Richard Charnigo

Renin inhibition reduces hypercholesterolemia-induced atherosclerosis in mice

The role of the renin angiotensin system (RAS) in atherosclerosis is complex because of the involvement of multiple peptides and receptors. Renin is the rate-limiting enzyme in the production of all angiotensin peptides. To determine the effects of renin inhibition on atherosclerosis, we administered the novel renin inhibitor aliskiren over a broad dose range to fat-fed LDL receptor-deficient (Ldlr(-/-)) mice. Renin inhibition resulted in striking reductions of atherosclerotic lesion size in both the aortic arch and the root. Subsequent studies demonstrated that cultured macrophages expressed all components of the RAS. To determine the role of macrophage-derived angiotensin in the development of atherosclerosis, we transplanted renin-deficient bone marrow to irradiated Ldlr(-/-) mice and observed a profound decrease in the size of atherosclerotic lesions. In similar experiments, transplantation of bone marrow deficient for angiotensin II type 1a receptors failed to influence lesion development. We conclude that renin-dependent angiotensin production in macrophages does not act in an autocrine/paracrine manner. Furthermore, in vitro studies demonstrated that coculture with renin-expressing macrophages augmented monocyte adhesion to endothelial cells. Therefore, although previous work suggests that angiotensin peptides have conflicting effects on atherogenesis, we found that renin inhibition profoundly decreased lesion development in mice.

Increased mortality among patients taking digoxin—analysis from the AFFIRM study

AIMS Digoxin is frequently used for rate control of atrial fibrillation (AF). It has, however, been associated with increased mortality. It remains unclear whether digoxin itself is responsible for the increased mortality (toxic drug effect) or whether it is prescribed to sicker patients with inherently higher mortality due to comorbidities. The goal of our study was to determine the relationship between digoxin and mortality in patients with AF. METHODS AND RESULTS The association between digoxin and mortality was assessed in patients enrolled in the AF Follow-Up Investigation of Rhythm Management (AFFIRM) trial using multivariate Cox proportional hazards models. Analyses were conducted in all patients and in subsets according to the presence or absence of heart failure (HF), as defined by a history of HF and/or an ejection fraction <40%. Digoxin was associated with an increase in all-cause mortality [estimated hazard ratio (EHR) 1.41, 95% confidence interval (CI) 1.19-1.67, P < 0.001], cardiovascular mortality (EHR 1.35, 95% CI 1.06-1.71, P = 0.016), and arrhythmic mortality (EHR 1.61, 95% CI 1.12-2.30, P = 0.009). The all-cause mortality was increased with digoxin in patients without or with HF (EHR 1.37, 95% CI 1.05-1.79, P = 0.019 and EHR 1.41, 95% CI 1.09-1.84, P = 0.010, respectively). There was no significant digoxin-gender interaction for all-cause (P = 0.70) or cardiovascular (P = 0.95) mortality. CONCLUSION Digoxin was associated with a significant increase in all-cause mortality in patients with AF after correcting for clinical characteristics and comorbidities, regardless of gender or of the presence or absence of HF. These findings call into question the widespread use of digoxin in patients with AF.

Obesity Promotes Inflammation in Periaortic Adipose Tissue and Angiotensin II-Induced Abdominal Aortic Aneurysm Formation

