Important role of endogenous norepinephrine and epinephrine in the development of in vivo pressure-overload cardiac hypertrophy

OBJECTIVES: We sought to define the role of norepinephrine and epinephrine in the development of cardiac hypertrophy and to determine whether the absence of circulating catecholamines alters the activation of downstream myocardial signaling pathways. BACKGROUND: Cardiac hypertrophy is associated with elevated plasma catecholamine levels and an increase in cardiac morbidity and mortality. Although considerable evidence suggests that G-protein-coupled receptors are involved in the hypertrophic response, it remains controversial whether catecholamines are required for the development of in vivo cardiac hypertrophy. METHODS: We performed transverse aortic constriction (TAC) in dopamine beta-hydroxylase knockout mice (Dbh(-/-), genetically altered mice that are completely devoid of endogenous norepinephrine and epinephrine) and littermate control mice. After induction of cardiac hypertrophy, the mitogen-activated protein kinase (MAPK) signaling pathways were measured in pressure-overloaded/wild-type and Dbh(-/-) hearts. RESULTS: Compared with the control animals, cardiac hypertrophy was significantly blunted in Dbh(-/-) mice, which was not associated with altered cardiac function, as assessed by transthoracic echocardiography in conscious mice. The extracellularly regulated kinase (ERK 1/2), c-jun-NH(2)-terminal kinase (JNK) and p38 MAPK pathways were all activated by two- to threefold after TAC in the control animals. In contrast, induction of the three pathways (ERK 1/2, JNK and p38) was completely abolished in Dbh(-/-) mice. CONCLUSIONS: These data demonstrate a nearly complete requirement of endogenous norepinephrine and epinephrine for the induction of in vivo pressure-overload cardiac hypertrophy and for the activation of hypertrophic signaling pathways

Gluteal compartment syndrome following elective unilateral internal iliac artery embolization before endovascular abdominal aortic aneurysm repair

AbstractDuring endovascular abdominal aortic aneurysm repair, aneurysmal involvement of the common or internal iliac arteries occasionally necessitates elective occlusion of one or both internal iliac arteries. Although elective internal iliac artery occlusion is often well tolerated, it can result in complications such as buttock claudication or rest pain, impotence, and colon ischemia. We report a case of gluteal compartment syndrome following elective unilateral internal iliac artery embolization prior to endovascular abdominal aortic aneurysm repair. On the first postoperative day, the patient developed sciatic nerve palsy, rhabdomyolysis, and renal failure, which promptly resolved after emergent operative exploration of his left buttock and debridement of all grossly necrotic muscle. This case emphasizes the point that, although elective internal iliac artery interruption is usually benign, it can have serious and unexpected complications that necessitate expeditious treatment for complete recovery

Association Between Advanced Age and Vascular Disease in Different Arterial Territories A Population Database of Over 3.6 Million Subjects

ObjectivesThis study sought to determine the relationship between vascular disease in different arterial territories and advanced age.BackgroundVascular disease in the peripheral circulation is associated with significant morbidity and mortality. There is little data to assess the prevalence of different phenotypes of vascular disease in the very elderly.MethodsOver 3.6 million self-referred participants from 2003 to 2008 who completed a medical and lifestyle questionnaire in the United States were evaluated by screening ankle brachial indices <0.9 for peripheral artery disease (PAD), and ultrasound imaging for carotid artery stenosis (CAS) >50% and abdominal aortic aneurysm (AAA) >3 cm. Participants were stratified by decade of life. Multivariate logistic regression analysis was used to estimate odds of disease in different age categories.ResultsOverall, the prevalence of PAD, CAS, and AAA, was 3.7%, 3.9%, and 0.9%, respectively. Prevalence of any vascular disease increased with age (40 to 50 years: 2%, 51 to 60 years: 3.5%, 61 to 70 years: 7.1%, 71 to 80 years: 13.0%, 81 to 90 years: 22.3%, 91 to 100 years: 32.5%; p < 0.0001). Prevalence of disease in each vascular territory increased with age. After adjustment for sex, race/ethnicity, body mass index, family history of cardiovascular disease, smoking, diabetes, hypertension, hypercholesterolemia, and exercise, the odds of PAD (odds ratio [OR]: 2.14; 95% confidence interval [CI]: 2.12 to 2.15), CAS (OR: 1.80; 95% CI: 1.79 to 1.81), and AAA (OR: 2.33; 95% CI: 2.30 to 2.36) increased with every decade of life.ConclusionsThere is a dramatic increase in the prevalence of PAD, CAS, and AAA with advanced age. More than 20% and 30% of octogenarians and nonagenarians, respectively, have vascular disease in at least 1 arterial territory

Early carotid endarterectomy in symptomatic patients is associated with poorer perioperative outcomes

