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Background: Microvascular angina is associated with dysregulation of the endothelin system and impairments in myocardial blood flow, exercise capacity, and health-related quality of life. The G allele of the noncoding single nucleotide polymorphism RS9349379 enhances expression of the endothelin-1 gene ( EDN1 ) in human vascular cells, potentially increasing circulating concentrations of Endothelin-1 (ET-1). Whether zibotentan, an oral ET-A receptor selective antagonist, is efficacious and safe for the treatment of microvascular angina is unknown., Methods: Patients with microvascular angina were enrolled in this double-blind, placebo-controlled, sequential crossover trial of zibotentan (10 mg daily for 12 weeks). The trial population was enriched to ensure a G allele frequency of 50% for the RS9349379 single nucleotide polymorphism. Participants and investigators were blinded to genotype. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The primary analysis estimated the mean within-participant difference in exercise duration after treatment with zibotentan versus placebo., Results: A total of 118 participants (mean±SD; years of age 63.5 [9.2]; 71 [60.2%] females; 25 [21.2%] with diabetes) were randomized. Among 103 participants with complete data, the mean exercise duration with zibotentan treatment compared with placebo was not different (between-treatment difference, -4.26 seconds [95% CI, -19.60 to 11.06] P =0.5871). Secondary outcomes showed no improvement with zibotentan. Zibotentan reduced blood pressure and increased plasma concentrations of ET-1. Adverse events were more common with zibotentan (60.2%) compared with placebo (14.4%; P <0.001)., Conclusions: Among patients with microvascular angina, short-term treatment with a relatively high dose (10 mg daily) of zibotentan was not beneficial. Target-related adverse effects were common., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04097314., Competing Interests: Dr Berry is employed by the University of Glasgow, which holds consultancy and research agreements with Abbott Vascular, AstraZeneca, Auxilius Pharma, Boehringer Ingelheim, Corflow, Coroventis, GlaxoSmithKline, HeartFlow, Menarini, Novartis, Siemens Healthcare, Somalogic, Xylocor and Valo Health. Dr Spyridopoulos receives research grants from Astra Zeneca, Cambridge, UK, and Kancera, Solna, Sweden. Dr Ford is a consultant/speaker/honorarium from Abbott Vascular, Boston Scientific, Boehringer Ingelheim, Biotronik, Bio-Excel, and Novartis. Dr Al-Lamee serves on advisory boards of Janssen Pharmaceuticals, Abbott, and Philips, and has received speaker honoraria from Abbott, Philips, Medtronic, Servier, Omniprex, and Menarini. These companies had no role in the design or conduct of the study or in the data collection or interpretation. Dr Davenport holds research grants from AstraZeneca and is a member of scientific advisory boards of Janssen, ENB Therapeutics, and Pharmazz. Drs Berry, Ford, and Davenport are named on a pending patent for the use of zibotentan for microvascular angina. The University of Glasgow holds the patent. None of the other authors have any relevant disclosures.

This study reviewed the current status of the use of outcome indicators in randomized controlled trial(RCT) on traditional Chinese medicine(TCM) treatment of microvascular angina(MVA) and analyzed the existing problems and possible solutions, aiming to provide a basis for the design of high-quality RCT and the establishment of core outcome sets for MVA. CNKI, Wanfang, VIP, SinoMed, PubMed, EMbase, Cochrane Library, Web of Science, and 2 clinical trial registries were searched for the RCT on TCM treatment of MVA according to pre-defined criteria. The Cochrane's risk of bias assessment tool was used to evaluate the methodological quality of the included RCT and the use of outcome indicators was summarized. A total of 69 RCTs were included, from which 100 outcome indicators were extracted, with the frequency of 430. The extracted outcome indicators belonged to 8 domains: response rate, symptoms and signs, physical and chemical examinations, TCM efficacy, safety, quality of life, economic evaluation, and long-term prognosis. The indicators of physical and chemical examinations were the most(70 indicators with the frequency of 211), followed by those of response rate(7 indicators with the frequency of 73) and symptoms and signs(7 indicators with the frequency of 54). The outcome indicators with higher frequency were adverse reactions, angina attack frequency, clinical efficacy, endothelin-1, total duration of treadmill exercise, and hypersensitive C-reactive protein. The RCT on TCM treatment of MVA had the following problems: irregular reporting of adverse reactions, diverse indicators with low frequency, lack of attention to the application of endpoint indicators, insufficient use of TCM differentiation and efficacy indicators, non-standard evaluation criteria and failure to reflect the basic characteristics of TCM. A unified MVA syndrome differentiation standard should be established, on the basis of which an MVA treatment efficacy evaluation system and core outcome indicator set that highlights the characteristics of TCM with patient-reported outcomes as the starting point should be established to improve the clinical research and research value.

Microvascular angina (MVA), historically called cardiac syndrome X, refers to angina with nonobstructive coronary artery disease. This female-predominant cardiovascular disorder adds considerable health-related costs due to repeated diagnostic angiography and frequent hospital admissions. Despite the high prevalence of this diagnosis in patients undergoing coronary angiography, it is still a therapeutic challenge for cardiologists. Unlike obstructive coronary artery disease, with multiple evidence-based therapies and management guidelines, little is known regarding the management of MVA. During the last decade, many therapeutic interventions have been suggested for the treatment of MVA. However, there is a lack of summarization tab and update of current knowledge about pharmacologic management of MVA, mostly due to unclear pathophysiology. In this article, we have reviewed the underlying mechanisms of MVA and the outcomes of various medications in patients with this disease. Contrary to vasospastic angina in which normal angiogram is observed as well, nitrates are not effective in the treatment of MVA. Beta-blockers and calcium channel blockers have the strongest evidence of improving the symptoms. Moreover, the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, statins, estrogen, and novel antianginal drugs has had promising outcomes. Investigations are still ongoing for vitamin D, omega-3, incretins, and n -acetyl cysteine, which have resulted in beneficial initial outcomes. We believe that the employment of the available results and results of the future large-scale trials into cardiac care guidelines would help reduce the global cost of cardiac care tremendously., Competing Interests: All authors declare that they do not have any conflicts of interest., (Copyright © 2022 Mosayeb Soleymani et al.)

There are currently multiple invasive and non-invasive methods that can be used to establish the diagnosis of microvascular dysfunction (MVD) in patients with INOCA (Ischemia with Non-Obstructive Coronary Arteries) and microvascular angina. However, we still do not have a specific treatment approach for this group of patients. The current trend is to adjust the treatment to the pathophysiological mechanism involved, adding calcium blockers in those patients where endothelial dysfunction is demonstrated or beta blockers in those patients who present smooth muscle-dependent dysfunction. We present three clinical cases of INOCA with suspected microvascular angina. Two of them underwent a non-invasive diagnosis of MVD by CZT-SPECT, using dipyridamole to evaluate the smooth muscle-dependent mechanism and cold pressor test to evaluate the endothelium-dependent mechanism. According to the results obtained, the treatment was adju sted, clinical follow-up was carried out and angina was assessed using the Seattle scale, with a new microcirculation assessment at 6 months. The third clinical case, on the other hand, was a patient who began empirical treatment for both mechanisms and subsequently abandoned the established treatment. Microvascular function was evaluated under pharmacological treatment and without it.

