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.

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.

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.

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).

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.

Vasodilatory efficacy and impact of papaverine on endothelium in radial artery predilatation for cabg surgery: in search for optimal concentration

Abstract Objective: The aim of this study was to compare the efficacy of two different papaverine concentrations (0.5 mg/ml and 2 mg/ml) for vasospasm prevention and their impact on endothelium integrity. Methods: We have studied distal segments of radial arteries obtained by no-touch technique from coronary artery bypass graft (CABG) patients (n=10). The vasodilatory effect of papaverine (concentrations of 0.5 mg/ml and 2 mg/ml) was assessed in vitro, in isometric tension studies using ex vivo myography (organ bath technique) and arterial rings precontracted with potassium chloride (KCl) and phenylephrine. The impact of papaverine on endothelial integrity was studied by measurement of the percentage of vessel's circumference revealing CD34 endothelial marker. Results: 2 mg/ml papaverine concentration showed stronger vasodilatatory effect than 0.5 mg/ml, but it caused significantly higher endothelial damage. Response to KCl was 7.35±3.33 mN for vessels protected with papaverine 0.5 mg/ml and 2.66±1.96 mN when papaverine in concentration of 2 mg/ml was used. The histological examination revealed a significant difference in the presence of undamaged endothelium between vessels incubated in papaverine 0.5 mg/ml (72.86±9.3%) and 2 mg/ml (50.23±13.42%), P=0.002. Conclusion: Papaverine 2 mg/ml caused the higher endothelial damage. Concentration of 0.5 mg/ml caused better preservation of the endothelial lining.

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.

Vasodilatory Efficacy and Impact of Papaverine on Endothelium in Radial Artery Predilatation for CABG Surgery: in Search for Optimal Concentration.

OBJECTIVE: The aim of this study was to compare the efficacy of two different papaverine concentrations (0.5 mg/ml and 2 mg/ml) for vasospasm prevention and their impact on endothelium integrity. METHODS: We have studied distal segments of radial arteries obtained by no-touch technique from coronary artery bypass graft (CABG) patients (n=10). The vasodilatory effect of papaverine (concentrations of 0.5 mg/ml and 2 mg/ml) was assessed in vitro, in isometric tension studies using ex vivo myography (organ bath technique) and arterial rings precontracted with potassium chloride (KCl) and phenylephrine. The impact of papaverine on endothelial integrity was studied by measurement of the percentage of vessel's circumference revealing CD34 endothelial marker. RESULTS: 2 mg/ml papaverine concentration showed stronger vasodilatatory effect than 0.5 mg/ml, but it caused significantly higher endothelial damage. Response to KCl was 7.35±3.33 mN for vessels protected with papaverine 0.5 mg/ml and 2.66±1.96 mN when papaverine in concentration of 2 mg/ml was used. The histological examination revealed a significant difference in the presence of undamaged endothelium between vessels incubated in papaverine 0.5 mg/ml (72.86±9.3%) and 2 mg/ml (50.23±13.42%), P=0.002. CONCLUSION: Papaverine 2 mg/ml caused the higher endothelial damage. Concentration of 0.5 mg/ml caused better preservation of the endothelial lining.

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.

Intraoperative chlorpromazine treatment for prevention of radial artery spasm in aortocoronary bypass grafting.

A detailed description of intraoperative prevention of radial artery graft spasm using a solution of the calmodulin inhibitor chlorpromazine is presented. This method is used in direct myocardial revascularization and can reliably prevent perioperative spasm of radial artery grafts, as confirmed by intraoperative flow measurement, bypass angiography in the postoperative period, and in vitro experimental data.

Endosomolytic Nano-Polyplex Platform Technology for Cytosolic Peptide Delivery To Inhibit Pathological Vasoconstriction.

A platform technology has been developed and tested for delivery of intracellular-acting peptides through electrostatically complexed nanoparticles, or nano-polyplexes, formulated from an anionic endosomolytic polymer and cationic therapeutic peptides. This delivery platform has been initially tested and optimized for delivery of two unique vasoactive peptides, a phosphomimetic of heat shock protein 20 and an inhibitor of MAPKAP kinase II, to prevent pathological vasoconstriction (i.e., vasospasm) in human vascular tissue. These peptides inhibit vasoconstriction and promote vasorelaxation by modulating actin dynamics in vascular smooth muscle cells. Formulating these peptides into nano-polyplexes significantly enhances peptide uptake and retention, facilitates cytosolic delivery through a pH-dependent endosomal escape mechanism, and enhances peptide bioactivity in vitro as measured by inhibition of F-actin stress fiber formation. In comparison to treatment with the free peptides, which were endowed with cell-penetrating sequences, the nano-polyplexes significantly increased vasorelaxation, inhibited vasoconstriction, and decreased F-actin formation in the human saphenous vein ex vivo. These results suggest that these formulations have significant potential for treatment of conditions such as cerebral vasospasm following subarachnoid hemorrhage. Furthermore, because many therapeutic peptides include cationic cell-penetrating segments, this simple and modular platform technology may have broad applicability as a cost-effective approach for enhancing the efficacy of cytosolically active peptides.

Intractable hyperkalemia due to nicorandil induced potassium channel syndrome.

