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Aims: Coronary microvascular dysfunction (CMD) carries a poor cardiovascular prognosis and may explain angina in women without obstructive coronary artery disease (CAD). Currently, no evidence-based treatment for CMD exists. We investigated whether reducing cardiovascular risk factors improves symptoms and microvascular function in women with non-endothelial dependent CMD and no obstructive CAD., Methods: We randomized 62 women aged 40-75, with body mass index (BMI) >25 kg/m2, angina ≥monthly, and coronary flow velocity reserve (CFVR) ≤2.5 to a 24-week intervention comprising low energy diet, exercise training, and optimized treatment of hypertension, dyslipidemia and diabetes or to control. Patients were assessed before randomization and after 24 weeks. Primary outcomes were CFVR assessed by transthoracic Doppler stress-echocardiography and angina burden by Seattle Angina Questionnaire (SAQ). Secondary outcomes were exercise capacity, body composition, glycemic control, myocardial function, and anxiety and depression symptoms., Results: Fifty-six participants (90%) completed the study. Median (IQR) age was 65.2 (57.1;70.7) years, BMI was 30.1 (28.4;32.7) kg/m2. The intervention resulted in relevant improvement in angina symptoms (9-21-point increase on SAQ-scales (all p<0.01)) but had no effect on CFVR (p = 0.468). Mean (CI) weight loss was 9.6 (7.80;11.48) kg, (p<0.0001). There was a significant mean (CI) decrease in depression symptoms = 1.16 (0.22;2.12), triglycerides = 0.52 (0.25;0.78) mmol/L, total cholesterol = 0.55 (0.12;0.98) mmol/L, and HbA1c in diabetics = 27.1 (1.60;52.6) mmol/mol but no effect on other secondary outcomes., Conclusion: A major weight loss and intensified risk factor control resulted in significantly improved angina burden but no improvement of coronary microvascular function among women with microvascular angina., Competing Interests: Cambridge Weight Plan supplied the LED diet. No funders nor any persons related to the Cambridge Weight Plan played any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective and importance : The antiphospholipid syndrome can manifest itself by silent (or not) myocardial infarction. Clinical presentation : We report the case of a 16-year-old girl who presented a myocardial infarction for whom a coronary-computer tomography did not reveal any coronary abnormalities or obstruction. She had a livedo reticularis on her physical exam. Intervention : The echocardiography showed a normal left ventricular function and a mild eccentric mitral regurgitation. A myocardial magnetic resonance imaging demonstrated transmural necrosis with microvascular obstruction at the inferobasal segment of the left ventricle, suggestive of a microvascular myocardial infarction. The blood test showed elevation of the three antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein). The lupus anticoagulant remained positive 12 weeks later, fulfilling the laboratory criteria for antiphospolipid carrier. The associated presence of this microvascular coronary obstruction was strongly suggestive of antiphospholipd syndrome, according to the revised Sapporo criteria. To our knowledge, this is the first reported case of antiphospholipid syndrome manifesting as an acute microvascular myocardial infarction, confirmed by myocardial magnetic resonance imaging. Conclusion : The antiphospholipid syndrome can manifest itself early by a microvascular myocardial infarction. The clinician has to be alerted by a livedo reticularis in these patients, which will be frequently associated with manifestations of antiphospholipid syndrome such as arterial thrombosis and valvulopathies.

The incidence of ST segment elevation myocardial infarction (STEMI) has decreased over the last two decades in developed countries, but mortality from STEMI despite widespread access to reperfusion therapy is still substantial as is the development of heart failure, particularly among an expanding older population. In developing countries, the incidence of STEMI is increasing and interventional reperfusion is often not available. We here review the pathophysiology of acute myocardial infarction and reperfusion, notably the temporal and spatial evolution of ischaemic and reperfusion injury, the different modes of cell death, and the resulting coronary microvascular dysfunction. We then go on to briefly characterize the cardioprotective phenomena of ischaemic preconditioning, ischaemic postconditioning, and remote ischaemic conditioning and their underlying signal transduction pathways. We discuss in detail the attempts to translate conditioning strategies and drug therapy into the clinical setting. Most attempts have failed so far to reduce infarct size and improve clinical outcomes in STEMI patients, and we discuss potential reasons for such failure. Currently, it appears that remote ischaemic conditioning and a few drugs (atrial natriuretic peptide, exenatide, metoprolol, and esmolol) reduce infarct size, but studies with clinical outcome as primary endpoint are still underway., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Background: Cardiac syndrome X (CSX) is typical angina pectoris with objective signs of myocardial ischaemia despite a normal coronary angiogram and may be due to microvascular dysfunction. The incidence of CSX has not been greatly investigated worldwide and its incidence in Ireland is unknown., Aims: We aimed to determine the incidence of CSX in Cork University Hospital (CUH) and to establish the phenotype of the typical Irish CSX patient., Methods: All patients undergoing coronary angiography in CUH during regular working hours over a 3-month period were investigated. CSX was diagnosed using standard criteria. An extended recruitment period of 14 months allowed enrolment of a sufficient number of CSX patients to enable phenotyping., Results: Only 5 of 372 (1.3 %) patients undergoing angiography to investigate chest pain met the diagnostic criteria for CSX. None were given a discharge diagnosis of CSX or received cardiology follow-up. Irish CSX patients were predominantly female (88 %) with a mean age of 59.2 ± 6.6 years. Although they were significantly less functionally limited than patients with obstructive CAD, they had an equally substantial impairment in quality of life., Conclusions: CSX is relatively uncommon in Ireland and is most frequently seen in middle-aged women with hyperlipidaemia. It has significant impacts on patients' quality of life. None of the CSX patients were diagnosed as such, highlighting the lack of awareness or acceptance of this condition in Ireland. These patients require diagnosis and active cardiology follow-up to effectively manage their symptoms.

