A case of vasospastic angina. Vasospasm physiopathology: a new therapeutic role for ranolazine?

We report the case of a 40-year-old man, transferred from another hospital to our ICU because of acute coronary syndrome. Coronarography did not show coronary stenosis. Twenty-four hours monitoring EKG allowed diagnosis of Prinzmetal angina and appropriate therapy was administered. Six months after discharge due recurrence of symptoms, ranolazine was added to therapy. After one year the patient is symptoms free.

Vasospastic Angina Presenting With Syncope and Chest Pain: A Case Report and Brief Literature Review.

A 65-year-old male presented to the hospital with chest pain associated with recurrent syncope. He had a history of coronary artery disease and a long-standing history of smoking. While he was hospitalized, he had an episode of chest pain during which he was found to have transient ST segment elevation in the inferior leads. He was also noted to have a brief cardiac tachyarrhythmia. Coronary arteriography revealed vasospasm of the left anterior descending artery and right coronary artery, which were relieved to a significant extent after administration of intracoronary nitroglycerin. Subsequent angiograms and fractional flow reserve studies, demonstrated underlying non-obstructive coronary artery disease at the sites of spasm. No percutaneous coronary intervention was pursued. The patient was started on a calcium channel blocker on dismissal from the hospital. Upon follow up several months later, he remained free of symptoms that brought him to the hospital.

[A CASE OF ASPIRIN-EXACERBATED RESPIRATORY DISEASE COMPLICATED BY REFRACTORY VARIANT ANGINA, WHICH SHOWED EXCELLENT RESPONSE TO STEROID TREATMENT].

A 47-year-old woman with aspirin-exacerbated respiratory disease visited our hospital complaining of persistent chest pain that manifested in the evenings and early mornings. Holter monitoring revealed ST elevation during chest pain and coronary angiography showed coronary vasospasm, which led to the diagnosis of variant angina. Chest pain persisted despite administration of a coronary vasodilator. The patient experienced an increase in peripheral blood eosinophils during the clinical course and received prednisolone for the same, which resulted in the resolution of her chest pain. Prednisolone was therefore seen to be effective for treating variant angina that manifested as a non-respiratory tract symptom of aspirin-exacerbated respiratory disease.

Coronary artery spasm: review and update.

Coronary artery spasm (CAS), an intense vasoconstriction of coronary arteries that causes total or subtotal vessel occlusion, plays an important role in myocardial ischemic syndromes including stable and unstable angina, acute myocardial infarction, and sudden cardiac death. Coronary angiography and provocative testing usually is required to establish a definitive diagnosis. While the mechanisms underlying the development of CAS are still poorly understood, CAS appears to be a multifactorial disease but is not associated with the traditional risk factors for coronary artery disease. The diagnosis of CAS has important therapeutic implications, as calcium antagonists, not ß-blockers, are the cornerstone of medical treatment. The prognosis is generally considered benign; however, recurrent episodes of angina are frequently observed. We provide a review of the literature and summarize the current state of knowledge regarding the pathogenesis of CAS.

Persistent coronary artery spasm documented by follow-up coronary angiography in patients with symptomatic remission of variant angina.

For patients with variant angina it is very important to start medical therapy using calcium-channel blockers. However, the decision of physicians regarding whether to decrease the dose of the drug or discontinue it is controversial. We investigated whether the nature of spasm is remissive and whether the termination of medications is safe. The subjects studied were included in the Vasospastic Angina in Catholic Medical Center Registry from March 2001 to December 2009. We analyzed 37 patients (62 lesions) with variant angina, diagnosed using coronary angiography (CAG) and he acetylcholine provocation test, without any organic coronary stenosis, whose symptoms were well controlled after medication. The follow-up CAG with provocation test was performed at a median interval of 44 months. The characteristics of spasm were analyzed on each pair of CAGs. The study group consisted of 23 men (62.2 %) and 14 women (37.8 %) with a mean age of 59 ± 11.1 years. The follow-up CAG with provocation test showed that the characteristics of the spasmodic nature were consistent with the first test in all patients. Although the patients with variant angina had no chest pain after medical treatment, the spasmodic nature of coronary arteries still remained. We may decrease the drug dosage after carefully checking the patient's symptoms but recommend not discontinuing therapy, even if the patient is asymptomatic.

