Cilostazol treatment for preventing adverse cardiovascular events in patients with type 2 diabetes and coronary atherosclerosis: Long-term follow-up of the ESCAPE study.

BACKGROUND: Previously, in the ESCAPE study, a randomized controlled trial, we found that 12 months of cilostazol administration significantly decreased coronary artery stenosis and the noncalcified plaque component compared with aspirin. The goal of the current study was to evaluate the effect of cilostazol treatment on cardiovascular events up to 7 years after the end of the original study. METHODS: After the end of the ESCAPE study with patients with type 2 diabetes mellitus (T2DM) and mild to moderate coronary artery stenosis, we decided to extend the ESCAPE study to investigate the long-term effect of cilostazol and aspirin, named the ESCAPE-extension study. The study participants had been investigated for cardiovascular events for up to 7 years, bringing the total follow-up time to a median of 5.2 years (interquartile range 3.6-6.7 years). Adverse events were also investigated. RESULTS: Among 100 participants from the original study, 88 were included in this extension study. Cilostazol treatment reduced the incidence of cardiovascular events in the patients with T2DM when compared with aspirin for a 5.2-year median follow-up (hazard ratio 0.24; 95% CI, 0.07-0.83). The cardiovascular benefit of cilostazol therapy was maintained along with age, sex, systolic blood pressure, low-density lipoprotein cholesterol, and coronary artery calcium score. No serious adverse events in the cilostazol group were noted in the follow-up period. CONCLUSIONS: In this ESCAPE-extension study, cilostazol treatment proved its efficacy in reducing cardiovascular events compared with aspirin in diabetic patients with subclinical coronary artery disease, suggesting the beneficial role of cilostazol in the primary prevention of cardiovascular disease.

All trans retinoic acid alleviates coronary stenosis by regulating smooth muscle cell function in a mouse model of Kawasaki disease.

Coronary artery (CA) stenosis is a detrimental and often life-threatening sequela in Kawasaki disease (KD) patients with coronary artery aneurysm (CAA). Therapeutic strategies for these patients have not yet been established. All-trans-retinoic acid (atRA) is a modulator of smooth muscle cell functions. The purpose of this study was to investigate the effect of atRA on CA stenosis in a mouse model of KD. Lactobacillus casei cell wall extract (LCWE) was intraperitoneally injected into 5-week-old male C57BL/6 J mice to induce CA stenosis. Two weeks later, the mice were orally administered atRA (30 mg/kg) 5 days per week for 14 weeks (LCWE + atRA group, n = 7). Mice in the untreated group (LCWE group, n = 6) received corn oil alone. Control mice were injected with phosphate-buffered saline (PBS, n = 5). Treatment with atRA significantly suppressed CA inflammation (19.3 ± 2.8 vs 4.4 ± 2.8, p < 0.0001) and reduced the incidence of CA stenosis (100% vs 18.5%, p < 0.05). In addition, atRA suppressed the migration of human coronary artery smooth muscle cells (HCASMCs) induced by platelet-derived growth factor subunit B homodimer (PDGF-BB). In conclusion, atRA dramatically alleviated CA stenosis by suppressing SMC migration. Therefore, it is expected to have clinical applications preventing CA stenosis in KD patients with CAA.

Differential incidence and morphology of provoked spasm between intracoronary acetylcholine and ergonovine testing: recommendation of supplementary use.

When cardiologists diagnose patients with coronary spastic angina, Japanese Circulation Society (JCS) guidelines recommend the intracoronary injection of acetylcholine (ACh) and ergonovine (ER) as class I. However, the pharmacological difference between ACh and ER is controversial in the clinic. We performed both ACh and ER tests in the same 528 patients during 26 years. We investigated the provoked spasm configuration, spasm site, and clinical characteristics of provoked spasm between ACh and ER, retrospectively. We defined positive spasm as ≥90% luminal narrowing. Provoked positive spasm was observed in 161 right coronary arteries (RCA) including 83 ACh just positive, 35 ER just positive, and 43 both positive. In contrast, positive spasm was documented in 172 left coronary arteries (LCA) including 94 ACh just positive, 28 ER just positive, and 50 both positive. ACh provoked spasm more distally and diffusely, while ER induced spasm more proximally and totally or focally in the RCA. In the LCA, ACh provoked spasm more proximally, whereas ER induced spasm more distally. ER testing after the negative ACh tests of RCA and LCA documented new positive spasms in 10.3% (35/340) and 7.4% (28/376), respectively. Coronary artery trees may each have a sensitive receptor on each segment. We recommend the supplementary use of ACh and ER to document coronary artery spasm in the cardiac catheterization laboratory.

