A Case of Ruptured Vertebrobasilar Junction Aneurysm Associated with Subclavian Steal Phenomenon.

A 77-year-old woman with arteriovenous shunt for hemodialysis in the left forearm suffered from subarachnoid hemorrhage due to the rupture of a saccular aneurysm located on the left lateral wall of vertebrobasilar junction. Her left subclavian artery was severely stenosed and subclavian steal phenomenon was demonstrated on the digital subtraction angiography. Embolization of the parent artery including the aneurysm using detachable coils resulted in the successful obliteration of the aneurysm through the revascularized left subclavian artery. This is the first case in which the vertebrobasilar junction aneurysm would be caused by the hemodynamic stress due to the subclavian steal phenomenon combined with the shunt for hemodialysis in the left forearm.

Assessment of carotid plaque neovascularization using quantitative analysis of contrast-enhanced ultrasound imaging is useful for risk stratification in patients with coronary artery disease.

BACKGROUND: Contrast-enhanced ultrasound (CEUS) of the carotid artery is a potential technique for imaging plaque neovascularization, a feature of unstable atherosclerotic plaques. This study examined whether assessment of intra-plaque neovascularization of the carotid artery using CEUS provides prognostic information in patients with coronary artery disease (CAD). METHODS: A total of 206 patients with stable CAD underwent a CEUS examination of the carotid artery and were followed up prospectively for <38 months or until a cardiac event (cardiac death, non-fatal myocardial infarction (MI), unstable angina pectoris (uAP) requiring unplanned coronary revascularization, or heart failure requiring hospitalization). The degree of contrast signals measured within the carotid plaque was quantified by calculating the mean gray scale level within the region of interest of the carotid plaque, expressed as plaque enhanced intensity. RESULTS: During the follow-up period, 31 events occurred (2 cardiac deaths, 7 non-fatal MIs, 16 uAP, and 6 heart failure). Multivariate Cox proportional hazard analysis showed that plaque enhanced intensity was a significant predictor of cardiac events independent of traditional risk factors (HR, 1.13; 95% CI, 1.05-1.21; p<0.001). The addition of the plaque enhanced intensity to traditional risk factors resulted in net reclassification improvement (NRI) and integrated discrimination improvement (IDI) (NRI 0.62, p=0.001; and IDI 0.106, p=0.002). CONCLUSIONS: The assessment of carotid plaque neovascularization using quantitative analysis of CEUS may be useful for risk stratification in patients with CAD.

The expression of groups IIE and V phospholipase A2 is associated with an increased expression of osteogenic molecules in human calcified aortic valves.

AIM: Eicosanoids play various pathogenic roles in aortic valve calcification. Eicosanoids are derived from the arachidonic acid generated by phospholipase A2 (PLA2). We therefore sought to determine whether PLA2s are expressed in human aortic valves and, if so, whether the expression of PLA2s is related to the expression of osteogenic molecules in these tissues. METHODS: Histological and gene expression analyses of 38 non-rheumatic aortic valves obtained at the time of cardiac valve replacement surgery were conducted. Moreover, gene expression analyses were performed using valve interstitial cells (VICs) obtained from human aortic valves. RESULTS: Among the PLA2s examined, the degree of immunoreactivity for PLA2s-IIE and -V was found to significantly correlate with the grade of calcification in the aortic valves. The degree of immunoreactivity and gene expression levels of PLA2s-IIE and -V significantly correlated with those of bone morphogenetic protein (BMP)-2, osteopontin and alkaline phosphatase (ALP). In addition, immunoreactivity for cyclooxygenase (COX)-1, COX-2 and 5-lipoxygenase, downstream enzymes of PLA2 in the arachidonic acid cascade, was co-localized with that for PLA2s-IIE and -V in cells expressing α-smooth muscle actin and macrophages expressing CD68. Furthermore, in the in vitro experiments using cultured VICs, the mRNA expression levels of BMP-2, osteopontin and ALP were suppressed by the inhibition of the expression of PLA2s-IIE or -V with specific siRNAs. CONCLUSIONS: The expression of PLA2s-IIE and -V correlates with the development of calcification as well as the expression of pro-osteogenic molecules in human aortic valves, and inhibiting the expression of PLA2s-IIE and -V suppresses the induction of osteogenic molecules in cultured cells. Therefore, PLA2s-IIE and -V may play a role in the pathogenesis of valve calcification.

Contrast-enhanced ultrasound imaging of carotid plaque neovascularization is useful for identifying high-risk patients with coronary artery disease.

