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Introduction and Objectives: Whole blood viscosity (WBV) is the intrinsic resistance of blood flow in vessels, and when elevated induces endothelial shear stress and endothelial inflammation and can accelerate the atherosclerotic process. This study aims to compare WBV levels in patients with microvascular angina (MVA), patients with coronary artery disease (CAD), and normal controls, and to identify the relationship between WBV and high-sensitivity C-reactive protein as a marker of inflammation in MVA and CAD., Methods: A total of 573 patients were studied. The MVA group consisted of 189 subjects, the CAD group consisted of 203 subjects, and the control group consisted of 181 age- and gender-matched individuals. WBV was calculated from hematocrit and plasma protein concentration at a low shear rate (0.5 s -1 ) and high shear rate (208 s -1 ) by a validated equation., Results: Patients with CAD and MVA had significantly higher WBV at both low and high shear rates compared to the control group. Correlation analysis revealed a significant relationship between high-sensitivity C-reactive protein and WBV at low (r=0.556; p<0.001) and high shear rates (r=0.562) in the CAD group and at low (r=0.475) and high shear rates (r=0.493) in the MVA group., Conclusions: Overall, this study demonstrated a significant and independent association between blood viscosity and the existence of endothelial inflammation and the atherosclerotic process., (Copyright © 2020 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: A sizeable proportion of patients with primary stable microvascular angina (MVA; exercise-induced angina, positive exercise stress test [EST], normal coronary arteries) have recurrent symptoms during follow-up. There have been no previous studies, however, on the long-term results of EST and their correlation with symptom outcome.Methods and Results:Follow-up EST was performed in 71 MVA patients at an average of 16.2 years (range, 5-25 years) from the first EST. Angina status was assessed on weekly frequency of angina episodes and nitroglycerin consumption and by whether symptoms had worsened, improved, or remained unchanged over time. At follow-up EST, 41 patients (group 1) had exercise-induced ischemia, whereas 30 patients (group 2) had negative EST. Compared to group 2, group 1 patients more frequently had exercise-induced dyspnea, and had a greater maximum ST-segment depression and a lower coronary blood flow response to adenosine and cold pressor test, but group 2 patients had a more frequent history of rest angina. No differences between the 2 groups were found at follow-up in angina status or change in symptom status during follow-up., Conclusions: Electrocardiogram results improve significantly in a sizeable proportion of patients with MVA. Changes in EST results, however, were not associated with clinical outcome.

Background: Microvascular angina (MVA) is an incompletely understood clinical entity. Computational analysis of coronary Computed Tomography Angiography (CTA) has shown an association between low coronary lumen volume to myocardial mass (V/M) ratio and lower Fractional Flow Reserve values, independent of plaque measures. We hypothesized that low V/M ratio may be present in patients with MVA., Methods: A retrospective case-control analysis was performed using patients fulfilling guideline criteria for MVA with controls matched for age, gender, coronary risk factors and atherosclerotic plaque burden. V/M was extracted off site (Heartflow Inc; Redwood City, CA) employing allometric scaling laws that allow the definition of the coronary circulation beyond the epicardium. FFR CT values were calculated in the major epicardial coronary arteries for each group., Results: A total of 30 patients with MVA and 32 matched controls were included in the study. Mean total coronary lumen volume (2302 mm 3  ± 109 vs 2978 mm 3  ± 134, p < 0.001) and mean myocardial mass (90.4 g ± 13.7 vs 100.4 g ± 20.1, p = 0.029) were lower in MVA patients compared to controls. Mean V/M ratio was significantly lower in MVA compared to controls (25.6 mm 3 /g ± 5.9 vs 30.0 mm 3 /g ± 6.5, p = 0.007; c-statistic 0.69). V/M ratio did not differ significantly between subclasses of angina severity (p = 0.747). No difference in mean nadir FFR CT values was found between MVA and control groups in the LAD (0.86 ± 0.07 vs 0.83 ± 0.07, p = 0.154), LCX (0.90 ± 0.05 vs 0.90 ± 0.06, p = 0.240) and RCA (0.90 ± 0.04 vs 0.90 ± 0.03, p = 0.773) vessels., Conclusion: Patients with microvascular angina demonstrate a significantly lower coronary CTA-derived coronary volume/myocardial mass ratio than asymptomatic controls., (Copyright © 2017 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to evaluate left atrial (LA) volume and function using real time three-dimensional echocardiography (RT3DE) in patients with cardiac syndrome X (CSX)., Methods: Fifty patients with CSX (28 females; mean age 50.9±10.9 years) and 50 age- and gender-matched healthy controls (30 females; mean age 52.3±9.8 years) who had negative treadmill exercise test and normal coronary arteries on invasive coronary angiography were included in the study. Comprehensive two-dimensional (2D), pulsed and tissue Doppler, speckle tracking echocardiography, and RT3DE for the assessment of LA dynamics were performed in all study participants., Results: Cardiac syndrome X and control groups have similar clinical characteristics regarding age, sex, body mass index, hypertension, diabetes, and smoking habit. 2D echocardiographic parameters were also similar between groups. Pulsed- and tissue Doppler parameters, IVRT, A, and A m values, were higher in CSX group, while E m , E/A, and E m /A m ratios were higher in the control group reflecting mild diastolic dysfunction. Regarding RT3DE parameters, LA maximum volume, minimum volume, volume before atrial contraction, LA maximum volume index, total and active stroke volumes were found to be increased in CSX patients. However, LA total stroke fraction, passive stroke volume, passive stroke fraction, peak systolic, and diastolic longitudinal strains were found to be lower in CSX patients., Conclusion: The main finding of this study was that CSX patients had altered LA booster pump, reservoir, and conduit functions. This finding may have clinical implications for early detection of abnormal LA dynamics in CSX patients., (© 2017, Wiley Periodicals, Inc.)

In patients with typical angina pectoris, inducible myocardial ischaemia and macroscopically normal coronaries (cardiac syndrome X (CSX)), a significantly elevated plasma level of terminal complement complex (TCC), the common end product of complement activation, has been observed without accompanying activation of the classical or the alternative pathways. Therefore, our aim was to clarify the role of the ficolin-lectin pathway in CSX. Eighteen patients with CSX, 37 stable angina patients with significant coronary stenosis (CHD) and 54 healthy volunteers (HC) were enrolled. Serum levels of ficolin-2 and ficolin-3, ficolin-3/MASP-2 complex and ficolin-3-mediated TCC deposition (FCN3-TCC) were determined. Plasma level of TCC was significantly higher in the CSX than in the HC or CHD group (5.45 versus 1.30 versus 2.04 AU/ml, P < 0.001). Serum levels of ficolin-2 and ficolin-3 were significantly lower in the CSX compared to the HC or CHD group (3.60 versus 5.80 or 5.20 μg/ml, P < 0.05; 17.80 versus 24.10 or 26.80 μg/ml, P < 0.05). The ficolin-3/MASP-2 complex was significantly lower in the CSX group compared to the HC group (92.90 versus 144.90 AU/ml, P = 0.006). FCN3-TCC deposition was significantly lower in the CSX group compared to the HC and CHD groups (67.8% versus 143.3% or 159.7%, P < 0.05). In the CSX group, a significant correlation was found between TCC and FCN3-TCC level (r = 0.507, P = 0.032) and between ficolin-3/MASP-2 complex level and FCN3-TCC deposition (r = 0.651, P = 0.003). In conclusion, in patients with typical angina and myocardial ischaemia despite macroscopically normal coronary arteries, low levels of several lectin pathway parameters were observed, indicating complement activation and consumption. Complement activation through the ficolin-lectin pathway might play a role in the complex pathomechanism of CSX., (© 2016 The Foundation for the Scandinavian Journal of Immunology.)