Objective—Obesity promotes macrophage infiltration into adipose tissue and is associated with increases in several cardiovascular diseases. Infusion of angiotensin II (AngII) to mice induces formation of abdominal aortic aneurysms (AAAs) with profound medial and adventitial macrophage infiltration. We sought to determine whether obesity promotes macrophage infiltration and proinflammatory cytokines in periaortic adipose tissue surrounding abdominal aortas and increases AngII-induced AAAs. Methods and Results—Hypertrophied white adipocytes surrounded abdominal aortas, whereas brown adipocytes surrounded thoracic aortas of obese mice. mRNA abundance of macrophage proinflammatory chemokines and their receptors were elevated with obesity to a greater extent in abdominal compared to thoracic periaortic adipose tissue. Periaortic adipose tissue explants surrounding abdominal aortas of obese mice released greater concentrations of MCP-1 and promoted more macrophage migration than explants from thoracic aortas. Male C57BL/6 mice were fed a high-fat (HF) diet for 1, 2, or 4 months and then infused with AngII (1000 ng/kg/min) for 28 days. AAA incidence increased progressively with the duration of HF feeding (18%, 36%,and 60%, respectively). Similarly, AngII-infused ob/ob mice exhibited increased AAAs compared to lean controls (76% compared to 32%, respectively, P<0.05). Infusion of AngII to obese mice promoted further macrophage infiltration into periaortic and visceral adipose tissue, and obese mice exhibiting AAAs had greater macrophage content in visceral adipose tissue than mice not developing AAAs. Conclusions—Increased macrophage accumulation in periaortic adipose tissue surrounding abdominal aortas of AngII-infused obese mice is associated with enhanced AAA formation.

ANG II infusion promotes abdominal aortic aneurysms independent of increased blood pressure in hypercholesterolemic mice

Infusion of ANG II in hyperlipidemic mice augments atherosclerosis and causes formation of abdominal aortic aneurysms (AAAs). The purpose of this study was to define the contribution of ANG II-induced hypertension to these vascular pathologies. Male apolipoprotein E (apoE)- and LDL receptor (LDLr)-deficient mice were infused with ANG II (1,000 ng.kg(-1).min(-1)) or norepinephrine (NE; 5.6 mg.kg(-1).day(-1)) for 28 days. Infusion of ANG II or NE increased mean arterial pressure (MAP; ANG II, 133 +/- 2.8; NE, 129 +/- 13 mmHg) to a similar extent compared with baseline blood pressures (MAP, 107 +/- 2 mmHg). Abdominal aortic width increased in both apoE-deficient (apoE(-/-)) or LDLr-deficient (LDLr(-/-)) mice infused with ANG II (apoE(-/-): 1.4 +/- 0.1; LDLr(-/-): 1.6 +/- 0.2 mm). In contrast, NE did not change diameters of abdominal aortas (apoE(-/-): 0.91 +/- 0.03; LDLr(-/-): 0.87 +/- 0.02 mm). Similarly, atherosclerotic lesions in aortic arches were much greater in mice infused with ANG II compared with NE. At a subpressor infusion rate of ANG II (500 ng.kg(-1).min(-1)), AAAs developed in 50% of apoE(-/-) mice. Alternatively, administration of hydralazine (250 mg/l) to ANG II-infused apoE(-/-) mice (1,000 ng.kg(-1).min(-1)) lowered systolic blood pressure (day 28: ANG II, 157 +/- 6; ANG II/hydralazine, 135 +/- 6 mmHg) but did not prevent AAA formation or atherosclerosis. These results demonstrate that infusion of ANG II to hyperlipidemic mice induces AAAs and augments atherosclerosis independent of increased blood pressure.

The stability of psychopathy across adolescence

The current diagnostic system suggests that personality disorder categories be applied to children and adolescents in rare circumstances because of expected changes in personality pathology across development. The present study examined the stability in personality pathology, specifically psychopathy, across childhood and adolescence. Using a short form of the CPS and mixed models incorporating fixed and random effects, we examined the reliability, individual stability, mean-level stability, and predictive utility of juvenile psychopathy as a function of age (i.e., from 7 to 17 years old) in over 1,500 boys from the three cohorts of the Pittsburgh Youth Study. If adolescent development contributes to instability in personality pathology, large age-related fluctuations in reliability, stability, and predictive utility should be observed, particularly in the latter part of adolescence when normative changes are hypothesized to influence levels of psychopathy. Such fluctuations were not observed. In general, juvenile psychopathy could be reliably assessed beginning in childhood, was fairly stable across short and long intervals, showed little mean-level fluctuation, and predicted delinquency across adolescence. These results suggest that concerns about large changes in personality pathology across childhood and adolescence may be overstated. Implications and future directions are discussed.

