Therapeutic Development in Cardiac Syndrome X: A Need to Target the Underlying Pathophysiology

Morbidity of patients with cardiac syndrome X (typical anginal‐like chest pain and normal coronary arteriogram) is high with continuing episodes of chest pain and frequent hospital readmissions. Management of this syndrome represents a major challenge for the treating physician. Conventional therapies with antianginal agents such as nitrates, calcium channel antagonists, classic β‐adrenoceptor blockers and nicorandil have been tried, with variable success. However, this might be related to a failure to target the underlying pathophysiology and, clearly, more effective therapies are needed. Supporting evidence for the important role of endothelial dysfunction and oxidative stress in the pathogenesis of cardiac syndrome X has come from the recent observation that basal superoxide production predicts future cardiovascular events in this patient group. This review will discuss the pathophysiology, current medical management and potential new pharmacological treatment for patients with cardiac syndrome X which target endothelial dysfunction and oxidative stress. What's already known about this topic? ?Morbidity of patients with cardiac syndrome X is high. ?The important role of endothelial dysfunction and oxidative stress in the pathogenesis of cardiac syndrome X. What does this article add? ?This review will discuss the pathophysiology, current medical management and potential new pharmacological treatment for patients with cardiac syndrome X which target endothelial dysfunction and oxidative stress.     

Cardiac syndrome X: Clinical characteristics revisited

Background

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

Objective

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

Methods

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

Results

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

Conclusions

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

Endothelin 1 and endothelial dysfunction in children with idiopathic nephrotic syndrome

BackgroundEndothelial dysfunction is the initial step for atherogenesis. Children with idiopathic nephrotic syndrome are at risk of endothelial dysfunction due to altered cholesterol metabolism which can lead to early atherosclerosis.MethodsIn this analytical study with longitudinal follow up 25 children with first episode of nephrotic syndrome (FENS) aged 1–16 years along with 25 age and gender matched healthy controls were enrolled. Endothelin 1 (ET 1) levels were measured by ELISA (Cloud Clone Corp. and assembled by USCN Inc, U.S.A). Other variables were measured using standard biochemical methods. Primary outcome measure was plasma ET 1 level in children with FENS and in controls. Secondary outcome measure was to observe the levels of ET 1 in children with FENS at 12 weeks in remission.ResultsThe level of ET 1 was significantly higher (p < 0.001) in children with FENS as compared to controls. The level of ET 1 was significantly higher (p = 0.006) in SSNS at the onset of nephrotic syndrome and was significantly lower (p = 0.04) after 12 weeks of drug induced remission as compared to controls. SRNS children had higher levels of ET 1 than the steroid sensitive patients at onset but in was not statistically significant (p = 0.062). ET 1 showed significant positive correlation with total cholesterol (r = 0.462; p = 0.001) and negative correlation with serum albumin (r = −0.565; p = 0.001).ConclusionPlasma ET 1 levels are raised in children with FENS posing a risk of endothelial dysfunction, which persists at least in short term. Long term effects of raised plasma ET 1 needs to be studied.     

Spontaneous slow flow in the saphenous vein graft: a relevant distinction of macrovascular endothelial dysfunction

Spontaneous slow flow without significant obstructive stenosis, as encountered during diagnostic angiography, has mostly been reported in native coronary arteries. This phenomenon has been associated with angina, myocardial ischemia and infarction. Slow flow and “no-reflow” in saphenous vein grafts (SVG) have mostly been observed during percutaneous interventions as a complication from distal embolization. Spontaneous slow SVG flow, however, is rarely reported and correlation with clinical events not as well documented. A case of spontaneous slow flow in a SVG without significant obstructive lesions is presented, which correlated with the patient's anginal symptoms and ischemia on the stress myocardial perfusion scintigraphy. Percutaneous coronary intervention in the bypassed native coronary artery was successful resulting in the restoration of TIMI-3 coronary flow, resolution of the patient's symptoms, and normalization of the myocardial perfusion defects. The restoration of normal flow through the stented native coronary artery suggested endothelial dysfunction of the initial slow flow state was localized at the macrovascular level, specifically at the SVG conduit. Since bypass graft failure, as with native arterial atherosclerosis, has been attributed to impaired endothelial function at both the macrovascular and microvascular levels, localization of macrovascular endothelial dysfunction in the SVG as shown may be an instructive observation.     

阻塞性睡眠呼吸暂停综合征与血管内皮功能障碍研究进展

阻塞性睡眠呼吸暂停综合征(obstructive sleep apnea hypopnea syndrome,OSAHS)是高血压、动脉粥样硬化等心血管疾病发病的重要危险因素之一,虽然目前机制尚未完全阐明,但与内皮功能障碍密切相关.本文就正常血管内皮功能、内皮功能障碍及评价方法 发、OSAHS与内皮功能障碍及治疗等进行综述.     

