Does preoperative dual antiplatelet therapy affect bleeding and mortality after total arch repair for acute type A dissection?

OBJECTIVES: Data are scarce and mixed regarding the impact of preoperative dual antiplatelet therapy (DAPT) on the surgical outcomes of acute type A aortic dissection (ATAAD). We seek to evaluate the impact of DAPT on bleeding-related events and early- and mid-term mortality after total arch replacement and frozen elephant trunk in such patients. METHODS: This study comprised 48 ATAAD patients on preoperative DAPT and 418 without DAPT (the whole series, i.e. unmatched cohort), from which 45 matched pairs were selected by propensity score (matched cohort). Bleeding-related events (reoperation for bleeding, bleeding of ≥1500 ml within the first 12 h postoperatively or transfusion of ≥10 units of red blood cell or use of recombinant activated factor VII), operative mortality and mid-term survival were compared in the unmatched and matched cohorts. The impact of preoperative DAPT was evaluated with multivariable analysis. RESULTS: In the unmatched cohort, bleeding of ≥1500 ml/12 h postoperatively was more common in the DAPT group (18.8% vs 8.4%, P = 0.020); operative mortality was 9.7%, which did not differ with DAPT (12.5% vs 9.3%, P = 0.48). Nor did bleeding-related events (54.2% vs 43.5%, P = 0.16) differ significantly between 2 groups. In the matched cohort, neither were drainage of ≥1500 ml/12 h (20% vs 6.7%, P = 0.063) and bleeding-related events (53.3% vs 42.2%, P = 0.30), nor operative mortality (13.8 vs 8.9%, P = 0.50) and mid-term survival (79.3% vs 76.4%, P = 0.93) significantly different between 2 groups. DAPT was not identified as a predictor for operative mortality [odd ratio (OR) 0.97, 95% confidence interval (CI) 0.31-3.08; P = 0.96; adjusted OR 1.28, 95% CI 0.22-7.20; P = 0.78] and bleeding-related events (OR 1.50, 95% CI 0.76-2.95; P = 0.24; adjusted OR 2.03, 95% CI 0.80-3.66; P = 0.14). CONCLUSIONS: In patients with ATAAD undergoing total arch replacement and frozen elephant trunk, although preoperative DAPT led to more postoperative bleeding, it did not increase bleeding-related events nor operative mortality nor mid-term death. The results of this study imply that for patients with ATAAD, emergency surgical repair, even if as extensive as total arch repair, should not be contraindicated or delayed simply because of ongoing DAPT.

Excess nicotinamide inhibits methylation-mediated degradation of catecholamines in normotensives and hypertensives.

Nicotinamide and catecholamines are both degraded by S-adenosylmethionine-dependent methylation. Whether excess nicotinamide affects the degradation of catecholamines is unknown. The aim of this study was to investigate the effect of nicotinamide on the methylation status of the body and methylation-mediated catecholamine degradation in both normotensives and hypertensives. The study was conducted in 19 normotensives and 27 hypertensives, using a nicotinamide-loading test (100 mg orally). Plasma nicotinamide, N(1)-methylnicotinamide, homocysteine (Hcy), betaine, norepinephrine, epinephrine, normetanephrine and metanephrine levels before and 5 h after nicotinamide loading were measured. Compared with normotensives, hypertensives had higher baseline (fasting) levels of plasma nicotinamide, Hcy and norepinephrine, but lower levels of plasma normetanephrine, a methylated norepinephrine derivative. Nicotinamide loading induced a significant increase in the levels of plasma N(1)-methylnicotinamide and norepinephrine, and a significant decrease in the levels of O-methylated epinephrine (metanephrine) and betaine, a major methyl donor, in both hypertensives and normotensives. Moreover, nicotinamide-loading significantly increased plasma Hcy levels, but decreased plasma normetanephrine levels in normotensives. The baseline levels of plasma epinephrine in hypertensives were similar to those of normotensives, but the post-nicotinamide-loading levels of plasma epinephrine in hypertensives were higher than those of normotensives. This study demonstrated that excess nicotinamide might deplete the labile methyl pool, increase Hcy generation and inhibit catecholamine degradation. It also revealed that hypertensives had an abnormal methylation pattern, characterized by elevated fasting plasma levels of unmethylated substrates, nicotinamide, Hcy and norepinephrine. Therefore, it seems likely that high nicotinamide intake may be involved in the pathogenesis of Hcy-related cardiovascular disease.

Nicotinamide overload may play a role in the development of type 2 diabetes.