Prognostic Impact of Chronic Vasodilator Therapy in Patients With Vasospastic Angina.

Background Chronic vasodilator therapy with long-acting nitrate is frequently used to treat vasospastic angina. However, the clinical benefits of this approach are controversial. We investigated the prognostic impact of vasodilator therapy in patients with vasospastic angina from the multicenter, prospective VA-KOREA (Vasospastic Angina in KOREA) registry. Methods and Results We analyzed data from 1895 patients with positive intracoronary ergonovine provocation test results. The patients were divided into 4 groups: no vasodilator (n=359), nonnitrate vasodilator (n=1187), conventional nitrate (n=209), and a combination of conventional nitrate and other vasodilators (n=140). The primary end point was a composite of cardiac death, acute coronary syndrome, and new-onset arrhythmia at 2 years. Secondary end points were the individual components of the primary end point, all-cause death, and rehospitalization due to recurrent angina. The groups did not differ in terms of the risk of the primary end point. However, the acute coronary syndrome risk was significantly higher in the conventional nitrate (hazard ratio [HR], 2.49; 95% CI, 1.01-6.14; P=0.047) and combination groups (HR, 3.34; 95% CI, 1.15-9.75, P=0.027) compared with the no-vasodilator group, as assessed using the inverse probability of treatment weights. Subgroup analyses revealed prominent adverse effects of nitrate in patients with an intermediate positive ergonovine provocation test result and in those with low Japanese Coronary Spasm Association scores. Conclusions Long-acting nitrate-based chronic vasodilator therapy was associated with an increased 2-year risk of acute coronary syndrome in patients with vasospastic angina, especially in low-risk patients.

Pericarditis as a trigger for Prinzmetal angina - a case report.

Prinzmetal angina is one of the causes of acute coronary syndromes, the exact etiology of which is still unknown. Here we introduce a 27-year-old man with no history of cardiovascular disease, with a history of hospitalization due to acute pericarditis in the previous month, who was discharged with a good response to ibuprofen treatment but had clinical and electrocardiographically recurrence of pericarditis with compressive retrosternal chest pain and electrocardiogram (ECG) changes in favor of acute infero-postero-right ventricular (RV) myocardial infarction (MI). Treatment with vasodilator improved compressive retrosternal chest pain and reversed acute myocardial infarction changes completely and left pleuritic chest pain and pericarditis changes in the ECG. Due to the typical chest pain, he was admitted to the emergency room; ECG revealed generalized ST-segment elevation with acute pericarditis pattern again. Acute infero-posterior and right ventricular acute myocardial infarction pattern was also evident. After treatment with nitroglycerin in the Critical Cardiac Unit (CCU), all ECG ischemic changes returned to baseline, and pericarditis remained in all leads. The patient was discharged with non-steroidal anti-inflammatory drugs (NSAIDs), calcium channel blockers, and a good general condition.

First report of the successful use of bosentan in refractory vasospastic angina.

Variant angina is caused by focal spasm of the epicardial coronary arteries and is variably associated with atherosclerotic coronary disease. We present the clinical course of profound coronary spasm in a woman which resulted in life-threatening symptoms. Although not previously reported, administration of the endothelin antagonist bosentan resulted in complete resolution of her symptoms which were refractory to commonly used anti-anginals, and these symptoms recurred when the drug was inadvertently withdrawn, confirming efficacy of the agent. The details of her clinical outcome and a review of the role of endothelin and its antagonists in coronary vasospasm are discussed.

Improved myocardial perfusion preceding clinical response on bosentan treatment for coronary vasospasm.

