A previous study indicated that plaque instability is not merely a local vascular occurrence, 11 but rather exists simultaneously at multiple sites in the systemic vascular bed. It is therefore possible that instability of coronary plaque could be assessed by evaluating plaque neovascularization in the carotid arteries. This study therefore examined whether CEUS of the carotid artery provided information on the severity and instability of coronary artery disease (CAD) and also assessed the efficacy of statin treatment in patients with CAD. ncreased neovascularization in atherosclerotic plaque has been shown to be associated with plaque progression and instability, leading to atherosclerotic occlusive cardiovascular events. 1-3 Contrast-enhanced ultrasound (CEUS) is an emerging valuable tool for visualizing plaque neovascularization in the carotid artery, with the properties of contrast agent microbubbles, making them act as pure intravascular tracers. 3-5 CEUS has the advantages of being a simple and minimally invasive in vivo technique. 3-5 The usefulness and reliability of CEUS have been validated by previous studies in animals and humans that showed the degree of plaque neovascularization assessed by CEUS correlated strongly with histological density of neovessels. 6-8 CEUS also showed a greater extent of plaque neovascularization of the carotid artery in symptomatic patients with previous cerebro- Background: Contrast-enhanced ultrasound (CEUS) in the carotid artery has potential as a technique for imaging plaque neovascularization. This study examined whether CEUS could provide information on the severity and instability of coronary artery disease (CAD).

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Sympathetic activity is heightened in chronic kidney disease (CKD). The increased sympathetic activity is a risk of future cardiovascular disease (CVD) events. Dopamine, a precursor of norepinephrine biosynthesis, is metabolized in the kidney and excreted into urine, and its plasma levels are increased in renal dysfunction. Thus, we examined whether plasma levels of endogenous dopamine may be related to future CVD events in patients with CKD. A total of 840 patients in stable condition with chronic heart disease (622 patients with ischemic heart disease and 218 with non-ischemic heart disease) (586 patients with GFR ≥ 60 ml/min/1.73 m 2 [normal/mild CKD]; 153 patients with 60 > GFR ≥ 30 [moderate CKD]; 101 patients with 30 > GRF [advanced CKD]) were prospectively followed-up for 5 years or until one of the following CVD events: cardiac death, non-fatal myocardial infarction, unstable angina pectoris requiring unplanned revascularization, worsening heart failure requiring hospitalization, or stroke. Plasma levels of endogenous free dopamine at entry were measured by high-performance liquid chromatography. Patients with a higher stage of CKD had higher dopamine levels than patients with a lower stage (63.0 ± 5.5, 45.0 ± 5.1, and 26 ± 1.2 pg/mL, respectively, ρ = 0.54, p < 0.0001 Spearman rank correlation test). During the follow-up period, 233 patients had CVD events (cardiac death in 54, myocardial infarction in 18, others events in 161) (113 events [19%] in normal/mild CKD, 64 [42%] in moderate CKD, and 56 [55%] in advanced CKD). In patients with moderate CKD and advanced CKD, higher dopamine levels (≥ 40 pg/mL, defined by ROC analysis) were the strongest predictor of CVD events (HR 2.1 and 3.3, 95% CI 1.2 – 3.7 and 1.5 – 7.2, p = 0.006 and 0.003, respectively) in a multivariate Cox hazards analysis using plasma norepinephrine and BNP levels, hypertension, and hyperlipidemia as covariates. In contrast, dopamine levels did not have predictive value in normal/mild CKD (HR 1.2, 95% CI 0.7 – 2.0, p = 0.5). High plasma levels of endogenous free dopamine are a risk factor for future CVD in patients with CKD independently of norepinephrine levels. Increases in plasma endogenous free dopamine levels may serve as a mechanistic link between CKD and CVD.

