Chemical defibrillation in acute myocardial ischaemia: a hypothesis.
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Analysis of Variance↗
Biomedical subjects
M J Curtis
Publications and source records attributed to M J Curtis.
Anions, membrane resistance and ventricular fibrillation.
Clinical success in prevention of sudden cardiac death has been poor. New approaches to prevention of ventricular fibrillation (VF), one of the main causes of sudden cardiac death, are clearly needed. In the present article we have reviewed some of our own data which support the notion that VF may be prevented by manipulation of chloride homeostasis. Our studies have revealed a novel approach to VF suppression via alteration of sarcolemmal membrane resistance.
Animals↗
Nupafant, a PAF-antagonist prototype for suppression of ventricular fibrillation without liability for QT prolongation?
BACKGROUND AND PURPOSE: PAF antagonists inhibit ischaemia-induced ventricular fibrillation (VF) in animals. However, unfavourable ancillary actions (on QT interval and coronary flow) have been reported with the PAF antagonist, BN-50739. If these are class actions, they would preclude development of PAF antagonists as novel anti-VF drugs. Our purpose was to examine this proposition using the hitherto untested PAF antagonist, nupafant. EXPERIMENTAL APPROACH: Two rat heart preparations (Langendorff and 'dual coronary' perfusion) were used to assay nupafant's effects on ischaemia-induced VF, coronary flow and QT interval, and to test for the site-selectivity necessary if any effects on VF are caused by PAF antagonism. KEY RESULTS: Global (whole-heart) delivery of 10 microM nupafant, reduced the incidence of ischaemia-induced VF and widened QT interval without affecting coronary flow. Importantly, lower concentrations (0.1 and 1 microM) had no effect on VF, yet widened QT almost identically to 10 microM nupafant. When nupafant was delivered selectively to (and entrapped within) the involved region it partially protected against VF (P<0.05). This occurred without change in QT interval. Selective nupafant delivery to the uninvolved region was without effect. CONCLUSIONS AND IMPLICATIONS: Nupafant protects against ischaemia-induced VF primarily by site-selective actions in the ischaemic region but, unlike BN-50739, the effect is unrelated to its QT widening action, and is not compromised by any effect on coronary flow. This establishes proof of concept that VF suppression by PAF antagonism need not invariably be associated with QT prolongation or vasodilatation, justifying further development of this drug class.
Animals↗
Coronary aneurysms and ankylosing spondylitis: what stenting option is truly optimal?
Vascular inflammation, particularly aortitis, is a known rare manifestation of ankylosing spondylitis. This condition has not been reported to date in the coronary circulation. We present the first documented case of a coronary aneurysm in a patient with ankylosing spondylitis. This association may limit treatment options in such patients, as newer drug-eluting stents may potentiate degeneration in established aneurysmal coronary arteries.
Blood Vessel Prosthesis Implantation↗
A new method of arthroscopic reconstruction of the dislocated acromio-clavicular joint.
BACKGROUND: Symptomatic total acromio-clavicular joint dislocation (Rockwood et al. types III-VI) may be treated by surgical reconstruction. AIM: To describe an arthroscopically assisted technique to reconstruct anatomically the coraco-clavicular ligaments in acute or chronic (> 6 weeks) acromio-clavicular joint dislocation. METHODS: This new technique involves arthroscopic exposure of the coracoid process. Prior to introducing this technique, cadaveric studies were undertaken. RESULTS: Five patients underwent this procedure. All engaged in regular sports or manual-type work. All patients were discharged the same day with the shoulder immobilised for 4 weeks, with no heavy lifting for 3 months. All patients were pain-free at 6 weeks with full function and maximum Constant scores at 3 months. There have been no complications. CONCLUSIONS: A new, safe technique is described which provides a cosmetically acceptable, anatomically solid reconstruction of the coraco-clavicular ligaments.
Acromioclavicular Joint↗
Acute lateral dislocation of the patella: correlation of ultrasound scanning with operative findings.