Many patients suffer from persistent angina due to coronary vasospasm despite optimal medical treatment. We treated a 46-year-old patient with severe and treatment-resistant coronary vasospasm with the endothelin-receptor antagonist bosentan. Using oxygen-15-labelled water in conjunction with oxygen 15-labelled carbon monoxide positron emission tomography (PET), we measured an impaired coronary flow reserve (CFR) in 6 out of 13 segments directly before the start of bosentan therapy. A repeated PET measurement after 16 weeks of bosentan revealed a completely normalized CFR in this patient. Furthermore, the patient reported less frequent and less severe chest pain. Our data suggest a potential role of endothelin-receptor antagonists for patients with severe coronary vasospasms.

Clopidogrel plus Aspirin Use is Associated with Worse Long-Term Outcomes, but Aspirin Use Alone is Safe in Patients with Vasospastic Angina: Results from the VA-Korea Registry, A Prospective Multi-Center Cohort.

Anti-platelet agents are commonly used in vasospastic angina (VA) patients with comorbidity like coronary artery disease. However, long-term clinical outcomes in the use of aspirin, clopidogrel or the two agents together have rarely been investigated in VA patients. In a prospective study, we enrolled 2960 patients who received coronary angiography and ergonovine provocation test at 11 university hospitals in Korea. Among them, 1838 patients were diagnosed either with definite (n = 680) or intermediate (n = 1212) VA, using the criteria of chest pain, ECG changes and ergonovine provocation test results. They were analyzed according to their use of aspirin, clopidogrel or both, or no anti-platelet agent at all. The primary outcome was time to composite events of death from any cause, acute coronary syndrome (ACS) and symptomatic arrhythmia during a 3-year follow-up. A primary composite outcome was significantly more common in the aspirin plus clopidogrel group, at 10.8% (14/130), as compared with the non-antiplatelet group, at 4.4% (44/1011), (hazard ratio [HR] 2.41, 95% confidence interval [CI], 1.32-4.40, p = 0.004). With regard to the person-time event rate, similar results were shown, with the highest rate in the aspirin plus clopidogrel user at 4.72/1000 person months (95% CI, 2.79-7.96, log-rank test for primary outcome p = 0.016). The person-time event of the ACS rate was also highest in that group, at 2.81 (95% CI, 1.46-5.40, log-rank test for ACS p = 0.116). Kaplan-Meier survival analysis demonstrated poor prognosis in primary outcomes and ACS in aspirin plus clopidogrel users (log-rank test, p = 0.005 and p = 0.0392, respectively). Cox-proportional hazard regression analysis, adjusting for age, sex, history of coronary heart disease, hypertension, diabetes, presence or not of definite spasm, use of calcium channel blocker, demonstrated that the use of aspirin plus clopidogrel is an independent risk for the primary outcome (HR 2.01, CI: 1.07-3.81, p = 0.031). The aspirin-alone group had a similar primary and individual event rate compared to the no-antiplatelet agent group (HR 0.96, CI, 0.59-1.55, p = 0.872). Smokers using aspirin plus clopidogrel had poorer outcomes than non-smokers, with HR 6.36 (CI 2.31-17.54, p = 0.045 for interaction). In conclusion, among VA patients, aspirin plus clopidogrel use is associated with a poor clinical outcome at 3 years, especially in ACS. Aspirin alone appears to be safe for use in those patients.

Treatment of coronary spastic angina with a statin in addition to a calcium channel blocker: a pilot study.

Combined therapy with a statin and a calcium channel blocker, which can improve lipid metabolism and reduce oxidative stress, may attenuate coronary vasoconstriction in patients with coronary spastic angina (CSA). After 6 months of therapy with benidipine and pravastatin, an acetylcholine provocation test was performed a second time in 25 patients with CSA. The patients were divided into 2 groups according to whether the result of this second test was positive (n = 13) or negative (n = 12). The test was designated as positive when the intracoronary injection of acetylcholine induced angiographically demonstrable total or subtotal occlusion (positive-test group). In the negative-test group, significant decrease in the plasma levels of low-density lipoprotein (LDL) cholesterol (-20.7 +/- 11.1%, P < 0.01 versus baseline) were observed along with a dramatic increase in the serum level of high-density lipoprotein (HDL) cholesterol (26.8 +/- 13.2%, P < 0.01 versus baseline). Furthermore, a significant decrease of the malondialdehyde-modified low-density lipoprotein (MDA-LDL) level, a marker of oxidative stress, was also observed (-22.6 +/- 14.1%, P < 0.01 versus baseline) in this group. In the positive-test group, however, no significant changes were found in any of the aforementioned parameters. The results showed that improvement of lipid metabolism, especially an increase of HDL cholesterol level and a reduction of MDA-LDL, may inhibit vascular contractility.

