Initial evidence of endothelial cell apoptosis as a mechanism of systemic capillary leak syndrome

BACKGROUND: Systemic capillary leak syndrome (SCLS) is a rare disorder of unknown etiology that is characterized by acute recurrent attacks of hypovolemic shock commonly following an inflammatory stimulus such as a viral illness. Prophylactic therapy is generally ineffective, and the outcome is frequently fatal. METHODS: In order to investigate the cellular mechanisms leading to SCLS, we examined the effects of sera from two patients with active SCLS on microvascular endothelial cell apoptosis in vitro. Apoptosis was determined by morphologic criteria, DNA fragmentation, annexin V stain, and by a quantitative photometric assay. The apoptotic pathway was investigated by Western blot of endothelial cells lysate after exposure to SCLS sera. RESULTS: The sera from patients with active SCLS mediated profound apoptosis of microvascular endothelial cells shortly after exposure. The exposed microvascular endothelial cells underwent immediate apoptosis as evidenced by morphologic changes, plasma membrane phosphatidylserine exposure, and by DNA fragmentation. Increased Bax/Bcl-2 ratio in endothelial cells exposed to SCLS sera was observed and suggested an oxidation injury as the possible mechanism for endothelial apoptosis. This potential mechanism was further explored by measuring intracellular reactive oxygen species (ROS) following SCLS serum exposure. Sera from both patients caused marked increases in ROS, initially detectable at 1 h and persisted for at least 12 h, with control serum from healthy subjects showing no effect on basal endothelial cell ROS concentrations. CONCLUSION: Components from the sera of patients with active systemic capillary leak syndrome in contrast to healthy subject sera mediate early and extensive endothelial apoptosis in vitro that is associated with oxidation injury. These data represent compelling initial evidence for oxidation-induced apoptosis as a likely mechanism for endothelial injury leading to SCLS.     

Are low total serum antioxidant status and elevated levels of C-reactive protein and monocyte chemotactic protein-1 associated with cardiac syndrome X?

BACKGROUND: Cardiac syndrome X, also known as microvascular angina, is characterized by exercise-induced chest pain occurring despite a normal coronary angiogram. Several causes and mechanisms have been proposed to explain both the chest pain and ST segment depression. In this study, the association, if any, between cardiac syndrome X and several factors, including blood total antioxidant status, C-reactive protein (CRP), and monocyte chemotactic protein-1 (MCP-1) levels, was investigated. METHODS AND RESULTS: The study group comprised 36 patients who had been diagnosed as cardiac syndrome X on the basis of a positive treadmill test and a normal coronary angiogram, and 24 control patients. Total serum antioxidant status and CRP were assessed, and the levels of P-selectin, MCP-1, and interleukins 6 and 10 were also measured. Total serum antioxidant levels were determined to be significantly lower in the cardiac syndrome X patients than in the controls. CRP and serum MCP-1 levels, however, were found to be significantly higher in the cardiac syndrome X group. The total serum antioxidant levels and serum MCP-1 levels were comparable with the levels observed in a group of chronic stable angina patients. CONCLUSIONS: In the present study, patients who had been diagnosed as cardiac syndrome X demonstrated increased systemic oxidative and enhanced inflammatory status.     

