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.

This review summarizes current knowledge about echocardiographic modalities used to assess microvascular function and left ventricular (LV) systolic function in women with ischemia and no obstructive coronary arteries (INOCA). Although the entire pathophysiological background of this clinical entity still remains elusive, it is primarily linked to microvascular dysfunction which can be assessed by coronary flow velocity reserve. Subtle impairments of LV systolic function in women with INOCA are difficult to assess by interpretation of wall motion abnormalities. LV longitudinal function impairment is considered to be an early marker of subclinical systolic dysfunction and can be assessed by global longitudinal strain quantification.

The aim of this study was to evaluate and compare the subfoveal choroidal thickness (SFCT) and peripapillary retinal nerve fiber layer thickness (pRNFLT) in patients with microvascular angina (MA), coronary slow flow phenomenon (CSFP) and healthy controls.

Thirty-two consecutive patients with MA, 35 consecutive patients with CSFP and 40 age and sex-matched controls were enrolled. SFCT, average pRNFLT and four quadrants of pRNFLT were measured by spectral domain- optical coherence tomography (SD-OCT).

The mean SCFT in patients with CSFP (267.57 ± 30.61 μm) was significantly thinner than those of patients with MA (288.84 ± 28.25 μm) and control (291.21 ± 31.75 μm) (p = 0.002) while SFCT of patients with MA were similar with those of controls. Patients with CSFP had thinner superior and inferior pRNFLT compared to patients with MA and controls (p < 0.001 and p = 0.005, respectively) while there were no significant differences in average pRNFLT, nasal and temporal quadrant of pRNFLTs among three groups. In the multivariate linear regression analyses, the presence of CSFP was found negatively correlated with SFCT and superior pRNFLT.

Patients with CSFP had thinner SFCT, superior and inferior quadrants of pRNFLT proposing the presence of a generalized endothelial dysfunction and increased microvascular resistance in these patients.

Coronary vasomotor dysfunction is an important mechanism for angina in patients with unobstructed coronary arteries.

The purpose of this study was to determine sex differences in the prevalence and clinical presentation of vasomotor dysfunction in a European population and to examine sex differences in the dose of acetylcholine leading to a positive acetylcholine provocation test (ACH test).

Between 2007 and 2014, we included 1,379 consecutive patients with stable angina, unobstructed coronaries and ACH test performed for epicardial vasospasm or coronary microvascular dysfunction (CMD) due to microvascular spasm. The predictive value of sex, risk factors, symptoms, and noninvasive test results was analyzed by means of logistic regression.

The mean patient age was 62 years, and 42% were male. There were 813 patients (59%) with a pathological ACH test, 33% for CMD and 26% for epicardial vasospasm. A pathological test was more common in females (70% vs. 43%; p < 0.001). In a multivariable logistic regression model the sex difference was statistically significant with a female-male odds ratio for CMD and epicardial vasospasm of 4.2 (95% confidence interval: 3.1 to 5.5; p < 0.001) and 2.3 (95% confidence interval: 1.7 to 3.1; p < 0.001), respectively. Effort-related symptoms, but neither risk factors nor noninvasive stress tests, contributed to predicting a pathological test. Female patients were more sensitive to acetylcholine with vasomotor dysfunction occurring at lower ACH doses compared with male patients.

Vasomotor dysfunction is frequent in patients with angina and unobstructed coronaries in a European population. Female patients have a higher prevalence of vasomotor dysfunction (especially CMD) compared with male patients. A pathological ACH test was observed at lower ACH doses in women compared with men.

