Clinical Limitations of Vasoreactivity Testing as a Diagnostic Tool in Patients with Vasospastic Angina.

The Japanese Circulation Society guidelines recommend a class I vasoreactivity test to diagnose patients with vasospastic angina (VSA). However, the acetylcholine or ergonovine test has been established as the gold standard for variant angina (VA). The sensitivity and specificity of intracoronary vasoreactivity testing in patients with VA were acceptable. Cardiologists have employed these vasoreactivity tests to conveniently diagnose the presence of coronary spasms in patients with all VSA. The majority of VSAs may have lower disease activity than VA cases. We have summarized the usefulness of spasm provocation tests in patients with VA and VSA. A positive-provoked spasm diagnosed by standard vasoreactivity testing may indicate a disease state similar to that of VA, whereas a negative-provoked spasm after standard vasoreactivity testing may indicate a lower disease state than that of VA. Cardiologists should reconsider the limited usefulness of vasoreactivity testing when diagnosing the presence of coronary spasms in all VSAs, but not VA.

A Case of Refractory Variant Angina.

Coronary vasospasm is defined as the abnormal contraction of an epicardial coronary artery. Variant angina is a severe form of coronary vasospasm, reflecting transmural ischemia with ST-T elevation on an electrocardiogram. A pharmacologic spasm provocation test during coronary angiography is the gold standard evaluation for patients who have not been diagnosed with coronary vasospasm by a non-invasive test. The sensitivity and specificity of pharmacologic spasm provocation testing have been reported to be very high in patients with variant angina. Here, we report the case of a 61-year-old woman who had refractory variant angina. Although a pharmacologic spasm provocation test did not lead to a definitive diagnosis, she had recurrent acute coronary syndrome due to coronary vasospasm. Physicians should be aware of the limitations of the spasm provocation test, even in patients with refractory variant angina.

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.

Recurrent syncope driven by unique-variant angina pectoris.

The patient's vasospastic variant angina manifested as syncope with asymptomatic ischemic episodes, and repeated 24-h dynamic electrocardiogram and coronary angiography examinations combined with coronary provocation spasm tests were necessary for its diagnosis and management.

Variant Angina and Cannabis-Induced Myocarditis: A Rare Presentation of Myocardial Inflammation.

Myocarditis is a rare but serious inflammatory disease of the myocardium, often caused by viral infections. We present a unique case of myocarditis in a previously healthy 29-year-old male who developed symptoms and electrocardiography changes of variant angina following cannabis use. This case report discusses the patient's atypical presentation, diagnostic evaluation, management, and outcome.

Anesthetic Management of a Patient With Prinzmetal Angina.

Prinzmetal angina (PA) is characterized by the development of reversible vasoconstriction of the coronary arteries, transient ischemic electrocardiographic changes in the ST segment, chest pain at rest, and prompt response to nitrates. Spasms of the coronary arteries can be precipitated during the perioperative period by an imbalance of vasodilator and vasoconstrictor factors of smooth muscle cells, which can lead to myocardial ischemia, cardiac arrhythmias, and death. Nevertheless, this is a relatively unrecognized topic, and literature is scarce about it. We present a case report detailing the successful anesthetic management of a patient diagnosed with PA and a documented nitrate allergy, who underwent bilateral ureterorenoscopy.

Management of Coronary Artery Spasm.

Calcium channel blockers (CCBs) are the first-line treatment for coronary artery spasm (CAS). When CAS-related angina symptoms are not well controlled by CCB therapy, long-acting nitrates or (where available) nicorandil can be added as second-line medications. In the case of CAS refractory to standard treatments, several other alternative drugs and interventions have been proposed, including the Rho-kinase inhibitor fasudil, anti-adrenergic drugs, neural therapies and percutaneous coronary interventions. In patients with syncope or cardiac arrest caused by CAS-related tachyarrhythmias, or even bradyarrhythmias, implantation of an ICD or pacemaker, respectively, should be considered according to the risk of recurrence and efficacy of vasodilator therapy.

Non-invasive diagnosis of vasospastic angina.

Vasospastic angina (VSA), or variant angina, is an under-recognized cause of chest pain and myocardial infarction, especially in Western countries. VSA leads to a declined quality of life and is associated with increased morbidity and mortality. Currently, the diagnosis of VSA relies on invasive testing that requires the direct intracoronary administration of ergonovine or acetylcholine. However, invasive vasoreactivity testing is underutilized. Several non-invasive imaging alternatives have been proposed to screen for VSA. This review aims to discuss the strengths and limitations of available non-invasive imaging tests for vasospastic angina.

Cellular Mechanisms of Coronary Artery Spasm.

