Determinants of Insufficient Optimal Medical Therapy after Acute Myocardial Infarction.

Objective Although the importance of evidence-based optimal medical therapy (OMT) after acute myocardial infarction (AMI) has been recognized, the prescription rate of OMT is not sufficiently high in real-word clinical settings. The purpose of this study was to identify the clinical characteristics of AMI patients who did not receive OMT. Methods The present study was a retrospective study. OMT was defined as the combination of antiplatelet therapy, angiotensin-converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARBs), beta-blockers, and statins at the time of hospital discharge. Non-OMT was defined as the lack of either antiplatelet therapy, ACE inhibitors/ARBs, beta-blockers, or statins. Results A total of 457 AMI patients were included as the final study population, and 98 patients (22.4%) lacked at least 1 OMT medication. The prescription rates of antiplatelet therapy, ACE inhibitors/ARBs, beta-blockers, and statins were 98.7%, 87.5%, 90.4%, and 96.7%, respectively. In the multivariate logistic regression analysis, age [per 1-year increase: odds ratio (OR) 1.033, 95% confidence interval (CI) 1.007-1.059, p=0.014], hemodialysis (vs. no hemodialysis: OR 2.707, 95% CI 1.082-6.774, p=0.033), estimated glomerular filtration rate <30 mL/min/1.73 m2 without hemodialysis (OR 4.585, 95% CI 1.975-10.644, p<0.001), AMI caused by vasospastic angina (VSA) (vs. no VSA: OR 13.198, 95% CI 1.809-96.260, p=0.011), and asthma (vs. no asthma: OR 7.241, 95% CI 1.716-30.559, p=0.007) were significantly associated with non-OMT, whereas heart rate on admission (per 1-bpm increase: 0.987, 95% CI 0.975-0.999, p=0.033), any PCI (vs. no PCI: OR 0.156, 95% CI 0.066-0.373, p<0.001), and ST-elevation myocardial infarction (STEMI) (vs. NSTEMI: OR 0.384, 95% CI 0.218-0.675, p=0.001) were inversely associated with non-OMT. Conclusion An advanced age, VSA, bradycardia, asthma, impaired renal function, non-PCI revascularization, and non-ST-elevation myocardial infarction were significantly associated with non-OMT.

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.

Temporal Trends and Outcomes of Hospitalizations With Prinzmetal Angina: Perspectives From a National Database.

BACKGROUND: Contemporary data regarding the temporal changes in prevalence and outcomes of hospitalizations with Prinzmetal angina are limited. METHODS: We queried the National Inpatient Sample Database for the years 2002-2015 to identify hospitalizations with Prinzmetal angina. We described the temporal trends and outcomes in patients with Prinzmetal angina. RESULTS: A total of 97,280 hospitalizations with Prinzmetal angina were identified. There was a significant increase in the number of hospitalizations with Prinzmetal angina (3678 in 2002 vs 8633 in 2015, Ptrend <.001) as well as the proportion of hospitalizations with Prinzmetal angina among those with chest pain (Ptrend <.001). There was an increase in the rates of in-hospital mortality (0.24% in 2002 vs 0.85% in 2015, Ptrend = .02), which corresponded to a progressive increase in the burden of comorbidities among patients with Prinzmetal angina. Age >65 years, history of heart failure, chronic kidney disease, chronic liver disease, and acute myocardial infarction upon presentation were independent predictors of in-hospital mortality. Compared with patients with acute myocardial infarction without Prinzmetal angina, those with Prinzmetal angina presenting with acute myocardial infarction had a lower incidence of in-hospital mortality (odds ratio 0.24, 95% confidence interval 0.14-0.41). CONCLUSIONS: In this large national analysis, there has been an increase in the prevalence of hospitalizations with Prinzmetal angina. Older age, heart failure, chronic kidney disease, chronic liver disease, and acute myocardial infarction were predictors of higher mortality among patients with Prinzmetal angina. Patients with Prinzmetal angina who developed acute myocardial infarction had more favorable outcomes compared with myocardial infarction without Prinzmetal angina.

Vasospastic angina: A literature review of current evidence.

