Structural Thickening of Medial Layer in Coronary Artery With Spasm in Patients With Myocardial Infarction.

Background The underlying pathophysiology of coronary artery spasm (CAS) remains unclear. We aim to determine whether coronary artery medial layer thickness is associated with CAS using optical coherence tomography. Methods and Results A total of 50 patients with previous myocardial infarction underwent optical coherence tomography of the left anterior descending artery: 20 with CAS and 30 without CAS. Intimal and medial layer areas were measured by planimetric analysis of optical coherence tomography images. The medial area/external elastic membrane (EEM) area was significantly greater in patients with than without CAS (0.13±0.01 versus 0.09±0.01, respectively, P<0.01), whereas the intimal area/EEM area was similar in the 2 groups. In patients without CAS, the relationship of intimal area/EEM area with medial area/EEM area and coronary diameter response to intracoronary injection of acetylcholine was characterized by an inverted U-shaped curve (y=-1.85x2+0.81x+0.01, R2=0.43, P<0.001) and a U-shaped curve (y=2993.2x2-1359.6x+117.1, R2=0.53, P<0.001), respectively. Thus, the medial layer became thin and the contractile response became weak in coronary arteries with greater intimal area in the non-CAS patients. In contrast, in patients with CAS, the intimal area/EEM area had no significant relationship with the medial area/EEM area in either linear correlation analysis or quadratic regression analysis. Thus, even when the intimal layer thickened, the medial layer did not thin in patients with CAS. Conclusions The structural thickness of the coronary medial layer was increased in patients with CAS, which may provide mechanistic insight into the pathogenesis of CAS. Registration URL: https://www.upload.umin.ac.jp; Unique identifier: UMIN000018432.

Evaluation of Therapeutic Agents Targeting the Pathogenesis of Coronary Artery Spasm: A Mini Review.

Coronary artery spasm (CAS) plays an important role in the pathogenesis of ischemic heart disease. The clinical manifestations of CAS include variant angina, myocardial infarction and sudden death. Although endothelial dysfunction and hyperreactivity of vascular smooth muscle cells have been associated with CAS, the underlying mechanisms remain unclear. Thus, there is a long way to go to truly understand the pathogenesis of CAS to formulate effective treatments. This article discusses the pathophysiological mechanisms as well as downstream molecular pathways of CAS, with a focus on potential therapeutic targets.

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.

Vasospasm-related Sudden Cardiac Death Has Outcomes Comparable with Coronary Stenosis in Out-of-Hospital Cardiac Arrest.

BACKGROUND: Characteristics of coronary vasospasm-related sudden cardiac death are not well understood. We aimed to compare the characteristics and clinical outcomes between coronary vasospasm and stenosis, in out-of-hospital cardiac arrest (OHCA) survivors, who underwent coronary angiogram (CAG). METHODS: We conducted a multicenter retrospective observational registry-based study at 8 Korean tertiary care centers. Data of OHCA survivors undergoing CAG between 2010 and 2015 were extracted. Patients were divided into vasospasm and stenosis (stenosis > 50%) groups based on CAG findings. The primary and the secondary outcomes were survival and a good neurologic outcome at 30 days after OHCA. Patients in the vasospasm and stenosis groups were propensity score matched. RESULTS: Of the 413 included patients, vasospasm and stenosis groups comprised 87 and 326 patients, respectively. There were 279 (66.7%) survivors and 206 (49.3%) patients with good neurologic outcomes. The vasospasm group had better clinical characteristics for outcome (younger age, less diabetes and hypertension, more prehospital restoration of spontaneous circulation, higher Glasgow Coma Scale, less ST segment elevation, and less requirement of circulatory support). The vasospasm group had better survival (75/87 vs. 204/326, P < 0.001) and good neurologic outcomes (62/87 vs. 144/326, P < 0.001). However, vasospasm was not independently associated with survival (odds ratio [OR], 0.980; 95% confidence interval [CI], 0.400-2.406) or neurologic outcomes (OR, 0.870; 95% CI, 0.359-2.108) after adjustment and vasospasm was not associated with survival and neurologic outcome in propensity score-matched cohorts. CONCLUSION: Our analysis of propensity score-matched cohorts finds that vasospasm OHCA survivors have survival and neurologic outcomes comparable with those of stenotic OHCA survivors.

