RESUMO
Background: Individuals suffering from PTSD following childhood abuse represent a large subgroup of patients attending mental health services. The aim of phase-based treatment is to tailor treatment to the specific needs to childhood abuse survivors with PTSD with a Skills Training in Affective and Interpersonal Regulation (STAIR) phase, in which emotion dysregulation and interpersonal problems are targeted, and a trauma-focused phase.Objective: The purpose of this study was to compare STAIR + Eye Movement Desensitization and Reprocessing (EMDR) vs. STAIR + Narrative Therapy (NT) as treatments for PTSD following childhood-onset trauma in a routine clinical setting.Method: Sixty-eight adults were randomly assigned to STAIR/EMDR (8 STAIR-sessions followed by 12 EMDR-sessions) or STAIR/NT (8 STAIR-sessions followed by 12 NT-sessions). Assessments took place at pre-treatment, after each treatment phase and at 3 and 12 months post-intervention follow-up. Primary outcomes were interviewer-rated and self-reported symptom levels of PTSD. Secondary outcomes included symptom levels of depression and disturbances in emotion regulation and interpersonal skills.Results: Multilevel analyses in the intent-to-treat sample indicated that patients in both treatments improved substantially on PTSD symptom severity (CAPS: d = 0.81 to 1.29; PDS: d = 1.68 to 2.15), as well as on symptom levels of depression, anxiety, emotion regulation, dissociation and interpersonal skills. Effects increased or were maintained until 12-month follow-up. At mid-treatment, after STAIR, patients in both treatments improved moderately on PTSD symptom severity (PDS: d = 1.68 to 2.15), as well as on symptom levels of depression (BDI: d = .32 to .31). Symptoms of anxiety, emotion dysregulation, interpersonal problems and dissociation were not decreased after STAIR. There were no significant differences between the two conditions on any outcome.Conclusion: PTSD in adult survivors of childhood interpersonal trauma can effectively be treated by phase-based interventions using either EMDR or NT in the trauma-processing phase.Trial registration: ClinicalTrials.gov identifier: NCT01443182..
The study directly compares Skills Training in Affective and Interpersonal Regulation (STAIR) followed by either EMDR or Narrative Therapy in the trauma-processing phase in routine clinical setting.The brief phase-based treatment was found to be effective in reducing both symptoms of PTSD as well as emotion regulation and interpersonal problems in survivors of childhood abuse.Posttraumatic Stress Disorder in adult survivors of childhood interpersonal trauma can effectively be treated by phase-based interventions using either EMDR or Narrative Therapy in the trauma-processing phase.
Assuntos
Sobreviventes Adultos de Maus-Tratos Infantis , Dessensibilização e Reprocessamento através dos Movimentos Oculares , Terapia Narrativa , Transtornos de Estresse Pós-Traumáticos , Adulto , Humanos , Transtornos de Estresse Pós-Traumáticos/psicologia , Resultado do TratamentoRESUMO
BACKGROUND: Promoting well-being and preventing poor mental health in young people is a major global priority. Building emotional competence (EC) skills via a mobile app may be an effective, scalable and acceptable way to do this. However, few large-scale controlled trials have examined the efficacy of mobile apps in promoting mental health in young people; none have tailored the app to individual profiles. METHOD/DESIGN: The Emotional Competence for Well-Being in Young Adults cohort multiple randomised controlled trial (cmRCT) involves a longitudinal prospective cohort to examine well-being, mental health and EC in 16-22 year olds across 12 months. Within the cohort, eligible participants are entered to either the PREVENT trial (if selected EC scores at baseline within worst-performing quartile) or to the PROMOTE trial (if selected EC scores not within worst-performing quartile). In both trials, participants are randomised (i) to continue with usual practice, repeated assessments and a self-monitoring app; (ii) to additionally receive generic cognitive-behavioural therapy self-help in app; (iii) to additionally receive personalised EC self-help in app. In total, 2142 participants aged 16 to 22 years, with no current or past history of major depression, bipolar disorder or psychosis will be recruited across UK, Germany, Spain, and Belgium. Assessments take place at baseline (pre-randomisation), 1, 3 and 12 months post-randomisation. Primary endpoint and outcome for PREVENT is level of depression symptoms on the Patient Health Questionnaire-9 at 3 months; primary endpoint and outcome for PROMOTE is emotional well-being assessed on the Warwick-Edinburgh Mental Wellbeing Scale at 3 months. Depressive symptoms, anxiety, well-being, health-related quality of life, functioning and cost-effectiveness are secondary outcomes. Compliance, adverse events and potentially mediating variables will be carefully monitored. CONCLUSIONS: The trial aims to provide a better understanding of the causal role of learning EC skills using interventions delivered via mobile phone apps with respect to promoting well-being and preventing poor mental health in young people. This knowledge will be used to develop and disseminate innovative evidence-based, feasible, and effective Mobile-health public health strategies for preventing poor mental health and promoting well-being. TRIAL REGISTRATION: ClinicalTrials.gov ( www.clinicaltrials.org ). Number of identification: NCT04148508 November 2019.
