Methods and Results— The Post-CABG Trial randomized patients with a history of coronary bypass graft surgery to either an aggressive or a moderate lipid-lowering strategy and to either warfarin or placebo. Coronary angiography was conducted at enrollment and after a median follow-up of 4.2 years. Depressive symptoms were assessed at enrollment with the Centers for Epidemiologic Studies Depression scale (CES-D) in 1319 patients with 2496 grafts. In models that adjusted for age, gender, race, treatment assignment, and years since coronary bypass graft surgery, a CES-D score ≥16 was positively associated with risk of substantial graft disease progression (OR 1.50, 95% CI 1.08 to 2.10, P=0.02) and marginally associated with a 0.11-mm (95% CI –0.22 to 0.01 mm, P=0.07) decrease in minimum lumen diameter, but not with risk of graft occlusion (P=0.30). Additional adjustment for past medical history, blood pressure, and renal function did not materially alter these results. This association was virtually absent among participants randomly assigned to aggressive lipid-lowering therapy.

Conclusions— These findings suggest that depressive symptoms are associated with a higher risk of atherosclerotic progression among patients with saphenous vein grafts and that aggressive lipid lowering can minimize this increased risk. Whether depressive symptoms increase progression in other types of coronary atherosclerosis and whether aggressive lipid lowering attenuates such progression will require additional study.

Methods and Results— A total of 1102 adult patients with congenital heart disease (age 36.0±14.2 years) attending our institution between 1999 and 2006 had creatinine concentration measured. Glomerular filtration rate (GFR) was calculated with the Modification of Diet in Renal Disease equation. Patients were divided into groups of normal GFR (≥90 mL · min^–1 · 1.73 m^–2), mildly impaired GFR (60 to 89 mL · min^–1 · 1.73 m^–2), and moderately/severely impaired GFR (<60 mL · min^–1 · 1.73 m^–2). Survival was compared between GFR groups by Cox regression. Median follow-up was 4.1 years, during which 103 patients died. Renal dysfunction was mild in 41% of patients and moderate or severe in 9%. A decrease in GFR was more common among patients with Eisenmenger physiology, of whom 72% had reduced GFR (<90 mL · min^–1 · 1.73 m^–2, P<0.0001 compared with the remainder), and in 18%, this was moderate or severe (P=0.007). Renal dysfunction had a substantial impact on mortality (propensity score–weighted hazard ratio 3.25, 95% CI 1.54 to 6.86, P=0.002 for moderately or severely impaired versus normal GFR).

Conclusions— Deranged physiology in adult patients with congenital heart disease is not limited to the heart but also affects the kidney. Mortality is 3-fold higher than normal in the 1 in 11 patients who have moderate or severe GFR reduction.

Methods and Results— In cultured cardiac myocytes, treatment of atrial natriuretic peptide stimulated the binding of guanosine 3',5'-cyclic monophosphate-dependent protein kinase (PKG) I- to RGS4, PKG-dependent phosphorylation of RGS4, and association of RGS4 and G_q. In contrast, blockade of GC-A by an antagonist, HS-142-1, attenuated the phosphorylation of RGS4 and association of RGS4 and G_q. Moreover, overexpressing a dominant negative form of RGS4 diminished the inhibitory effects of atrial natriuretic peptide on endothelin-1–stimulated inositol 1,4,5-triphosphate production, [³H]leucine incorporation, and atrial natriuretic peptide gene expression. Furthermore, expression and phosphorylation of RGS4 were significantly reduced in the hearts of GC-A knockout (GC-A-KO) mice compared with wild-type mice. For further investigation, we constructed cardiomyocyte-specific RGS4 transgenic mice and crossbred them with GC-A-KO mice. The cardiac RGS4 overexpression in GC-A-KO mice significantly reduced the ratio of heart to body weight (P<0.001), cardiomyocyte size (P<0.01), and ventricular calcineurin activity (P<0.05) to 80%, 76%, and 67% of nontransgenic GC-A-KO mice, respectively. It also significantly suppressed the augmented cardiac expression of hypertrophy-related genes in GC-A-KO mice.

Conclusions— These results provide evidence that GC-A activates cardiac RGS4, which attenuates G_q and its downstream hypertrophic signaling, and that RGS4 plays important roles in GC-A–mediated inhibition of cardiac hypertrophy.

Methods and Results— Here, we show that endothelium and cardiac and vascular myocytes express a functional GLP-1R as GLP-1 administration increased glucose uptake, cAMP and cGMP release, left ventricular developed pressure, and coronary flow in isolated mouse hearts. GLP-1 also increased functional recovery and cardiomyocyte viability after ischemia-reperfusion injury of isolated hearts and dilated preconstricted arteries from wild-type mice. Unexpectedly, many of these actions of GLP-1 were preserved in Glp1r^–/– mice. Furthermore, GLP-1(9-36) administration during reperfusion reduced ischemic damage after ischemia-reperfusion and increased cGMP release, vasodilatation, and coronary flow in wild-type and Glp1r^–/– mice, with modest effects on glucose uptake. Studies using a DPP-4–resistant GLP-1R agonist and inhibitors of DPP-4 and nitric oxide synthase showed that the effects of GLP-1(7-36) were partly mediated by GLP-1(9-36) through a nitric oxide synthase–requiring mechanism that is independent of the known GLP-1R.

Conclusions— These data describe cardioprotective actions of GLP-1(7-36) mediated through the known GLP-1R and novel cardiac and vascular actions of GLP-1(7-36) and its metabolite GLP-1(9-36) independent of the known GLP-1R. Our data suggest that the extent to which GLP-1 is metabolized to GLP-1(9-36) may have functional implications in the cardiovascular system.

