Calcium-mediated activation of pyruvate dehydrogenase in severely injured postischemic myocardium.

Indirect evidence suggests that activity of pyruvate dehydrogenase (PDH) influences recovery of the myocardium after transient ischemia. The present study examined the relationship between postischemic injury and activity of PDH and the role of mitochondrial calcium uptake for observed changes in PDH activity. Isovolumically beating isolated rat hearts perfused with erythrocyte-enriched buffer containing glucose, palmitate, and insulin were submitted to either 20 or 35 min of no-flow ischemia. After 20 min of no-flow ischemia, hearts exhibited complete recovery of developed left ventricular pressure (DLVP). The proportion of myocardial PDH in the active state was modestly increased to 38% (compared with 13% in control hearts) without a change in glucose oxidation. In contrast, in hearts subjected to 35 min of no-flow ischemia (which exhibited poor recovery of DLVP), there was marked stimulation of glucose oxidation (+460%; P < 0.01) and pronounced increase in the active fraction of PDH to 72% (P < 0.01). Glycolytic flux was not significantly altered. Ruthenium red (6 microM) completely abolished the activation of PDH and the increase in glucose oxidation. The results indicate that variable stimulation of glucose oxidation during reperfusion is related to different degrees of activation of PDH, which depends on the severity of the ischemic injury. Activation of PDH seems to be mediated by myocardial calcium uptake.

7

Ischaemic heart disease as the result of impaired blood supply is currently the leading cause of failure and death. Ischaemic heart disease refers to a group of clinicopathological symptoms including angina pectoris, acute myocardial infection, chronic ischemic heart disease, as well as heart failure and sudden cardiac death. Coronary artery ischemic heart disease, as well as heart failure and sudden cardiac death. Coronary artery thrombosis is the most common cause of acute myocardial infarction and sudden cardiac death. A thrombotic event is the result of two different processes: plaque disruption and endothelial erosion. The morphology of a "vulnerable plaque" is more clinically indicative than the plaque volume and the degree of luminal stenosis. However, identification of patients with vulnerable plaques remains very challenging and demands the development of new methods of coronary plaque imaging. Sudden death resulting from ventricular fibrillation or AV block frequently complicates coronary thrombosis, accounting for up to 50% of mortality.If a coronary artery is occluded for more than 20 min, irreversible damage to the pericardium occurs. Timely coronary recanalization and myocardial reperfusion limit the extent of myocardial necrosis, but may induce "reperfusion injuries", stunned myocardium, or reperfused myocardial hemorrhagic infarcts, all of which are related to infarct siz and coronary occlusion time. Reperfusion injuries have been described after cardiac surgery, percutaneous transluminal coronary angioplasty, and fibrinolysis. A prolonged imbalance between the supply of and demand for myocardial oxygen and nutrition leads to a subacute, acute, or chronic state (aka hibernating myocardium) of myocardial ischemia. Ischemic heart disease is bwelieved to be the underlying cause of heart failure in approximately two-thirds of patients, resulting from acute and/or chronic injury to the heart.

Transmyocardial laser revascularisation in acutely ischaemic myocardium.

OBJECTIVE: Although recent experience suggests that transmyocardial laser revascularisation (TMLR) relieves angina, its mechanism of action remains undefined. We examined its functional effects and analysed its morphological features in an animal model of acute ischaemia. METHODS: A total of 15 pigs were randomised to ligation of left marginal arteries (infarction group, n = 5), to TMLR of the left lateral wall using a holmium:yttrium-aluminium garnet (Ho:YAG) laser (laser group, n = 5), and to both (laser-infarction group, n = 5). All the animals were sacrificed 1 month after the procedure. Haemodynamics and echocardiography with segmental wall motion score were carried out at both time intervals (scale 0-3: 0, normal; 1, hypokinesia; 2, akinesia; 3, dyskinesia). Histology of the involved area was analysed. RESULTS: Laser group showed no change of the segmental wall motion score of the involved area 30 min after the laser channels were made (score: 0 +/- 0). Infarction and laser infarction groups both showed a persistent and definitive increase of the segmental wall motion score (at 30 min: 1.6 +/- 0.3 and 2 +/- 0, respectively; at 1 month: 1.8 +/- 0.2 and 1.8 +/- 0.4, respectively). These increases were all statistically significant in comparison with baseline values (P < 0.5), however comparison between infarction and laser-infarction groups showed no significant difference. On macroscopic examination of the endocardial surface, no channel was opened. On histology, there were signs of neovascularisation around the channels in the laser group, whereas in the laser-infarction group the channels were embedded in the infarction scar. CONCLUSIONS: In this acute pig model, TMLR did not provide improvement of contractility of the ischaemic myocardium. To the degree that the present study pertains to the clinical setting, the results suggest that mechanisms other than blood flow through the channels should be considered, such as a laser-induced triggering of neovascularisation or neural destruction.

