Role of myeloperoxidase in abdominal aortic aneurysm formation: mitigation by taurine.

Oxidative stress plays a fundamental role in abdominal aortic aneurysm (AAA) formation. Activated polymorphonuclear leukocytes (or neutrophils) are associated with AAA and express myeloperoxidase (MPO), which promotes inflammation, matrix degradation, and other pathological features of AAA, including enhanced oxidative stress through generation of reactive oxygen species. Both plasma and aortic MPO levels are elevated in patients with AAA, but the role of MPO in AAA pathogenesis has, heretofore, never been investigated. Here, we show that MPO gene deletion attenuates AAA formation in two animal models: ANG II infusion in apolipoprotein E-deficient mice and elastase perfusion in C57BL/6 mice. Oral administration of taurine [1% or 4% (wt/vol) in drinking water], an amino acid known to react rapidly with MPO-generated oxidants like hypochlorous acid, also prevented AAA formation in the ANG II and elastase models as well as the CaCl2 application model of AAA formation while reducing aortic peroxidase activity and aortic protein-bound dityrosine levels, an oxidative cross link formed by MPO. Both MPO gene deletion and taurine supplementation blunted aortic macrophage accumulation, elastin fragmentation, and matrix metalloproteinase activation, key features of AAA pathogenesis. Moreover, MPO gene deletion and taurine administration significantly attenuated the induction of serum amyloid A, which promotes ANG II-induced AAAs. These data implicate MPO in AAA pathogenesis and suggest that studies exploring whether taurine can serve as a potential therapeutic for the prevention or treatment of AAA in patients merit consideration.NEW & NOTEWORTHY Neutrophils are abundant in abdominal aortic aneurysm (AAA), and myeloperoxidase (MPO), prominently expressed in neutrophils, is associated with AAA in humans. This study demonstrates that MPO gene deletion or supplementation with the natural product taurine, which can scavenge MPO-generated oxidants, can prevent AAA formation, suggesting an attractive potential therapeutic strategy for AAA.

A second look with prone SPECT myocardial perfusion imaging reduces the need for angiography in patients at low risk for cardiac death or MI.

BACKGROUND: Correction for soft tissue signal attenuation can improve the diagnostic accuracy of single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI). The aim of this study was to correlate SPECT-MPI findings with clinical outcomes in patients who underwent stress imaging in the supine position, who also underwent "second look" stress imaging in the prone position. METHODS: Patients without perfusion abnormalities were considered Normal (N = 270). Those with apparent supine stress perfusion abnormalities which all resolved during prone imaging formed the Normal-Prone group (N = 309). Patients with matched perfusion abnormalities during both supine and prone stress imaging were considered Abnormal (N = 169). RESULTS: During follow-up (187 ± 96 days), utilization rates for invasive coronary angiography were similar for Normal vs Normal-Prone patients (3.5% vs 3.8%; P = NS), but were significantly higher in Abnormal patients (42.4%, P < .0001). Coronary revascularization occurred in 0.78%, 0.64%, and 17.7% of Normal, Normal-Prone, and Abnormal patients, respectively (P < .001). Cardiac death or myocardial infarction occurred in 2.2%, 2.3%, and 6.3% of Normal, Normal-Prone, and Abnormal patients, respectively (P = .02). CONCLUSIONS: Second look SPECT-MPI identifies patients at low risk for death or myocardial infarction, who infrequently require invasive coronary angiography.

CD14 directs adventitial macrophage precursor recruitment: role in early abdominal aortic aneurysm formation.

BACKGROUND: Recruitment of macrophage precursors to the adventitia plays a key role in the pathogenesis of abdominal aortic aneurysms (AAAs), but molecular mechanisms remain undefined. The innate immune signaling molecule CD14 was reported to be upregulated in adventitial macrophages in a murine model of AAA and in monocytes cocultured with aortic adventitial fibroblasts (AoAf) in vitro, concurrent with increased interleukin-6 (IL-6) expression. We hypothesized that CD14 plays a crucial role in adventitial macrophage precursor recruitment early during AAA formation. METHODS AND RESULTS: CD14(-/-) mice were resistant to AAA formation induced by 2 different AAA induction models: aortic elastase infusion and systemic angiotensin II (AngII) infusion. CD14 gene deletion led to reduced aortic macrophage infiltration and diminished elastin degradation. Adventitial monocyte binding to AngII-infused aorta in vitro was dependent on CD14, and incubation of human acute monocytic leukemia cell line-1 (THP-1) monocytes with IL-6 or conditioned medium from perivascular adipose tissue (PVAT) upregulated CD14 expression. Conditioned medium from AoAf and PVAT induced CD14-dependent monocyte chemotaxis, which was potentiated by IL-6. CD14 expression in aorta and plasma CD14 levels were increased in AAA patients compared with controls. CONCLUSIONS: These findings link CD14 innate immune signaling via a novel IL-6 amplification loop to adventitial macrophage precursor recruitment in the pathogenesis of AAA.

Exercise-induced left ventricular systolic dysfunction in women heterozygous for dystrophinopathy.

BACKGROUND: Mutations in the X-linked gene encoding dystrophin cause skeletal and cardiac muscle diseases in men. Female "carriers" also can develop overt disease. The purpose of this study was to ascertain the prevalence of cardiac contractile abnormalities in dystrophinopathy carriers. METHODS: Twenty-four dystrophinopathy heterozygotes and 24 normal women each underwent standard exercise stress echocardiography. RESULTS: Heterozygotes demonstrated mildly lower left ventricular ejection fractions (LVEFs) at rest compared with controls (0.56 + or - 0.10 vs 0.62 + or - 0.07, P = .02). After exercise, the mean LVEF fell to 0.53 + or - 0.14 in heterozygotes but rose to 0.73 + or - 0.07 in controls (P < .001). Twenty-one of 24 dystrophinopathy heterozygotes demonstrated > or = 1 of the following: abnormal resting LVEF, abnormal LVEF response to exercise, or exercise-induced wall motion abnormality. CONCLUSIONS: Women heterozygous for dystrophinopathy demonstrate significant left ventricular systolic dysfunction, which is unmasked by exercise. This finding has mechanistic implications for both inherited and acquired cardiac disease states.