In 2006, Takotsubo syndrome (TTC) was described as a distinct type of stress-induced cardiomyopathy (stress cardiomyopathy). However, when thinking about Takotsubo cardiomyopathy from the viewpoints of the AHA and ESC classifications, 2 possible problems may arise. The first potential problem is that a forecast of disease outcome is lacking in the ESC classification, whereas the AHA only states that 'outcome is favorable with appropriate medical therapy'. However, based on the literature data, one can make a general conclusion that occurrence of myocardial lesions in TTC (i.e., myocardial fibrosis and contraction-band necrosis) causes the same effects as in other diseases with similar levels of myocardial damage and should not be considered to have a lesser impact on mortality. To summarise, TTC can cause not only severe complications such as pulmonary oedema, cardiogenic shock, and dangerous ventricular arrhythmias, but also damage to the myocardium, which can result in the development of potentially fatal conditions even after the disappearance of LV apical ballooning. The second potential problem arises from the definition of TTC as a stress cardiomyopathy in the AHA classification. In fact, the main factors leading to TTC are stress and microvascular anginas, since, as has been already discussed, coronary spasm can cause myocardium stunning, resulting in persistent apical ballooning. Thus, based on this review, 3 distinct types of stress cardiomyopathies exist (variant angina, microvascular angina, and TTC), with poor prognosis. Adding these diseases to the classification of cardiomyopathies will facilitate diagnosis and preventive prolonged treatment, which should include intensive anti-stress therapy.

Cardiac syndrome X includes a heterogenous group of patients with angina but normal epicardial coronaries in angiography.

Our objective was to study the clinical characteristics of patients with cardiac syndrome X.

Data of patients who underwent coronary angiography over a period of one year was retrospectively analyzed. Those with normal or non-obstructive coronaries in angiography with chest pain were included in this study.

1203 patients underwent coronary angiography during the study period. 105 (8.7%) patients fulfilled the inclusion criteria. There were 52 (49.5%) males and 53 (50.5%) females including 31 (29.5%) postmenopausal women. Many patients had atherosclerotic risk factors. Typical angina and atypical chest pain were reported by 63 (60%) and 42 (40%) patients, respectively. ECG was normal in 46 (43.8%) and abnormal in 59 (56.2%) patients. The most common abnormal finding in ECG was ST-T changes seen in 49 (46.7%) patients. Regional wall motion abnormality with mild left ventricular systolic dysfunction was seen in 4 (3.8%) patients while 101 (96.2%) patients had normal ventricular function in echocardiography. TMT was positive for inducible ischemia in 35 (33.3%) patients and inconclusive in 10 (9.5%) patients. Angiography showed normal epicardial coronaries in 85 (80.9%) patients.

Cardiac syndrome X constitutes a significant subset of patients undergoing coronary angiography. It is essential to identify and treat them specifically for microvascular angina. Many of them have atherosclerotic risk factors but their presentation is different from those with obstructive coronaries.

Epidemiologic data for cardiac abnormality predating decreased kidney function are sparse. We investigated the associations of high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) with end-stage renal disease (ESRD) risk in a community-based cohort.

A prospective cohort study.

10,749 white and black participants at the fourth visit (1996-1998) of the Atherosclerosis Risk in Communities (ARIC) Study with follow-up through 2010.

hs-cTnT (3, 6, 9, and 14ng/L) and NT-proBNP (41.6, 81.0, 142.5, and 272.5pg/mL) levels were divided into 5 categories at the same percentiles (32th, 57th, 77th, and 91th; corresponding to ordinary thresholds of hs-cTnT), with the lowest category as a reference.

Incident ESRD defined as initiation of dialysis therapy, transplantation, or death due to kidney disease.

Relative risk and risk prediction of ESRD according to hs-cTnT and NT-proBNP levels based on Cox proportional hazards models.

