Tommaso Gori

Is oxidative stress a therapeutic target in cardiovascular disease

An abnormal production of reactive oxygen species (ROS) and the subsequent decrease in vascular bioavailability of nitric oxide (NO) have long been proposed to be the common pathogenetic mechanism of the endothelial dysfunction, resulting from diverse cardiovascular risk factors such as hypercholesterolaemia, diabetes mellitus, chronic smoking, metabolic syndrome, and hypertension. Superoxide produced by the nicotinamide dinucleotide phosphate (NADPH) oxidase, mitochondrial sources, or the xanthine oxidase may react with NO, thereby resulting in excessive formation of peroxynitrite, a reactive nitrogen species that has been demonstrated to accelerate the atherosclerotic process by causing direct structural damage and by causing further ROS production. Despite this sound biological rationale and a number of pre-clinical and clinical lines of evidence, studies testing the effects of classical antioxidants such as vitamin C, vitamin E, or folic acid in combination with vitamin E have been disappointing. Rather, substances such as statins, angiotensin-converting enzyme inhibitors, or AT1-receptor blockers, which possess indirect antioxidant properties mediated by the stimulation of NO production and simultaneous inhibition of superoxide production (e.g. from the NADPH oxidase), have been shown to improve vascular function in pre-clinical and clinical studies and to reduce the incidence of cardiovascular events in patients with cardiovascular disease. Today, oxidative stress remains an attractive target for cardiovascular prevention and therapy. However, a deeper understanding of its source, and of its role in vascular pathology, is necessary before new trials are attempted.

Oxidative stress and endothelial dysfunction in hypertension

Systemic arterial hypertension is a highly prevalent cardiovascular risk factor that causes significant morbidity and mortality, and is becoming an increasingly common health problem because of the increasing longevity and prevalence of predisposing factors such as sedentary lifestyle, obesity and nutritional habits. Further complicating the impact of this disease, mild and moderate hypertension are usually asymptomatic, and their presence (and the subsequent increase in cardiovascular risk) is often unrecognized. The pathophysiology of hypertension involves a complex interaction of multiple vascular effectors including the activation of the sympathetic nervous system, of the renin–angiotensin–aldosterone system and of the inflammatory mediators. Subsequent vasoconstriction and inflammation ensue, leading to vessel wall remodeling and, finally, to the formation of atherosclerotic lesions as the hallmark of advanced disease. Oxidative stress and endothelial dysfunction are consistently observed in hypertensive subjects, but emerging evidence suggests that they also have a causal role in the molecular processes leading to hypertension. Reactive oxygen species (ROS) may directly alter vascular function or cause changes in vascular tone by several mechanisms including altered nitric oxide (NO) bioavailability or signaling. ROS-producing enzymes involved in the increased vascular oxidative stress observed during hypertension include the NADPH oxidase, xanthine oxidase, the mitochondrial respiratory chain and an uncoupled endothelial NO synthase. In the current review, we will summarize our current understanding of the molecular mechanisms in the development of hypertension with an emphasis on oxidative stress and endothelial dysfunction.

Bioresorbable Coronary Scaffold Thrombosis : Multicenter Comprehensive Analysis of Clinical Presentation, Mechanisms, and Predictors

BACKGROUND Recent reports suggest an elevated incidence of bioresorbable vascular scaffold (BVS) thrombosis (scaffold thrombosis [ScT]). OBJECTIVES This study investigated occurrence rates, clinical and angiographic characteristics, and possible mechanisms of ScT in all-comer patients undergoing BVS implantation at 2 German and 2 Swiss hospitals. METHODS A total of 1,305 consecutive patients (mean age 64 years, 78% male) who received 1,870 BVS (mean 1.4 ± 0.8 BVS/patient) were enrolled. Clinical/procedural characteristics, mortality, and ScT data at 485 days (range 312 to 652 days) were examined. RESULTS ScT occurred in 42 patients. The incidence of probable and definite ScT was 1.8% at 30 days and 3.0% at 12 months, without differences among centers (p = 0.60). A total of 22 (52%) ScTs presented as ST-segment elevation myocardial infarction and 6 (17%) as sudden cardiac death. In multivariable analysis, ostial lesions (p = 0.049) and impaired left ventricular ejection fraction (p = 0.019) were independently associated with ScT. Nine (21%) of the ScTs occurred in patients who had suspended dual antiplatelet therapy, in 6 cases prematurely. Lower post-procedural minimum lumen and reference vessel diameters were hallmarks of ScT (all p < 0.0001). The risk of ScT appeared to rapidly increase for post-procedural minimum lumen diameters below 2.4 mm (for the 2.5- to 3.0-mm BVS) and 2.8 mm (for the 3.5-mm BVS). When a BVS-specific implantation strategy was implemented, 12-month ScT rates fell from 3.3% to 1.0%, an effect that remained significant when adjusted for multivariable propensity score (p = 0.012; hazard ratio: 0.19; 95% confidence interval: 0.05 to 0.70). CONCLUSIONS The 12-month incidence of ScT reached 3% and could be significantly reduced when an optimized implantation strategy was employed. (retrospective multicentric registry and Mainz Intracoronary Database. The Coronary Slow-flow and Microvascular Diseases Registry [MICAT]; NCT02180178).

