Safety of tooth extraction in patients receiving direct oral anticoagulant treatment versus warfarin: a prospective observation study.

The aim of this study was to compare the safety of tooth extraction in patients receiving direct oral anticoagulants (DOACs) or warfarin without cessation of their antithrombotic treatment. This prospective observational study included 367 patients undergoing tooth extraction (119 receiving DOACs and 248 receiving warfarin). All extractions in DOAC patients were performed 6-7h after taking DOACs in consideration of the half-life in blood under continued antithrombotic treatment. To examine the potential postoperative bleeding risk related to the time of extraction and the drug concentration of blood, activated partial thromboplastin time (APTT) in dabigatran and prothrombin time (PT) in rivaroxaban were measured three times after administration. A total of 390 tooth extractions were performed: 128 in the DOAC patients and 262 in warfarin patients. Postoperative bleeding occurred in four extractions (3.1%) in the DOAC group and in 23 (8.8%) in the warfarin group. There was no statistically significant difference between the two groups (odds ratio: 2.362, 95% confidence interval (CI) 0.819-6.815, p=0.112). APTT and PT prolongation in almost all cases decreased with time after taking the medicine. Our findings suggest that interruption of DOAC therapy is not necessary for tooth extraction if the procedure is performed at least 6h after the last dose.

Integrative effects of nitric oxide and endothelium-derived hyperpolarizing factor induced by acetylcholine and bradykinin in rat hindquarter perfusion.

We investigated the roles of endothelium-derived vasodilative factors in rat hindquarter perfusion using a system for the direct measurement of nitric oxide (NO). Acetylcholine (ACh) induced the dose-dependent release of NO with a concomitant decrease in perfusion pressure. Under the influence of N(G)-monomethyl-l-arginine (l-NMMA), NO release in response to ACh was blocked, while the perfusion pressure still decreased. In the presence of tetraethylammonium (TEA), the decrease in perfusion pressure in response to ACh was attenuated compared to the control value. The decrease in perfusion pressure in response to ACh was almost abolished in the presence of both l-NMMA and TEA or with deendothelialization. Bradykinin (BK) also induced NO release and biphasic effects on the perfusion pressure. The perfusion pressure decreased with a lower concentration of BK and increased with a higher concentration. l-NMMA and TEA each abolished the decrease in perfusion pressure induced by BK. Furthermore, in the presence of both l-NMMA and TEA, the perfusion pressure actually increased in response to BK. These results suggest that ACh and BK induce vasodilation through NO release and a potassium channel dependent mechanism via endothelium.

Effect of magnesium deficiency on autonomic circulatory regulation in conscious rats.

A close relationship between magnesium and cardiovascular function has been reported; however, the effect of magnesium deficiency on autonomic cardiovascular regulation has not been clarified. We investigated the effect of magnesium deficiency on the autonomic regulation of oscillations of the R-R interval, arterial blood pressure (BP), and renal sympathetic nerve activity (RSNA) by using the maximum entropy method in conscious rats. Its effect on baroreflex control of RSNA and heart rate were also investigated with a logistic function curve. Mean BP in magnesium-deficient rats was higher than that in control rats (mean+/-SE, 114.0+/-4.3 versus 101.6+/-3.4 mm Hg; P<0.05), and urinary excretion of catecholamine was increased by 2.4-fold. The fraction of low-frequency oscillation of RSNA was reduced (31.7+/-0.9% versus 36.2+/-1.5%, P<0.05) and the correlation between low-frequency oscillations of BP and RSNA was weakened in magnesium-deficient rats. There was no difference in high-frequency oscillation of the R-R interval, which is related to vagal tone, whereas sympathetic tone became dominant (square root of low-frequency/high-frequency ratio of R-R interval, 1.00+/-0.05 versus 0.67+/-0.05, P<0.0001) in magnesium-deficient rats. The maximal gain in the BP-RSNA relation tended to be reduced in magnesium-deficient rats (-7.7+/-1.1% versus -12.2+/-1.9%/mm Hg, P=0. 07); however, that in the BP-heart rate relation was increased (-8. 1+/-0.7 versus -4.5+/-0.5 bpm/mm Hg, P<0.01). These results suggest that magnesium deficiency induces sympathetic excitation, which results in hypertension but attenuates the baroreflex-related response of sympathetic nerves, whereas magnesium deficiency enhances the sensitivity of the sinus node to autonomic regulation.

Brainstem mechanisms of autonomic dysfunction in encephalopathy-associated Shiga toxin 2 intoxication.

