Nicotine and angiogenesis: a new paradigm for tobacco‐related diseases

The pathophysiology of tobacco‐related diseases is complex and multifactorial. Among the approximately 4,000 compounds in tobacco smoke are carcinogens such as nitro‐samines, irritants such as a variety of phenolic compounds, volatiles such as carbon monoxide, and of course nicotine. Nicotine itself has quite complex actions, mediated in part by nicotinic cholinergic receptors that may have extraneuronal, as well as neuronal distribution. This review discusses the mechanisms by which nicotine contributes to tobacco‐related disease, with a focus on the surprising new finding that nicotine is a potent angiogenic agent. Nicotine hijacks an endogenous nicotinic cholinergic pathway present in endothelial cells that is involved in physiological, as well as pathological angiogenesis.     

Identification of vulnerable atherosclerotic plaques

There has been great interest in the possibility of identifying plaques that might be the site of future acute coronary events. These plaques are termed vulnerable and the majority are lipid-rich with an abundance of inflammatory cells and a thin fibrous cap. Several techniques developed to identify these plaques are in various stages of development and in the near future, one might employ a strategy to potentially identify and therapeutically modify such lesions during percutaneous intervention to avoid future acute events. Although this approach of identifying the vulnerable plaque seems promising, there are significant potential limitations. The natural history of a vulnerable plaque is unknown and clinical trials utilizing this strategy of identification and therapeutic intervention are lacking. Moreover, in any given patient, multiple vulnerable plaques are likely to be present. This article reviews some of the techniques for identifying a vulnerable plaque and discusses the potential advantages and limitations of this strategy.     

Gout: new insights into an old disease

Gout is an autoinflammatory disorder associated with deposition of monosodium urate (MSU) crystals in joints and periarticular tissues. Recent advances suggest that the innate immune system may drive the gouty inflammatory response to MSU. These findings prompt questions concerning how the innate immune system recognizes MSU and the identities of the receptors involved. In this issue of the JCI, Chen et al. show that the IL-1 receptor and its signaling protein myeloid differentiation primary response protein 88 (MyD88) but not the "classical" innate immune receptors, TLRs, are central for MSU-induced inflammation (see the related article beginning on page 2262).     

Hypercalcemia of malignancy--new insights into an old syndrome

Hypercalcemia is a common paraneoplastic syndrome. Tumors induce hypercalcemia by a local mechanism associated with the tumor's production of various cytokines increasing bone osteolysis. In addition, many tumors release humoral factors, mainly parathyroid hormone (PTH)-related protein (PTHrP), which stimulates bone resorption and/or tubular calcium reabsorption leading to hypercalcemia. Interaction of PTHrP with other tumor-elaborated cytokines might explain some nonPTH-like features associated with the hypercalcemia of malignancy syndrome. Using assays recognizing various PTHrP epitopes, the majority of hypercalcemic cancer patients have higher immunoreactive PTHrP levels in either plasma or urine than normal subjects. Present data support the concept that PTHrP might also be a factor which promotes tumor growth and also the development of osteolytic metastasis. A variety of therapeutic approaches are available to lower serum calcium in hypercalcemic cancer patients. The pathophysiological mechanisms of hypercalcemia appear to be a determinant of the efficacy of different antihypercalcemic treatments.     

Increased coronary sinus blood temperature: correlation with systemic inflammation

