冠状动脉钙化研究进展

冠状动脉钙化(CAC)是导致一般人群和冠状动脉性心脏病患者不良结局的危险因素。CAC的发病机制和骨形成有共同的途径,目前已经确定了一些导致CAC发生和发展的危险因素。用药物治疗控制CAC的努力没有取得成功,而冠状动脉钙化的患者经皮冠脉介入术和冠状动脉搭桥术后的无事件生存率也较低。虽然应用药物洗脱支架和斑块修饰装置对钙化血管的预后有一定改善,但不良事件发生率仍然很高。在未来,仍需创新的药物和器械治疗来改善CAC患者的不良预后。     

Current understanding of coronary artery calcification

Coronary artery calcification (CAC) is highly prevalent in patients with coronary heart disease (CHD) and is associated with major ad-verse cardiovascular events. There are two recognized type of CAC—intimal and medial calcification, and each of them have specific risk factors. Several theories about the mechanism of vascular calcification have been put forward, and we currently believe that vascular calcifi-cation is an active, regulated process. CAC can usually be found in patients with severe CHD, and this asymptomatic phenomenon make early diagnosis of CAC important. Coronary computed tomographic angiography is the main noninvasive tool to detect calcified lesions. Measurement of coronary artery calcification by scoring is a reasonable metric for cardiovascular risk assessment in asymptomatic adults at intermediate risk. To date, effective medical treatment of CAC has not been identified. Several strategies of percutaneous coronary interven-tion have been applied to CHD patients with CAC, but with unsatisfactory results. Prognosis of CAC is still a major problem of CHD patients. Thus, more details about the mechanisms of CAC need to be elucidated in order to improve the understanding and treatment of CAC.     

Vascular calcification in patients with chronic kidney disease

Vascular calcification is very prevalent in patients with chronic kidney disease (CKD). In addition to having more traditional cardiovascular (CV) risk factors, CKD patients also have a number of non-traditional CV risk factors that may play a prominent role in the pathogenesis of vascular calcification. The transformation of vascular smooth muscle cells into osteoblast-like cells seems to be a key element in the pathogenesis of vascular calcification in the presence of calcium (Ca) and phosphorus (P) deposition due to abnormal bone metabolism and impaired renal excretion. Vascular calcification causes increased arterial stiffness, left ventricular hypertrophy, decreased coronary artery perfusion, myocardial ischemia, and increased cardiovascular morbidity and mortality. Although current treatment strategies focus on correcting abnormal Ca, P, parathyroid hormone, or vitamin D levels in CKD, a better understanding of the mechanisms of abnormal tissue calcification may lead to the development of new therapeutic agents that are capable of reducing vascular calcification and improving the CV outcome of CKD patients. This review article summarizes the following: (i) the pathophysiological mechanism responsible for vascular calcification; (ii) the methods of detecting vascular calcification in CKD patients; and (iii) the treatment of vascular calcification in CKD patients.     

螺旋CT检测冠状动脉钙化的临床应用

目的：研究螺旋CT检测冠状动脉钙化(CAC)在冠心病诊断中的应用价值。方法：27例既往确诊为冠心病或经心电图负荷试验和／或冠状动脉造影临床确诊的冠心病患(冠心病组)和35例非冠心病患(对照组)分别进行螺旋CT检查。结果：受检随着年龄的增长钙化率逐渐增高，冠心病组冠状动脉钙化率比对照组明显增高，但随年龄的增长冠心病组钙化的特异性降低(降至11．12％)。钙化血管以累及一支血管最常见，多为左前降支(LAD)，三支血管钙化主要见于60岁以上。结论：螺旋CT检测冠状动脉钙化对早期诊断冠心病和预测冠心病事件有与病理相符的临床价值。     

Elevated Serum Bone Morphogenetic Protein 4 in Patients with Chronic Kidney Disease and Coronary Artery Disease

Chronic kidney disease (CKD) is associated with increased coronary artery disease (CAD) and coronary artery calcification. We hypothesized that the osteogenic factor, bone morphogenetic protein-4 (sBMP-4), is elevated in subjects with both CKD and CAD. Serum was collected from 79 subjects undergoing diagnostic angiography and stratified according to CAD and CKD status. Subjects with both CAD and CKD had significantly elevated sBMP-4 compared to those with only one or no disease. sBMP-4 continued to be associated with the presence of both diseases after adjustment for other risk factors. To determine if sBMP-4 is associated with coronary artery calcification, we compared coronary artery calcium scores (CAC) to sBMP-4 in 22 subjects. A positive correlation between CAC and sBMP-4 was seen. In conclusion, sBMP-4 is elevated in patients with both CAD and CKD and positively correlates with CAC, suggesting a role for sBMP-4 in the increased CAD seen in CKD patients.     