ObjectiveThe optimal timing of carotid endarterectomy (CEA) after ipsilateral hemispheric stroke is controversial. Although early studies suggested that an interval of about 6 weeks after a completed stroke was preferred, more recent data have suggested that delaying CEA for this period of time is not necessary. With these issues in mind, we reviewed our experience to examine perioperative outcome with respect to the timing of CEA in previously symptomatic patients.MethodsA retrospective review of a prospectively maintained database of all CEAs performed at our institution from 1992 to 2003 showed that 2537 CEA were performed, of which 1158 (45.6%) were in symptomatic patients. Patients who were operated on emergently ≤48 hours of symptoms for crescendo transient ischemic attacks (TIAs) or stroke-in-evolution were excluded from analysis (n = 25). CEA was considered “early” if performed ≤4 weeks of symptoms, and “delayed” if performed after a minimum of a 4-week interval following the most recent symptom.ResultsOf nonurgent CEAs in symptomatic patients, in 87 instances the exact time interval from symptoms to surgery could not be precisely determined secondary to the remoteness of the symptoms (>18 months), and these were excluded from further analysis. Of the remaining 1046 cases, 62.7% had TIAs and 37.3% had completed strokes as their indication for surgery. Among the entire cohort, patients who underwent early CEA were significantly more likely to experience a perioperative stroke than patients who underwent delayed CEA (5.1% vs 1.6%, P = .002). Patients with TIAs alone were more likely to be operated on early rather than in a delayed fashion (64.3% vs 46.7%, P < .0001), likely reflecting institutional bias in selecting delayed CEA for stroke patients. However, even when examined as two separate groups, both TIA patients (n = 656) and CVA patients (n = 390) were significantly more likely to experience a perioperative stroke when operated upon early rather than in a delayed fashion (TIA patients, 3.3% vs 0.9%, P = .05; CVA patients, 9.4% vs 2.4%, P = .003). There were no significant differences in demographics or other meaningful variables between patients who underwent early CEA and those who underwent delayed CEA.ConclusionsIn a large institutional experience, patients who underwent CEA ≤4 weeks of ipsilateral TIA or stroke experienced a significantly increased rate of perioperative stroke compared with patients who underwent CEA in a more delayed fashion. This was true for both TIA and stroke patients, although the results were more impressive among stroke patients. On the basis of these results, we continue to recommend that waiting period of 4 weeks be considered in stroke patients who are candidates for CEA

Clinical and operative predictors of outcomes of carotid endarterectomy

ObjectiveThe net benefit for patients undergoing carotid endarterectomy is critically dependent on the risk of perioperative stroke and death. Information about risk factors can aid appropriate selection of patients and inform efforts to reduce complication rates. This study identifies the clinical, radiographic, surgical, and anesthesia variables that are independent predictors of deaths and stroke following carotid endarterectomy.MethodsA retrospective cohort study of patients undergoing carotid endarterectomy in 1997 and 1998 by 64 surgeons in 6 hospitals was performed (N = 1972). Detailed information on clinical, radiographic, surgical, anesthesia, and medical management variables and deaths or strokes within 30 days of surgery were abstracted from inpatient and outpatient records. Multivariate logistic regression models identified independent clinical characteristics and operative techniques associated with risk-adjusted rates of combined death and nonfatal stroke as well as all strokes.ResultsDeath or stroke occurred in 2.28% of patients without carotid symptoms, 2.93% of those with carotid transient ischemic attacks, and 7.11% of those with strokes (P < .0001). Three clinical factors increased the risk-adjusted odds of complications: stroke as the indication for surgery (odds ratio [OR], 2.84; 95% confidence interval [CI] = 1.55-5.20), presence of active coronary artery disease (OR, 3.58; 95% CI = 1.53-8.36), and contralateral carotid stenosis ≥50% (OR, 2.32; 95% CI = 1.33-4.02). Two surgical techniques reduced the risk-adjusted odds of death or stroke: use of local anesthesia (OR, 0.30; 95% CI = 0.16-0.58) and patch closure (OR, 0.43; 95% CI = 0.24-0.76).ConclusionsInformation about these risk factors may help physicians weigh the risks and benefits of carotid endarterectomy in individual patients. Two operative techniques (use of local anesthesia and patch closure) may lower the risk of death or stroke

Phosphoinositide 3-kinase regulates β2-adrenergic receptor endocytosis by AP-2 recruitment to the receptor/β-arrestin complex

Internalization of β-adrenergic receptors (βARs) occurs by the sequential binding of β-arrestin, the clathrin adaptor AP-2, and clathrin. D-3 phosphoinositides, generated by the action of phosphoinositide 3-kinase (PI3K) may regulate the endocytic process; however, the precise molecular mechanism is unknown. Here we demonstrate that βARKinase1 directly interacts with the PIK domain of PI3K to form a cytosolic complex. Overexpression of the PIK domain displaces endogenous PI3K from βARK1 and prevents βARK1-mediated translocation of PI3K to activated β2ARs. Furthermore, disruption of the βARK1/PI3K interaction inhibits agonist-stimulated AP-2 adaptor protein recruitment to the β2AR and receptor endocytosis without affecting the internalization of other clathrin dependent processes such as internalization of the transferrin receptor. In contrast, AP-2 recruitment is enhanced in the presence of D-3 phospholipids, and receptor internalization is blocked in presence of the specific phosphatidylinositol-3,4,5-trisphosphate lipid phosphatase PTEN. These findings provide a molecular mechanism for the agonist-dependent recruitment of PI3K to βARs, and support a role for the localized generation of D-3 phosphoinositides in regulating the recruitment of the receptor/cargo to clathrin-coated pits