Assuntos
Telefone Celular , Aplicativos Móveis , Adolescente , Adulto , Bélgica , Alemanha , Humanos , Saúde Mental , Estudos Prospectivos , Qualidade de Vida , Espanha , Adulto JovemRESUMO
BACKGROUND: Intrusive re-experiencing in post-traumatic stress disorder (PTSD) comprises distressing sensory impressions from the trauma that seem to occur 'out of the blue'. A key question is how intrusions are triggered. One possibility is that PTSD is characterized by a processing advantage for stimuli that resemble those that accompanied the trauma, which would lead to increased detection of such cues in the environment. METHOD: We used a blurred picture identification task in a cross-sectional (n=99) and a prospective study (n=221) of trauma survivors. RESULTS: Participants with acute stress disorder (ASD) or PTSD, but not trauma survivors without these disorders, identified trauma-related pictures, but not general threat pictures, better than neutral pictures. There were no group differences in the rate of trauma-related answers to other picture categories. The relative processing advantage for trauma-related pictures correlated with re-experiencing and dissociation, and predicted PTSD at follow-up. CONCLUSIONS: A perceptual processing bias for trauma-related stimuli may contribute to the involuntary triggering of intrusive trauma memories in PTSD.
Assuntos
Sinais (Psicologia) , Rememoração Mental , Transtornos de Estresse Pós-Traumáticos/psicologia , Sobreviventes/psicologia , Percepção Visual , Acidentes de Trânsito/psicologia , Adulto , Análise de Variância , Atenção , Estudos Transversais , Transtornos Dissociativos/psicologia , Medo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação Luminosa/métodos , Estudos Prospectivos , Índice de Gravidade de Doença , Fatores Socioeconômicos , Violência/psicologiaRESUMO
The evaluation of regional myocardial blood flow (RMBF) during cardiac catheterization is of particular diagnostic interest. The purpose of this investigation was to validate x-ray densitometric parameters for the evaluation of RMBF. In five anesthetized dogs, arterial flow in the circumflex coronary artery was measured continuously with an electromagnetic flowmeter, and RMBF was determined by colored microspheres. Five different perfusion levels were created by mechanical obstruction of the coronary artery or by intravenous infusion of adenosine. At each steady-state perfusion level, digital subtraction coronary angiograms were obtained for densitometric analysis. Results documented a close correlation between the related time parameters 1/Mean Transit Time (1/MTT, r2 = 0.969), and 1/Rise Time (1/RT, r2 = 0.965) and RMBF over a wide range between 0.36 ml/(min x g) and 11.16 ml/(min x g). Maximum myocardial contrast density (Imax) also showed a good, but inverse correlation (r2 = 0.889) with RMBF and, therefore, did not reflect vascular volume. Contrast medium Appearance Time (AT) showed no correlation to RMBF (r2 = 0.017). Repeat densitometric measurements for different perfusion levels revealed a good reproducibility for MTT (accuracy: 0.001 s; precision: 0.447 s or 6.7 %) and RT (accuracy: 0.014 s; precision: 0.202 s or 10.4 %), while AT (accuracy: 0.072 s; precision: 0.420 s or 68.5%) and Imax (accuracy: 0.022 GL; precision: 1.197 GL or 44.5%) showed substantial variation. Myocardial perfusion reserve (MPR) calculated from RT (r2 = 0.90) or MTT (r2 = 0.94) showed better correlations to RMBF reserve than MPR calculated from AT (r2 = 0.04). In conclusion, only 1/MTT and 1/RT showed a good reproducibility and a close correlation to RMBF. Therefore, only these parameters can be recommended for calculations of RMBF and its reserve under clinical conditions.