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). METHODS AND RESULTS: A total of 304 patients with CAD and carotid plaque underwent CEUS examination of the carotid artery. Intraplaque neovascularization was identified on the basis of microbubbles within the plaque and graded as: G0, not visible; G1, moderate; or G2, extensive microbubbles. The complexity and extent of the coronary lesions were assessed angiographically. A higher grade of CEUS-assessed plaque neovascularization of the carotid artery was associated significantly with greater complexity (ρ=0.48 by Spearman's rank correlation test) and extent (ρ=0.51) of coronary lesions. G2 plaque neovascularization was a risk for acute coronary syndrome, independent of traditional risk factors (odds ratio 1.91, 95% confidence interval 1.04-3.53, P<0.01). Subgroup analysis showed that carotid CEUS-assessed neovascularization regressed in 12 (46%) of 26 plaques in patients during 6 months of statin treatment, whereas regression occurred in 2 (14%) of 14 plaques in patients not taking a statin (P=0.04, Chi-square test). CONCLUSIONS: CEUS examination of the carotid artery may provide valuable information on the severity and instability of CAD and also the efficacy of antiatherosclerotic treatment.

Chronic depletion of glutathione exacerbates ventricular remodelling and dysfunction in the pressure-overloaded heart.

AIMS: Chronic depletion of myocardial glutathione (GSH) may play a role in cardiac remodelling and dysfunction. This study examined the relationship between chronic GSH depletion and cardiac failure induced by pressure overload in mice lacking the modifier subunit (GCLM) of glutamate-cysteine ligase, the rate-limiting enzyme for GSH synthesis. In addition, we examined the association between idiopathic dilated cardiomyopathy (DCM) in humans and -588C/T polymorphism of the GCLM gene, which reduces plasma levels of GSH. METHODS AND RESULTS: Pressure overload in mice was created by transverse aortic constriction (TAC). Myocardial GSH levels after TAC in GCLM(-/-) mice were 31% of those in GCLM(+/+) mice. TAC resulted in greater heart and lung-weight-to-body-weight ratios, greater dilation and dysfunction of left ventricle, more extensive myocardial fibrosis, and worse survival in GCLM(-/-) than GCLM(+/+) mice. Supplementation of GSH diethyl ester reversed the left-ventricular dilation and contractile dysfunction and the increased myocardial fibrosis after TAC in GCLM(-/-) mice. The prevalence of -588T polymorphism of the GCLM gene was significantly higher in DCM patients (n = 205) than in age- and sex-matched control subjects (n = 253) (36 vs. 19%, respectively, P < 0.001). The -588T polymorphism increased the risk of DCM that was independent of age, diabetes, and systolic blood pressure (OR 3.13, 95% CI: 2.28-4.44; P < 0.0001). CONCLUSION: Chronic depletion of GSH exacerbates remodelling and dysfunction in the pressure-overloaded heart. The clinical relevance of this mouse model is supported by a significant association between -588T polymorphism of the GCLM gene and patients with DCM.

Disruption of group IVA cytosolic phospholipase A(2) attenuates myocardial ischemia-reperfusion injury partly through inhibition of TNF-α-mediated pathway.

Group IVA cytosolic phospholipase A(2) (cPLA(2)α), which preferentially cleaves arachidonic acid from phospholipids, plays a role in apoptosis and tissue injury. Downstream signals in response to tumor necrosis factor (TNF)-α, a mediator of myocardial ischemia-reperfusion (I/R) injury, involve cPLA(2)α activation. This study examined the potential role of cPLA(2)α and its mechanistic link with TNF-α in myocardial I/R injury using cPLA(2)α knockout (cPLA(2)α(-/-)) mice. Myocardial I/R was created with 10-wk-old male mice by 1 h ligation of the left anterior descending coronary artery, followed by 24 h of reperfusion. As a result, compared with wild-type (cPLA(2)α(+/+)) mice, cPLA(2)α(-/-) mice had a 47% decrease in myocardial infarct size, preservation of echocardiographic left ventricle (LV) function (%fractional shortening: 14 vs. 21%, respectively), and lower content of leukotriene B(4) and thromboxane B(2) (62 and 50% lower, respectively) in the ischemic myocardium after I/R. Treatment with the TNF-α inhibitor (soluble TNF receptor II/IgG1 Fc fusion protein, sTNFR:Fc) decreased myocardial I/R injury and LV dysfunction in cPLA(2)α(+/+) mice but not cPLA(2)α(-/-) mice. sTNFR:Fc also suppressed cPLA(2)α phosphorylation in the ischemic myocardium after I/R of cPLA(2)α(+/+) mice. Similarly, sTNFR:Fc exerted protective effects against hypoxia-reoxygenation (H/R)-induced injury in the cultured cardiomyocytes from cPLA(2)α(+/+) mice but not cPLA(2)α(-/-) cardiomyocytes. H/R and TNF-α induced cPLA(2)α phosphorylation in cPLA(2)α(+/+) cardiomyocytes, which was reversible by sTNFR:Fc. In cPLA(2)α(-/-) cardiomyocytes, TNF-α induced apoptosis and release of arachidonic acid to a lesser extent than in cPLA(2)α(+/+) cardiomyocytes. In conclusion, disruption of cPLA(2)α attenuates myocardial I/R injury partly through inhibition of TNF-α-mediated pathways.

Group X secretory PLA2 in neutrophils plays a pathogenic role in abdominal aortic aneurysms in mice.