Background: Although a common symptom in patients with severe aortic stenosis (AS) without obstructive coronary artery disease (CAD), little is known about the pathogenesis of exertional angina., Objectives: This study sought to prove that microvascular dysfunction is responsible for chest pain in patients with severe AS and normal epicardial coronary arteries using adenosine-stress cardiac magnetic resonance (CMR) imaging., Methods: Between June 2012 and April 2015, 117 patients with severe AS without obstructive CAD and 20 normal controls were enrolled prospectively. After exclusions, study patients were divided into 2 groups according to presence of exertional chest pain: an angina group (n = 43) and an asymptomatic group (n = 41), and the semiquantitative myocardial perfusion reserve index (MPRI) was calculated., Results: MPRI values were significantly lower in severe AS patients than in normal controls (0.90 ± 0.31 vs. 1.25 ± 0.21; p < 0.001), and were much lower in the angina group than the asymptomatic group (0.74 ± 0.25 vs. 1.08 ± 0.28; p < 0.001). In logistic regression analysis, the only independent predictor for angina was MPRI (odds ratio: 0.003; p < 0.001). Univariate associations with MPRI were identified for diastolic blood pressure, E/e' ratio, left ventricular volume and ejection fraction, cardiac index, presence of late gadolinium enhancement, and left ventricular mass index (LVMI). In multivariate analysis, LVMI was the strongest contributing factor to MPRI (standardization coefficient: -0.428; p < 0.001)., Conclusions: Our results suggest that, in patients with severe AS without obstructive CAD, angina is related to impaired coronary microvascular function along with LV hypertrophy detectable by semiquantitative MPRI using adenosine-stress CMR., Clinical Trial Registration: NCT02575768., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Microvascular angina was included in the European guidelines on the management of patients with stable coronary artery disease in 2013. Topical aspects of etiology, pathogenesis, clinical course, diagnosis, and treatment of microvascular angina are discussed in this review.

Since first performed coronary angiography it was noticed that many patients with chest pain, abnormal rest electrocardiogram and positive stress test have normal result of coronary angiogram. The cause of this wasn't known. For the first time this disorder was named cardiac syndrome X by Harvey Kemp in 1973. In the new 2013 European Society of Cardiology guidelines regarding diagnosis and treatment of stable coronary artery disease, term cardiac syndrome X was substituted by "angina with normal coronary arteries". This article elaborates epidemiology, diagnostics, ethiopatoghenesis, prognosis and treatment of patients with diagnosis of term cardiac syndrome X in the light of the latest studies and guidelines.

We sometimes encounter patients with microvascular angina (MVA), a disease characterized by anginal pain without abnormal coronary arteriographic findings or coronary spasm. More than 40 years have passed since MVA was first confirmed. The terms 'syndrome X', 'cardiac syndrome X' and 'microvascular dysfunction' have also been used to describe conditions similar to MVA, but all with slightly different definitions. The cause of MVA seems almost certain to be organic and functional abnormalities of the small arteries of the heart. Patients with MVA are likely to suffer from endothelial dysfunction and other microvascular abnormalities of both the coronary and peripheral arteries. The major treatment of MVA has been medication, most often calcium channel blockers. The prognosis of MVA is generally excellent, although symptoms remain in many studies. Some MVA patients with accompanying hypertensive heart disease have gone on to develop progressive left ventricular dysfunction, with poor prognosis. The different definitions applied to the terms used to describe this condition, what we refer to here as MVA, can confound issues involved in diagnosis, prognosis and proper treatment. Therefore, it is extremely important to distinguish primary MVA without underlying heart disease from secondary MVA to explore the disease mechanism and examine the clinical characteristics. It is more than 40 years since Likoff first confirmed this disease; therefore, all researchers know that strict diagnostic criteria for MVA should be immediately established., (© 2015 Stichting European Society for Clinical Investigation Journal Foundation.)