Vasospastic angina (VSA) is a variant form of angina pectoris, in which angina occurs at rest, with transient electrocardiogram modifications and preserved exercise capacity. VSA can be involved in many clinical scenarios, such as stable angina, sudden cardiac death, acute coronary syndrome, arrhythmia or syncope. Coronary vasospasm is a heterogeneous phenomenon that can occur in patients with or without coronary atherosclerosis, can be focal or diffuse, and can affect epicardial or microvasculature coronary arteries. This disease remains underdiagnosed, and provocative tests are rarely performed. VSA diagnosis involves three considerations: classical clinical manifestations of VSA; documentation of myocardial ischaemia during spontaneous episodes; and demonstration of coronary artery spasm. The gold standard diagnostic approach uses invasive coronary angiography to directly image coronary spasm using acetylcholine, ergonovine or methylergonovine as the provocative stimulus. Lifestyle changes, avoidance of vasospastic agents and pharmacotherapy, such as calcium channel blockers, nitrates, statins, aspirin, alpha1-adrenergic receptor antagonists, rho-kinase inhibitors or nicorandil, could be proposed to patients with VSA. This review discusses the pathophysiology, clinical spectrum and management of VSA for clinicians, as well as diagnostic criteria and the provocative tests available for use by interventional cardiologists.

The association of chronic air pollutants with coronary artery spasm, vasospastic angina, and endothelial dysfunction.

BACKGROUND: We evaluated the effect of chronic exposure to air pollutants (APs) on coronary endothelial function and significant coronary artery spasm (CAS) as assessed by intracoronary acetylcholine (ACH) provocation test. PATIENTS AND METHODS: A total of 6430 patients with typical or atypical chest pain who underwent intracoronary ACH provocation test were enrolled. We obtained data on APs from the Korean National Institute of Environmental Research (http://www.nier.go.kr/). APs are largely divided into two types: particulate matter with aerodynamic diameter of less than or equal to 10 µm in size (PM10) and gaseous pollutants such as nitrogen dioxide, sulfur dioxide, carbon monoxide, and ozone. The primary endpoint is the incidence of significant CAS and its associated parameters during ACH provocation test. RESULTS: The incidence of CAS was positively correlated with an exposure duration of PM10, whereas nitrogen dioxide, sulfur dioxide, carbon monoxide, and ozone were shown to be unrelated to CAS. During the ACH provocation test, as PM10 increased, the frequency of CAS was increased, and the incidence of transient ST-segment elevation was also increased. There was a trend toward higher incidence of spontaneous spasm as PM10 increased. The mean exposure level of PM10 was 51.3±25.4 µg/m. The CAS risk increased by 4% when the level of PM10 increased by 20 µg/m by an adjusted Cox regression analysis. CONCLUSION: CAS incidence is closely related to exposure to PMs but not to gaseous pollutants. Particularly, higher exposure concentrations and longer exposure duration of PM10 increased the risk of CAS. These important findings provide a plausible mechanism that links air pollution to vasospastic angina and provide new insights into environmental factors.

Prognostic impacts of Rho-kinase activity in circulating leucocytes in patients with vasospastic angina.

Aims: Rho-kinase activity in circulating leucocytes is a useful biomarker for diagnosis and disease activity assessment of vasospastic angina (VSA). The present study aimed to examine the long-term prognostic impact of Rho-kinase activity in circulating leucocytes in VSA patients. Methods and results: We prospectively enrolled 174 consecutive patients with VSA and 50 non-VSA patients, in whom we measured Rho-kinase activity in circulating leucocytes, and they were followed for a median of 16 months. The primary endpoint was cardiac events including cardiac death, non-fatal myocardial infarction, and hospitalization for unstable angina. During the follow-up period, cardiac events occurred in 10 VSA patients (5.7%) but in none of the non-VSA patients. When we divided VSA patients into two groups by a median value of their Rho-kinase activity, the Kaplan-Meier survival analysis showed a significantly worse prognosis in VSA patients with high Rho-kinase activity compared with those with low activity or non-VSA patients (log-rank; P < 0.05, respectively). Receiver-operating characteristic curve analysis showed that Rho-kinase activity value of 1.24 was the best cut-off level to predict cardiac events in VSA patients, and multivariable analysis showed that a value above the cut-off point had the largest hazard ratio to predict poor outcome in VSA patients [hazard ratio (95% confidence interval) 11.19 (1.41-88.95); P = 0.022]. Importantly, combination of the Japanese Coronary Spasm Association risk score and Rho-kinase activity significantly improved the prognostic impact in VSA patients as compared with either alone. Conclusion: Rho-kinase activity in circulating leucocytes is useful for prognostic stratification of VSA patients.

Clinical Outcomes of Vasospastic Angina Patients Presenting With Acute Coronary Syndrome.