Microcirculatory dysfunction in cardiac syndrome X: role of abnormal blood rheology

Objective: Cardiac syndrome X (CSX) is of clinical interest, yet the underlying pathophysiological mechanisms have not been fully elucidated. It is well known that elevated blood viscosity and red blood cell (RBC) aggregation can adversely affect microcirculatory blood flow. The present study was designed to explore whether CSX is associated with abnormalities of blood rheology. Methods: Blood samples were obtained from 152 adult angina patients undergoing diagnostic coronary angiography; geometric and flow‐velocity data were obtained. Rheologic measurements were performed in a blinded manner; 21 subjects were later identified with CSX. Hemorheologic and clinical laboratory data were compared to 21 age‐ and gender‐matched healthy controls. Results: CSX patients had markedly abnormal blood rheology: (1) higher RBC aggregation and aggregability as judged by erythrocyte sedimentation rate and Myrenne indices at stasis and low shear (p < 0.001) and (2) elevated hematocrit‐corrected blood viscosity, plasma viscosity (p < 0.001), and yield stress (p < 0.01). White blood cell counts and high‐sensitivity C‐reactive protein levels were significantly elevated in CSX; coronary‐flow velocities were below normal. Conclusions: Abnormal hemorheologic parameters exist in subjects with CSX and may contribute to the pathophysiology of the disease, presumably via adversely affecting blood flow in the coronary microcirculation. Therapeutic measures aimed at normalizing blood rheology and hence microcirculatory flow should be explored.     

Insulin sensitivity in cardiological syndrome X

Objectives. To test whether cardiological syndrome X is an insulin-resistant state. Setting, design and subjects. The coronary care unit of a referral centre for angina pectoris in Pisa, Italy. A case-control study, involving 10 patients with unequivocal (angiographycally proven) cardiological syndrome X, but normal glucose tolerance, blood pressure and lipid levels, and 13 matched healthy subjects. Main outcome measures. Insulin sensitivity and pattern of substrate oxidation (assessed by the euglycaemic insulin clamp technique in combination with indirect calorimetry). Results. Fasting plasma glucose and insulin levels were 5.05±0.11 versus 4.88±0.11 mmol l^-1 and 68±10 versus 56±6 pmol l^-1, respectively (controls versus patients, ns). During the insulin clamp, glucose disposal rate was nearly identical in patients and controls (25.9±1.8 and 27.2±1.8 μmol kg^-1 min^-1, respectively, P=0.88). Non-oxidative glucose disposal accounted for similar proportions of total glucose uptake (59 versus 53%, patients versus controls, ns). Resting energy expenditure (13.7±0.6 versus 13.8±0.8 cal kg^-1 min^-1, ns) and insulin-induced thermogenesis were similar in the two groups. Fasting plasma NEFA concentrations (0.64±0.09 and 0.64±0.06 mmol l^-1, patients and controls, ns) fell in a similar time-course and to virtually identical nadirs (0.13±0.02 and 0.14±0.02 mmol l^-1) after insulin infusion. Fasting plasma potassium was similar in patients and controls (3.99±0.10 and 4.16±0.04 mmol l^-1, ns), and insulin induced equivalent hypokalaemia (-14 versus -19%). Conclusions. None of the in vivo actions of insulin were impaired in patients with when compared to matched controls. Therefore, we conclude that cardiological syndrome X is not an insulin resistant state per se, and that any decrease in insulin sensitivity found in this condition is likely to be secondary.     

Influence of endothelial dysfunction on telomere length in subjects with metabolic syndrome: LIPGENE study

Previous evidences support that increased oxidative stress (OxS) may play an important role in metabolic syndrome (MetS) and both are closely linked to vascular dysfunction. This study determined whether there is a relationship between endothelial function and relative telomere length (RTL) in MetS subjects. In this cross-sectional study from the LIPGENE cohort, a total of 88 subjects (36 men and 52 women) were divided into four groups by quartiles of telomere length. We measured ischemic reactive hyperemia (IRH), total nitrite (NO) and protein carbonyl (PC) plasma levels, F2-isoprostanes urinary levels, and superoxide dismutase (SOD) and glutathione peroxidase (GPx) plasma activities. IRH and NO plasma levels were higher in subjects with longer RTL (quartiles 3 and 4), while PC plasma levels, F2-isoprostanes urinary levels, and GPx and SOD plasma activities were lower in quartile 4 subjects (longest RTL). Additionally, MetS subjects with longer RTL had greater homeostatic model assessment-β level and lower triglycerides plasma levels. Our results suggest that endothelial dysfunction, associated with high levels of OxS, could be entailed in an increment of telomere attrition. Thus, further support of the molecular and cellular mechanisms involved in vascular dysfunction may contribute to the development of strategies to decelerate vascular aging or prevent cardiovascular disease.     