Abstract: Most cases of primary microvascular angina pectoris (PMVA) are diagnosed clinically, but the etiology and pathological mechanisms are unknown. The effect of routine clinical medications is minimal, and PMVA can progress to serious cardiovascular events. To improve the diagnosis and effective treatment of this disease, this study was designed to diagnose PMVA via cardiovascular magnetic resonance (CMR) and the coronary angiography thrombolysis in myocardial infarction (TIMI) blood flow grade, as well as to analyze vascular endothelial function to elucidate the pathogenesis of PMVA and compare the effects of routine clinical medications.The present randomized controlled trial including a parallel control group will be conducted on 63 PMVA patients in our cardiovascular department. The patients will be selected and randomly divided into the control, diltiazem, and nicorandil groups. The control group will be administered routine drug treatments (aspirin, atorvastatin, betaloc ZOK, perindopril, and isosorbidemononitrate sustained-release tablets). The diltiazem group will be additionally treated with 90 mg qd diltiazem sustained-release capsules. The nicorandil group was additionally given 5 mg tid nicorandil tablets. Coronary angiography will be performed before treatment, the severity and frequency of chest pain will be evaluated before and after 9 months of treatment, and homocysteine and von Willebrand factor levels will be measured. Electrocardiography, echocardiography, dynamic electrocardiography, a treadmill exercise test, and CMR will be performed. Sex, age, body mass index, complications, smoking, and family history will also be recorded. The SPSS19.0 statistical software package will be used to analyze the data. The measurements will be expressed as the mean ± standard deviation. Measurement data will be compared between the groups using Student's t-test. A relative number description will be used for the counting data, and the chi-squaretest will be used to compare the groups. A multivariate logistic regression analysis will be performed A P-value < .05 will be considered significant.The direct indices (CMR and coronary angiographic TIMI blood flow grade) may improve after adding diltiazem or nicorandil during routine drug treatments (such as aspirin, statins, and nitrates) in PMVA patients, and indirect indices (homocysteine and von Willebrand factor levels) may be reduced., Trial Registration: Chinese Clinical Trial Registry (http://www.chictr.org.cn/showprojen.aspx?proj=41894), No. CHiCTR1900025319, Registered on August 23, 2019; pre initiation., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Microvascular angina has become a clinical and frequent cardiovascular disease in recent years, which is complicated and there is no clear treatment. Today, Western medicine still deals with microvascular angina with standardized treatment based on the stable angina. Firstly, it is to control the risk factors of atherosclerosis, and the second is to reduce the oxygen consumption of the patient's heart muscle. In the previous randomized controlled clinical trials, it has shown that nicorandil can improve the symptoms of angina for the treatment of microvascular angina, but there is a lack of high-quality randomized controlled trials on the clinical effectiveness and safety of nicorandil in the treatment of microvascular angina, and the lack of evaluation of its effectiveness and safety. Therefore, this paper aims to understand whether nicorandil can further improve the prognosis of patients with microvascular angina and the safety of the drug through the method of systematic evaluation., Methods: Retrieval of relevant network electronic databases by computer: SinoMed, CNKI, WanFang Data, VIP, PubMed, EMbase and The Cochrane Library, the retrieval time is from the establishment of each database to December 2017, to collect randomized controlled studies of nicorandil in the treatment of microvascular angina. At the same time, it is supplemented by manual search of the included literature references, as far as possible to increase the included literature imformation. Two researchers independently browse the topics and abstracts, and select, find, read the full text of the relevant literature, and screen the literature according to the criteria for inclusion and exclusion established in advance, then extract the data, and cross-check, and resolve the differences through multi-person discussion. Data analysis of collected information is performed by using RevMan 5.3 software., Results: The data of the included literature are statistically analyzed by meta-analysis, and the key outcome indicators are used to determine whether nicorandil can further improve the prognosis of patients with microvascular angina and the safety of the drug., Conclusion: Through the method of evidence-based medicine, this study finds the existing problems and defects in the current research, which will provide high-quality evidence-based medical evidence for nicorandil's treatment of microvascular angina, and it help the clinical treatment and further research., Osf Registration Number: DOI 10.17605/OSF.IO/DSQG9., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Blood-activating drugs (BADs) are widely used to treat microvascular angina in China. This study aims to summarize relevant evidence from randomized controlled trials (RCTs) to assess the efficacy and safety of BADs in the treatment of microvascular angina., Methods: We searched for relevant studies before June 2019 from seven databases. Twenty-four studies were included of 1903 patients with microvascular angina. All studies compared the use of traditional Chinese medicine for activating blood circulation (BADs) and Western medicine (WM) with the use of Western medicine alone., Results: In all, 15 trials reported a significant effect of BADs on improving clinical symptoms compared with the control treatment (P < .00001), and 8 trials reported significant effects of BADs on reducing the frequency of angina pectoris attacks compared with Western medicine treatment (P < .00001). The pooled results also demonstrated that BADs provided a significant benefit in reducing the dosage of nitroglycerin required (P = .02), the maximum range of ST-segment depression (P = .003) and the descending degree of the ST-T segment of ECG (P = .0002); prolonging the total time of treadmill exercise (P < .00001) and the time of ST-segment depression of 1 mm (P = .002); enhancing the total effective rate of Traditional Chinese Medicine (TCM) syndromes (P < .00001); improving endothelial function (P < .00001); and reducing the levels of high-sensitivity C-reactive protein (hs-CRP) (P < .00001). BAD treatment showed no statistically significant effect on the levels of TNF-a (P = .8) or IL-6 (P = .13). No severe adverse events were reported., Conclusion: This meta-analysis shows that BADs are effective for the treatment of microvascular angina. Although concerns regarding selective bias and low methodological quality were raised, our findings suggest that BADs are beneficial for patients with microvascular angina and should be given priority for future clinical studies., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Microvascular angina is caused by cardiac small vessel disease, and dysregulation of the endothelin system is implicated. The minor G allele of the non-coding single nucleotide polymorphism (SNP) rs9349379 enhances expression of the endothelin 1 gene in human vascular cells, increasing circulating concentrations of ET-1. The prevalence of this allele is higher in patients with ischemic heart disease. Zibotentan is a potent, selective inhibitor of the ET A receptor. We have identified zibotentan as a potential disease-modifying therapy for patients with microvascular angina. METHODS: We will assess the efficacy and safety of adjunctive treatment with oral zibotentan (10 mg daily) in patients with microvascular angina and assess whether rs9349379 (minor G allele; population prevalence ~36%) acts as a theragnostic biomarker of the response to treatment with zibotentan. The PRIZE trial is a prospective, randomized, double-blind, placebo-controlled, sequential cross-over trial. The study population will be enriched to ensure a G-allele frequency of 50% for the rs9349379 SNP. The participants will receive a single-blind placebo run-in followed by treatment with either 10 mg of zibotentan daily for 12 weeks then placebo for 12 weeks, or vice versa, in random order. The primary outcome is treadmill exercise duration using the Bruce protocol. The primary analysis will assess the within-subject difference in exercise duration following treatment with zibotentan versus placebo. CONCLUSION: PRIZE invokes precision medicine in microvascular angina. Should our hypotheses be confirmed, this developmental trial will inform the rationale and design for undertaking a larger multicenter trial., Competing Interests: Disclosures CB is employed by the University of Glasgow which holds consultancy and research agreements with Abbott Vascular, AstraZeneca, Boehringer Ingelheim, Coroventis, GSK, HeartFlow, Menarini, Neovasc, Novartis, and Siemens Healthcare. APD is a member of the scientific advisory board of ENB Therapeutics. AW is a full-time employee of AstraZeneca. The remaining authors have no disclosures., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The prevalence of cardiac syndrome X (CSX) is considerable. Some patients show recurrent angina attacks and have a poor prognosis. However, the knowledge of CSX pathophysiological mechanism is still limited, and the treatment fails to achieve a satisfactory suppression of symptoms. Nicorandil has a beneficial effect on improving coronary microvascular dysfunction (CMD). This study aims to evaluate the clinical effects and safety of nicorandil on CSX patients., Methods: The Cochrane Library, Pubmed, EMBASE, ClinicalTrials.gov and 4 Chinese databases were searched to identify relevant studies. The Cochrane "Risk of bias" tool was used to assess the methodological quality of eligible studies. Meta-analysis was performed by RevMan 5.3 software. The Eggers test and meta-regression were performed by software Stata 14.0. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach., Results: Twenty four randomized controlled trials (RCTs) involving 2323 patients were included. Most of the included studies were classified as having an unclear risk of bias because of poor reported methodology. The main outcomes are angina symptoms improvement, resting electrocardiogram (ECG) improvement, treadmill test result, and endothelial function. Meta-analysis showed that nicorandil had some benefit on improving angina symptoms (RR 1.24, 95% CI 1.19 to 1.29, I = 20%, P < .00001), resting ECG (RR = 1.24, 95% IC: 1.15 to 1.33, I = 0%, P < .00001), and prolonged the time to 1 mm ST-segment depression in treadmill test result (WMD = 38.41, 95% IC: 18.46 to 58.36, I = 0%, P = .0002). Besides nicorandil could reduce the level of endothelin-1 (ET-1) (SMD = -2.22, 95% IC: -2.61 to -1.83, I = 77%, P < .00001) and increase the level of nitric oxide (NO) (WMD = 27.45, 95% IC: 125.65 to 29.24, I = 81%, P < .00001). No serious adverse drug event was reported. The Eggers test showed that significant statistical publication bias was detected (Eggers test P = .000). The quality of evidence ranged from very low to low., Conclusions: Nicorandil shows the potential of improving angina symptoms, ECG, and endothelial dysfunction in patients with CSX. However, there is insufficient evidence for the clinical benefits of nicorandil due to the very low-quality evidence.