Nicorandil is a commonly used antianginal agent, which has both nitrate-like and ATP-sensitive potassium (K ATP ) channel activator properties. Activation of potassium channels by nicorandil causes expulsion of potassium ions into the extracellular space leading to membrane hyperpolarization, closure of voltage-gated calcium channels and finally vasodilatation. However, on the other hand, being an activator of K ATP channel, it can expel K + ions out of the cells and can cause hyperkalemia. Here, we report a case of nicorandil induced hyperkalemia unresponsive to medical treatment in a patient with diabetic nephropathy.

Clinical features and prognosis of type 2 myocardial infarction in vasospastic angina.

BACKGROUND: Although generally the prognosis of vasospastic angina is considered excellent, vasospasm has been shown to be a cause of type 2 myocardial infarction. This study was performed to investigate the clinical characteristics and prognosis of patients with vasospastic angina complicated with type 2 myocardial infarction. METHODS: We performed a retrospective analysis of 171 consecutive patients with definite vasospastic angina (median age, 64 years; 55.0% were male) who visited the Kameda Medical Center with chest pain and in whom cardiac troponin I level was measured between 2005 and 2013. The patients were divided into type 2 myocardial infarction and non-type 2 myocardial infarction groups. A diagnosis of type 2 myocardial infarction was based on a serum cardiac troponin I value >99th percentile upper reference limit. The primary end point was a combination of nonfatal myocardial infarction or death by any cause. RESULTS: A total of 42 patients (24.6%) were diagnosed with type 2 myocardial infarction, and the type 2 myocardial infarction group had a higher incidence of combined end point than the non-type 2 myocardial infarction group during the median follow-up of 4.4 years (26.2% vs 9.3%, respectively, P = .008). Type 2 myocardial infarction remained an independent predictor of combined end point even after adjusting by the Japanese Coronary Spasm Association risk factors for combined end point (hazard ratio, 2.84; 95% confidence interval, 1.22-6.61; P = .02). CONCLUSIONS: Approximately one quarter of patients with vasospastic angina were associated with type 2 myocardial infarction, and this population should be identified as a new high-risk subgroup of those with vasospastic angina requiring an alternative treatment strategy.

Pioglitazone, a peroxisome proliferator-activated receptor γ activator, suppresses coronary spasm.

OBJECTIVE: We examined whether a peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, pioglitazone, suppresses coronary spasm. BACKGROUND: Patients with coronary spastic angina (CSA) also have endothelial dysfunction and inflammation. Activation of PPAR-γ improves endothelial dysfunction and inflammation. PARTICIPANTS AND METHODS: The study participants included 73 consecutive CSA patients (47 men and 26 women, mean age 63.6±10.4 years) who were admitted to our institution with a suspicion of CSA because of episodes of chest discomfort occurring mostly at rest in whom coronary spasm was induced by an intracoronary acetylcholine injection and a repeat acetylcholine provocation injection was administered after 6 months of follow-up. Thirty-six of the patients were administered pioglitazone15-30 mg/day added on calcium channel blockers (CCBs) (pioglitazone group) and 37 were administered CCBs alone (control group). Clinical and laboratory data were also examined before and after 6 months of follow-up and the results between the two groups were compared. RESULTS: Coronary spasm was suppressed in 18/36 patients (50.0%) in the pioglitazone group (P<0.001) and 8/37 patients (21.6%) in the control group (P=0.008) after 6 months of treatment. Coronary spasm was thus significantly reduced in the pioglitazone group compared with the control group (P=0.011). The levels of total white blood cell count and high-sensitivity C-reactive protein decreased significantly (P<0.001 and P<0.001, respectively) in the pioglitazone group, whereas these levels did not differ in the control group (P=0.15 and 0.39, respectively) after the treatment. CONCLUSION: Pioglitazone added on CCBs significantly reduced coronary spasm compared with CCBs alone after 6 months of treatment. Pioglitazone may thus prove to be a novel therapy for coronary spasm.

Highly flexible and rapidly degradable papaverine-loaded electrospun fibrous membranes for preventing vasospasm and repairing vascular tissue.

Vasospasm is a common post-operative complication after vascular anastomosis. Currently, the main treatment is a local injection of antispasmodic drugs. However, this method has a high rate of relapse and is subject to a large degree of individual variation, and repeated injections cause additional pain for patients. In this study, we developed highly flexible and rapidly degradable papaverine-loaded electrospun fibrous membranes to be wrapped around vascular suturing to prevent vasospasm. Poly-l-lactic acid/polyethylene glycol (PLLA/PEG) electrospun fibers containing papaverine maintained a high degree of flexibility and could withstand any folding, and are therefore suitable for wrapping vascular suturing. A rapid release of papaverine, between 2 and 7 days, was achieved by adjusting the proportions of PEG and PLLA. PLLA electrospun fibers containing 40% PEG (PLLA-40%) could control drug release and polymer degradation most effectively during the first 2 weeks post-operation. Testing using an in vivo rabbit model showed that PLLA-40% fibrous membranes produced significant antispasmodic effect without observable inflammation or hyperplasia, and the fibrous membranes were ideally biodegradable, with no impact on regional blood flow, pressure, vessel diameter or surrounding tissue hyperplasia. Therefore, papaverine-loaded electrospun fibrous membranes show the potential to greatly reduce post-operative vasospasm and maintain regular vascular morphology during antispasmodic therapy.