Coronary artery spasm (CAS) is a reversible phenomenon caused by spontaneous excessive vascular smooth muscle contractility and vascular wall hypertonicity, which results in partial or complete closure of the lumen of normal or atherosclerotic coronary arteries. The clinical picture of CAS includes chest discomfort which is similar in quality to that of stable effort angina. Mechanisms underlying the development of CAS are still unclear. CAS certainly is a multifactorial disease. In this review, we paid attention to the role of the main pathophysiologic mechanisms in CAS: endothelial dysfunction, chronic inflammation, oxidative stress, smooth muscle hypercontractility, atherosclerosis and thrombosis, and mutations leading to deficient aldehyde dehydrogenase 2 (ALDH2) activity. These findings might shed novel insight on the underlying mechanisms and identify potential diagnostic and therapeutic targets for cardiovascular diseases in the future.

Successful infusional 5-fluorouracil administration in a patient with vasospastic angina.

A 48-year-old female with metastatic colon adenocarcinoma and history of pre-existing coronary vasospasm with ventricular tachycardia (VT) successfully tolerated de novo 5-fluorouracil (5-FU) chemotherapy infusions with prophylactic administration and optimization of anti-spasm medications. 5-FU has been reported to produce severe cardiotoxic side effects, including coronary vasospasm, ventricular arrhythmias, and sudden cardiac death, and is not typically reported in individuals with pre-existing coronary vasospasm.

Variant Angina is Associated with Myocarditis.

Background: Vasospastic angina (VSA) is caused by severe diffuse or segmental coronary artery spasms. Patients with variant angina have poor clinical outcomes, although nitrates and calcium blockers help improve patient symptoms because there is no understanding of the etiology and causal treatment. The present study investigated whether VSA is associated with inflammation of the heart. Patients and Methods: A total of 109 patients with VSA diagnosed by the presence of recurrent angina pectoris, typical electrocardiography, and coronary angiography were recruited, and 61 normal participants and 61 patients with acute myocardial infarction (AMI) and coronary artery stenosis were recruited as controls. The plasma levels of 24 cytokines were measured using a magnetic Luminex assay, and endothelin-1 and histamine levels tested using enzyme-linked immunosorbent assay and mass-spectrometry, respectively, for all participants. Furthermore, four patients with VSA underwent 18-fluorine fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT). Results: The plasma levels of interleukin (IL)-12p70, IL-13, PDL-1, IL-10, IL-6, IL-15, macrophage inflammatory protein (MIP)-1α, and MIP-1ß in patients with VSA were significantly higher than those in both normal controls and patients with AMI (p<0.001) but did not differ between normal controls and patients with AMI. 18F-FDG PET/CT showed that the left ventricle, coronary perivascular tissue volume, and coronary perivascular FDG uptake were significantly increased in all four patients. Conclusion: Our findings demonstrate that VSA patients have significantly elevated plasma cytokine levels and myocardial and pericoronary inflammation, suggesting that VSA is associated with myocarditis. This study provides novel insights into the etiology and treatment of VSA.

Tailoring therapeutic effect for chronotherapy of variant angina based on pharmacodynamic/deconvolution integrated model method.

The onset of variant angina (VA) shows circadian rhythmicity that its attacks occur most often from midnight to early morning. Thus, chronotherapeutic treatments should be tailored accordingly to its occurrence frequency. Tanshinol (TS), the bioactive component of Salvia miltiorrhiza was used as the model drug. The pharmacokinetics, pharmacodynamics and PK-PD relationship of TS was investigated in angina model rabbits. The therapeutic effect of TS was evaluated from different aspects including cardiac injury, oxidative stress and vascular endothelium by measuring the serum levels of cTn-I, CK-MB, SOD and NO. In addition, the change of cTn-I levels from baseline as the pharmacodynamic endpoint was used for establishing the pharmacodynamic model. To synchronize the therapeutic effect profile of TS to the occurrence frequency of VA, ideal time courses of therapeutic effect, plasma concentration and drug release were simulated and calculated based on pharmacodynamic/deconvolution integrated model method. Then, sustained release pellets of TS (TS-SRPs) were developed according to the above calculated results and evaluated in vitro-in vivo. The established pharmacodynamic model of TS could precisely quantify the relationship between its effect and concentration. Then, ideal time courses of therapeutic effect, plasma concentration and release of TS were simulated and calculated successfully. After formulation optimization, the prepared TS-SRPs exhibited similar in vitro and in vivo behaviors to the corresponding ideal ones. Meanwhile, the effect curves of TS were synchronous with the occurrence frequency of VA, implying that appropriate therapeutic effect could be provided according to the needs of patients. In conclusion, the tailor of therapeutic effect based on integrated model method is efficient, feasible and reliable.