The Biochemical Markers Associated with the Occurrence of Coronary Spasm.

Coronary artery spasm (CAS) is one of the mechanisms of angina pectoris. Unlike the diagnosis of acute myocardial infarction which is based on the elevation of cardiac markers, the diagnosis of CAS is difficult and sometimes requires sophisticated and risky provocative test which is not widely accepted in China. There is no well-established biomarker for the diagnosis or prediction of CAS. However, there are some biomarkers proven to be associated with the occurrence of CAS. For example, inflammatory factors including C-reactive protein and cytokines, lipoprotein (a), and cystatin-C might be precipitating factor for CAS. Rho-kinase as a mediator involved in multiple mechanisms of CAS, serotonin, and endothelin-1 as powerful vasoconstrictors leading to vasospasm were all observed being elevated in patients with CAS. Thioredoxin and nitrotyrosine reflected the oxidative status and could be observed to be elevated after the occurrence of CAS. In some cases doubted to be CAS without the evidence of provocative test, the blood test for the biomarkers mentioned above could be useful for the diagnosis of CAS.

Spontaneous coronary artery dissection and associated myocardial bridging: Current evidence from cohort study and case reports.

Spontaneous coronary artery dissection (SCAD) is a relatively uncommon and under-diagnosed disease characterized by the dissociation of intima and media of coronary artery wall due to an intimal tear or intramural hemorrhage. The exact pathophysiology of SCAD remains elusive and may involve multiple predisposing or precipitating factors including genetic abnormalities, inherited or acquired vasculopathies, hormonal influences, inflammation, intense exercise, emotional stress, and recreational drugs. Accruing reports, including five case reports and one cohort study, have recently addressed the concurrence of SCAD and myocardial bridging (MB), an anatomic variant in which a segment of the epicardial coronary descends and traverses in the myocardium. Among the patients with coexisting MB and SCAD, the left anterior descending artery was the only artery that harbors both pathologies, with SCAD locating either within the tunneled segment or distal to the MB. No other predisposing factors or precipitating stressors for SCAD were noted. It is hypothesized that the predilection for vasospasm, impaired endothelial function, and disturbed coronary flow dynamics associated with MB bridging could collectively contribute to the development of SCAD. Future studies are warranted to explore the mechanistic implications of MB in patients with SCAD.

Coronary Computed Tomography Angiography for the Diagnosis of Vasospastic Angina: Comparison with Invasive Coronary Angiography and Ergonovine Provocation Test.

OBJECTIVE: To investigate the diagnostic validity of coronary computed tomography angiography (cCTA) in vasospastic angina (VA) and factors associated with discrepant results between invasive coronary angiography with the ergonovine provocation test (iCAG-EPT) and cCTA. MATERIALS AND METHODS: Of the 1397 patients diagnosed with VA from 2006 to 2016, 33 patients (75 lesions) with available cCTA data from within 6 months before iCAG-EPT were included. The severity of spasm (% diameter stenosis [%DS]) on iCAG-EPT and cCTA was assessed, and the difference in %DS (Δ%DS) was calculated. Δ%DS was compared after classifying the lesions according to pre-cCTA-administered sublingual nitroglycerin (SL-NG) or beta-blockers. The lesions were further categorized with %DS ≥ 50% on iCAG-EPT or cCTA defined as a significant spasm, and the diagnostic performance of cCTA on identifying significant spasm relative to iCAG-EPT was assessed. RESULTS: Compared to lesions without SL-NG treatment, those with SL-NG treatment showed a higher Δ%DS (39.2% vs. 22.1%, p = 0.002). However, there was no difference in Δ%DS with or without beta-blocker treatment (35.1% vs. 32.6%, p = 0.643). The significant difference in Δ%DS associated with SL-NG was more prominent in patients who were aged < 60 years, were male, had body mass index < 25 kg/m², and had no history of hypertension, diabetes, or dyslipidemia. Based on iCAG-EPT as the reference, the per-lesion-based sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of cCTA for VA diagnosis were 7.5%, 94.0%, 60.0%, 47.1%, and 48.0%, respectively. CONCLUSION: For patients with clinically suspected VA, confirmation with iCAG-EPT needs to be considered without completely excluding the diagnosis of VA simply based on cCTA results, although further prospective studies are required for confirmation.