Group X secretory PLA(2) (sPLA(2)-X) is expressed in neutrophils and plays a role in the pathogenesis of neutrophil-mediated tissue inflammation and injury. This study tested the hypothesis that sPLA(2)-X in neutrophils may contribute to the pathogenesis of abdominal aortic aneurysms (AAA) using sPLA(2)-X(-/-) mice. AAA was created by application of CaCl(2) to external surface of aorta. As a result, the aortas of sPLA(2)-X(-/-) mice had smaller diameters (percent increase from baseline; 24.8 ± 3.5% vs. 49.9 ± 9.1%, respectively; P < 0.01), a reduced grade of elastin degradation, and lower activities of elastase and gelatinase (26% and 19% lower, respectively) after CaCl(2) treatment compared with sPLA(2)-X(+/+) mice. In sPLA(2)-X(+/+) mice, immunofluorescence microscopic images showed that the immunoreactivity of sPLA(2)-X was detected only in neutrophils within aortic walls 3 days, 1, 2, and 6 wk after CaCl(2) treatment, whereas the immunoreactivity was not detected in macrophages or mast cells in aortic walls. sPLA(2)-X immunoreactivity also was colocalized in cells expressing matrix metalloproteinase (MMP)-9. Neutrophils isolated from sPLA(2)-X(-/-) mice had lower activities of elastase, gelatinase, and MMP-9 in response to stimuli compared with sPLA(2)-X(+/+) mice. The attenuated release of elastase and gelatinase from sPLA(2)-X(-/-) neutrophils was reversed by exogenous addition of mouse sPLA(2)-X protein. The adoptive transfer of sPLA(2)-X(+/+) neutrophils days 0 and 3 after CaCl(2) treatment reversed aortic diameters and elastin degradation grades in the lethally irradiated sPLA(2)-X(+/+) mice reconstituted with sPLA(2)-X(-/-) bone marrow to an extent similar to that seen in sPLA(2)-X(+/+) mice. In conclusion, sPLA(2)-X in neutrophils plays a pathogenic role in AAA in a mice model.

Mice lacking the glutamate-cysteine ligase modifier subunit are susceptible to myocardial ischaemia-reperfusion injury.

AIMS: Glutamate-cysteine ligase (GCL), a rate-limiting enzyme for glutathione (GSH) synthesis, is composed of catalytic and modifier subunits. This study examined the pathogenic role of GCL modifier subunits (GCLM) in myocardial ischaemia-reperfusion (I/R) injury using mice lacking the GCLM (GCLM(-/-)). METHODS AND RESULTS: The GCLM(-/-)mice had an increase in myocardial I/R injury and apoptosis in ischaemic myocardium compared with GCLM(+/+) mice. There was a decrease in mitochondrial glutathione (GSH) levels in ischaemic myocardium that was more pronounced in GCLM(-/-) mice than in GCLM(+/+) mice (12 vs. 55% of baseline GCLM(+/+), respectively). The ESR signal intensity of the dimethyl-1-pyrroline-N-oxide-hydroxyl radical adducts in ischaemic myocardium was higher in GCLM(-/-) mice than in GCLM(+/+) mice. Hypoxia-reoxygenation induced greater mitochondrial damage in cultured cardiomyocytes from GCLM(-/-) mice than from GCLM(+/+) mice, as evidenced by a reduced membrane potential and increased protein carbonyl content in isolated mitochondria, together with enhanced cytochrome c translocation into the cytosol. Administration of GSH ethyl-ester attenuated myocardial I/R injury and reversed the mitochondrial damage in parallel with the mitochondrial GSH restoration in the myocardium or the cardiomyocytes of GCLM(-/-) mice. CONCLUSION: GCLM(-/-) mice were susceptible to myocardial I/R injury partly through an increased vulnerability of mitochondria to oxidative damage owing to mitochondrial GSH reduction.

Rapid stabilization of vulnerable carotid plaque within 1 month of pitavastatin treatment in patients with acute coronary syndrome.

We determined time course of stabilization of echolucent carotid plaques by statin therapy in patients with acute coronary syndrome (ACS). Treatment with 4 mg/d pitavastatin (n = 33) or placebo (n = 32) was initiated within 3 days after onset of ACS in 65 patients with echolucent carotid plaque. Vulnerable carotid plaques were assessed by measuring plaque echolucency using carotid ultrasound with integrated backscatter (IBS) analysis before and 1 month after treatment in all patients. The calibrated IBS value (intima-media IBS value minus adventia IBS) of vulnerable carotid plaques favorably changed at 1 month after treatment in both groups, but the echolucency at 1 month improved more in the pitavastatin than in the placebo group (pitavastatin group: -18.7 +/- 3.3 dB at pretreatment versus -12.7 +/- 2.3 dB at 1 month *P < 0.001; placebo: -19.0 +/- 3.5 dB versus -16.9 +/- 3.2 dB, P < 0.05, *P < 0.01 versus the value at 1 month in placebo group). Levels of CRP, VEGF, and TNFalpha at 1 month were significantly lower in pitavastatin than placebo group. In conclusion, pitavastatin improved carotid plaque echolucency within 1 month of therapy in patients with ACS, in association with decrease in the inflammatory biomarkers related to vulnerable plaques.