Dellsperger KC. Oxidative stress contributes to pulmonary hypertension in the transgenic (mRen2)27 rat. Am J Physiol Heart Circ Physiol 294: H2659-H2668, 2008. First published April 18, 2008 doi:10.1152/ajpheart.00953.2007.-The transgenic (mRen2)27 (Ren2) rat overexpresses mouse renin in extrarenal tissues, causing increased local synthesis of ANG II, oxidative stress, and hypertension. However, little is known about the role of oxidative stress induced by the tissue renin-angiotensin system (RAS) as a contributing factor in pulmonary hypertension (PH). Using male Ren2 rats, we test the hypothesis that lung tissue RAS overexpression and resultant oxidative stress contribute to PH and pulmonary vascular remodeling. Mean arterial pressure (MAP), right ventricular systolic pressure (RVSP), and wall thickness of small pulmonary arteries (PA), as well as intrapulmonary NADPH oxidase activity and subunit protein expression and reactive oxygen species (ROS), were compared in age-matched Ren2 and Sprague-Dawley (SD) rats pretreated with the SOD/catalase mimetic tempol for 21 days. In placebo-treated Ren2 rats, MAP and RVSP, as well as intrapulmonary NADPH oxidase activity and subunits (Nox2, p22 phox , and Rac-1) and ROS, were elevated compared with placebo-treated SD rats (P Ͻ 0.05). Tempol decreased RVSP (P Ͻ 0.05), but not MAP, in Ren2 rats. Tempol also reduced intrapulmonary NADPH oxidase activity, Nox2, p22 phox , and Rac-1 protein expression, and ROS in Ren2 rats (P Ͻ 0.05). Compared with SD rats, the cross-sectional surface area of small PA was 38% greater (P Ͻ 0.001) and luminal surface area was 54% less (P Ͻ 0.001) in Ren2 rats. Wall surface area was reduced and luminal area was increased in tempol-treated SD and Ren2 rats compared with untreated controls (P Ͻ 0.05). Collectively, the results of this investigation support a seminal role for enhanced tissue RAS/oxidative stress as factors in development of PH and pulmonary vascular remodeling. renin; angiotensin II; NADPH oxidase CARDIOVASCULAR GENERATION of reactive oxygen species (ROS), such as superoxide and H 2 O 2 , has been implicated in the pathogenesis of hypertension, cardiac hypertrophy, pulmonary hypertension (PH), and heart failure (7). Molecular complexes known to generate superoxide within vascular endothelial and smooth muscle cells (SMC) include the NADPH oxidases (18), xanthine oxidase (32), the mitochondrial transport chain, and uncoupled nitric oxide synthase (NOS) (10,19). NADPH oxidase is a major source of ROS in the vasculature and is activated by hormones, growth factors, cytokines, and shear stress (16). An important stimulus for NADPH oxidase-generated ROS is ANG II. In fact, many of the deleterious effects of ANG II on vascular structure and function are mediated by ROS generation (16,73). ANG II causes rapid induction of NADPH oxidase-dependent superoxide synthesis via PKC (15) and more prolonged stimulation via transactivation of growth factors (62, 69). ANG II also causes redox-sensitive xanthine oxidase activation and endothelial N...

A subset of subjects undergoing myocardial perfusion imaging has perfusion abnormalities that are subsequently labeled false positive based on coronary angiography. We evaluated the long-term prevalence of cardiovascular events in these patients. We retrospectively identified 48 patients who had reversible perfusion abnormalities with myocardial perfusion imaging and normal coronary angiography. Patients with known coronary artery disease, left ventricular dysfunction, valvular disease, and cardiomyopathy were excluded. Patient follow-up, conducted for at least 3 (mean interval, 7.4) years from the index myocardial perfusion imaging, was accomplished by a review of medical records and telephone interviews. Study endpoints were cardiovascular events defined as sudden cardiac death, myocardial infarction, percutaneous coronary revascularization, coronary artery bypass grafting, and cerebrovascular or peripheral revascularization. Thirty-one percent (15 of 48) of the patients had cardiovascular events. Six of the 48 patients had coronary events. These patients had abnormal myocardial perfusion imaging and normal coronary angiogram. The time between myocardial perfusion imaging and coronary event was 0.5 to 8.67 years. There was a strong correlation between the regions of original perfusion abnormality and the ultimate coronary ischemia or revascularization. Abnormal findings on myocardial perfusion imaging may predict a higher prevalence of coronary and peripheral vascular events than suggested by a normal coronary angiogram.

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Apical ballooning syndrome (ABS) is increasingly diagnosed in critical care settings. Widespread application of echocardiography and cardiac enzyme testing has increased its recognition. Our experience of 4 subjects illustrates the association of ABS with a wide spectrum of acute pulmonary disorders seen in critical care settings. All had ABS proven by normal coronary angiogram and subsequent normalization of left ventricular dysfunction. Bronchospasm due to chronic obstructive pulmonary disease exacerbation or cardiac failure warrants the use of beta agonists. ABS, on the other hand, being caused by excess sympathetic activity could potentially improve with beta blockade. Coexistence of ABS and pulmonary disease in critical-care settings presents unique therapeutic challenges and outcomes can be optimized by judicious use of available medical options.