Assuntos
Absorciometria de Fóton , Circulação Coronária , Animais , Velocidade do Fluxo Sanguíneo , Cães , Microesferas , Reprodutibilidade dos TestesRESUMO
Dihydropyridine (DHP) calcium antagonists are established drugs in the management of hypertension and chronic stable angina. However, recently a dose-related increase in the mortality of patients with coronary artery disease with nifedipine has been suggested. The conclusions of this study were seriously contradicted. Therefore, in our laboratory, the effect of the DHP calcium antagonist nisoldipine on ischaemic myocardial blood flow and function, infarct size, and the functional recovery of reversibly injured, reperfused myocardium was once more investigated in controlled in vivo models. In anaesthetized dogs, in the presence of a severe coronary artery stenosis, intravenous nisoldipine decreased poststenotic subendocardial blood flow and contractile function when arterial pressure was decreased. In contrast, when hypotension was prevented by inflation of an intra-aortic balloon, no aggravation of myocardial ischaemia was seen. During exercise, when aortic pressure is raised by catecholamines, nisoldipine may therefore not exert a pro-ischaemic effect, but may rather improve regional myocardial blood flow and function in the ischaemic region. As has been shown for nifedipine, the functional antagonism of alpha-adrenergic coronary vasomotor tone contributes to the improvement of myocardial blood flow and function of the ischaemic region, in particular during exercise. In anaesthetized pigs, intracoronary administration of nisoldipine prior to a 90-min low-flow ischaemia tended to decrease infarct size. Infarct size resulting from prolonged and severe myocardial ischaemia is reduced by one or more preceding short episodes of ischaemia and reperfusion, a phenomenon called ischaemic preconditioning. A transient exposure to exogenous calcium has been shown to mimic ischaemic preconditioning. Thus, a blockade of calcium channels may interfere with this reduction of infarct size. However, in anaesthetized pigs, nisoldipine did not prevent the reduction of infarct size by ischaemic preconditioning. Reperfused myocardium after short periods of myocardial ischaemia is characterized by a reversible, prolonged depression of myocardial function, a phenomenon called myocardial stunning. In anaesthetized dogs, pre-ischaemic intravenous administration of nisoldipine improved the functional recovery of stunned myocardium following a 15-min complete occlusion of the left circumflex coronary artery. Since myocardial blood flow during myocardial ischaemia and reperfusion was not altered and afterload was kept constant by an intra-aortic balloon, the beneficial effect of nisoldipine appears to be related to an attenuated calcium overload during early myocardial ischaemia. In conclusion, pro-ischaemic effects of calcium antagonists can be avoided when the dosage or mode of administration are adjusted to prevent significant decreases in arterial pressure. Patients in such a way under treatment with calcium antagonists will experience an increase in exercise tolerance and also a better recovery of contractile function after the termination of ischaemia.
Assuntos
Bloqueadores dos Canais de Cálcio , Di-Hidropiridinas , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Nisoldipino , Animais , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/efeitos adversos , Circulação Coronária , Vasos Coronários/efeitos dos fármacos , Di-Hidropiridinas/administração & dosagem , Di-Hidropiridinas/efeitos adversos , Cães , Humanos , Isquemia Miocárdica/fisiopatologia , Miocárdio Atordoado/tratamento farmacológico , Nisoldipino/administração & dosagem , Nisoldipino/efeitos adversos , Vasoconstrição/efeitos dos fármacosRESUMO
Myocardial ischaemia, when severe and sustained for more than 40 minutes, results in irreversible damage, i.e. myocardial infarction. However, with early reperfusion, damage is reversible. Complete recovery of contractile function requires some time, despite fully or almost fully restored blood flow. This phenomenon has been termed myocardial stunning. There is experimental evidence showing that angiotensin converting enzyme (ACE) inhibitors limit the development of infarct size, reduce the incidence of ischaemic and reperfusion arrhythmias, and enhance the recovery of contractile function of stunned myocardium. These cardioprotective effects of ACE inhibitors are mediated by an attenuated degradation of bradykinin.
