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Case Report
Refractory Coronary Vasospasm following Drug-Eluting Stent Placement Treated with Cyproheptadine
February 2006
Over the years, there have been many implicated mechanisms in the pathogenesis of coronary vasospasm. Some of these have included the release of endothelin by vascular endothelial cells,1 loss of endothelial-dependent relaxation following angioplasty,2 local modification of vessel wall arachidonate metabolism after angioplasty3 and serotonin-induced adrenergic dysfunction. More recently, the release of serotonin from aggregating platelets following endothelial damage has been shown to play an important role in the regulation of coronary arterial tone.
Case Report. A 55-year-old Hispanic man with a history of hypertension presented with severe, substernal chest pain. An electrocardiogram revealed ST-segment elevation of up to 5 mm in leads V2–V6 and a troponin-I level of 4.1 ng/mL. He responded to intravenous (IV) nitroglycerin, eptifibatide, clopidogrel, IV heparin and an angiotensin converting enzyme inhibitor, and was promptly transferred to our tertiary hospital for percutaneous intervention. An angiogram revealed a 70% mid-left anterior descending lesion (Figure 1) that was successfully treated with a 2.5 mm x 16 mm Taxus® stent (Boston Scientific Corp., Natick, Massachusetts).
The evening following the procedure, the patient developed chest pain similar in nature to his prior episode. An ECG showed T-wave inversion in leads V2–V6 (Figure 2). A repeat angiogram revealed a patent stent, with no evidence of dissection or thrombosis (Figure 3). The patient was returned to the ICU on IV nitroglycerin 60–120 µg/hour, amlodipine 10 mg daily, clopidogrel 75 mg daily, and IV heparin.
On day 2, the patient developed another episode of chest pain associated with ST-elevation in leads V2–V5, I, and aVL (Figure 4) after the patient was weaned off the IV nitroglycerin. During this episode, his troponin-I level peaked to 44 ng/ml. He was therefore restarted on IV nitroglycerin with complete resolution of his chest pain and ST-elevation. Isosorbide mononitrate 60 mg daily was added to this regimen.
On day 3, an attempt to wean the patient off IV nitroglycerin resulted in the return of the same chest pain with ST-elevation over the anterior leads. The chest pain completely resolved after IV nitroglycerin administration. PFA epinephrine revealed normal closure times while on therapeutic doses of clopidogrel, indicating platelet resistance. The patient was therefore switched to ticlopidine.
The following day, verapamil SR 120 mg daily was added to his regimen to assist in weaning the patient off IV nitroglycerin. However, the patient’s chest pain recurred, prompting the addition of a maximal dose of verapamil. Despite maximal doses of two calcium channel blockers and an oral nitrate, the patient continued to experience chest pain with ST-elevation anteriorly following IV nitroglycerin weaning (Figure 5). His chest pain completely resolved after restarting IV nitroglycerin.
After a literature review, cyproheptadine 4 mg every 8 hours was added to this regimen, which was eventually increased to every 6 hours, with full resolution of these chest pain episodes on day seven of his hospital stay. The patient was successfully weaned off the IV nitroglycerin and discharged home on cyproheptadine. Presently, the patient is doing well and has had no recurrence of chest pain two months post-discharge on cyproheptadine.
Throughout his hospital stay, laboratory studies, including complete blood count, electrolytes, serum thyroid stimulating hormone, brain natriuretic peptide and homocystine were within normal limits. Partial thromboplastin times were therapeutic while on heparin, and his lipid profile included an LDL of 91 mg/dL, HDL of 35 mg/dL, total cholesterol of 143 mg/dL and triglycerides of 84 mg/dL.
Discussion
Variant angina was first described by Prinzmetal et al. in 1959 as a syndrome of chest pain occurring at rest, associated with ST-segment elevation.4 In the 1970s, coronary vasospasm was angiographically demonstrated during episodes of variant angina.5,6 Currently, Prinzmetal Angina is a well-documented phenomenon of focal coronary vasospasm, usually occurring adjacent to areas of atherosclerotic lesions and/or endothelial damage. Calcium channel antagonists and nitrates are the current standard of therapy for variant angina.