Overview of gender aspects of cardiac syndrome X

Cardiac syndrome X, a condition defined by the presence of angina-like chest pain, a positive response to stress testing and normal coronary arteriograms, has been shown to occur in approximately 20--30% of angina patients undergoing coronary arteriography. The prevalence of syndrome X is significantly higher in women compared to men. In the majority of patients with chest pain and normal coronary arteriograms, symptoms are likely to be non-cardiac in origin. However, myocardial ischaemia may be the pathogenic mechanism in a proportion of syndrome X patients. Indeed, the clinical characteristics, the ischaemic electrocardiographic findings and the presence of myocardial perfusion defects during stress testing are similar in syndrome X and coronary artery disease patients. Moreover, coronary sinus oxygen saturation abnormalities and pH changes, as well as myocardial lactate production and alterations of cardiac high energy phosphate are seen during stress testing in patients with syndrome X and appear to endorse an ischaemic origin of symptoms in at least a proportion of these individuals. Patients with chest pain and normal coronary arteries have abnormal vasodilatory coronary blood flow responses and an increased sensitivity of the coronary microcirculation to vasoconstrictor stimuli (microvascular angina). Microvascular endothelial dysfunction appears to be responsible for these coronary microcirculation abnormalities. Given the high prevalence of peri- and post-menopausal women in cardiac syndrome X, it has been hypothesized that oestrogen deficiency may play a major role in the pathogenesis of this condition. Oestrogen vasoactive properties involve endothelium-dependent effects and, in postmenopausal women, forearm vasodilatation induced by acetylcholine is potentiated by the acute local administration of intravenous oestradiol. This suggests that endothelium-dependent responses in the peripheral circulation may be modulated by steroid hormones. Impairment of endothelial function in post-menopausal women with syndrome X has been reported by various groups and it could be hypothesized that oestrogen deficiency may contribute to the development of microvascular angina through endothelial dysfunction and that exogenous oestrogen administration may have a beneficial effect in syndrome X patients. This article reviews current knowledge regarding the role of oestrogen deficiency in the pathogenesis of syndrome X and the potential therapeutic role of oestrogen replacement therapy in women with chest pain and normal coronary arteriograms     

Coronary endothelial vasomotor function and vascular remodeling in heart transplant recipients randomized for tacrolimus or cyclosporine immunosuppression.

OBJECTIVES: This study aimed to compare changes in coronary endothelial function, systemic endothelin-1 (ET-1) levels, and vascular remodeling in heart transplant recipients randomized to cyclosporin A (CyA) or tacrolimus (Tac) immunosuppression. BACKGROUND: Functional endothelial abnormalities and intimal thickening are sensitive measures of early cardiac allograft vasculopathy (CAV). METHODS: The randomized, prospective study was performed in two groups of 22 patients, maintained on Tac or CyA and mycophenolate mofetil immunosuppression, 1 and 12 months after heart transplantation. We investigated epicardial luminal diameter, coronary blood flow velocity, and ET-1 plasma levels at 1 and 12 months after transplantation. Structural coronary alterations were determined using intravascular ultrasound. RESULTS: Epicardial vasomotor function at baseline and during follow-up was comparable between the groups. Deterioration of microvascular endothelial function during follow-up was significantly enhanced in the CyA versus Tac group (p < 0.05). Circulating ET-1 concentration increased in the CyA group but significantly decreased over time in the Tac group (CyA +17% vs. Tac -25%; p < 0.05). The time-dependent increase in mean intimal area was significantly enhanced in the CyA versus Tac group, whereas the vessel area significantly increased during follow-up in the Tac compared with the CyA group. CONCLUSIONS: Epicardial endothelial function is comparable between CyA- and Tac-treated patients. Microvascular endothelial function deteriorates more in CyA-treated patients, a finding that correlates with enhanced ET-1 concentration and an increased intimal area during follow-up. The mean vessel area in the Tac group increased over time, indicating positive vascular remodeling. Tac is superior to CyA with respect to microvascular endothelial function, intimal thickening, and vascular remodeling.     

Differential mononuclear cell activity and endothelial inflammation in coronary artery disease and cardiac syndrome X

BACKGROUND: Circulating mononuclear cells could be activated with endothelial inflammation in patients with coronary artery disease (CAD). In some patients with normal coronary angiograms, myocardial ischemia could also present with coronary microvascular dysfunction (cardiac syndrome X). This study was undertaken to investigate whether mononuclear cell activation and endothelial inflammation can present in syndrome X patients. METHODS: We evaluated the biochemical parameters, circulating soluble adhesion molecules, circulating superoxide free radicals, and mononuclear cell activity in 32 patients with syndrome X, 34 with angiographically documented CAD, and 17 age- and gender-matched healthy control subjects. RESULTS: Compared to that in control subjects, plasma high-density lipoprotein was reduced (P<0.001) and insulin to glucose ratio increased (P=0.02) in CAD patients. Circulating level of soluble intracellular adhesion molecule-1 was significantly higher in both syndrome X and CAD patients than in control subjects (P<0.01), whereas the levels of soluble vascular cell adhesion molecule (P=0.02) and von Willebrand factor (P=0.01) were increased in CAD patients only. The peak (P<0.001) and total counts of superoxide free radicals in whole blood (P<0.001) was significantly higher in syndrome X patients than in the other two groups. However, phorbol-12-myristate-13-acetate-induced superoxide free radical generation of mononuclear cells was increased in CAD (10.5+/-4.6%, P=0.01) but not in syndrome X patients (8.7+/-2.0%) as compared with control subjects (7.7+/-0.5%). CONCLUSIONS: The results indicated that the activity of mononuclear cells was increased with significant endothelial inflammation and injury in CAD patients. In syndrome X patients, though circulating superoxide free radicals were increased, there was minimal endothelial inflammation without mononuclear cell activation. The relatively preserved lipid and metabolic profiles might contribute to less vascular inflammation in syndrome X patients.     

