Dysregulated circulating SOCS3 and haptoglobin expression associated with stable coronary artery disease and acute coronary syndrome: An integrated study based on bioinformatics analysis and case-control validation.
Zhang Xunnan,Lv Xi,Li Xiandong,Wang Yaping,Lin Hao-Yu,Zhang Jicai,Peng Chunyan
Anatolian journal of cardiology
OBJECTIVE:To extensively use blood transcriptome analysis to identify potential diagnostic and therapeutic targets for cardiovascular diseases. METHODS:Two gene expression datasets (GSE59867 and GSE62646) were downloaded from GEO DataSets to identify altered blood transcriptomes in patients with ST-segment elevation myocardial infarction (STEMI) compared to stable coronary artery disease (CAD). Thereafter, several computational approaches were taken to determine functional roles and regulatory networks of differentially expressed genes (DEGs). Finally, the expression of dysregulated two hub genes-suppressor of cytokine signaling 3 (SOCS3) and haptoglobin (HP)-were validated in a case-control study. RESULTS:A total of 119 DEGs were identified in the discovery phase, consisting of 71 downregulated genes and 48 upregulated genes; two hub modules consisting of two hub genes-SOCS3 and HP-were identified. In the validation phase, both SOCS3 and HP were significantly downregulated in the stable CAD and acute coronary syndrome (ACS) patients when compared with healthy controls. Meanwhile, HP was significantly upregulated in STEMI patients when compared with stable CAD patients (p=0.041). Logistic regression analysis indicated that: downregulated expression of HP correlated with increased risk of CAD [odds ratio (OR)=0.52, 95% confidence interval (CI)=0.31~0.87, p=0.013]; and downregulated expression of SOCS3 correlated with increased risk of ACS (OR=0.66, 95% CI=0.46~0.94, p=0.023) when age, gender, history of hyperlipidemia, diabetes and hypertension were included as covariates. CONCLUSION:Future clarification of how SOCS3 and HP influence the pathogenesis of disease may pave the way for the development of novel diagnostic and therapeutic methods.
East asian variant of aldehyde dehydrogenase 2 is associated with coronary spastic angina: possible roles of reactive aldehydes and implications of alcohol flushing syndrome.
Mizuno Yuji,Harada Eisaku,Morita Sumio,Kinoshita Kenji,Hayashida Mariko,Shono Makoto,Morikawa Yoshinobu,Murohara Toyoaki,Nakayama Masafumi,Yoshimura Michihiro,Yasue Hirofumi
BACKGROUND:Coronary spastic angina (CSA) is a common disease among East Asians, including Japanese. The prevalence of alcohol flushing syndrome associated with deficient activity of the variant aldehyde dehydrogenase 2 (ALDH2*2) genotype is prevalent among East Asians. We examined whether CSA is associated with the ALDH2*2 genotype in Japanese. METHODS AND RESULTS:The study subjects consisted of 202 patients in whom intracoronary injection of acetylcholine was performed by angiography on suspicion of CSA (119 men and 83 women; mean age, 66.2±11.4 years). They were divided into CSA (112 patients) and control groups (90 patients). ALDH2 genotyping was performed by the direct application of the TaqMan polymerase chain reaction system on dried whole blood. Clinical and laboratory data were examined using conventional methods. The frequencies of male sex, ALDH2*2 genotype carriers, alcohol flushing syndrome, tobacco smoking, and the plasma level of uric acid were higher (P<0.001, P<0.001, P<0.001, P<0.001, and P=0.007, respectively) and the plasma high-density lipoprotein cholesterol levels were lower (P<0.001) in the CSA group than in the control group. The multivariable logistic regression analysis revealed that ALDH2*2 genotype and smoking were significantly associated with CSA (P<0.001 and P=0.024, respectively). CONCLUSIONS:East Asian variant ALDH2*2 genotypes and, hence, deficient ALDH2 activity were associated with CSA in Japanese. These data support further investigation of treatment targeting aldehydes for CSA.
3-year follow-up of patients with coronary artery spasm as cause of acute coronary syndrome: the CASPAR (coronary artery spasm in patients with acute coronary syndrome) study follow-up.