Clinical outcome according to spasm type of single coronary artery provoked by intracoronary ergonovine tests in patients without significant organic stenosis.

BACKGROUND: This study aimed to evaluate clinical implications of single vessel coronary spasm provoked by intracoronary ergonovine provocation test in Korean population. METHOD: A total of 1248 patients who presented with single vessel coronary artery spasm induced by intracoronary ergonovine provocation test, excluding 1712 with negative spasms, multiple and mixed coronary artery spasms and missing data among 2960 patients in the VA-KOREA (Vasospastic Angina in Korea) registry, were classified into diffuse (n=705) and focal (n=543) groups. RESULTS: The 24-month incidences of a composite primary endpoints (cardiac death, new-onset arrhythmia, and acute coronary syndrome) were determined. Over a median follow-up of 30months, the composite primary end point occurred more frequently in the focal type patients than in the diffuse type patients (primary endpoint: adjusted hazard ratio [aHR], 1.658; 95% confidence interval [CI] 1.272 to 2.162, P<0.001). Especially, unstable angina in ACS components played a major role in this effect (hazard ratio [HR], 2.365; 95% confidence interval [CI] 1.100 to 5.087, P=0.028). CONCLUSION: Focal type of single vessel coronary artery spasm in vasospastic angina (VSA) patients is found to be associated with worse clinical outcomes. It is thought that the effect is stemmed from unstable angina among ACS rather than the other components of primary endpoint. Therefore, focal type of single vessel coronary artery spasm in patients with VSA should be more carefully assessed and managed with appropriate medication.

The importance of ß2-agonists in myocardial infarction: Findings from the Eastern Danish Heart Registry.

PURPOSE: ß2-Agonists are widely used for relief of respiratory symptoms. Studies so far have reported conflicting results regarding use of ß2-agonists and risk of myocardial infarction (MI). Yet, coronary angiographical data and longitudinal outcomes data are sparse and could help explain if there is an association between use of ß2-agonists and MI. METHODS: Using a novel data-linkage of the Eastern Danish Heart Registry and nationwide administrative registries we identified a cohort of patients referred for acute coronary angiography due to ST-elevation MI (STEMI). Clinical and angiographical findings were compared between ß2-agonist users and non-users. RESULTS: Among 66,234 patients undergoing coronary angiography, 9857 patients had STEMI. Of these, 933 (9%) patients used ß2-agonists. ß2-Agonist users were more often without significant coronary stenosis (15% in ß2-agonist users vs 9% in non-users; p<0.0001), odds ratio (OR) 1.68 (95% confidence interval (CI) 1.37-2.07; p<0.0001). The association was correlated to the number of filled prescriptions. One prescription: OR=1.00 (CI 95% 0.66-1.50; p=1.00)), 2-5 prescriptions: OR= 2.02 (CI 95% 1.47-2.78; p<0.0001), more than five prescriptions: OR=2.30 (CI 95% 1.69-3.12; p<0.0001). All-cause mortality during up to 14 years of follow-up was significantly higher among the ß2-agonist-user group compared to the non-user group (34% vs 23%; p<0.0001), hazard ratio 1.36, 95% CI 1.18-1.56; p<0.0001). CONCLUSION: Among patients referred to urgent coronary angiography for STEMI, use of ß2-agonists was associated with a lower frequency of significant coronary stenosis and a higher mortality compared with non-users.

Estimation of coronary artery stenosis by low-dose adenosine stress real-time myocardial contrast echocardiography: a quantitative study.