Long-term angiotensin-converting enzyme inhibition reduces plasma asymmetric dimethylarginine and improves endothelial nitric oxide bioavailability and coronary microvascular function in patients with syndrome X

Angiotensin-converting enzyme (ACE) inhibition has been shown to improve clinical myocardial ischemia in patients with syndrome X (angina pectoris, positive treadmill exercise test, normal coronary angiograms, and no evidence of coronary spasm). This study was conducted to investigate the effects of long-term ACE inhibitors on endothelial nitric oxide (NO) metabolism and coronary microvascular function in patients with syndrome X. After a 2-week washout period, 20 patients with syndrome X were randomized to receive either enalapril, an ACE inhibitor, 5 mg twice daily (n = 10) or placebo (n = 10) in a double-blind design for 8 weeks. Another 6 age- and gender-matched subjects with negative treadmill exercise tests were also studied as controls. Compared with control subjects, patients with syndrome X had significantly reduced coronary flow reserve, reduced plasma levels of nitrate and nitrite (NOx), and a reduced plasma L-arginine to asymmetric dimethylarginine (ADMA) ratio (an index of systemic NO metabolism), as well as reduced endothelial function. These patients also had increased plasma levels of ADMA, which is an endogenous inhibitor of NO synthase and of von Willebrand factor, a marker of endothelial injury. Baseline characteristics including exercise performance and coronary flow reserve were similar between enalapril and placebo groups. After an 8-week treatment period, exercise duration (p = 0.001) and coronary flow reserve (p = 0.001) significantly improved with enalapril but not with placebo. Enalapril treatment, but not placebo, reduced plasma von Willebrand factor (p = 0.03) and ADMA levels (p = 0.01) and increased NOx levels (p = 0.01) and the ratio of L-arginine to ADMA (p <0.01). In patients with syndrome X, the plasma NOx level was positively and ADMA level inversely correlated with coronary flow reserve before and after the treatment. In conclusion, long-term ACE inhibitor treatment with enalapril improved coronary microvascular function as well as myocardial ischemia in patients with syndrome X. This may be related to the improvement of endothelial NO bioavailability with the reduction of plasma ADMA levels.     

Role of Endothelial Dysfunction and Insulin Resistance in Angina Pectoris and Normal Coronary Angiogram

Abstract Angina pectoris and a normal coronary angiogram or cardiac syndrome X is a heterogeneous syndrome that probably encompasses different pathophysiological entities. Patients affected by cardiac syndrome X are often women presenting with severe, invalidating chest pain. However, there is a significant discrepancy among the severity of symptoms, the lack of hemodynamic evidence of myocardial ischemia and the relatively benign long-term prognosis. The vascular endothelium has numerous important functions, including the regulation of vascular tone, blood flow and permeability, secreting both vasorelaxing and vasoconstricting factors. It has been found that both endothelium and non-endothelium-mediated coronary blood flow are impaired in patients with cardiac syndrome X. Interestingly, it has been shown that impaired nitric oxide-dependent vasodilation could increase coronary microvessel tone and produce spasm. It has also been reported that circulating endothelin-1 levels are elevated with a direct relationship between endothelin-1 levels and impaired coronary flow reserve in these patients. In addition, patients with high endothelin-1 levels showed a time onset of chest pain during exercise significantly lower compared to patients with low endothelin-1 concentrations. Moreover, the nitric oxide/endothelin-1 ratio was found decreased in patients with cardiac syndrome X and endothelin-1 levels were also positively correlated with fasting asymmetric dimethylarginine levels. All in all, these data suggest a role of endothelial dysfunction as a cause of regional myocardial and peripheral blood flow abnormalities. Further studies are necessary to characterize the prevailing mechanisms determining alterations in nitric oxide/endothelin-1 pathway in these patients, in order to find new therapies able to improve both quality of life and prognosis.     