BACKGROUND: Recent studies have shown that patients with single vessel coronary artery disease (CAD) suffering from acute coronary syndromes (ACS) have increased coronary sinus (CS) blood temperature compared with the right atrium (RA). The aim of this study was to investigate whether there is a correlation between systemic inflammatory indexes and CS temperature and whether there is a difference in CS temperature between patients with single vs. multivessel disease. MATERIALS AND METHODS We included consecutive patients scheduled for coronary angiography for recent-onset chest pain evaluation. We measured C-reactive protein (CRP) levels in the study population. Coronary sinus and RA blood temperature measurements were performed by a 7F thermography catheter. DeltaTau was calculated by subtracting the RA from the CS blood temperature. RESULTS: The study population comprised 53 patients with ACS, 25 patients with stable angina (SA) and 22 subjects without CAD (control group). DeltaTau was greater in patients with ACS and with SA compared with the control group (0.22 +/- 0.10 degrees C, 0.18 +/- 0.04 degrees C vs. 0.14 +/- 0.07 degrees C, P < 0.01 for both comparisons). The ACS group had greater DeltaTau compared with the SA group, although the difference did not reach statistical significance (P = 0.09). Eighteen (39.1%) out of 46 patients with multivessel disease had three-vessel disease and 28 (60.8%) had two-vessel disease. DeltaTau between patients with multivessel and single vessel disease was similar (0.22 +/- 0.01 degrees C, 0.19 +/- 0.01 degrees C, P = 0.17). The levels of CRP were well correlated with DeltaTau (R = 0.35b, P < 0.01). CONCLUSIONS: Systemic inflammation is well correlated with CS temperature; thus, an inflammatory process could be the underlying mechanism for increased heat production from the myocardium.     

A case with coarctation of the aorta accompanied by coronary ectasia and dilatation of the ascending aorta

Coarctation of the aorta is one of the congenital heart diseases diagnosed primarily in childhood and early adolescence. A 67-year-old female was admitted to the hospital with chest pain. Angiography revealed a coarctation of the aorta, coronary ectasia and dilatation of the ascending aorta. This case attracted our attention because the first diagnosis was made at such an advanced age and coarctation was accompanied by coronary ectasia and dilatation of the ascending aorta. Therefore, we decided to report the case.     

The assessment of the vulnerable atherosclerotic plaque using MR imaging: a brief review

The study of atherosclerotic disease during its natural history and after therapeutic intervention may enhance our understanding of the progression and regression of this disease and will aid in selecting the appropriate medical treatments or surgical interventions. Several invasive and non-invasive imaging techniques are available to assess atherosclerotic disease vessels. Most of these techniques are strong in identifying the morphological features of the disease such as lumenal diameter and stenosis or wall thickness, and in some cases provide an assessment of the relative risk associated with the atherosclerotic disease. However, none of these techniques can fully characterize the composition of the atherosclerotic plaque in the vessel wall and therefore are incapable of identifying the vulnerable plaques. High-resolution, multi-contrast, magnetic resonance (MR) can non-invasively image vulnerable plaques and characterize plaques in terms of lipid and fibrous content and identify the presence of thrombus or calcium. Application of MR imaging opens up whole new areas for diagnosis, prevention, and treatment of atherosclerosis.     

Phosphate toxicity: new insights into an old problem

Phosphorus is an essential nutrient required for critical biological reactions that maintain the normal homoeostatic control of the cell. This element is an important component of different cellular structures, including nucleic acids and cell membranes. Adequate phosphorus balance is vital for maintaining basic cellular functions, ranging from energy metabolism to cell signalling. In addition, many intracellular pathways utilize phosphate ions for important cellular reactions; therefore, homoeostatic control of phosphate is one of the most delicate biological regulations. Impaired phosphorus balance can affect the functionality of almost every human system, including musculoskeletal and cardiovascular systems, ultimately leading to an increase in morbidity and mortality of the affected patients. Human and experimental studies have found that delicate balance among circulating factors, like vitamin D, PTH (parathyroid hormone) and FGF23 (fibroblast growth factor 23), are essential for regulation of physiological phosphate balance. Dysregulation of these factors, either alone or in combination, can induce phosphorus imbalance. Recent studies have shown that suppression of the FGF23-klotho system can lead to hyperphosphataemia with extensive tissue damage caused by phosphate toxicity. The cause and consequences of phosphate toxicity will be briefly summarized in the present review.     