During a median follow-up of 13.1 years, 235 participants developed ESRD (1.8 cases/1,000 person-years). hs-cTnT and NT-proBNP levels were associated with ESRD risk independently of each other and of potential confounders, including kidney function and albuminuria (adjusted HRs for highest category, 4.43 [95% CI, 2.43-8.09] and 2.28 [95% CI, 1.44-3.60], respectively). For hs-cTnT level, the association was significant even at the third category (HR for 6-8ng/L of hs-cTnT, 2.74 [95% CI, 1.54-4.88]). Their associations were largely consistent even among persons without decreased kidney function or history of cardiovascular disease. hs-cTnT and NT-proBNP levels both significantly improved ESRD prediction (C statistic differences of 0.0084 [95% CI, 0.0005-0.0164] and 0.0045 [95% CI, 0.0004-0.0087], respectively, from 0.884 with conventional risk factors).

Relatively small number of ESRD cases and single measurement of hs-cTnT and NT-proBNP.

hs-cTnT and NT-proBNP levels independently predicted ESRD risk in the general population, with more evident results for hs-cTnT. These results suggest the involvement of cardiac abnormality, particularly cardiac injury, in the progression of reduced kidney function and/or may reflect the useful property of hs-cTnT as an end-organ damage marker.

Many patients undergoing coronary angiography because of chest pain syndromes, believed to be indicative of obstructive atherosclerosis of the epicardial coronary arteries, are found to have normal angiograms. In the past two decades, a number of studies have reported that abnormalities in the function and structure of the coronary microcirculation may occur in patients without obstructive atherosclerosis, but with risk factors or with myocardial diseases as well as in patients with obstructive atherosclerosis; furthermore, coronary microvascular dysfunction (CMD) can be iatrogenic. In some instances, CMD represents an epiphenomenon, whereas in others it is an important marker of risk or may even contribute to the pathogenesis of cardiovascular and myocardial diseases, thus becoming a therapeutic target. This review article provides an update on the clinical relevance of CMD in different clinical settings and also the implications for therapy.

Cardiovascular disease typically is associated with dysfunction of the coronary vasculature and microvasculature. The study of cardiovascular disease typically involves imaging of the large coronary vessels and quantification of cardiac blood perfusion. These methods, however, are not well suited for imaging of the cardiac microvasculature. We used the optical histology method, which combines chemical optical clearing and optical imaging, to create high-resolution, wide-field maps of the cardiac microvasculature in ventral slices of mouse heart. We have demonstrated the ability of the optical histology method to enable wide-field visualization of the cardiac microvasculature in high-resolution and anticipate that optical histology may have significant impact in studying cardiovascular disease.

The aim of this study was to ascertain whether coronary microvascular dysfunction (CMD) and inflammation are related in cardiac syndrome X (CSX).

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.

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).

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.

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.

Syndrome X in women is thought to be caused by coronary microvascular dysfunction, the exact site of which is unknown. The aim of this study was to characterize the microvascular site of dysfunction in these patients using myocardial contrast echocardiography.

Women with exertional angina, positive test results on stress imaging, but no coronary artery disease (the study group, n = 18) and age-matched control women also with no coronary artery disease (n = 17) were enrolled. Myocardial contrast echocardiography was performed at rest and during dipyridamole-induced hyperemia. Mean microbubble velocity (β) and myocardial blood volume (A) were measured, and myocardial blood flow (A · β) was computed. In addition, plasma concentrations of eicosanoids, female sex hormones, and C-reactive protein were measured.

Rest β and myocardial blood flow (A · β) were higher in the study compared with the control women (1.61 ± 0.68 vs. 0.74 ± 0.44, P = .0001, and 157 ± 121 vs. 54 ± 54, P = 0.0001, respectively) despite similar heart rates and systolic blood pressures. After the administration of dipyridamole, whereas the changes in A and A · β were not significantly different between the two groups, β reserve (the ratio of stress β to rest β) was markedly lower in the study group (1.48 ± 0.62 vs. 2.78 ± 0.94, P = .0001). Blood hematocrit, eicosanoids, female sex hormones, glucose, and C-reactive protein were not different between the two groups.

Coronary autoregulation is abnormal in patients with syndrome X (higher resting β and myocardial blood flow and lower β reserve), which suggests that the coronary resistance vessels are the site of microvascular abnormality.