Acute encephalopathy is the major determinant of death in an early stage of Shiga toxin (Stx)-producing Escherichia coli infection. Rapid progress toward refractory hypotension and dysfunction of breathing implies autonomic center dysfunction of patients. To clarify whether autonomic dysfunction becomes an ultimate cause of death in Shiga toxemia, we injected purified Stx2 (20 microg/kg) intravenously into rabbits, and monitored changes in cardiovascular and respiratory function together with renal sympathetic nerve activity (RSNA) in the conscious state. After an approximately 24-hour silent (lag) period, all rabbits given Stx2 developed hemorrhagic diarrhea (25.7 +/- 1.1 hours) and limb paralysis (31.2 +/- 1.3 hours). This limb paralysis was observed initially in the hind legs, and then it gradually extended to the forelegs. After 23.2 +/- 2.3 hours, RSNA increased gradually, and arterial blood pressure was maintained within normal limits together with an increase in the maximum gain of baroreflex response. Severe hypotension developed within 34.8 +/- 2.2 hours, without any increase in heart rate; RSNA significantly increased by 39.5 +/- 0.9 hours. In the final stage, RSNA decreased concurrently with decreases in arterial blood pressure, heart rate, and baroreflex response, suggesting dysfunction of the baroreflex control system. Thereafter, all rabbits died within 47.8 +/- 1.2 hours after the intravenous Stx2 injection. Magnetic resonance imagings of the central nervous system (T2-weighted images) showed high-intensity areas in the dorsal two-thirds of the cervical spinal cord and brainstem 48 hours after Stx2 administration. These results show that the cause of death is circulatory failure caused by impairment of the cardiovascular center in the medulla. We believe that this animal model helps to clarify the mechanism of rapid progress to death of patients with Shiga toxin-producing E. coli infection.

Antioxidant function of the mitochondrial protein SP-22 in the cardiovascular system.

The mitochondrial protein SP-22 has recently been reported to be a member of the thioredoxin-dependent peroxide reductase family, suggesting that it may be one of the antioxidant systems in mitochondria, which are the major site of reactive oxygen intermediate generation. The aim of this study was to examine whether SP-22 is involved in mitochondrial antioxidant mechanisms and whether its expression is induced by oxidative stresses, particularly those in mitochondria. The expression of SP-22 protein was enhanced by about 1.5-4.6-fold when bovine aortic endothelial cells (BAEC) were exposed to various oxidative stresses, including mitochondrial respiratory inhibitors which increased the superoxide generation in BAEC mitochondria. The expression of SP-22 mRNA increased 2.0-3.5-fold with a peak at 3-6 h after exposure to Fe2+/dithiothreitol or a respiratory inhibitor, antimycin A. BAEC with an increased level of SP-22 protein caused by pretreatment with mild oxidative stress became tolerant to subsequent intense oxidative stress. On the other hand, BAEC that had been depleted of SP-22 with an antisense oligodeoxynucleotide against SP-22 mRNA became more labile to oxidative stress than control BAEC. The induction of SP-22 protein by oxidative stress in vivo was demonstrated in an experimental model of myocardial infarction in rat heart. These findings indicate that SP-22 functions as an antioxidant in mitochondria of the cardiovascular system.

Effects of systemic hypoxia on R-R interval and blood pressure variabilities in conscious rats.

The effects of systemic hypoxia with different levels of CO2 on R-R interval (RRI) and systolic blood pressure (SBP) variabilities were investigated in conscious rats. Wistar rats chronically instrumented for the measurement of blood pressure, electrocardiogram, and renal sympathetic nerve activity (RSNA) were exposed to hypocapnic (Hypo), isocapnic (Iso), and hypercapnic (Hyper) hypoxia. On another day, the rats were treated with atropine and exposed to the same type of hypoxia. Sinoaortic denervation (SAD)-treated rats were exposed to Iso and Hyper, and RRI and SBP variabilities before and during hypoxia were analyzed using the maximum-entropy method with high resolution. With regard to RRI variability, very low frequency (VLF), low frequency (LF), and high frequency (HF) powers all decreased during Hypo, increased during Hyper, and did not change during Iso in intact rats. Changes during Hypo were attenuated by atropine, and those during Hyper were abolished by either atropine or SAD. The ratio of LF power to HF power decreased independently of increases in RSNA during each type of hypoxia. On the other hand, there were no changes in VLF, LF, or HF power in SBP variability during each type of hypoxia in intact rats. In atropine-treated rats, LF power increased during Iso and Hyper and HF power increased during each type of hypoxia. There was no difference in respiratory frequency among the three kinds of hypoxia in both intact and atropine-treated rats. The results suggest that arterial PCO2 level rather than respiration frequency produces changes in powers of RRI variability through changes in parasympathetic nerve activity and that with regard to SBP variability, parasympathetic nerve activity masks changes in LF power that reflect an increase in RSNA and those in HF power that reflect a mechanical consequence of respiration.

Effects of lidocaine and diltiazem on recovery of electrophysiologic activity during partial reperfusion following severe myocardial ischemia in canine hearts.