In recent years, human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have emerged as a vital cell source for in vitro modeling of genetic cardiovascular disorders, drug screening, and in vivo cardiac regeneration research. Looking forward, the ability to efficiently cryopreserve hPSC-CMs without compromising their normal biochemical and physiologic functions will dramatically facilitate their various biomedical applications. Although working protocols for freezing, storing, and thawing hPSC-CMs have been established, the question remains as to whether they are optimal. In this chapter, we discuss our current understanding of cryopreservation appertaining to hPSC-CMs, and proffer key questions regarding the mechanical, contractile, and regenerative properties of cryopreserved hPSC-CMs.

The aim of this study was to explore the significance of different ST-segment changes before and after percutaneous coronary intervention (PCI), in relation to cardiac magnetic resonance (CMR)-verified microvascular obstruction (MVO) along with intramyocardial hemorrhage (IMH) in ST-elevation myocardial infarction (STEMI) patients.This study enrolled 108 STEMI patients who received primary PCI and had no contraindication of CMR investigation. Sum ST-segment elevation (STE), maximal STE on admission and sum ST-segment resolution (STR), and single-lead STR and residual STE at 60 minutes after primary PCI were assessed. MVO and IMH were determined by contrast-enhanced CMR.Patients were classified into 3 groups: 30 patients with MVO(-)/IMH(-), 25 with MVO(+)/IMH(-), and 53 with MVO(+)/IMH(+). Sum STE (P = 0.001), maximal STE (P < 0.001), and residual STE (P = 0.025) were highest and single-lead STR was lowest (P = 0.044) in the MVO(+)/IMH(+) group. Receiver operator characteristics curve analysis revealed that maximal STE was the most powerful factor for distinguishing between MVO(+) and MVO(-) patients (optimal threshold = 0.5 mV, area under the curve, AUC = 0.718, P < 0.001), or IMH(+) and IMH(-) patients (optimal threshold = 0.5 mV, AUC = 0.697, P < 0.001). In multivariate analysis, maximal STE was identified as the most powerful independent predictor of MVO (odds ratio [OR] = 4.30, P < 0.001) and IMH (OR = 2.44, P = 0.001), whereas sum STE was the strongest correlate of both the number of MVO segments (r = 0.42, P < 0.001) and IMH segments (r = 0.43, P < 0.001).The presence of MVO and IMH in infarcted tissue was relevant to ST-segment changes in STEMI patients. Maximal STE was a powerful independent predictor of the presence of MVO and IMH, whereas sum STE was a strong correlate of the number of MVO and IMH segments.

A decreased nitric oxide (NO) bioavailability and an increased oxidative stress play a pivotal role in different cardiovascular pathologies. As red blood cells (RBCs) participate in NO formation in the bloodstream, the aim of this study was to outline the metabolic profile of L-arginine (Arg)/NO pathway and of oxidative stress status in RBCs and in plasma of patients with microvascular angina (MVA), investigating similarities and differences with respect to coronary artery disease (CAD) patients or healthy controls (Ctrl). Analytes involved in Arg/NO pathway and the ratio of oxidized and reduced forms of glutathione were measured by LC-MS/MS. The arginase and the NO synthase (NOS) expression were evaluated by immunofluorescence staining. RBCs from MVA patients show increased levels of NO synthesis inhibitors, parallel to that found in plasma, and a reduction of NO synthase expression. When summary scores were computed, both patient groups were associated with a positive oxidative score and a negative NO score, with the CAD group located in a more extreme position with respect to Ctrl. This finding points out to an impairment of the capacity of RBCs to produce NO in a pathological condition characterized mostly by alterations at the microvascular bed with no significant coronary stenosis.

Background: Circulating endothelial progenitor cells (EPCs) might limit endothelial dysfunction in patients with microvascular angina (MVA). Endothelial colony-forming cells (ECFCs; displaying the CD34+/KDR+/CD45- phenotype) are currently regarded as true EPCs. The aim of this study was to evaluate exercise-induced ECFC mobilization and platelet reactivity in patients with MVA or with obstructive coronary artery disease (CAD)., Methods and Results: Exercise stress test (EST) was performed in 20 MVA patients, 20 CAD patients and 20 controls. Platelet reactivity was assessed before and after EST as formation of monocyte-platelet aggregates (MPAs) and CD41 platelet expression, without and with adenosine diphosphate (ADP) stimulation. ECFC number was measured before and 24h after EST. At rest, MPAs and CD41 platelet expression increased more with ADP in MVA patients (+71±11.0% and +37±7.5%, respectively), than in CAD patients (+37±8.6% and +19±4.5%, respectively) and controls (+29±3.5% and +21±3.1%, respectively; P<0.001 for both). At rest, ECFCs tended to be lower in CAD patients, compared to MVA patients and controls (4.1±5.0%, 7.2±6.0% and 7.3±7.0% cells/10(5), respectively; P=0.056). After EST, ECFCs increased less in MVA patients (+2.8±11) compared to CAD patients (+3.3±15; P<0.05) and controls (+7.4±24; P<0.01)., Conclusions: In MVA patients, EST is able to blunt the peculiar increase of platelet reactivity to ADP present at rest; in contrast, no potential protective response of ECFCs to exercise was seen in these patients.