Postmortem chemistry update part II.

As a continuation of "Postmortem Chemistry Update Part I," Part II deals with molecules linked to liver and cardiac functions, alcohol intake and alcohol misuse, myocardial ischemia, inflammation, sepsis, anaphylaxis, and hormonal disturbances. A very important array of new material concerning these situations had appeared in the forensic literature over the last two decades. Some molecules, such as procalcitonin and C-reactive protein, are currently researched in cases of suspected sepsis and inflammation, whereas many other analytes are not integrated into routine casework. As in part I, a literature review concerning a large panel of molecules of forensic interest is presented, as well as the results of our own observations, where possible.

Inhibition of bicarbonate transport protects embryonic heart against reoxygenation-induced dysfunction.

It has not been well established whether the mechanisms participating in pH regulation in the anoxic-reoxygenated developing myocardium resemble those operating in the adult. We have specially examined the importance of Na+/H+ exchange (NHE) and HCO3-dependent transports in cardiac activity after changes in extracellular pH (pHo). Spontaneously contracting hearts isolated from 4-day-old chick embryos were submitted to single or repeated anoxia (1 min) followed by reoxygenation (10 min). The chronotropic, dromotropic and inotropic responses of the hearts were determined in standard HCO3- buffer at pHo 7.4 and at pHo 6.5 (hypercapnic acidosis). In distinct experiments, acidotic anoxia preceded reoxygenation at pHo 7.4. NHE was blocked with amiloride derivative HMA (1 micro mol/l) and HCO3-dependent transports were inactivated by replacement of HCO3 or blockade with stilbene derivative DIDS (100 micro mol/l). Anoxia caused transient tachycardia, depressed mechanical function and induced contracture. Reoxygenation temporarily provoked cardiac arrest, atrio-ventricular (AV) block, arrhythmias and depression of contractility. Addition of DIDS or substitution of HCO3 at pHo 7.4 had the same effects as acidosis per se, i.e. shortened contractile activity and increased incidence of arrhythmias during anoxia, prolonged cardioplegia and provoked arrhythmias at reoxygenation. Under anoxia at pHo 6.5/reoxygenation at pHo 7.4, cardioplegia, AV block and arrhythmias were all markedly prolonged. Interestingly, in the latter protocol, DIDS suppressed AV block and arrhythmias during reoxygenation, whereas HMA had no effect. Thus, intracellular pH regulation in the anoxic-reoxygenated embryonic heart appears to depend predominantly on HCO3 availability and transport. Furthermore, pharmacological inhibition of anion transport can protect against reoxygenation-induced dysfunction.

Indications à la coronarographie en urgence. Partie I: syndromes coronariens aigus avec élévation du segment ST [Indications for urgent coronary angiography. Part I: ST-segment elevation acute coronary syndromes]

The indications for urgent coronary angiography are stated in the guidelines for treatment of acute coronary syndromes. An invasive approach is considered the treatment of choice for patients presenting with ST elevation myocardial infarction within 12 hours of the beginning of symptoms. In the absence of contraindication, intravenous thrombolysis continues to be a valuable alternative to primary angioplasty within 3 hours of the beginning of clinical symptoms. Urgent coronary angiography continues to be recommended following the failure of thrombolysis, persistent myocardial ischemia after 12 hours of symptoms, recurrent myocardial ischemia following myocardial infarction or in the case of cardiogenic shock.

Thoracic aortic dissection associated with cocaine abuse.

Cardiovascular complications of cocaine abuse include myocardial ischemia and infarction, dysrhythmias, cardiomyopathies and aortic dissection. The case in point pertains to a 26-year-old, Caucasian male, substance abuser who suffered a thoracic aortic dissection following the use of crack cocaine. The autopsy and histological findings showed a connective tissue abnormality including a focal microcystic medial necrosis and a fragmentation of the elastic fibers in the arterial walls. Blood concentrations of cocaine and benzoylecgonine, taken individually, were considered to be within a potentially toxic range. Blood concentrations of methadone also indicated use of this drug at the same time. The small amounts of morphine found in the blood and urine were compatible with heroine or morphine use more than 24 h before death.

A case of suicide by self-injection of adrenaline.