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.

Background: Cardiac syndrome X (CSX) is linked with changes in the heart's micro-vasculature, without significant changes in main coronary vessels. According to ESC 2013 stable coronary artery disease criteria, CSX was replaced by Microvascular Angina (MA). While no changes in main coronary vessels are present, most patients still suffer from angina-like chest pains, which significantly diminish their quality of life. CSX is recognized among other coronary diseases and is now considered to be a form of stable angina. In most CSX patients we can visualize perfusion changes in the left ventricle., Objectives: Since it is well known that the kind of diet can greatly influence the development of coronary disease, our aim was to evaluate the influence of diet on the myocardial perfusion in the group of patients who were diagnosed of CSX. In addition, we tried to verify whether there is any correlation between dietary patterns and perfusion changes visualized in this group of patients., Material and Methods: Toward this goal we screened for the presence of CSX a group of 436 women who suffered from angina-like symptoms and whose routinely performed angiography revealed no changes in coronary vessels. Out of these, 55 women with CSX diagnosis, completed questionnaires regarding their nutritional patterns and underwent both myocardial perfusion studies (MPI) and exercise tests., Results: In the studied group dietary patterns were far from normal values, with the majority of women consuming too much protein, animal fats and sugars in their daily diet, and too low amounts of complex carbohydrates and oils. We were not able to find definite correlations between diet and perfusion changes; however, women whose diet included too high fat and protein intake, seemed to have worse perfusion pattern in MPI., Conclusions: Nutritional pattern seems to have an impact on development of myocardial perfusion changes in CSX patients.

Coronary heart disease (CHD) represents an important problem worldwide. At present, more women than men are evaluated for CHD and it has been recognized that the prevalence of this pathology in women is at least the same as in men. We have learned that cardiac syndrome X (CSX) is frequent because worldwide each year millions of people (mostly women) with angina pectoris without flow-limiting epicardial pathology are identified. Data from large myocardial infarction registries suggest a 5% to 25% prevalence of cases without flow-limiting coronary pathology. It must, however, be considered that these people are said to have normal coronary arteries by visual analysis of biplane coronarography. On the other hand, as demonstrated from autopsy, and in vivo by ultrasound intravascular studies, it would be more appropriate to say that in the majority of these cases no obstructive or flow-limiting coronary pathology was detected by coronarography. In CSX, endothelial dysfunction and microvascular dysfunction, sometimes with coronary microvascular spasm and epicardial coronary artery spasm, have been recognized as pathophysiologic mechanisms. In CSX, symptoms and pathologic signs are the same in patients with flow-limiting coronary pathology. The difference lies in the fact that the mechanisms of myocardial ischemia are microvascular and flow-limiting epicardial coronary pathology is absent. By interplay, the pathologic entities at work in CSX are linked with poor long-term outcome. The prevalence of these outcomes is probably smaller than in patients with flow-limiting coronary pathology but we lack precise values. Nonetheless, severe cardiovascular complications are frequent in CSX and it is thus the pathology is not benign. Drugs used in coronary ischemic disease are empirically prescribed to treat CSX, but we lack data from specific trials. It seems that statins and ranolazine might exert positive effects. However, specific research to target interventions in CSX would be necessary.

Nearly 50% of subjects of coronary artery disease suffer from coronary microvascular dysfunction. Various etiopathogenetic factors have been proposed by different workers but no hypothesis can explain the genesis of microvascular angina in all patients. We have made an attempt to review the literature to find caveats in our knowledge so that future studies can be better designed., (Copyright © 2014 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

Angina and myocardial ischemia without obstructive coronary artery disease are common clinical findings, often neglected for the assumption of a good prognosis. Most often, such patients are neither further investigated nor offered specific treatment beyond reassurance. However, the absence of significant coronary stenoses on angiography does not necessarily imply a "healthy" coronary tree. In such cases, myocardial ischemia may result from different types of functional disease involving the epicardial coronary arteries, the coronary microcirculation, or both; an accurate assessment of these components should be systematically performed after exclusion of organic epicardial disease because a correct diagnosis has relevant prognostic and therapeutic implications. Here we discuss the basic principles of diagnostic tests in this setting and propose a diagnostic sequence of reasonable practical implementation that may help identify patients at risk of future cardiac events., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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.)

Gender differences play an important role in coronary heart disease (CHD). Not only in the presentation of symptoms, but also in their underlying pathophysiology. Women with persistent angina without obstructive coronary artery disease (CAD) pose a diagnostic and therapeutic challenge. Half of these women have microvascular coronary dysfunction (MCD). The 2013 guidelines on management of stable angina now acknowledge this condition, but our understanding of MCD is still limited. In this clinical case presentation we elaborate on contemporary methods of diagnosing and managing microvascular angina based on the cases of two women who attended our outpatient clinic. The availability of non-invasive tools to diagnose MCD is still limited. Current treatment is based on reduction of cardiovascular risk factors but physicians and patients should be aware that although therapy usually reduces symptoms, they do not completely disappear. More research on diagnostic methods and effective therapy for MCD is eagerly awaited.