BACKGROUND: Coronary vasospasm is an important pathogenesis of acute coronary syndrome (ACS). However, the clinical features and prognosis of vasospastic angina (VA) patients presenting with ACS (VAACS) are still unclear. We aimed to evaluate the clinical characteristics and long-term outcomes of VAACS patients without significant coronary artery stenosis. METHODS AND RESULTS: A total of 986 VA patients confirmed by ergonovine provocation test were analyzed. VAACS was defined as VA patients visiting the emergency room with documented electrocardiographic changes, significant arrhythmias, or elevated cardiac biomarkers. VA patients with elevated cardiac biomarkers were further considered to have myocardial infarction (MI; VAMI). During 4.4 years of median follow-up, we investigated major adverse cardiac events including cardiac death, MI, revascularization, and rehospitalization because of recurrent angina. The VAACS group consisted of 149 patients (15.1%), and VAMI occurred in 81 patients (8.2%). VAACS patients were younger and had a higher prevalence of diabetes mellitus, MI history, and higher levels of inflammatory markers compared with non-VAACS patients. In multivariable Cox regression analyses, VAACS patients were associated with an increased risk of major adverse cardiac events (hazard ratio, 1.65; 95% CI 1.14-2.37; P=0.007) and recurrent MI hazard ratio, 2.57; 95% CI, 1.35-4.87; P=0.004). In addition, VAMI patients had an increased risk of major adverse cardiac events (hazard ratio, 1.75; 95% CI, 1.11-2.76; P=0.016) and recurrent MI (hazard ratio, 2.43; 95% CI, 1.09-5.40; P=0.03). CONCLUSION: VAACS patients showed worse clinical outcomes, driven mainly by recurrent MI. Therefore, intensive medical treatment might be required in VAACS patients.

Impact of Statin Therapy on Clinical Outcome in Patients With Coronary Spasm.

BACKGROUND: Statin therapy reduces the risk of cardiovascular events in patients with obstructive coronary artery disease. The aim of the present study was to determine the effects of statins on the prognosis of patients with coronary vasospastic angina (VSA) free of significant atherosclerotic stenosis. METHODS AND RESULTS: After exclusion of 475 from 1877 consecutive patients who underwent an acetylcholine-provocation test between January 1991 and December 2010, data of 640 VSA patients without significant organic stenosis of the remaining 1402 were analyzed retrospectively. Propensity score matching was performed to reduce the effect of treatment-selection bias and possible confounders. The primary endpoint was major adverse cardiac events (MACE), including cardiac death, nonfatal myocardial infarction, and unstable angina. Among the study population, dyslipidemia on admission was identified in 160 of 168 (95.2%) patients of the statin group compared with only 125 of 472 (26.5%) of the no-statin group. Of the 640 patients, 24 (3.8%) developed MACE. Multivariate Cox hazard regression analysis identified statin therapy as a significant negative predictor of MACE (hazard ratio, 0.11; 95% CI, 0.02-0.84; P=0.033). In the propensity-score matched cohorts (n=128 each), Kaplan-Meier survival curve showed a better 5-year MACE-free survival rate for patients of the statin group compared to the no-statin group (100% vs 91.7%, respectively; P=0.002). CONCLUSIONS: Statin therapy correlated with a lower rate of cardiovascular events in VSA patients free of significant organic stenosis. Statins seems to improve the prognosis of VSA patients free of significant organic stenosis.

Incidence and Risk Factors Associated With Hospitalization for Variant Angina in Korea.

This study aimed to determine the incidence and the risk factors of hospitalization for variant angina (VA) in Korean patients. Using the National Inpatient Sample (NIS) database, manufactured and released by the Health Insurance Review and Assessment Service (HIRA) in Korea, the incidence of hospitalization and rehospitalization for VA were calculated. The numbers of patients hospitalized for VA were estimated to be 14,362 in 2009, 17,492 in 2010, and 20,592 in 2011. The standardized incidence rates of hospitalization for VA were 31.4% in 2009, 36.5% in 2010, and 41.7% in 2011 (relative increase rate from 2009 to 2011, 33.0%, P for trend < 0.0001). VA patients predominantly belonged to the middle-age group between 40 and 69 years (75.5%), and there were 54.3% male. Based on the hospitalization episodes, the number of rehospitalization was calculated to be 879, 1141, and 1446 patients out of 1867, 2274, and 2677 patients from 2009, 2010, and 2011, respectively. The rates of rehospitalization for VA were 47.1% in 2009, 50.2% in 2010, and 54.0% in 2011 (P for trend < 0.0001). Age was an independent factor associated with rehospitalization for VA. Hospitalization for VA occurred most frequently in fall from 2009 to 2011. In conclusion, hospitalization rates for VA steadily increased from 2009 to 2011 in Korea, and about a half of VA patients was hospitalized more than once a year in 2009 to 2011. Proper health policy and patient education are warranted to control the high rate of hospitalization for VA.