Cardiovascular effects of environmental noise exposure

The role of noise as an environmental pollutant and its impact on health are being increasingly recognized. Beyond its effects on the auditory system, noise causes annoyance and disturbs sleep, and it impairs cognitive performance. Furthermore, evidence from epidemiologic studies demonstrates that environmental noise is associated with an increased incidence of arterial hypertension, myocardial infarction, and stroke. Both observational and experimental studies indicate that in particular night-time noise can cause disruptions of sleep structure, vegetative arousals (e.g. increases of blood pressure and heart rate) and increases in stress hormone levels and oxidative stress, which in turn may result in endothelial dysfunction and arterial hypertension. This review focuses on the cardiovascular consequences of environmental noise exposure and stresses the importance of noise mitigation strategies for public health.

Nitrate tolerance: a unifying hypothesis.

) production, endo-thelial dysfunction, and the neurohormonal activation that followlong-term administration of organic nitrates. In this issue ofCirculation, we will try to integrate these observations withother separate, and, to a certain extent, antagonistic hypothesesthat have been proposed for the development of nitrate toler-ance.

Nebivolol: The Somewhat-Different β-Adrenergic Receptor Blocker

Although its clinical use in Europe dates almost 10 years, nebivolol is a beta-blocker that has been only recently introduced in the U.S. market. Like carvedilol, nebivolol belongs to the third generation of beta-blockers, which possess direct vasodilator properties in addition to their adrenergic blocking characteristics. Nebivolol has the highest beta(1)-receptor affinity among beta-blockers and, most interestingly, it substantially improves endothelial dysfunction via its strong stimulatory effects on the activity of the endothelial nitric oxide synthase and via its antioxidative properties. Because impaired endothelial activity is attributed a major causal role in the pathophysiology of hypertension, coronary artery disease, and congestive heart failure, the endothelium-agonistic properties of nebivolol suggest that this drug might provide additional benefit beyond beta-receptor blockade. Although lesser beta-blocker-related side effects have been reported in patients with chronic obstructive pulmonary disease or impotence taking nebivolol, side effects and contraindications overlap those of other beta-blockers. Clinically, this compound has been proven to have antihypertensive and anti-ischemic effects as well as beneficial effects on hemodynamics and prognosis in patients with chronic congestive heart failure. Further studies are now necessary to compare the benefit of nebivolol with that of other drugs in the same class and, most importantly, its prognostic impact in patients with hypertension.

Sildenafil Prevents Endothelial Dysfunction Induced by Ischemia and Reperfusion via Opening of Adenosine Triphosphate–Sensitive Potassium Channels A Human In Vivo Study

Background—Animal studies have demonstrated that administration of sildenafil can limit myocardial damage induced by prolonged ischemia, an effect that appears to be mediated by opening of adenosine triphosphate–sensitive potassium (KATP) channels. No study has investigated whether sildenafil can also prevent the impairment in endothelium-dependent vasodilatation induced by ischemia-reperfusion (IR) in humans. Methods and Results—In a double-blind, placebo-controlled, crossover design, 10 healthy male volunteers (25 to 45 years old) were randomized to oral sildenafil (50 mg) or placebo. Two hours later, endothelium-dependent, flow-mediated dilatation (FMD) of the radial artery was measured before and after IR (15 minutes of ischemia at the level of the brachial artery followed by 15 minutes of reperfusion). Seven days later, subjects received the other treatment (ie, placebo or sildenafil) and underwent the same protocol. Pre-IR radial artery diameter and FMD, as well as baseline radial artery diameter after IR, were similar between visits (P=NS). After placebo administration, IR significantly blunted FMD (before IR: 7.9±1.1%; after IR: 1.2±0.7%, P<0.01). Importantly, sildenafil limited this impairment in endothelium-dependent vasodilatation (before IR: 7.0±0.9%; after IR: 6.2±1.1%, P=NS; P<0.01 compared with placebo). In a separate protocol, this protective effect was completely prevented by previous administration of the sulfonylurea glibenclamide (glyburide, 5 mg), a blocker of KATP channels (n=7; FMD before IR: 10.3±1.5%; after IR: 1.3±1.4%, P<0.05). Conclusions—In humans, oral sildenafil induces potent protection against IR-induced endothelial dysfunction through opening of KATP channels. Further studies are needed to test the potential clinical implications of this finding.