Microvascular angina is a rather widely spread disease which is associated with high rate of unfavorable outcomes and substantial economical cost of examination and treatment. However problems of noninvasive diagnostics of the disease have not been entirely solved as well as clear-cut algorithm of management has not been elaborated. We present in this paper consideration of contemporary aspects of etiology, pathogenesis, clinical course, diagnosis, and treatment of microvascular angina in accordance with European recommendations on management of patients with stable ischemic heart disease.

Migraine is a common neurovascular disorder characterized by attacks of severe headache, autonomic and neurologic symptoms. Migraine can affect many systems in the body, yet its effects on cardiovascular system are unclear. We hypothesized that migraine and coronary microvascular angina may be manifestations of a common systemic microvascular dysfunction and clinically associated. Forty patients with migraine and 35 healthy volunteers were included into the study. Using transthoracic Doppler echocardiography, coronary flow was visualized in the middle or distal part of the left anterior descending artery. Coronary diastolic peak flow velocities were measured with pulse wave Doppler at baseline and after dipyridamole infusion (0.56 mg/kg/4 min). Coronary flow reserve of <2 was considered normal. In addition, thorough 2-dimensional and Doppler echocardiographic examinations were also performed. Fifty-two women and 23 men were included. Coronary flow reserve was significantly lesser in the migraine group than in the control group (1.99 ± 0.3 vs 2.90 ± 0.5, p <0.05). In addition, mitral annular velocities were lower and the ratio of early mitral inflow velocity to early mitral annular velocity (E/E' lateral and E/E' septal) was higher in migraineurs than in the control group (p <0.05 for all), indicating diastolic function abnormalities in the migraine group. In conclusion, these findings suggest that there is an association between coronary microvascular dysfunction and migraine independently of the metabolic state of the patients. A common pathophysiologic pathway of impaired endothelial vasodilatation, vasomotor dysfunction, and increased systemic inflammatory factors may play a role in these 2 clinical conditions and could be the underlying cause of subclinical systolic and diastolic left ventricular dysfunction in migraineurs., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to ascertain whether coronary microvascular dysfunction (CMD) and inflammation are related in cardiac syndrome X (CSX)., Background: CMD can lead to CSX, defined as typical angina and transient myocardial ischemia despite normal coronary arteriograms. Inflammation has been suggested to play a role in the pathogenesis of myocardial ischemia in CSX., Methods: We assessed 21 CSX patients (age 52 ± 10 years; 17 women) without traditional cardiovascular risk factors and 21 matched apparently healthy control subjects. Positron emission tomography was used to measure myocardial blood flow (MBF) and coronary flow reserve (CFR) in response to intravenous adenosine, whereas high-sensitivity C-reactive protein (CRP) was measured to assess inflammation. Patients were subdivided a priori into 2 groups according to CRP concentrations at study entry (i.e., ≤3 or >3 mg/l)., Results: There were no differences in resting (1.20 ± 0.23 ml/min/g vs. 1.14 ± 0.20 ml/min/g; p = 0.32) or hyperemic MBF (3.28 ± 1.02 ml/min/g vs. 3.68 ± 0.89 ml/min/g; p = 0.18) between CSX patients and the control group, whereas CFR was mildly reduced in CSX patients compared with the control group (2.77 ± 0.80 vs. 3.38 ± 0.80; p = 0.02). Patients with CRP >3 mg/l had more severe impairment of CFR (2.14 ± 0.33 vs. 3.16 ± 0.76; p = 0.001) and more ischemic electrocardiographic changes during adenosine administration than patients with lower CRP, and a negative correlation between CRP levels and CFR (r = -0.49, p = 0.02) was found in CSX patients., Conclusions: CSX patients with elevated CRP levels had a significantly reduced CFR compared with the control group, which is indicative of CMD. Our study thus suggests a role for inflammation in the modulation of coronary microvascular responses in patients with CSX., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The pathophysiology of cardiac syndrome X (CSX) is still unclear, but most patients with CSX have endothelial dysfunction. It has been shown that adropin uniquely effects the regulation of endothelial function. The purpose of the study was to evaluate the role of adropin in CSX. Eighty-six consecutive cardiac syndrome X-diagnosed patients and 86 age-sex matched healthy subjects were enrolled into the study. Serum adropin levels, nitrite/nitrate levels were measured in each subject. The adropin levels were significantly lower in patients with CSX than healthy subjects (1.7 ± 0.8 ng/mL and 3.4 ± 1.8 ng/mL, respectively; P < 0.001). The BMI values of patients with CSX were significantly higher than control subjects (28.1 ± 2.4 kg/m(2) and 26.0 ± 3.7 kg/m(2) , respectively; P < 0.001). Plasma nitrite/nitrate levels were lower in patients with CSX than control subjects (15.9 ± 1.6 μmol/L vs. 25.4 ± 2.8 μmol/L, respectively; P < 0.001), and they have a significantly positive correlation with plasma adropin levels (r = 0.463, P < 0.001). In the multiple linear regression analysis, nitrite/nitrate levels, BMI, and adropin were found to be independent risk factors for CSX. A ROC curve is used to identify the ability of adropin levels to predict the cardiac syndrome X. The area under the ROC curve was 0.854 for adropin levels (P = 0.0001). The sensitivity and specificity values of adropin levels were 90.7 and 70.9%, respectively (cut-off value 2.73). In conclusion, lower serum adropin levels were associated with CSX. Adropin is an independent risk factor for CSX., (© 2013 Blackwell Publishing Ltd.)

