Mechanisms of nitrate tolerance

Summary There is now little dispute that clinical tolerance of organic nitrates occurs, particularly when these drugs are used by themselves to treat patients with stable angina pectoris and congestive heart failure. Classical hypotheses of nitrate tolerance suggest the phenomenon to result from vascular depletion of critical sulfhydryl groups, which are necessary to bring about vasorelaxation from nitrates. While this mechanism of nitrate tolerance probably operates when isolated blood vessels are exposed to high concentrations of nitrate in vitro, there is little evidence to suggest that it contributes to clinical nitrate tolerance. Instead, emerging data suggest that nitrates can cause significant shifts in fluid distribution and secretion of neurohormonal factors that can modulate their vasorelaxant effects. use of angiotensin converting enzyme inhibitors and diuretics in conjunction with nitrates may alleviate the development of tolerance, but the experience has not been universally favorable. Other receptor-effector systems that affect cardiovascular function, such as the adrenergic system, may also be affected by nitrate tolerance. The mechanisms of nitrate tolerance are therefore likely to be multifactorial, involving vascular biochemical changes, physiologic compensation, and possibly receptor regulation.     

Ointments and transdermal nitroglycerin patches for stable angina pectoris

Summary Nitroglycerin (NTG) ointment is used for the prophylaxis against angina pectoris, but there are no data to support its effectiveness during long-term therapy. Continuous, once-daily application of isosorbide dinitrate cream produces tolerance with complete loss of efficacy within 1 week. Nitroglycerin patches are very popular and continuous once-daily application is still claimed by some investigators to provide 24 hour antiischemic and antianginal efficacy. This claim is based on data from postmarketing studies in a very large number of patients and placebo-controlled studies in smaller groups of patients from Italy, Yugoslavia, Greece, and Germany. In contrast, studies from the United States, Canada, England, and some centers in Germany have failed to show superiority of patches over placebo during continuous therapy. This controversy was addressed by the NTG cooperative study group, in which a total of 562 patients who were responders to sublingual nitroglycerin were studied. Patients received either placebo or NTG patches delivering low (15–30 mg/24 hr), moderate (45–60 mg/ 24 hr), or large (75 and 105 mg/24 hr) amounts of NTG. Four hours after the initial application, NTG patches increased exercise duration compared to placebo, but this beneficial effect had disappeared by 24 hours. Furthermore, after 8 weeks of continuous therapy, none of the NTG patches were superior to placebo, whether patients were or were not taking concomitant beta-blockers. Therefore, current opinion is that continous therapy with NTG patches produces pharmacologic tolerance and is ineffective. Pharmacologic tolerance can be minimized when patches are applied every morning and removed after 10–12 hours at night. However, patches delivering >15 mg NTG/24 hr are required to maintain an increased exercise duration for up to hour 8 after the patch application. Intermittent therapy with patches, however, may lead to rebound nocturnal angina in some patients. Also, intermittent therapy with patches has been associated with worsening of exercise performance in the morning prior to the patch renewal, compared to therapy with placebo patches. This has been referred to as the zero-hour effect and probably represents a rebound phenomenon following nitrate withdrawal. Patients experiencing either nocturnal or early morning angina during intermittent therapy with patches should either be switched to oral long-acting nitrates or should in addition be treated with a beta-blocker, provided there are no contraindications to beta-blocker treatment.The opinions expressed here are those of the authors and should not be taken as those of FDA.     

Once- versus twice-daily administration of controlled-release isosorbide-5-mononitrate 60 mg in the treatment of stable angina pectoris: A randomized, double-blind, cross-over study

Thirty-seven patients with chronic, stable angina pectoris wereincluded in a randomized, double-blind cross-over study to assessthe efficacy of once- and twice-daily dosage regimens of 60mg isosorbide-5-mononitrate, in a controlied release formulation(5-ISMN Durules^® Astra). After 2 weeks of treatment, duringa symptom-limited bicycle ergometer exercise test performed3 h after the dose, the time to 1 mm ST segment depression wasobserved to be longer by once-daily than by a twice-daily dosageregimen (614 ± 165 vs 561 ± 148 s, P<0·01).The time to the end of exercise was also significantly prolongedby once-daily dosage, as compared with placebo (693 ±158 and 645 ± 173 s, respectively; P<0·05),which was not observed with the twice-daily regimen. Both dosageregimens still had a significant effect on the prolongationof the time to onset of angina 9 h after the dose: 420 ±164 s by placebo, 492 ± 161 s by once-daily dosage; P<0·01and 466 ± 154 s by twice-daily dosage; P<0·05.Anginal attack rate and nitroglycerin consumption was significantlylower during the once-daily dosage period as compared with placebo;this difference was not evident during the twice-daily administrationof the drug. Controlled-release 5-ISMN 60 mg given once daily was effectivein angina pectoris patients for at least 9 h after the doseand showed no clinical signs of tolerance after 2 weeks of thetreatment. Attenuation of the clinical effect was observed withthe twice-daily (in 12 h intervals) dosage regimen, presumablycaused by constantly high 5-ISMN plasma concentration.     