Endothelial Cell–Specific Deficiency of Ang II Type 1a Receptors Attenuates Ang II–Induced Ascending Aortic Aneurysms in LDL Receptor−/− Mice

Rationale: Human studies and mouse models have provided evidence for angiotensin II (Ang II)–based mechanisms as an underlying cause of aneurysms localized to the ascending aorta. In agreement with this associative evidence, we have published recently that Ang II infusion induces aneurysmal pathology in the ascending aorta. Objective: The aim of this study was to define the role of angiotensin II type 1a (AT1a) receptors and their cellular location in Ang II–induced ascending aortic aneurysms (AAs). Methods and Results: Male LDL receptor−/− mice were fed a saturated fat–enriched diet for 1 week before osmotic mini-pump implantation and infused with either saline or Ang II (1000 ng/kg per minute) for 28 days. Intimal surface areas of ascending aortas were measured to quantify ascending AAs. Whole body AT1a receptor deficiency ablated Ang II–induced ascending AAs (P<0.001). To determine the role of AT1a receptors on leukocytes, LDL receptor−/−×AT1a receptor+/+ or AT1a receptor−/− mice were irradiated and repopulated with bone marrow–derived cells isolated from either AT1a receptor+/+ or AT1a receptor−/− mice. Deficiency of AT1a receptors in bone marrow–derived cells had no effect on Ang II–induced ascending AAs. To determine the role of AT1a receptors on vascular wall cells, we developed AT1a receptor floxed mice with depletion on either smooth muscle or endothelial cells using Cre driven by either SM22 or Tek, respectively. AT1a receptor deletion in smooth muscle cells had no effect on ascending AAs. In contrast, endothelial-specific depletion attenuated this pathology. Conclusions: Ang II infusion promotes aneurysms in the ascending aorta via stimulation of AT1a receptors that are expressed on endothelial cells.

Prolonged infusion of angiotensin II in apoE(-/-) mice promotes macrophage recruitment with continued expansion of abdominal aortic aneurysm.

Angiotensin II (AngII) infusion initiates abdominal aortic aneurysm (AAA) development due to medial disruption and results in luminal dilation and thrombus formation. The objective of this study was to determine whether AAA progressed during protracted AngII infusion. Male apoE(-/-) mice were infused with AngII using miniosmotic pumps. On day 27, suprarenal aortic luminal diameters were ultrasonically measured to identify mice exhibiting AAAs. Mice were designated to three groups with similar mean luminal dilation. Group 1 mice were sacrificed on day 28. Group 2 and 3 mice were subsequently infused with saline or AngII, respectively, for an additional 56 days. In Group 2, saline infusion-after the initial 28 days of AngII infusion-led to an immediate decrease in systolic blood pressure. Over the subsequent 56 days of saline infusion, there were no aneurysm-related deaths or significant changes in luminal diameter. In contrast, continuous AngII infusion in Group 3 maintained persistently increased systolic blood pressure, with aneurysmal rupture-associated deaths, increased luminal diameters, and tissue remodeling. Aortic aneurysmal segments that expanded during continuous AngII infusion exhibited macrophage accumulation in regions of medial disruption, predominantly on the adventitial aspect. Macrophages immunostained for CD206 more than for iNOS, consistent with an M2 phenotype. In conclusion, prolonged AngII infusion promotes AAA expansion, and is associated with enhanced rupture rates and increased macrophage infiltration.