Vascular tone is affected by a myriad of factors, some of which are well documented and others that are still being defined. The role of serotonin (5-hydroxytryptamine) on coronary arterial tone is divergent, depending on vascular endothelium. In the presence of normal coronary endothelium, serotonin induces the release of endothelium-derived relaxing factor (EDRF), now known to be nitric oxide, which causes relaxation of the underlying smooth muscle. In the presence of damaged endothelium, serotonin interacts directly with 5-HT receptors on vascular smooth muscle to cause vasoconstriction.7 In addition, damaged vascular endothelium leads to decreased production of prostacyclin, a known vasodilator and platelet inhibitor, which further favors vasoconstriction.8
Elevated levels of serotonin in response to damaged endothelium have been demonstrated in both animal and human studies. During myocardial ischemia, Fu and Longhurst noted increased concentrations of serotonin in the cardiac venous plasma of cats when compared to pre-ischemia levels, which was even further elevated during reperfusion.9 In humans, Golino et al. showed that following angioplasty, elevated levels of serotonin were released into the coronary vascular bed.10 This elevated serotonin contributed to vasoconstriction distal to the area of angioplasty, an effect which was reduced by ketanserin, a selective 5-HT2 receptor antagonist. More recently, transcardiac plasma levels of serotonin were elevated in patients with vasospastic angina during nonischemic intervals when compared with control patients.11 The authors noted that plasma norepinephrine levels and the generation of prostacyclin in the coronary sinus and aorta were similar among patients with vasospastic angina and their controls, suggesting an impaired endothelium rather than dysfunctional platelets.
Although there have been numerous conflicting studies regarding the effects of serotonin on coronary vasculature, more recent literature has illuminated its divergent influence on normal and damaged endothelium. Sheridan et al. demonstrated the effects of serotonin on canine coronary arteries with intact endothelium, damaged endothelium and removed endothelium.12 There was a biphasic response to serotonin in coronary arteries with intact endothelium (constriction at lower concentrations and dilation at higher concentrations), and a constrictive response in those arteries without an endothelium. In addition, the authors showed an enhanced constrictive response in vessels that were damaged by ischemia and reperfusion, indicating a greater sensitivity to serotonin in damaged endothelium.12
The biphasic results that were obtained by Sheridan et al. were opposite to those made by McFadden et al. in human coronary vessels.13 Intracoronary infusions of serotonin produced dilation at lower concentrations and constriction at higher concentrations in a dose-dependent fashion in patients with normal coronary angiograms. However, in patients with stable angina, only the constricting effects of serotonin were observed, in a dose-dependent manner.13 Chest pain symptoms were noted in all of these patients, and ischemic electrocardiographic changes were noted in two-thirds of them. In areas of atherosclerosis, there was a noted enhanced sensitivity to the vasoconstrictive effects of serotonin, similar to the findings of Sheridan et al. In patients with variant angina, localized occlusion and ischemic electrocardiographic changes occurred at lower concentrations of serotonin. In another study, angiographically normal coronary arteries infused with serotonin lead to dilation and increased coronary blood flow.14 In atherosclerosed arteries, serotonin caused dose-dependent vasoconstriction and decreased coronary blood flow, once again demonstrating the dual effects of serotonin.14
While numerous studies were demonstrating the importance of serotonin in coronary vasospasm, multiple serotonin subtypes were being characterized. Serotonin receptor “families”15 have emerged and include several subtypes: 5-HT1 receptors (5-HT1A, 5-HT1B, 5-HT1D), 5-HT2 receptors (5-HT1C, 5-HT2A, 5-HT2B), 5-HT3 receptors, and more recently, 5-HT4 receptors. Both 5-HT1 and 5-HT2 receptors are expressed in human coronary arteries.16 The exact role of these receptor subtypes in mediating the effects of serotonin in the coronary vasculature has been an issue of debate.