Background: The pathophysiology of chest pain in patients with cardiac syndrome X remains controversial. Advances in perfusion imaging with cardiovascular magnetic resonance (CMR) now enable absolute quantification of regional myocardial blood flow (MBF). Furthermore, blood oxygen level-dependent (BOLD) or oxygenation-sensitive CMR provides the unprecedented capability to assess regional myocardial oxygenation. We hypothesized that the combined assessment of regional perfusion and oxygenation with CMR could clarify whether patients with syndrome X show evidence of myocardial ischemia (reduced perfusion and oxygenation) during vasodilator stress compared with normal volunteers., Methods and Results: Eighteen patients with syndrome X (chest pain, abnormal exercise treadmill test, normal coronary angiogram without other causes of microvascular dysfunction) and 14 controls underwent CMR scanning at 3 T. Myocardial function, scar, perfusion (2-3 short-axis slices), and oxygenation were assessed. Absolute MBF was measured during adenosine stress (140 μg/kg per minute) and at rest by model-independent deconvolution. For oxygenation, using a T2-prepared BOLD sequence, signal intensity was measured at adenosine stress and rest in the slice matched to the midventricular slice of the perfusion scan. There were no significant differences in MBF at stress (2.35 versus 2.37 mL/min per gram; P=0.91), BOLD signal change (17.3% versus 17.09%; P=0.91), and coronary flow reserve measurements (2.63 versus 2.53; P=0.60) in patients with syndrome X and controls, respectively. Oxygenation and perfusion measurements per coronary territory were also similar between the 2 groups. More patients with syndrome X (17/18 [94%]) developed chest pain during adenosine stress than controls (6/14 [43%]; P=0.004)., Conclusions: Patients with syndrome X show greater sensitivity to chest pain compared with controls but no evidence of deoxygenation or hypoperfusion during vasodilatory stress.

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.

Objective: Cardiac syndrome X (CSX) is defined by an angina-like chest pain, a positive response to stress testing and normal or near normal coronary angiogram. We evaluated the angiographic findings in patients with cardiac syndrome X and compared it with myocardial perfusion scintigraphy findings., Patients and Methods: The study included 39 females aged 40-58 years (mean, 49.79 +/- 4.69 [SD] and 13 males ranging from 40 to 54 years (mean, 47.54 +/- 3.76 [SD] with CSX. By reviewing the angiographic film, some variables including stenosis (less than 30% of vessel diameter), delay run off, delay wash out, calcification and tortuosity were evaluated. Thirty-two had been undergone on myocardial perfusion imaging (MPI)., Results: The most frequent abnormal angiographic finding in three territories was stenosis item. Overall, 22 of 32 (68.75%) CSX patients had ischemia on MPI. The result of the myocardial perfusion imaging was not concordant with five angiographic findings., Conclusion: We suggest that the presence of angiographic coronary findings such as stenosis, delay run off, delay wash out, calcification and tortuosity are not invariably associated with atherosclerosis, and also seen in CSX patients.

Women exhibit a greater symptom burden, more functional disability, and a higher prevalence of no obstructive coronary artery disease compared to men when evaluated for signs and symptoms of myocardial ischemia. Microvascular coronary dysfunction (MCD), defined as limited coronary flow reserve and/or coronary endothelial dysfunction, is the predominant etiologic mechanism of ischemia in women with the triad of persistent chest pain, no obstructive coronary artery disease, and ischemia evidenced by stress testing. Evidence shows that approximately 50% of these patients have physiological evidence of MCD. MCD is associated with a 2.5% annual major adverse event rate that includes death, nonfatal myocardial infarction, nonfatal stroke, and congestive heart failure. Although tests such as adenosine stress cardiac magnetic resonance imaging may be a useful noninvasive method to predict subendocardial ischemia, the gold standard test to diagnose MCD is an invasive coronary reactivity testing. Early identification of MCD by coronary reactivity testing may be beneficial in prognostication and stratifying these patients for optimal medical therapy. Currently, understanding of MCD pathophysiology can be used to guide diagnosis and therapy. Continued research in MCD is needed to further advance our understanding., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Microvascular angina (MVA) is an often overlooked cause of significant chest pain. Decreased myocardial perfusion secondary to dysregulated blood flow in the microvasculature can occur in the presence or absence of obstructive epicardial coronary artery disease. The corresponding myocardial ischemia and angina is now a well-established diagnosis, made by detection of decreased coronary flow reserve (CFR). Although low CFR and MVA are associated with poor prognosis, there is initial evidence for reversibility of this abnormal vascular regulation with aggressive medical therapy and control of associated risk factors. Current assessment of MVA is carried out predominantly during cardiac catheterization; however, noninvasive techniques to assess CFR are being developed, including PET, MRI, and CT modalities. Quantitative tracer techniques or imaging of metabolic disturbances reflecting ischemia will likely enhance diagnostic approaches for such patients as well as allow more frequent monitoring of response to therapy.

Background: Acute hyperglycaemia has been associated with impaired microvascular function after acute myocardial infarction (AMI), whereas pre-infarction angina (PIA) occurring shortly before the onset of AMI has been shown to reduce microvascular injury after reperfusion., Objective: To examine whether acute hyperglycaemia prevents the protective effect of PIA on microvascular function after AMI., Methods: We studied 205 patients with a first anterior wall AMI who underwent primary angioplasty within 12 hours of onset. Coronary flow velocity parameters were assessed immediately after reperfusion using a Doppler guidewire. Severe microvascular injury was defined as the presence of systolic flow reversal and diastolic deceleration time <600 ms. Echocardiographic wall motion was analysed before revascularisation and 4 weeks later., Results: Acute hyperglycaemia, defined as a blood glucose level of >or=198 mg/dl on admission, was found in 67 (33%) patients. In patients without acute hyperglycaemia, PIA was associated with a lower incidence of systolic flow reversal, a longer diastolic deceleration time and a higher coronary flow reserve. However, in patients with acute hyperglycaemia there was no significant difference in these same parameters between patients with and without PIA. In the presence of acute hyperglycaemia PIA did not improve the change in wall motion score. In a multivariate model, the absence of PIA was an independent determinant of severe microvascular injury in patients without acute hyperglycaemia (odds ratio 6.28, p = 0.001), but not in patients with acute hyperglycaemia., Conclusion: The protective effect of PIA on microvascular function was attenuated in patients with acute hyperglycaemia, resulting in unfavourable functional recovery.

Background: In patients with cardiac syndrome X (CSX) who present with refractory angina episodes, spinal cord stimulation (SCS) has beneficial effects. The mechanisms of SCS, however, remain speculative. We assessed the effects of SCS on cardiac sympathetic function in these patients., Methods and Results: We studied 11 CSX patients treated by SCS for refractory angina (mean age, 60 +/- 9 years; 5 men and 6 women), both during SCS therapy (SCS-ON) and after withdrawal of SCS therapy (SCS-OFF), using a randomized crossover design. Planar and single photon emission computed tomography iodine 123 metaiodobenzylguanidine (MIBG) myocardial scintigraphy and technetium 99m sestamibi (MIBI) bicycle exercise stress testing were performed at the end of each period. Compared with 10 healthy control subjects, CSX patients showed a lower heart-mediastinum ratio for MIBG uptake (2.19 +/- 0.3 vs 1.69 +/- 0.3, P = .001) and a higher cardiac MIBG uptake score (4.0 +/- 2.5 vs 19.7 +/- 27, P = .08). There were no differences in CSX patients during the SCS-ON and SCS-OFF phases of the study in heart-mediastinum ratio (1.74 +/- 0.3 vs 1.69 +/- 0.3, P = .13), cardiac washout rate of MIBG (42.9% +/- 14% vs 43.3% +/- 14%, P = .08), or MIBG defect score (18.7 +/- 25 vs 19.7 +/- 27, P = .22). Reversible perfusion defects during the SCS-OFF phase were detected in 8 patients; an improvement in perfusion defects was observed in 2 patients (25%) during the SCS-ON phase., Conclusions: Our data confirm the presence of abnormal cardiac adrenergic nerve function in CSX patients. SCS was unable to result in significant improvement of cardiac MIBG uptake abnormalities, suggesting that its therapeutic effects are unlikely to be mediated by modulation of cardiac adrenergic nerve activity.