The effects of lidocaine and diltiazem on recovery of electrophysiologic activity during partial reperfusion following severe myocardial ischemia were investigated in 28 dogs. The left anterior descending artery was ligated, and the distal end was connected to the carotid artery. Myocardial ischemia was induced by retrograde blood flow for 10 minutes, after which flow-limited reperfusion (30-60% of the coronary flow before ischemia) was performed. The dogs were divided according to the agent administered before ischemia into the following three groups: saline (group S, n = 11); lidocaine (group L, n = 8, 0.07 mg/kg/min by intravenous drip infusion following 2 mg/kg intravenous injection); and diltiazem (group D, n = 9, 0.02 mg/kg/min by intravenous drip infusion. There were no significant differences among the three groups in the incidence of ventricular tachyarrhythmia, which occurred as ventricular tachycardia (VT) or ventricular fibrillation (VF). In each group, the occurrence of VT was frequently preceded by delayed potential which was initiated after reperfusion, with depressed conduction in the epicardium, suggesting reentry (82%, 96%, and 87%, not significant). The determining factors for VT with degeneration into VF were long duration of VT in groups S and L (VT with degeneration into VF vs VT without, 1.2 +/- 0.2 seconds vs 0.6 +/- 0.1 seconds, P < .05, in group S and 11.6 +/- 2.5 seconds vs 2.2 +/- 0.4 seconds, P < .05, in group L), and decrease in average R-R interval during VT in groups L and D (195 +/- 8 ms vs 313 +/- 17 ms, P< .01, in group L and 201 +/- 11 ms vs 327 +/- 28 ms, P< 0.01, in group D). In addition, occurrence of epicardial electrophysiologic activity with reduced time from onset of the QRS complex in the surface electrocardiogram to the onset of the activity during VT preceded VF in group L (VT with degeneration into VF vs VT without, 130.0 +/- 15.1 ms vs 185.8 +/- 21.4 ms, P < .05), while that with prolongation of the time had this effect in group D (116.0 +/- 15.7 ms vs 69.0 +/- 10.7 ms, P < .05). It is concluded that, even when partial reperfusion is applied, neither lidocaine nor diltiazem suppresses VT because neither drug decreases delayed potential acting as a triggering factor or suppresses VF, since the alteration of the epicardial conductivity during VT can change the VT circuit to a smaller one.

Effects of lidocaine and diltiazem on ventricular tachyarrhythmia and dispersion of conduction during severe myocardial ischemia in canine hearts.

The purpose of this study was to investigate the effects of lidocaine and diltiazem on ventricular tachyarrhythmia and dispersion of conduction during severe myocardial ischemia in dogs. Myocardial ischemia was produced by a 10-min occlusion of the left anterior descending artery by the retrograde blood flow technique. Saline, lidocaine, and diltiazem were infused intravenously before and during occlusion in groups A (n = 16), B (n = 22) and C (n = 13), respectively. The incidence of ventricular tachycardia (VT) consisting of ten or more VPC was 19% in group A, 73% in group B and 31% in group C (A vs. B, P < 0.01), and that of ventricular fibrillation (VF) was 31%, 64%, and 15%, respectively (A vs. B, P < 0.05). The time of the onset of VT preceding VF was shorter in group B than in group A (207.9 +/- 13.9 vs. 353.2 +/- 70.7 sec, P < 0.05). The time taken to reach maximal dispersion of conduction delay in the epicardium was shorter in group B than in group A (192.1 +/- 11.9 vs. 337.5 +/- 38.2 sec, P < 0.01), and the dispersion of conduction delay in the intramyocardial layers was smaller in group B than in group A (229.9 +/- 24.5 vs. 360.0 +/- 35.6 sec, P < 0.01). The time taken to reach maximal dispersion of conduction delay in the endocardium was greater in group C than in group A (400.8 +/- 38.8 vs. 274.4 +/- 23.9 sec, P < 0.01). However, there were no significant differences among the three groups with regard to the maximal dispersion of conduction delay in the epicardium, in the endocardium, or intramyocardial layer. These results suggest that lidocaine increased ventricular tachyarrhythmia due to an acute increase in dispersion of conduction in the epicardium and intramural layer, and that diltiazem was not effective in preventing ventricular tachyarrhythmia and did not affect the dispersion of conduction in the epicardium or intramural layer despite improvement in the endocardium.

Complete atrioventricular block during left heart catheterization.

A 75-year-old male underwent cardiac catheterization for frequent ventricular premature contractions and reduced left ventricular function. ECG on admission showed complete right bundle branch block (RBBB) and left anterior hemiblock. Right heart catheterization was performed uneventfully, but complete atrioventricular block (CAVB) occurred suddenly when a pig-tail catheter was inserted into the left ventricle. Electrophysiological study identified this CAVB as HV block, and demonstrated HV prolongation in sinus rhythm. The coronary angiogram revealed no obstructive lesion or spasm with ergonovine. The reproducibility of the CAVB was demonstrated. The final CAVB developed and persisted for more than one week, requiring the implantation of a permanent pacemaker (DDD). Complete atrioventricular block induced during left heart catheterization is very rare. Pre-existing RBBB with left anterior or posterior hemiblock and reduced left ventricular function may be common factors in patients with this condition. Emergency pacing equipment should always be on-line when left heart catheterization is conducted in such patients.