Myocardial glucose metabolism assessed by positron emission tomography and the histopathologic findings of microvessels in syndrome X.

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.     

Relationship Between Angiographic Graft Vessel Disease and Microvascular Reaction After Heart Transplantation

This study tests the correlation of coronary angiographic findings with the extent of microvascular reaction in right ventricular endomyocardial biopsies (EMBs) in transplanted hearts. In EMBs (n = 209) of 30 heart transplant patients (8 female, 22 male, mean age 48 years) microvascular reaction, i.e. endothelial cell swelling and vascular wall thickening (both grade 0-2), was graded by light microscopy at ×200. Patients' first and last coronary angiography (CA) (mean time after heart transplantation [HTx] 8 and 44 months) were graded according to the Stanford Classification and the presence of diameter irregularities was evaluated semi-quantitatively. We found a correlation of angiographic type B lesions with endothelial cell swelling during the first 5 months and vascular wall thickening during the fifth to fourteenth month after HTx (p<0.05). In patients with diameter irregularities and type B1 lesions in their first CA and type C lesions in their last CA, there was pronounced endothelial cell swelling in the early postoperative period (p<0.05). There was a tendency towards an increased vascular wall thickening in these patients during the later postoperative period. Graft vessel disease affects large and small coronary arteries and capillaries. Small vessel disease is characterized by architectural changes in blood vessel walls. Serial investigations of EMBs for diagnosis of small vessel disease complement the present diagnostic tools.     

Brachial artery flow-mediated vasodilation in patients with cardiac syndrome X

Cardiac syndrome X (CSX) differs from coronary artery disease (CAD) and is characterized by angina, positive stress test, and patent coronary arteries. The probable mechanism is a microvascular disorder associated with endothelial dysfunction. In this study, brachial artery flow-mediated vasodilation was used as well as the endothelin-1 assay to assess endothelial function in patients with cardiac syndrome X (CSX), coronary artery disease (CAD), and healthy controls. All subjects underwent a 2-step brachial artery flow-related vasodilatation test. Serum endothelin-1, one of the most potent constricting factors, was measured for all participants. Patients with CSX had a lower brachial artery dilation ratio than controls but higher than that of CAD patients. Control subjects and CSX patients had higher endothelin-1 levels than CAD patients. CSX patients were found to have worse endothelial function than healthy volunteers, but patients with CAD had even worse endothelium function than CSX patients.     

Mechanisms of coronary dysfunction in obesity and insulin resistance

The incidence of obesity and the metabolic syndrome has reached epidemic proportions and alterations in coronary microvascular function could contribute to the increased cardiovascular morbidity and mortality observed in these patients. This review highlights key mechanisms of impaired control of coronary blood flow in the metabolic syndrome. Specifically, coronary endothelial dysfunction, altered neurohumoral control, and the potential roles of smooth muscle ion channels are addressed. Recent studies indicate that alterations in endothelial-dependent vasodilation or endothelial-dependent vasoconstriction contribute little to obesity-induced impairments in coronary vascular control. In contrast, augmented vasoconstriction in response to neurohumoral mediators appears to play a significant role in coronary vascular dysfunction. The authors conclude that coronary dysfunction in the metabolic syndrome is characterized by an imbalance between coronary blood flow and myocardial metabolism that may be mediated by sensitization of vasoconstrictor pathways. Further, they suggest that alterations in smooth muscle ion channels, Ca(2+) handling, and cell signaling may be important mechanisms leading to coronary microvascular dysfunction. Importantly, however, more research is needed to clearly delineate specific mechanisms and identify potential therapeutic targets.     