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Inibidores da Enzima Conversora de Angiotensina/farmacologia , Bradicinina/fisiologia , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controle , Arritmias Cardíacas/prevenção & controle , Pressão Sanguínea/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Ensaios Clínicos como Assunto , Inibidores de Ciclo-Oxigenase/farmacologia , Interações Medicamentosas , Humanos , Contração Miocárdica/efeitos dos fármacos , Infarto do Miocárdio/fisiopatologia , Miocárdio Atordoado/prevenção & controle , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase/antagonistas & inibidores , Prostaglandinas/fisiologiaRESUMO
The attenuation of myocardial stunning by the ACE inhibitor ramiprilat is prevented by cyclooxygenase inhibition with indomethacin. In the clinical setting of ischemia/reperfusion however, the cyclooxygenase inhibitor aspirin is widely used to prevent platelet aggregation. The present study therefore investigated whether aspirin in dosages sufficient to inhibit platelet aggregation interferes with the attenuation of myocardial stunning by ramiprilat. Fifteen dogs received either 1 mg/(kg.day) (group I, n = 7) or 10 mg/(kg.day) (group II, n = 8) aspirin orally for 1 week. Both dosages of aspirin inhibited ADP-induced platelet aggregation. The dogs were then anesthetized thoracotomized and subjected to 15 min LCx-occlusion and 4 h reperfusion. Before LCx-occlusion, groups I and II received ramiprilat (20 micrograms/kg, i.v.). Systemic hemodynamics, posterior myocardial blood flow (PMBF, colored microspheres) and wall thickening (PWT, sonomicrometry) of these groups were measured and data compared to placebo-controls (group III, n = 11) and dogs receiving only ramiprilat before LCx-occlusion (group IV, n = 11). Four dogs received 10 mg/(kg.day) aspirin without ramiprilat (group V). Mean aortic pressure was kept constant by an intra-aortic balloon, and heart rate did not change. PMBF was not different between the five groups. Under control conditions and during myocardial ischemia PWT was also not different. At 4 h reperfusion PWT was still depressed in group III (-5 +/- 20% of control) and group V (-23 +/- 6%) whereas PWT recovered to the same extent in groups I (46 +/- 23%), II (50 +/- 15%) and IV (58 +/- 18%) (all P < 0.05 v groups III and V). The attenuation of myocardial stunning by the ACE inhibitor ramiprilat is not prevented by aspirin in dosages which are nevertheless sufficient to inhibit platelet aggregation.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Aspirina/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Coração/efeitos dos fármacos , Miocárdio Atordoado/induzido quimicamente , Ramipril/análogos & derivados , Animais , Cães , Interações Medicamentosas , Coração/fisiologia , Hemodinâmica/efeitos dos fármacos , Miocárdio Atordoado/prevenção & controle , Agregação Plaquetária/efeitos dos fármacos , Mudanças Depois da Morte , Ramipril/farmacologia , Fluxo Sanguíneo RegionalRESUMO
Myocardial "stunning" is characterized by a reversible postischemic contractile dysfunction despite full restoration of blood flow. The underlying mechanisms are not clearly understood. Inadequate energy supply and impaired sympathetic neurotransmission may have been excluded. Potential mechanisms, which are not mutually exclusive, may include damage to membranes and enzymes by free radicals, an increase in free cytosolic calcium during ischemia and reperfusion, and a lower calcium sensitivity of myofibrils. The equally pronounced increases in regional contractility in normal and stunned myocardium during postextrasystolic potentiation and the infusion of calcium or the calcium-sensitizing agent AR-L-57, however, suggest an unchanged calcium sensitivity in reperfused myocardium. Pretreatment with calcium antagonists before ischemia attenuates myocardial stunning. This effect is probably related to a lessened myocardial calcium overload during early ischemia. The potential benefit of treatment with calcium antagonists after reperfusion is established remains controversial.
Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Miocárdio Atordoado/prevenção & controle , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Cães , Humanos , Técnicas In Vitro , Contração Miocárdica/efeitos dos fármacos , Isquemia Miocárdica/tratamento farmacológico , Pré-Medicação , Ratos , Estimulação QuímicaRESUMO
Ischemia-reperfusion-induced injury of the coronary vasculature could result in an attenuated vasodilator or increased vasoconstrictor tone that might impact on myocardial recovery and viability. In 30 open-chest dogs the left circumflex coronary artery was occluded for 15 or 60 min and then reperfused, and responses to intracoronary acetylcholine, the alpha 1-adrenergic agonist methoxamine, and the alpha 2-adrenergic agonist BHT-933 (n = 10 each) were measured. In the experiments with 60 min of occlusion, triphenyltetrazolium chloride (TTC) staining was used to distinguish reversibly (TTC+) and irreversibly (TTC-) injured myocardium. After 15 min of occlusion, the vasodilator response to acetylcholine was not altered but was significantly reduced in TTC+ subendocardium and midmyocardium after 60 min of occlusion and was further reduced in TTC- subendocardium, midmyocardium, and also in subepicardium. The vasoconstrictor responses to methoxamine and BHT-933 were not altered after 15 or 60 min of occlusion in both TTC+ and TTC- myocardium. Posterior wall thickening was not affected by acetylcholine, methoxamine, or BHT-933. Thus, in reversibly injured myocardium after 15 min of occlusion, cholinergic and alpha-adrenergic coronary vasomotor responses are unchanged. With increasing duration of ischemia, reversibly and even more so irreversibly injured reperfused myocardium are characterized by an impaired cholinergic coronary vasodilation but not an enhanced alpha-adrenergic coronary vaso-constriction.