AIM: To investigate whether nicotinamide overload plays a role in type 2 diabetes. METHODS: Nicotinamide metabolic patterns of 14 diabetic and 14 non-diabetic subjects were compared using HPLC. Cumulative effects of nicotinamide and N(1)-methylnicotinamide on glucose metabolism, plasma H(2)O(2) levels and tissue nicotinamide adenine dinucleotide (NAD) contents of adult Sprague-Dawley rats were observed. The role of human sweat glands and rat skin in nicotinamide metabolism was investigated using sauna and burn injury, respectively. RESULTS: Diabetic subjects had significantly higher plasma N(1)-methylnicotinamide levels 5 h after a 100-mg nicotinamide load than the non-diabetic subjects (0.89 +/- 0.13 micromol/L vs 0.6 +/- 0.13 micromol/L, P < 0.001). Cumulative doses of nicotinamide (2 g/kg) significantly increased rat plasma N(1)-methylnicotinamide concentrations associated with severe insulin resistance, which was mimicked by N(1)-methylnicotinamide. Moreover, cumulative exposure to N(1)-methylnicotinamide (2 g/kg) markedly reduced rat muscle and liver NAD contents and erythrocyte NAD/NADH ratio, and increased plasma H(2)O(2) levels. Decrease in NAD/NADH ratio and increase in H(2)O(2) generation were also observed in human erythrocytes after exposure to N(1)-methylnicotinamide in vitro. Sweating eliminated excessive nicotinamide (5.3-fold increase in sweat nicotinamide concentration 1 h after a 100-mg nicotinamide load). Skin damage or aldehyde oxidase inhibition with tamoxifen or olanzapine, both being notorious for impairing glucose tolerance, delayed N(1)-methylnicotinamide clearance. CONCLUSION: These findings suggest that nicotinamide overload, which induced an increase in plasma N(1)-methylnicotinamide, associated with oxidative stress and insulin resistance, plays a role in type 2 diabetes.

Effects of acute cooling/rewarming on membrane potential and K(+) currents in rat ventricular myocytes.

The effects of acute cooling/rewarming on cardiac K(+) currents and membrane potential were investigated. Membrane potential and current were assessed with whole-cell patch-clamp technique in current- and voltage-clamp modes. When the temperature of bath solution was decreased from 25 °C; to 4 °C, the transient outward current (I(to)) was completely abolished, the sustained outward K(+) current (I(ss)) at +60 mV and the inward rectifier K(+) current (I(K1)) at -120 mV were depressed by (48.5±14.1)% and (35.7±18.2)%, respectively, and the membrane potential became more positive. After the temperature of bath solution was raised from 4 °C; to 36 °C;, the membrane potential exhibited a transient hyperpolarization and then was maintained at a stable level. In some myocytes (36 out of 58), activation of the ATP-sensitive K(+) (K(ATP)) channels after rewarming was observed. The rewarming-induced change in the membrane potential was inhibited by the Na(+)/K(+)-ATPase inhibitor ouabain (100 µmol/L), and the rewarming-elicited activation of K(ATP) channels was inhibited by the protein kinase A inhibitor H-89 (100 µmol/L). Moreover, decrease of the temperature from 25 °C; to 4 °C; did not induce any significant change in cell volume when the cell membrane potential was clamped at 0 mV. However, significant cell shrinkage with spots was observed soon after rewarming-induced activation of K(ATP) channels. These data demonstrate that acute cooling/rewarming has a profound influence on the membrane potential and K(+) currents of ventricular myocytes, and suggest that activation of K(ATP) channels may play a role in cardiac cooling/rewarming injury.

Effects of monocarboxylic acid-derived Cl- channel blockers on depolarization-activated potassium currents in rat ventricular myocytes.

The effects of monocarboxylic acid-derived Cl(-) channel blockers on cardiac depolarization-activated K(+) currents were investigated. Membrane currents in rat ventricular myocytes were recorded using the whole-cell configuration of the patch-clamp technique. 5-Nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) and niflumic acid (NFA) induced an outward current at 0 mV. Both NPPB and NFA failed to induce any current when used intracellularly or after K(+) in the bath and pipette solutions was replaced by equimolar Cs(+). Voltage pulse protocols revealed that NPPB and NFA enhanced the steady-state K(+) current but inhibited the transient outward K(+) current. Genistein, a tyrosine kinase (PTK) inhibitor, inhibited NPPB- and NFA-induced outward current. Another PTK inhibitor, lavendustin A, produced a comparable effect. In contrast, the inactive analogue of genistein, daidzein, was ineffective. Orthovanadate, a tyrosine phosphatase inhibitor, markedly slowed the deactivation of the outward current induced by NPPB and NFA. The protein kinase A (PKA) inhibitor H-89 inhibited NPPB-induced outward current at 0 mV. In contrast, the protein kinase C (PKC) inhibitor H-7 was without significant effect on the action of NPPB. Pretreatment of the myocytes with genistein or H-89 prevented the enhancing effect of NPPB. Increasing intracellular Cl(-) from 22 to 132 mm slightly reduced NPPB-induced outward current at 0 mV. These results demonstrate that the monocarboxylic acid-derived Cl(-) channel blockers NPPB and NFA enhance cardiac steady-state K(+) current, and suggest that the enhancing effect of the Cl(-) channel blockers is mediated by stimulation of PKA and PTK signalling pathways.