Background: Regardless of normal coronary angiograms, coronary artery calcium (CAC) can be found in cardiac syndrome X (CSX) patients. According to some data, a relationship between the CAC score and markers of early atherosclerosis in CSX has been observed. Our aim was to assess whether the extent of the CAC score assessed by multislice computed tomography (MSCT) with a 64-slice system in CSX patients is related to brachial artery reactivity, intima-media thickness (IMT), and arterial compliance indexes., Methods and Results: High-resolution ultrasound was used to measure flow-mediated dilatation (FMD) and nitroglycerin-mediated vasodilatation, as well as the following parameters of arterial structural changes: IMT, pulse wave velocity, total arterial compliance, and stiffness index. MSCT was used to assess the presence and the quantity of CAC. The study group consisted of 46 CSX patients (mean age, 56.3 +/- 9 years), whereas the control group comprised 21 healthy subjects (mean age, 54.9 +/- 7 years). The assessment of the vascular parameters showed significantly decreased FMD and increased IMT in the CSX subjects (9.06% +/- 3.2% and 0.67 +/- 0.1 mm, respectively) in comparison to the control subjects (17.42% +/- 8.4% [P = .008] and 0.57 +/- 0.2 mm [P = .021], respectively). CAC was detectable in 19 CSX patients (41%) (CAC range according to Agatston score, 2-500; mean, 101.6; median, 26.5) and in 1 control subject (4.8%) (CAC value, 13). CSX patients with detectable CAC were characterized by a significantly higher age (P = .001), lower body mass index (P = .017), and increased stiffness index (P = .020); there were no differences in FMD and IMT values. In a multivariate logistic and linear regression analysis, age was the only risk factor independently associated with the presence of CAC (P = .001) and the log(CAC + 1) value (P = .01). In the subgroup of women, log(CAC + 1) significantly correlated with age (r = 0.587, P = .002) and stiffness index (r = 0.427, P = .024), and in a borderline significant manner, it correlated with weight (r = -0.329, P = .07) and waist-hip ratio (r = 0.315, P = .07). There were no significant correlations in the male subgroup., Conclusions: Low ranges of CAC are frequently detectable in CSX patients, and the results are age-related and independent of impaired early indexes of functional and structural vascular remodeling.

Objectives: The purpose of this study was to investigate whether a direct relation can be demonstrated between myocardial perfusion defects detected during dobutamine stress test (DST) by cardiovascular magnetic resonance (CMR) and impairment of coronary microvascular dilatory function in patients with cardiac syndrome X (CSX)., Background: Despite the fact that coronary microvascular dysfunction has been shown in most patients with CSX, the ischemic origin of CSX remains debated. No previous study assessed whether a strict relation exists between abnormalities in myocardial perfusion and coronary microvascular dysfunction in CSX patients., Methods: Eighteen CSX patients (mean age 58 +/- 7 years, 7 men) and 10 healthy control subjects (mean age 54 +/- 8 years, 4 men) underwent myocardial perfusion study by gadolinium-enhanced CMR at rest and at peak DST (maximal dose 40 microg/kg/min). Coronary flow response (CFR) to adenosine (140 microg/kg/min in 90 s) in the left anterior descending (LAD) coronary artery was assessed by high-resolution transthoracic echo-Doppler and expressed as the ratio between coronary flow velocity at peak adenosine and at rest., Results: At peak DST, reversible perfusion defects on CMR were found in 10 CSX patients (56%) but in none of the control subjects (p = 0.004). The CFR to adenosine in the LAD coronary artery was lower in CSX patients than in control subjects (2.03 +/- 0.63 vs. 3.29 +/- 1.0, p = 0.0004). The CSX patients with DST-induced myocardial perfusion defects in the LAD territory on CMR had a lower CFR to adenosine compared with those without perfusion defects in the LAD territory (1.69 +/- 0.5 vs. 2.31 +/- 0.6, p = 0.01). A significant correlation was found in CSX patients between CFR to adenosine and a DST perfusion defect score on CMR in the LAD territory (r = -0.45, p = 0.019)., Conclusions: Our data concurrently show DST-induced myocardial perfusion defects on CMR and reduced CFR in the LAD coronary artery territory in CSX patients, thus giving strong evidence that a dysfunction of coronary microcirculation resulting in myocardial perfusion abnormalities is present in these patients.

The pathogenesis and pathohistological changes of CSX, a syndrome characterized by anginal chest pain and normal coronary arteries on coronary angiography, is poorly understood. The purpose of this study was to analyse morphological changes in small blood vessels of the CSX patients with increased CRP levels (above 5 mg/l). EMB was performed for diagnostic purposes in 31 female patients with CSX, and EMB specimens were histologically and immunohistochemically analysed. Increased CRP was found in 18 (58.1%) female patients with CSX. Signs of inflammation in the walls of small blood vessels were demonstrated in 13 (76%) and TUNEL-positive endothelial cells in 3 (17%) women with increased CRP. Morphological analysis of small blood vessels in EMB in CSX female patients with increased CRP levels revealed signs of inflammation and apoptosis of endothelial cells, indicating the role of inflammation in the pathogenesis of CSX.

Objective: To determine the possible differences in lipid, thrombogenic and inflammatory marker concentrations and the presence of chronic and acute coronary artery disease (stable and unstable angina, respectively), comparing them with a group of control patients with normal coronary arteries., Material and Methods: This prospective cohort study included 125 patients with unstable angina, 189 with stable angina and a control group of 83 patients with normal coronary arteries. Marker concentrations were measured in all 3 groups. Logistic regression analysis was performed to determine whether such factors could predict unstable or stable angina., Results: Lipid parameter concentrations were similar in the 2 coronary disease groups and significantly lower than in controls. Haemostatic and inflammatory marker concentrations were higher in patients with coronary disease, but were statistically significant only when comparing unstable angina patients with normal controls. Unstable angina patients had significantly higher levels of lipoprotein (a) [Lp(a)], fibrinogen, C-reactive protein (CRP) and leucocytes. Multiple logistic regression analysis showed that CRP (OR 2.635, 95% CI 1.417-4.898), smoking (OR 3.416, 95% CI 1.773-6.584), leucocytes (OR 2.034, 95% CI 1.079-3.836) and Lp(a) (OR 2.269, 95% CI 1.188-4.334) were independent risk factors of unstable versus stable angina., Conclusions: Patients with unstable angina present a more atherogenic profile than patients with stable angina. Together with smoking, elevated Lp(a), CRP and leucocyte concentrations proved to be associated with the presence of unstable angina., (Copyright 2009 S. Karger AG, Basel.)