Ong Peter,Athanasiadis Anastasios,Borgulya Gabor,Voehringer Matthias,Sechtem Udo
Journal of the American College of Cardiology
OBJECTIVES:We sought to determine the prognosis of patients with acute coronary syndrome without culprit lesion and proof of coronary spasm during 3 years of follow-up. BACKGROUND:Coronary artery spasm has been identified as an alternative cause for acute coronary syndrome (ACS) in patients without culprit lesion. In the CASPAR (Coronary Artery Spasm as a Frequent Cause for Acute Coronary Syndrome) study, we recently showed that ∼50% of ACS patients without culprit lesion, in whom intracoronary acetylcholine provocation was performed, had coronary spasm. However, data on prognosis in these patients are sparse. METHODS:After 3 years of follow-up, data regarding the following end points were obtained: death (cardiac and noncardiac), nonfatal myocardial infarction, and recurrent angina leading to repeated coronary angiography. The analysis focused on patients with a culprit lesion (n = 270) and patients without a culprit lesion (n = 76) but with acetylcholine provocation (total n = 346). RESULTS:In patients without culprit lesion, there was no cardiac death or nonfatal myocardial infarction during follow-up; 1 patient died due to a noncardiac cause. However, 38 of 76 patients reported persistent angina requiring repeated angiography in 3 cases (3.9%). Thirty of 270 patients with culprit lesion died due to a cardiac cause (11.1%) and 13 due to a noncardiac cause (4.8%). Eleven patients had nonfatal myocardial infarction (4.1%) and 27 repeated angiography due to persistent or recurrent angina (10%). Patients with a culprit lesion had a higher mortality and more coronary events compared with those without (p < 0.0005, log-rank test). CONCLUSIONS:ACS patients without culprit lesion and proof of coronary spasm have an excellent prognosis for survival and coronary events after 3 years compared with patients with obstructive ACS. However, persistent angina represents a challenging problem in these patients, leading in some cases to repeated coronary angiography.
Clinical impact of coronary artery spasm in patients with no significant coronary stenosis who are experiencing acute coronary syndrome.
Satoh Shinji,Omura Soichiro,Inoue Hiroko,Mori Takahiro,Takenaka Katsuhiko,Numaguchi Kotaro,Mori Etsuo,Aso Akemi,Nakamura Toshihiro,Hiyamuta Koji
Journal of cardiology
BACKGROUND AND OBJECTIVE:To clarify the clinical features of coronary artery spasm (CAS) with no significant coronary stenosis in patients with suspected acute coronary syndrome (ACS) in real practice. METHODS:This is a retrospective observational study of patients with suspected ACS (n=645) based on symptoms, electrocardiographic changes, and/or positive cardiac biomarkers and vasospastic angina (VSA, n=90). ACS patients were divided into two groups: (1) organic ACS (n=515), culprit lesion ≥75% coronary stenosis with/without thrombosis; (2) spastic ACS (n=70), coronary stenosis <75%, either with positive acetylcholine (ACh) test (n=51) or without ACh test but verified spontaneous spasm (n=19). The study compared clinical characteristics among organic ACS, spastic ACS, and VSA. RESULTS:One hundred and thirty suspected ACS patients had a coronary organic stenosis <75% (130/645, 20%). Seventy of those patients (70/130, 54%) were confirmed to have CAS, and these accounted for 11% of all ACS patients (70/645). The rate of cigarette smoking was highest in the spastic ACS. No spastic ACS patients died during their hospital stay or after discharge, whereas acute myocardial infarction occurred in 19%, aborted sudden cardiac death in 6%, multivessel spasm was provoked in 78%, and diffuse spasm was more frequently provoked than in the VSA group (82% vs. 62%). CONCLUSIONS:CAS is not a rare cause of ACS. Although the prognosis of spastic ACS is good, there are occasional critical cases. An initial differential diagnosis including an ACh test is thus important to decide the treatment strategy of ACS.
Activation of the monocytic α7 nicotinic acetylcholine receptor modulates oxidative stress and inflammation-associated development of coronary artery spasm via a p38 MAP-kinase signaling-dependent pathway.