Sensation Seeking and Impulsivity: Combined Associations with Risky Sexual Behavior in a Large Sample of Young Adults

Although prior studies have shown that sensation seeking and impulsive decision-making are related to sexual risk-taking, it is still unclear whether these personality traits operate independently or synergistically. The purpose of this study was to elucidate the joint contribution of these personality traits to HIV and sexually transmitted disease (STD) risk behaviors using data from a large sample of sexually active young adults (N = 2,386). Regression modeling indicated that both sensation seeking and impulsive decision-making were consistently associated with sexual risk behaviors across 11 risk-related outcomes. Results further indicated that sensation seeking and impulsive decision-making operated synergistically with respect to the outcome variables of sex acts using drugs, acts with a partner using alcohol, and acts with a partner using drugs. In contrast to this, sensation seeking and impulsive decision-making operated independently with respect to the other sexual risk outcomes. Theoretical implications, as well as implications for HIV/STD prevention among high sensation seekers and impulsive decision-makers, are discussed.

A Brief, Clinic-Based, Safer Sex Intervention for Heterosexual African American Men Newly Diagnosed With an STD: A Randomized Controlled Trial

OBJECTIVE We evaluated the efficacy of a brief, clinic-based, safer sex program administered by a lay health adviser for young heterosexual African American men newly diagnosed with a sexually transmitted disease (STD). METHODS Subsequent to STD diagnosis, eligible men (N = 266; aged 18-29 years) were randomized to either a personalized, single-session intervention (delivered by a lay health adviser) or standard of care. We conducted behavioral assessments at baseline and 3 months postintervention (retention was 74.1%). We also conducted a 6-month clinic record review. RESULTS Compared to men randomized to the control condition, those receiving the intervention were significantly less likely to acquire subsequent STDs (50.4% vs 31.9%; P = .002) and more likely to report using condoms during last sexual intercourse (72.4% vs 53.9%; P = .008). They also reported fewer sexual partners (mean 2.06 vs 4.15; P < .001) and fewer acts of unprotected sex (mean 12.3 vs 29.4; P = .045). Based on a 9-point rating scale, men in the intervention group had higher proficiency scores for condom application skills (mean difference = 3.17; P < .001). CONCLUSION A brief clinic-based intervention delivered by a lay health adviser may be an efficacious strategy to reduce incident STDs among young heterosexual African American men.

Adipocyte Deficiency of Angiotensinogen Prevents Obesity-Induced Hypertension in Male Mice

Previous studies demonstrated that diet-induced obesity increased plasma angiotensin II concentrations and elevated systolic blood pressures in male mice. Adipocytes express angiotensinogen and secrete angiotensin peptides. We hypothesize that adipocyte-derived angiotensin II mediates obesity-induced increases in systolic blood pressure in male high fat-fed C57BL/6 mice. Systolic blood pressure was measured by radiotelemetry during week 16 of low-fat or high-fat feeding in Agtfl/fl and adipocyte angiotensinogen-deficient mice (AgtaP2). Adipocyte angiotensinogen deficiency had no effect on diet-induced obesity. Basal 24-hour systolic blood pressure was not different in low fat-fed Agtfl/fl compared with AgtaP2 mice (124±3 versus 128±3 mm Hg, respectively). In Agtfl/fl mice, high-fat feeding significantly increased systolic blood pressure (24 hours; 134±2 mm Hg; P<0.05). In contrast, high fat-fed AgtaP2 mice did not exhibit an increase in systolic blood pressure (126±2 mm Hg). Plasma angiotensin II concentrations were increased by high-fat feeding in Agtfl/fl mice (low fat, 32±14; high fat, 219±58 pg/mL; P<0.05). In contrast, high fat-fed AgtaP2 mice did not exhibit elevated plasma angiotensin II concentrations (high fat, 18±7 pg/mL). Similarly, adipose tissue concentrations of angiotensin II were significantly decreased in low fat- and high fat-fed AgtaP2 mice compared with controls. In conclusion, adipocyte angiotensinogen deficiency prevented high fat-induced elevations in plasma angiotensin II concentrations and systolic blood pressure. These results suggest that adipose tissue serves as a major source of angiotensin II in the development of obesity hypertension.