Objective: The role of adipokines in the development of cardiac syndrome X (CSX) remains unknown., Methods: Fifty-nine CSX subjects were retrospectively enrolled from our catheterization databank. Another 54 subjects with valvular heart disease or arrhythmia served as controls. Adipokines were measured by ELISA tests., Results: The CSX had lower circulating adiponectin but higher leptin and higher leptin/adiponectin ratio (×1000) (3.78 ± 4.96 vs. 2.14 ± 5.67, p < 0.001) than those of the controls. In a multivariate analysis, a higher leptin/adiponectin ratio was a predictor of CSX, while insulin-resistance index was not., Conclusions: Adipokines may be implicated in the pathogenesis of CSX.

The study population included 208 patients with chest pain and uninjured coronary arteries that we split into two populations: diabetics (72 patients) and non-diabetics (136 patients). We split patients with chest pain and uninjured coronary arteries that had a myocardial scintigraphy into two populations: patients with positive scintigraphy and negative. We calculated, on angiographic images of each patient, stored on suitable digital supports, Timi Frame Count (TFC), Myocardial Blush Grade (MBG) and Total Myocardial Blush Score (TMBS) using the protocol described by Gibson and Yusuf. On the basis of Yusuf's experience we imagined a new index: the Total Timi Frame Count as the sum of the three coronary Timi Frame Count. From our results we found a worse coronary microcirculation in diabetic patients with lower values of TFC, MBG and TMBS (p=0.02),compared with non- diabetics. New index TTFC is usually higher in diabetics than non-diabetic patients. Patients with positive scintigraphy had a worse TMBS than patients with a negative one, with a high statistical significance (p=0.003).We focused on the correlation between scintigraphy defect and angiography data in the arteries of ischemia relieved by nuclear imaging. The analysis showed that healthy vessels had a lower TFC than diseased vessels and therefore a better microcirculation with a high statistical significance (p=0.0001). According to the literature, diabetic population has a major microcirculation disease; moreover the study of microcirculation by coronary angiography and myocardial scintigraphy shows a good correlation between two methods.

Far more extensive than the epicardial coronary vasculature that can be visualized angiographically is the coronary microcirculation, which foregoes routine imaging. Probably due to the lack of techniques able to provide tangible evidence of its crucial role, the clinical importance of coronary microvascular dysfunction is not fully appreciated. However, evidence gathered over the last several decades indicates that both functional and structural abnormalities of the coronary microvasculature can lead to myocardial ischaemia, often comparable with that caused by obstructive coronary artery disease. Indeed, a marked increase in coronary microvascular resistance can impair coronary blood flow and trigger angina pectoris, ischaemic ECG shifts, and myocardial perfusion defects, and lead to left ventricular dysfunction in patients who otherwise have patent epicardial coronary arteries. This condition--often referred to as 'chest pain with normal coronary arteries' or 'cardiac syndrome X'--encompasses several pathogenic mechanisms involving the coronary microcirculation. Of importance, coronary microvascular dysfunction can occur in conjunction with several other cardiac disease processes. In this article, we review the pathogenic mechanisms leading to coronary microvascular dysfunction and its diagnostic assessment, as well as the different clinical presentations and prognostic implications of microvascular angina. As such, this review aims to remove at least some of the mystery surrounding the notion of coronary microvascular dysfunction and to show why it represents a true clinical entity.