X综合征冠状循环内血浆内皮素浓度变化

目的　探讨X综合征患者中冠状血管内皮功能的变化。方法　采用心房起搏术,观察X综合征患者（n=8）冠状静脉窦血浆内皮素浓度水平,同时与年龄、性别相匹配的健康人（n=6）作对照。结果　X综合征组在整个试验过程中,冠状静脉窦血浆内皮素浓度明显增加（P<0.05）;并且在不同时点间的浓度均不同（P<0.05）。结论　X综合征患者冠状循环内血浆内皮素浓度增高,可能存在有内皮功能异常。     

Menschliche kardiale mikro- und makrovaskul?re Endothelzellen zeigen ein unterschiedliches Expressionsmuster von Adh?sionsmolekülen und reagieren unterschiedlich auf oxidierte LDL

While the cellular mechanisms of atherosclerosis have been intensively studied, the mechanisms leading to preferential localization of atherosclerotic lesions are less well understood. To further define these mechanisms, endothelial cells from coronary arteries, i.e., vessels with frequent atherosclerotic lesions, were isolated and grown in vitro. In order to compare the reactions of both cell types, endothelial cells derived from microvessels of human hearts were isolated and cultured under identical conditions. Incubation of endothelial cells with oxidized LDL (75 microg/ml protein) induced a significant increase in PAI-1 activity (182%, p < 0.05) in coronary macrovascular endothelial cells. This stimulatory effect of ox-LDL was less significant in microvascular endothelial cells (144%, p < 0.05). n-LDL did not influence secreted PAI-1 activity. Stimulation with angiotensin II induced expression of E-selectin more effectively in coronary macrovascular than in microvascular endothelial cells. In addition, angiotensin II-induced E-selectin expression led to increased E-selectin-dependent adhesion of HL60 cells to coronary macrovascular endothelial cells under flow conditions, while only little effect was observed with cardiac microvascular endothelial cells. In contrast, L-selectin-dependent adhesion, which has been shown to play an important role in inflammatory reactions, was preferentially observed in cardiac microvascular endothelial cells and could only be stimulated with TNFalpha, not by angiotensin II. Therefore, these cellular differences may in part explain specific properties of cardiac endothelial cells: Such that atherosclerotic lesions are localized in macrovascular vessel segments, whereas inflammatory responses are predominantly found in the microvasculature.     

Cardiac syndrome X and endothelial dysfunction: new concepts in prognosis and treatment

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.     

Long-acting calcium channel blocker benidipine suppresses expression of angiogenic growth factors and prevents cardiac remodelling in a Type II diabetic rat model

Aims/hypothesis: Calcium channel blockers, widely used for the treatment of hypertension and angina, could prevent cardiovascular complications in patients with diabetes. They can improve cardiac remodelling in animal models of a variety of cardiovascular diseases. Here, we examined the therapeutic effect of benidipine, a long-acting calcium channel blocker, on cardiac remodelling in Otsuka-Long-Evans-Tokushima-Fatty (OLETF) rats, a Type II (non-insulin-dependent) diabetes mellitus model. Methods: The methods for morphometric analysis included double staining for coronary capillaries, dye-binding staining for collagen content and Masson's trichrome staining for perivascular fibrosis. Immunohistochemical and in situ hybridization techniques were used for detecting protein and mRNA expressions for vascular endothelial growth factors (VEGF), basic fibroblast growth factors (bFGF) and TGF-β ₁, endothelial nitric oxide synthase (eNOS), and anti- and pro-apoptotic markers. Results: OLETF rats showed an increased coronary capillary density, a reduced venular capillary proportion, an increased cardiac collagen content and prominent cardiac perivascular fibrosis. In OLETF rat hearts, significant increases in vascular expressions for VEGF, bFGF and TGF-β ₁ were found. Furthermore, the apoptosis signalling pathways, involving eNOS and apoptotic markers, were markedly altered, and coronary endothelial cell apoptosis was lower. These alterations with the exception of eNOS expression were significantly blocked by benidipine treatment. Conclusion/interpretation: The suppressive effect of benidipine on overproduction of angiogenic growth factors could prevent cardiac angiogenesis and fibrosis, resulting in an improvement of cardiac remodelling in diabetes. As VEGF and bFGF potently block endothelial cell apoptosis execution, physiological apoptosis revived by benidipine treatment could also contribute to coronary vessel regression. [Diabetologia (2002) 45: 402–415] Received: 16 July 2001 and in revised form: 5 November 2001     