慢性肾脏病患者血管钙化相关生物学标志物

血管钙化是慢性肾脏病患者心血管死亡的主要原因,是患者死亡率强有力的预测因子。随着慢性肾脏病的进展,血管钙化发生率不断增加。因此需要找到预测血管钙化的生物标志物,用来预测未来心血管事件发生率和致死率,进行相应干预,改善患者预后。现已有不少关于慢性肾脏病患者血管钙化生物标志物的相关研究,文章就这些生物标志物进行了简要的综述。     

慢性肾脏病血管钙化机制的研究进展

慢性肾脏病（chronic kidney disease, CKD）是世界公认的健康问题,我国CKD的患病率约为10.8%,并且CKD的死亡率也很高。心血管疾病（cardiovascular disease, CVD）是CKD最常见的死亡原因,而血管钙化（vascular calcification, VC)是导致CVD的重要危险因素。因此本文对CKD血管钙化的流行病学现状、病理学特点、危险因素、发病机制等方面进行综述,希望能为血管钙化的防治提供新的思路。     

Incidental coronary calcifications on routine chest CT: Clinical implications

Coronary artery calcification (CAC) is a marker of atherosclerosis and an independent risk factor for cardiac-related mortality, with much of the 50% decline in mortality over the past 30 years being attributed to early detection of coronary disease and intervention of modifiable risk factors. With over 10 million computed tomography (CT) examinations of the chest performed in the United States yearly, CAC can be identified in a very large number of patients. In this review, we discuss the clinical evidence underlying the relationship between radiologic identification of CAC, atherosclerosis, and cardiac outcomes and the implications of its assessment on standard chest CT. We conclude that reporting of incidental coronary calcification found on non-gated chest CT would have a great impact on both management and mortality and thus, in the appropriate setting, should be noted in the impression of the radiologic report when identified.     

Association Between Angiotensin‐Converting Enzyme 2 and Coronary Artery Calcification in Patients on Maintenance Hemodialysis Therapy

While all mechanisms that contribute to the pathogenesis of coronary artery calcification (CAC) are unknown, angiotensin‐converting enzyme 2 (ACE2) may be involved in this process in maintenance hemodialysis (MHD) patients. The aim of this study was to investigate the association between ACE2 and CAC in patients on MHD therapy. Ninety patients on MHD therapy were involved in this prospective study. CAC was quantified by CAC score (CACs) using the Agatston method and a multi‐slice CT scanner. Univariate and multivariate logistic regression were used to analyze the association between ACE2 and CACs. In the univariate analysis, CACs positively correlated with ACE2 (r = 0.666, P < 0.001). After adjusting for age, sex, smoking, hypertension, body mass index, diabetes mellitus, and hyperlipidemia, ACE2 levels continued to significantly and independently predict the presence of CAC. ROC curve analysis showed that the serum ACE2 level can predict the extent of CAC. These findings indicate that elevated serum ACE2 may be involved in vascular calcification in patients receiving MHD therapy.     

Chronic kidney disease in postmenopausal women

Menopause is derived from the Greek words men (month) and pauses (cessation) and means permanent cessation of menstruation after the loss of ovarian activity. Chronic kidney disease (CKD) has recently been associated with cardiovascular events in several studies. CKD patients have a heavy burden of traditional cardiovascular risk factors in addition to a range of nontraditional risk factors such as inflammation and abnormal metabolism of calcium and phosphate. In this review, the association of CKD and cardiovascular disease (CVD), as well as of osteoporosis in postmenopausal women is discussed. CKD mineral and bone disorder, characterized by disturbances of calcium/phosphate/parathyroid hormone, bone abnormalities and vascular and soft tissue calcification, is highly prevalent in CKD and is a strong, independent predictor of bone fracture, CVD and death. Estrogen has been shown to: (a) decrease the expression of angiotensin type 1 receptors in vasculature and kidneys; (b) reduce the expression and activity of angiotensin-converting enzyme, and (c) cause the release of angiotensinogen substrate from the liver. However, the degree of activation or suppression of the renin-angiotensin-aldosterone system by estrogen has not been clearly established. Clinical data on the effects of estrogen therapy on bone mineral densities are extremely limited in the ESRD population. CVD is the most common cause of death in postmenopausal women with CKD and many contributing factors have been explored. Future research for prevention of CVD in postmenopausal women with CKD would focus on the biology of vascular calcification as well as bone loss.     