Variant angina in an adolescent coexisting with intermittent Wolff-Parkinson-White syndrome.

Chest pain is not an uncommon complaint among adolescents; however, it often leads them to seek emergency medical care. The variant angina (coronary artery spasm) with resulting acute myocardial ischemia is an extremely rare cause of chest pain among the pediatric population, and there are very few cases reported. We describe a 13-year-old boy with underlying intermittent Wolff-Parkinson-White syndrome and who had an acute coronary artery syndrome due to coronary artery vasospasm.

Management of chronic stable angina pectoris.

Agina pectoris is a discomfort in the chest or adjacent areas caused by myocardial ischemia. It is most commonly caused by the inability of narrowed atherosclerotic coronary arteries to supply adequate oxygen to the heart under conditions of increase demand. This review article will focus in the medical treatment of chronic stable angina, with a focus in new strategies or medications. Treatment by revascularization techniques will not be discussed in this article. The goal of treatment is to improve quality of life, decrease cardiovascular events and mortality. All patients should be evaluated for reversible causes of their angina, such as anemia, hyperthyroidism, sympathomimetic drugs and hypertension. Sublingual nitroglycerin should be used for immediate relief of symptoms. In general, all patients should be on aspirin (ASA) unless they are allergic or other contraindications, if so; clopidogrel should be added to the therapy. In addition to the antiplatelet therapy, which decreases mortality, patients should be started on beta blockers and nitrates. If there is no improvement in symptoms then a calcium channel blockers of the dihydropyridine family should be added. Patients with Diabetes Mellitus and/or left ventricular systolic dysfunction should be also started on angiotensin converting enzyme inhibitors. If the patient continues with limiting angina, ranolazine should be started and finally enhanced external counterpulsation should be considered in those patients who have not responded to maximal drug therapy.

Fluctuations in the amplitude of ST-segment elevation in vasospastic angina: Two case reports.

RATIONALE: ST-segment elevation localizes an ischemic lesion to the coronary artery supplying the area of the myocardium reflected by the electrocardiographic leads. Dynamic ST-segment elevation can be due to severe transmural ischemia secondary to a thrombus, vasospasm, or a tightly fixed coronary artery lesion or a combination of these situations. PATIENT CONCERNS: In this study, we report on two patients with angina who had fluctuations in ST-segment amplitude on serial electrocardiograms. The amplitude of ST-segment elevation varied between 1-20 mm. DIAGNOSES: Vasospastic angina (VSA) was diagnosed based on electrocardiography and coronary angiography. INTERVENTIONS: Calcium antagonists were prescribed for both patients. OUTCOMES: No recurrent VSA was noted during outpatient follow-up. LESSONS: VSA can be associated with fluctuations in the amplitude of ST-segment elevation, indicating dynamic coronary vasospasm in different locations and extensions in patients with VSA.

Ultra-long acting calcium channel blockers may decrease accuracy of the acetylcholine provocation test.