高敏C反应蛋白和颈动脉粥样硬化斑块对急性冠状动脉综合征的预示和诊断价值

目的 探讨高敏C反应蛋白(hs-CRP)和颈动脉粥样硬化斑块与急性冠状动脉综合征(ACS)的关系,研究两者对ACS的预示和诊断价值.方法 采用前瞻性队列研究方法,选择68例ACS患者、39例稳定型心绞痛(SAP)患者和39例冠状动脉造影正常成年人为正常对照组,测定hs-CRP并用彩色多普勒超声诊断仪检查颈动脉粥样硬化斑块.结果 ACS组的hs-CRP明显高于SAP组,中位数士四分位数间距是(13.39±10.24)mg/L vs(2.10±2.16) mg/L(P＜0.01)和正常对照组(1.90±3.05)mg/L(P＜0.01),SAP组与正常对照组差异无统计学意义.ACS组斑决指数和Crouse积分明显高于SAP组,分别为3.00±1.00 vs 2.00±2.00和5.20±7.25 vs 4.60±6.80(均P＜0.01),SAP组又明显高于正常对照组,分别为2.00±2.00 vs 0.00±1.90和4.60±6.80 vs 0.00±1.90(均P＜0.01).ACS组和SAP组的斑块数目明显多于正常对照组,分别为2.00±2.00、2.00±2.00 vs 0.00±1.00(均P＜0.01),ACS组斑块数目与SAP组之间差异无统计学意义.ACS组和SAP组的内中膜厚度(IMT)明显多于正常对照组,分别为(1.15±0.85)mm、(0.90± 1.00)mm vs(0.60±0.10)mm(均P＜0.01),但ACS组与SAP组间差异无统计学意义.Logistic遥步回归分析显示只有hs-CRP、斑块指数与ACS高度密切相关(P＜0.01).结论 hs-CRP、颈动脉斑块指数与ACS关系密切,hs-CRP联合颈动脉粥样硬化斑块超声检查有较好预示和诊断ACS作用.     

单纯性冠状动脉扩张的临床分析

目的研究单纯性冠状动脉扩张的发生率、影像学及临床特点、预后。方法回顾性总结分析自1998—02～2004—06期间在哈尔滨医科大学第一临床医学院行选择性冠状动脉造影术的2863例冠状动脉造影人群。结果2863例行选择性冠状动脉造影术的人群中，共检出单纯性冠状动脉扩张20例，发生率0．698％；好发部位依次为左主干、右冠状动脉、前降支、回旋支；大多数单纯性冠状动脉扩张的病人是男性（85％）、吸烟者（90％）；随访期间1例死亡，2例发生心肌梗死，12例仍有阵发性心绞痛发作；糖尿病是与单纯性冠状动脉扩张呈负相关的独立因素。结论单纯性冠状动脉扩张在冠状动脉造影中少见，与除糖尿病外所有冠心病的危险因素相关。单纯性冠状动脉扩张不是良性病变，必须小心监控。     

The Role of Colchicine in Acute Coronary Syndromes

Purpose

Because inflammation is a key process implicated in the pathogenesis of atherosclerosis at all stages, including plaque formation, progression, instability, and rupture, and because colchicine has unique anti-inflammatory properties, this review article summarizes the pathophysiologic mechanisms underpinning inflammation in atherosclerosis and acute coronary syndrome (ACS), outlines anti-inflammatory therapeutic approaches that have been tested thus far, and evaluates the evidence supporting the potential role of colchicine in improving outcomes and reducing cardiovascular morbidity and mortality in patients after ACS.

Diagnostic performance of plasma high sensitive C‐reactive protein in detecting three‐vessel coronary artery disease: modification by apolipoprotein E genotype