丹红注射液治疗心脏X综合征的临床疗效

目的观察常规治疗基础上加用丹红注射液治疗心脏X综合征(CSX)患者的近期临床疗效。方法选择CSX患者60例,随机分为观察组(n=30)和对照组(n=30),对照组给予常规治疗,观察组在常规治疗基础上加用丹红注射液治疗,治疗10 d,在治疗前后观察患者的临床疗效,包括心绞痛的发作情况、心电图及运动负荷试验的变化情况,以及血清中内皮素-1(ET-1)、血栓调节蛋白(TM)及选择素-E(Es)的水平。结果观察组与对照组胸痛症状缓解总有效率分别为93.33%vs.73.33%;心电图改善总有效率分别为83.33%vs.56.67%,差异均有统计学意义(P0.05)。观察组与对照组运动负荷试验中运动总时间分别为(486.9±83.0)s vs.(438.3±85.6)s;从运动开始至ST段压低1 mm的时间分别为(351.9±69.2)s vs.(310.7±79.2)s,观察组患者运动负荷改善情况优于对照组,差异具有统计学意义(P0.05)。观察组与对照组治疗前血清ET-1、TM、Es水平无统计学差异(P0.05);治疗后两组血清ET-1水平分别为(54.58±7.95)ng/L vs.(76.21±1.78)ng/L;TM水平分别为(7.01±1.49)μg/L vs.(11.10±1.68)μg/L;Es水平分别为(7.50±2.71)ng/m L vs.(10.71±3.56)ng/m L,差异均具有统计学意义(P0.01)。两组均未见不良反应发生。结论丹红注射液能够改善心脏X综合征患者临床症状,降低CSX患者血清ET-1、TM及Es水平。     

缬沙坦对心脏X综合征患者内皮功能的影响及其临床意义

目的探讨缬沙坦对心脏X综合征患者血清一氧化氮(NO)、内皮素-1(ET-1)及内皮依赖性血管舒张功能的影响。方法 36例心脏X综合征患者给予缬沙坦80mg,1次/d,随访治疗12周,另入选同期健康体检者26例。复查心脏X综合征患者治疗前后NO、ET-1及血流介导的肱动脉内皮依赖性血管舒张功能(FMD)及运动平板试验的变化。结果用药12周后,与治疗前比较,心脏X综合征患者的NO上升和FMD提高(P<0.05);ET-1降低和最大ST段压低幅度明显降低(P<0.05);运动总时间、ST段压低1mm时间明显延长。结论缬沙坦可改善血管内皮功能,并提高患者的运动耐量。     

微血管性心绞痛冠状动脉血流速度与内皮损伤的研究

目的　通过冠状动脉血流多普勒检测 ,探讨微血管病变患者的冠状动脉血流速度及其与血管内皮损伤、局部微血栓的关系。方法　对有胸痛而冠状动脉造影正常的 16例患者的 43支血管 (右冠状动脉 14支 ,左前降支 15支 ,左回旋支 14支 )行冠状动脉内多普勒超声血流检查 ,记录基础血流参数和充血相血流参数 ,同时记录冠状动脉血流速率储备 (CFVR)。以CFVR 2 5为标准 ,分为正常组 (A组 )和微血管病变组 (B组 ) ,比较二组的冠状动脉血流速度参数及血浆血管性假血友病因子(vWF)的差异。结果　A组包括 7例患者的 19支血管 ,B组包括 9例患者的 2 4支血管。A组的基础平均峰值流速 (bAPV)显著小于B组 [(17 7± 4 8)vs (2 0 9± 5 4)cm s ,P <0 0 0 1];而充血相平均峰值流速 (hAPV)A组显著大于B组 [(5 1 0± 13 3)vs (4 2 5± 11 3)cm s ,P <0 0 5 ];A组的CFVR显著大于B组 [(2 9± 0 5 )vs (2 0± 0 3) ,P <0 0 0 1];A组的血浆vWF显著小于B组 [(112 5± 2 7 5 ) %vs(173 2± 40 8) % ,P <0 0 5 ]。结论　微血管病变患者的基础平均峰血流速度显著增大 ,而充血相平均峰血流速度显著减小 ,可能与冠状动脉内皮损伤及局部微血栓形成有关。     