Stromal cell-derived factor-1 alpha (SDF-1α) is expressed in injured myocardium and plays a key role in the repair of the injured myocardium. This study examined whether SDF-1α in the circulation may have a prognostic information in patients with heart failure (HF). SDF-1α levels in plasma from a peripheral vein (PV) were measured using ELISA in 297 patients with chronic HF defined by the Framingham criteria, who had LV functional abnormalities (102 patients in NYHA class II, 65 in NYHA III, 32 in NYHA IV), and in 50 age- and sex-matched controls. The levels were also measured in plasma from the aorta (AO) and the coronary sinus (CS) in a subgroup of 82 HF patients. Then, all patients with HF were prospectively followed for 60 months or until occurrence of cardiac death or hospitalization with worsening HF. PV levels of SDF-1α were higher in HF patients than controls (2661 ± 67 vs. 2320 ± 55 pg/mL, p < 0.01), and patients with higher NYHA class had higher SDF-1α levels (ρ = 0.41, p < 0.0001). The PV levels of SDF-1α were similar between patients with ischemic HF (n = 204) and non-ischemic HF (n = 93). During follow-up, 19 cardiac death and 69 hospitalization occurred. The PV levels of SDF-1α were higher in patients with an event than those without an event (2820 ± 78 vs. 2490 ± 38 pg/mL, p < 0.01). In a multivariate Cox hazards analysis, a higher level of SDF-1α (> 3040 pg/mL, defined by ROC analysis) was a predictor of events that was independent of age, LVEF, use of medications, and BNP levels (HR 2.1, 95% CI 1.2–4.2, p < 0.01). Moreover, the CS - AO difference in SDF-1α levels, reflecting release from the heart, was higher in patients with (n = 21) than without an event (n = 67) (80 ± 46 vs. −32 ± 33 pg/mL, p < 0.01). The CS - AO difference in SDF-1α levels was positively correlated with the PV levels (r = 0.22, p < 0.05). Both the CS - AO difference in SDF-1α levels and the PV levels had a significant positive correlation with PV levels of BNP and an inverse correlation with LVEF. Higher SDF-1α levels in the peripheral circulation independently predict a worse outcome in patients with chronic HF. SDF-1α is released from the heart in proportion to the severity of LV dysfunction via a compensatory mechanism and may partly contribute to increased circulating levels of SDF-1α in chronic HF.

Remnant lipoproteinemia is a strong risk factor for atherosclerotic cardiovascular diseases (CVD). However, it remains unclear whether the lowering of remnant lipoprotein levels can prevent CVD events, and it is uncertain which lipid-lowering drug is most effective in reducing remnant lipoprotein levels or CVD events. Thus, this study examined if lowering of remnant lipoprotein levels can reduce CVD risk and which of two common lipid-lowering drugs (fibrate or statin) is more effective. The serum levels of remnant lipoproteins were measured by an immunoseparation method (remnant-like lipoprotein particles cholesterol; RLP-C). This multi-center study recruited 202 patients with chronic coronary artery disease (CAD), high RLP-C levels (≥ 5.0 mg/dL), and mild hypercholesterolemia (≥ 180 and < 260 mg/dL). They were randomly assigned to receive bezafibrate (Beza, 200 ~ 400 mg/day, n = 101) or pravastatin (Prava, 10 ~ 20 mg/day, n = 101), and were prospectively followed-up for 1 year or until the occurrence of a CVD event: cardiac death, nonfatal myocardial infarction, unstable angina pectoris requiring unplanned revascularization, or ischemic stroke. The 2 groups had similar baseline levels of RLP-C (average in total patients, 9.8 ± 0.4 mg/dL), LDL-C (126 ± 6.0 mg/dL), HDL-C (43 ± 1.2 mg/dL), and triglycerides (212 ± 9.7 mg/dL). RLP-C levels at 1 year of treatment were reduced in Beza more than Prava (by - 30% and - 19% from baseline, respectively), whereas reduction of LDL-C levels was less in Beza than Prava (by - 7% and -15%). During follow up, CVD events occurred in 3 patients treated with Beza and in 11 patients with Prava (p = 0.03 by chi-square test) (cardiac death in 0 and 1, unstable angina in 2 and 10, and stroke in 1 and 0, respectively). In a multivariate Cox hazards analysis, reduction of 1-SD (38%) of percent change in RLP-C levels decreased risk of future CVD events by 36% independently of change in LDL-C and HDL-C levels (HR 0.64, 95% CI 0.46 – 0.90, p = 0.01). Bezafibrate therapy decreased RLP-C levels and CVD events to a greater extent than pravastatin in CAD patients with high RLP-C levels and mild hypercholesterolemia. Reduction of remnant lipoprotein levels may improve outcomes in CAD patients with high remnant lipoprotein levels.