Adrenaline (epinephrine) auto-injectors provide life-saving pre-hospital treatment for individuals experiencing anaphylaxis in a community setting. Errors in handling adrenaline auto-injectors, particularly by children and healthcare professionals, have been reported. Reports of adrenaline overdoses are limited in the medical literature. In most of these cases, accidental adrenaline administration results from medical error. Exogenous administration of catecholamine is responsible for cardiovascular and metabolic responses, which may cause supraventricular tachycardia, ventricular dysrhythmias and myocardial ischemia. The authors present a unique autopsy case involving a 34 year-old woman who intentionally self-injected adrenaline using an adrenaline auto-injector as part of a suicide plan. Catecholamines and metanephrines were measured in peripheral and cardiac blood as well as urine and vitreous humor. Based on the results of all postmortem investigations, the cause of death was determined to be cardiac dysrhythmia and cardiac arrest following adrenaline self-injection.

Cardiac magnetic resonance imaging in clinical practice

Objective To evaluate and describe indications, mainly diagnoses and cardiac magnetic resonance imaging findings observed in clinical practice. Materials and Methods Retrospective and descriptive study of cardiac magnetic resonance performed at a private hospital and clinic in the city of Niterói, RJ, Brazil, in the period from May 2007 to April 2011. Results The sample included a total of 1000 studies performed in patients with a mean age of 53.7 ± 16.2 years and predominance for male gender (57.2%). The majority of indications were related to assessment of myocardial perfusion at rest and under pharmacological stress (507/1000; 51%), with positive results in 36.2% of them. Suspected myocarditis was the second most frequent indication (140/1000; 14%), with positive results in 63.4% of cases. These two indications were followed by study of arrhythmias (116/1000; 12%), myocardial viability (69/1000; 7%) and evaluation of cardiomyopathies (47/1000; 5%). In a subanalysis, it was possible to identify that most patients were assessed on an outpatient basis (58.42%). Conclusion Cardiac magnetic resonance has been routinely performed in clinical practice, either on an outpatient or emergency/inpatient basis, and myocardial ischemia represented the main indication, followed by investigation of myocarditis, arrhythmogenic right ventricular dysplasia and myocardial viability.

Cholinergic stimulation with pyridostigmine reduces the QTc interval in coronary artery disease

Parasympathetic dysfunction is an independent risk factor in patients with coronary artery disease; thus, cholinergic stimulation is a potential therapeutic measure that may be protective by acting on ventricular repolarization. The purpose of the present study was to determine the effects of pyridostigmine bromide (PYR), a reversible anticholinesterase agent, on the electrocardiographic variables, particularly QTc interval, in patients with stable coronary artery disease. In a randomized double-blind crossover placebo-controlled study, simultaneous 12-lead electrocardiographic tracings were obtained at rest from 10 patients with exercise-induced myocardial ischemia before and 2 h after the oral administration of 45 mg PYR or placebo. PYR increased the RR intervals (pre: 921 ± 27 ms vs post: 1127 ± 37 ms; P<0.01) and, in contrast with placebo, decreased the QTc interval (pre: 401 ± 3 ms vs post: 382 ± 3 ms; P<0.01). No other electrocardiographic variables were modified (PR segment, QT interval, QT and QTc dispersions). Cholinergic stimulation with PYR caused bradycardia and reduced the QTc interval without important side effects in patients with coronary disease. These effects, if confirmed in studies over longer periods of administration, may suggest a cardioprotection by cholinergic stimulation with PYR.

Assessment of the cardiovascular effects of electroconvulsive therapy in individuals older than 50 years

To evaluate the impact of electroconvulsive therapy on arterial blood pressure, heart rate, heart rate variability, and the occurrence of ischemia or arrhythmias, 38 (18 men) depressive patients free from systemic diseases, 50 to 83 years old (mean: 64.7 ± 8.6) underwent electroconvulsive therapy. All patients were studied with simultaneous 24-h ambulatory blood pressure and Holter monitoring, starting 18 h before and continuing for 3 h after electroconvulsive therapy. Blood pressure, heart rate, heart rate variability, arrhythmias, and ischemic episodes were recorded. Before each session of electroconvulsive therapy, blood pressure and heart rate were in the normal range; supraventricular ectopic beats occurred in all patients and ventricular ectopic beats in 27/38; 2 patients had non-sustained ventricular tachycardia. After shock, systolic, mean and diastolic blood pressure increased 29, 25, and 24% (P < 0.001), respectively, and returned to baseline values within 1 h. Maximum, mean and minimum heart rate increased 56, 52, and 49% (P < 0.001), respectively, followed by a significant decrease within 5 min; heart rate gradually increased again thereafter and remained elevated for 1 h. Analysis of heart rate variability showed increased sympathetic activity during shock with a decrease in both sympathetic and parasympathetic drive afterwards. No serious adverse effects occurred; electroconvulsive therapy did not trigger any malignant arrhythmias or ischemia. In middle-aged and elderly people free from systemic diseases, electroconvulsive therapy caused transitory increases in blood pressure and heart rate and a decrease in heart rate variability but these changes were not associated with serious adverse clinical events.