Chest pain with normal coronary arteriograms represents a major diagnostic and therapeutic challenge to contemporary cardiology. Cardiac syndrome X (CSX), defined as typical angina-like chest pain, a positive response to exercise stress testing and normal coronary arteriograms, encompasses patients with a variety of pathogenic mechanisms. Cardiac ischemia has been documented in approximately 25% of CSX patients and is associated with endothelial dysfunction and microvascular vasodilator abnormalities. Increased endothelin-1, a powerful vasoconstrictor, has been suggested to play a pathogenic role. There is a high prevalence of postmenopausal women with CSX and thus estrogen deficiency has also been proposed to represent a possible pathogenic mechanism. Inflammatory mechanisms and endothelial dysfunction at the coronary microvascular level appear to be important in the pathogenesis of CSX. Treatment with agents that have protective effects on the vasculature and also anti-inflammatory properties, such as statins and angiotensin-converting enzyme inhibitors have been effective in improving both symptoms and electrocardiographic signs of myocardial ischemia in patients with CSX. This review discusses the roles for endothelial dysfunction and inflammation in the pathogenesis of CSX, as well as the potential therapeutic implications of these mechanisms.

To evaluate left ventricular (LV) systolic and diastolic myocardial function, and their relation to coronary flow reserve in patients with non-insulin-dependent diabetes mellitus (DM) and microvascular angina.

We selected a population of 45 normotensive patients with DM (56.3 ± 8.2 years; 25 males) with LV ejection fraction >50% and microvascular angina (anginal pain, positive imaging stress test and normal coronary angiography). Thirty-five age- and sex-matched healthy controls were also enrolled. All the patients underwent standard echocardiography, Tissue Doppler (TDI), two-dimensional strain (2DSE) imaging, and coronary flow reserve (CFR) measurement. LV myocardial early diastolic peak velocities (E(m)) and peak systolic 2DSE were reduced in both interventricular septum (IVS) and LV lateral wall (p<0.01) in DM, as well as CFR (1.89 ± 0.7 vs 2.55 ± 0.56, p<0.0001) compared with controls. By multivariate analysis, the independent determinants of E(m) were glycated haemoglobin (β coefficient=-0.36; p<0.01) and age (β=-0.46, p<0.001), while global longitudinal strain was predicted by glycated haemoglobin (β=0.48, P<0.001) and by the duration of the disease (β=0.38, P<0.005). An independent association between LV global longitudinal strain and CFR (β coefficient=-0.47, p<0.001) in DM patients was also evidenced.

TDI, 2DSE and CFR are valuable non-invasive and easy-repeatable tools for detecting LV myocardial and coronary function in DM patients with microvascular angina.

Microvascular coronary dysfunction (MCD) is associated with symptoms and signs of ischemia, and also adverse outcomes in women without macrovascular obstructive coronary artery disease (M-CAD). Although MCD can be quantified using coronary flow reserve (CFR), treatment is poorly defined.

Phosphodiesterase type 5 (PDE-5) inhibition acutely improves MCD in these women.

The subjects were 23 symptomatic women (age 54 ± 11 y) participating in an ancillary study of the Women's Ischemia Syndrome Evaluation with baseline CFR ≤3.0 (Doppler flow wire and intracoronary adenosine) and without M-CAD. Coronary flow reserve was remeasured 45 minutes after PDE-5 inhibition (100 mg oral sildenafil). The primary measure of interest was change in CFR adjusted for baseline variables.

The relationship between log(2)-transformed CFR post-PDE-5 inhibition (adjusted) and baseline was different from the line of identity (slope: 0.55 vs 1.0, P = 0.008; intercept: 0.73 vs 0.0, P = 0.01), indicating that PDE-5 inhibition improves CFR and the lower the baseline CFR, the greater the response. Among women with baseline CFR ≤2.5 (n = 11), CFR increased from 2.1 ± 0.2 to 2.7 ± 0.6 (P = 0.006). For women with baseline CFR >2.5 (n = 12), CFR did not change (3.1 ± 0.3 to 3.0 ± 0.6; P = 0.70).