BACKGROUND: Coronary microcirculation reserve is an important field in the research of coronary artery disease, but it is difficult to identify clinically. Currently it is widely accepted that myocardial contrast echocardiography (MCE) is a safe, inexpensive method and has comparatively high image resolution. The present study used quantitative low-dose adenosine stress real-time (RT)-MCE to estimate myocardial perfusion and the coronary stenosis. METHODS: Forty-nine left ventricular (LV) segments from 14 unselected patients were divided into three groups according to the coronary angiography or CT angiography results: group 1 (n = 20, 41%) without significant stenosis (< 70%), group 2 (n = 12, 24%) with successful percutaneous coronary intervention (PCI), and group 3 (n = 17, 35%) with significant stenosis (> 70%). RT-MCE was performed in these patients with low-dose adenosine stress and continuous infusion of Sonovue. The replenishing curves were drawn according to the contrast density measured at the end-diastolic frame of every cardiac circle by ACQ software. RESULTS: Forty-nine LV segments with satisfactory image quality were picked for quantitative contrast echo analysis. The replenishing curves were analyzed at baseline and after stress. Perfusion of group 3 did not decrease significantly at baseline, and showed no improvement during adenosine stress and was significantly different from groups 1 and 2 (P < 0.05). The A·ß and ß increased more significantly in group 1 than in groups 2 and 3 (P < 0.05). In a receiver operating characteristic (ROC) curve analysis, A·ß under adenosine stress < 1.74 dB/s had a sensitivity and specificity of 71% for diagnosis of coronary artery stenosis, reduced adenosine-induced rise (percentage of A·ß < 81%) had a sensitivity and specificity of 83% and 79% for the diagnosis of low-reserve, and ß < 54% had a sensitivity of 86% and specificity of 79%. CONCLUSIONS: Rest perfusion of severely stenosed arteries may be normal, but adenosine stress can detect the impaired perfusion reserve. Low-dose adenosine stress RT-MCE provides good accuracy for the evaluation of coronary perfusion reserve and hence coronary stenosis.

Development of coronary artery stenosis in a patient with metastatic renal cell carcinoma treated with sorafenib.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are currently approved for the treatment of metastatic renal cell carcinoma (mRCC). The cardiotoxic effects of sorafenib and sunitinib may cause hypertension, left ventricular ejection fraction (LVEF) dysfunction and/or congestive heart failure (CHF), and arterial thrombo-embolic events (ATE). Only three cases of coronary artery disease related to sorafenib therapy have been described in the literature, and all were due to arterial vasospasm without evidence of coronary artery stenosis on angiography. Cardiotoxicity is commonly associated with the presence of cardiovascular risk factors, such as a history of hypertension or coronary artery disease. CASE PRESENTATION: We describe a patient who experienced an unusual cardiac event after 2 years of sorafenib treatment. A 58-year-old man with mRCC developed acute coronary syndrome (ischemia/infarction) associated with critical sub-occlusion of the common trunk of the left coronary artery and some of its branches, which was documented on coronary angiography. The patient underwent triple coronary artery bypass surgery, and sorafenib treatment was discontinued. He did not have any cardiovascular risk factors, and his cardiac function and morphology were normal prior to sorafenib treatment. CONCLUSIONS: Further investigation of a larger patient population is needed to better understand cardiac damage due to TKI treatment. Understanding the usefulness of careful cardiovascular monitoring might be important for the prevention of fatal cardiovascular events, and to avoid discontinuation of therapy for the underlying cancer.

Ostial left coronary stenosis following aortic root reconstruction with BioGlue.

Haemorrhage is a major concern during repair of acute aortic dissection. In such circumstances, glue is often used for tissue reconstruction and also to fortify vascular anastomoses. In this report, we describe a rare case of ostial left main coronary artery stenosis potentially related to previous use of BioGlue.

Life-threatening complications associated with the tyrosine kinase inhibitor sunitinib malate.

Adverse events associated with sunitinib, such as cardiac toxicities, renal damage, and hemostatic complications, are well known. The authors report 3 cases in which patients experienced severe life-threatening complications after commencing sunitinib treatment. One patient developed heart failure with dilation of the left ventricle and decrease in the ejection fraction after one cycle of sunitinib and required treatment with an angiotensin-converting enzyme inhibitor, loop diuretics, and dobutamine. Another patient developed coronary artery stenosis after one cycle of sunitinib and was managed through percutaneous coronary intervention. Although follow-on coronary angiography revealed normal findings after 6 further cycles of sunitinib, this patient eventually expired due to multi-organ failure. The third patient had chronic renal failure before sunitinib treatment and required hemodialysis due to acute-on-chronic renal failure after commencing sunitinib treatment.

Wandering coronary stenoses: adrenaline-induced coronary artery spasm in a patient resuscitated from cardiac arrest.