Methods and Results— The acute vasorelaxant effect of drugs was assessed in rat aortic rings and perfused rat kidney in vitro and in the anesthetized rat in vivo. The chronic effect of GYY4137 on blood pressure in normotensive and spontaneously hypertensive rats was determined by tail-cuff plethysmography. GYY4137 released H₂S slowly both in aqueous solution in vitro and after intravenous or intraperitoneal administration in anesthetized rats in vivo. GYY4137 caused a slow relaxation of rat aortic rings and dilated the perfused rat renal vasculature by opening vascular smooth muscle K_ATP channels. GYY4137 did not affect rat heart rate or force of contraction in vitro. GYY4137 exhibited antihypertensive activity as evidenced by ability to reduce N^G-nitro-l-arginine methyl ester–evoked hypertension in the anesthetized rat and after chronic (14-day) administration in spontaneously hypertensive rats.

Conclusions— These results identify GYY4137 as a slow-releasing H₂S compound with vasodilator and antihypertensive activity. GYY4137 is likely to prove useful in the study of the many and varied biological effects of H₂S. GYY4137 may also prove of therapeutic value in cardiovascular disease.

Methods and Results— A cohort was randomly selected after blood pressure screening of Minneapolis, Minn, school children. Studies were done 3 times on this cohort and once on their siblings (996 observations on 507 individuals from 363 families). Insulin sensitivity was determined by euglycemic clamp. Body mass index and waist circumference increased similarly in both sexes from ages 11 to 19 years. Body fat decreased in males and increased in females (P<0.001). Lean body mass increased at a steeper rate in males (P<0.0001). Insulin resistance was lower in males at 11 years but increased steadily to 19 years (P=0.003); in contrast, it did not increase in females. Thus, despite being less insulin resistant at 11 years and decreasing in fatness during puberty, males became more insulin resistant than females by 19 years of age. Triglycerides increased in males and high-density lipoprotein cholesterol decreased, whereas the opposite pattern was seen in females, which resulted in higher triglycerides and lower high-density lipoprotein cholesterol in males at 19 years. No gender difference in low-density lipoprotein or total cholesterol was seen. Systolic blood pressure increased in both sexes but at a greater rate in boys (P=0.03).

Conclusions— During the transition from late childhood through adolescence, insulin resistance in males increased in association with increased triglycerides and decreased high-density lipoprotein cholesterol, despite a concurrent reduction in body fatness, whereas the opposite occurred in females. These gender-related developmental changes in insulin resistance, which were independent from changes in fatness, total cholesterol, and low-density lipoprotein cholesterol, are consistent with an early role for insulin resistance in the increased cardiovascular risk found in males.

Methods and Results— TRL apoB-48 and apoB-100 metabolism were examined in 12 healthy men during a constant fed state. The studies were as follows, respectively: (1) Intralipid/heparin was infused intravenously immediately before and during the kinetics study to induce an 3-fold difference in plasma FFA compared with the saline study; (2) saline was infused intravenously as a control. ApoB-48– and apoB-100–containing TRL production and clearance were determined with a 12-hour primed constant infusion of [D3]l-leucine and multicompartmental kinetic modeling. TRL apoB-48 production rate was 69% higher in the Intralipid/heparin study than in the saline control (5.95±1.13 versus 3.53±0.58 mg/kg per day; P=0.027), and there was no significant difference in TRL apoB-48 clearance. TRL apoB-100 concentrations were also increased (P<0.001) and TRL apoB-100 production rate was 35% higher in the Intralipid/heparin study compared with saline (28±4 versus 21±3 mg/kg per day; P=0.020).

Conclusions— This is the first study to demonstrate that intestinal TRL apoB-48 production is increased after short-term elevation of plasma FFAs in humans in the fed state, similar to the well-described stimulation of hepatic TRL apoB100–containing particles by FFAs.

Methods and Results— Male apolipoprotein E–deficient mice fed a high-cholesterol diet were treated with ivabradine (10 mg · kg^–1 · d^–1) or vehicle for 6 weeks (n=10 per group). Ivabradine reduced heart rate by 13.4% (472±9 versus 545±11 bpm; P<0.01) but did not alter blood pressure or lipid levels. Endothelium-dependent relaxation of aortic rings was significantly improved in ivabradine-fed animals (P<0.01). Ivabradine decreased atherosclerotic plaque size in the aortic root by >40% and in the ascending aorta by >70% (P<0.05). Heart rate reduction by ivabradine had no effect on the number of endothelial progenitor cells and did not alter aortic endothelial nitric oxide synthase, phosphorylated Akt, vascular cell adhesion molecule-1, or intercellular adhesion molecule-1 expression but decreased monocyte chemotactic protein-1 mRNA and exerted potent antioxidative effects. Ivabradine reduced vascular NADPH oxidase activity to 48±6% and decreased markers of superoxide production and lipid peroxidation in the aortic wall (P<0.05). The in vivo effects of ivabradine were absent at a dose that did not lower heart rate, in aortic rings treated ex vivo, and in cultured vascular cells. In contrast to ivabradine, treatment with hydralazine (25 mg · kg^–1 · d^–1 for 6 weeks) reduced blood pressure (–15%) but increased heart rate (37%) and did not improve endothelial function, atherosclerosis, or oxidative stress.

Conclusions— Selective heart rate reduction with ivabradine decreases markers of vascular oxidative stress, improves endothelial function, and reduces atherosclerotic plaque formation in apolipoprotein E–deficient mice.