Background: Ranolazine is approved in the United States and Europe for chronic stable angina. Microvascular angina (MVA) is defined as angina with no obstructive coronary artery disease., Study Question: Our objective was to assess the effectiveness of ranolazine at improving angina scores and quality of life in a Canadian cohort with severe refractory angina due to MVA., Study Design: We administered questionnaires to 31 patients at baseline and after at least 6 weeks of ranolazine treatment., Measures and Outcomes: Validated, clinically significant changes for each Seattle Angina Questionnaire domain and the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form were obtained from the literature. Score changes between baseline and postranolazine use were analyzed using sign test., Results: Patients were mostly female (27 of 31 patients) with a median age of 57 years. After initiation of ranolazine treatment, patients experienced improvements in Quality of Life Enjoyment and Satisfaction Questionnaire Short Form scores (80.6%; P < 0.01) and in 3 of the 4 domains of the Seattle Angina Questionnaire (physical limitation: 73.3%; P = 0.02; treatment satisfaction: 80.6%; P < 0.01; and disease perception: 77.4%; P < 0.01). Patients were less likely to have interactions with the health care system after ranolazine treatment as compared with before (35.5% vs. 93.5%; P < 0.01)., Conclusions: Ranolazine significantly improves symptom control and quality of life in patients with MVA and severe refractory angina and reduces their interaction with the health care system. Given the potentially debilitating effect of chronic angina in MVA, ranolazine may be an effective treatment option.

Introduction: Many women undergoing coronary angiography for chest pain have no or only minimal coronary artery disease (CAD). However, despite the lack of obstructive CAD, they still have an increased risk of major adverse cardiovascular events. Pleiotropic effects of statins may influence microvascular function, but if statins improve microvascular function in unselected chest pain patients is not well studied. This study assessed microvascular function by using the thermodilution-derived test "the index of microvascular resistance" (IMR) with the aim of determining the (i) IMR level in women with chest pain and non-obstructive CAD and if (ii) IMR is modified by high-dose statin treatment in these patients. Additional objectives were to identify the influence of statins on the health status as assessed with generic health questionnaires and on biomarkers of endothelial activation., Materials and Methods: The study was a randomized, double-blind, single-center trial comparing 6 months of rosuvastatin treatment with placebo. In total, 66 women without obstructive CAD were included. Mean age was 52.7 years and 55.5 years in the placebo and rosuvastatin group, respectively. Microvascular function was assessed using the IMR, health status was assessed using the SF-36 and EQ-5D questionnaires, and biochemical values were assessed at baseline and 6 months later., Results and Conclusions: In the placebo group IMR was 14.6 (SD 5.7) at baseline and 14.4 (SD 6.5) at follow-up. In the rosuvastatin group IMR was 16.5 (SD 7.5) at baseline and 14.2 (SD 5.8) at follow-up. IMR did not differ significantly between the two study groups at follow-up controlled for preintervention values. C-reactive protein (CRP) was comparable between the groups at baseline, while at follow-up CRP was significantly lower in the rosuvastatin group compared to placebo [0.6 (±0.5) mg/L vs. 2.6 (±3.0) mg/L; p = 0.002]. Whereas rosuvastatin treatment for 6 months attenuated CRP levels, it did not improve microvascular function as assessed by IMR (Clinical Trials.gov NCT01582165, EUDRACT 2011-002630-39.3tcAZ)., (© 2019 Wiley Periodicals, Inc.)

Objective: Studies have suggested a beneficial effect of angiotensin-converting enzyme (ACE) inhibition. To explore whether the ACE inhibitor ramipril has a direct effect on the microvasculature beyond the blood pressure (BP) lowering effect, we investigated whether ramipril improved coronary microvascular function in normotensive women with coronary microvascular dysfunction (CMD)., Methods: We included 63 normotensive women with angina, no epicardial stenosis>50% and CMD defined as a coronary flow velocity reserve (CFVR)<2.2 assessed by adenosine stress-echocardiography in a randomized double-blinded, superiority trial with 1:1 allocation to placebo or ramipril (maximum dose 10 mg depending on blood pressure) for 24±6 weeks. Primary outcome was CFVR. Secondary outcomes were left ventricular systolic and diastolic function and symptoms evaluated by Seattle Angina Questionnaire (clinicaltrials.gov, NCT02525081)., Results: Follow-up was available on 55 patients. BP remained unchanged during treatment in both groups. CFVR improved in both the ramipril (p = 0.004) and placebo group (p = 0.026) with no difference between groups (p = 0.63). Symptoms improved in both groups with no significant between-group differences. No changes were detected in parameters of systolic and diastolic function. No serious adverse reactions were reported., Conclusions: In normotensive women with angina and CMD, treatment with ramipril had no significant effect on CFVR or symptoms compared with placebo. The effect of ACE inhibition previously reported may be mediated by blood pressure reduction., Competing Interests: The authors have declared that no competing interests exist.

