- Depressive Symptoms and the Risk of Atherosclerotic Progression Among Patients With Coronary Artery Bypass Grafts
- Prevalence, Predictors, and Prognostic Value of Renal Dysfunction in Adults With Congenital Heart Disease
- Regulator of G-Protein Signaling Subtype 4 Mediates Antihypertrophic Effect of Locally Secreted Natriuretic Peptides in the Heart
- Cardioprotective and Vasodilatory Actions of Glucagon-Like Peptide 1 Receptor Are Mediated Through Both Glucagon-Like Peptide 1 Receptor–Dependent and –Independent Pathways
- Characterization of a Novel, Water-Soluble Hydrogen Sulfide–Releasing Molecule (GYY4137): New Insights Into the Biology of Hydrogen Sulfide
- Changes in Insulin Resistance and Cardiovascular Risk During Adolescence: Establishment of Differential Risk in Males and Females
- Both Intestinal and Hepatic Lipoprotein Production Are Stimulated by an Acute Elevation of Plasma Free Fatty Acids in Humans
- Heart Rate Reduction by Ivabradine Reduces Oxidative Stress, Improves Endothelial Function, and Prevents Atherosclerosis in Apolipoprotein E–Deficient Mice
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Depressive Symptoms and the Risk of Atherosclerotic Progression Among Patients With Coronary Artery Bypass Grafts
Depression and depressive symptoms are highly prevalent among patients with coronary artery disease and independently predict adverse cardiovascular events. Several mechanisms have been proposed to explain this association, including decreased adherence to treatment and increased prevalence of unfavorable lifestyle characteristics, among others; however, few studies have investigated the potential link between depressive symptoms and progression of atherosclerosis. Accordingly, we evaluated the hypothesis that depressive symptoms are associated with progression of atherosclerosis among individuals with previous coronary artery bypass graft surgery and saphenous vein grafts enrolled in the Post-CABG Trial. Depressive symptoms over the previous week were assessed at trial enrollment, and quantitative coronary angiography was conducted at enrollment and 4 to 5 years later. We found that the presence of depressive symptoms was associated with a higher risk of substantial progression of saphenous vein graft atherosclerosis and a decrease in minimum lumen diameter and that this association was virtually eliminated by random assignment to aggressive lipid lowering with high-dose lovastatin. Our analysis provides prospective evidence for a direct association between depressive symptoms and atherosclerotic progression as a potential mechanism for the corresponding association of depressive symptoms with clinical prognosis. See p 2313.
Prevalence, Predictors, and Prognostic Value of Renal Dysfunction in Adults With Congenital Heart Disease
The prognosis of adults with congenital heart disease is importantly influenced by noncardiac comorbidities. In this study on 1102 adult patients with congenital heart disease from a single specialist center, renal dysfunction was found to be a common complication of congenital heart disease, with 41% of patients having mild and 9% having moderate or severe reduction in glomerular filtration rate. Renal dysfunction was also found to be a strong predictor of survival, with a 3-fold adjusted increase in mortality in patients with moderately or severely impaired renal function. These data support routine, periodic screening of renal function in all adult patients with congenital heart disease to obtain broader prognostic information. See p 2320.
Regulator of G-Protein Signaling Subtype 4 Mediates Antihypertrophic Effect of Locally Secreted Natriuretic Peptides in the Heart
Cardiac myocytes respond to mechanical stress and neurohumoral factors by undergoing a hypertrophic response. Although some of this hypertrophy is adaptive, much of it is maladaptive and can ultimately result in cardiac failure. On the other hand, apart from acting as circulating hormones, atrial natriuretic peptide and brain natriuretic peptide have some functionality as autocrine and/or paracrine factors. Recently, we reported that in situ activation of cardiac guanylyl cyclase-A (GC-A), a natriuretic peptide receptor, by locally secreted natriuretic peptides protects the heart from cardiac hypertrophy by guanosine 3′,5′-cyclic monophosphate-dependent protein kinase (PKG)–mediated inhibition of calcineurin and its downstream mediator, nuclear factor of activated T cells. However, the molecular mechanism underlying GC-A–mediated inhibition of the calcineurin–nuclear factor of activated T cells pathway remains to be elucidated. GTPase-activating proteins for Gα have recently been identified and named regulator of G-protein signaling (RGS) proteins. In the present study, we investigated the role of RGS in GC-A–mediated inhibition of cardiac hypertrophy. Our findings indicate that GC-A activates RGS4 via PKG in cardiac myocytes; this attenuates Gαq and downstream hypertrophic signaling. Nakayama et al previously described a functional mutation in the 5′-flanking region of the human GC-A gene that is associated with essential hypertension and cardiac hypertrophy. GC-A gene expression is most likely diminished in these patients because of the mutation, predisposing them to cardiac hypertrophy similar to that seen in GC-A knockout mice. In such patients, it is possible that inhibition of the calcineurin–nuclear factor of activated T cells pathway by RGS4 would be a useful treatment for the prevention of cardiac remodeling. See p 2329.
