K M Channon

Resting Myocardial Blood Flow Is Impaired in Hibernating Myocardium. A Magnetic Resonance Study of Quantitative Perfusion Assessment

Background— Although impairment in perfusion reserve is well recognized in hibernating myocardium, there is substantial controversy as to whether resting myocardial blood flow (MBF) is reduced in such circumstances. Quantitative first-pass cardiovascular magnetic resonance (CMR) perfusion imaging allows absolute quantification of MBF. We hypothesized that MBF assessed at rest by quantitative CMR perfusion imaging is reduced in hibernating myocardium. Methods and Results— Twenty-seven patients with 1 or 2-vessel coronary disease and at least 1 dysfunctional myocardial segment undergoing PCI were studied with preprocedure, early (24 hours), and late (9 months) postprocedure CMR imaging. First-pass perfusion images at rest were acquired in 3 short-axis planes by use of a T1-weighted turboFLASH sequence. In each slice, MBF was determined for 8 myocardial segments in mL · min−1 · g−1 by deconvolution of signal intensity curves with an arterial input function measured in the left ventricular blood pool. Cine MRI for assessment of global and segmental function and delayed enhancement MRI for detection of viability were also obtained. All coronary lesions were 80% to 95% stenosis in severity. Over all segments, mean MBF normalized by rate-pressure product (“corrected MBF”) was 1.2±0.3 mL · min−1 · g−1 · (mm Hg · bpm/104)−1 in segments without significant coronary stenosis and 0.7±0.2 mL · min−1 · g−1 · (mm Hg · bpm/104)−1 in segments with coronary stenosis before PCI (mixed model controlling for slice and segment z=−23.9, P<0.001). Early after the procedure, the MBF was 1.2±0.2 mL · min−1 · g−1 · (mm Hg · bpm/104)−1 in revascularized segments and 1.3±0.2 mL · min−1 · g−1 · (mm Hg · bpm/104)−1 in nondiseased segments (z=−6.1, P<0.001). Late after PCI, the systolic wall thickening and end-diastolic wall thickness both increased significantly more (both P<0.001) in the myocardial segments subtended by severe coronary stenosis (8±17% to 40±19% and 6.5±1.1 to 9.3±2 mm, respectively) than in the myocardial segments supplied by nondiseased vessels. Mean MBF in dysfunctional segments with significantly improved contraction after revascularization was 0.8±0.2 mL · min−1 · g−1 · (mm Hg · bpm/104)−1 before PCI and 1.2±0.2 mL · min−1 · g−1 · (mm Hg · bpm/104)−1 after PCI (z=2.0, P=0.04). Conclusions— CMR perfusion imaging detects impaired resting MBF in hibernating myocardial segments.

ENDOTHELIAL SPECIFIC NOX2 OVER-EXPRESSION INCREASES SUSCEPTIBILITY TO ANGIOTENSIN II INDUCED AORTIC DISSECTION

Aortic dissection is a detrimental disease with high mortality. However, the mechanisms regulating the susceptibility to aortic dissection remain unknown. We hypothesise that endothelial oxidative stress due to the activation of the reactive oxygen species (ROS)-generating Nox2 enzyme play an important role in the development of aortic dissection. To investigate this, we generated transgenic mice (C57BL/6J background) with endothelial specific over-expression of Nox2 (Nox2-Tg) under the control of a tie-2 promoter. Expression of the human Nox2 transgene was confirmed by qRT-PCR to be found only in endothelial cells (EC) isolated from transgenic mice, and not in WT EC or vascular smooth muscle cells (VSMC) and macrophages isolated from either genotype. Wild-type (WT) littermates and Nox2-Tg male mice (6u2005months, n=11) were treated with vehicle or AngII (1u2005mg/kg/day) via subcutaneous mini-pump for 28u2005days. There was no significant difference in the pressor responses to AngII between WT and Nox2-Tg mice (WT 121±7u2005mmu2002Hg vs Nox2-Tg 122±6u2005mmu2002Hg). However, 5/11 Nox2-Tg mice developed aortic dissections compared to 0/11 WT mice after AngII infusion (p<0.001). Immunohistochemistry revealed significant increases in endothelial VCAM-1 expression, MMP activity and CD45+ inflammatory cell recruitment in the aortas of Nox2-Tg mice after 5u2005days of AngII infusion. Inflammatory cell recruitment was further confirmed by FACS analysis of cells derived from explanted aortas (p<0.05). Explanted aortas from Nox2-Tg had significantly higher levels of secreted pro-inflammatory cytokine, cyclophilin A (Cypa) at both baseline and after 5u2005days of in vivo AngII treatment compared to WT littermates. Compared to primary WT EC and VSMC, Nox2-Tg primary EC, but not primary VSMC, had increased ROS production which was accompanied by increased Cypa secretion and ERK1/2 activation. Furthermore, conditioned media from Nox2-Tg EC induced a greater ERK1/2 phosphorylation compared to the media of WT controls. In conclusion, we demonstrate for the first time that a specific increase in endothelial ROS through the over-expression of Nox2 is sufficient to induce aortic dissection in response to AngII stimulation. Endothelial secreted Cypa could be the signalling mechanism by which increased endothelial ROS regulates the inflammatory response and the susceptibility to aortic dissection.