Background: The pathophysiological mechanism in cardiac syndrome X has been suggested as impairment in normal endothelial function of the coronary microvasculature, resulting in inadequate flow reserve. However, despite the extensive studies, the precise mechanisms in cardiac syndrome X remain unclear., Purpose: The present study was, therefore, to investigate whether inflammatory cells and markers such as C-reactive protein (CRP) and interleukin-6 (IL-6) might be involved in the pathogenesis of cardiac syndrome X., Methods: Thirty-six female patients with cardiac syndrome X and 30 sex-matched normal controls were prospectively enrolled in this study. Blood samples were drawn for measuring white blood and monocyte cells, inflammatory markers such as CRP and IL-6, and data were compared between patients with cardiac syndrome X and normal controls., Results: The data showed that increased numbers of white blood and monocyte cells were found in patients with cardiac syndrome X compared with normal controls (white blood cells: 7072+/-1146/mm(3) vs. 6138+/-1079/mm(3); monocyte cells: 612+/-186/mm(3) vs. 539+/-190/mm(3)p<0.05, respectively). Moreover, patients with cardiac syndrome X were detected to have significantly higher plasma CRP and IL-6 levels in comparison with patients with normal controls (CRP: 0.48+/-0.26 mg/L vs. 0.22+/-0.15 mg/L; IL-6: 13.4+/-1.2 pg/dl vs. 6.2+/-0.6 pg/dl, p<0.01, respectively). The multivariate analysis showed that CRP was the independent variable most strongly associated with cardiac syndrome X., Conclusions: Our data suggested that low-grade, chronic inflammation might contribute to the development of cardiac syndrome X manifested by increased plasma levels of inflammatory cells and inflammatory markers.

Background/objectives: The extent of microvascular obstruction (MVO) during myocardial infarction referred to as the "no-reflow phenomenon", may determine myocardial damage. Our study aimed to investigate the incidence and the influencing factors of MVO in patients with ST-elevation myocardial infarction (STEMI) treated by primary percutaneous intervention (PCI)., Patients, Methods: Using contrast-enhanced MRI, microvascular obstruction was defined as early hypoenhancement. Contrast defects were scored from 0 (no hypoenhancement) to 3 (strong hypoenhancement). 50 patients (56+/-11 years) with STEMI underwent PCI. Contrast-enhanced MRI (6+/-2 days after STEMI) and biochemical parameters were evaluated., Results: Microvascular obstruction (score 1 to 3) was observed in 90% of the patients and major microvascular obstruction (score 2-3) in 54%. In univariate analysis, leukocytes and CRP levels were associated with MVO, whereas pre-infarction angina and prior medication by aspirin or calcium channel antagonist appeared protective. Microvascular obstruction intensity positively correlated with baseline inflammation status assessed by C-reactive protein and leukocytes (rho=0.43 and rho=0.44; p=0.003), the peak of CK (rho=0.56; p=0.01) or Troponin I (rho=0.59; p=0.01) and negatively correlated with LVEF (rho=-0.44; p=0.002). Multivariate analysis identified the absence of pre-infarction angina as the only independent predictor for microvascular obstruction (odds ratio, 8.35, 95% confidence interval 1.27-54.71; p=0.027)., Conclusion: MRI-detected microvascular obstruction has a high incidence in patients with STEMI treated by primary PCI and determines post-MI LVEF even in patients with post PCI TIMI 3 flow score. Pre-infarction angina appears to be an independent determinant of the extent of MVO detected by MRI.

Infarct size has been considered an established marker of left ventricular (LV) remodeling. We assessed the predictive value of myocardial/microvascular injury assessed by delayed enhanced magnetic resonance imaging (MRI) on LV remodeling and LV ejection fraction after primary coronary intervention (PCI) compared with peak troponin levels, an established index of myocardial infarct size. We performed MRI in 76 patients with first acute myocardial infarction 6 +/- 2 days after successful PCI. Necrosis was judged as transmural when delayed enhancement was extended to >or=75% of LV segment thickness. Severe microvascular obstruction was identified as areas of late hypoenhancement surrounded by delayed enhancement. Infarct size was expressed as an index by dividing the total percentage of delayed enhancement involvement by the number of LV segments. LV end-diastolic volume index and function were quantified by 2-dimensional echocardiography at 6 +/- 1 months after acute myocardial infarction. Remodeling was evaluated as a change in LV end-diastolic volume index at follow-up compared with baseline. At univariate analyses, transmural necrosis, severe microvascular obstruction, infarct size, and troponin level were correlated directly with remodeling and inversely with LV function at follow-up (p <0.001). At multiple regression, only transmural necrosis and troponin level remained independent predictors of LV remodeling and function. With respect to troponin, transmural necrosis improved the predictive power of LV remodeling (R2 for change = 0.19) and function (R2 for change = 0.16). In conclusion, in patients with acute myocardial infarction undergoing PCI, the amount of transmural necrosis as assessed by MRI is a major determinant of LV remodeling and function, with significant additional predictive value to infarct size and severe microvascular obstruction.

Background: The combination of angina pectoris, angiographically normal coronary arteries, and a positive exercise stress test (EST) is referred to as cardiac syndrome X. However, a large group of patients suspected of syndrome X reveals a normal exercise stress test and weakens the diagnosis of syndrome X. Previous studies demonstrated an impaired coronary flow reserve on ammonia positron emission tomography (PET) in patients with syndrome X., Aim: To evaluate the coronary flow reserve in patients suspected of syndrome X with positive and negative EST findings, using [(13)N]ammonia PET as the diagnostic aid., Methods: Forty-two patients with chest pain and a normal coronary angiography, were analysed by exercise stress testing (EST) and the dypyridamole stress test (DST) on [(13)N]ammonia PET. Two subgroups were predefined, based on outcome of EST: an EST positive and negative group. A normal control group was used as the reference method., Results: A total of 24 (57%) out of 42 patients had significant ST-T changes (EST positive). [(13)N]ammonia PET showed a significantly lower rest flow in the EST positive and EST negative group compared to controls (P<0.001 and P=0.0028, respectively). DST [(13)N]ammonia PET perfusion was significantly reduced in flow in both the EST positive and EST negative groups (P<0.001 both), as was the DST/rest [(13)N]ammonia perfusion reserve (P<0.001 for both), compared to normal controls., Conclusion: PET demonstrates a reduced coronary flow reserve in patients suspected of syndrome X, irrespective of the EST findings.

