Adrenergic signaling and oxidative stress: a role for sirtuins?

The adrenergic system plays a central role in stress signaling and stress is often associated with increased production of ROS. However, ROS overproduction generates oxidative stress, that occurs in response to several stressors. ß-adrenergic signaling is markedly attenuated in conditions such as heart failure, with downregulation and desensitization of the receptors and their uncoupling from adenylyl cyclase. Transgenic activation of ß2-adrenoceptor leads to elevation of NADPH oxidase activity, with greater ROS production and p38MAPK phosphorylation. Inhibition of NADPH oxidase or ROS significantly reduced the p38MAPK signaling cascade. Chronic ß2-adrenoceptor activation is associated with greater cardiac dilatation and dysfunction, augmented pro-inflammatory and profibrotic signaling, while antioxidant treatment protected hearts against these abnormalities, indicating ROS production to be central to the detrimental signaling of ß2-adrenoceptors. It has been demonstrated that sirtuins are involved in modulating the cellular stress response directly by deacetylation of some factors. Sirt1 increases cellular stress resistance, by an increased insulin sensitivity, a decreased circulating free fatty acids and insulin-like growth factor (IGF-1), an increased activity of AMPK, increased activity of PGC-1a, and increased mitochondrial number. Sirt1 acts by involving signaling molecules such P-I-3-kinase-Akt, MAPK and p38-MAPK-ß. ßAR stimulation antagonizes the protective effect of the AKT pathway through inhibiting induction of Hif-1α and Sirt1 genes, key elements in cell survival. More studies are needed to better clarify the involvement of sirtuins in the ß-adrenergic response and, overall, to better define the mechanisms by which tools such as exercise training are able to counteract the oxidative stress, by both activation of sirtuins and inhibition of GRK2 in many cardiovascular conditions and can be used to prevent or treat diseases such as heart failure.

Six-minute walking test but not ejection fraction predicts mortality in elderly patients undergoing cardiac rehabilitation following coronary artery bypass grafting.

BACKGROUND: Age-related effects on the ability of 6-min walking test (6MWT) and ejection fraction (EF) to predict mortality in coronary artery bypass grafting (CABG) patients undergoing cardiac rehabilitation (CR) is still debated. DESIGN AND METHODS: In order to verify the role of 6MWT and EF on all-cause mortality in patients undergoing CR following CABG, 882 CABG patients undergoing CR stratified in adults (<65 years) and elderly (≥65 years) were studied. RESULTS: At the admission, EF was 52.6 ± 9.1% in adults and 51.3 ± 8.9% in elderly (p = 0.234, NS) while 6MWT was 343.8 ± 93.5 m in adults and 258.9 ± 95.7 m in elderly (p < 0.001). After 42.9 ± 14.1 months follow up, mortality was 8.2% in adults and 10.9% in elderly (p = 0.176, NS). Cox regression analysis shows that EF ≥ 50% and 6MWT ≥300 m are protective on mortality in all CABG patients before CR. However, EF ≥50% in adults (HR 0.18, 95% CI 0.06-0.49, p < 0.005) but not in elderly (HR 1.16, 95% CI 0.45-3.42, p = 0.354, NS) and 6MWT ≥300 m in elderly (HR 0.34, 95% CI 0.10-0.79, p = 0.033) but not in adults (HR 0.76, 95% CI 0.31-2.12, p = 0.654, NS) exert a protective role on mortality. CONCLUSIONS: Our results indicate that both EF ≥ 50% and 6MWT ≥ 300 m independently protect against mortality in CABG patients before CR. However, their protective role is age dependent. In fact, EF ≥ 50% is protective in adults but not in elderly while 6MWT ≥ 300 m is protective in elderly but not in adult patients.

Joint effect of physical activity and body mass index on mortality for acute myocardial infarction in the elderly: role of preinfarction angina as equivalent of ischemic preconditioning.