Coronary blood flow in patients with cardiac syndrome X

BACKGROUND: Epicardial coronary arteries are normal in patients with cardiac syndrome X. It is, however, unclear whether there is an abnormality at the level of microvascular circulation. In this study, our aim was to evaluate the epicardial coronary blood flow and myocardial perfusion in patients with cardiac syndrome X. METHODS: Two hundred and three patients (mean age 53+/-10 years, 85 men) were included in the study. The diagnosis of cardiac syndrome X was made in patients who had a complaint of typical anginal chest pain and had ischemic findings on either myocardial perfusion scintigraphy or a treadmill exercise test, and whose coronary angiograms did not reveal any pathology. Fifty patients (mean age 54+/-11 years, 24 men) who had a complaint of typical anginal chest pain and had a normal myocardial perfusion test and normal coronary arteries were recruited as the control group. Epicardial coronary blood flow was evaluated with the thrombolysis in myocardial infarction frame count method and myocardial perfusion was evaluated with the myocardial blush grade method. A myocardial blush grade of < or =2 in any vessel was considered abnormal. RESULTS: Although the right coronary thrombolysis in myocardial infarction frame count was higher in patients with syndrome X (14.9+/-7.6 vs. 11.7+/-4.4 in controls; P=0.014), there were no statistically significant differences between the groups in terms of mean thrombolysis in myocardial infarction frame count in the coronary arteries. Abnormal myocardial blush grade was present in 85 patients (42.3%) with syndrome X, and in 17 patients (34.7%) in the control group (P>0.05). CONCLUSION: We found that the epicardial coronary blood flow, as assessed by thrombolysis in myocardial infarction frame count, and myocardial perfusion, as assessed by myocardial blush grade, were normal in patients with cardiac syndrome X.     

No effects of bosentan on microvasculature in patients with limited cutaneous systemic sclerosis

The endothelium-derived vasoconstrictor molecule endothelin-1 (ET-1) has been suggested to play a role in the pathogenesis of Raynaud’s phenomenon (RP) and systemic sclerosis (SSc). We studied the effect of bosentan on microvascular structure and function in patients with RP secondary to limited cutaneous SSc in a mechanistic pilot study. In this single center, open study, 15 patients with limited cutaneous SSc were treated with bosentan for 16 weeks with a follow-up period of 4 weeks. Changes in microvascular structure and function were studied with assessment of vasodilatory microvascular responses using laser Doppler fluxmetry combined with iontophoresis, capillary permeability using fluorescence videomicroscopy, nailfold capillary microscopy, and serological markers of endothelial activation. No significant changes were seen in vasodilator responses to acetylcholine and sodium nitroprusside following bosentan treatment. No effect was noted on capillary permeability during treatment. The number of nailfold capillaries remained unchanged. The endothelial activation marker vascular cell adhesion molecule did not change during treatment, but levels of thrombomodulin significantly decreased after 12 weeks of treatment. Bosentan did not induce significant changes in vasodilator responses, capillary permeability, and capillary density during treatment, so no evidence was obtained for structural improvement of microvascular structure and function in this short-time mechanistic pilot study in patients with lcSSc.     

Microvascular function, metabolic syndrome, and novel risk factor status in women with cardiac syndrome X

To characterize microvascular function, candidate risk pathways, and metabolic syndrome prevalence in women with cardiac syndrome X, 52 nondiabetic women with angiographically normal epicardial arteries but >1 mm of planar ST depression during exercise testing (patients) and 24 healthy controls of similar age were recruited. In addition to fasting blood samples and anthropometric measurements, forearm cutaneous microvascular function after iontophoresis of acetylcholine and sodium nitroprusside was assessed by laser Doppler imaging. Despite body mass index correction and a larger proportion on statin therapy, patients had high levels of insulin (p=0.016), triglycerides (p=0.018), intercellular adhesion molecule-1 (p=0.021), von Willebrand factor (p=0.005), and leptin (p=0.005) and lower levels of high-density lipoprotein cholesterol (p=0.042) compared with controls. Consistent with these data, 30% of patients but only 8% of controls fulfilled criteria for the metabolic syndrome as defined by the National Cholesterol Education Program (p=0.015). Endothelium-dependent and -independent microvascular functions were markedly impaired in patients (p<0.001), and the odds ratio for cardiac syndrome X was 7.38 (95% confidence interval 2.2 to 24.7) if the acetylcholine response was <8,710 flux units. In conclusion, women with cardiac syndrome X more commonly have metabolic syndrome and related adiposity, metabolic, and inflammatory derangements. They also have significantly impaired skin microvascular function as assessed by laser Doppler imaging, consistent with generalized vascular dysfunction, a finding with potential diagnostic implications.