Effects of sedation during upper gastrointestinal endoscopy on endocrine response and cardiorespiratory function

Upper gastrointestinal endoscopy is often accompanied by tachycardia which is known to be an important pathogenic factor in the development of myocardial ischemia. The pathogenesis of tachycardia is unknown but the condition is thought to be due to the endocrine response to endoscopy. The purpose of the present study was to investigate the effects of sedation on the endocrine response and cardiorespiratory function. Forty patients scheduled for diagnostic upper gastrointestinal endoscopy were randomized into 2 groups. While the patients in the first group did not receive sedation during upper gastrointestinal endoscopy, the patients in the second group were sedated with intravenous midazolam at the dose of 5 mg for those under 65 years or 2.5 mg for those aged 65 years or more. Midazolam was administered by slow infusion. In both groups, blood pressure, ECG tracing, heart rate, and peripheral oxygen saturation (SpO2) were monitored during endoscopy. In addition, blood samples for the determination of cortisol, glucose and C-reactive protein levels were obtained from patients in both groups prior to and following endoscopy. Heart rate and systolic arterial pressure changes were within normal limits in both groups. Comparison of the two groups regarding the values of these two parameters did not reveal a significant difference, while a statistically significant reduction in SpO2 was found in the sedation group. No significant differences in serum cortisol, glucose or C-reactive protein levels were observed between the sedated and non-sedated group. Sedation with midazolam did not reduce the endocrine response and the tachycardia developing during upper gastrointestinal endoscopy, but increased the reduction in SpO2.

Effects of conventional vs high-dose rocuronium on the QTc interval during anesthesia induction and intubation in patients undergoing coronary artery surgery: a randomized, double-blind, parallel trial

Myocardial ischemia, as well as the induction agents used in anesthesia, may cause corrected QT interval (QTc) prolongation. The objective of this randomized, double-blind trial was to determine the effects of high- vs conventional-dose bolus rocuronium on QTc duration and the incidence of dysrhythmias following anesthesia induction and intubation. Fifty patients about to undergo coronary artery surgery were randomly allocated to receive conventional-dose (0.6 mg/kg, group C, n=25) or high-dose (1.2 mg/kg, group H, n=25) rocuronium after induction with etomidate and fentanyl. QTc, heart rate, and mean arterial pressure were recorded before induction (T0), after induction (T1), after rocuronium (just before laryngoscopy; T2), 2 min after intubation (T3), and 5 min after intubation (T4). The occurrence of dysrhythmias was recorded. In both groups, QTc was significantly longer at T3 than at baseline [475 vs 429 ms in group C (P=0.001), and 459 vs 434 ms in group H (P=0.005)]. The incidence of dysrhythmias in group C (28%) and in group H (24%) was similar. The QTc after high-dose rocuronium was not significantly longer than after conventional-dose rocuronium in patients about to undergo coronary artery surgery who were induced with etomidate and fentanyl. In both groups, compared with baseline, QTc was most prolonged at 2 min after intubation, suggesting that QTc prolongation may be due to the nociceptive stimulus of intubation.

Validation des modèles de pharmacologie de sécurité et évaluation de la valeur thérapeutique de l'oxytocine dans le traitement de l'infarctus du myocarde

