SIRT1-mediated deacetylation of NF-κB inhibits the MLCK/MLC2 pathway and the expression of ET-1, thus alleviating the development of coronary artery spasm.

Coronary artery spasm (CAS) is an intense vasoconstriction of coronary arteries that causes total or subtotal vessel occlusion. The cardioprotective effect of sirtuin-1 (SIRT1) has been extensively highlighted in coronary artery diseases. The aims within this study include the investigation of the molecular mechanism by which SIRT1 alleviates CAS. SIRT1 expression was first determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis in an endothelin-1 (ET-1)-induced rat CAS model. Interaction among SIRT1, nuclear factor-kappaB (NF-κB), myosin light chain kinase/myosin light chain-2 (MLCK/MLC2), and ET-1 was analyzed using luciferase reporter assay, RT-qPCR, and Western blot analysis. After ectopic expression and depletion experiments in vascular smooth muscle cells (VSMCs), contraction and proliferation of VSMCs and expression of contraction-related proteins (α-SMA, calponin, and SM22α) were measured by collagen gel contraction, 5-ethynyl-2'-deoxyuridine (EdU) assay, RT-qPCR, and Western blot analysis. The obtained results showed that SIRT1 expression was reduced in rat CAS models. However, overexpression of SIRT1 inhibited the contraction and proliferation of VSMCs in vitro. Mechanistic investigation indicated that SIRT1 inhibited NF-κB expression through deacetylation. Moreover, NF-κB could activate the MLCK/MLC2 pathway and upregulate ET-1 expression by binding to their promoter regions, thus inducing VSMC contraction and proliferation in vitro. In vivo experimental results also revealed that SIRT1 alleviated CAS through regulation of the NF-κB/MLCK/MLC2/ET-1 signaling axis. Collectively, our data suggested that SIRT1 could mediate the deacetylation of NF-κB, disrupt the MLCK/MLC2 pathway, and inhibit the expression of ET-1 to relieve CAS, providing a theoretical basis for the prospect of CAS treatment and prevention.NEW & NOTEWORTHY Rat coronary artery spasm models exhibit reduced expression of SIRT1. Overexpression of SIRT1 inhibits contraction and proliferation of VSMCs. SIRT1 inhibits NF-κB through deacetylation to modulate VSMC contraction and proliferation. NF-κB activates the MLCK/MLC2 pathway. NF-κB upregulates ET-1 to modulate VSMC contraction and proliferation.

Characteristics and Prognosis of Patients with Vasospastic Angina Diagnosed by a Provocation Test with Secondary Prevention Implantable Cardioverter Defibrillator.

This study aimed to evaluate the characteristics and prognosis of patients with vasospastic angina (VSA) diagnosed by a provocation test with a secondary prevention implantable cardioverter defibrillator (ICD), compared with patients with organic coronary stenosis. We retrospectively evaluated 309 consecutive patients who received an ICD implantation between January 2010 and March 2018 in our institutions. Of these patients, 206 were implanted with an ICD for secondary prevention. In these 206 patients, 40 with VSA and 72 with organic coronary stenosis were evaluated. Patients with VSA were characterized by younger age (56.1 ± 13.1 versus 69.2 ± 9.5 years, respectively), and a lower prevalence of diabetes (15.0% versus 40.3%, respectively) and heart failure (2.5% versus 26.4%, respectively) than patients with organic coronary stenosis (P < 0.001). Using the Kaplan-Meier analysis, with the VSA group as the reference, the incidence of appropriate ICD shock was similar between the two groups (hazard ratio, 0.85; 95% confidence interval, 0.341-2.109; P = 0.722). The incidence of ventricular fibrillation was significantly higher in the VSA group (hazard ratio, 0.22; 95% confidence interval, 0.057-0.814; P = 0.024), whereas the incidence of major adverse cardiac events, including cardiac death, nonfatal myocardial infarction, hospitalization for unstable angina pectoris, and heart failure, was significantly higher in the organic coronary stenosis group (hazard ratio, 13.1; 95% confidence interval, 1.756-98.17; P = 0.012). In conclusion, patients with VSA with an ICD implanted for secondary prevention have a higher risk of ventricular fibrillation and lower risk of major adverse cardiac events than patients with organic coronary stenosis.

