Exploring the mechanisms of Guizhifuling pills in the treatment of coronary spastic angina based on network pharmacology combined with molecular docking.

Coronary spastic angina (CSA) is common, and treatment options for refractory vasospastic angina are sometimes limited. Guizhifuling pills (GFP) have demonstrated efficacy in reducing CSA episodes, but their pharmacological mechanism remains unclear. To explore the mechanism of action of GFP in preventing and treating CSA, we employed network pharmacology and molecular docking to predict targets and analyze networks. We searched GFP chemical composition information and related targets from databases. The drug-target and drug-target pathway networks were constructed using Cytoscape. Then the protein-protein interaction was analyzed using the STRING database. Gene Ontology biological functions and Kyoto Encyclopedia of Genes and Genomes pathways were performed by the Metascape database, and molecular docking validation of vital active ingredients and action targets of GFP was performed using AutoDock Vina software. The 51 active components in GFP are expected to influence CSA by controlling 279 target genes and 151 signaling pathways. Among them, 6 core components, such as quercetin, ß-sitosterol, and baicalein, may regulate CSA by affecting 10 key target genes such as STAT3, IL-6, TP53, AKT1, and EGFR. In addition, they are involved in various critical signaling pathways such as apelin, calcium, advanced glycation end product-receptor for advanced glycation end product, and necroptosis. Molecular docking analysis confirms favorable binding interactions between the active components of GFP and the selected target proteins. The effects of GFP in treating CSA involve multiple components, targets, and pathways, offering a theoretical basis for its clinical use and enhancing our understanding of how it works.

A case of early repolarization syndrome in which hyponatremia and coronary vasospasms induced ventricular fibrillation.

A 60-year-old man was referred to our hospital presenting with unconsciousness due to severe hyponatremia. The twelve­lead ECG on admission exhibited prominent J waves in the inferolateral leads. During the treatment for hyponatremia, ventricular fibrillation (VF) occurred and the electrogram (ECG) after the VF incident exhibited marked ST elevation in the inferolateral leads. An Ach provocation test induced vasospasms in the right and left coronary arteries and J wave augmentation, suggesting a high risk for vasospastic angina. Finally, a subcutaneous implantable cardioverter defibrillator was implanted in the patient. We hereby discuss the possible contribution of hyponatremia to VF episodes in early repolarization syndrome based on the present case.

RNF213 Variants, Vasospastic Angina, and Risk of Fatal Myocardial Infarction.

Importance: Vasospastic angina (VSA) is vasospasm of the coronary artery and is particularly prevalent in East Asian populations. However, the specific genetic architecture for VSA at genome-wide levels is not fully understood. Objective: To identify genetic factors associated with VSA. Design, Setting, and Participants: This was a case-control genome-wide association study of VSA. Data from Biobank Japan (BBJ; enrolled patients from 2002-2008 and 2013-2018) were used, and controls without coronary artery disease (CAD) were enrolled. Patients from the BBJ were genotyped using arrays or a set of arrays. Patients recruited between 2002 and 2005 were classified within the first dataset, and those recruited between 2006 and 2008 were classified within the second dataset. To replicate the genome-wide association study in the first and second datasets, VSA cases and control samples from the latest patients in the BBJ recruited between 2013 and 2018 were analyzed in a third dataset. Exposures: Single-nucleotide variants associated with VSA. Main Outcomes and Measures: Cases with VSA and controls without CAD. Results: A total of 5720 cases (mean [SD] age, 67 [10] years; 3672 male [64.2%]) and 153 864 controls (mean [SD] age, 62 [15] years; 77 362 male [50.3%]) in 3 datasets were included in this study. The variants at the RNF213 locus showed the strongest association with VSA across the 3 datasets (odds ratio [OR], 2.34; 95% CI, 1.99-2.74; P = 4.4 × 10-25). Additionally, rs112735431, an Asian-specific rare deleterious variant (p.Arg4810Lys) experimentally shown to be associated with reduced angiogenesis and a well-known causal risk for Moyamoya disease was the most promising candidate for a causal variant explaining the association. The effect size of rs112735431 on VSA was distinct from that of other CADs. Furthermore, homozygous carriers of rs112735431 showed an association with VSA characterized by a large effect estimate (OR, 18.34; 95% CI, 5.15-65.22; P = 7.0 × 10-6), deviating from the additive model (OR, 4.35; 95% CI, 1.18-16.05; P = .03). Stratified analyses revealed that rs112735431 exhibited a stronger association in males (χ21 = 7.24; P = .007) and a younger age group (OR, 3.06; 95% CI, 2.24-4.19), corresponding to the epidemiologic features of VSA. In the registry, carriers without CAD of the risk allele rs112735431 had a strikingly high mortality rate due to acute myocardial infarction during the follow-up period (hazard ratio, 2.71; 95% CI, 1.57-4.65; P = 3.3 × 10-4). As previously reported, a possible overlap between VSA and Moyamoya disease was not found. Conclusions and Relevance: Results of this study suggest that vascular cell dysfunction mediated by variants in the RNF213 locus may promote coronary vasospasm, and the presence of the risk allele could serve as a predictive factor for the prognosis.