Acute lateral dislocation of the patella has been associated with disruption of the medial restraints of the patella. Following non-operative management there is a re-dislocation rate of up to 44%. The purpose of this study was to test whether sonography is a reliable method of assessing the medial retinaculum after acute dislocation of the patella. Ten patients following acute patellar dislocation had an ultrasound scan (USS) performed by an experienced musculoskeletal radiologist. Each patient subsequently had an examination under anaesthetic, arthroscopy, and repair of the ruptured structures. The ultrasound reports were compared to the surgical findings to determine the accuracy of this investigation. USS located deficiencies in the ligamentous attachments to the medial border of the patella and the presence of avulsed bony fragments, all of which were confirmed at operation. The sonographic diagnosis of haematoma or torn fibres in the vastus medialis obliquus (VMO) corresponded with our operative findings. The most significant findings were the correlation of free fluid around the medial collateral ligament (MCL) with avulsion of the femoral attachment of the medial patellofemoral ligament (MPFL) and the presence of avulsed fragments of bone from the medial border of the patella.
Adolescent↗
Use of the Shirodkar suture in shoulder surgery.
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Humans↗
Augmentation of patellar tendon repair with poly-p-dioxannone cord.
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Adult↗
Validation of three myocardial jeopardy scores in a population-based cardiac catheterization cohort.
BACKGROUND: The Jeopardy Score from Duke University and the Myocardial Jeopardy Index from the Bypass Angioplasty Revascularization Investigation (BARI) have been validated but never applied to a large unselected cohort. We assessed the prognostic value of these existing jeopardy scores, along with that of a new Lesion Score developed for the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH), a clinical data collection initiative capturing all patients undergoing cardiac catheterization in the province of Alberta. METHODS: The predictive value of these three scores were compared in a cohort of >20,000 patients (9922 treated medically, 6334 treated with percutaneous intervention, and 3811 treated with bypass surgery). Scores were considered individually in logistic regression models for their ability to predict outcome and then added to models containing sociodemographic data, comorbidities, ejection fraction, indication for procedure, and descriptors of coronary anatomy. RESULTS: All scores were found to be predictive of 1-year mortality, especially when patients are treated medically or with percutaneous intervention. In these patients, the APPROACH Lesion Score performed slightly better than the other jeopardy scores. The Duke Jeopardy Score was most predictive in those patients undergoing coronary bypass surgery. CONCLUSIONS: Myocardial jeopardy scores provide independent prognostic information for patients with ischemic heart disease, especially if those patients are treated medically or with percutaneous intervention. These scores represent potentially valuable tools in cardiovascular outcome studies. The APPROACH Lesion Score may perform slightly better than previously developed jeopardy scores.
Adult↗
Modulation of ventricular arrhythmias by catecholamines during evolving infarction in the isolated perfused rat heart.
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Adrenergic beta-Antagonists↗
Inadequate ischaemia-selectivity limits the antiarrhythmic efficacy of mibefradil during regional ischaemia and reperfusion in the rat isolated perfused heart.
