Intensive medical therapy with risk factor modification is essential in the management of patients with coronary artery disease. While high-risk patients gain a survival benefit from CABG, low- and moderate-risk patients have equivalent outcomes with respect to mortality with either approach (medical management or revascularization). Appropriate medical therapy would include antiplatelet agents, beta-blockers, lipid-lowering agents, and probably angiotensin-converting enzyme (ACE) inhibitors in diabetics and patients with impaired LV function. Since the degree and extent of ischemia predict future events, MPI has been used to assess the impact of medical management on the burden of myocardial ischemia in patients with known coronary disease. Importantly, the use of antianginal medications is usually avoided before performing diagnostic SPECT MPI studies for the detection of CAD, however, it is important to perform the studies while patient is on antianginal regimen for the purpose of assessing prognosis and response to therapy. Data from Mahmarian et al. demonstrated that quantitative exercise Tl-201 MPI is highly reproducible and can be used to accurately interpret temporal changes in MPI in individual patients.47 Moreover, in the ADVANCE MPI trials, Mahmarian et al. demonstrated, in same patient controls, that adenosine and regadenoson produce similar perfusion defects; thus temporal changes with repeat testing can be followed when either of these vasodilator stress agents is used.48
The beneficial impact of various pharmacologic interventions on the clinical outcomes of patients with CAD has been well established. Medical therapy has been associated with improvement in myocardial perfusion defects as a result of either decreased oxygen demand (beta blockers)49–51 or improved coronary blood flow (nitrates, calcium channel blockers [CCBs], and statins).52–54 In asymptomatic patients with CAD and known myocardial perfusion abnormalities, the 2013 ACCF/AHA/ASNC multimodality AUC for radionuclide MPI deem stress testing "rarely appropriate" when last stress imaging study was done <2 years prior, but "may be appropriate" if previous stress imaging was performed ≥2 years prior.40
Among the antianginal medications, beta-blockers have been shown in multiple studies to markedly decrease the burden of exercise-induced ischemia or even normalize the test.49,55 The anti-ischemic effect of beta-blockers is mediated primarily by decreasing the heart rate, prolonging diastole, increasing coronary perfusion time and myocardial oxygen extraction, and decreasing myocardial oxygen consumption in ischemic tissue.50 At the cellular level, beta blockers alter myocyte metabolism providing additional myocardial protection against ischemia. One week of oral propranolol treatment has been shown to improve MPI abnormalities in men with established CAD.49 Similarly, acute propranolol administration in patients with dobutamine-induced reversible perfusion abnormalities has been shown to dampen heart rate response (peak heart rate 83 ± 18 vs. 125 ± 17, p < 0.001), rate–pressure product (14,169 ± 4,248 vs. 19,894 ± 3,985; p < 0.001), and myocardial ischemia score (6.9 ± 5.8 vs. 10.1 ± 7.1, p = 0.047) despite a higher infusion dose.50 The extent of perfusion abnormalities has been shown to be significantly reduced with beta blockers even with the use of vasodilator stress.55
The anti-ischemic effect of nitroglycerin has been attributed to the redistribution of blood flow from normal to ischemic myocardium through dilation of collateral vessels. In addition, nitroglycerine reduces myocardial oxygen consumption by producing a systemic venodilation leading to a reduction in systemic venous return, left ventricular dimensions, and myocardial wall stress.