The Great Masquerade: Not All Coronary Artery Stenosis Are Created Equal.

We present the case of a 60-year-old male, with active smoking and cocaine use disorder, who reported progressive chest pain. Various anatomical and functional cardiac imaging, performed to further evaluate chest pain etiology, revealed changing severity and distribution of left main artery (LMA) stenosis, raising suspicion for vasospasm. Intracoronary nitroglycerin relieved the vasospasm, with resolution of the LMA pseudostenosis. A diagnosis of vasospastic angina (VA) led to starting appropriate medical therapy with lifestyle modification counselling. This case highlights VA, a frequently underdiagnosed etiology of angina pectoris. We discuss when to suspect VA, its appropriate work-up, and management.

Multivessel Coronary Function Testing Increases Diagnostic Yield in Patients With Angina and Nonobstructive Coronary Arteries.

BACKGROUND: Invasive CFT is the gold standard for diagnosing coronary vasomotor dysfunction in patients with ANOCA. Most institutions recommend only testing the left coronary circulation. Therefore, it is unknown whether testing multiple coronary territories would increase diagnostic yield. OBJECTIVES: The aim of this study was to evaluate the diagnostic yield of multivessel, compared with single-vessel, invasive coronary function testing (CFT) in patients with angina and nonobstructive coronary arteries (ANOCA). METHODS: Multivessel CFT was systematically performed in patients with suspected ANOCA. Vasoreactivity testing was performed using acetylcholine provocation in the left (20 to 200 µg) and right (20 to 80µg) coronary arteries. A pressure-temperature sensor guidewire was used for coronary physiology assessment in all three epicardial vessels. RESULTS: This multicenter study included a total of 228 vessels from 80 patients (57.8 ± 11.8 years of age, 60% women). Compared with single-vessel CFT, multivessel testing resulted in more patients diagnosed with coronary vasomotor dysfunction (86.3% vs 68.8%; P = 0.0005), coronary artery spasm (60.0% vs 47.5%; P = 0.004), and CMD (62.5% vs 36.3%; P < 0.001). Coronary artery spasm (n = 48) predominated in the left coronary system (n = 38), though isolated right coronary spasm was noted in 20.8% (n = 10). Coronary microvascular dysfunction (CMD), defined by abnormal index of microcirculatory resistance and/or coronary flow reserve, was present 62.5% of the cohort (n = 50). Among the cohort with CMD, 27 patients (33.8%) had 1-vessel CMD, 15 patients (18.8%) had 2-vessel CMD, and 8 patients (10%) had 3-vessel CMD. CMD was observed at a similar rate in the territories supplied by all 3 major coronary vessels (left anterior descending coronary artery = 36.3%, left circumflex coronary artery = 33.8%, right coronary artery = 31.3%; P = 0.486). CONCLUSIONS: Multivessel CFT resulted in an increased diagnostic yield in patients with ANOCA compared with single-vessel testing. The results of this study suggest that multivessel CFT has a role in the management of patients with ANOCA.

Profound Coronary Vasospasm Associated with Intraoperative Ketamine Administration: A Case Report.

We report a case of a 62-year-old woman with a decade-long history of atypical chest pain resulting in a largely negative cardiac workup, who developed significant angiographically demonstrated coronary vasospasm thought to be due to a small dose of intravenous ketamine. In patients with a history of atypical chest pain despite a reassuring cardiac evaluation, providers should carefully consider medications that may precipitate coronary vasospasm and be prepared to treat it accordingly.

Long-acting cilostazol versus isosorbide mononitrate for patients with vasospastic angina: a randomized controlled trial.