Cardioprotective and Vasodilatory Actions of Glucagon-Like Peptide 1 Receptor Are Mediated Through Both Glucagon-Like Peptide 1 Receptor–Dependent and –Independent Pathways
Two therapeutic strategies based on potentiation of glucagon-like peptide 1 action are now used to treat type 2 diabetes mellitus: glucagon-like peptide 1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. Most GLP-1R agonists under development for the treatment of diabetes are resistant to cleavage by the DPP-4 enzyme; many also exhibit structural differences relative to native GLP-1 and hence may not give rise to GLP-1(9-36) in vivo. Similarly, DPP-4 inhibitors, although enhancing the stability of cardioprotective molecules such as SDF-1, prevent the enzymatic cleavage of native GLP-1 to GLP-1(9-36). The data presented here extend previous findings on the biology of GLP-1(9-36) by demonstrating that this peptide metabolite exerts cardioprotective actions in the murine heart. Moreover, these actions are independent of the known GLP-1R, invoking a novel signaling mechanism for the DPP-4–generated GLP-1 metabolite. These findings suggest that GLP-1(9-36) itself may have therapeutic benefit in the setting of cardiovascular injury, a hypothesis that can be tested in future clinical studies. Moreover, the increasing complexity of the cardiovascular actions of GLP-1 and its cardioactive metabolite GLP-1(9-36) underscores the need for clinical studies examining the cardiovascular actions of GLP-1R agonists and DPP-4 inhibitors in subjects with type 2 diabetes. See p 2340.
Characterization of a Novel, Water-Soluble Hydrogen Sulfide–Releasing Molecule (GYY4137): New Insights Into the Biology of Hydrogen Sulfide
The potential biological and clinical significance of hydrogen sulfide (H2S) has been the subject of intense debate in recent years. Despite considerable progress in our understanding of this gas, much still needs to be learned. By analogy with other gases (eg, nitric oxide, carbon monoxide), a better understanding of the biological effects of H2S would be expected by using drugs with the ability to release this gas over extended periods of time. Unfortunately, until now, no such drug has been available. We report here that morpholin-4-IM4 methoxyphenyl(morpholino) phosphinodithioate (GYY4137) is a water-soluble compound that releases H2S over the space of several hours. GYY4137 causes slow dilation of blood vessels both in vitro and in vivo without influencing vascular smooth muscle cell viability in culture. When administered to conscious, spontaneously hypertensive rats, GYY4137 lowered blood pressure without affecting heart rate and without weight loss or other signs of toxicity. The vasodepressor effect of GYY4137 was reversed when drug administration was halted, and there was no rebound rise in blood pressure. We believe that the slow release of H2S from GYY4137 better mimics the generation of this gas in vivo, and as such the spectrum of activity of this compound provides a more accurate reflection of the biological effects of this gas than has hitherto been available. Moreover, the clear antihypertensive effect of GYY4137 raises the possibility that this compound, or a like slow-releasing H2S donor, may be of therapeutic benefit in clinical conditions associated with excessive vasoconstriction. See p 2351.