Objectives. Plasma high sensitive C‐reactive protein (hsCRP) concentration is an important clinical test of systemic inflammation and, like apoE ε4 allele, an important risk factor of coronary artery disease (CAD). We investigated whether the diagnostic performance of plasma hsCRP in detecting severe 3‐vessel CAD may be modified by apoE ε4 carrier status. Methods. The study population (Angiography and Genes Study) comprised 485 Finnish subjects (336 men and 149 women, mean age 64.0±1.0) undergoing coronary angiography. ApoE genotypes were determined by the PCR‐based method and by hsCRP using an automatic analyser. Results. The diagnostic performance of hsCRP concentration in distinguishing 3‐vessel CAD from its less widespread forms (non‐3‐vessel CAD) was assessed by receiver operating characteristic curve (ROC) analysis separately in apoE ε4 non‐carriers and ε4 carriers. ROC analysis showed that hsCRP predicted 3‐vessel CAD in apoE ε4 non‐carriers (AUC 0.646; SE 0.035; p = 0.0001; 95?% CI 0.578–0.714) but not in ε4 carriers (AUC 0.518; SE 0.049; p = 0.719; 95?% CI 0.422–0.615). Multinomial logistic regression analysis revealed a significant (p<0.05) apoE ε4 group versus hsCRP group (<1.0?mg/L/?1.0?mg/L) interaction in relation to incidence of 3‐vessel CAD. In apoE ε4 non‐carriers, high hsCRP (?1.0?mg/L) was significantly (OR 2.1; 95?% CI 1.233–3.562; p = 0.006) associated with high incidence of 3‐vessel CAD after adjustment for major CAD risk factors. Conclusion. The diagnostic performance of hsCRP in distinguishing 3‐vessel CAD from less extensive forms of coronary atherosclerosis is more accurate in a group of subjects without the apoE ε4 allele than in patients with it.     

Aneurysm involving bifurcation of left main coronary artery presenting with transient ischemic attack, paroxysmal atrial fibrillation and ventricular tachycardia

Coronary artery aneurysm, especially left main coronary artery (LMCA) aneurysm is a rare phenomenon. The disease may be congenital or acquired. The most common cause of coronary artery aneurysm is atherosclerosis. We presented a man with a large LMCA aneurysm presenting with unstable angina, transient ischemic attack, ventricular tachycardia and paroxysmal atrial fibrillation.     

Novel insights into the development of atherosclerosis in hemophilia A mouse models

Summary. Background: Cardiovascular diseases in aging people with hemophilia (PWH) represent a growing concern. The underlying hypocoagulability probably provides a protective effect against acute thrombus formation, but the limited data available show no preventive effect against the development of atherogenesis in PWH. Atherosclerosis‐prone mice are attractive tools for the study of atherosclerosis development, and may provide insights into disease progression in PWH. Methods: Severe hemophilia A (factor VIII‐deficient [FVIII^o]) mice were crossed with mice lacking apolipoprotein E (ApoE^?/?) or mice lacking the LDL receptor (LDLR^?/?), and then compared to hemostatically normal littermate controls. After mice had received atherogenic diets for 8, 22 or 37 weeks, atherosclerotic lesion size and phenotypic characterization were analyzed in the aortic sinus and whole aortas. Results: ApoE^?/?/FVIII^o mice showed a time‐dependent protective effect against the development of atherosclerosis, beginning after 22 diet‐weeks and persisting to 37 diet‐weeks in both the aorta sinus and whole aorta as compared with ApoE^?/? mice. Notably, the FVIII deficiency did not influence the progression of atherosclerosis in the FVIII^o/LDLR^?/? model as compared with controls at early or late time points. Conclusions: Hypocoagulability ameliorates vascular disease in the ApoE‐deficient model in a lipid‐independent manner. Interestingly, FVIII deficiency did not affect the development of atherosclerosis in LDLR^?/? mice. In contrast to the ApoE model, the LDLR model resembles the lipid profile that is commonly observed in humans with atherosclerosis. These findings, to a certain extent, support the notion of atherosclerosis development in the complete absence of FVIII.     

急性冠状动脉综合征患者血浆氧化脂蛋白(a)水平

目的探讨急性冠状动脉综合征(ACS)患者血浆氧化脂蛋白(a)[ox-Lp(a)]水平的变化及机制。方法分别检测96例ACS、89例非ACS患者和100例健康人血浆ox-Lp(a)水平,冠状动脉造影确认冠状动脉病变程度。结果ACS组和非ACS组ox-Lp(a)水平均高于对照组,且ACS组ox-Lp(a)水平显著高于非ACS组。ACS组ox-Lp(a)/Lp(a)比值高于非ACS组和健康对照组,后两者中该比值无显著差别。ACS患者中ox-Lp(a)水平与冠状动脉病变程度相关(r=0.370,P=0.000),非ACS组中两者不相关(r=0.051,P=0.634)。多因素分析显示,ox-Lp(a)、TG水平及年龄解释ACS患者15.1%的病变程度。结论高ox-Lp(a)水平与ACS的发生、病变程度有关,有益于鉴别ACS。     