For women with symptoms and signs of ischemia and no M-CAD, PDE-5 inhibition is associated with acute improvement in CFR, and the effect concentrates among those with CFR ≤2.5. If these acute effects are sustained, then PDE-5 inhibition would provide a rational strategy for management of MCD in symptomatic women without M-CAD. The longer-term effects warrant study in a randomized trial using a sustained-acting PDE-5 inhibitor.

We set out to describe the clinical characteristics of patients presenting with acute or stable coronary syndromes and no stenosis in epicardial coronaries. Although the existence of patients who experience typical angina and who have intact epicardial coronaries is well accepted, the pathophysiology of cardiac ischemia in this setting remains poorly understood. In typical coronary syndrome X, it is believed that at least two components play a role: the first is the incapacity of coronary resistance vessels to adapt to situations of increased blood demand, resulting in demand ischemia; the second is an inappropriate transduction or generation or pain stimuli within the central nervous system. These two mechanisms concur to determine episodes of precordial pain and electrocardiogram (ECG) evidence of ischemia during exercise. In contrast, the coronary slow-flow phenomenon, or syndrome Y, is an angiographic finding that is characterized by delayed progression of the contrast medium during coronary angiography. Although the mechanism of this phenomenon remains largely unknown, it has been proposed that it might depend on the presence of inappropriately high resting coronary resistances, causing reduced blood flow and therefore low-flow ischemia and unstable angina. Importantly, the prognosis of many of the patients presenting with coronary slow-flow does not appear to be favorable, with recurrence of acute coronary syndromes and life-threatening arrhythmias. In the present article, we revise the current evidence regarding these two phenomena, and propose that syndrome Y should be considered a separate clinical entity.

There is no consensus regarding the definition of cardiac syndrome X (CSX). We systematically reviewed recent literature using a standardized search strategy. We included 57 articles. A total of 47 studies mentioned a male/female distribution. A meta-analysis yielded a pooled proportion of females of 0.56 (n = 1,934 patients, with 95% confidence interval: 0.54-0.59). As much as 9 inclusion criteria and 43 exclusion criteria were found in the 57 articles. Applying these criteria to a population with normal coronary angiograms and treated in 1 year at a general hospital, the attributable CSX incidence varied between 3 and 11%. The many inclusion and exclusion criteria result in a wide range of definitions of CSX and these have large effects on the incidence. This shows the need for a generally accepted definition of CSX.

Cardiac syndrome X defines patients with typical angina, a positive exercise ECG stress test and angiographically documented normal coronary arteries. In previous studies, post-stress prolonged left ventricular dysfunction (PLVD) using gated SPECT (G-SPECT) had been well correlated with myocardial perfusion abnormalities and degree of stenotic vessels in CAG in patients with coronary artery disease. However, evaluation of left ventricular myocardial perfusion, wall motion and left ventricular ejection fraction (LVEF) in patients with cardiac syndrome X, using G-SPECT had not been studied yet. Thus, the aim of this study was to analyse PLVD using (99m)Tc-MIBI GSPECT in patients with cardiac syndrome X.

Of the patients in whom G-SPECT was performed in our institution between 2004 and 2006, 17 patients with anginal chest pain, positive exercise ECG stress test and normal coronary angiograms were retrospectively included to the study (group I). Fifteen patients with normal myocardial perfusion and another 15 patients with ischaemia on G-SPECT were selected as control groups (groups II and III). (99m)Tc-MIBI G-SPECT was performed for all patients according to 2 day (stress-rest) protocol. Stress and rest LVEF were derived automatically (SLVEF and RLVEF). Difference LVEF (DLVEF) (stress-rest) was calculated. Semiquantitative analyses were made both for myocardial perfusion and wall motion (WM), using a 20-segment model and a 5-point scoring system. DLVEF, perfusion and WM scores of all groups were compared among three groups and relationship between DLVEF, perfusion and WM scores were evaluated.