Background: Although acute hyperglycemia (AHG) is associated with poor outcomes in ST-segment elevation myocardial infarction (STEMI) patients, underlying mechanisms have not been fully elucidated. We investigated the influence of AHG on myocardial microcirculation in reperfused STEMI patients., Methods and Results: Thirty-four STEMI patients were divided into 2 groups according to the presence (Group H, n 5 11) or the absence (Group L, n 5 23) of AHG. Myocardial blood flow (MBF) and myocardial flow reserve (MFR) in the infarct-related area were compared between 2 groups, using ¹³N-ammonia positron emission tomography. Wall motion abnormality scores (WMASs) and end-diastolic volume indices (EDVI) were also assessed at 1 and 6 months after the onset. Although resting MBF was similar, MFR was lower in Group H than in Group L (1.69 ± 0.37 vs 2.39 ± 0.56, P = .001). WMAS was greater in Group H than in Group L at both 1 month (7.4 ± 3.7 vs 3.7 ± 3.0, P = .011) and 6 months (7.3 ± 3.9 vs 3.1 ± 3.4, P = .015). EDVI tended to be greater in Group H than in Group L at 6 months (103.8 ± 42.9 vs 73.9 ± 16.0 mL/m2, P = .071). Multivariate analysis showed AHG to be independently associated with low MFR., Conclusions: In STEMI patients, AHG impaired myocardial microcirculation, leading to poor functional recovery and remodeling despite successful reperfusion.

New data suggest that persistent chest pain, despite normal coronary angiography, is less benign than previously thought. It has long been recognized that cardiac syndrome X (CSX) is associated with significant suffering, disability, and health care costs, but the biggest shift in thinking comes in terms of long-term risk. It is now recognized that the prognosis is not benign and that a significant proportion of patients are at increased cardiovascular disease risk. Of major debate is the question of whether the mechanisms that explain this chest pain are cardiac vs noncardiac. The most current definition of CSX is the triad of angina, ischemia, and normal coronary arteries, which is associated with an increased cardiovascular risk. This paper provides a review of CSX, epidemiology of the problem, proposed explanatory mechanisms, and important next steps in research. Central to this review is the proposition that new insights into CSX will be fostered by both clinical and scientific collaboration between cardiovascular and pain scientists., (Copyright © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Coronary computed tomography angiography (CTA) is a reliable diagnostic test for the anatomic diagnosis of obstructive coronary artery disease (CAD). Although coronary CTA shows high sensitivity and negative predictive value for detecting stenosis greater than or equal to 50% diameter, it is limited in its ability to diagnose myocardial ischemia. Advances in computed tomography (CT) technology alone and technology that hybridizes CT with single-photon emission CT and positron emission tomography allow for the combined anatomic and physiologic diagnosis of CAD. This article summarizes these combined technologies, emphasizing the merits and limitations of each technology and their clinical implications., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aims: The interaction between coronary β(2)-adrenoreceptors and segmental plaque burden is complex and poorly understood in humans. We aimed to validate intracoronary (IC) salbutamol as a novel endothelium-dependent vasodilator utilizing intravascular ultrasound (IVUS), and thus assess relationships between coronary β(2)-adrenoreceptors, regional plaque burden and segmental endothelial function., Methods and Results: In 29 patients with near-normal coronary angiograms, IVUS-upon-Doppler Flowire imaging protocols were performed. Protocol 1: incremental IC salbutamol (0.15, 0.30, 0.60 μg/min) infusions (15 patients, 103 segments); protocol 2: salbutamol (0.30 μg/min) infusion before and after IC administration of N(G)-monomethyl-L-arginine (L-NMMA) (10 patients, 82 segments). Vehicle infusions (IC dextrose) were performed in 4 patients (21 segments). Macrovascular response [% change segmental lumen volume (ΔSLV)] and plaque burden [per cent atheroma volume (PAV)] were studied in 5-mm coronary segments. Microvascular response [per cent change in coronary blood flow (ΔCBF)] was calculated following each infusion. Intracoronary salbutamol demonstrated significant dose-response ΔSLV and ΔCBF from baseline, respectively (0.15 μg/min: 3.5 ± 1.3%, 28 ± 14%, P = 0.04, P = NS; 0.30 μg/min: 5.5 ± 1.4%, 54 ± 17%, P = 0.001, P < 0.0001; 0.60 μg/min: 4.8 ± 1.6%, 66 ± 15%, P = 0.02, P < 0.0001), with ΔSLV responses further exemplified in low vs. high plaque burden groups. Salbutamol vasomotor responses were suppressed by l-NMMA, supporting nitric oxide-dependent mechanisms. Vehicle infusions resulted in no significant ΔSLV or ΔCBF. Multivariate analysis including conventional cardiovascular risk factors, PAV, segmental remodelling and plaque eccentricity indices identified PAV as the only significant predictor of a ΔSLV to IC salbutamol (coefficient -0.18, 95% CI -0.32 to -0.044, P = 0.015). Conclusions Intracoronary salbutamol is a novel endothelium-dependent epicardial and microvascular coronary vasodilator. Intravascular ultrasound-derived regional plaque burden is a major determinant of segmental coronary endothelial function.