Stellate ganglion ischemia on the prevention of pulmonary vasospasm during bilateral carotid artery ligation: The first experimental study.

Fatal pulmonary edema and hemorrhage are significant complications of endovascular treatment in steno-occlusive carotid artery disease; a rational mechanism has not been adequately examined in the literature so far. We investigated if cervical sympathetic ganglia ischemia prevents pulmonary vasospasm on the prognosis of bilateral common carotid artery ligation (BCCAL). Twenty-three adult New Zealand rabbits (4.2 ± 0.3 kg) were randomly divided into three groups: the control group (G1, n = 5), the sham group (G2, n = 6), and the BCCAL group (G3, n = 12). Common carotid arteries were dissected bilaterally in G2/G3, and permanent BCCAL was applied to only in G3. All animals were followed for 3 weeks and decapitated under general anesthesia. Histopathological changes in stellate ganglia and severity of pulmonary vasospasm-related lung edema and hemorrhage were investigated. Results were analyzed by the Kruskal-Wallis test. Two animals of G3 dead within three weeks and the remainder were sacrificed three weeks later. Subpleural petechial foci and an endotracheal bloody fluid collection were grossly observed in the lungs. Histopathologically, pulmonary artery vasospasm, perivascular and subintimal edema, interalveolar hemorrhage, and alveolar wall destructions were observed with less ischemic-degenerated neuron density-determined stellate ganglia animals. Neurodegeneration of stellate ganglia may have a beneficial effect on the prevention of lung injury during steno-occlusive carotid artery disease.

Successful Management of Unremitting Spasm after Myocardial Revascularization Exclusively with Bilateral Internal Thoracic Arteries in Y-graft Configuration: A Case Report.

Coronary artery spasm (CAS) after coronary artery bypass grafting (CABG) is rare, and in time may be fatal for the patient if undiagnosed. The purpose of the present study is to report the case of a patient who survived after experiencing a persistent spasm of all native coronary arteries following successful arterial myocardial revascularization. Furthermore, we aimed to discuss the therapeutic strategies which may prevent the occurrence of a coronary artery spasm in settings of myocardial revascularization, in the context of reviewed specific literature evidences.

How to avoid severe coronary vasoconstriction in potassium induced cardioplegia.

OBJECTIVES: The aim of this study was to investigate how high K+ concentrations can be safely used in cardioplegic solutions without causing severe coronary artery vasocontraction. DESIGN: Twenty-four 50 kg pigs were used. The distal part of the left anterior descending coronary artery was cut into ring segments and transferred into organ baths with Krebs solution bubbled with 95% O2 and 5% CO2. K+ concentrations between 16 and 127 mM were used to induce vasocontractions at 37, 22, 15, and 8 °C. Mg2+ (0-20 mM) were used to attenuate K+ induced vasocontractions. RESULTS: K+-Krebs solution 127 mM at 37 °C induced a strong, sustained vasocontraction defined as 100%. The contractions induced by 16, 23, 30 and 127 mM K+ were: 7.7, 38, 72 and 100% at 37 °C; 1.7, 7.4, 21 and 65% at 22 °C; 1, 6.6, 15 and 33% at 15 °C; 0.6, 2.1, 6 and 14% at 8 °C, respectively. Mg2+ reduced the K+-induced contraction at 37 °C in a concentration-dependent way and Mg2+ at 8 mM practically eliminated the risk for severe vasocontraction. CONCLUSIONS: Hypothermia (8 °C) abolishes coronary contraction induced by K+-cardioplegic solutions. In normothermic cardioplegia 8 mM Mg2+ prevents vasoconstriction.

The challenges of treating recurrent polymorphic ventricular tachycardia due to coronary vasospasm: Lessons from an interesting case.

Coronary artery vasospasm can cause recurrent anginal episodes with ST-segment elevation. Vasospasm induced myocardial ischemia can lead to arrhythmias including life threatening ventricular tachycardia (VT). Percutaneous coronary intervention (PCI), although not routinely recommended for treating vasospastic angina, can be considered for discrete coronary spasm that is not amenable to vasodilator therapy. We present a challenging case of a 41-year-old lady with recurrent episodes of vasospastic angina and VT refractory to medical therapy, which was successfully treated with PCI and an implantable cardioverter defibrillator.