1. Mibefradil was compared with (+/-)-verapamil for effects on ischaemia- and reperfusion-induced ventricular fibrillation (VF), and the role of ischaemia-selective L-channel block was examined. Langendorff perfused rat hearts (n=12/group) were used. 2. Neither drug at up to 100 nM reduced the incidence of VF during 30 min regional ischaemia. 300 and 600 nM (+/-)-verapamil abolished VF (P<0. 05); mibefradil was effective only at 600 nM (P<0.05). Reperfusion-induced VF incidence was reduced only by 600 nM (+/-)-verapamil (P<0.05). Both drugs at >/=100 nM increased coronary flow (P<0.05) with a similar potency and maximum effectiveness. 3. In separate hearts perfused with Krebs' solution containing 3 mM K+ (the same as that used for arrhythmia studies) neither drug at up to 600 nM affected ventricular contractility. With K+ raised to 6 mM, (+/-)-verapamil >/=30 nM reduced developed pressure (P<0.05); mibefradil did so only at 600 nM (P<0.05). With K+ raised to 10 mM the effects of (+/-)-verapamil were further increased (P<0.05) and mibefradil became active at >/=100 nM (P<0.05). Likewise both drugs impaired diastolic relaxation, with raised K+ exacerbating the effects and (+/-)-verapamil being more potent and its effects more greatly exacerbated by K+. In contrast, when K+ was normal (3 mM), coronary flow was increased by each drug at >/=30 nM (P<0.05) indicating a marked vascular : myocardial selectivity. 4. In conclusion, mibefradil differed from (+/-)-verapamil in its myocardial effects only in terms of its lower potency. As mibefradil is the more potent T-channel blocker, the T-channel is unlikely to represent the molecular target for these effects. The K+ elevations that occur in the ischaemic milieu determine the ability of both drugs to block myocardial L-channels; this is sufficient to account for the drugs' actions on VF. Neither drug possesses sufficient selectivity for ischaemic myocardium versus blood vessels to permit efficacy (VF suppression without marked vasodilatation) and so inappropriate hypotension is likely to preclude the safe use of mibefradil (or similar analogue) in VF suppression, and explains the lack of clinical effectiveness of (+/-)-verapamil.
Animals↗
Protection against ventricular fibrillation by the PAF antagonist, BN-50739, involves an ischaemia-selective mechanism.
The platelet-activating factor (PAF) antagonist BN-50739 can suppress certain cardiac arrhythmias. PAF is released from ischaemic myocardium and may contribute to initiation of ischaemia-induced ventricular fibrillation (VF). In this study we characterised the action of BN-50739 on left regional ischaemia-induced VF and examined whether effects are mediated within the ischaemic territory, or are nonspecific. In rat isolated Langendorff perfused hearts (n = 12/group), 10 microM BN-50739 reduced the incidence of ischaemia-induced VF from 75 to 17% (p<0.05). This was accompanied by QT widening and an increase in coronary flow. Heart rate and PR interval were not affected by the drug. In separate studies, isolated rat hearts were perfused by using a dual-lumen tube that allows independent delivery of solution to the left and right coronary beds. Successful regional localisation of drug delivery was confirmed by observing, before ischaemia, a regionally selective increase in coronary flow (p<0.05), measured by using two in-line flow meters. Protection against ischaemia-induced VF (p<0.05) was achieved by pretreatment with BN-50739, delivered selectively and entrapped within the involved region, but not when the drug was delivered to the uninvolved region. In conclusion, BN-50739 protects against ischaemia-induced VF by eliciting a pharmacologic action in the involved (ischaemic) myocardium. This supports the hypothesis that BN-50739 suppresses an arrhythmogenic effect of endogenous PAF released within the ischaemic tissue.
Animals↗
Characterisation, utilisation and clinical relevance of isolated perfused heart models of ischaemia-induced ventricular fibrillation.
The isolated perfused heart has been used increasingly during the last decade as a model for identifying actions of drugs on ventricular fibrillation (VF) induced by myocardial ischaemia. In addition, it has been used to explore the mechanisms responsible for the initiation and maintenance of VF, the concept of endogenous myocardial protection and the phenomenon of preconditioning. This article is a review of the available data (effects of drugs, sources of variation, comparison with other models and man, etc.) and an attempt to evaluate the possible clinical relevance. For several reasons, it is not possible to make a precise judgement on the absolute value of the model in terms of its ability to accurately predict the effectiveness of drugs in the prevention of sudden cardiac death, the main reason being the lack of a positive control, i.e. a drug with proven effectiveness against sudden cardiac death caused by VF in man. Nevertheless, the means by which one may reliably and reproducibly generate ischaemia-induced VF in different isolated heart preparations, and the factors (such as species, heart rate, perfusion constituents and involved zone size) that determine the incidence of VF are now well documented. Careful selection of species and experimental conditions permits the isolated heart of smaller inexpensive animals to function as a first line model for detecting anti-VF activity of probable relevance to phase 1 arrhythmogenesis (i.e., arrhythmogenesis during the first 30 min of ischaemia). In view of the absence of a clinical template from which to evaluate how well it predicts drug effectiveness in man, this model's clinical relevance, like that of all other preparations and models, can yet be neither accepted nor dismissed. Recent publication patterns suggest an increasing use of the model. Therefore, recommendations are made to facilitate its effective use.