Relationship between Kidney Function and Subclinical Atherosclerosis Progression Evaluated by Coronary Artery Calcification

Aims: The roles of urinary albumin, eGFRcystatin (eGFRcys), and eGFRcreatinine (eGFRcre) in the progression of coronary artery calcification (CAC) remain unclear. Therefore, the present study investigated the relationship between kidney function and CAC progression. Methods: A total of 760 Japanese men aged 40-79 years were enrolled in this population-based study. Kidney function was measured using eGFRcre, eGFRcys, and the urine albumin-to-creatinine ratio. CAC scores were calculated using the Agatston method. CAC progression was defined as an annual increase of ＞10 Agatston units (AU) among men with 0＜CAC＜100 AU at baseline, that of ＞10% among those with CAC ≥ 100 AU, and any progression for those with CAC=0 at baseline. The relative risk (RR) of CAC progression based on kidney function was assessed using a robust Poisson regression model. Results: The mean follow-up period was 4.9 years. CAC progression was detected in 45.8% of participants. Positive associations between CAC progression and albuminuria (＞30mg/g) (RR: 1.29; 1.09 to 1.53;p=0.004) and low eGFRcys (＜60ml/min/1.73m²) (RR: 1.27; 1.05 to 1.53;p=0.012) remained significant after adjustments for age, the follow-up time, and computerized tomography type. Following further adjustments for hypertension, diabetes mellitus, dyslipidemia, C-reactive protein, and lifestyle factors, CAC progression was associated with albuminuria (RR: 1.20; 1.01 to 1.43;p=0.04) and low eGFRcys (RR: 1.19; 0.99 to 1.43;p=0.066), but not with eGFRcre. Conclusion: CAC progression was associated with albuminuria; however, its relationship with eGFRcys was weakened by adjustments for risk factors.     

Relationship of change in traditional cardiometabolic risk factors to change in coronary artery calcification among individuals with detectable subclinical atherosclerosis: The multi-ethnic study of atherosclerosis

Background/Objectives

Data describing relationships between change in risk factors and coronary artery calcification (CAC) are lacking and could inform optimal cardiovascular disease prevention and treatment strategies. This study aimed to examine how change in traditional cardiometabolic risk factors related to change in CAC among individuals with detectable subclinical atherosclerosis.

Methods

Latent growth modeling was used to examine change in cardiometabolic risk factors (waist circumference, body mass index, systolic and diastolic blood pressure, high- and low-density lipoprotein cholesterol, triglycerides, and glucose) related to change in CAC up to an average 4.9-year follow-up in a multi-ethnic cohort of 3398 asymptomatic individuals (57.8% men) who had detectable CAC (score > 0) at baseline, adjusting for baseline risk factor levels and CAC values, age, gender, race/ethnicity, smoking, family history of CVD, income, and use of antihypertensive, lipid-lowering, and glucose-lowering medications.

Results

Greater declines in blood pressure (systolic and diastolic) and low-density lipoprotein cholesterol at follow-up were each associated with greater CAC progression. The observed inverse associations were attributable to greater CAC progression in participants taking antihypertensive and lipid-lowering drugs who, as expected, had declines in blood pressure and lipid levels, respectively. These inverse associations did not emerge in participants not taking these medications.

Conclusions

Among individuals with subclinical atherosclerosis, the unexpected inverse associations observed between change in blood pressure and lipid levels with CAC progression emphasize the importance of considering medication use, and, when feasible, the severity and duration of disease, in exploring associations between risk factors and CAC change.     

Facteurs de risque de progression des calcifications des artères coronaires après 5 ans d’évolution en dialyse