Abnormal perfusion were detected in eight (47.1%) of patients, while the remaining nine (52.9%) had normal myocardial perfusion, in group I. Six of 17 (35.3%) patients in group I had post-stress WM abnormalities. Mean of DLVEF values were -3.1+/-3.0%, 4.4+/-2.0% and -6.0+/-5.1% in groups I, II and III, respectively (P<0.05 for group II vs. group I and group III; P>0.05 for group I vs. group III). LVEF response impairment (< or =5% increase from rest to post-stress images) was found in 17 (100%), seven (46.6%), 14 (93.3%) of patients in groups I, II and III, respectively.

Abnormal myocardial perfusion, concordant transient segmental WM abnormalities and LVEF response impairment are not uncommon in patients with cardiac syndrome X of this cohort of the study population. Therefore, post-stress prolonged stunning may be attributed to these findings in some of cardiac syndrome X patients as in true ischaemic patients. However, further studies with larger number of subjects and long-term follow-up are necessary to support these findings.

Cardiac syndrome X (CSX) encompasses the constellation of anginal chest pain in the presence of a pathological functional test and a normal coronary angiogram. Endothelial progenitor cells (EPCs) in the peripheral circulation contribute to tissue vascularisation.

To investigate the number and functional properties of circulating EPCs in patients with CSX.

17 patients with CSX and a referent population (n = 20) were matched for age, atherosclerotic risk factors and use of drugs. Numbers of EPCs were studied by FACS, and their functional properties, including their proliferative capacity, adherence to matrix and mature endothelial cells as well as their ability to support in vitro tube formation, were investigated. Levels of soluble markers that associate with peripheral mobilisation and homing were studied in the serum samples of all subjects.

Patients with CSX had significantly increased numbers of circulating EPCs as compared with the referent population (both CD34+/KDR and CD34+/CD133+). The proliferative capacity of EPCs and their ability to support in vitro tube formation were significantly impaired in patients with CSX as compared with the referent population. However, adhesiveness of EPCs from patients with CSX to fibronectin and cultured mature endothelial cells was enhanced as compared with the referent population. Serum vascular endothelial growth factor correlated with peripheral CD34+/KDR cell numbers, whereas serum concentration of erythropoietin correlated with the number of circulating CD34+/CD133+ cells

Patients with CSX have a significantly altered circulating EPC phenotype that could potentially aid in understanding the complex pathogenesis of the syndrome.

Chest pain is one of the most common symptoms for seeking acute medical care. Evidence of myocardial ischemia, however, can only be established in a minority of patients. The establishment or ruling out of myocardial ischemia is difficult and the cost is high. An effective rationale for ischemia detection, without unnecessary hospital admission, is needed. The development of chest pain units potentially offers a rapid, effective way of identifying patients at high risk for acute coronary syndromes, as well as those with a low probability of ischemia. Other cardiac or noncardiac causes of chest pain should also be considered.

Recent developments in chest pain, including the ruling in or out of ischemic pain by triage and different ischemia detection methods, are discussed. Other causes of chest pain such as esophageal, drug related, psychiatric and post-coronary bypass surgery pain are also discussed. Recent findings on syndrome X are reviewed and patients with myocardial infarction presenting without chest pain are discussed.

The possibility of safely and quickly ruling out myocardial ischemia by point-of-care biochemical analyses is reviewed, which might influence our clinical handling of chest pain patients. The importance of biopsychosocial factors, pain perception, esophageal dysfunction, drugs and the coronary artery bypass procedure in itself, is discussed and vital clinical information is provided for the handling of our chest pain patients.