Differential incidence and type of spasm according to coronary arterial location.

BACKGROUND: We encounter a less provoked spasm in the left circumflex artery (LCX) by acetylcholine (ACh) testing compared with left anterior descending artery and right coronary artery (RCA) in the real world. OBJECTIVES: We investigated the clinical characteristics of provoked spasm in the LCX by ACh testing. METHODS: We retrospectively analyzed consecutive 1392 ACh testing over 20 years (1991-2011). The maximal ACh dose was 100 µg into the left coronary artery and 80 µg into the RCA. Positive spasm was defined as transient of more than or equal to 90% narrowing and usual chest symptoms or ischemic ECG changes. RESULTS: Positive provoked spasm was recognized in 622 patients (44.7%) including 456 RCA spasms, 448 left anterior descending artery spasms, and 176 LCX spasms. LCX-provoked spasm was significantly lower than other vessels (P<0.001). LCX-provoked spasm was observed in 176 patients, of whom 113 patients (64.2%) had triple-vessel spasm, 46 patients (26.1%) had double-vessel spasm, and 17 patients (9.7%) had single-vessel spasm. More than 90% patients with LCX-provoked spasm had multiple spasms. Of 17 patients with LCX single-vessel spasm, 15 patients (88.2%) had focal spasm. CONCLUSION: Under a maximal ACh dose of 100 µg into the left coronary artery, LCX-provoked spasm was significantly lower than other vessels and more than 90% of patients had multiple spasms.

Coronary vasomotor response to intracoronary acetylcholine injection, clinical features, and long-term prognosis in 873 consecutive patients with coronary spasm: analysis of a single-center study over 20 years.

BACKGROUND: The aim of this study was to elucidate the correlation between angiographic coronary vasomotor responses to intracoronary acetylcholine (ACh) injection, clinical features, and long-term prognosis in patients with vasospastic angina (VSA). METHODS AND RESULTS: This is a retrospective, observational, single-center study of 1877 consecutive patients who underwent ACh-provocation test between January 1991 and December 2010. ACh-provoked coronary spasm was observed in 873 of 1637 patients included in the present analysis. ACh-positive patients were more likely to be older male smokers with dyslipidemia, to have a family history of ischemic heart disease, and to have a comorbidity of coronary epicardial stenosis than were ACh-negative patients. ACh-positive patients were divided into 2 groups: those with focal (total or subtotal obstruction, n=511) and those with diffuse (severe diffuse vasoconstriction, n=362) spasm patterns. Multivariable logistic regression analysis identified female sex and low comorbidity of coronary epicardial stenosis to correlate with the ACh-provoked diffuse spasm pattern in patients with VSA. Kaplan-Meier survival curve indicated better 5-year survival rates free from major adverse cardiovascular events in patients with diffuse spasm pattern compared with those with focal spasm pattern (P=0.019). Multivariable Cox hazard regression analysis identified diffuse spasm pattern as a negative predictor of major adverse cardiovascular events in patients with VSA. CONCLUSIONS: ACh-induced diffuse coronary spasm was frequently observed in female VSA patients free of severe coronary epicardial stenosis and was associated with better prognosis than focal spasm. These results suggest the need to identify the ACh-provoked coronary spasm subtypes in patients with VSA.

Impact of high-density lipoprotein cholesterol level in patients with variant angina pectoris.

BACKGROUND: It is generally considered that patients with variant angina pectoris (VAP) have a potential disturbance in the coronary endothelium. High-density lipoprotein (HDL) has been shown to mediate vasodilation as a result of its endothelium-enhancing property; however, the significance of low HDL in patients with VAP has not been clarified. We sought to determine the association between a low level of high-density lipoprotein cholesterol (HDL-C) and VAP. METHODS: We examined a total of 174 consecutive patients who were suspected of having VAP and underwent spasm provocation test by direct injection of acetylcholine into the coronary arteries. One hundred and three patients (59%) were consequently diagnosed as having VAP. Serum HDL-C, fasting plasma glucose (FPG), and glycohemoglobin levels were measured in all patients. RESULTS: HDL-C in quartiles showed a significant negative correlation with the presence of VAP. Multivariate analysis revealed that the lowest HDL-C quartile (<43 mg/dl), as well as cigarette smoking and impaired fasting glucose/diabetes mellitus, was an independent determinant of VAP (odds ratio=3.39, P=0.010). Patients in the highest FPG quartile (> or =106 mg/dl) or with cigarette smoking habit in combination with the lowest HDL-C quartile showed an increased risk for VAP (relative risk=2.01 and 1.88, respectively). CONCLUSIONS: A low level of HDL-C is an independent determinant for VAP. Endothelial dysfunction caused by a low HDL state may play a role in the development of VAP.