Background: Angina with normal coronary arteries, cardiac syndrome X, is a diagnosis of exclusion. The exact mechanism of this clinical syndrome remains unclear. Although the prognosis is as good as equal to that of normal population, symptoms related with the syndrome impair largely quality of life. Mean platelet volume showing the platelet size is an indicator of platelet function. Larger platelets are more active than smaller ones., Methods and Results: We designed a study, evaluated mean platelet volume of the patients with cardiac syndrome X (group A) and stable angina (group B) and investigated the relation between groups. Eighty patients with cardiac syndrome X with a mean age of 51.08 +/- 9.79 years and 67 patients with stable angina with a mean age of 55.16 +/- 11.96 years were studied. At the end of the study, mean platelet volume of group A was significantly higher than that of group B, 10.55 +/- 1.08 fl vs. 9.39 +/- 0.58 fl, respectively (P < 0.001)., Conclusion: Raised platelet size has been shown to be associated with adverse cardiac events. Mean platelet volume has increased in acute coronary syndromes and also in cardiac syndrome X in our study. Life style modification may optimize platelet size and improve symptoms in these patients.

Background: Syndrome X has been recognized as a disease that is primarily reflected in the cardiac microvasculature. Myocardial metabolism in this condition has been studied, but not in relation to small vessel pathology., Methods and Results: In order to examine the relationship between myocardial metabolism and small vessel pathology, 24 consecutive patients with syndrome X (7 men, 17 women; mean age 58 years) were evaluated by the thallium exercise stress test, positron emission tomography using F-18 fluoro-deoxyglucose (FDG), and an endomyocardial biopsy. All patients showed either diffuse or focal increase in the myocardial uptake of FDG, but only 17 patients (71%) showed hypoperfused areas with partial or complete redistribution in the thallium study. Quantification of myocardial FDG uptake revealed that the value in syndrome X patients was 10-fold higher than in controls (p<0.0001). Histopathological examination revealed that in syndrome X there is an extensive increase in smooth muscle cells and thickening of the vascular wall, even in capillary vessels, and the small vessel lumen was markedly narrowed. There was a significant inverse correlation between FDG myocardial uptake and the microvessel luminal area., Conclusions: In syndrome X patients, myocardial FDG uptake is increased extensively, which is strongly associated with narrowed myocardial microvasculature.

Aim: Recently, the close relationship between aortic stiffness and cardiovascular mortality has aroused the interest of investigators in carrying out studies related to aortic stiffness. This study aims to investigate the aortic stiffness parameters in patients with cardiac syndrome X, a disorder that is believed to be a generalized disturbance of the vasodilator function of small arteries., Material and Methods: 18 patients with typical chest pain and angiographically normal coronary arteries associated with a positive exercise test were included in the study. The control group consisted of 27 patients with angiographically normal coronary arteries and no ischaemia on exercise testing. Antianginal medication was withheld 4 weeks before the study and transthoracic echocardiography was performed using a Hewlett-Packard Sonos 1500 instrument with a 2.5 MHz phased array transducer. Ascending aorta diameters were measured on the M-mode tracing at a level 3 cm above the aortic valve. Diameter change, pulse pressure, aortic strain and distensibility were measured as aortic stiffness parameters., Results: The aortic diameter change was less in the syndrome X group than in the control group (0.15 +/- 0.04 cm/m2 vs. 0.28 +/- 0.12 cm/m2, p < 0.001). Likewise, aortic strain (9 +/- 3% vs. 18 +/- 8%, p < 0.001) and distensibility (4.01 +/- 1.71 cm2 x dyn(-1) x 10(-3) vs. 9.95 +/- 5.08 cm2 x dyn(-1) x 10(-3), p < 0.001) was significantly lower in the syndrome X group than in the control group., Conclusion: The deterioration in aortic elasticity properties in patients with cardiac syndrome X suggests that this disease may be a more generalized disturbance of the vasculature.

Arteriosclerosis of the small arteries is one of the main causes of microvascular angina, and although some reports have shown favorable prognoses, there is progressive reduction in left ventricular function. The present study evaluated the prognosis of microvascular angina in 86 Japanese patients (51 women, 35 men; average age, 59+/-9 years) who had ischemic ST segment depression, normal coronary angiograms and small artery sclerosis confirmed by endomyocardial biopsies. The mean follow-up period was 7.2+/-3.4 years. Questionnaires regarding their symptoms, cardiac medication, and new events were sent to all patients. Eighty-five patients (98.9%) were still alive at the end of the follow-up period. Chest pain remained in 35.3%; the degree of pain was unchanged in 18.8%, and had lessened in 11.8%. None of the patients died of cardiac events or suffered from a myocardial infarction. At the end of the follow-up period, calcium antagonist was used in 63.5% of patients. Seventeen patients (20.0%) were free of antianginal medication. The prognosis of microvascular angina diagnosed by strict criteria was favorable.

Background: In cardiac syndrome X (a syndrome characterized by typical angina, abnormal exercise-test results, and normal coronary arteries), conventional investigations have not found that chest pain is due to myocardial ischemia. Magnetic resonance techniques have higher resolution and therefore may be more sensitive., Methods: We performed myocardial-perfusion cardiovascular magnetic resonance imaging in 20 patients with syndrome X and 10 matched controls, both at rest and during an infusion of adenosine. Quantitative perfusion analysis was performed by using the normalized upslope of myocardial signal enhancement to derive the myocardial perfusion index and the myocardial-perfusion reserve index (defined as the ratio of the myocardial perfusion index during stress to the index at rest)., Results: In the controls, the myocardial perfusion index increased in both myocardial layers with adenosine (in the subendocardium, from a mean [+/-SD] of 0.12+/-0.03 to 0.16+/-0.03 [P=0.02]; in the subepicardium, from 0.11+/-0.02 to 0.17+/-0.05 [P=0.002]); in patients with syndrome X, the myocardial perfusion index did not change significantly in the subendocardium (0.13+/-0.02 vs. 0.14+/-0.03, P=0.11; P=0.09 as compared with controls) but increased in the subepicardium (from 0.11+/-0.02 to 0.20+/-0.04, P<0.001; P=0.11 for the comparison with controls). Adenosine provoked chest pain in 95 percent of patients with syndrome X and 40 percent of controls (P<0.001)., Conclusions: In patients with syndrome X, cardiovascular magnetic resonance imaging demonstrates subendocardial hypoperfusion during the intravenous administration of adenosine, which is associated with intense chest pain. These data support the notion that the chest pain may have an ischemic cause.