Cardiac syndrome X (CSX), or angina with no flow-limiting stenosis on coronary angiogram, has been regarded as a condition with an excellent prognosis despite variable symptomatic improvement. Newer data show that patients with CSX with endothelial dysfunction have an increased risk for future adverse cardiac events. Current hypotheses of CSX pathophysiology emphasize a dysfunctional vascular endothelium that leads to microvascular ischemia. Treatments that target improving endothelial function, such as statins, angiotensin-converting enzyme inhibitors, estrogen, and lifestyle modification, are promising additions to treatment regimens for CSX. The goal of this article is to provide information for improved diagnosis, risk stratification, and therapy for the population with CSX.

The prevalence of ischemic heart disease is lower in premenopausal females than in males of corresponding age. This should be related to gender differences in coronary functions. We tested whether biomechanical differences exist between intramural coronary resistance arteries of male and female rats. Intramural branches of the left anterior descending coronary artery (uniformly approximately 200microm in diameter) were isolated, cannulated and studied by microarteriography. Intraluminal pressure was increased from 2 to 90mmHg in steps and steady-state diameters were measured. Measurements were repeated in the presence of vasoconstrictor U46619 (10(-6)M) and the endothelial coronary vasodilator bradykinin (BK) (10(-6)M). Finally, passive diameters were recorded in calcium-free saline. A similar inner radius and a higher wall thickness (41.5+/-2.9microm vs. 31.4+/-2.7microm at 50mmHg in the passive condition, p<0.05) resulted in lower tangential wall stresses in male rats (18.9+/-1.9kPa vs. 24.9+/-2.5kPa at 50mmHg, p<0.05). Isobaric elastic modulus of vessels from male animals was significantly smaller at higher pressures. Vasoconstrictor response was significantly stronger in male than in female animals. Endothelial relaxations induced by BK were not different. This is the first demonstration that biomechanical characteristics of intramural coronary resistance arteries of a mammalian species are different in the male and female sexes. Higher wall thickness and higher vascular contractility in males are associated with similar endothelial function and larger high-pressure elasticity compared to females. These gender differences in biomechanics of coronary resistance arteries of rats may contribute to our better understanding the characteristic physiological and pathological differences in humans.

Cardiac syndrome X (CSX), defined as typical exertional chest pain, a positive response to stress testing, and normal coronary arteriograms, encompasses different pathogenic subgroups. Both cardiac and non-cardiac mechanisms have been suggested to play a pathogenic role, and it has been shown that the syndrome is associated with myocardial ischaemia in at least a proportion of patients. Radionuclide myocardial perfusion defects, coronary sinus oxygen saturation abnormalities and pH changes, myocardial lactate production and stress-induced alterations of cardiac high energy phosphate have been reported in CSX patients, suggesting an ischaemic origin for their symptoms. Microvascular abnormalities often caused by endothelial dysfunction appear to be responsible for myocardial ischaemia in these patients. CSX is more prevalent in women than in men, and the majority of women with CSX are peri- or post-menopausal. Thus oestrogen deficiency has been suggested to have a pathogenic role in CSX. Additional factors such as abnormal pain perception may also contribute to the genesis of chest pain in patients with angina and normal coronary angiograms. The management of this syndrome is difficult because of the heterogeneity of pathogenic mechanisms and uncertainties as to its origin. This article discusses the problem of CSX in women, the potential pathogenic role of oestrogen deficiency, and practical clinical management.