Animals↗
Correlation of waiting time with adverse events in patients admitted for nonelective permanent pacemaker implantation.
OBJECTIVE: To determine the effect of a dedicated permanent pacemaker implantation procedure room on waiting time and waiting time-related morbidity. DESIGN: Retrospective chart review. SETTING: Two tertiary care teaching hospitals in southern Ontario; one with a dedicated procedure room (centre B) and one without (centre A). PATIENTS: Two hundred and fourteen consecutive patients who required permanent pacing urgently or emergently. METHODS: Charts were examined retrospectively at centre A (131 patients) and centre B (83 patients) to determine the waiting time for and the number of preoperative adverse events in nonelective permanent pacemaker implantation. RESULTS: Patients in centre A waited a mean of 4.5 +/- 3.0 days while patients in centre B waited a mean of 1.9 +/- 1.6 days (P = 0.0001). Centre A patients experienced a total of 57 adverse events that were likely or possibly related to the waiting period, while patients at centre B experienced eight such events (P < 0.0001). Thirty-three per cent of the centre A patients experienced at least one adverse event, while 8% of centre B patients experienced at least one adverse event (P < 0.00001). Of the centre A patients who waited for more than six days (26 patients), 58% had at least one adverse event, compared with 26% of those who waited less than six days (105 patients, P = 0.0009). CONCLUSIONS: Delays in implanting nonelective permanent pacemakers are strongly associated with an increase in adverse events. Measures to shorten the waiting time are likely to result in a reduction in morbidity in conjunction with a beneficial impact on health care resource utilization.
Humans↗
Nitric oxide supplementation or synthesis block--which is the better approach to treatment of heart disease?
Nitric oxide (NO) released from endothelium mediates the vasodilatation caused by numerous autacoids. Nitric oxide can also be exogenous in that some drugs used in cardiovascular disease are NO donors (e.g. glyceryl trinitrate, sodium nitroprusside and isosorbide mononitrate used in angina). However, the notion that NO is a cardiac protectant, whose mimicry or supplementation is desirable, has recently been questioned by data that suggest it is an innocent bystander in some conditions, and even a pathological mediator of dysfunction in others. This important issue is discussed by Mike Curtis and Ravinder Pabla who suggest it is necessary to reappraise the role of NO modulation in cardiac pharmacotherapy.
Heart Diseases↗
Mechanism of actions of sumatriptan on coronary flow before and after endothelial dysfunction in guinea-pig isolated heart.