Bicoronary-pulmonary fistulae with coexistent mitral valve prolapse: a case report and literature review of coronary-pulmonary fistula

Bicoronary-pulmonary artery fistulae are rare congenital coronaryartery fistulae. We report the case of a 57-year-old man whopresented with biventricular failure and angina pectoris. Atangiography the coronary arteries were normal, but bicoronary-pulmonaryfistulae were noted; severe mitral regurgitation secondary tomitral valve prolapse was also present. At right heart catheterizationthe calculated left to right shunt was 2.1. Fistula ligationand repair of both mitral and tricuspid valves was undertaken.The literature regarding coronary-pulmonary fistula is alsoreviewed.     

Electrophysiologic Basis for T Wave Alternans as an Index of Vulnerability to Ventricular Fibrillation

Electrophysiologic Basis for T Wave Alternans. Substantial evidence indicates that T wave alternans is an intrinsic property of ischemic myocardium. The electrophysiologic basis appears to be spatial and temporal heterogeneity of repolarization resulting from changes in action potential morphology rather than in activation sequence. Ischemia-induced changes in postrepolarization refractoriness and depressed electrical restitution of action potential duration have also been implicated. The main underlying ionic basis for T-wave alternans during coronary occlusion appears to be derangements in intracellular cycling of calcium. Accumulation of potassium in the extracellular space adjoining ischemic cells and disruption in electro-genie sodium-calcium exchange may also be involved. In humans, T wave alternans has been observed in Prinzmetal's and classical angina, angioplasty, and bypass graft occlusion. Under these conditions associated with acute myocardial ischemia, alternans is restricted to the ischemic zone, and alternation in action potential morphology is an underlying factor. Recently, repolarization alternans has been shown to be a statistically significant predictor of the results of electro physiologic testing and arrhythmia-free survival in individuals with and without organic heart disease. Collectively, these observations provide a rationale for quantitation of T-wave alternans magnitude for assessment of vulnerability to life-threatening ventricular arrhythmias both in response to and independent of the effects of myocardial ischemia.     

稳定性心绞痛在骨科关节置换术后致心血管意外的表现

目的研究分析稳定性心绞痛患者经骨科关节置换术治疗致心血管意外的相关因素。方法选取2016年3月—2017年12月本院接收的68例稳定性心绞痛患者作为研究对象。所有患者均经骨科关节置换术治疗,采用Logistic回归模型对心血管意外相关因素进行分析。结果多因素分析显示冠心病合并肥胖、冠心病合并高血压、冠心病合并糖尿病、心功能Ⅱ～Ⅲ级是患者行关节置换术诱发心血管意外的独立危险因素。结论行关节置换术的稳定性心绞痛患者若冠心病合并肥胖、冠心病合并糖尿病、Ⅱ级<心功能<Ⅲ级,会增加心血管意外的发生风险,临床应加大重视度,对患者进行细致、全面观测,严防心血管意外事件发生。     

Probability of a return to work after either coronary balloon dilatation or coronary bypass surgery

To examine whether coronary angioplasty has a different effect on work resumption than has coronary artery bypass surgery, we studied the work status of patients before and at least 1 year after either intervention. The population consisted of men aged less than 60 years, submitted to these procedures from September 1983 to July 1984. Of the 261 eligible patients, 219 (84%) participated, 94 after an angioplasty and 125 after a bypass procedure. 6 months preceding the intervention, 52% of the men were working. This had decreased to 47% at follow-up. Multiple logistic regression analysis showed that failure to resume work was correlated with bypass surgery vs balloon dilatation (rate ratio 1.8; 95% CI, 1.0-3.4), not working beforehand (rate ratio 6.5; 1.2-4.3), age greater than 55 years vs less than or equal to 50 years (rate ratio 2.6; 1.3-5.4) and with angina at follow-up (rate ratio 1.8; 1.0-3.3). Taking these additional risk factors into account permits a prediction of the probability of a return to work.     