Prognostic Impact of Chronic Vasodilator Therapy in Patients With Vasospastic Angina.

Background Chronic vasodilator therapy with long-acting nitrate is frequently used to treat vasospastic angina. However, the clinical benefits of this approach are controversial. We investigated the prognostic impact of vasodilator therapy in patients with vasospastic angina from the multicenter, prospective VA-KOREA (Vasospastic Angina in KOREA) registry. Methods and Results We analyzed data from 1895 patients with positive intracoronary ergonovine provocation test results. The patients were divided into 4 groups: no vasodilator (n=359), nonnitrate vasodilator (n=1187), conventional nitrate (n=209), and a combination of conventional nitrate and other vasodilators (n=140). The primary end point was a composite of cardiac death, acute coronary syndrome, and new-onset arrhythmia at 2 years. Secondary end points were the individual components of the primary end point, all-cause death, and rehospitalization due to recurrent angina. The groups did not differ in terms of the risk of the primary end point. However, the acute coronary syndrome risk was significantly higher in the conventional nitrate (hazard ratio [HR], 2.49; 95% CI, 1.01-6.14; P=0.047) and combination groups (HR, 3.34; 95% CI, 1.15-9.75, P=0.027) compared with the no-vasodilator group, as assessed using the inverse probability of treatment weights. Subgroup analyses revealed prominent adverse effects of nitrate in patients with an intermediate positive ergonovine provocation test result and in those with low Japanese Coronary Spasm Association scores. Conclusions Long-acting nitrate-based chronic vasodilator therapy was associated with an increased 2-year risk of acute coronary syndrome in patients with vasospastic angina, especially in low-risk patients.

Fragmented QRS as a risk marker for the occurrence of ventricular fibrillation in patients with variant angina.

BACKGROUND: Variant angina (VA) is caused by reversible coronary artery spasm, which is characterized by chest pain with ST-segment elevations on standard 12-lead electrocardiogram (ECG) at rest. Ventricular fibrillation (VF) is often caused by VA attack, but the risk stratification is not well understood. The purpose of this study was to evaluate the impact of fragmented QRS (fQRS) on VF occurrence in VA patients. METHODS: Ninety-four patients who showed ST elevation on 12-lead ECGs with total or nearly total occlusion in response to coronary spasm provocation test were enrolled. Among them, 16 patients had documented VF before hospital admission (n = 12) or experienced VF during provocation test (n = 4) (VF occurrence group). The fQRS was defined as the presence of spikes within the QRS complex of two or more consecutive leads. RESULTS: The prevalence of fQRS was more often observed in the VF occurrence group than in the non-VF occurrence group (63% [10/16] vs. 27% [21/78], p = 0.009). Univariate analyses revealed that age, history of syncope, QTc, and the presence of fQRS were associated with VF occurrence (p = 0.004, 0.005, 0.029, and 0.008, respectively). Furthermore, upon multivariate analyses using those risk factors, age, QTc, and fQRS predicted VF occurrence independently (p = 0.007, 0.041, and 0.014, respectively). CONCLUSIONS: The present study demonstrated that fQRS in VA patients is a risk factor for VF. The fQRS may be a useful factor for the risk stratification of VF occurrence in VA patients.

5-Fluorouracil, capecitabine and vasospasm: a scoping review of pathogenesis, management options and future research considerations.

BACKGROUND: 5-Fluorouracil (5-FU) is a widely used chemotherapeutic agent that can cause cardiotoxicity manifesting, among others, as chest pain. Capecitabine is an oral prodrug of 5-FU, with reported preferential activation in malignant cells that may also cause cardiotoxic reactions. Standard treatment of 5-FU and capecitabine induced chest pain with vasodilators is mostly effective, but there are several cases of patients unresponsive to these agents. METHODS: We performed a PubMed search on 31st May 2020. We used a three keyword search strategy using Boolean search operators. More specifically, we included fluorouracil or 5-FU or capecitabine and chest pain or angina and mechanism or treatment or management. We included primary reports of clinical and non-clinical data, as well as systematic reviews. Narrative reviews, expert opinions, letters to the editor and other forms of non-primary literature were excluded. RESULTS: Our search yielded a total of 1595 reports. Of these, 1460 were narrative reviews or irrelevant to the topic and were excluded. A total of 135 reports were used for our review. We used 81 reports for data extraction, which included 13 clinical trials, 4 retrospective reports, 61 case reports, and 3 systematic reviews. CONCLUSION: We report the incidence and predisposing factors, the value of available diagnostic procedures, and standard medical and invasive treatments. We also speculate on the potential benefit of arginine as a promising option both in prevention as well as treatment of 5-FU-induced chest pain. Finally, gaps of evidence are identified and proposals are made in terms of future research.