The role of endothelial dysfunction and oxidative stress in the pathogenesis of cardiac syndrome X has recently been recognized. Allopurinol has previously been shown to improve endothelial dysfunction, reduce oxidative stress burden, and improve myocardial efficiency. In this "proof of concept" study, we investigated the effect of allopurinol on exercise capacity, coronary and peripheral endothelial function, and serum B-type natriuretic peptide (BNP: a marker of cardiac function and myocardial ischemia) in patients with cardiac syndrome X., Methods and Results: This study was a randomized, double-blind, placebo-control crossover trial. Nineteen patients (mean age 59 ± 10 years, 11 women and 8 men) with cardiac syndrome X were randomized to a 6-week treatment with either allopurinol (600 mg/day) or placebo. After 4 weeks of washout period, they were crossed over to the other arm. Outcomes measured at baseline and after treatment were maximum exercise time (ET) derived from Bruce protocol exercise treadmill test, serum BNP measurement, coronary flow reserve (CFR) as assessed by measuring the response of flow velocity in the left anterior descending artery to adenosine, and flow-mediated vasodilatation of the brachial artery (FMD). Allopurinol significantly reduced serum uric acid levels when compared with placebo (-48 ± 24% vs 1.9 ± 11%, P < .001). There was no significant difference in maximum ET, CFR, and FMD between allopurinol and placebo. However, there was a trend that allopurinol reduced serum BNP when compared to placebo (-8% [interquartile range -22% to 65%] vs 44% [interquartile range -18% to 140%]; P = .07)., Conclusion: In patients with cardiac syndrome X, high-dose allopurinol did not improve exercise capacity, and coronary or peripheral endothelial function., (© 2017 John Wiley & Sons Ltd.)

Bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF)-A, is currently used to treat patients with ovarian or colon cancer. While several cardiovascular toxicities related to bevacizumab-containing regimens have been reported, the effect of bevacizumab on the coronary microcirculation has not been fully elucidated. Here we report a case of 54-year-old female patient who developed microvascular angina after a series of bevacizumab-containing chemotherapeutic regimen. The discontinuation of bevacizumab and nicorandil administration was effective in alleviating her chest discomfort and the ischemic changes on her ECG. This highlights the possibility that coronary microvascular angina can be induced in patients treated with bevacizumab-containing chemotherapy. It should also be noted that nicorandil can be effective in managing microvascular angina.

Stable angina is the most frequent manifestation of ischemic heart disease (IHD) in women as compared to men (65% versus 37%). IHD in women has more favorable clinical course because myocardial infarction develops twice as rare as in men. Coronary angiography of angina patients demonstrates normal coronary arteries more frequently in women than in men. Microvascular angina (MVA) is found to be a rather common form of stable IHD as that particular diagnosis is made later in 20-30% of patients who previously underwent coronary angiography. The disease occurs three times as often in women than in men irrespective of age. Most of these patients are in their perimenopausal age - 45-60 years. The major role in MVA development is considered to be decreased coronary flow reserve resulting from evident endothelial dysfunction of minor coronary arteries. MVA is characterized by great variability of its course and low response to conventional antianginal therapy, particularly in women. In view of this the problem of antianginal drugs which can be used in addition to standard therapy remains to be solved. Ranolazine is a new original antianginal medicine which improves left ventricular diastolic filling by selective inhibition of late Na-flow leading to more effective coronary vessels filling in diastole. The article presents the results of multicenter studies of ranolazine as to its effect on diastolic and systolic functions of the left ventricle, clinical manifestations of angina and heart failure as well as the data on antiarrhythmic action of ranolazine. This article describes the case of successful use of ranolazine as an additional anti-anginal medicine in the 46- year-old female patient diagnosed with microvascular angina. Before taking ranolazine, on the background of conventional treatment of coronary heart disease, the patient developed stable angina and persistent left bundle branch block, atrial fibrillation. After receiving ranolazine, 1000 mg per day for a month, Holter ECG monitoring showed not only significantly reduced number of strokes, the left bundle branch block and atrial fibrillation dissappeared as well. The results indicate a high efficiency of ranolazine as an antianginal, anti-ischemic and anti-arrythmic medicine.

Microvascular angina (MVA) is rather a common form of stable ischemic coronary disease (CAD) as that such diagnosis is made in 20-30% of patients who previously underwent coronary angiography. The disease occurs three times more frequently in women than in men irrespective of age. Most of these patients are 45-60 years old. According to available data, the long-term outcome in patients with MVA is comparable with that in general population. MVA characterizes great variability of its course and low response to conventional antianginal therapy. However, patients with MVA experience chest pain, which in most cases tend to strengthen and increase the number of pain episodes, significantly deteriorating the quality of life of these patients. In view of this, the problem of antianginal drugs which can be used in addition to standard therapy remains to be solved. The major role in MVA development plays the decreased coronary flow reserve resulting from evident endothelial dysfunction of small coronary arteries. Ranolazine is a new original antianginal drug which improves left ventricular diastolic filling by selective inhibition of late sodium current leading to more effective coronary vessel filling in diastole. The article presents the case of the successful administration of ranolazine in a woman with MVA and persistent atrial fibrillation.

Background Various pathophysiological mechanisms such as microvascular and endothelial dysfunction, small vessel disease, diffuse atherosclerosis, and inflammation have been held responsible in the etiology of coronary slow flow. It is also thought to be a reflection of a systemic slow-flow phenomenon in the coronary arterial tree. Case Report A 44-year-old man presented with chest pain causing fatigue, together with blurred vision for the last 2 years, which disappeared after resting. He had used corticosteroid therapy for facial paralysis 1 month ago. Coronary slow flow was detected in all 3 major coronary arteries on coronary angiography. TIMI measurements for the left anterior descending artery, circumflex, and right coronary artery were 64, 72, and 55, respectively. In fundus fluorescein angiography, retinal vascularity was normal, the arm-to-retina circulation time was 21.8 s, and the arteriovenous transit time was 4.3 s. In the early arteriovenous phase, choroidal filling was long, with physiological patchy type. Diltiazem 90 mg/day and acetylsalicylic acid 100 mg/day were given. His chest pain and visual symptoms disappeared after medical treatment. Conclusions Physicians should be aware that glucocorticoids might cause an increase in the symptoms of coronary slow flow and some circulation problems, which might lead to systematic symptoms.

In women receiving evaluation for suspected ischemic symptoms, a "normal" diagnosis is five times more common than it is in men. These women are often labeled as having cardiac syndrome X, also known as microvascular angina (MVA). MVA is defined as angina pectoris caused by abnormalities of the small coronary arteries, and is characterized by effort chest pain and evidence of myocardial ischemia with a non-invasive stress test, although the coronary arteries can appear normal or near normal by angiography. MVA patients are often neglected due to the assumption of a good prognosis. However, MVA has important prognostic implications and a proper diagnosis is necessary in order to relieve the patients' symptoms and improve clinical outcomes. The coronary microvasculature cannot be directly imaged using coronary angiography, due to the small diameter of the vessels; therefore, the coronary microvascular must be assessed functionally. Treatment of MVA initially includes standard anti-ischemic drugs (β-blockers, calcium antagonists, and nitrates), although control of symptoms is often insufficient. In this review, we discuss the pathophysiology, diagnosis, and treatment of MVA.