Background: The cause of chest pain in patients with normal coronary arteriograms (CAG) remains poorly understood., Methods and Results: Left ventricular endomyocardial biopsies from 11 anginal patients with normal CAG and normal left ventriculograms and from seven anginal patients with coronary stenosis were studied by light and electron microscopy. Biopsies from seven non-anginal patients (non-ischemic electrocardiogram abnormalities but no evident heart or systemic diseases) served as controls. In anginal patients with normal CAG, both cardiocytic diameter (17.2 +/- 5.5 microm) and interstitial space percentage area (37.6 +/- 14.9%) were significantly larger than those (13.7 +/- 0.9 microm, 14.9 +/- 2.9%) in control participants. Some cardiocytic nuclei (1.9% of 2000 randomly selected nuclei) exhibited DNA degradation by in-situ nick-end labeling. Electron microscopy revealed cardiocytic nuclei with distinct apoptotic ultrastructures (2.8% of 200 nuclei), phagocytic degradation of cardiocytic cytoplasm, and capillary endothelial swelling (7.1% of 200 capillary transverse sections). No significant infiltration of inflammatory cells was seen. In anginal patients with coronary narrowing (cardiocytic diameter, 16.8 +/- 1.1 microm; interstitial space, 20.1 +/- 5.8%; DNA degraded nuclei, 1.3%), there were however no apoptotic cardiocytic nuclei or cytoplasm and less capillary endothelial swelling (1.6%) in ultrastructure., Conclusions: In biopsies from anginal patients with normal CAG, the presence of cardiocytic hypertrophy and replacement fibrosis are both abnormal. Cardiocytic apoptosis and capillary endothelial swelling, found by others as characteristic of experimental myocardial reperfusion injury, are evident. This supports the possibility of myocardial transient ischemia and reperfusion injury in patients with angina and normal CAG.

A 39-year-old woman had exercise-induced ST segment depression associated with chest pain. Cardiac evaluation revealed moderate aortic stenosis (AS), related to the bicuspid valves, with an aortic mean pressure gradient of 22 mmHg, a calculated aortic valve area of 1.3 cm2 and normal left ventricular (LV) peak systolic and end-diastolic pressures, but no LV hypertrophy, resulting in normal LV wall stress. Although the coronary arteries were angiographically normal, rapid atrial pacing and an intracoronary papaverine injection revealed a significantly decreased coronary flow reserve (CFR), which may have played an important role in the pathogenesis of angina pectoris in this patient. Though the CFR is usually decreased in patients with AS, as well as in microvascular angina, in this particular case, it appeared to have decreased as a consequence of microvascular dysfunction rather than of AS-related mechanisms.

Muscle infarction is a rare complication in patients with diabetes mellitus, probably because of the rich vascular supply of this tissue. We describe a patient with type 1 diabetes who had infarction of the muscles in her right thigh. We report, for the first time, that the patient, in addition to an advanced microvascular disease in the muscle, had increased plasma total homocysteine levels and increased platelet aggregation. These pathologies might have a synergistic effect on the development of this rare complication and should be treated aggressively to prevent further episodes.

Overnutrition during critical developmental periods is suggested to be a risk factor for obesity and associated metabolic disorders in later life. Underlying mechanisms are unknown. Neuropeptides are essentially involved in the central nervous regulation of body weight. For instance, hypothalamic galanin (GAL) is a stimulator of food intake and body weight gain. To investigate long-term consequences of early postnatal overfeeding, the normal litter size of Wistar rats (n=10; controls) was reduced from day 3 to day 21 of life to only 3 pups per mother (small litters, SL; overnutrition). Throughout life, SL rats displayed hyperphagia (p<0.01), overweight (p<0.0001), hyperinsulinemia (p<0.01), impaired glucose tolerance (p<0.001), elevated triglycerides (p<0.001), and an increased systolic blood pressure (p<0.05). In adulthood, an increase of GAL-neurons in the arcuate hypothalamic nucleus (ARC) was found (p<0.001), positively correlated to body weight (p<0.001). A second experiment revealed hyperinsulinemia (p<0.001) and increased hypothalamic insulin levels (p<0.05) in SL rats during early postnatal life. Already on day 21 of life, i.e., at the end of the critical hypothalamic differentiation period, in SL rats the number of GAL-neurons was increased in the ARC (p<0.001), showing a positive correlation to body weight and insulin (p<0.05). In conclusion, neonatally acquired persisting malformation of hypothalamic galaninergic neurons, induced by early overfeeding and hyperinsulinism, might promote the development of overweight and syndrome X-like alterations during life., (Copyright 1999 Elsevier Science B.V.)

Objectives: The aim of this project was to study the responsible site(s) and underlying cardiac disease(s) of patients with transient ST-segment elevation and normal coronary angiograms., Background: Transient ST-segment elevation has been demonstrated in patients with variant angina or unstable angina. In those patients, epicardial coronary arteries, not microvessels, are always the responsible site for the transient ST-segment elevation., Methods: This study consisted of three cases with a transient ST-segment elevation and normal coronary angiograms. Treadmill testings were performed before coronary angiography in all cases. Coronary angiography was undertaken during the control state and during ST-segment elevation and, when possible, a Doppler guide wire was positioned in the left anterior descending artery (LAD). Coronary responses to vasodilators were observed. Finally, cardiac biopsy was performed and pathologic observation was conducted., Results: All three cases had significant ST-segment depression during treadmill testing in II, III, aVF and V4-6 leads; however, no angiographic coronary stenosis was demonstrated and vasospasm was not provoked. A transient ST-segment elevation associated with chest pain was observed in V1-5 leads, but normal coronary angiograms during ST-segment elevation were observed in every case. Coronary blood flow (CBF) velocity profile remained normal during ST-segment elevation. In one case, vasodilator responses to the LAD during ST-segment elevation were also measured. A 0.5 mg intracoronary injection of nitroglycerin increased CBF velocity (220%), but ST-segment elevation was not normalized and chest pain persisted. A 10 mg intracoronary injection of papaverine (PVN) further increased CBF velocity up to 340%, and this normalized ST-segment elevation and relieved chest pain quickly. Either endothelium-dependent coronary flow reserve (CFR) measured with a 100 microg intracoronary infusion of acetylcholine, or flow-dependent CFR by a 10 mg intracoronary injection of PVN was reduced in one of two cases measured. Pathologic findings supported syndrome X as the underlying cardiac disease in all cases., Conclusions: These findings suggested a new clinical implication involving transient ST-segment elevation mimicking variant angina and normal coronary angiograms in patients with syndrome X. The major responsible site for this phenomenon was suggested to be coronary arterioles of less than 200 microm in diameter.

