be a useful index of the functional severity of the stenosis and the need for coronary revascularization. An FFR value of less than 0.75 demonstrates a reversible myocardial ischemia (Fig. 7-14) with a sensitivity of about 90% and a specificity of 100%.
FIGURE 7-14 Fractional flow reserve. A, A 0.014-in pressure wire (solid arrow) is positioned distal to a stenosis (open arrow) in the proximal right coronary artery. B, After pharmaceutical hyperemia, pressure measurements are obtained distally to the stenosis and proximally into the aorta. Fractional flow reserve (FFR) is measured at 0.70, given a hemodynamically significant stenosis. Stent implantation was then performed.
The length of the coronary stenosis also determines blood flow, although its effect is complex. When the diameter is constricted by less than 50%, stenoses of up to 15 mm in length have little effect on flow during reactive hyperemia. As the diameter of a stenosis is increased to 70%, a stenosis 10 mm long results in a reduction in distal flow. Long stenoses in the presence of borderline reduction in diameter (40% to 70%) may greatly alter coronary hemodynamics during stress. Although Poiseuille’s equation suggests that the length of a stenosis would decrease flow linearly, this cannot be precisely observed because there are neural and biochemical factors and collateral flow that also regulate blood flow. Moreover, the distal coronary vascular bed may vasodilate in a nonuniform manner from endocardium to epicardium. Because a proximal stenosis reduces coronary pressure, the endocardium becomes anoxic before the epicardium does, and there is increased lactate production and a fall in highenergy phosphate mediators. The end result is that vascular resistance distal to a stenosis in an ischemic myocardium varies in a complex way.
Multiple consecutive stenoses are frequently encountered in clinical practice, and therefore their cumulative effects need to be considered. If a critical stenosis is in series with a mild stenosis, flow is governed by the more severe stenosis. If two critical (i.e., severe enough to reduce blood flow) stenoses are in the same artery, their combined effect is additive.