Patients with cardiac syndrome X (typical chest pain and normal coronary arteriograms) represent a heterogeneous syndrome, which encompasses different pathogenic mechanisms. Although symptoms in most patients with cardiac syndrome X are non-cardiac, a sizable proportion of them have angina pectoris due to transient myocardial ischemia. Thus radionuclide myocardial perfusion defects, coronary sinus oxygen saturation abnormalities and pH changes, myocardial lactate production and stress-induced alterations of cardiac high energy phosphate suggest an ischemic origin of symptoms in at least a proportion of patients with cardiac syndrome X. Microvascular abnormalities, caused by endothelial dysfunction, appear to be responsible for myocardial ischemia in patients with cardiac syndrome X. Endothelial dysfunction is likely to be multifactorial in these patients and it is conceivable that risk factors such as hypertension, hypercholesterolemia, diabetes mellitus and smoking can contribute to its development. Most patients with cardiac syndrome X are postmenopausal women and estrogen deficiency has been therefore proposed as a pathogenic factor in female patients. Additional factors such as abnormal pain perception may contribute to the pathogenesis of chest pain in patients with angina pectoris and normal coronary angiograms. Although prognosis is good regarding survival, patients with cardiac syndrome X have an impaired quality of life. Management of this syndrome represents a major challenge to the treating physician. Understanding the mechanism underlying the condition is of vital importance for patient management. Thus diagnostic tests should aim at identifying the cause of the symptoms in the individual patient, i.e. myocardial ischemia, increased pain perception, abnormalities of adrenergic tone, non-cardiac mechanisms, etc. Moreover, it is important to bear in mind that treatment of cardiac syndrome X should be mainly directed towards improving quality of life, as prognosis is usually good in these patients. Conventional antianginal agents such nitrates, calcium channel antagonists, beta-adrenoceptor antagonists and nicorandil are effective particularly in patients in whom chest pain and ECG changes are clearly suggestive of myocardial ischemia and in those with objective documentation of ischemia. Angiotensin-converting enzyme inhibitors have been shown to be useful in syndrome X patients with increased adrenergic tone, borderline systemic hypertension, and those with documented endothelial dysfunction. Analgesic interventions of different sorts have been proposed based on the hypothesis that somatic and visceral perception of pain is altered in cardiac syndrome X patients. Pharmacological agents such as imipramine and aminophylline, and neural electrical stimulation techniques have been assessed in recent years with encouraging results. Psychological treatment, particularly cognitive therapy, appears to be useful in defined patient subsets. Relaxation techniques such as transcendental meditation have been successfully used in small studies and shown to improve not only chest pain but also exercise-induced ST segment changes. Reports indicate that these techniques improve quality of life.

Metabolic syndrome is more prevalent in men than in women. In an experimental dietary model of metabolic syndrome, the high-fructose-fed rat, oxidative stress has been observed in males. Given that estradiol has been documented to exert an antioxidant effect, we investigated whether female rats were better protected than males against the adverse effects of a high-sucrose diet, and we studied the influence of hormonal status in female rats. Males and females were first fed a sucrose-based or starch-based diet for 2 weeks. In the males, the plasma triglyceride (TG)-raising effect of sucrose was accompanied by significantly lowered plasma alpha-tocopherol and a significantly lowered alpha-tocopherol/TG ratio (30%), suggesting that vitamin E depletion may predispose lipoproteins to subsequent oxidative stress. In males, after exposure of heart tissue homogenate to iron-induced lipid peroxidation, thiobarbituric reactive substances were significantly higher in the sucrose-fed than in the starch-fed rats. In contrast, in sucrose-fed females, neither a decrease in vitamin E/TG ratio nor an increased susceptibility of heart tissue to peroxidation was observed, despite both a significantly decreased heart superoxide dismutase activity (14%) and a significant 3-fold increase in plasma nitric oxide concentration compared with starch-fed females. The influence of hormonal status in female rats was then assessed using intact, ovariectomized, or estradiol-supplemented ovariectomized female rats fed the sucrose or starch diet for 2 weeks. After exposure of heart tissue to iron-induced lipid peroxidation, higher susceptibility to peroxidation was found only in ovariectomized females fed the sucrose diet compared with the starch group and not in intact females or ovariectomized females supplemented with estradiol. Thus, estrogens, by their effects on antioxidant capacity, might explain the sexual difference in the pro-oxidant effect of sucrose diet resulting in metabolic syndrome in rats.