BACKGROUND: Preinfarction angina (PrA), clinical equivalent of ischemic preconditioning, confers protection against in-hospital mortality for acute myocardial infarction (AMI) in adult but not in elderly patients. This study aims to examine the interaction between physical activity and body mass index (BMI) in preserving the cardioprotective effect of PrA in elderly patients with AMI. DESIGN: Elderly patients (>/=65 years old) with AMI admitted to Coronary Care Unit. METHODS: Elderly patients with AMI were retrospectively stratified for the presence and absence of PrA, and for quartiles of BMI and physical activity. In-hospital outcomes (death, cardiogenic shock, and reinfarction and creatine kinase-MB peak) were evaluated. RESULTS: In-hospital mortality of 1014 elderly patients with AMI was 19.2% in those with PrA and 22.7% in those without (P=0.18, NS). Mortality further decreased with increased physical activity and reduced BMI, a trend that was not observed in patients without PrA. When physical activity and BMI were considered together, lowest in-hospital mortality was observed in patients with highest physical activity and normal BMI (from 18.2 to 9.6%; P<0.01) with the greatest reduction observed in patients with PrA (from 18.3 to 5.1%; P=0.02). Multivariate analysis showed that PrA did not exert a protective effect in all patients irrespective of physical activity and BMI. A protective role was, however, observed in patients with highest physical activity or normal BMI and reached a maximum protective role in patients who showed both highest physical activity and normal BMI [odds ratio=0.08; 95% confidence interval=0.02-0.72; P<0.01]. CONCLUSION: The cardioprotective effect of PrA was preserved in elderly patients who showed the highest physical activity and a normal BMI.

Hypermagnesemia predicts mortality in elderly with congestive heart disease: relationship with laxative and antacid use.

The aim of this study was to evaluate the role of magnesium levels on 3-year survival in the elderly with congestive heart failure (CHF) admitted to the Rehabilitative Cardiology Unit of S. Maugeri Foundation Scientific Institute of Telese/Campoli. All elderly patients > or = 65 years old with a diagnosis of CHF underwent clinical and instrumental examination, and their demographics, co-morbidity, and in-hospital and 3-year mortality rates were recorded. Hypomagnesemia was found in 4.8%, normomagnesemia in 67.5%, and hypermagnesemia in 27.8% of subjects. The hypomagnesemic group was excluded for numerical exiguity; the analysis was performed on a total of 199 elderly patients. Hypermagnesemia was found in 29.1% and normomagnesemia in 70.9%. At the univariate analysis no differences were found in hypermagnesemia in respect to normomagnesemia group, except for slightly higher levels of creatininemia (1.35 +/- 0.61 vs. 1.13 +/- 0.55 mg/dL, respectively; p < 0.02), greater disability (lost ADL, 2.69 +/- 1.57 vs. 2.15 +/- 1.56, respectively; p < 0.05), more mortality for CHF (32.6 vs. 48.3%; p < 0.05), and higher antacid and laxative use (82.7 vs. 24.8%, respectively; p < 0.0001). Patients with higher magnesium showed less probability to survive at a 3-year follow-up than did patients with lower levels (17.32 +/- 15.93 vs. 22.46 +/- 16.16 months; p < 0.05), and this finding remained significant in the multivariate analysis after adjusting for some confounders. Finally hypermagnesemia should also be considered in the absence of pre-existing renal failure clinical evidence because of its negative prognostic value, especially in elderly patients with CHF. The shown relationship between hypermagnesemia and laxative/antacid use should induce physicians to pay more attention to abuse of these drugs.

Effect of losartan in treatment of exercise-induced myocardial ischemia.

Because no controlled clinical studies are available about the possible role of angiotensin II receptor blockers in preventing effort myocardial ischemia, we evaluated the effect of angiotensin II receptor blocker/losartan in preventing exercise-induced myocardial ischemia in patients with coronary artery disease. Twenty-four sedentary patients with chronic stable ischemia were prospectively randomized to 28 days (double blind) of losartan 100 mg or losartan placebo in 2 divided doses. In each patient the treatment was crossed over to the alternative regimen (28 days, double blind) after a 1-week placebo period (single blind). At the end of each phase a new exercise stress test was performed. At baseline, systolic blood pressure was significantly decreased after losartan 100 mg compared with losartan placebo. At submaximal exercise, systolic blood pressure and rate-pressure product were lower after losartan 100 mg administration compared with losartan placebo, and these findings remained significant at 1-mm ST depression and at peak exercise. Losartan 100 mg administration versus losartan placebo significantly delayed the time to 1-mm ST-depression onset and decreased ST-segment depression at peak exercise and time to recovery of ST-segment depression. Losartan 100 mg administration compared with losartan placebo was able to significantly increase exercise duration and maximal workload during exercise stress testing. In conclusion, in our study, losartan decreased electrocardiographic parameters of myocardial ischemia in patients with coronary artery disease, suggesting a possible role of this drug in treatment of patients with effort myocardial ischemia.