BACKGROUND: When drug-induced coronary spasm provocation tests are performed, a washout period of >48h for calcium channel blockers (CCBs) is uniformly recommended. However, each CCB has a distinct half-life, and little is known about the influence of prior oral administration of CCBs on acetylcholine provocation test to evaluate coronary vasomotor reaction. METHODS AND RESULTS: We examined 245 consecutive patients with suspected vasospastic angina who had undergone acetylcholine provocation test. Of those patients, 29 patients had been on amlodipine, an ultra-long term acting CCB (group A), 34 on other CCBs (group O), and 182 patients on no CCB (group N). After CCBs had been withheld > 48h, we performed acetylcholine provocation, which resulted in 152 positive, 36 intermediate, and 57 negative reactions. We evaluated coronary artery tone calculated as follows: (luminal diameter after nitrate-baseline luminal diameter)÷(luminal diameter after nitrate)×100 (%). In group A patients, coronary artery tone was lower (A:9.1±6.9% vs. O:11.7±8.3% vs. N:12.1±8.5%, p=0.0011) and the positive rate of acetylcholine provocation test was lower than group O and group N (A:41% vs. O:68% vs. N:64%, p=0.047). Multivariate logistic analysis showed that taking amlodipine until 2days before acetylcholine provocation test was a significant inverse predictor for acetylcholine-provoked coronary spasm (odds ratio 0.327; 95% confidence interval 0.125-0.858, p=0.023). CONCLUSIONS: Residual vasodilatory effects of ultra-long acting CCB may decrease coronary artery tone and the vasoconstrictive reaction to acetylcholine suggesting that a 2-day pre-test drug holiday may not be long enough.

Stent implantation in variant angina refractory to medical treatment.

BACKGROUND: Vasospastic angina usually responds well to medical treatment. HYPOTHESIS: The present study describes our experience in patients who received a coronary stent because of recurrent variant angina refractory to medical treatment and evaluates stent implantation as an alternative treatment. MATERIALS AND METHODS: Between March 1998 and February 2005, recurrent variant angina was diagnosed in 22 patients admitted to our coronary care unit. Of these, five patients (22.7%), were refractory to pharmacologic treatment. Coronary angiography and coronary stents were indicated. Clinical follow-up was 29 +/- 6 months. RESULTS: Stenting was performed during diagnostic coronary angiography in two patients. In the other three patients, the stent was implanted 24-48 h later. We observed coronary spasm recurrences proximal or distal to the stent in four patients-two during the stent implantation procedure and the other two in the coronary care unit within 48 h post angioplasty. Three patients where treated with additional stenting and the fourth patient improved with pharmacologic treatment. During follow-up three patients remained asymptomatic. The fourth patient had diffuse in-stent restenosis in the third month, and the fifth patient showed a de novo lesion in the treated segment 2 years later. CONCLUSIONS: Stent implantation in patients with recurrent variant angina refractory to medical treatment may be an alternative treatment in carefully selected, clinically unstable patients. Spasm recurrences may occur in other segments of the treated artery, probably due to the diffuse nature of the disease. Immediate and continued surveillance is recommended because of the risk of adverse clinical events.

[Effectiveness and safety of clopidogrel bisulfate in complex therapy of patients with acute coronary syndrome with ST segment elevation].

UNLABELLED: Efficacy of clopidogrel in acute myocardial infarction (AMI) was studied only in two trials. However efficacy and safety of loading dose of this drug and its long-term effectiveness were not studied in these trials. AIM: To assess effects of clopidogrel loading dose and long term therapy in addition to standard treatment on death, re-infarction, recurrence of angina and bleedings rate in patients with ST segment elevation acute coronary syndrome. METHODS: Patients (n=107) with AMI who met the criteria for thrombolytic therapy (TLT) were assigned randomly into either clopidogrel group A (n=51) or conventional therapy group B (n=56). Group A received loading dose of clopidogrel (300 mg) in addition to conventional therapy (TLT, aspirin, statin, ACE inhibitor and beta-blocker). Group B received only conventional therapy. The follow-up was 6 months after inclusion during which patients in group A continued to receive clopidogrel (75 mg/day after Day 2 of the study). Primary endpoint included death, re-infarction, recurrence of angina and bleedings. In addition, changes of ST segment after TLT and local contractility were assessed. RESULTS: During 30 days of follow-up rates of primary endpoint were 2.0 and 41.1% in groups A and B, respectively (p=0.003). Subgroup analyses showed that this difference depended on the rate of angina recurrence (2.4 and 36.1% in groups A and B, respectively, p=0.002). These differences were maintained during all follow-up period. Odds ratios for clopidogrel were 0.235 for primary endpoint (95% CI 0.104-0.528, p=0.0003), 0.078 for angina recurrence (95% CI 0.022-0.279, p=0,0001). No significant differences were obtained for mortality, re-infarction and bleeding rate. TLT in group A was more effective. ST depression 90 min after TLT was 86.23+/-4.38 and 61.00+/-6.97% (p=0.010), reperfusion arrhythmia rate - 72.6+/-3.27 and 33.9+/-2.78% (p=0.005) in groups A and B, respectively. CONCLUSION: The use of clopidogrel in addition to standard therapy for AMI is safe and effective. Long-term clopidogrel treatment decreases angina recurrence rate.