Prinzmetal angina.

Prinzmetal angina is a syndrome of cyclical chest pain at rest caused by vasospasm and associated with ST-segment elevation.

High incidence of repeat anginal attacks despite treatment with calcium-channel blockers in patients with coronary spastic angina.

BACKGROUND: Calcium-channel blockers (CCBs) are highly effective in suppressing coronary spasm and are widely used as the standard therapy for coronary spastic angina, but it is unclear if CCB treatment completely suppresses the symptoms. METHODS AND RESULTS: The clinical course of the symptoms caused by coronary spasm was investigated in patients taking CCBs: 90 patients were evaluated and 80 patients were followed. The mean follow-up period was 1,796+/-1,169 days. There were no cardiac deaths, but 3 patients were admitted to the hospital, 1 because of the onset of non-Q wave myocardial infarction and 2 because of repeat anginal attacks. In those 2 patients, medical therapy was discontinued at their discretion. In the follow-up analysis, we found that the incidence of symptoms caused by repeat anginal attacks was 37.0% (27/73) in the first year and was increasing every year. CONCLUSIONS: CCBs are strongly recommended for improving the prognosis of coronary spasm, but in many cases they do not suppress completely symptoms.

Examination of the microcirculation damage in smokers versus nonsmokers with vasospastic angina pectoris.

Endothelial dysfunction is considered one of the mechanisms underlying vasospastic angina pectoris (VSA). It is also known that smokers have abnormalities in endothelial dysfunction. Although smoking is a major risk factor for coronary artery disease, microvascular abnormalities have not been well shown. We investigated clinical characteristics and coronary reactivity with adenosine triphosphate in smokers with VSA. Twenty-two consecutive patients whose coronary spasm was documented in the left anterior descending (LAD) coronary artery with acetylcholine were enrolled. Coronary blood flow responses were also evaluated by intracoronary Doppler flow velocity recordings in the LAD coronary artery. Average peak velocities (APVs) were measured at baseline and intracoronary administration of adenosine triphosphate (50 microg) in 11 smokers (age 60+/-9 years; 8 men) and 11 nonsmokers (age 61+/-10 years, 5 men). Coronary flow reserve (CFR) was calculated by the ratio of baseline to hyperemic APV. Multivessel spasm was demonstrated in 6 smokers and only 2 nonsmokers (p<0.05). APV at rest in smokers (13.4+/-3.0 cm/s) was similar to that in nonsmokers (13.5+/-2.9 cm/s). However, CFR in smokers (2.6+/-0.7) was significantly lower than in nonsmokers (3.4+/-0.8; p<0.05). In conclusion, multivessel spasm was demonstrated in smokers in clinical settings, and microcirculation damage is prominent in smokers with VSA.

Anomalous left coronary artery from aorta with Prinzmetal's angina: a postoperative dilemma successfully managed.

Anomalous aortic origin of one of the coronary arteries is uncommon. There have been few reports of the left coronary artery arising from the noncoronary sinus. The occurrence of Prinzmetal's angina in association with anomalous aortic origin is extremely rare. We report a case of such a combination and discuss the diagnostic options and therapeutic decision making.

Vasospastic angina and microvascular angina are differentially influenced by PON1 A632G polymorphism in the Japanese.

BACKGROUND: Ethnicity and smoking are well-known risk factors for the pathogenesis of coronary vasospasm. Oxidative stress induced by smoking plays a crucial role in coronary vasospasm, but is not enough to account for the pathogenesis of coronary vasospasm, indicating that genetic factors are strongly involved. METHODS AND RESULTS: The study group comprised 162 vasospastic angina patients (VSAs), 61 microvascular angina patients (MVAs) and 61 non-responders (NRs) diagnosed by acetylcholine provocation test. Four polymorphisms of the oxidative stress related genes, cytochrome b-245, alpha polypeptide gene (CYBA) C242T and A640G, paraoxonase 1 gene (PON1) A632G, phospholipase A2 group VII gene (PLA2G7) G994T were genotyped. Allele frequency of PON1 632-G was significantly higher in both the VSA with dominant fashion and the MVA with recessive fashion compared with NR. This association was strongly influenced by gender in the MVA only. There were no significant associations between the other polymorphisms and coronary vasospasm. In addition, the allele frequency of PON1 632-G in the Japanese was higher than in Caucasians. CONCLUSIONS: There was a significant association between PON1 A632G polymorphism and MVA as well as VSA, but the impact of this on VSA and MVA is different in the Japanese.