Coronary microvascular hyperplasia is a cause of microvessel angina, although the underlying cellular mechanisms remain unclear. We examined how mononuclear cells expressing β-actin (β-MNCs), which were identified in coronary vessels, induce coronary microvascular hyperplasia.The presence of β-MNCs in coronary hyperplastic arterial (HAM) and venous microvessels (HVM) was examined by endomyocardial biopsy in 25 patients with suspected microvessel angina. β-MNCs were identified in 14 HAMs obtained from 11 patients. Basic fibroblast growth factor and heparin sulfate were injected into the infarcted myocardium to induce HAM and HVM in 28 beagles, and then we examined the role of β-MNCs in the onset of HAM and HVM. The following changes were observed after infarction induction in beagles: (a) migration of β-MNCs from the existing microvessels into the interstitial space at 1-2 weeks; (b) those traversing the adventitia into the media, but not intima, of microvessels; (c) their transformation to smooth muscle cells (SMCs) and/or connective tissues (collagen and elastin fibers); (d) and medial hyperplasia without intimal hyperplasia. Medial hyperplasia was classified into SMC-proliferative and both SMC- and connective tissue-proliferative types. β-MNCs expressed CD(34) but did not express other major vessel-related cell markers.β-MNCs are a vascular progenitor, and migrate out of the adventitia into media, and participate in the etiology of coronary microvascular medial hyperplasia.

Isolated left ventricular noncompaction (LVNC) is a rare hereditary cardiomyopathy characterized by prominent intraventricular trabeculations separated by deep intertrabecular recessus. While cardiac ischemia due to microvascular dysfunction is common in these patients, ST-segment elevation myocardial infarction (STEMI) is rare and usually seen as a consequence of coincidental coronary artery disease. We report the case of a 20 year-old male patient admitted to our emergency department with a complaint of squeezing chest pain who was subsequently diagnosed with STEMI according to electrocardiographic findings, although an emergent coronary angiogram demonstrated normal coronary arteries. Echocardiography revealed isolated LVNC, and the diagnosis was confirmed via magnetic resonance imaging. Repeat coronary catheterization with acetylcholine infusion and coronary flow reserve measurement failed to demonstrate vasospasm or microvascular dysfunction. As no apparent cause was found, this case was designated 'idiopathic' myocardial infarction. Coronary thromboembolism due to stagnation of blood in the left ventricular cavity remained as the most probable mechanism underlying myocardial infarction.

Background: Helicobacter pylori (H.pylori) has been implicated in the pathogenesis of several diseases such as cardiac syndrome X (CSX), which includes chest pain, positive exercise stress test and normal angiography. Also, elevation of homocysteine (Hcy) level is associated with CSX, as it can severely disturb vascular endothelial function. We aimed to elucidate whether the infection of H.pylori affect the level of Hcy in CSX., Methods: Eighty-eight patients with CSX (32 men, 56 women; mean age: 53.8 ± 11.9) and 97 healthy controls (36 men, 61 women; mean age: 45.7 ± 7.3) were enrolled. Plasma samples were tested for the presence of IgG antibody to H.pylori using enzyme linked immunosorbent assay method. Hcy levels were measured enzymatically., Results: Plasma Hcy concentration in CSX patients is higher than control group (13.1 ± 2.6 vs. 11.8 ± 2.5 mmol/L; p = 0.002). There was no significant difference between Hcy in H.pylori(+) and H.pylori(-) individuals in CSX group (13.1 ± 2.7 vs. 12.2 ± 0.6 mmol/L; p = 0.554) and between two groups in controls, respectively (12.1 ± 2.2 vs. 11.4 ± 2.9 mmol/L; p = 0.148)., Conclusions: Although there is Hcy level increase in H.pylori(+) CSX patients and controls comparing to H.pylori(-) subjects, but other factors may affect on Hcy level, too. (Cardiol J 2012; 19, 5: 466-469).

Background: The causes of coronary microvascular dysfunction (CMVD) in patients with cardiac syndrome X (CSX) are largely unknown. Common cardiovascular risk factors (CVRFs) and increased markers of inflammation have been associated with CMVD in some studies, but their role in determining CMVD in CSX patients remains poorly known., Methods and Results: We studied 71 CSX patients (56 ± 9 years, 23 men) and 20 healthy volunteers (52 ± 7 years, nine men). Using transthoracic Doppler echocardiography, coronary microvascular vasodilator function was assessed in the left anterior descending coronary artery as the ratio of diastolic coronary blood flow (CBF) velocity at peak intravenous adenosine administration and during cold pressor test (CPT) to the respective basal CBF velocity values. Common CVRFs tended to be more frequent and C-reactive protein (CRP) levels were higher (P < 0.001) in CSX patients than in controls. Both CBF responses to adenosine (2.05 ± 0.6 vs. 2.92 ± 0.9, P < 0.001) and to CPT (1.71 ± 0.6 vs. 2.42 ± 0.7, P < 0.001) were lower in CSX patients than in controls. The differences between the two groups in CBF response to adenosine and in CBF response to CPT remained highly significant (P < 0.01 for both) after adjustment for all CVRFs, including serum CRP levels., Conclusion: In CSX patients, both endothelium-dependent and endothelium-independent CMVD cannot be reliably predicted by CVRFs (including serum CRP levels), alone or in combination.