Impact of Renin-Angiotensin System Inhibitors on Long-Term Clinical Outcomes of Patients With Coronary Artery Spasm.

BACKGROUND: Coronary artery spasm (CAS) is a well-known endothelial dysfunction, and a major cause of vasospastic angina (VSA). The renin-angiotensin system (RAS) is known to be closely associated with endothelial function. However, there are only a few studies that investigated the impact of RAS inhibitor on long-term clinical outcomes in VSA patients. METHODS AND RESULTS: A total of 3349 patients with no significant coronary artery disease, diagnosed with CAS by acetylcholine provocation test were enrolled for this study. Significant CAS was defined as having ≥70% narrowing of the artery after incremental injections of 20, 50, and 100 µg of acetylcholine into the left coronary artery. Patients were divided into 2 groups according to whether the prescription included RAS inhibitor or not (RAS inhibitor group: n=666, non-RAS inhibitor group; n=2683). To adjust for any potential confounders that could cause bias, propensity score matching (PSM) analysis was performed using a logistic regression model. After PSM analysis, 2 matched groups (524 pairs, n=1048 patients, C-statistic=0.845) were generated and their baseline characteristics were balanced. During the 5-year clinical follow-up, the RAS inhibitor group showed a lower incidence of recurrent angina (8.7% versus 14.1%, P=0.027), total death (0.0% versus 1.3%, P=0.045), and total major adverse cardiovascular events (1.0% versus 4.1%, P=0.026) than the non-RAS inhibitor group. CONCLUSIONS: Chronic RAS inhibitor therapy was associated with lower incidence of cardiovascular events in VSA patients in the 5-year clinical follow-up.

Pharmacotherapy of Vasospastic Angina.

Vasospastic angina is a diagnosis of exclusion that manifests with signs and symptoms, which overlap with obstructive coronary artery disease, most often ST-segment elevation myocardial infarction. The pharmacotherapy that is available to treat vasospastic angina can help ameliorate angina symptoms. However, the etiology of vasospastic angina is ill-defined, making targeted pharmacotherapy difficult. Most patients receive pharmacotherapy that includes calcium channel blockers and/or long-acting nitrates. This article reviews the efficacy and safety of the pharmacotherapy used to treat vasospastic angina. High-dose calcium channel blockers possess the most evidence, with respect to decreasing angina incidence, frequency, and duration. However, not all patients respond to calcium channel blockers. Nitrates and/or alpha1-adrenergic receptor antagonists can be used in patients who respond poorly to calcium channel blockers. Albeit, evidence for use of nitrates and alpha1-adrenergic receptor antagonists in vasospastic angina is not as robust as calcium channel blockers and can exacerbate adverse effects when added to calcium channel blocker therapy. Despite having a clear benefit in patients with obstructive coronary artery disease, the benefit of beta-adrenergic receptor antagonists, statins, and aspirin remains unclear. More data are needed to elucidate whether or not these agents are beneficial or harmful to patients being treated for vasospastic angina. Overall, the use of pharmacotherapy for the treatment of vasospastic angina should be guided by patient-specific factors, such as tolerability, adverse effects, drug-drug, and drug-disease interactions.