BackgroundAlthough progression of coronary artery calcification (CAC) has been established as an important marker for cardiovascular morbidity, very few studies have studied it in end-stage renal disease patients. Thus we examined and evaluate risk factors of calcification changes in dialysis patients.MethodAmong 28 hemodialysis (HD) patients, CAC was measured in Agatston units at baseline and after five years using the 64 multi-slice ultra-fast CT. The HD patients were classified as progressors or no progressors according to the change in the CAC score across these 2 measurements.ResultsOver an average 63 months follow-up, participants without CAC at baseline had no incident CAC. The progression of CAC was slow and was found only in 6 patients (21.4%). It was significantly associated with several cardiovascular risk factors, namely, older age (P = 0.03), diabetes (P = 0.05), male sex (P = 0.02), hypercholesterolemia (P = 0.05), anemia (P = 0.017), inflammation (P = 0.05), and hyperphosphataemia (P = 0.012). However, calcemia, parathormone levels, dialysis duration, tobacco, high blood pressure and dialysis dose did not seem to influence the progression of CAC in our series. A strong association was found between basal calcification scores and Delta increment at 5 years.ConclusionsOur study suggests that CAC progression in dialysis is a complex phenomenon, associated with several risk factors with special regard to elevated basal scores. This progression can be avoided or slowed with appropriate management, which must begin in the early stages of chronic kidney disease.     

Inflammation and vascular calcification

Both vascular calcification and inflammation are common in patients with chronic kidney disease (CKD). In patients on dialysis, there is increased coronary artery and peripheral artery calcification compared to the general population. Both intimal (atherosclerotic) and medial calcification in CKD patients are associated with increased morbidity and mortality. Vascular calcification is an active cell-mediated process, and likely reflects a transformation of vascular smooth muscle cells to osteoblast-like cells. Pooled uremic serum can induce this transformation, but the mechanism by which it does so is not yet clear. Several mediators of inflammation such as oxidation, carbonyl stress, C-reactive protein, and cytokines may directly stimulate vascular calcification. In addition, inflammation itself reduces fetuin-A, a naturally occurring inhibitor of vascular calcification which binds excess mineral in serum. The combination of the acceleration of vascular calcification together with impaired defense mechanisms creates a uremic milieu primed for extra-osseous calcification.     

数字荧光透视检出冠状动脉钙化与冠状动脉造影的对比研究

目的　评价数字荧光透视检出冠状动脉钙化 (CAC)对诊断冠心病的价值。方法　 114例患者于冠状动脉造影前经数字荧光透视检查 CAC,以冠状动脉造影存在 1支以上的管径狭窄≥ 5 0 %为诊断冠心病的标准。结果　 114例患者中 ,冠心病患者 63例 ,无冠心病患者 5 1例。冠心病组 CAC阳性率明显高于造影无冠心病组 (71.4%对13 .7% ) ,P<0 .0 1;以数字荧光透视有无 CAC判断冠心病与冠状动脉造影对比 ,总符合率为 78.1% ;不同年龄、性别患者以及不同类型冠心病之间其符合率无明显差异 ,P>0 .0 5。结论　数字荧光透视检出 CAC简便易行 ,无创伤性 ,与冠状动脉造影对比符合率高 ,可广泛用于临床预测及诊断冠心病     

老年人骨质疏松与冠状动脉钙化的关系

目的　探讨骨质疏松与动脉硬化的关系。方法　对 59例冠心病、原发性高血压、脑动脉硬化症等老年患者采用双能 X线骨密度仪测定腰椎、髋部、前臂的骨密度 ,螺旋 CT检测冠状动脉钙化积分及冠脉总钙化积分 ,同时测定血甲状旁腺激素全段、骨钙素、血钙。根据骨密度分骨质疏松组、非骨质疏松组。结果　骨质疏松组冠状动脉各分支钙化积分及冠脉总钙化积分高于非骨质疏松组 (P<0 .0 5)。钙化积分与甲状旁腺激素呈正相关 ,与骨钙素、血钙呈负相关 ,与各部位的骨密度呈负相关。结论　提示骨质疏松症与心血管疾病有密切的关系 ,骨质疏松时骨吸收增加 ,骨钙动员入血 ,异常沉积在血管内膜中 ,造成动脉粥样硬化、钙化     

Valvular and perivalvular involvement in patients with chronic kidney disease

Mitral annular calcification (MAC) and aortic valve calcification (AVC) are the most common valvular and perivalvular abnormalities in patients with chronic kidney disease (CKD). Both MAC and AVC occur at a younger age in CKD patients than in the general population. AVC progresses to aortic stenosis and mild aortic stenosis progresses to severe aortic stenosis at a more rapid rate in patients with CKD than in the general population. The use of calcium-free phosphate binders in such patients may reduce the calcium burden in valvular and perivalvular structures and retard the rate of progression of aortic stenosis. Despite high rates of morbidity and mortality, the prognosis associated with valve surgery in patients with CKD is better than without valve surgery. Infective endocarditis remains an important complication of CKD, particularly in those treated with hemodialysis.     