Changes in Insulin Resistance and Cardiovascular Risk During Adolescence: Establishment of Differential Risk in Males and Females
The present study assessed changes in insulin resistance and overall cardiovascular risk during the transition from late childhood through adolescence (ie, age 11 to 19 years). During these years, boys decreased their percentage of body fat and become more lean and muscular, whereas girls gained body fat. Insulin resistance at age 11 years was significantly lower in boys but increased during adolescence, so that by age 19, boys were more insulin resistant than girls. Over the same period, triglycerides increased and high-density lipoprotein cholesterol decreased in males, whereas the opposite pattern was seen in females, and systolic blood pressure increased at a greater rate in males. Total cholesterol and low-density lipoprotein cholesterol changes did not differ between the sexes. Thus, adolescence in males was associated with increased insulin resistance despite decreased adiposity, as well as an increase in cardiovascular risk. Because this was independent of adverse changes in low-density lipoprotein and total cholesterol, it suggests that early development of risk is related to insulin resistance. Although the cause of these sex-related changes is not clear, it is possible that the increased cardiovascular risk that emerges in males during normal adolescence is related to hormonal differences between the sexes. See p 2361.
Both Intestinal and Hepatic Lipoprotein Production Are Stimulated by an Acute Elevation of Plasma Free Fatty Acids in Humans
Dyslipidemia is a prominent feature of both insulin resistance and type 2 diabetes mellitus and contributes to the increased risk of cardiovascular events in these conditions. The typical hypertriglyceridemia of insulin-resistant states has been determined in numerous previous studies to be due predominantly to overproduction of hepatic (apolipoprotein B-100–containing) very-low-density lipoproteins, as well as impairment in the clearance of these particles from the circulation. The mechanism of hepatic very-low-density lipoprotein overproduction in insulin resistance is complex, but elevated free fatty acid flux, predominantly from insulin-resistant adipose tissue to the liver, is an important mechanism accounting for this phenomenon. Recent studies in animal models of insulin resistance and in humans have demonstrated that the production rate of intestinal (apolipoprotein B-48–containing) chylomicrons is also increased in insulin-resistant states. Intestinal chylomicron production is stimulated mainly by fat ingestion, which is efficiently absorbed from the intestinal lumen by the intestinal enterocyte and packaged into chylomicron particles, which enter the circulation via the lymphatic duct. Here we have shown, for the first time in humans, that an acute elevation of plasma free fatty acids stimulates not only hepatic but also intestinal triglyceride-rich lipoprotein production. We speculate that chronic elevation of plasma free fatty acids, as seen in insulin-resistant and type 2 diabetic individuals, is likely to play an important role in the overproduction of intestinal lipoproteins, thereby contributing to the dyslipidemia of insulin-resistant humans. See p 2369.
Heart Rate Reduction by Ivabradine Reduces Oxidative Stress, Improves Endothelial Function, and Prevents Atherosclerosis in Apolipoprotein E–Deficient Mice
Epidemiological studies have shown that elevated heart rate is a risk factor for cardiovascular morbidity. Experimental data suggest that sustained elevations of heart rate may play a role in the pathogenesis of coronary atherosclerosis. Ivabradine, a selective inhibitor of the I(f) channel, reduces resting and exercise heart rates without an effect on cardiac contractility. In the present study of apolipoprotein E–deficient mice fed a high-cholesterol diet, ivabradine reduced heart rate without affecting blood pressure or lipid levels. Endothelium-dependent relaxation of aortic rings was significantly improved in ivabradine-fed animals, and ivabradine decreased the development of atherosclerotic lesions. The main underlying molecular observation was a potent antioxidative effect of ivabradine that was mediated by the reduction of heart rate. There was no evidence for a heart rate–independent action of the drug. In summary, long-term heart rate reduction by ivabradine leads to inhibition of vascular oxidative stress, endothelial dysfunction, and atherosclerotic lesion formation in apolipoprotein E–deficient mice, regardless of blood pressure and plasma cholesterol levels. The experiments support the potential of heart rate reduction as an intervention to improve endothelial function and to attenuate progression of atherosclerosis in vascular prevention in addition to the symptomatic treatment of angina pectoris. Pharmacological inhibition of the I(f) current may represent a novel intervention to prevent endothelial dysfunction that should be tested in a prospective clinical investigation. See p 2377.
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