Either in conjunction with beta blockers51 or alone,52,54 both of these agents decrease the size of reversible defects (particularly in patients with large ischemic perfusion defects). Mahmarian et al. prospectively evaluated whether short-term (6.1 ± 1.8 days) transdermal nitroglycerin patches could limit the extent of exercise-induced LV ischemia as assessed by quantitative Tl-201 tomography. Patients randomized to receive active patch therapy had a significant reduction in their total perfusion defect size (–8.9 ± 11.1%) compared with placebo-treated patients (−1.8 ± 6.1%, p = 0.04). The reduction in perfusion defect size was most apparent in those with the largest (≥20%) baseline perfusion defects (–11.4 ± 13.4% vs. 1.0 ± 3.6%, respectively, p < 0.02). Nitrate therapy did not significantly reduce heart rate, blood pressure, or double product, in consistence with its known mechanisms of action.54
The primary benefit of CCBs seems to be a reduction in myocardial oxygen demand, which is achieved by decreasing arterial tone, peripheral vascular resistance, intraventricular pressure, and wall stress. CCBs also enhance myocardial perfusion through their effects on myocardial microcirculation and metabolism. They improve coronary flow in CAD by selectively dilating larger arterioles and may prevent coronary spasm.52
Limited data suggest that acute administration of nifedipine before exercise planar MPI resulted in significant improvement in perfusion (defined as >20% increase) in approximately one-half of patients and in one-fourth of segments compared with no CCB administration. Chronic administration of nifedipine and nicorandil in two separate studies before exercise SPECT reduced the defect extent and severity.52
The impact of lipid-lowering agents in the secondary prevention of coronary disease has been demonstrated in multiple large studies, such as CARE,53 CTT,56 4S,57 TNT,58 PROVE-IT,59 and JUPITER.60 Statins improve endothelial function and preserve coronary perfusion independent of their reduction in cholesterol. They increase smooth muscle relaxation, decrease oxidative stress, and prevent vascular inflammation. Although statins may halt the progression or cause a regression of atherosclerosis as assessed by coronary angiography and intravascular ultrasound, the degree of regression is slight compared with the substantial improvement in clinical outcomes which is likely related to plaque stabilization. Using rest-dipyridamole positron emission tomography (PET), Gould et al. demonstrated that there were statistically significant improvements in size and severity of perfusion abnormalities after intensive 90-day cholesterol lowering compared to baseline control.61 Thus, short-term intensive cholesterol lowering improves myocardial perfusion before anatomic regression of stenosis occurs. Schwartz et al. used SPECT imaging in patients with CAD and hypercholesterolemia to assess serial changes in myocardial perfusion associated with cholesterol-lowering therapy.62 Following improvement in total cholesterol (pretreatment: 223 ± 51, posttreatment: 147 ± 33, p < 0.001), the stress defect score (% ischemic myocardium) was significantly improved (pretreatment: 19 ± 16, posttreatment: 9 ± 13, p = 0.022). Furthermore, the same investigators studied the effect of short-term (6 weeks) or long-term (6 months) pravastatin in dyslipidemic patients with baseline MPI ischemic defects.63,64 Despite a significant reduction of low-density lipoprotein (LDL) at 6 weeks (33%, p < 0.001), myocardial perfusion scores were reduced only at 6 months (12.6 ± 5.7 at baseline, 9.4 ± 6.2 at 6 months, p < 0.01). The time course of reduced perfusion abnormalities, rather than LDL reduction, paralleled documented clinical benefit.53,57,61,65
Angiotensin-Converting Enzyme Inhibitors
There is notable evidence that ACE inhibitors exert a beneficial effect in patients with known coronary disease. The mechanism for ACE inhibitors benefit is complex (improved endothelial function, vasodilation and reduced afterload, antiplatelet effect, and inhibition of neurohormonal activation). There is no large study to examine their direct anti-ischemic mechanism using MPI. In two studies, ACE inhibition was associated with improved epicardial66 and microvascular blood flow67; the mechanism is predominantly endothelium mediated. After 12 weeks of treatment, enalapril delayed the onset of ischemic ST-segment depression during ETT (5.6 ± 1.9 minutes in the enalapril group vs. 4.4 ± 1.3 minutes in the placebo group, p < 0.05) without affecting the double product.68 Further studies are needed to elucidate a direct anti-ischemic mechanism of ACE inhibitors and explore the role of MPI in monitoring such an effect.
The widespread interest in the noninvasive management of coronary atherosclerosis has brought new attention to the impact of various lifestyle changes on the prognosis of coronary disease. Diet, exercise, and behavioral interventions are generally advised for patients with documented coronary disease. The impact of these changes on the extent of atherosclerosis, as determined by angiography, is modest. However, after 5 years of intensive risk factor modification, the size and severity of perfusion abnormalities on rest-dipyridamole PET imaging improved in the intervention group compared to controls.69