Hung Ming-Yow,Wu Yi-Hong,Bamodu Oluwaseun Adebayo,Chen Xi,Lin Yen-Kuang,Hu Patrick,Chang Nen-Chung,Pang Jong-Hwei Su,Yeh Chi-Tai
Free radical biology & medicine
OBJECTIVE:Smoking and high-sensitivity C-reactive protein (hs-CRP) are risk factors for coronary artery spasm (CAS), which is characterized by the increased interleukin-6 (IL-6) level and monocyte counts; however, limited data are available regarding the role of cigarette-embedded nicotine in the modulation of monocytic inflammatory activity in CAS. APPROACH:We investigated and elucidated the putative roles and associations of nicotine, monocytic IL-6, α7 nicotinic acetylcholine receptor (α7-nAChR), and CRP in CAS development. RESULTS:We demonstrated that a significantly increased α7-nAChR (p = 0.001) and IL-6 (p = 0.0036) messenger RNA (mRNA) expression in the serum of patients with CAS. Serum hs-CRP levels exhibited a strong positive correlation with the monocytic mRNA expression of α7-nAChR (r = 0.71, p < 0.001) and IL-6 (r = 0.49, p = 0.006). The α7-nAChR and IL-6 expression levels of the CAS group were also positively correlated (r = 0.63, p < 0.001). Compared with the untreated controls, THP-1 cells and patient-derived monocytes treated with different concentrations of CRP displayed significantly increased expression levels of α7-nAChR mRNA and protein (p = 0.0054), in a dose-dependent manner. We also demonstrated that compared with the IL-6 expression elicited by CRP alone (p = 0.0489), the CRP-induced rise in monocytic IL-6 mRNA and protein expression in the presence of nicotine (p = 0.0002), is mediated by α7-nAChR activation and the deregulation of the human p38 mitogen-activated protein kinases (MAPK) signaling pathway. CONCLUSIONS:Our data demonstrate that the elevated monocytic IL-6 and α7-nAChR mRNA and protein expression levels are associated with the interaction between nicotine and CRP positively modulates CAS development. Our study suggests the potential role of α7-nAChR mRNA and/or protein expression as a diagnostic biomarker for CAS.
Patients with acute myocardial infarction and non-obstructive coronary arteries: safety and prognostic relevance of invasive coronary provocative tests.
Montone Rocco A,Niccoli Giampaolo,Fracassi Francesco,Russo Michele,Gurgoglione Filippo,Cammà Giulia,Lanza Gaetano A,Crea Filippo
European heart journal
Aims:Functional alterations of epicardial coronary arteries or coronary microcirculation represent a frequent cause of myocardial infarction and non-obstructive coronary arteries (MINOCA). We aimed at assessing the prognostic value of intracoronary provocative tests in patients presenting with MINOCA and in which other causes of MINOCA have been excluded. Methods and results:We prospectively evaluated patients with a diagnosis of MINOCA, excluding patients with aetiologies other than suspected coronary vasomotor abnormalities. Immediately after coronary angiography, an invasive provocative test using acetylcholine or ergonovine was performed. The incidence of death from any cause, cardiac death, and recurrence of acute coronary syndrome (ACS) was assessed at follow-up. We also assessed angina status using Seattle Angina Questionnaires (SAQ). We enrolled 80 consecutive patients [mean age 63.0 ± 10.7 years, 40 (50%) male]. Provocative test was positive in 37 (46.2%) patients without any complication. Among patients with a positive test, epicardial spasm was detected in 24 (64.9%) patients and microvascular spasm in 13 (35.1%) patients. After a median follow-up of 36.0 (range 12.0-60.0) months, patients with a positive test had a significantly higher occurrence of death from any cause [12 (32.4%) vs. 2 (4.7%); P = 0.002], cardiac death [7 (18.9%) vs. 0 (0.0%); P = 0.005], and readmission for ACS [10 (27.0%) vs. 3 (7.0%); P = 0.015] as well as a worse angina status as assessed by SAQ [Seattle score: 88.0 (33.0-100.0) vs. 100.0 (44.0-100.0); P = 0.001] when compared with patients with a negative test. Conclusions:We demonstrate that in patients presenting with MINOCA and suspected coronary vasomotor abnormalities, a positive provocative test for spasm is safe and identifies a high-risk subset of patients.