Unexpectedly High Prevalence of Coronary Spastic Angina in Patients With Anderson-Fabry Disease.

BACKGROUND: Although we and others have reported cases of patients with Anderson-Fabry disease (AFD) complicated by coronary spastic angina (CSA), the prevalence of CSA in these patients remains unknown. Methods and Results: We performed the acetylcholine-induced provocation test, according to the Japanese guidelines for the diagnosis and treatment of patients with CSA, in 9 consecutive patients having 5 independent AFD pedigrees. Coronary spasms were provoked in conjunction with symptoms and ECG ischemic changes in 8 of 9 (89%) patients with AFD. CONCLUSIONS: We found an unexpectedly high prevalence of CSA in patients with AFD.

Angioscopic differences of coronary intima between diffuse and focal coronary vasospasm: Comparison of optical coherence tomography findings.

BACKGROUND: Coronary artery vasospasm (CS) can be identified as either a diffuse type or focal type; however, the difference in endothelial characteristics between these spasm types remains unclear. The features of coronary intima associated with diffuse spasm and focal spasm using coronary angioscopy (CAS) were evaluated and the optical coherence tomography (OCT) findings were compared. METHODS: CAS and/or OCT observational analysis was performed in 55 patients (mean age: 61.4 years, 31 men) who had acetylcholine-provoked CS (diffuse CS, 31 patients; focal CS, 24 patients). The yellowness of the intima, presence of thrombus in CAS, and intimal characteristics based on the OCT results were evaluated. RESULTS: CAS showed more atherosclerotic yellow plaques at the focal spasm segment than at the diffuse spasm segment (p=0.032). Moreover, there were more thrombi at the focal spasm segment (p=0.039). In addition, OCT results revealed that the intima area, maximum intima thickness, and lipid content in the focal CS group were larger than the diffuse CS group (4.22±1.67mm2 vs. 3.45±2.36mm2; 0.71±0.29mm vs. 0.53±0.30mm; 55.9% vs. 32.0%, p<0.001, respectively). CONCLUSIONS: These results indicate that the presence of atherosclerotic plaques at the spasm site is likely to be related to the occurrence of a focal vasospasm. This may support the difference of features between focal CS and diffuse CS and contribute to precise treatment for each spasm type.

[Research Progress and Forensic Application on the Pathogenesis of Coronary Artery Spasm].

Coronary artery spasm （CAS） is a hyper-contraction of segmental coronary artery in response to multiple stimuli. At present, it's still in lack of specific diagnostic indicators of sudden cardiac death caused by CAS. This review summarizes current researches on the mechanisms of CAS and describes the roles of vascular endothelial dysfunction and vascular smooth muscle hypersensitivity in the course of CAS. Furthermore, the molecular mechanisms of the endogenous NO and endothelin-1 cause vascular endothelial dysfunction, and the phosphorylation of MLC2, Rho kinase and endoplasmic reticulum stress related to vascular smooth muscle hypersensitivity are discussed. Meanwhile, the possibility of forensic application for the related molecules on the diagnosis of sudden cardiac death caused by CAS are also explored.

Differential Incidence and Morphology of Spasm According to Coronary Arterial Location by Intracoronary Ergonovine Spasm Provocation Testing.

BACKGROUND: We reported less provoked spasm in the left circumflex artery (LCX) by acetylcholine testing compared with the left anterior descending artery (LAD) and right coronary artery (RCA), so we investigated the clinical characteristics of provoked spasm in the LCX by ergonovine (ER) testing.Methods and Results:We retrospectively analyzed 1,185 consecutive cases of intracoronary ER testing during 25 years. Maximal ER dose was 64 µg into the left coronary artery (LCA) and 40 µg into the RCA. Positive spasm was defined as a transient ≥90% narrowing and usual chest symptoms or ischemic ECG changes. Positive provoked spasm was recognized in 347 patients (29.3%), including 207 RCA spasms, 166 LAD spasms, and 79 LCX spasms. Spasm was provoked in the LCX significantly less than in the other vessels (P<0.001). LCX-provoked spasm was obtained in 79 patients consisting of 16 patients (20.3%) with triple-vessel spasm, 38 patients (48.1%) with double-vessel spasm and 25 patients (31.6%) with single-vessel spasm. Less than 70% patients with LCX-provoked spasm had multiple spasms, whereas approximately 60% patients had single-vessel spasm in the RCA (64.3%) or LAD (59.6%). In 25 patients with LCX single-vessel spasm, 18 patients (72.0%) had a focal spasm. CONCLUSIONS: Under maximal ER dose of 64 µg into the LCA, LCX-provoked spasm occurred significantly less than spasm in the other vessels and less than 70% patients had multiple spasms.