1. The mechanism of action of sumatriptan on coronary flow was examined before and after two different forms of endothelial ablation in guinea-pig isolated hearts. The mechanism was assessed in terms of the influence of the integrity of the coronary endothelium, the role of release of nitric oxide (NO) from the endothelium, and the receptor subtypes mediating the effects. 2. Continuous perfusion with sumatriptan reduced coronary flow, but the concentration-response curve was v-shaped. Sumatriptan (0.001-0.1 microM) caused a concentration-dependent decrease in coronary flow with the maximum effect achieved at 0.23 +/- 0.04 microM. The pEC50 was 8.49 +/- 0.07. At higher concentrations (0.1-10 microM) there was a concentration-dependent diminution of the vasoconstrictor effect. Endothelial ablation by saponin removed the diminution in the vasoconstrictor effect. In contrast pretreatment with NG-nitro L-arginine methyl ester (L-NAME) (100 microM. 45 min perfusion) did not affect it. This was despite both saponin and L-NAME being effective in reducing basal release of NO into the coronary effluent (measured by chemiluminescence) to the same extent (71 +/- 3 and 73 +/- 2%, respectively). 3. GR127935, a selective 5-hydroxytryptamine1D (5-HT1D) receptor antagonist (3 and 10 nM), which by itself had no effect on coronary flow or NO release, antagonized the vasoconstrictor response to sumatriptan and unmasked a sumatriptan-induced concentration-dependent increase in coronary flow and NO release. These increases in coronary flow and NO release were abolished by pretreatment with either saponin or L-NAME. 4. Mesulergine, a 5-HT2 receptor antagonist which had no effect by itself on basal coronary flow or NO release, inhibited the vasodilator response to sumatriptan that occurred in the presence of GR127935, and actually enhanced the vasoconstrictor response, increasing the max mum fall in coronary flow from -3.9 +/- 0.4 to -5.2 +/- 0.4 ml min-1 g-1 (P < 0.05). The diminution of vasoconstrictor effect of sumatriptan was abolished by mesulergine and by pretreatment with saponin, but not by L-NAME. 5. In conclusion, guinea-pig coronary arteries constrict to low concentrations of sumatriptan, causing a reduction in coronary flow. This effect appears to be caused by 5-HT1D agonism with the receptors located on the coronary vascular smooth muscle. With higher concentrations of sumatriptan this is partially offset by a weaker vasodilator effect, which is caused by low affinity 5-HT2 agonism. Although this effect is endothelium-dependent. It is not caused by the release of NO. Interestingly, when the vasoconstrictor effect of sumatriptan was inhibited by the 5-HT1D antagonist GR127935, a high affinity vasodilator effect of sumatriptan was unmasked. This is 5-HT2 receptor mediated and is caused by release of NO from the coronary endothelium. 6. In man, sumatriptan, and 5-HT may both be capable of causing pathogenic coronary vasoconstriction. The implications of the present data are that the scope for this may depend greatly on (i) the extent of underlying endothelial dysfunction, (ii) the extent of endothelial 5-HT2 receptor-mediated release of vasodilator autacoids (which include NO) and (iii) the extent of smooth muscle 5-HT1D receptor-mediated vasoconstriction.
Animals↗
Involvement of 5-HT(1B/1D) and 5-HT2A receptors in 5-HT-induced contraction of endothelium-denuded rabbit epicardial coronary arteries.
1. The receptors responsible for 5-hydroxytryptamine (5-HT)-mediated contraction of rabbit isolated epicardial coronary artery denuded of endothelium was examined by bioassay. 2. A variety of 5-HT mimetics caused concentration-dependent contractions. The rank order of agonist potency was 5-carboxamidotryptamine (5-CT) > 5-HT > (+/-)-alpha-methyl-5-hydroxytryptamine ((+/-)-alpha-me-5-HT) = sumatriptan. This was not consistent with relative potencies at any single recognized 5-HT receptor, suggesting the presence of a mixed receptor population. In one subset of preparations precontracted with U46619 (10-30 nM) with the endothelium intact, none of the agonists caused a relaxation. 