Vascular endothelial dysfunction and pharmacological treatment

The endothelium exerts multiple actions involving regulation of vascular permeability and tone, coagulation and fibrinolysis, inflammatory and immunological reactions and cell growth. Alterations of one or more such actions may cause vascular endothelial dysfunction. Different risk factors such as hypercholesterolemia, homocystinemia, hyperglycemia, hypertension, smoking, inflammation, and aging contribute to the development of endothelial dysfunction. Mechanisms underlying endothelial dysfunction are multiple, including impaired endothelium-derived vasodilators, enhanced endothelium-derived vasoconstrictors, over production of reactive oxygen species and reactive nitrogen species, activation of inflammatory and immune reactions, and imbalance of coagulation and fibrinolysis. Endothelial dysfunction occurs in many cardiovascular diseases, which involves different mechanisms, depending on specific risk factors affecting the disease. Among these mechanisms, a reduction in nitric oxide (NO) bioavailability plays a central role in the development of endothelial dysfunction because NO exerts diverse physiological actions, including vasodilation, anti-inflammation, antiplatelet, antiproliferation and antimigration. Experimental and clinical studies have demonstrated that a variety of currently used or investigational drugs, such as angiotensin-converting enzyme inhibitors, angiotensin AT1 receptors blockers, angiotensin-(1-7), antioxidants, beta-blockers, calcium channel blockers, endothelial NO synthase enhancers, phosphodiesterase 5 inhibitors, sphingosine-1-phosphate and statins, exert endothelial protective effects. Due to the difference in mechanisms of action, these drugs need to be used according to specific mechanisms underlying endothelial dysfunction of the disease.     

Structural and functional abnormality of systemic microvessels in cardiac syndrome X

BACKGROUND AND AIM: Microvascular damage of coronary bed has been considered the main pathogenetic factor of cardiac syndrome X (chest pain, exercise-induced ischemic ST-segment changes and angiographically normal coronary arteries). Previous studies have demonstrated that vascular abnormalities are not confined to the heart, suggesting a peripheral vascular dysfunction. On the hypothesis of a generalized microvascular disturbance in cardiac syndrome X, we performed a morphologic and functional study of systemic microcirculation in patients with syndrome X compared to normal subjects. METHODS AND RESULTS: Microvessels were evaluated with intravital videocapillaroscopy (VCP) executed in peripheral and conjunctival observation sites which explore micro and paramicrocirculation; biohumoral study included markers of inflammation and of endothelial function, coagulative-fibrinolytic system and lipid metabolism. Videocapillaroscopy showed several morphologic changes (present in high percent of patients with syndrome X and not in controls) and significant quantitative alterations (capillary density, granular flow score, alterations of vessel profile, length of capillary loop branches and of arteriole/venule diameter) which indicated a severe alteration of whole vessel structure and an important rearrangement of microvascular disposition. In a similar way, the humoral study showed some significant changes of endothelial (vWF, ICAM-1, E-sel, PAI-1), inflammatory (C-reactive protein (CRP), fibrinogen) and metabolic factors (HDL-chol) which are commonly associated with inflammatory response. CONCLUSIONS: We conclude that patients with cardiac syndrome X exhibited some structural and functional alterations of systemic microvasculature; the pattern is similar to that detected in systemic inflammatory diseases and suggests a vascular lesion of inflammatory type. The same changes could be operating also in coronary microvessels of patients with syndrome X.     

C-反应蛋白、内皮功能变化与急性冠状动脉综合征相关性研究

目的　探讨 C-反应蛋白及肱动脉流量介导的血管舒张在急性冠状动脉综合征中的变化及其相关性。方法　急性冠状动脉综合征 (ACS)组 5 1例 ,其中急性心肌梗死 (AMI) 15例 ,不稳定性心绞痛 (U AP) 36例 ;选择 2 2例冠状动脉造影除外冠心病的患者为对照组。用速率散射比浊法测血清 C-反应蛋白 (CRP) ,用高分辨率超声测肱动脉反应性充血引起的流量介导血管扩张 (FMD)与硝酸甘油介导的血管扩张 (NTG)。结果　 ACS组 CRP高于对照组(0 .94± 1.45 mg/ dl vs0 .2 7± 0 .2 1mg/ dl,P<0 .0 5 ) ,AMI亚组 CRP明显高于 UAP亚组与对照组 (1.6 4± 1.82mg/ dl vs0 .6 5± 1.17m g/ dl、 0 .2 7± 0 .2 1m g/ dl,P<0 .0 5 ) ,UAP亚组高于对照组 (0 .6 5± 1.82 m g/ dl vs0 .2 7±0 .2 1m g/ dl,P>0 .0 5 )。ACS组的 FMD明显低于对照组 (4 .6 1± 2 .2 1mm vs9.2 3± 3.45 mm,P<0 .0 5 ) ,而 NTG与对照组比较则无差别。经 logisitic回归分析 ,CRP的风险比值 (OR)值大于 1,是 ACS的危险因素 ,FMD的 OR值小于 1,是 ACS的保护因素。经前进法观察 CRP与 FMD在急性冠脉综合征中的作用是相互独立的。结论　急性冠状动脉综合征患者 C-反应蛋白升高 ,内皮功能受损 ,二者是 ACS发生的独立危险因素     