Nitroglycerin to Ameliorate Coronary Artery Spasm During Focal Pulsed-Field Ablation for Atrial Fibrillation.

BACKGROUND: In treating atrial fibrillation, pulsed-field ablation (PFA) has comparable efficacy to conventional thermal ablation, but with important safety advantages: no esophageal injury or pulmonary vein stenosis, and rare phrenic nerve injury. However, when PFA is delivered in proximity to coronary arteries using a pentaspline catheter, which generates a broad electrical field, severe vasospasm can be provoked. OBJECTIVES: The authors sought to study the vasospastic potential of a focal PFA catheter with a narrower electrical field and develop a preventive strategy with nitroglycerin. METHODS: During atrial fibrillation ablation, a focal PFA catheter was used for cavotricuspid isthmus ablation. Angiography of the right coronary artery (some with fractional flow reserve measurement) was performed before, during, and after PFA. Beyond no nitroglycerin (n = 5), and a few testing strategies (n = 8), 2 primary nitroglycerin administration strategies were studied: 1) multiple boluses (3-2 mg every 2 min) into the right atrium (n = 10), and 2) a bolus (3 mg) into the right atrium with continuous peripheral intravenous infusion (1 mg/min; n = 10). RESULTS: Without nitroglycerin, cavotricuspid isthmus ablation provoked moderate-severe vasospasm in 4 of 5 (80%) patients (fractional flow reserve 0.71 ± 0.08). With repetitive nitroglycerin boluses, severe spasm did not occur, and mild-moderate vasospasm occurred in only 2 of 10 (20%). Using the bolus + infusion strategy, severe and mild-moderate spasm occurred in 1 and 3 of 10 patients (aggregate 40%). No patient had ST-segment changes. CONCLUSIONS: Ablation of the cavotricuspid isthmus using a focal PFA catheter routinely provokes right coronary vasospasm. Pretreatment with high doses of parenteral nitroglycerin prevents severe spasm.

Pharmacokinetics of intraluminally administered serum papaverine for spasm prophylaxis of the internal mammary artery.

BACKGROUND: Papaverine (Paveron N™ Linden Arzneimittel Vertrieb GmbH, Germany) is a widely used agent for preventing spasm in mammary artery preparations. The question addressed in this study is whether the intraluminal administration of papaverine can result in detectable absorption of the drug into the systemic arterial circulation. METHODS: In 15 patients (age 65 ± 6 years; body mass index 28.9 ± 3.7), an internal mammary artery (IMA) was prepared during coronary artery bypass grafting (CABG). A maximum of 3 mL of a 1 mg/1 mL diluted papaverine solution was injected intravascularly (intraluminally) for spasm prophylaxis. The IMA was closed proximally and distally with bulldog clamps. Blood samples were taken immediately after administration (T1), after 20 minutes (T2), and at the end of the operation (T3). Samples were measured in a liquid chromatography-tandem mass spectrometry (LC-MS/MS) system consisting of a binary pump from Agilent (Waldbronn, Germany) coupled to a high-throughput screening (HTS) PAL injection system (CTC, Zwingen, Switzerland) and a tandem mass spectrometer (API 4000, AB Sciex, Darmstadt, Germany). Papaverine was analyzed in positive mode using an electrospray ion source. Quantitation was performed using Analyst 1.5 software (AB Sciex, Darmstadt, Germany). RESULTS: The newly developed LC-MS/MS method was successfully established for the detection of papaverine in plasma samples. The highest plasma papaverine levels were determined at time point T1 (mean 54.7 ± 39 ng/mL, range 16.6-179 ng/mL). The concentration was already halved 20 minutes after administration (T2) (mean 23.3 ± 2 ng/mL, range 4.6-118 ng/mL). Because of the short half-life and the hemodilution in the extracorporeal circulation, at the end of the operation papaverine (T3) had already fallen to just above the limit of detection (mean 4.1 ± 3.9 ng/mL, range 1.3-16.9 ng/mL). At time point T1, a significant negative correlation was determined between plasma levels and systemic diastolic, but not systolic, blood pressure. CONCLUSION: Papaverine was successfully determined systemically in plasma by LC-MS/MS after intraluminal administration in the IMA. Systemic circulatory effects are dependent on the detected quantity. Group size and the absence of a control group are considerable limitations.