Insulin-induced changes in beta-adrenergic response: an experimental study in the isolated rat papillary muscle.

BACKGROUND: The aim was to investigate the ability of insulin to modulate the response to beta-adrenergic action on myocardial contractility, assessed as percentage changes of developed tension, in isolated rat papillary muscle. METHODS: Dose-response curves for isoproterenol, calcium, and forskolin were constructed in an incremental fashion with the presence or absence of insulin at the dose of 50 muU/mL. Dose-response curves for isoproterenol on insulin background were also assessed in the presence and absence of a selective antagonist for beta(2)-adrenoceptor, ICI, at the dose of 5 x 10(-8) mol/L. RESULTS: Insulin did not modify the dose-response curve to calcium (EC(50): 1.4 +/- 0.4 mmol/Lfor insulin, n = 8 v 1.5 +/- 0.3 mmol/L for control, n = 8; P = not significant), whereas it was able to shift to the left the dose-response curve and reduce significantly the EC(50) of isoproterenol (EC(50): 0.2 +/- 0.2 nmol/L for insulin, n = 13 v 1.1 +/- 0.4 nmol/L for control, n = 12; P < .01). ICI shifted to the right dose-response curve of isoproterenol and increased about 10-fold the EC(50) value of isoproterenol, but insulin was still able to shift to the left dose-response curve of isoproterenol and to reduce significantly the EC(50) of isoproterenol also in the presence of ICI (EC(50): 11.0 +/- 1.5 nmol/L for ICI, n = 7 v 1.9 +/- 0.8 nmol/L for ICI + insulin, n = 7; P < .01). Insulin did not modify the dose-response curve to forskolin. CONCLUSIONS: Our results suggest that the insulin-induced modulation of contractility is calcium independent and insulin leads to a supersensitization on the beta(1)-adrenoceptors without effects on beta-adrenoceptor independent adenylate cyclase-related pathway.

Mortality and blood pressure in elderly people with and without cognitive impairment.

BACKGROUND: Controversial data are available on the association between mortality, blood pressure and cognitive impairment in the elderly. OBJECTIVE: To verify the role of blood pressure on mortality in an elderly population with and without cognitive impairment. METHODS: A cross-sectional survey with a 6-year mortality evaluation was conducted in a region of southern Italy in elderly subjects with and without cognitive impairment. Subjects were divided into 4 groups on the basis of systolic, diastolic, mean and pulse blood pressure values. RESULTS: Mortality shows a linear relationship with pulse blood pressure and a U-curve shape for diastolic blood pressure. This phenomenon was more evident in subjects with cognitive impairment showing the greatest risk of mortality at the lowest and highest levels of diastolic blood pressure. CONCLUSION: The study shows that mortality increases linearly with increasing blood pressure in the elderly. In contrast, mortality shows a U-shape curve for diastolic blood pressure; cognitively impaired patients with the lowest and highest diastolic blood pressures show the greatest relative risk of mortality.

Angiotensin II-receptor antagonist losartan does not prevent nitroglycerin tolerance in patients with coronary artery disease.

The study evaluated the effect of Losartan in preventing nitrate tolerance during continuous transdermal nitroglycerin (TD-GTN) therapy in patients with coronary disease. Fifteen subjects with chronic stable ischemia evaluated by exercise test, were randomized to 28 days of TD-GTN 20 mg once a day without free interval plus Losartan 100 mg or Losartan-placebo with a double blind crossover design. Myocardial ischemic parameters during stress test were evaluated after each test period and results of Losartan therapy were compared to those with placebo. Time to onset 1 mm ST-depression was significantly higher after acute TD-GTN 20 mg with respect to placebo run-in, sustained TD-GTN 20 mg plus Losartan 100 mg or Losartan-placebo (p < 0.001). ST-depression at peak exercise and time to recovery of ST segment were markedly lower after acute TD-GTN 20 mg compared to placebo run-in (p < 0.05), sustained TD-GTN 20 mg plus Losartan 100 mg (p < 0.001) or Losartan-placebo (p < 0.05). At 1 mm-ST depression and at peak exercise, systolic blood pressure and rate-pressure product significantly decreased after sustained TD-GTN 20 mg plus Losartan 100 mg (p < 0.001, p < 0.05 respectively) with respect to placebo run-in, acute and sustained TD-GTN 20 mg plus Losartan-placebo. Moreover at peak exercise, these data were also observed after acute TD-GTN 20 mg compared to placebo run-in and sustained TD-GTN 20 mg plus Losartan-placebo (p < 0.001). The AT(1) antagonist Losartan administration does not prevent the development of nitrate tolerance during continuous TD-GTN therapy.