Ranolazine is a novel well-tolerated anti-ischemic drug, which selectively inhibits late sodium current and exerts metabolic properties without any hemodynamic effect. Ranolazine has been approved as a second-line medical treatment for symptomatic stable coronary artery disease. Primary microvascular angina (MVA) is suspected when angina symptoms occur in patients with demonstrated myocardial ischemia, absence of myocardial disease and normal coronary artery angiography. Recent clinical data suggest that MVA represents a complex entity, which has been increasingly recognized as a significant cause of morbidity. High variability and low response to traditional anti-anginal treatment characterize primary MVA. Despite the fact that clinical and preclinical evidence provides information regarding ranolazine usefulness in primary MVA management, only three recent small randomized trials have investigated this issue. By selecting peer-reviewed literature in Pubmed and Cochrane Library, this review provides an overview on ranolazine pharmacology and efficacy, focusing on recent evidence suggesting its usefulness in management of primary MVA., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objectives: To assess the effects of isosorbide-5-mononitrate (ISMN) in patients with microvascular angina (MVA)., Methods: We randomized 20 MVA patients, treated with a β-blocker or a calcium antagonist, to 60 mg slow-release ISMN (halved to 30 mg if not tolerated) or placebo once a day for 4 weeks; the patients were then switched to the other treatment for another 4 weeks. Their clinical status was assessed with the Seattle Angina Questionnaire (SAQ) and the EuroQoL score for quality of life. The exercise stress test (EST), coronary blood flow (CBF) response to nitrate and the cold pressor test (CPT), brachial artery flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD) were also assessed., Results: Nine patients (45%) did not complete the ISMN phase due to side effects; 2 patients refused a follow-up. Nine patients completed the study. The SAQ and EuroQoL scores were significantly better with ISMN than with placebo, although the differences were small. No differences were found between the treatments in the EST results, CBF response to nitroglycerin (p = 0.55) and the CPT (p = 0.54), FMD (p = 0.26) and NMD (p = 0.35)., Conclusions: In this study, a high proportion of MVA patients showed an intolerance to ISMN; in those tolerating the drug, significant effects on their angina status were observed, but the benefit appeared to be modest and independent of effects on coronary microvascular function., (© 2015 S. Karger AG, Basel.)

Coronary microvascular dysfunction (CMD) has been increasingly recognized as an important cardiac condition that can cause signs and symptoms of myocardial ischaemia in various clinical settings. The dysfunction is located on the level of the coronary microcirculation with a vessel diameter of <500 µm and can be characterized by structural as well as functional vascular alterations. The underlying mechanisms are diverse, frequently overlapping and still incompletely understood. A common and often underdiagnosed clinical manifestation of CMD is in patients who have angina symptoms yet no obstructive epicardial coronary artery disease nor myocardial disease. There are still very few data regarding the effectiveness of pharmacological treatments for CMD. The current ESC guidelines on the management of stable coronary artery disease suggest using aspirin and statins as well as β-blockers and/or calcium-channel blockers for the treatment of CMD. This review gives an overview of the currently available pharmacological concepts for the treatment of coronary microvascular dysfunction in patients without epicardial coronary artery disease and without myocardial disease., (Published on behalf of the European Society of Cardiology. All rights reserved. ©The Author 2015. For permissions please email: journals.permissions@oup.com.)

We report an extremely rare case of thebesian vein microfistulae to both ventricles. A 65-year-old woman, with no major cardiovascular risk factors, presented with multiple episodes of chest pain. The resting electrocardiogram showed T-wave inversion in leads V(1) -V(4). A Dipyridamole myocardial perfusion imaging revealed large and severe inferior defect with complete reversibility. Coronary angiography showed no coronary artery disease. On contrast injection, an exaggerated capillary blush from the distal portions of the right and left coronary artery systems was seen in both ventricles, mimicking the image of ventriculography. This appearance suggests prominent thebesian vessels, a congenital communication between the coronaries and the two ventricles. The clinical relevance of these myocardial sinusoids is still not well established. Although the majority of these fistulas are small in size and with no clinical significance, they can rarely present with chest pain, cardiac arrhythmia, syncope, myocardial infarction, and/or pulmonary hypertension. These fistulae when excessive can cause significant shunting of blood to the ventricles, leading to coronary steal phenomena and ischemia. This phenomenon is facilitated by the low resistance in these microfistulae as opposed to the higher resistance in the normal coronary circulation. Due to the diffuse nature of these microfistulae, neither surgery nor transcatheter therapy is feasible. This condition can only be managed medically; however, it should be noted that vasodilator agents, such as nitrates, can worsen the coronary steal phenomenon. Our patient was treated with ranolazine with significant improvement in her symptoms, which was not reported previously. Multiple coronary artery microfistulae could be an underestimated condition of angina in patient with normal coronaries., (© 2013 Wiley Periodicals, Inc.)

Microvascular angina (MVA) is defined as angina pectoris caused by abnormalities of small coronary arteries. In its most typical presentation, MVA is characterized by angina attacks mainly caused by effort, evidence of myocardial ischemia on non-invasive stress tests, but normal coronary arteries at angiography. Patients with stable MVA have excellent long-term prognoses, but often present with persistent and/or worsening of angina symptoms. Treatment of MVA is initially based on standard anti-ischemic drugs (beta-blockers, calcium antagonists, and nitrates), but control of symptoms is often insufficient. In these cases, several additional drugs, with different potential anti-ischemic effects, have been proposed, including ranolazine, ivabradine, angiotensin-converting enzyme (ACE) inhibitors, xanthine derivatives, nicorandil, statins, alpha-blockers and, in perimenopausal women, estrogens. In patients with 'refractory MVA', some further alternative therapies (e.g., spinal cord stimulation, pain-inhibiting substances such as imipramine, rehabilitation programs) have shown favorable results.

Objectives: Statins and calcium channel blockers have been proven beneficial toward improvement of endothelial function. The aim of this study was to compare the effect of combination therapy of statin and calcium channel blocker with solo treatment in patients with cardiac syndrome X., Methods and Results: Sixty-eight patients with cardiac syndrome X were divided randomly into three groups: fluvastatin (40 mg/day, n=23), diltiazem (90 mg/day, n=22), and combination of fluvastatin (40 mg/day) and diltiazem (90 mg/day, n=23). At the end of 90 days, the coronary flow reserve was improved in the three groups (fluvastatin-treated group: 23.2%; diltiazem-treated group: 12.4%; fluvastatin+diltiazem-treated group: 29.1%, all P<0.05). The time to 1 mm ST segment depression increased significantly in the fluvastatin-treated group (from 241±97 to 410±140 s, P<0.05), the diltiazem-treated group (from 258±91 to 392±124 s, P<0.05), and the fluvastatin+diltiazem-treated group (from 250±104 to 446±164 s, P<0.05). The improvement in coronary flow reserve and prolonged time to 1 mm ST segment depression in the combination treatment group were more remarkable than in those who received monotherapy. Combination therapy also induced a significant increase (35.6%, P<0.05) in nitric oxide and an apparent reduction (48.7%, P<0.05) in endothelin-1., Conclusion: Combination treatment with fluvastatin and diltiazem is more effective on endothelial function and exercise tolerance than solo treatment in patients with cardiac syndrome X. The benefits of these drugs may be related to the elevation of nitric oxide and reduction of endothelin-1.