Intraoperative administration of clevidipine to prevent vasospasm after radial and internal mammary artery grafts during coronary artery bypass grafting.

During coronary artery bypass graft surgery, various arterial and venous conduits have been used to carry blood flow from the aorta to the coronary vasculature. Arterial conduits provide certain advantages over the saphenous vein, including superior long-term patency, relative resistance to the development of atherosclerosis, and greater endothelium-dependent relaxation. However, the perioperative release of catecholamines and thromboxane A, mechanical manipulation, and underlying endothelial cell dysfunction may result in vasoconstriction or vasospasm of the arterial conduit and a compromise of myocardial perfusion. Given these issues, pharmacologic therapy is frequently initiated intraoperatively to prevent vasospasm. Clevidipine is a rapidly acting calcium channel antagonist. Like nicardipine, it is a member of the dihydropyridine subgroup. Its rapid metabolism by tissue and plasma esterases results in an effective half-life of 1 to 3 minutes. We report, for the first time, the perioperative use of clevidipine to prevent vasospasm after coronary artery bypass graft surgery with the use of internal mammary artery and bilateral radial artery conduits. Its potential application in this scenario and advantages when compared with other commonly used agents is discussed.

Secondary preventive effects of a calcium antagonist for ischemic heart attack: randomized parallel comparison with ß-blockers.

BACKGROUND: Beta-blockers (BB) have been widely used in the management of hypertension and acute myocardial infarction (AMI), and both national and international guidelines have recommended them as first-line agents. Calcium channel antagonists (CCA) are also effective in the treatment of hypertension and angina pectoris. However, the efficacy of CCA in the prevention of cardiovascular events in post-myocardial infarction (MI) patients in comparison to that of BB remains unclear. METHODS AND RESULTS: A total of 120 post-MI patients (71 patients who were at least 1 month after the onset AMI and 49 stable coronary artery disease patients with a history of MI) were randomly assigned to receive a BB (atenolol, 25-50mg/day, n=60) or a CCA (benidipine, 4-8 mg/day, n=60). All patients with AMI within the previous 1 month or with vasospastic angina were excluded from the present study. The baseline clinical characteristics were generally similar in the BB and CCA groups. The rate of primary composite outcome was 26.3% in the BB group in comparison to 13.3% in the CCA group, with no significant between-group differences (hazard ratio with the CCA group 0.640, P=0.276). Both treatments were well tolerated with few severe adverse events. CONCLUSIONS: CCA treatment was found to be as effective as BB in reducing cardiovascular events in post-MI patients.

Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm.

Cardiovascular disease, the major cause of death in post-menopausal women, can be reduced by replacement of ovarian steroid hormones. To compare medroxyprogesterone with progesterone as the progestin in hormone replacement therapy from the standpoint of coronary artery vasospasm, we treated ovariectomized rhesus monkeys with physiological levels of estradiol-17 beta in combination with medroxyprogesterone or progesterone for four weeks. Coronary vasospasm in response to pathophysiological stimulation without injury showed that progesterone plus estradiol protected but medroxyprogesterone plus estradiol failed to protect, allowing vasospasm. We conclude that medroxyprogesterone in contrast to progesterone increases the risk of coronary vasospasm.

Sorafenib-associated multivessel coronary artery vasospasm.

Cardiotoxicity associated with cancer treatment is an important field of interest especially as the new class of VEGF signaling pathway inhibitors (VSP) continues to grow. Small molecule tyrosine kinase inhibitors such as sorafenib, sunitinib, and pazopanib inhibit the downstream pathways of all three of the vascular endothelial growth factor receptors (VEGFR 1, 2, and 3). Other targets of these agents include kinases involved in vascular and myocardial homoeostasis. These agents are all known to frequently cause hypertension, their most common side-effect. Myocardial ischemia has also been reported, but the frequency and etiology of VSP-related ischemia is poorly characterized. This manuscript describes the first reported case of sorafenib-associated multivessel coronary vasospasm in a 57-year-old patient with hepatocellular carcinoma. He underwent sorafenib treatment, a tyrosinase inhibitor, 400 mg twice a day. The vasospasm was reversible under nitroglycerin. Possible mechanisms are also discussed.