A 68-year-old ex-smoker man with history of allergy, presented to the emergency department with progressive dyspnea one hour following self-medication with aspirin for troublesome headache. Examination revealed diffuse sibilant rhonchi over both lungs. Electrocardiogram showed signs of ischemia. In the intensive care unit, he received bronchodilators, nitroglycerin, and aspirin. Bronchospasm increased, and then the patient was shocked, and developed cardiac arrest. After resuscitation, he was kept on mechanical ventilation and adrenaline infusion. He was scheduled for coronary angiography. The left system demonstrated stenosis of the mid-segment of the left anterior descending artery (LAD), which was totally occluded distally, stenosis of the left circumflex (LCx) with a mild plaque in its marginal branch. The right system demonstrated stenosis of the mid-segment of the right coronary artery (RCA), with diffusely diseased posterior descending artery (PDA) and posterolateral left ventricular branch (PLLV). Successful direct stenting was performed to the RCA. Angiography demonstrated worsening of the distal stenosis in the PLLV and complete occlusion of the PDA. Balloon dilatation of the PLLV was adequate, but dilatation of the PDA failed. Repeat angiography of the left system revealed an occluded LCx with critical stenosis of its marginal branch; nevertheless, the LAD was as before. Balloon dilatation of the distal LAD was attempted without improvement, yet, angiography therein, demonstrated "migration" of the stenoses in the LCx. The procedure was halted, adrenaline infusion discontinued, and an intra-aortic balloon pump inserted. The patient was discharged one day later. Follow-up angiography 6 months later demonstrated mild atherosclerotic coronary irregularities.

Optimal starting time of acquisition and feasibility of complementary administration of nitroglycerin with intravenous beta-blocker in multislice computed tomography.

OBJECTIVES: We determined the optimal starting time of acquisition after sublingual nitroglycerin (NTG) administration and evaluated the effects on multislice computed tomographic (MSCT) images of a complementary administration of sublingual NTG with beta-blocker. METHODS: Sixty patients who underwent MSCT coronary angiography (CA) were randomly divided into 2 groups as follows: 30 patients given an intravenous administration of beta-blocker (landiolol hydrochloride, mean dose of 0.032 mg/kg per minute; group B); and 30 patients given a coadministration of intravenous beta-blocker and sublingual NTG (0.3 mg; group N). Blood pressure and heart rate were recorded every 1 minute after NTG administration. In addition, the maximum diameters of the proximal and distal lesions in each coronary artery were measured, and the number of assessable segments was calculated. RESULTS: Blood pressure significantly decreased and heart rate significantly increased 4 minutes after NTG administration. The number of assessable segments was significantly greater in group N than in group B. The maximum diameters of the distal lesions of the left anterior descending and left circumflex arteries and both proximal and distal lesions of the right coronary artery were significantly larger in group N than in group B. CONCLUSIONS: It is advisable to obtain MSCT images after sublingual NTG administration because nitrates are always given during conventional CA and may prevent beta-blocker-induced coronary spasm. The optimal starting time for MSCT CA is approximately 3 minutes after sublingual NTG administration.

Intermediate fixed coronary artery stenosis at the site of ergonovine-provoked spasm as a predictor of long-term major adverse cardiac events of patients with coronary spastic angina.

BACKGROUND: Organic coronary artery stenosis is a significant prognostic factor in patients with coronary spastic angina (CSA), so the present study was focused on assessing the impact of intermediate fixed stenosis at sites of provoked spasm on the long-term outcomes of CSA patients. METHODS AND RESULTS: CSA patients diagnosed on the basis of ergonovine-provoked spasm were enrolled and the clinical background and long-term prognosis of CSA patients with intermediate fixed stenosis at the site of provoked spasm (with-fixed-stenosis group, n=37) and those without fixed stenosis (without-fixed-stenosis group, n=126) were retrospectively compared. During the follow-up period (average 4.01 years for with-fixed-stenosis, 4.47 years for without-fixed-stenosis), the with-fixed-stenosis group had a significantly lower event-free survival rate, as well as a higher frequency of admission for unstable angina and percutaneous coronary intervention than the without-fixed-stenosis group, whereas the survival rate did not differ significantly between the 2 groups. In the multivariate analysis, intermediate fixed stenosis at the site of provoked spasm was a predictor of long-term major adverse cardiac events (MACE). CONCLUSIONS: Intermediate fixed stenosis at the site of ergonovine-provoked spasm is an independent risk factor for MACE during the long-term period in CSA patients.

[Case of electrocardiogram showing ST depression after nonionic contrast media (iopromide) administration].

A 77-year-old man with coronary artery stenosis underwent the left limb artery bypass grafting. When the contrast media was administered on intraoperative limb reperfusion after revascularization, electrocardiogram showed ST depression without skin symptoms and blood pressure decline. The change was not in the right coronary artery area (99% stenosis), but in the left coronary artery area (50% stenosis). The nonionic contrast media may elicit coronary artery vasoconstriction, although there are few side effects including anaphylactic in comparison with the ionic contrast media. In administration of the nonionic contrast media to the patient with coronary artery stenosis (50% or more), it is important to examine electrocardiogram, and is advisable to administer coronary artery dilating drug before-hand.