Glucose-independent improvement of vascular dysfunction in experimental sepsis by dipeptidyl-peptidase 4 inhibition

AIMS Dipeptidyl peptidase-4 (DPP-4) inhibitors are a novel class of drugs for the treatment of hyperglycaemia. Preliminary evidence suggests that their antioxidant and anti-inflammatory effects may have beneficial effects on the cardiovascular complications of diabetes. In the present study, we investigate in an experimental sepsis model whether linagliptin exerts pleiotropic vascular effects independent of its glucose-lowering properties. METHODS AND RESULTS Linagliptin (83 mg/kg chow for 7 days) was administered in a rat model of lipopolysaccharide (LPS) (10 mg/kg, single i.p. dose/24 h)-induced sepsis. Vascular relaxation, reactive oxygen species (ROS) formation, expression of NADPH oxidase subunits and proinflammatory markers, and white blood cell infiltration in the vasculature were determined. Oxidative burst and adhesion of isolated human neutrophils to endothelial cells were measured in the presence of different DPP-4 inhibitors, and their direct vasodilatory effects (isometric tension in isolated aortic rings) were compared. In vivo linagliptin treatment ameliorated LPS-induced endothelial dysfunction and was associated with reduced formation of vascular, cardiac, and blood ROS, aortic expression of inflammatory genes and NADPH oxidase subunits in addition to reduced aortic infiltration with inflammatory cells. Linagliptin was the most potent inhibitor of oxidative burst in isolated activated human neutrophils and it suppressed their adhesion to activated endothelial cells. Of the inhibitors tested, linagliptin and alogliptin had the most pronounced direct vasodilatory potency. CONCLUSION Linagliptin demonstrated pleiotropic vasodilatory, antioxidant, and anti-inflammatory properties independent of its glucose-lowering properties. These pleiotropic properties are generally not shared by other DPP-4 inhibitors and might translate into cardiovascular benefits in diabetic patients.

Evidence supporting abnormalities in nitric oxide synthase function induced by nitroglycerin in humans.

OBJECTIVES We studied the effects of nitroglycerin (GTN) therapy on the response to endothelium-dependent and independent vasoactive agents in the forearm circulation of healthy subjects. BACKGROUND Recent evidence suggests that therapy with GTN may induce specific changes in endothelial cell function, including increased superoxide anion production and sensitivity to vasoconstrictors. Additionally, continuous GTN therapy worsens endothelial function in the coronary circulation of patients with ischemic heart disease. METHODS Forearm blood flow was measured with venous occlusion, mercury-in-silastic strain gauge plethysmography. RESULTS Sixteen male volunteers (26 +/- 6 years) were randomized to no therapy (control) or GTN, 0.6 mg/h/24 h, for six days in an investigator-blind, parallel-design study. The flow responses to brachial artery infusions of acetylcholine ([Ach] 7.5, 15.0, 30.0 microg/min), N-monomethyl-L-arginine (L-NMMA) (1, 2, 4 micromol/min) and sodium nitroprusside (SNP) (0.8, 1.6, 3.2 microg/min) were recorded. The vasodilator responses to Ach were blunted in the GTN group as compared with the control group (p < 0.05). The vasoconstrictor responses to L-NMMA were also blunted in the GTN group (p < 0.001). In the GTN group, paradoxical vasodilation was observed in response to the lowest infused concentration of L-NMMA. The vasodilator responses to SNP did not differ between groups. CONCLUSIONS The response to Ach confirms the hypothesis that continuous GTN causes endothelial dysfunction. The responses to L-NMMA suggest that GTN therapy causes abnormalities in nitric oxide synthase (NOS) function; the vasodilation observed at the lowest infused concentration of L-NMMA in the GTN group also suggests that continuous GTN therapy is associated with a NOS-mediated production of a vasoconstrictor.

First Evidence for a Crosstalk Between Mitochondrial and NADPH Oxidase-Derived Reactive Oxygen Species in Nitroglycerin-Triggered Vascular Dysfunction

Chronic nitroglycerin treatment results in development of nitrate tolerance associated with endothelial dysfunction (ED). We sought to clarify how mitochondria- and NADPH oxidase (Nox)-derived reactive oxygen species (ROS) contribute to nitrate tolerance and nitroglycerin-induced ED. Nitrate tolerance was induced by nitroglycerin infusion in male Wistar rats (100 microg/h/4 day) and in C57/Bl6, p47(phox/) and gp91(phox/) mice (50 microg/h/4 day). Protein and mRNA expression of Nox subunits were unaltered by chronic nitroglycerin treatment. Oxidative stress was determined in vascular rings and mitochondrial fractions of nitroglycerin-treated animals by L-012 enhanced chemiluminescence, revealing a dominant role of mitochondria for nitrate tolerance development. Isometric tension studies revealed that genetic deletion or inhibition (apocynin, 0.35 mg/h/4 day) of Nox improved ED, whereas nitrate tolerance was unaltered. Vice versa, nitrate tolerance was attenuated by co-treatment with the respiratory chain complex I inhibitor rotenone (100 microg/h/4 day) or the mitochondrial permeability transition pore blocker cyclosporine A (50 microg/h/4 day). Both compounds improved ED, suggesting a link between mitochondrial and Nox-derived ROS. Mitochondrial respiratory chain-derived ROS are critical for the development of nitrate tolerance, whereas Nox-derived ROS mediate nitrate tolerance-associated ED. This suggests a crosstalk between mitochondrial and Nox-derived ROS with distinct mechanistic effects and sites for pharmacological intervention.