BACKGROUND: Cilostazol has a vasodilatory function that may be beneficial for patients with vasospastic angina (VSA). We conducted a randomized, open-label, controlled trial to compare the efficacy and safety of long-acting cilostazol and isosorbide mononitrate (ISMN) for VSA. METHODS: The study included patients with confirmed VSA between September 2019 and May 2021. Participants were randomly assigned to receive long-acting cilostazol (test group, 200 mg once daily) or conventional ISMN therapy (control group, 20 mg twice daily) for 4 weeks. The clinical efficacy and safety were evaluated using weekly questionnaires. RESULTS: Forty patients were enrolled in the study (long-acting cilostazol, n  = 20; ISMN, n  = 20). Baseline characteristics were balanced between the two groups. Long acting cilostazol showed better angina symptom control within the first week compared to ISMN [reduction of pain intensity score, 6.0 (4.0-8.0) vs. 4.0 (1.0-5.0), P  = 0.005; frequency of angina symptom, 0 (0-2.0) vs. 2.0 (0-3.0), P  = 0.027, respectively]. The rate of neurological adverse reactions was lower in the cilostazol group than in the ISMN group (headache or dizziness, 40 vs. 85%, P  = 0.009; headache, 30 vs. 70%, P  = 0.027). CONCLUSION: Long-acting cilostazol provided comparable control of angina and fewer adverse neurologic reactions within 4 weeks compared to ISMN. Long-acting cilostazol provides more intensive control of angina within 1 week, suggesting that it may be an initial choice for the treatment of VSA.

Severe ST-segment elevation and AV block during pulsed-field ablation due to vasospastic angina - a novel observation.

Catheter ablation of atrial fibrillation using non-thermal electroporation represents a promising ablation modality due to its believed superior safety profile. Still, if electroporation is delivered in proximity to a coronary artery, vasospasms can occur. We report the first case of severe right coronary artery vasospasm resulting in ST-segment elevation and AV block despite a remote distance from the ablation site to the right coronary artery, indicating a different mechanism. In this case, electroporation most likely triggered a previously unknown Prinzmetal vasospastic angina in the patient, resulting in the coronary vasospasm. Thus, meticulous monitoring of ST-segment changes following PFA delivery even from regions remote to coronary arteries is required.

Ponatinib-Related Vasospastic Angina.

Tyrosine kinase inhibitors (TKIs) are essential drugs for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Cardiovascular or arteriothrombotic adverse events have been reported in patients treated with TKIs. We report 3 cases of Ponatinib-related vasospastic angina, in which prophylactic administration of nitrates or calcium channel blockers was effective.

A Case of Ventricular Fibrillation in Masked Long-QT Syndrome Coexisting with Coronary Vasospasm.

Although long-QT syndrome (LQTS) with a normal range QT interval at rest leads to fatal ventricular arrhythmias, it is difficult to diagnose. In this article, we present a rare case of a patient who suffered a cardiac arrest and was recently diagnosed with LQTS and coronary vasospasm. A 62-year-old man with no syncopal episodes had a cardiopulmonary arrest while running. During coronary angiography, vasospasm was induced and we prescribed coronary vasodilators, including calcium channel blockers. An exercise stress test was performed to evaluate the effect of medications and accidentally unveiled exercise-induced QT prolongation. He was diagnosed with LQTS based on diagnostic criteria. Pharmacotherapy and an implantable cardioverter defibrillator were used for his medical management. It is extremely rare for LQTS and coronary vasospasm to coexist. In cases of exercise-induced arrhythmic events, the exercise stress test might be helpful to diagnose underlying disease.

Predicting the response to acetylcholine in ischemia or infarction with non-obstructive coronary arteries: The ABCD score.

BACKGROUND AND AIMS: Acetylcholine (ACh) provocation testing can detect vasomotor disorders in patients with ischemia and non-obstructed coronary arteries (INOCA) or myocardial infarction and non-obstructed coronary arteries (MINOCA). We aimed to derive and validate a simple risk score to predict a positive ACh test response. METHODS: We prospectively enrolled consecutive INOCA and MINOCA patients undergoing ACh provocation testing. Patients were split in two cohorts (derivation and validation) according to time of enrolment. The score was derived in 386 patients (derivation cohort) and then validated in 165 patients (validation cohort). RESULTS: 551 patients were enrolled, 371 (67.3%) INOCA and 180 (32.7%) MINOCA. ACh test was positive in 288 (52.3%) patients. MINOCA, myocardial bridge (MB), C-reactive protein (CRP) and dyslipidaemia were independent predictors of a positive ACh test in the derivation cohort. The ABCD (Acute presentation, Bridge, CRP, Dyslipidaemia) score was derived: 2 points were assigned to MINOCA, 3 to MB, 1 to elevated CRP and 1 to dyslipidaemia. The ABCD score accurately identified patients with a positive ACh test response with an AUC of 0.703 (CI 95% 0.652-0.754,p < 0.001) in the derivation cohort, and 0.705 (CI 95% 0.626-0.784, p < 0.001) in the validation cohort. In the whole population, an ABCD score ≥4 portended 94.3% risk of a positive ACh test and all patients with an ABCD score ≥6 presented a positive test. CONCLUSIONS: The ABCD score could avoid the need of ACh provocation testing in patients with a high score, reducing procedural risks, time, and costs, and allowing the implementation of a tailored treatment strategy. These results are hypothesis generating and further research involving larger cohorts and multicentre trials is needed to validate and refine the ABCD score.