Objectives: The spectrum of patients with 'angina and normal coronary arteries' ranges from severe vasospasm to atypical chest pain. Among those with typical angina, however, little is known about similarities in the clinical profile and circadian presentation between typical nonvasospastic angina and normal coronary arteries (tANCA) and vasospastic angina (VA)., Materials and Methods: Clinical, ECG, and angiographic features as well as the circadian characteristics of angina were compared between 384 tANCA and 273 VA patients. Follow-up events were also analyzed., Results: tANCA patients had greater female predominance (61 vs. 18%), higher incidence of dyspnea to moderate exertion (49 vs. 12%), lower incidence of tobacco smoking (25 vs. 67%), but a similar low rate of diabetes (8.9 vs. 4.4%). In both groups, however, dyspnea and smoking were associated with female and male sex, respectively. tANCA patients showed lower but non-negligible frequency of early morning (25 vs. 67%) and evening angina (37 vs. 54%), similar rate of nocturnal angina (47 vs. 50%), and higher rate of emotional angina (49 vs. 31%). Moreover, a high proportion of patients gained pain relief with nitroglycerin (97% in VA, 246/253, and 76% in tANCA, 231/306). At 140 months, frequent angina (>10 episodes/year) was rare (VA: 7.1% vs. tANCA: 6.3%) as was the rate of cardiac death/myocardial infarction (7.3 vs. 6.0%, P=0.524)., Conclusion: Despite differences in the clinical profile between VA and tANCA patients, there is notable sharing of circadian presentation of rest angina, response to nitroglycerin, and long-term presence and frequency of angina that suggests more similarities in underlying mechanisms than heretofore suspected.

Objective: We conducted a clinical trial to examine the effect of ω-3 fatty acids in patients with cardiac syndrome X (CSX). We aimed to evaluate the potential impact of ω-3 fatty acids on endothelial function, oxidative stress, and symptom relief in the CSX., Methods and Results: Eighteen patients with CSX were enrolled according to a double-blind, randomized, placebo-controlled design. Patients were randomized to ω-3 fatty acids (1440 mg/day, n=8) or placebo (n=10) for 4 months. We assessed plasma levels of malondialdehyde (MDA), endothelium-dependent vasodilatation [flow-mediated dilatation (FMD)], endothelium-independent vasodilatation [nitroglycerin-mediated dilatation (NMD)], and status of symptom [score with Seattle Angina Questionnaire (SAQ)] before and after the treatment. After 4 months, patients who were treated with ω-3 fatty acids showed significant increases in the FMD (from 47±48 to 104±23%, P<0.05) and NMD (from 51±53 to 93±35%, P<0.05) values, and significant decreases in the plasma MDA levels (4.4±0.86 to 3.35±0.33 µmol/l, P=0.012). SAQ scores were increased significantly in both groups (from 60±14 to 73±15%, P<0.05 placebo, from 67±10 to 81±9%, P<0.05 treatment group). NMD was correlated negatively with the plasma MDA levels., Conclusion: Four months of therapy with a moderate dose of ω-3 fatty acids improved the endothelial function and reduced oxidative stress in patients with CSX.

Objective: To master the syndrome patterns characteristics and explore the effective therapy methods of Traditional Chinese Medicine (TCM) for cardiac syndrome X (CSX)., Methods: The TCM syndrome characteristics were mastered and the TCM intervention programs were determined by clinical investigations for TCM syndrome patterns characteristics of CSX patients. Then, the clinical efficacy studies on TCM intervention for CSX were carried out through randomized controlled trials., Results: CSX is a clinical syndrome with the main manifestations of chest pain and chest stuffiness, and Qi stagnation, phlegm retention and blood stasis are the basic symptoms of CSX. As a result, the Qi-regulating, chest-relaxing and blood-activating therapy integrated with some Western Medicines was adopted for treatment. The effect of Qi-regulating, chest-relaxing and blood-activating therapy can reduce the frequency and degree of angina, improve the symptoms and exercise the tolerance of patients, inhibit the inflammatory response of vascular walls and protect the function of vascular endothelial cells, which is better than that of the simple and conventional Western Medicine alone., Conclusion: A good effect was achieved in the integration of Chinese and Western Medicines for CSX. The therapy is worthy to be applied further in clinical practice. On the other hand, more long-term and randomised controlled studies with large samples are still required to further determine the clinical efficacy and safety of the therapy.

Background: Treatment of cardiac syndrome X with unknown pathological mechanism remains a big challenge for clinicians. Complementary and alternative medicine may bring a new choice for its management. The aim of this study is to evaluate the clinical effects of traditional Chinese medicine on cardiac syndrome X patients., Methods: We systematically searched databases such as Cochrane CENTRAL, PubMed, EMBASE, CBM, Chinese National Knowledge Infrastructure (CNKI), WanFang and VIP, and handsearched relevant journals to identify randomized controlled trials. Following the steps of systematic review recommended by the Cochrane group, we assessed the quality of included studies, extracted valid data and undertook meta-analysis., Results: Twenty one moderate-to low-quality randomized controlled trials involving 1143 patients were included. The results showed that traditional Chinese medicine could improve angina [OR=1.34, 95% CI: 1.2 to 1.50], electrocardiogram (ECG), endothelin-1 (ET-1) levels, prolong exercise duration in treadmill tests, and reduce angina frequency per week compared with routine treatment. No other side effect was reported except two cases of stomach pain., Conclusion: Compared with conventional treatment, traditional Chinese medicine shows the potential of optimizing symptomatic outcomes and improving ECG and exercise duration. The efficacy of TCM may find explanation in its pharmacological activity of adjusting the endothelial function. TCM, as a kind of alternative and complementary medicine, may provide another choice for CSX patients.

Several studies in the last years have shown that a dysfunction of coronary microcirculation may be responsible for abnormalities in coronary blood flow and some clinical pictures. Coronary microvascular dysfunction, in absence of other coronary artery abnormalities, can cause anginal symptoms, resulting in a condition named microvascular angina (MVA). MVA can occur in a chronic form, predominantly related to effort (stable MVA), more frequently referred as cardiac syndrome X, or in an acute form, most frequently ensuing at rest, which simulates an acute coronary syndrome (unstable MVA). The main abnormalities characterizing these two forms of MVA consist of an impaired vasodilation and an increased vasoconstriction of small resistive coronary arteries, respectively. The mechanisms responsible for stable MVA are still unclear, but seem to include, together with the known traditional cardiovascular risk factors, an abnormally increased cardiac adrenergic activity. The prognosis of stable MVA is good, but some patients have progressive worsening of symptoms. Clinical outcome of patients with unstable MVA is substantially unknown, as there are no specific studies about this population. Treatment of stable MVA includes traditional anti-ischemic drugs as first step; in case of persisting symptoms several other drugs have been proposed, including xanthine derivatives, ACE-inhibitors, statins and, in women, estrogens. Severe forms of intense constriction (or spasm) of small coronary arteries may cause transmural myocardial ischemia, as the microvascular form of variant angina and the tako-tsubo syndrome.