Chester et al. demonstrated a prominence of the effect of 5-HT1-like receptors (including receptor subtypes) over 5-HT2 receptors in an area distally adjacent to atherosclerotic occlusions in human coronary arteries.17 In another study, the 5-HT2 receptor antagonist, ketanserin, was ineffective in dilating vessels after the infusion of serotonin in variant angina, stable angina and control patients.18 Both of these studies concluded that serotonin’s vasoconstrictive effects were mediated by 5-HT1-like receptors.
These findings were the opposite of those observed by Golino et al.14 who noted that the vasoconstrictive effect of serotonin in atherosclerosed arteries was inhibited by ketanserin, indicating the 5-HT2 receptor in serotonin-induced vasospasm. In addition, in normal coronary arteries, the vasodilating effects of serotonin were further enhanced by ketanserin, suggesting a shift in the interaction of serotonin to 5-HT1-like receptors.14 In a similar study, intracoronary ketanserin injection following angioplasty resulted in dilation of the vasoconstricted distal segment of the artery.19 More recently, in a porcine model of coronary atherosclerosis, sarpogrelate, a selective 5-HT2A receptor antagonist was shown to inhibit serotonin-induced vasospasm.20 The authors suggested that serotonin-induced vasospasm was mediated by the selective inhibition of the 5-HT2A receptor, and that ketanserin’s inconsistent inhibition of serotonin-induced vasoconstriction in prior studies was due to its alpha1 adrenergic receptor inhibition.20 These conflicting findings may represent individual variations in the contributions of 5-HT1–like and 5-HT2 receptors in coronary vasospasm, as suggested by Kaumann et al.21
The use of nonselective 5-HT receptor antagonist, such as methiothepin, have consistently inhibited serotonin-induced vasospasm in studies.17,21 Recently, there has been a case report of two patients with refractory Prinzmetal angina who responded to treatment with cyproheptadine, a nonselective serotonin and histamine H1 receptor antagonist.22
The receptor subtype which mediates serotonin-induced coronary vasospasm remains elusive. It is conceivable that in areas of endothelial damage, such as atherosclerosis or postcatheterization, a certain 5-HT receptor subtype may become more prominently expressed through mechanisms which are yet understood. This predominance of a certain receptor subtype may facilitate serotonin-induced vasospasm.
Endothelial damage has been shown to occur following coronary catheterization and angioplasty.23 This endothelial damage leads to a decreased production of prostacyclin, a known platelet inhibitor, favoring platelet aggregation and the release of vasoactive mediators such as serotonin, adenosine diphosphate, and thromboxane A2, leading to vasoconstriction through direct interaction with vascular smooth muscle. However, in the presence of normal endothelium, these vasoactive substances induce the release of endothelial-derived relaxing factor (nitric oxide), leading to vessel relaxation. The former cascade of events could explain the mechanism behind our patient’s vasospasm following coronary catheterization and stent placement and its response to cyproheptadine.
In addition, areas of atherosclerosis have demonstrated impaired endothelial function,24 which in the presence of such mediators as serotonin, may lead to vessel vasoconstriction in nonrevascularized coronary arteries. Oemar et al. demonstrated a decreased expression of endothelial nitric oxide synthase and the production of nitric oxide in areas of vessel atherosclerosis,25 further supporting the premise of altered endothelial function in coronary vasospasm. Recently, endothelial nitric oxide synthase mutations have been demonstrated in patients with coronary vasospasm in the absence of atherosclerosis.26 In canine coronary arteries, recombinant gene transfer of endothelial nitric oxide synthase increased vessel relaxation during hypoxia, suggesting the role of endothelial mutations in nonrevascularized coronary vasospasm.27
Conclusion
Coronary vasospasm is a phenomenon that can be observed in angiographically normal arteries, atherosclerosed arteries and following percutaneous intervention. Although multiple factors may be involved in the pathogenesis of vasospasm, serotonin has been demonstrated to play an important role in the vascular tone of atherosclerosed and revascularized arteries. Although the 5-HT receptor subtype by which serotonin mediates its effects on spastic coronary arteries has yet to be determined, the use of serotonin antagonists in patients refractory to calcium channel antagonists and nitrates postpercutaneous intervention may provide clinical benefit.
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