[Coronary artery spasm during neurosurgical anesthesia].

We experienced a case of coronary artery spasm during neurosurgical anesthesia. A 69-year-old man was scheduled for craniotomy for cerebello-pontine angle meningioma. He had a history of cigarette smoking, but no history or evidence of ischemic heart disease. After the dura mater was opened, marked ST elevation on the ECG monitor followed by ventricular fibrillation was noticed. After successful resuscitation, the surgery was cancelled. Because the coronary angiography, immediately after surgery, demonstrated normal coronary arteries, coronary artery spasm was considered to be the cause of the ECG change. Possible triggering factor in this case was vagal stimulation due to surgical manipulation. Careful anesthetic management is required to prevent intraoperative coronary artery spasm even in patients without a history of ischemic heart disease during neurosurgery.

Impact of aspirin use on clinical outcomes in patients with vasospastic angina: a systematic review and meta-analysis.

OBJECTIVES: The use of aspirin to prevent cardiovascular disease in vasospastic angina (VSA) patients without significant stenosis has yet to be investigated. This study aimed to investigate the efficacy of aspirin use among VSA patients. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Web of Science and Cochrane Central Register of Controlled Trials were searched for relevant information prior to October 2020. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Aspirin use versus no aspirin use (placebo or no treatment) among VSA patients without significant stenosis. DATA EXTRACTION AND SYNTHESIS: Two investigators extracted the study data. ORs and 95% CIs were calculated and graphed as forest plots. The Newcastle-Ottawa Quality Assessment Scale tool and Begg's funnel plot were used to assess risk of bias. RESULTS: Four propensity-matched cohorts, one retrospective analysis and one prospective multicentre cohort, in total comprising 3661 patients (aspirin use group, n=1695; no aspirin use group, n=1966) were included in this meta-analysis. Aspirin use and the incidence of major cardiovascular adverse events with follow-up of 1-5 years were not significantly correlated (combined OR=0.90, 95% CI: 0.55 to 1.68, p=0.829, I2=82.2%; subgroup analysis: OR=1.09, 95% CI: 0.81 to 1.47, I2=0%). No significant difference was found between aspirin use and the incidence of myocardial infarction (OR=0.62, 95% CI: 0.09 to 4.36, p=0.615, I2=73.8%) or cardiac death (OR=1.73, 95% CI: 0.61 to 4.94, p=0.444, I2=0%) during follow-up. CONCLUSION: Aspirin use may not reduce the risk of future cardiovascular events in VSA patients without significant stenosis. PROSPERO REGISTRATION NUMBER: CRD42020214891.

Beta blockers versus calcium channel blockers for provocation of vasospastic angina after drug-eluting stent implantation: a multicentre prospective randomised trial.

BACKGROUND: Drug-eluting stent-induced vasospastic angina (DES-VSA) has emerged as a novel complication in the modern era of percutaneous coronary intervention (PCI). Although beta blockers (BBs) are generally recommended for coronary heart disease, they may promote incidence of DES-VSA. This study aimed to compare the effects of calcium channel blockers (CCBs) perceived to be protective against DES-VSA and BBs on subsequent coronary events after second-generation drug-eluting stent implantation. METHODS: In this multicentre prospective, randomised study, 52 patients with coronary artery disease who underwent PCI for a single-vessel lesion with everolimus-eluting stent placement were randomised into post-stenting BB (N=26) and CCB (N=26) groups and followed for 24 months to detect any major cardiovascular events (MACE). A positive result on acetylcholine provocation testing during diagnostic coronary angiography (CAG) at 9 months was the primary endpoint for equivalence. MACE included all-cause death, non-fatal myocardial infarction, unstable angina, cerebrovascular disease or coronary revascularisation for stable coronary artery disease after index PCI. RESULTS: At 9 months, 42 patients (80.8%) underwent diagnostic coronary angiography and acetylcholine provocation testing. Among them, seven patients in each group were diagnosed with definite vasospasm (intention-to-treat analysis 26.9% vs 26.9%, risk difference 0 (-0.241, 0.241)). Meanwhile, the secondary endpoint, 24-month MACE, was higher in the CCB group (19.2%) than in the BB group (3.8%) (p=0.01). In detail, coronary revascularisation for stable coronary artery disease was the predominant endpoint that contributed to the greater proportion of MACE in the CCB group (CCB (19.2%) vs BB (3.8%), p=0.03). CONCLUSIONS: The incidence of acetylcholine-induced coronary artery spasms did not differ between patients receiving BBs or CCBs at 9 months after PCI. However, a higher incidence of 2-year MACE was observed in the CCB group, suggesting the importance of BB administration. TRIAL REGISTRATION NUMBER: This study was registered at the Japanese University Hospital Medical Information Network (UMIN) Clinical Trial Registry (The Prospective Randomized Trial for Optimizing Medical Therapy After Stenting: Calcium-Beta Trial; UMIN000008321, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009536).