Objectives: We conducted a pilot study for a large definitive clinical trial evaluating the impact of ranolazine in women with angina, evidence of myocardial ischemia, and no obstructive coronary artery disease (CAD)., Background: Women with angina, evidence of myocardial ischemia, but no obstructive CAD frequently have microvascular coronary dysfunction. The impact of ranolazine in this patient group is unknown., Methods: A pilot randomized, double-blind, placebo-controlled, crossover trial was conducted in 20 women with angina, no obstructive CAD, and ≥ 10% ischemic myocardium on adenosine stress cardiac magnetic resonance (CMR) imaging. Participants were assigned to ranolazine or placebo for 4 weeks separated by a 2-week washout. The Seattle Angina Questionnaire and CMR were evaluated after each treatment. Invasive coronary flow reserve (CFR) was available in patients who underwent clinically indicated coronary reactivity testing. CMR data analysis included the percentage of ischemic myocardium and quantitative myocardial perfusion reserve index (MPRI)., Results: The mean age of subjects was 57 ± 11 years. Compared with placebo, patients on ranolazine had significantly higher (better) Seattle Angina Questionnaire scores, including physical functioning (p = 0.046), angina stability (p = 0.008), and quality of life (p = 0.021). There was a trend toward a higher (better) CMR mid-ventricular MPRI (2.4 [2.0 minimum, 2.8 maximum] vs. 2.1 [1.7 minimum, 2.5 maximum], p = 0.074) on ranolazine. Among women with coronary reactivity testing (n = 13), those with CFR ≤ 3.0 had a significantly improved MPRI on ranolazine versus placebo compared to women with CFR > 3.0 (Δ in MPRI 0.48 vs. -0.82, p = 0.04)., Conclusions: In women with angina, evidence of ischemia, and no obstructive CAD, this pilot randomized, controlled trial revealed that ranolazine improves angina. Myocardial ischemia may also improve, particularly among women with low CFR. These data document approach feasibility and provide outcome variability estimates for planning a definitive large clinical trial to evaluate the role of ranolazine in women with microvascular coronary dysfunction. (Microvascular Coronary Disease In Women: Impact Of Ranolazine; NCT00570089)., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Coronary microvascular dysfunction has been reported along with myocardial viral infection. Whether intramural coronary vessels infection plays a role in patients with cardiac syndrome X (CSX) is unknown., Methods: Thirteen consecutive patients (four men, nine women, mean age 51±10.5 years) with drug-resistant CSX underwent left ventricular endomyocardial biopsy. Myocardial tissue was examined for histology, immunohistochemistry and for the presence of cardiotropic viruses by PCR analysis. In the presence of a viral infection on the whole tissue, laser microdissection was performed to analyse the viral genome selectively in intramural vessels and cardiomyocytes. Controls were surgical cardiac biopsies from patients with chronic stable angina and from patients with mitral stenosis and normal cardiac function (normal controls)., Results: Histology showed hypertrophy and degeneration of cardiomyocytes with interstitial and replacement fibrosis in all CSX, while focal lymphocytic myocarditis was additionally recognised in three patients. No vasculitis was observed. Viral genomes were detected in nine of 13 CSX (Epstein-Barr virus in four, adenovirus in three, human herpes virus (HHV) 6 in one, Epstein-Barr adenovirus co-infection in one). Laser microdissection showed that Epstein-Barr and adenovirus localised both in cardiomyocytes and intramural vessels, while HHV-6 infection was confined to the vessel wall., Conclusions: Viral genomes can be detected in intramural vessels of up to 69% of drug-resistant CSX. Coronary small vessels infection represents an alternative pathophysiological mechanism of this syndrome and can explain the poor response to anti-ischaemic drugs.

Cardiac syndrome X (CSX) is defined as a typical anginal-like chest pain with a transient ischemic electrocardiogram, but without abnormal coronary angiography. It is usually accepted that endothelial dysfunction, inflammation, oxidative stress and estrogen deficiency are the main reasons of CSX. There are some methods to treat CSX including statins, b blocker, angiotensin converting enzyme inhibitors, nitrates, estrogen, and so on. The estrogen replacement therapy (ERT), in particular, has been reported by many researchers to significantly reduce the frequency of chest pain after administration of estrogen, which has been explained as estrogen acting on its receptor to improve the endothelial function. However, it has been suggested that ERT must not be used for coronary heart disease due to its adverse effects. However, some selective estrogen receptor modulators (SERMs) can inhibit inflammatory response as well as oxidative stress, and improve the endothelial function, to reduce the occurrence of chest pain. Here, we hypothesize that SERMs may be the beneficial selection for patients with CSX.

Endothelial dysfunction is major pathophysiologic mechanism in cardiac syndrome X (CSX), which causes a decrease in plasma nitrite oxide (NO) levels. It was demonstrated that nebivolol improves endothelial function and increases NO release. Despite this pathophysiologic relation, the effect of nebivolol therapy on endothelial function in patients with CSX is unknown. The aim of this study is to evaluate the effect of nebivolol on patients in CSX. Thirty-eight patients who were diagnosed with CSX were prospectively enrolled in the study. The treatment group consisted of 20 patients and the control group consisted of 18 patients. An oral 5-mg dose of nebivolol was given daily and maintained for 4 weeks in the treatment group. Ultrasonographic parameters (brachial artery flow-mediated dilatation [FMD], brachial artery lumen diameters) and inflammatory markers (high-sensitivity C-reactive protein [hsCRP], von Willebrand factor [vWf], and fibrinogen) were measured at baseline and end of the 4 weeks. Brachial baseline lumen diameter, brachial lumen diameter after reactive hyperemia, and FMD were 4.61 +/- 0.49 mm, 4.87 +/- 0.53 mm, and 5.6% +/- 2.3% at baseline. After the nebivolol therapy, there was a significant increase in both brachial artery baseline lumen diameter and lumen diameter after reactive hyperemia (P < 0.001 and P = 0.002). However, there was no significant change in FMD (5.6% +/- 2.2% vs 5.3% +/- 2.1%, P not significant). Levels of hsCRP, vWf, and fibrinogen were significantly decreased (hsCRP: 3.4 +/- 0.49 mg/dl vs 2.97 +/- 0.74 mg/dl, P = 0.001; vWf: 107 +/- 62 vs 86 +/- 58, P = 0.004; fibrinogen: 341 +/- 89 mg/dl vs 299 +/- 87 mg/ dl, P = 0.01) in the treatment group. Nebivolol therapy may have a favorable effect on endothelial function in CSX. Further studies are needed to confirm the clinical significance of nebivolol therapy in CSX.

Introduction: Development of intraventricular gradients (IVG) on exertion seldom occurs in an unselected population. We performed exercise stress echocardiography (SE) in a 23-year-old athlete with a positive treadmill ECG and normal resting echocardiogram, but without angiographically demonstrable coronary disease (cardiac syndrome X), during which he developed an IVG of 102 mmHg and systolic anterior motion (SAM) of the mitral valve. Subsequently, we performed SE in 91 patients, 44 of whom were women, mean age 51.4 +/- 12.1 years (20-72), under similar circumstances--positive treadmill testing and no angiographically demonstrable coronary disease. In 33 (36%) of these, SE disclosed IVG with a mean end-systolic peak of 86 +/- 34 mmHg (30-165), together with mitral valve SAM in 23. The 20 patients who repeated SE under beta-blocker therapy constitute the study population. Seven (35%) of them were women, mean age 50.7 +/- 13.4 years (23 to 72)., Objective: To assess the effect of beta-blockers on the occurrence of IVG and mitral valve SAM in patients with cardiac syndrome X., Methods: We repeated SE in 20 of the 33 patient that developed IVG on exertion, under beta-blocker therapy. They all underwent 2D and Doppler echocardiographic assessment before, during and after treadmill exercise., Results: Mean IVG in the 20 patients in the study population was 971 +/- 31 mmHg on the first SE assessment. In the assessment performed under beta-blocker therapy, 11 did not develop IVG, and in 9 the gradient was significantly reduced, to a mean of 46 +/- 13 mmHg. Mean heart rate at peak exercise was 161 +/- 17 bpm in the first SE assessment and 143 +/- 12 bpm under treatment with beta-blockers (p < 0.0001). Fifteen of these patients showed clinical improvement during follow-up, while no change in clinical status was seen in the other five., Conclusions: In patients with cardiac syndrome X and IVG on exertion, treatment with oral beta-blockers prevented the occurrence of IVG or significantly reduced their magnitude. These changes were associated with significant reduction in heart rate at peak exercise and with clinical improvement in 75% of the study population.