Ligation of ameroid-stenosed coronary artery leads to reproducible myocardial infarction--a pilot study in a porcine model.

OBJECTIVE: Myocardial gene and cellular therapies have revived the use of porcine ischemic heart models. Commonly applied ameroid-obstruction produces inconsistent coronary stenoses and myocardial lesions, whereas abrupt coronary occlusion causes arrhythmias and sudden death. To produce a constant myocardial lesion after adaptation to ischemia, we surgically modified the ameroid-model by ligation. As a pilot study for further cell therapy research, the spontaneous myocardial response is described. MATERIALS AND METHODS: Simultaneously with ameroid application, a loose loop of nonabsorbable thread was placed around the left circumflex artery (LCx) on 11 domestic piglets. Three weeks later, the loop was tightened. Coronary arteriograms with Rentrop collateral grading from 0 to 3, and 99mTc-single photon emission computerized tomography studies were performed 1 to 5 wk after ligation. At autopsy, the hearts were analyzed macroscopically, histologically, and with von Willebrandt factor-staining. RESULTS: LCx-banding was well-tolerated in nine animals, of which angiographic occlusion was gained in eight. Postmortem analysis revealed a 5 to 10 cm(2) transmural or subendocardial lateral myocardial infarction in all except one heart. One week after occlusion, LCx showed well-developed collateral filling (Rentrop-grade 2.7 +/- 0.4), which remained unchanged at 5 wk. On single photon emission computerized tomography-scans, lateral wall perfusion increased spontaneously between 1 and 5 wk (P = 0.02), and von Willebrandt factor revealed clusters of neovascularization at the borders of infarct areas. CONCLUSIONS: This new modification of ameroid model standardizes myocardial lesion, which might reduce animal number in preclinical studies, thus having ethical aspect. The remarked potential for spontaneous recovery in ischemic porcine myocardium should be considered in preclinical therapeutic studies.

Rebound platelet activation after termination of prasugrel and aspirin therapy due to confirmed non-compliance in patient enrolled in the JUMBO Trial.

Therapy with aspirin and/or adenosine diphosphate (ADP) receptor blockers is associated with better outcomes via inhibition of platelet activity, and subsequent reduction of ischemic vascular events. Non-compliance (NC) is a well-recognised hazard limiting the clinical utility of antiplatelet agents, and, probably worsening outcomes. However, comprehensive platelet characteristics of a confirmed NC patient after acute vascular event have never been reported within a major randomised trial with ADP-receptor antagonists. A 48-year-old male patient, well-educated, was among patients enrolled in the platelet sub-study for the JUMBO trial. He received 325 mg of aspirin daily for 9 months, presented with unstable angina for urgent coronary intervention, and was successfully reperfused with two intracoronary stents. The patient was randomised to a 60 mg prasugrel loading dose, and 10 mg of prasugrel daily for 30 days. Platelets were assessed at baseline, 4 and 24 h, and at 30 days after acute coronary event utilising ADP-, and collagen-induced conventional aggregometry, rapid cartridge-based analyser and flow cytometry. Loading with prasugrel resulted in significant inhibition of platelet activity during and after stenting. However, after assessing platelet biomarkers at 30 days, voluntary withdrawal from the antiplatelet agents was suspected. Based on the platelet activity characteristics, NC was later confirmed, and the patient admitted that he stopped taking both prasugrel and aspirin shortly after discharge due to minor bleeding episodes after shaving. Major platelet activity biomarkers of the index NC patient were compared with those from compliant prasugrel-, clopidogrel-treated patients, and healthy controls. The platelet tests uniformly revealed rebound activation by all platelet measures (at least twofold increase) while being especially high for ADP-, and collagen-induced aggregation, platelet/endothelial cell adhesion molecule-1 (PECAM-1), glycoprotein (GP)Ib, GPIIb/IIIa activity, P-selectin, protease activated receptor (PAR)-1 thrombin receptor (activated and intact epitopes), and thrombospondin expression. The clinical benefits of antiplatelet agents are not only denied in NC outpatients, but may put them at additional risk for worsened vascular outcomes due to the rebound platelet activation. Proclaimed 'resistance' to antiplatelet agents may at least in part be a result of NC, especially in the chronic uncontrolled setting. Enforcing compliance will improve outcomes in the clinical trials, and save lives of patients really receiving antiplatelet therapy.