Recurrent syncope due to ischemia with non-obstructive coronary artery disease: a case report.

BACKGROUND: Ischemia with non-obstructive coronary artery disease is a prevalent form of ischemic heart disease. The majority of ischemia with non-obstructive coronary artery disease cases are attributed to underlying factors such as coronary microvascular dysfunction (CMD) and/or coronary artery spasm. Ischemia with non-obstructive coronary artery disease can present with various clinical manifestations. Recurrent syncope is an atypical complaint in patients with ischemia with non-obstructive coronary artery disease. CASE PRESENTATION: This case report describes the presentation of a 58-year-old Chinese male patient who experienced repeated episodes of syncope. The syncope was found to be caused by concomitant coronary artery spasm and presumptive coronary microvascular dysfunctionc suggested by "slow flow" on coronary angiography. The patient was prescribed diltiazem sustained-release capsules, nicorandil, and atorvastatin. During the three-month follow-up conducted on our outpatient basis, the patient did not experience a recurrence of syncope. CONCLUSION: This study highlights the importance of considering ischemia with non-obstructive coronary artery disease as a potential cause of syncope in the differential diagnosis. It emphasizes the need for early diagnosis of ischemia with non-obstructive coronary artery disease to facilitate more effective management strategies.

Phosphorylated CPI-17 and MLC2 as Biomarkers of Coronary Artery Spasm-Induced Sudden Cardiac Death.

Coronary artery spasm (CAS) plays an important role in the pathogeneses of various ischemic heart diseases and has gradually become a common cause of life-threatening arrhythmia. The specific molecular mechanism of CAS has not been fully elucidated, nor are there any specific diagnostic markers for the condition. Therefore, this study aimed to examine the specific molecular mechanism underlying CAS, and screen for potential diagnostic markers. To this end, we successfully constructed a rat CAS model and achieved in vitro culture of a human coronary-artery smooth-muscle cell (hCASMC) contraction model. Possible molecular mechanisms by which protein kinase C (PKC) regulated CAS through the C kinase-potentiated protein phosphatase 1 inhibitor of 17 kDa (CPI-17)/myosin II regulatory light chain (MLC2) pathway were studied in vivo and in vitro to screen for potential molecular markers of CAS. We performed hematoxylin and eosin staining, myocardial zymogram, and transmission electron microscopy to determine myocardial and coronary artery injury in CAS rats. Then, using immunohistochemical staining, immunofluorescence staining, and Western blotting, we further demonstrated a potential molecular mechanism by which PKC regulated CAS via the CPI-17/MLC2 pathway. The results showed that membrane translocation of PKCα occurred in the coronary arteries of CAS rats. CPI-17/MLC2 signaling was observably activated in coronary arteries undergoing CAS. In addition, in vitro treatment of hCASMCs with angiotensin II (Ang II) increased PKCα membrane translocation while consistently activating CPI-17/MLC2 signaling. Conversely, GF-109203X and calphostin C, specific inhibitors of PKC, inactivated CPI-17/MLC2 signaling. We also collected the coronary artery tissues from deceased subjects suspected to have died of CAS and measured their levels of phosphorylated CPI-17 (p-CPI-17) and MLC2 (p-MLC2). Immunohistochemical staining was positive for p-CPI-17 and p-MLC2 in the tissues of these subjects. These findings suggest that PKCα induced CAS through the CPI-17/MLC2 pathway; therefore, p-CPI-17 and p-MLC2 could be used as potential markers for CAS. Our data provide novel evidence that therapeutic strategies against PKC or CPI-17/MLC2 signaling might be promising in the treatment of CAS.

Relation of Vasoreactivity in the Left and Right Coronary Arteries During Acetylcholine Spasm Provocation Testing.