Renal Denervation in Patients with Resistant Hypertension-Assessment by 3T Renal 23Na-MRI: Preliminary Results.

BACKGROUND/AIM: Renal denervation (RDN) has been considered a promising therapy option for patients suffering from therapy-resistant hypertension. Besides, in blood-pressure regularization, the kidneys play a fundamental role in sodium ((23)Na) homeostasis. This study assesses the effect of RDN on renal (23)Na concentration using (23)Na magnetic resonance imaging (MRI). PATIENTS AND METHODS: Two patients with therapy-resistant hypertension underwent RDN. (23)Na-MRI, (1)H-MRI, including diffusion weighted imaging (DWI), as well as endothelial dysfunction assessment, were performed 1 day prior, as well as 1, 30 and 90 days after RDN. RESULTS: The renal corticomedullary (23)Na gradient did not change after RDN for all time points. Additionally, functional imaging and retinal vessel parameters were not influenced by RDN. Results regarding blood pressure changes and arterial stiffness, as well as patients' clinical outcome, were heterogeneous. CONCLUSION: RDN does not seem to alter renal (23)Na concentration gradients, as measured by MRI.

Unraveling of the Effect of Nodose Ganglion Degeneration on the Coronary Artery Vasospasm After Subarachnoid Hemorrhage: An Experimental Study.

BACKGROUND: Cardiac arrest is a major life-threatening complication of subarachnoid hemorrhage (SAH). Although medullary cardiocirculatuar center injury and central sympathetic overactivity have been suspected of initiating coronary artery spasm-induced cardiac arrest, we aimed to elucidate the effects of vagal ischemia at the brainstem on coronary vasospasm and sudden death in SAH. METHODS: Twenty-six rabbits were randomly divided into 3 groups. Control (n = 5); SHAM (n = 8), and SAH group (n = 13). Experimental SAH was applied by injecting homologous blood into the cisterna magna, and the SHAM group was injected with isotonic saline solution also in the cisterna magna., Twenty-one days after the injection, histopathologic changes of the neuron density of nodose ganglia, the vasospasm index values of the coronary arteries, and the electrocardiographic events were analyzed. RESULTS: Increased vasospasm index of the coronary arteries and degenerated neuron density of nodose ganglion were significantly different between animals with SAH, control, and SHAM groups (P < 0.005). If neurons of the nodose ganglia are lesioned due to ischemic insult during SAH, the heart rhythm regulation by vagus afferent reflexes is disturbed. CONCLUSIONS: We found that there is causal relationship between nodose ganglion degeneration and coronary vasospasm. Our finding could be the reason that many cardiac events occur in patients with SAH. Vagal pathway paralysis induced by indirect sympathetic overactivity may trigger coronary vasospasm and heart rhythm disturbances. Our findings will aid in the planning of future experimental studies and in determining the clinical relevance of such studies.

OCT-Defined Morphological Characteristics of Coronary Artery Spasm Sites in Vasospastic Angina.