Biomarkers of endothelial dysfunction are elevated and related to prognosis in chronic heart failure patients with diabetes but not in those without diabetes

BACKGROUND: Biomarkers of endothelial dysfunction, such as soluble E-selectin, and von Willebrand factor (vWf) are elevated in patients with chronic heart failure (CHF). The impact of diabetes mellitus (DM) on these biomarkers, and their relation to prognosis remains unknown. AIMS: to investigate the impact of DM on plasma levels and the prognostic value of E-selectin and vWf in patients with CHF. METHODS AND RESULTS: Plasma levels of E-selectin and vWf were measured in 195 CHF patients with (n=48, 24.5%), and without DM, and in 116 age-matched healthy controls. Compared with controls, median plasma E-selectin levels were higher in CHF patients with DM (P=0.012), but not in CHF patients without DM (P=0.45); vWf levels were also higher in CHF patients with DM (P<0.001), but not without DM (P=0.108). E-selectin was associated with risk of recurrent ischaemic cardiovascular events among CHF patients with DM (HR 2.60; P=0.009), but not among patients without DM (HR 1.09; P=0.60) per 1 SD increment in log transformed variable. vWf was not related with outcome in CHF patients with or without DM. CONCLUSIONS: Plasma levels of E-selectin and vWf are elevated in CHF patients with DM but not in those without DM. High E-selectin levels may be associated with ischaemic events in patients with DM.     

Deficiency of a New Protein Associated with Cardiac Syndrome X; Called Adropin

The pathophysiology of cardiac syndrome X (CSX) is still unclear, but most patients with CSX have endothelial dysfunction. It has been shown that adropin uniquely effects the regulation of endothelial function. The purpose of the study was to evaluate the role of adropin in CSX. Eighty‐six consecutive cardiac syndrome X‐diagnosed patients and 86 age‐sex matched healthy subjects were enrolled into the study. Serum adropin levels, nitrite/nitrate levels were measured in each subject. The adropin levels were significantly lower in patients with CSX than healthy subjects (1.7 ± 0.8 ng/mL and 3.4 ± 1.8 ng/mL, respectively; P < 0.001). The BMI values of patients with CSX were significantly higher than control subjects (28.1 ± 2.4 kg/m² and 26.0 ± 3.7 kg/m², respectively; P < 0.001). Plasma nitrite/nitrate levels were lower in patients with CSX than control subjects (15.9 ± 1.6   μmol/L vs. 25.4 ± 2.8 μmol/L, respectively; P < 0.001), and they have a significantly positive correlation with plasma adropin levels (r = 0.463, P < 0.001). In the multiple linear regression analysis, nitrite/nitrate levels, BMI, and adropin were found to be independent risk factors for CSX. A ROC curve is used to identify the ability of adropin levels to predict the cardiac syndrome X. The area under the ROC curve was 0.854 for adropin levels (P = 0.0001). The sensitivity and specificity values of adropin levels were 90.7 and 70.9%, respectively (cut‐off value 2.73). In conclusion, lower serum adropin levels were associated with CSX. Adropin is an independent risk factor for CSX.     

内皮功能异常在X综合征患者中的发病学意义

目的 研究内皮功能异常在Ｘ综合征患者中的发病学意义。方法 测定了１５例Ｘ综合征患者胸痛发作前后血中循环内皮细胞数（ＣＥＣ）和内皮素（ＥＴ）－１含量,并采用高分辨超声技术检测其血管内皮依赖性舒张功能的变化,与２０例正常人进行对照。结果 （１）Ｘ综合征患者ＣＥＣ数及ＥＴ－１水平明显高于正常对照组（Ｐ值均〈０．０１）。ＥＴ－１含量与ＣＥＣ数变化呈显著的正相关（ｒ＝０．６７,Ｐ〈０．０１）。（２）Ｘ综合征