Coronary artery calcification correlates with the presence and severity of valve calcification

Aim

To investigate the prevalence of coronary artery calcification (CAC) in symptomatic individuals with CT evidence for left heart valve calcification, aortic valve (AVC), mitral valve (MAC) or both.

Methods

This is a retrospective study of 282 consecutive patients with calcification in either the aortic valve or mitral annulus. Calcium scoring of the coronary artery, aortic and mitral valve was measured using the Agatston score.

Results

AVC was more prevalent than MAC (64% vs. 2.5%, p < 0.001), with 34% having both. Absence of CAC was noted in 12.7% of the study population. AVC + CAC were observed in 53.5%, MAC and CAC in 2.1%, and combined AVC, MAC and CAC in 31.6%. The median CAC score was higher in individuals with combined AVC + MAC, followed by those with AVC and lowest was in the MAC group. The majority (40%) of individuals with AVC had CAC score > 400, and only in 16% had CAC = 0. The same pattern was more evident in individuals with AVC + MAC, where 70% had CAC score > 400 and only 6% had CAC score of 0. These results were irrespective of gender. There was no correlation between AVC and MAC but there was modest correlation between CAC score and AVC score (r = 0.28, p = 0.0001), MAC (r = 0.36, p = 0.0001) and with combined AVC + MAC (r = 0.5, p = 0.0001). AVC score of 262 had a sensitivity of 78% and specificity of 92% for the prediction of presence of CAC.

Conclusion

The presence and extent of calcification in the aortic valve or/and mitral valves are associated with severe coronary artery calcification.     

Is Coronary Artery Calcification Associated with Vertebral Bone Density in Nondialyzed Chronic Kidney Disease Patients?

Summary

Background and objectives

Low bone mineral density and coronary artery calcification (CAC) are highly prevalent among chronic kidney disease (CKD) patients, and both conditions are strongly associated with higher mortality. The study presented here aimed to investigate whether reduced vertebral bone density (VBD) was associated with the presence of CAC in the earlier stages of CKD.

Design, setting, participants, & measurements

Seventy-two nondialyzed CKD patients (age 52 ± 11.7 years, 70% male, 42% diabetics, creatinine clearance 40.4 ± 18.2 ml/min per 1.73 m²) were studied. VBD and CAC were quantified by computed tomography.

Results

CAC > 10 Agatston units (AU) was observed in 50% of the patients (median 120 AU [interquartile range 32 to 584 AU]), and a calcification score ≥ 400 AU was found in 19% (736 [527 to 1012] AU). VBD (190 ± 52 Hounsfield units) correlated inversely with age (r = −0.41, P < 0.001) and calcium score (r = −0.31, P = 0.01), and no correlation was found with gender, creatinine clearance, proteinuria, lipid profile, mineral parameters, body mass index, and diabetes. Patients in the lowest tertile of VBD had expressively increased calcium score in comparison to the middle and highest tertile groups. In the multiple logistic regression analysis adjusting for confounding variables, low VBD was independently associated with the presence of CAC.

Conclusions

Low VBD was associated with CAC in nondialyzed CKD patients. The authors suggest that low VBD might constitute another nontraditional risk factor for cardiovascular disease in CKD.     

Nuevos mecanismos implicados en el desarrollo de la enfermedad cardiovascular en la enfermedad renal crónica

Chronic kidney disease (CKD) is a pathology with a high worldwide incidence and an upward trend affecting the elderly. When CKD is very advanced, the use of renal replacement therapies is required to prolong its life (dialysis or kidney transplantation). Although dialysis improves many complications of CKD, the disease does not reverse completely. These patients present an increase in oxidative stress, chronic inflammation and the release of extracellular vesicles (EVs), which cause endothelial damage and the development of different cardiovascular diseases (CVD). CKD patients develop premature diseases associated with advanced age, such as CVD. EVs play an essential role in developing CVD in patients with CKD since their number increases in plasma and their content is modified. The EVs of patients with CKD cause endothelial dysfunction, senescence and vascular calcification. In addition, miRNAs free or transported in EVs together with other components carried in these EVs promote endothelial dysfunction, thrombotic and vascular calcification in CKD, among other effects. This review describes the classic factors and focuses on the role of new mechanisms involved in the development of CVD associated with CKD, emphasizing the role of EVs in the development of cardiovascular pathologies in the context of CKD. Moreover, the review summarized the EVs’ role as diagnostic and therapeutic tools, acting on EV release or content to avoid the development of CVD in CKD patients.