RhoA/ROK pathway related to the mechanism of higher susceptibility to spasm in RA than in IMA.

BACKGROUND AND AIM OF THE STUDY: By investigating the expression and function of RhoA/Rho kinase pathway in the radial artery (RA), internal mammary artery (IMA), and great saphenous vein (GSV), this study aimed to elucidate the mechanism for a higher susceptibility of spasm in the RA and provide an effective drug candidate to prevent and treat RA spasm. METHODS: RA, IMA, and GSV that would otherwise have been discarded were collected from 25 patients who underwent coronary artery bypass grafting. Eleven matched rings of RA, IMA, and GSV were used to evaluate the vasodilatory properties of 10(-7-)10(-4) mol/l of fasudil, a Rho-kinase inhibitor, by using in vitro organ chambers. Another 14 matched RA, IMA, and GSV were used to demonstrate the immunohistochemistry (IHC) of RhoA and mRNA of RhoA and Rho kinase. RESULTS: The maximal vasodilation of RA to fasudil was significantly greater than IMA. RhoA protein IHC staining was different in IMA, RA, and GSV (RA > GSV >IMA). The expression of RhoA and Rho kinase mRNA in the RA was significantly greater than in the IMA. CONCLUSIONS: The expression of RhoA/Rho kinase mRNA and protein and function in the RA were significantly stronger than in the IMA, suggesting that RhoA/Rho kinase pathway may be one mechanism by which RA is more susceptible to spasm than IMA. Rho kinase inhibitors can be effective drug candidates to prevent and treat vasospasm.

[Pharmacological studies on responsiveness of 5-hydroxytryptamine in overcoming perioperative spasm of coronary artery bypass graft].

In ischemic heart diseases, the use of the internal thoracic artery (ITA) as an arterial graft has been associated with longer survival and better quality of life. However, it has been reported that vasospasm of the ITA graft frequently occurs and increases perioperative and postoperative morbidity. Serotonin (5-HT) plays an important role in the occurrence of vasospasm. We examined 5-HT receptor subtypes responsible for the 5-HT-induced vasocontraction in the human ITA. The contractile response caused by 5-HT was mediated by activation of not only 5-HT(2A) receptors but also 5-HT(1B) receptors. We also examined the relationship between 5-HT-induced vasocontraction of the rabbit femoral artery and arteriosclerosis using the arteriosclerosis model of repeated balloon-injury. The contractile response caused by 5-HT in the femoral artery with arteriosclerosis was significantly greater than that in the normal artery. Additionally, we demonstrated that insulin induced internalization of 5-HT(2A) receptors from the plasma membrane in HEK293 cells. Diabetes mellitus (DM) is a risk factor for ischemic heart diseases. We evaluated the 5-HT-induced vasocontraction, mediated by activation of 5-HT(2A) and 5-HT(1B) receptors, in the ITA obtained from patients with DM or without DM undergoing coronary bypass surgery. The contractile response caused by 5-HT in the ITA from patients with DM was significantly greater than that from patients without DM. Our findings suggest that when the ITA is used as an arterial graft, simultaneous treatment with 5-HT(2A) and 5-HT(1B) receptor antagonists is useful to prevent 5-HT-induced vasospasm, especially in patients with DM.