Leptin is an adipocyte-derived hormone that interacts with a putative receptor(s) in the hypothalamus to regulate body weight. The relationship of leptin to metabolic abnormalities associated with obesity together with hormonal and substrate regulation of leptin have not been extensively studied. Therefore, 116 subjects (62 men and 54 women) with a wide range of body weight [body mass index (BMI), 17-54 kg/m2] were characterized on a metabolic ward with regard to body composition, glucose intolerance, insulin sensitivity, energy expenditure, substrate utilization, and blood pressure. Eighty-five of the subjects had normal glucose tolerance (50 men and 35 women), and 31 had noninsulin-dependent diabetes mellitus (12 men and 19 women). In both men and women, fasting leptin levels were highly correlated with BMI (r = 0.87 and r = 0.88, respectively) and percent body fat (r = 0.82 and r = 0.88, respectively; all P < 0.0001). However, men exhibited lower leptin levels at any given measure of obesity. Compared with those in men, leptin levels rose 3.4-fold more rapidly as a function of BMI in women [leptin = 1.815 (BMI)-31.103 in women; leptin = 0.534 (BMI)-8.437 in men] and 3.2 times more rapidly as a function of body fat [leptin = 1.293 (% body fat)-24.817 in women; leptin = 0.402 (% body fat)-3.087 in men]. Hyperleptinemia was associated with insulin resistance (r = -0.57; P < 0.0001) and high waist to hip ratio (r = 0.75; P < 0.0001) only in men. On the other hand, during the hyperinsulinemic euglycemic clamp studies, hyperinsulinemia acutely increased leptin concentrations (20%) only in women. There was no correlation noted between fasting leptin levels and either resting energy expenditure or insulin-induced thermogenesis in men or women (P = NS). In stepwise and multiple regression models with leptin as the dependent variable, noninsulin-dependent diabetes mellitus did not enter the equations at a statistically significant level. The data indicate that there are important gender-based differences in the regulation and action of leptin in humans. Serum leptin levels increase with progressive obesity in both men and women. However, for any given measure of obesity, leptin levels are higher in women than in men, consistent with a state of relative leptin resistance. These findings have important implications regarding differences in body composition in men and women. The observation that serum leptin is not related to energy expenditure rates suggests that leptin regulates body fat predominantly by altering eating behavior rather than calorigenesis.

1. There is increasing evidence that a substantial number of patients who suffer from angina have normal epicardial arteries (Syndrome X), and it has been suggested that these individuals have a generalized disorder of small vessels not confined to the intramyocardial vasculature. 2. Small arteries were therefore obtained from biopsies of skin and subcutaneous fat from nine normotensive patients with Syndrome X and nine matched control subjects. Vessels were dissected and mounted as ring preparations in a myograph for morphological and functional assessment. 3. Morphological measurements revealed a significant increase in media thickness/lumen diameter ratio in arteries from patients with Syndrome X. Contractile responses to U46619 were similar in arteries from patients and control subjects. Endothelium-dependent relaxation induced with acetylcholine and bradykinin was greater in arteries from patients although differences were not statistically significant. Endothelium-independent relaxation induced by forskolin and sodium nitroprusside was not different. 4. In conclusion, these data demonstrate that subcutaneous small arteries from patients with Syndrome X are characterized by increased media thickness/lumen diameter ratios, although contractile responses were normal. Additionally, endothelium-dependent relaxation was not impaired in arteries from these patients. Thus, no significant functional abnormalities were associated with the observed structural differences.

The clinical value of oesophago-gastro-duodenoscopy and distal oesophageal biopsies was investigated in 49 patients with angina pectoris and normal coronary angiograms. The results were compared to 24 hour oesophageal pH-monitoring of the patients and of a control group of 22 healthy sons. Macroscopic esophagitis--mainly grade I was found in 31% of the patients and microscopic oesophagitis in 25%. The only major abnormalities were the identification of three peptic ulcers (6%). Median (range) reflux index was 1.3 (0.0-13.4) in the patient group and 2.1 (0.0-9.9) in the controls (p = 0.49). There were no differences with respect to endoscopical findings or reflux index between patients with a positive and patients with a normal exercise electrocardiogram. At a median 36 months post study 38% of the patients had undergone acid secretion inhibitor treatment with an effect on symptoms in only 4%. The study provides evidence that routine oesophago-gastro-duodenoscopy is of limited value in this patient group.

Objectives: We used intravascular ultrasound imaging of the epicardial vessels to assess coronary morphology, vasomotor response to exercise and exercise-vasomotion after beta-adrenoceptor blockade in patients with syndrome X., Background: Syndrome X is defined as chest pain, abnormal exercise test results and normal coronary angiographic findings. Because of the limitations of coronary angiography, intravascular ultrasound was used to define coronary pathophysiology., Methods: Thirty patients with syndrome X were studied with intravascular ultrasound imaging (30 MHz, 4.3F catheter) of all three major epicardial vessels. Supine arm exercise was performed during coronary imaging. Lumen area was assessed at rest and during peak exercise. The exercise-imaging protocol was repeated after loading with 0.1 mg/kg body weight of intravenous propranolol., Results: Three morphologic groups were identified using intravascular ultrasound: normal coronary arteries (no plaque, intimal thickness < 0.25 mm, n = 12), atheromatous disease (mean [+/- SD] area stenosis 37.9 +/- 7.2%, n = 10) and marked intimal thickening (0.73 +/- 0.11 mm, n = 8). Patients with normal coronary arteries displayed a vasodilatory response to exercise (+16.9% area increase); patients with abnormal coronary arteries displayed a vasoconstrictive response to exercise (-17.4% in the group with plaque; -17.6% in the group with intimal thickening). Propranolol loading attenuated the vasodilatory response in the group with normal coronary arteries (+6.4% area increase) and attenuated the vasoconstrictive response in the two groups with abnormal coronary arteries (-8.0% in the group with plaque; -8.8% in the group with intimal thickening)., Conclusions: Most patients with syndrome X have abnormal coronary arteries by intravascular ultrasound. Intravascular ultrasound identifies three distinct morphologic groups: normal coronary arteries, atheromatous plaque and intimal thickening. Exercise-vasomotion is normal in patients with syndrome X who have normal coronary arteries by ultrasound; patients with abnormal arteries (plaque or intimal thickening) have an abnormal (constrictive) response to exercise. Propranolol loading attenuates vasoreactivity in all subgroups, suggesting divergent therapeutic utility.

Blood capillary abnormalities accompanied by intramural small arterial lesions were reported in patients with microvascular angina (MVA), hypertrophic cardiomyopathy (HCM), and dilated cardiomyopathy (DCM). We compared the ultrastructural changes of blood capillaries in myocardial biopsy samples from MVA, HCM, and DCM patients using electron microscopy and ultrastructural morphometry. Ten cross-sectioned views were selected from each patient at random, and the degree of cytoplasmic swelling of the endothelial cells was measured (transverse area of endothelial cell cytoplasm (E)/transverse area of the blood capillary (C)). The thickness of the basal lamina was also assessed (transverse area of basal lamina (BL)/C). The average value of the E/C ratio was in the order of control group < HCM < MVA < DCM, with significant differences among the groups (p < 0.001). The average value of the BL/C ratio was in the order of control group < MVA < HCM < DCM, with significant differences (p < 0.001) among the groups except between the HCM and DCM groups. In conclusion, swelling of the endothelial cells as well as luminal stenosis of small arteries and arterioles may be related to disturbed microcirculation in these patients.