En février, 2009 un rapport de PHRMA (Pharmaceutical Research and Manufacturers of America) confirmait que plus de 300 médicaments pour le traitement des maladies cardiaques étaient en phase d’essais cliniques ou en révision par les agences règlementaires. Malgré cette abondance de nouvelles thérapies cardiovasculaires, le nombre de nouveaux médicaments approuvés chaque année (toutes indications confondues) est en déclin avec seulement 17 et 24 nouveaux médicaments approuvés en 2007 et 2008, respectivement. Seulement 1 médicament sur 5000 sera approuvé après 10 à 15 ans de développement au coût moyen de 800 millions $. De nombreuses initiatives ont été lancées par les agences règlementaires afin d’augmenter le taux de succès lors du développement des nouveaux médicaments mais les résultats tardent. Cette stagnation est attribuée au manque d’efficacité du nouveau médicament dans bien des cas mais les évaluations d’innocuité remportent la palme des causes d’arrêt de développement. Primum non nocere, la maxime d’Hippocrate, père de la médecine, demeure d’actualité en développement préclinique et clinique des médicaments. Environ 3% des médicaments approuvés au cours des 20 dernières années ont, par la suite, été retirés du marché suite à l’identification d’effets adverses. Les effets adverses cardiovasculaires représentent la plus fréquente cause d’arrêt de développement ou de retrait de médicament (27%) suivi par les effets sur le système nerveux. Après avoir défini le contexte des évaluations de pharmacologie de sécurité et l’utilisation des bio-marqueurs, nous avons validé des modèles d’évaluation de l’innocuité des nouveaux médicaments sur les systèmes cardiovasculaires, respiratoires et nerveux. Évoluant parmi les contraintes et les défis des programmes de développements des médicaments, nous avons évalué l’efficacité et l’innocuité de l’oxytocine (OT), un peptide endogène à des fins thérapeutiques. L’OT, une hormone historiquement associée à la reproduction, a démontré la capacité d’induire la différentiation in vitro de lignées cellulaires (P19) mais aussi de cellules souches embryonnaires en cardiomyocytes battants. Ces observations nous ont amené à considérer l’utilisation de l’OT dans le traitement de l’infarctus du myocarde. Afin d’arriver à cet objectif ultime, nous avons d’abord évalué la pharmacocinétique de l’OT dans un modèle de rat anesthésié. Ces études ont mis en évidence des caractéristiques uniques de l’OT dont une courte demi-vie et un profil pharmacocinétique non-linéaire en relation avec la dose administrée. Ensuite, nous avons évalué les effets cardiovasculaires de l’OT sur des animaux sains de différentes espèces. En recherche préclinique, l’utilisation de plusieurs espèces ainsi que de différents états (conscients et anesthésiés) est reconnue comme étant une des meilleures approches afin d’accroître la valeur prédictive des résultats obtenus chez les animaux à la réponse chez l’humain. Des modèles de rats anesthésiés et éveillés, de chiens anesthésiés et éveillés et de singes éveillés avec suivi cardiovasculaire par télémétrie ont été utilisés. L’OT s’est avéré être un agent ayant d’importants effets hémodynamiques présentant une réponse variable selon l’état (anesthésié ou éveillé), la dose, le mode d’administration (bolus ou infusion) et l’espèce utilisée. Ces études nous ont permis d’établir les doses et régimes de traitement n’ayant pas d’effets cardiovasculaires adverses et pouvant être utilisées dans le cadre des études d’efficacité subséquentes. Un modèle porcin d’infarctus du myocarde avec reperfusion a été utilisé afin d’évaluer les effets de l’OT dans le traitement de l’infarctus du myocarde. Dans le cadre d’un projet pilote, l’infusion continue d’OT initiée immédiatement au moment de la reperfusion coronarienne a induit des effets cardiovasculaires adverses chez tous les animaux traités incluant une réduction de la fraction de raccourcissement ventriculaire gauche et une aggravation de la cardiomyopathie dilatée suite à l’infarctus. Considérant ces observations, l’approche thérapeutique fût révisée afin d’éviter le traitement pendant la période d’inflammation aigüe considérée maximale autour du 3ième jour suite à l’ischémie. Lorsqu’initié 8 jours après l’ischémie myocardique, l’infusion d’OT a engendré des effets adverses chez les animaux ayant des niveaux endogènes d’OT élevés. Par ailleurs, aucun effet adverse (amélioration non-significative) ne fût observé chez les animaux ayant un faible niveau endogène d’OT. Chez les animaux du groupe placebo, une tendance à observer une meilleure récupération chez ceux ayant des niveaux endogènes initiaux élevés fût notée. Bien que la taille de la zone ischémique à risque soit comparable à celle rencontrée chez les patients atteints d’infarctus, l’utilisation d’animaux juvéniles et l’absence de maladies coronariennes sont des limitations importantes du modèle porcin utilisé. Le potentiel de l’OT pour le traitement de l’infarctus du myocarde demeure mais nos résultats suggèrent qu’une administration systémique à titre de thérapie de remplacement de l’OT devrait être considérée en fonction du niveau endogène. De plus amples évaluations de la sécurité du traitement avec l’OT dans des modèles animaux d’infarctus du myocarde seront nécessaires avant de considérer l’utilisation d’OT dans une population de patients atteint d’un infarctus du myocarde. En contre partie, les niveaux endogènes d’OT pourraient posséder une valeur pronostique et des études cliniques à cet égard pourraient être d’intérêt.