Thoracic epidural anaesthesia in patients with unstable angina pectoris

The effect of high thoracic epidural anaesthesia with intermittentepidural bolus injections of bupivacaine (2.5 or 5 mg ml^-1)was studied in 28 patients with unstable angina pectoris. Themajority of the patients had a history of previous acute myocardialinfarction(s) and/or angina pectoris and severe coronary arterydisease. All patients were treated wth nitroglycerin infusionfor gt;24 h and were included in the study if they had chestpain, not caused by acute myocardial infarction, at bed restor recurrent anginal pain at rest < 2 days after infarction.4.4 ± 0.3 ml of bupivacaine induced a blockade of theupper seven sympathetic segments ( Th_1-7) for 98 ± 9min.Heart rate decreased significantly from 70 ± 3 to 64± 3 beats min^-1 while blood pressure was unaffected bythoracic epidural anaesthesia. In 27 patients (96%) the anaesthesiainduced complete analgesia. Nitroglycerin infusion was discontinueddefinitely within 3 h in 26 patients (93%) and pain was thereaftercontrolled by means of thoracic epidural anaesthesia as thesole treatment in 23 patients (82%) and as the major treatmentin 25 patients (89%). Twenty-one patients (75%) were fully mobilizedand stabilized. Treatment with thoracic epidural anaesthesialasted for 6.0 ± 1.1 days. The number of daily epiduralinjections decreased significantly with time from 2.7 ±0.3the first day to 0.9 ± 0.3 the fourth day (P>0.01,n = 19). Two patients developed acute myocardial infarctionduring the anaesthesia treatment period, and one of these patientsdied. Exercise stress testing was performed on eight patients threeto five days after the start of thoracic epidural anaesthesia.At a comparable workload, ST-segment depression was significantly(P>0.05) less pronounced during anaesthesia ( – 0.6± 0.1 mm) compared with control ( – 1.3 ±0.2mm). The respective heart rate values were 95 ± 7and 107 ± 7 beats min ^-1 (P > 0.05), while systolicor diastolic blood pressure did not differ between the two conditions. We conclude that blockade of cardiac sympathetic afferents andefferents by means of thoracic epidural anaesthesia can effectivelytreat pain and stabilize patients with unstable angina pectorisrefractory to medical treatment. Furthermore, thoracic epiduralanaesthesia attenuates stress-induced myocardial ischaemia;thus, it may be an efficient supplementary treatment for thecontrol of pain and for stabilizing patients with unstable anginapectoris during diagnostic procedures and prior to coronarysurgery or angioplasty.     

Time Dependent Variations of Stimulus Requirements in Spinal Cord Stimulation for Angina Pectoris

The aim of the study was to observe changes over time of the stimulation requirements in spinal cord stimulation (SCS). Of 60 patients treated with SCS, 25 patients were selected because they had neurostimulators capable of measuring impedance noninvasively, and had not experienced electrode displacement. All 25 patients had Medtronic Pisces Quad 3487A (Medtronic, Inc.) neuroelectrodes with the tip positioned in the thoracic epidural space. The accuracy of the neurostimulators impedance measuring circuit was investigated in a test circuit. The error was < 11%. Stimulus requirements and impedance were recorded at the implantation and at follow-ups during a period of 24 months. During the first month after implantation, the stimulus requirements for satisfactory effect varied between +406% and -34%. After that period, only minor deviations were observed in most patients. To optimize the pain reducing effect of the spinal cord stimulation, frequent follow-ups are recommended during the first month; later on, the follow-up intervals can be extended. No tolerance development or pain resistance developed during SCS treatment     

普乐林注射液治疗心绞痛疗效观察

目的：观察普乐林注射液（主要成分为葛根素）对心肌缺血的治疗及改善作用。方法：选择１０２例冠心病稳定型心绞痛患者，应用普乐林注射液５０ｍｇ静滴治疗，每日１次，１０日为１个疗程。３０例患者治疗前后分别进行２４小时动态心电图检查，２０例患者治疗前后分别行运动平板试验检查。结果：治疗后显效１５例，有效６６例，总有效率为７９．４１％；治疗后３０例患者２４小时动态心电图ＳＴ段最大压低值明显减小〔治疗前为（２．９７±１．１６）ｍｍ，治疗后为（１．３４±０．８９）ｍｍ，Ｐ＜０．０１〕，２０例运动平板试验检查患者治疗后缺血型ＳＴ段改变出现时间明显延长〔治疗前为（３．７６±１．７８）分钟，治疗后为（５．８９±１．８７）分钟，Ｐ＜０．０１〕，治疗后缺血型ＳＴ段改变恢复时间缩短〔治疗前为（９．８６±１．３８）分钟，治疗后为（６．２７±１．４２）分钟，Ｐ＜０．０５〕。结论：普乐林注射液对冠心病稳定型心绞痛患者有较好的治疗作用，并可增加患者的运动耐受性。