Novel insights into the pathophysiology of different forms of stress testing

Background

The impact of different forms of cardiac stress testing (exercise versus pharmacological stress testing) on cardiac wall stress and myocardial ischemia is incompletely understood.

Methods

In a prospective study, 331 consecutive patients with suspected myocardial ischemia referred for nuclear perfusion imaging were enrolled: 266 underwent exercise (bicycle) stress testing and 65 adenosine stress testing. Levels of B-type natriuretic peptide (BNP) measured before and 1 min after stress testing, ischemic ECG changes, and typical angina symptoms were used to compare the 2 testing modalities.

Results

Cardiac wall stress as quantified by changes in BNP levels significantly increased in the exercise stress group, but not in the adenosine group (increase in BNP levels 22 pg/ml (IQR 6–46) versus − 3 pg/ml (IQR − 3 to 28); p < 0.001). In the bicycle exercise stress group, patients with reversible defects on nuclear perfusion imaging more often had angina symptoms (25% vs. 9%, p = 0.0001) and ischemic ECG changes (33% vs. 12%, p = 0.0001) during the stress test, and a greater increase in BNP levels (28 (IQR 11–58) versus 16 (IQR 3–34) pg/ml, p = 0.001) compared to those without reversible defects. Those differences between patients with and without reversible defects were not observed with the adenosine protocol (p-values all > 0.05).

Conclusion

Exercise stress testing but not adenosine stress results in an increase of cardiac wall stress, angina symptoms and ECG changes. The absence of these surrogates of myocardial ischemia suggests that adenosine stress does not induce acute myocardial ischemia, but rather displays relative perfusion differences.     

Emergence of targeted molecular imaging in atherosclerotic cardiovascular disease

Atherosclerosis, a systemic disease, remains one of the leading causes of morbidity and mortality in the world. Our improved understanding of the molecular mechanisms underlying atherosclerotic lesion progression and sudden transformation into unstable plaques, indicate complex interactions of lipid metabolism, inflammatory processes and genetic predisposition. Currently, novel imaging approaches to visualize the process of atherosclerosis, particularly at the molecular level, are actively being developed. Important targets include inflammatory and endothelial cells, as well as apoptosis and angiogenesis. The next decade should solidify the role of targeted molecular imaging in all aspects of cardiovascular medicine.     

Screening angiography of supraaortic vessels performed by invasive cardiologists at the time of cardiac catheterization: indications and results

An aging population makes multiple vascular distributions more likely in patients arriving at the cath lab for coronary artery angiography or complete cardiac catheterization. Whether or not screening angiography of supraaortic vessels can be performed at the time of cardiac catheterization by the invasive cardiologist is still debatable. We sought to determine safety and utility of performing angiography of supraaortic vessels during cardiac catheterization. Medical records of all patients undergoing combined coronary and noncoronary angiography between May 1998 and December 2002 was retrospectively reviewed. One hundred and forty patients (80 males, mean age 67.8 ± 5.4 years) underwent combined cardiac catheterization and angiography of supraaortic vessels. Carotid artery angiography was performed at the same time of cardiac catheterization in 62 patients and subclavian artery angiography in the other 78 patients. Significant findings were reported in 32 (22.8%) patients. Complications included 1 transient ischemic attack and 2 carotid spasm resolved with nitrates infusion. In most cases the same standard catheters used during coronary angiography were used also for noncoronary angiography (119 patients, 85%). The incidence of significant angiographic findings and the relatively frequent association of CAD with supraaortic vessel atherosclerosis supports combined cardiac catheterization and angiography of supraaortic arteries but only in patients with multivessel coronary artery disease.