OBJECTIVES: The aim of this study was to define the morphological features of coronary artery spasm sites using optical coherence tomography (OCT) in patients with vasospastic angina (VSA). BACKGROUND: Plaque characteristics at coronary artery spasm sites have not been investigated systematically. METHODS: Sixty-nine consecutive patients (80 spasm sites) presenting with VSA who underwent OCT imaging were included in this study. Fibrous cap disruption was identified by the discontinuation of fibrous cap with or without intraplaque cavity formation. OCT-defined erosion was established by the presence of thrombus with or without lumen irregularity overlying an intact fibrous cap on multiple adjacent OCT frames. Other morphological features such as the absence of thrombus with or without lumen irregularity and those not in the previously mentioned criteria were also documented. RESULTS: Plaque was seen on OCT in 79 of the 80 spasm sites. Fibrous cap disruption was detected at 3 sites (4%). OCT-defined erosion was observed at 21 spasm sites (26%). Thrombus with lumen irregularity was observed in 20 sites, whereas 1 site had thrombus without lumen irregularity. Lumen irregularity without thrombus was observed at 49 spasm sites (61%). Spontaneous spasm was seen more frequently in patients with acute myocardial infarction and out-of-hospital cardiac arrest than in patients without these conditions (50.0% vs. 19.3%, p = 0.025). CONCLUSIONS: Our results show that OCT-defined erosion at spasm sites occurred in more than one-fourth of patients in this study. Luminal irregularity was observed in nearly two-thirds of the patients without overlying thrombus. These findings suggest the potential role of antiplatelet therapy in VSA.

Structural and Functional Coronary Artery Abnormalities in Patients With Vasospastic Angina Pectoris.

Coronary spasm is involved in many clinical scenarios, such as stable angina, acute coronary syndrome, sudden cardiac death, non-ischemic cardiomyopathy, arrhythmia and syncope. In recent years, imaging tools such as computerized tomographic angiography, intravascular ultrasound or optical coherence tomography have been applied to study the coronary pathology in patients with vasospastic angina. Patients with vasospastic angina represent a heterogeneous cohort of patients with regard to the extent of concomitant coronary atherosclerosis. They share the common pathophysiological phenomenon of vascular smooth muscle hyperreactivity leading to spasm caused by various factors that may also overlap. Focal coronary spasm is related to epicardial atherosclerosis and in the presence of obstructive coronary artery disease it may be useful to treat the lesion to prevent further spasm. The aim of this article is to review structural and functional coronary artery abnormalities in patients with vasospastic angina.

Association of Adventitial Vasa Vasorum and Inflammation With Coronary Hyperconstriction After Drug-Eluting Stent Implantation in Pigs In Vivo.

BACKGROUND: The importance of adventitial inflammation has been implicated for the pathogenesis of coronary artery disease. However, the roles of adventitial changes in drug-eluting stent (DES)-induced coronary hyperconstriction remain largely unknown. In the present study, this issue in pigs in vivo with a special reference to adventitial vasa vasorum (VV) formation and Rho-kinase activation, a central mechanism of coronary vasospasm, was examined. METHODS AND RESULTS: Each animal received a sirolimus-eluting stent (SES) and a biolimus A9-eluting stent (BES), one in the left anterior descending and another in the left circumflex coronary arteries in a randomized manner (n=18). After 1, 3 and 6 months, coronary vasomotion was examined. At 1 month, coronary vasoconstriction to serotonin was significantly enhanced at the SES edges as compared with the BES edges (SES, 52±7% vs. BES, 22±3%, P<0.01), which was equally prevented by a selective Rho-kinase inhibitor, hydroxyfasudil. A significant difference in vasoconstriction between SES and BES was sustained for 6 months. A micro-CT showed VV augmentation at the SES site, extending to the proximal and distal edges. Immunostainings demonstrated that VV formation, macrophage infiltration in the adventitia and Rho-kinase expressions/activation were significantly enhanced at the SES edges as compared with the BES edges. CONCLUSIONS: The DES with durable polymers enhances VV formation and inflammation in the adventitia, associating with the pathogenesis of DES-induced coronary hyperconstriction through Rho-kinase activation in pigs in vivo.

Development of Coronary Vasospasm during Adenosine-Stress Myocardial Perfusion CT Imaging.

Adenosine is a short-acting coronary vasodilator, and it is widely used during pharmacological stress myocardial perfusion imaging. It has a well-established safety profile, and most of its side effects are known to be mild and transient. Until now, coronary vasospasm has been rarely reported as a side effect of adenosine during or after adenosine stress test. This study reports a case of coronary vasospasm which was documented on stress myocardial perfusion CT imaging during adenosine stress test.