3. Contractions to 5-HT were antagonized by ketanserin, a 5-HT2A-selective antagonist, but the displacement of concentration-response curves was inconsistent with an interaction between 5-HT and a single receptor population; the slope of regression between antagonist log M concentration and agonist log (concentration-ratio -1) was shallow (0.57). Responses to 5-HT were also antagonized by the 5-HT(1B/1D)-receptor antagonist GR127935 and, again, the slope of regression was shallow (0.68). These data suggest a possible involvement of 5-HT2A and 5-HT1B or 5-HT1D receptors in the response to 5-HT. 4. Contractions to (+/-)-alpha-me-5-HT, which is selective for 5-HT2A over 5-HT1B and 5-HT1D receptors, were competitively antagonized by low concentrations of ketanserin. The regression between antagonist log M concentration and agonist log (concentration-ratio -1) fitted the Schild equation with a slope that was not significantly different from unity (0.95), giving a pA2 value of 9.0. GR127935 (3-30 nM), had no effect on the contractile response to (+/-)-alpha-me-5-HT. These data establish, unequivocally, the presence of 5-HT2A receptors in the tissue. 5. Sumatriptan, a relatively selective 5-HT(1B/1D)-receptor agonist, induced contractions that were antagonized competitively by GR127935 (3-30 nM), although there was a reduction in the maximum response when concentrations of GR127935 exceeded 3 nM. The apparent pA2 (estimated by imposing a unit slope on the log agonist (concentration-ratio -1) value in the presence of 3 nM GR127935) was 8.92. Contractions to sumatriptan were not affected by low (5-HT2A receptor-selective) concentrations of ketanserin, but were antagonized in a competitive manner at higher concentrations (pA2 6.5). These data appear to confirm the presence of 5-HT1B and/or 5-HT1D receptors in the tissue. 6. Antagonism of 5-HT responses by GR127935 was reassessed after blockade of 5-HT2A receptors with 1 microM ketanserin. Under these conditions, GR127935 was able to antagonize 5-HT-induced contractions fully. The slope of regression between log M antagonist concentration and log agonist (concentration-ratio -1) fitted the Schild equation with a slope not significantly different from unity (1.1) (albeit there was still a reduction in maximum response when GR127935 concentration exceeded 3 nM). The apparent pA2 value was 8.8. This reinforces the evidence that 5-HT1B and/or 5-HT1D receptors contribute to the effects of 5-HT in the tissue. 7. In conclusion, in endothelium denuded rabbit epicardial coronary arteries, 5-HT activates 5-HT2A and 5-HT1D and/or 5-HT1B receptors to cause contraction. This appears to be similar to the situation in man.
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
Endogenous protection against reperfusion-induced ventricular fibrillation: role of neuronal versus non-neuronal sources of nitric oxide and species dependence in the rat versus rabbit isolated heart.
Nitric oxide (NO) is an endogenous protectant against reperfusion-induced ventricular fibrillation (VF) in the rat isolated heart. Here, the following were investigated: (1) the tissue source of cardioprotective NO using a novel inhibitor (7-nitro indazole; 7-NI) of the neuronal form of NO synthase (NOS) and direct detection of coronary effluent NO by chemiluminescence; and (2) the species dependence by comparing rat and rabbit hearts. Perfusion with modified Krebs solution was followed by 60 min left regional ischemia and 10 min reperfusion. 7-NI (1 microM) increased the incidence of VF from 0% to 60% in rat hearts (n = 10; P < 0.05). Co-perfusion with L-arginine (1 mM) reduced VF incidence to 20% (P:N.S. v controls). The inactive analog of 7-NI (6-amino indazole: 6-AI) had no pro-fibrillatory activity. Neither 7-NI nor 6-AI affected coronary flow or recovery of flow during reperfusion. 7-NI reduced basal coronary effluent NO levels to below the limit of detection (< 1 pmol), but a massive increase in NO levels occurred when L-arginine was co-perfused with 7-NI. Although 7-NI had no effect on basal coronary flow and, by implication, resting NO release, it was found, in separate studies, to antagonise substance P-induced vasodilatation and NO release, suggesting that its neuronal selectivity is lost in the presence of an exogenously administered activator of endothelial NOS in rat hearts. In rabbit hearts, in contrast, 7-NI had no effect on VF or NO levels. However, in rabbit hearts the isozyme non-selective NO synthase blocker, NG-nitro-L-arginine methyl ester (L-NAME; 100 microM), increased VF incidence from 0 to 50% (P < 0.05) and, during the first minute of reperfusion, reduced NO levels from 4929 +/- 893 to 2505 +/- 483 pmol/min/g (P < 0.05) and recovery of coronary flow by 22% (P < 0.05). Each of these effects were prevented by L-arginine co-perfusion. These data indicate a role for basally released NO as an endogenous antifibrillatory cardioprotectant in rat and rabbit isolated heart and indicate that the tissue source (neuronal in rat but not in rabbit heart) is species-dependent.
Animals↗