Angina due to coronary artery spasm (variant angina): diagnosis and intervention strategies.

INTRODUCTION: Since Prinzmetal first described a 'variant' form of angina pectoris, with predominantly resting episodes of pain and cyclic severity variations, it has gradually become apparent that this clinical presentation is caused by episodes of coronary artery spasm (CAS) involving focal or diffuse changes in large and/or small coronary arteries in the presence or absence of 'fixed' coronary artery stenoses. However, most clinicians have only limited understanding of this group of disorders. AREAS COVERED: We examine the clinical presentation of CAS, associated pathologies outside the coronary vasculature, impediments to making the diagnosis, provocative diagnostic tests, available and emerging treatments, and the current understanding of pathogenesis. EXPERT OPINION: CAS is often debilitating and substantially under-diagnosed and occur mainly in women. Many patients presenting with CAS crises have non-diagnostic ECGs and normal serum troponin concentrations, but CAS can be suspected on the basis of history and association with migraine, Raynaud's phenomenon and Kounis syndrome. Definitive diagnosis requires provocative testing at coronary angiography. Treatment still centers around the use of calcium antagonists, but with greater understanding of pathogenesis, new management options are emerging.

Coronary vasospasm: A narrative review.

Coronary artery vasospasm (CAVS) plays an important role in acute chest pain syndrome caused by transient and partial or complete occlusion of the coronary arteries. Pathophysiology of the disease remains incompletely understood, with autonomic and endothelial dysfunction thought to play an important role. Due to the dynamic nature of the disease, its exact prevalence is not entirely clear but is found to be more prevalent in East Asian and female population. Cigarette smoking remains a prominent risk factor, although CAVS does not follow traditional coronary artery disease risk factors. Many triggers continue to be identified, with recent findings identifying chemotherapeutics, allergens, and inflammatory mediators as playing some role in the exacerbation of CAVS. Provocative testing with direct visualization is currently the gold-standard for diagnosis, but non-invasive tests, including the use of biomarkers, are being increasingly studied to aid in the diagnosis. Treatment of the CAVS is an area of active research. Apart from risk factor modification, calcium channel blockers are currently the first line treatment, with nitrates playing an important adjunct role. High-risk patients with life-threatening complications should be considered for implantable cardioverter defibrillator (ICD), although timing criteria for escalated therapy require further investigation. The role of pharmaceuticals targeting oxidative stress remains incompletely understood.

Coronary vasospasm as an etiology of recurrent ventricular fibrillation in the absence of coronary artery disease: a case report.

Background: Vasospastic angina (VA), or Prinzmetal's angina, is characterized by symptoms of coronary angina caused by coronary vasospasm, usually in the absence of atherosclerotic changes. It typically presents with chest pain, which can be accompanied by transient electrocardiographic changes, if visualized during the attack. It can also rarely present with severe manifestations of acute myocardial angina, ventricular fibrillation, or cardiac arrest. Case presentation: We present a case of a 50-year-old Caucasian male who initially presented to the hospital with chest pain and was diagnosed with VA. Later, he was brought to the hospital by emergency medical services later with ventricular fibrillation, despite normal coronary anatomy on angiogram. He was managed with placement of an intra-cardiac defibrillator (ICD) for secondary prevention. The patient continued to have recurrent episodes of ventricular fibrillation with associated ICD shocks, and had multiple admissions to the hospital with similar presentations. Symptoms and arrhythmia improved after optimizing antianginal therapy. Conclusions: Ventricular fibrillation can be an uncommon but severe manifestation during VA crises. In cases with normal coronary vasculature, it is important to recognize VA as a cause of recurrent ventricular fibrillation in order to optimize medical management for prevention of fatal arrhythmias.

[Recurrent torsades and asystole without structural heart disease]. / Rezidivierende Torsaden und Asystolie ohne strukturelle Herzerkrankung.

We report on a 67-year-old female patient with recurrent syncope induced by asystole and polymorphic ventricular tachycardia without relevant structural heart disease. After secondary prophylactic ICD implantation, beta-blocker and flecainide therapy, the patient suffered from recurrent syncope and ICD shocks due to ventricular fibrillation. A rare cause of polymorphic ventricular tachycardia in patients without structural heart disease was found and successfully treated.

A case of variant angina associated with syncope detected by an implantable loop recorder.

The implantable loop recorder (ILR) is a small device used to monitor the electrical activity of the heart by recording a single­lead bipolar electrocardiograph signal over a long period of time. The ILR is a valid diagnostic tool but has been vastly underused. In addition to arrhythmia, the ILR may be a useful tool for the detection of repolarization disorders in patients with myocardial ischemia.