The diagnosis of vasospastic angina (VSA) according to Japanese guidelines involves an initial intracoronary acetylcholine (ACh) provocation test in the left coronary artery (LCA) followed by testing in the right coronary artery (RCA). However, global variations in test protocols often lead to the omission of ACh provocation in the RCA, potentially resulting in the underdiagnosis of VSA. This study assessed the validity of the LCA-only ACh provocation approach for the VSA diagnosis and whether vasoreactivity in the LCA aids in determining further provocation in the RCA. A total of 273 patients who underwent sequential intracoronary ACh provocation testing in the LCA and RCA were included. Patients with a positive ACh provocation test in the LCA were excluded. Relations between vasoreactivity in the LCA and ACh test outcomes (positivity and adverse events) in the RCA were evaluated. In patients with negative ACh test results in the LCA, subsequent ACh testing was positive in the RCA in 23 of 273 (8.4%) patients. In patients with minimal LCA vasoconstriction (<25%), only 3.0% had a positive ACh test in the RCA, whereas the ACh test in the RCA was positive in 13.5% of those with LCA constriction of 25% to 90% (p = 0.002). No major adverse events occurred during ACh testing in the RCA. In conclusion, for the VSA diagnosis, the omission of ACh provocation in the RCA may be clinically acceptable, particularly when vasoconstriction induced by ACh injection was minimal in the LCA. Further studies are needed to define ACh provocation protocols worldwide.

[Angina and no obstruction on coronary angiography : New approaches to the diagnosis and treatment of vasomotor disorders]. / Angina pectoris ohne Stenosen in der Koronarangiographie : Neue Wege zur Diagnose und Therapie von Vasomotionsstörungen.

BACKGROUND: Clinical management of patients with angina and no obstructive coronary artery disease (ANOCA) is still challenging. This scenario affects up to 50% of patients undergoing diagnostic coronary angiography due to suspected coronary artery disease. Many patients report a long and debilitating history before adequate diagnostics and management are initiated. OBJECTIVES: This article describes the current recommendations for diagnostic assessments and treatment in patients with ANOCA. Focus is placed on invasive diagnostics in the catheter laboratory, pharmacological/interventional treatment as well as the patient journey. RESULTS: In patients with ANOCA, the current European Society of Cardiology (ESC) guidelines suggest that invasive assessments using acetylcholine and adenosine for the diagnosis of an underlying coronary vasomotor disorder should be considered. Acetylcholine is used to diagnose coronary spasm, whereas adenosine is used in conjunction with a wire-based assessment for the measurement of coronary flow reserve and microvascular resistance. The invasive assessments allow the determination of what are referred to as endotypes (coronary spasm, impaired coronary flow reserve, enhanced microvascular resistance or a combination thereof). Establishing a diagnosis is helpful to: (a) initiate targeted treatment to improve quality of life, (b) reassure the patient that a cardiac cause is found and (c) to assess individual prognosis. CONCLUSIONS: Currently, patients with ANOCA are often not adequately managed. Referral to specialised centres is recommended to prevent long and debilitating patient histories until expertise in diagnosis and treatment becomes more widespread.

Elevated white blood cell count and long-term clinical outcomes of patients with vasospastic angina.

OBJECTIVES: Inflammation is known as one of key pathophysiologic mechanisms of coronary artery disease. We aimed to investigate the relationship between white blood cell (WBC) count and long-term clinical outcomes of patients with vasospastic angina (VA). METHODS: A total of 823 patients who were diagnosed as VA without significant coronary lesion by coronary angiography with ergonovine provocation test were enrolled for analysis. Patients were divided according to WBC count tertile at the time of diagnosis: group I, tertile 1 and 2 (n = 546, <7490/ml); group II, tertile 3 (n = 277, ≥7490/ml). Primary outcome was defined as major adverse cardiovascular events (MACE), a composite outcome of all-cause death, cardiac death, myocardial infarction (MI), readmission due to cardiac symptoms, and revascularization. RESULTS: Median follow-up duration was 4.3 years. No significant difference of primary outcome was observed between group I and group II (14.7% vs. 20.2%, hazard ratio (HR) 1.29, confidence interval (CI) 0.90-1.83, P  = 0.162), while incidence of cardiac death and MI was significantly higher in group II (1.5% vs. 4.3%, HR 2.86, CI 1.14-7.17), P  = 0.025). In multivariate Cox regression model, elevated WBC count at the time of diagnosis of VA was an independent predictor of MI (HR 3.43, CI 1.02-11.59, P  = 0.047). CONCLUSION: Elevated WBC count at the time of diagnosis was associated with a significantly increased risk of cardiac death and MI during long-term follow-up in VA patients.