Cardioprotective effect of ischemic preconditioning is preserved in food-restricted senescent rats.

Ischemic preconditioning (PC) has been proposed as an endogenous form of protection against-ischemia reperfusion injury. We have shown that PC does not prevent postischemic dysfunction in the aging heart. This phenomenon could be due to the reduction of cardiac norepinephrine release, and it has also been previously demonstrated that age-related decrease of norepinephrine release from cardiac adrenergic nerves may be restored by caloric restriction. We investigated the effects on mechanical parameters of PC against 20 min of global ischemia followed by 40 min of reperfusion in isolated hearts from adult (6 mo) and "ad libitum"-fed and food-restricted senescent (24 mo) rats. Norepinephrine release in coronary effluent was determined by high-performance liquid chromatography. Final recovery of percent developed pressure was significantly improved after PC in adult hearts versus unconditioned controls (85.2 +/- 19% vs. 51.5 +/- 10%, P < 0.01). The effect of PC on developed pressure recovery was absent in ad libitum-fed rats, but it was restored in food-restricted senescent hearts (66.6 +/- 13% vs. 38.3 +/- 11%, P < 0.05). Accordingly, norepinephrine release significantly increased after PC in both adult and in food-restricted senescent hearts, and depletion of myocardial norepinephrine stores by reserpine abolished the PC effect in both adult and in food-restricted senescent hearts. We conclude that PC reduces postischemic dysfunction in the hearts from adult and food-restricted but not in ad libitum-fed senescent rats. Despite the possibility of multiple age-related mechanisms, the protection afforded by PC was correlated with increased norepinephrine release, and it was blocked by reserpine in both adult and food-restricted senescent hearts. Thus caloric restriction may restore PC in the aging heart probably via increased norepinephrine release.

Efficacy of transdermal nitroglycerin patches evaluated by dipyridamole-induced myocardial ischemia in patients with coronary artery disease. Comparison between continuous and intermittent schedule.

Nitrate tolerance remains a problem despite an enormous number of studies on this phenomenon. The aim of the present study was to compare the efficacy of nitroglycerin transdermal patches intermittently or continuously administered to patients with myocardial ischemia evaluated by the echocardiography dipyridamole stress test. We prospectively studied 34 coronary patients with stable myocardial ischemia. A double-blind, randomized, crossover study technique was used. After a run-in period (1 week) they underwent a dipyridamole stress test to evaluate nitrate responsiveness and then were randomized to 1 week of transdermal nitroglycerine 20 mg/24 h (two patches of 10 mg/24) administered either intermittently or continuously for 1 week. During the following week all patients were given placebo. In the final week, therapy was crossed over the alternate regimen. No significant changes in heart rate, systolic and diastolic blood pressure and rate-pressure product were observed at basal conditions and at peak of dipyridamole infusion among patients after placebo run-in period, after acute, 1 week of intermittent and 1 week of continuous nitroglycerine administration. At peak of dipyridamole infusion after acute administration of nitrate we observed a significant decrease in wall motion score index with respect to placebo. This pattern was similar during intermittent, but not continuous, patch therapy (p < 0.001). Our results suggest that transdermal nitroglycerin patches are an effective anti-ischemic medication, in reducing transient myocardial ischemia induced by dipyridamole. This anti-ischemic effect is lost when an overnight nitrate free dose interval is not used. Moreover the dipyridamole echocardiographic stress test, besides evaluating myocardial ischemia-induced wall motion abnormalities, is adequate to assess both the efficacy and the tolerance of transdermal nitrate therapy.