Nicotine and Nicotine Replacement Therapy Use During Myocardial Perfusion Imaging

Chest pain is one of the most common concerns in patients presenting to the emergency department in the United States, accounting for approximately 7.6 million visits annually.¹ Given the high mortality rate associated with acute coronary syndromes, prompt evaluation of chest pain is essential.² Even in mild cases, recognition of newly onset or worsening coronary artery disease (CAD) is crucial to ensure that patients receive optimal medication therapy.

In symptomatic patients with risk factors for CAD, such as advanced age, hypertension, hyperlipidemia, obesity, and diabetes mellitus, myocardial perfusion imaging (MPI) is frequently used as a modality to assess the presence, location, and severity of ischemic or infarcted myocardium.² MPI requires administration of a radiopharmaceutical before and after the patient undergoes a form of stress.² This radiopharmaceutical is then detected in the myocardium with a nuclear camera, and images are obtained of the heart to assess myocardial blood flow.²

MPI can be performed using exercise-induced stress via a treadmill, or medication-induced stress (Table 1). In both strategies, healthy coronary arteries dilate to provide the myocardium with more blood flow to meet the increasing myocardial oxygen demand during this period of stress. While healthy vessels are able to dilate appropriately, coronary arteries with flow-limiting stenoses are unable to dilate to the same extent in response to stress.² Because radioactive isotope uptake by the myocardium is directly related to arterial blood flow, MPI is able to demonstrate a mismatch in coronary blood flow between healthy and diseased coronary arteries indicated by differences in radioisotope uptake.² The presence of such a mismatch, in conjunction with clinical history, potentially suggests the presence of CAD.

Prior to conducting MPI with a medication, certain substances should be avoided. For instance, methylxanthines, such as caffeine, aminophylline, and theophylline, antagonize adenosine receptors and can have major drug interactions with regadenoson, adenosine, and dipyridamole. Therefore, it is advised that these substances be stopped for at least 12 hours before testing.³ In some cases, other medications that can affect coronary blood flow, such as long-acting nitrates, β-blockers, and calcium channel blockers, are recommended to be avoided for 12 to 48 hours in order to obtain the most accurate depiction of underlying coronary disease.⁴

Because nicotine and nicotine replacement therapy (NRT) may have substantial effects on coronary circulation, a current area of controversy is whether these should be stopped prior to the use of a stress-inducing medication during MPI. To date, no formal drug interaction studies have been conducted between nicotine and regadenoson.⁵ Similarly, the ADVANCE MPI 2 Trial, which led to the US Food and Drug Administration approval of regadenoson, did not specify restrictions on the use of nicotine prior to stress testing in the protocol.⁶ However, as this trial was multicenter, investigators admit that individual study sites could have had their own restrictions on the use of nicotine prior to stress testing with regadenoson, but this information was not collected.⁶ The current review focuses on how the simultaneous use of nicotine or NRT during MPI with pharmacologic agents, such as regadenoson, may affect the accuracy of imaging results and the clinical impact of this interaction.

Nicotine Coronary Artery Effect

It is well documented that long-term cigarette smoking is a major risk factor for CAD.⁷ Compared with nonsmokers, cigarette smokers experience 2 times greater risk of morbidity and mortality from ischemic heart disease.⁷ There are several mechanisms by which nicotine induces damage to the myocardium (Figure). Nicotine has direct effects on both the sympathetic nervous system (SNS) and myocardial endothelium.⁸ Together, these factors result in reduced coronary blood flow, leading to less oxygen supply to meet an increased oxygen demand, resulting in myocardial ischemia.

Nicotine’s effect on coronary vasomotor tone occurs primarily through noradrenergic stimulation of α and β receptors associated with coronary vasoconstriction or vasodilation, respectively.^9,10 These competing influences on coronary blood flow appear to manifest differently based on whether patients are at rest or in a stressed state. A study by Czerin and colleagues demonstrated that in healthy patients with relatively short smoking histories and in a healthy nonsmoker control group, coronary blood flow increased by 25% and 40%, respectively, with nicotine use at rest.⁹ However, when these patients were stressed with dipyramidole and while smoking during the examination, myocardial blood flow was reduced by 11% in the study group and 14% in the control group.⁹ This is likely because the patients studied had relatively healthy coronary arteries that were able to maximally dilate when stressed. In this scenario, nicotine’s dilatory effects are offset by nicotine’s α-receptor–mediated vasoconstriction effects.⁹ Of note, patients in the study group experienced a somewhat diminished increase in coronary blood flow at rest with nicotine use, suggesting that even a short smoking history may damage the myocardial endothelium, rendering it less responsive to nicotine’s vasodilatory effects.⁹