This review aims at demonstrating current concepts for the occurrence of angina pectoris (AP) and myocardial ischemia in patients without significant epicardial stenoses based on typical clinical examples. For applying these concepts, it is of utmost importance to clinically distinguish patients with resting AP only from those with exercise-induced symptoms or both. Resting AP may not only be caused by plaque rupture and subsequent coronary thrombosis, but may also be due (especially when repeated attacks occur in the early morning hours) to coronary vasospasm (in the microvasculature as well as in epicardial coronary segments). Similarly, exercise-induced AP and/or a pathological exercise test result may not only be caused by severe coronary stenoses, but may also be due to a reduced coronary perfusion reserve secondary to microvascular dysfunction. Hence, a pathological non-invasive stress-test result should not be necessarily described as "false positive" in case of the absence of any significant stenosis. In principle, proatherogenic cardiovascular risk factors are not only associated with atherosclerotic coronary artery disease (CAD), but also with the occurrence of a coronary vasomotility disorder. Both disease entities are characterised by the occurrence of myocardial ischemia. So far, the exact pathomechanism of respective subforms of coronary vasomotility disorders has not yet been not elucidated in detail. Endothelial dysfunction, abnormalities of the smooth muscle cells in the media as well as genetic predisposition or specific immunological abnormalities are discussed as underlying reasons. Intracoronary provocative testing (such as the acetylcholine-test) may help to diagnose as well as to differentiate the different subforms of coronary vasomotility disorders., (© Georg Thieme Verlag KG Stuttgart · New York.)

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.

Background: The cause of myocardial ischemia and chest pain in patients with cardiac syndrome X (CSX) has been explained by mechanisms including endothelial dysfunction. CSX patients have higher levels of asymmetric dimethylarginine (ADMA) and increased mean common carotid intima-media thickness (C-IMT). Accordingly, this study was designed to examine C-IMT with its association serum endothelial function parameters in patients with CSX., Methods: The study population consisted of 30 enrolled consecutive patients with diagnosis of CSX. As a control group, 30 individuals with the complaint of anginal chest pain without any ischemia on myocardial perfusion scintigraphy and with normal coronary angiographies were selected. C-IMT was measured by recording ultrasonographic images of both the left and the right common carotid artery. Plasma levels of L-arginine, ADMA, and nitrate/nitrite (NO(x)) were measured from blood samples., Results: Both C-IMT (mm) and carotid atherosclerotic plaques were significantly higher in patients with CSX than in control group. Also, the plasma level of NO(x), L-arginine, and L-arginine/ADMA ratio were lower in patients with CSX than they were in the control group subjects. Plasma ADMA level increased in the CSX patients group. Correlation analysis showed significant positive correlation with C-IMT and plasma ADMA levels and showed significant negative correlation with plasma NO(x) and L-arginine levels. L-arginine/ADMA ratio and C-IMT was also showed significant negative correlation with the same analysis., Conclusions: CSX patients had higher plasma ADMA levels and C-IMT values than the controls, reflecting the presence of subclinical atherosclerosis. These findings suggest that, besides endothelial dysfunction, presence of atherosclerosis may also contribute to the etiopathogenesis of the CSX phenomenon.

Aim: To investigate the frequency of gastroenterological diseases in the etiology and the efficacy of proton pump inhibitors (PPIs) in the treatment of cardiac syndrome X (CSX) as a subform of non-cardiac chest pain (NCCP)., Methods: We investigated 114 patients with CSX using symptom questionnaires. A subgroup of these patients were investigated regarding upper gastrointestinal disorders (GIs) and treated with PPI. Patients not willing to participate in investigation and treatment served as control group., Results: Thirty-six patients denied any residual symptoms and were not further evaluated. After informed consent in 27 of the remaining 78 patients, we determined the prevalence of disorders of the upper GI tract and quantified the effect of treatment with pantoprazole. We found a high prevalence of gastroenterological pathologies (26/27 patients, 97%) with gastritis, gastroesophageal reflux disease (GERD) and acid reflux as the most common associated disorders. If treated according to the study protocol, these patients showed a significant improvement in the symptom score. Patients treated by primary care physicians, not according to the study protocol had a minor response to treatment (n = 19, -43%), while patients not treated at all (n = 26) had no improvement of symptoms (-0%)., Conclusion: Disorders of the upper GI tract are a frequent origin of CSX in a German population and can be treated with pantoprazole if given for a longer period.