Objective: We sought to determine whether nebivolol affects coronary endothelial function and exercise induced ischemia in patients with cardiac syndrome X (CSX)., Methods: The study protocol undertaken was based on a single-blind randomized controlled prospective study. After a 2-week washout period, 38 patients with cardiac syndrome X were randomized to receive either nebivolol 5 mg daily (n=19) or metoprolol 50 mg daily (n=19) in a single- blind design for 12 weeks. The control group under study was consisted of 16 age- and gender-matched subjects with negative treadmill exercise tests. Plasma endothelial nitric oxide (NOx), L-arginine, and asymmetric dimethylarginine (ADMA) were measured in all patients at baseline and after 12 weeks of treatment. Statistical differences among groups were tested by one-way analysis of variance and unpaired samples t test for parametric; Kruskal-Wallis and Mann-Whitney U tests for non-parametric variables, respectively. A paired samples t test was used to compare continuous variables before and after drug therapy., Results: At baseline, plasma level of NOx, L-arginine, and L-arginine/ADMA ratio were lower (p<0.001 for all) in patients with CSX than in the control patients. Whereas, the plasma ADMA levels were increased in the patient group (p<0.001). After 12 weeks of drug therapy, the patients taking nebivolol had increased levels of plasma NOx , plasma L-arginine, the L-arginine/ADMA ratio and decreased levels of plasma ADMA compared to those of the patients taking metoprolol (p<0.001). In addition, exercise duration to 1-mm ST depression and total exercise duration significantly increased after treatment in the nebivolol group compared to the metoprolol group (p<0.01). In the nebivolol group, Canadian Cardiovascular Society (CCS) angina classification improved by one or more categories in 12 (70%) patients, whereas it deteriorated or remained in the same category in 5 (30%) patients. Meanwhile, in the metoprolol group, the CCS angina classification improved by one or more categories in 7 (41%), whereas it deteriorated or remained in the same category in 10 (59%) patients., Conclusion: Circulating endothelial function parameters (plasma ADMA, L-arginine, NOx levels) were impaired in patients with CSX. Nebivolol treatment was associated with better improvements in both circulating endothelial function and exercise stress test parameters than metoprolol. We believe that further studies are needed to evaluate the effects of nebivolol treatment on long-term clinical outcomes in patients with CSX.

Prinzmetal's variant angina (VA) and cardiac syndrome X (CSX) are two distinct, usually easily recognizable, forms of angina syndromes, caused by epicardial spasm, usually responsible for transient transmural myocardial ischemia at rest and by coronary microvascular dysfunction (CMVD), usually responsible for effort induced subendocardial ischemia, respectively. In this article we report clinical evidence in three patients of the simultaneous occurrence of angina episodes typical of both VA and CSX, suggesting that common pathogenetic factors may be responsible for clinical manifestations both of functional macrovascular and microvascular coronary artery abnormalities in some angina patients.

Purpose: To present information about cardiac syndrome X (CSX) including its (a) definition, (b) etiology and pathology, (c) epidemiology, (d) symptomatology, (e) diagnosis, (f) treatment, and (g) prognosis. Clinical recommendations will also be presented., Data Sources: Articles used in this review were found by searching CINAHL, Medline, the Cochrane Library, Web of Science (ISI), Academic Search Premier, and Health Source: Nursing/Academic Edition., Conclusions: The causes of CSX remain unknown; however, CSX is easy to diagnose and can be treated. Medication therapy and risk factor modification can greatly improve the quality of life by decreasing pain occurrence and lessening pain intensity., Implications for Practice: Too often, providers reassure patients of a healthy heart because of normal coronary arteries despite persistent chest pain and ST segment changes on the electrocardiogram. Chest pain, one of the primary signs and symptoms of CSX, can be reduced through common medications and interventions if the diagnosis of CSX is initiated.

Background: Free radical-mediated oxidative stress has been implicated in the etiopathogenesis of several disorders. The aim of this study was to elucidate the effect of treatment with nebivolol on the metabolic state of oxidative stress, and antioxidant status markers in patients with cardiac syndrome-X (CSX), additionally, to compare with the effect of metoprolol treatment., Methods: Thirty patients, 17 female and 13 male, with CSX were enrolled in the study. Nebivolol (5 mg/day) or metoprolol (50 mg/day) was administrated for 12 weeks. Twelve hour fasting blood samples, taken at the initiation and on the third month of therapy, were analyzed for the levels of malondialdehyde (MDA), nitrite+nitrate (NOx), and the activity of myeloperoxidase (MPO), superoxide dismutase (SOD). No patient presented additional risk factors for increased reactive oxygen species levels., Results: Compared with sixteen control participants, patients with CSX had significantly higher activity of MPO and levels of MDA, but significantly lower SOD activity and levels of NOx before treatment. After treatment, MPO activity and MDA levels were significantly reduced; SOD activity and NOx levels were significantly increased with nebivolol but remained unchanged with metoprolol., Conclusion: We have shown that patients with CSX who taken nebivolol have lower serum MPO activity, levels of MDA and higher serum SOD activity, NOx levels when compared with metoprolol treatment. Exercise stress test parameters were also ameliorated in patients who had taken nebivolol in contrast to metoprolol. Nebivolol treatment may be a novel treatment strategy in cases with CSX in the future.

Patients with persistent chest pain and no obstructive coronary artery disease are often labeled as having noncardiac pain and not offered further cardiologic testing or treatment. Diagnostic uncertainty for persistent chest pain is associated with adverse quality of life, morbidity, and health care costs. Two underdiagnosed cardiac causes for persistent chest pain include microvascular coronary disease and abnormal cardiac nociception. Microvascular coronary disease is associated with an increased risk of adverse cardiovascular events such as myocardial infarction, congestive heart failure, and sudden cardiac death, and treatment directed at improving endothelial function can improve outcomes. Abnormal cardiac nociception is also a cause for persistent chest pain caused by heightened coronary pain perception. Coronary reactivity testing allows for direct measurement of blood flow characteristics in response to vasoactive agents for the diagnoses of microvascular coronary disease and can be a useful tool to differentiate causes of chest pain. Coronary reactivity testing is an invasive method for assessing coronary vascular function, with current evidence suggesting that its associated risk is relatively low compared with the adverse prognosis associated with microvascular coronary dysfunction. Accurate diagnosis in patients with persistent chest pain and normal coronary arteries can be challenging and deserves adequate investigation in light of the associated morbidity, mortality, and health care costs.