Assuntos
Agonistas alfa-Adrenérgicos/farmacologia , Colinérgicos/farmacologia , Circulação Coronária/efeitos dos fármacos , Isquemia Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Vasoconstrição , Acetilcolina/farmacologia , Animais , Azepinas/farmacologia , Cães , Hemodinâmica/efeitos dos fármacos , Metoxamina/farmacologia , Isquemia Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologiaRESUMO
BACKGROUND: Attenuation of myocardial stunning by several angiotensin-converting enzyme (ACE) inhibitors has been demonstrated. However, the signal cascade mediating such protective effect has not been analyzed in detail so far. METHODS AND RESULTS: In a first protocol, we addressed the role of bradykinin and analyzed the effect of the ACE inhibitor ramiprilat without and with added bradykinin B2 receptor antagonist HOE 140 on regional myocardial blood flow (colored microspheres) and function (sonomicrometry). Thirty-two enflurane/N2O-anesthetized open-chest dogs were subjected to 15 minutes of occlusion of the left circumflex coronary artery (LCx) and 4 hours of subsequent reperfusion. Eight dogs served as placebo controls (group 1), and 8 dogs received ramiprilat (20 micrograms/kg IV) before LCx occlusion (group 2). Eight dogs received a continuous intracoronary infusion of HOE 140 [0.5 ng/(mL.min) IC] during ischemia and reperfusion (group 3), and in 8 dogs HOE 140 was infused continuously during ischemia and reperfusion, starting 45 minutes before the administration of ramiprilat (group 4). Mean aortic pressure was kept constant with an intra-aortic balloon, and heart rate did not change throughout the experimental protocols. Under control conditions and during myocardial ischemia, posterior transmural blood flow (BF) and systolic wall thickening (WT) were not different in the four groups of dogs. However, at 4 hours of reperfusion, WT was still depressed in groups 1 (-10 +/- 20% of control [mean +/- SD]), 3 (-18 +/- 12% of control), and 4 (-12 +/- 21% of control), whereas WT in group 2 had recovered to 55 +/- 20% of control (P < .05 versus group 1). BF at 4 hours of reperfusion was not different in the four groups of dogs. Thus, the beneficial effect of ramiprilat on the functional recovery of stunned myocardium was obviously mediated by bradykinin. Since bradykinin stimulates the formation of both prostaglandins and nitric oxide, we tested in a second protocol which of these mediators was further involved in the beneficial effects of ramiprilat. Twenty-four additional dogs were subjected to 15 minutes of LCx occlusion and 4 hours of reperfusion. Six dogs received the cyclooxygenase inhibitor indomethacin (10 mg/kg IV) (group 5) and 6 dogs a combination of indomethacin with ramiprilat (group 6) before LCx occlusion. Six dogs received the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) (20 mg/kg IV) (group 7) and 6 dogs a combination of L-NAME with ramiprilat (group 8) before LCx occlusion. BF and WT before and during myocardial ischemia were not different in groups 5 and 6 and groups 7 and 8. However, at 4 hours of reperfusion, WT was still depressed in groups 5 (-10 +/- 38% of control), 6 (-7 +/- 18% of control), and 7 (-12 +/- 14% of control), whereas WT in group 8 had recovered to 47 +/- 28% of control (P < .05 versus group 7). BF at 4 hours of reperfusion was not different in the four groups of dogs. CONCLUSIONS: In summary, the attenuation of stunning by the ACE inhibitor ramiprilat involves a signal cascade of bradykinin and prostaglandins but not nitric oxide.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Bradicinina/fisiologia , Miocárdio Atordoado/fisiopatologia , Prostaglandinas/fisiologia , Ramipril/análogos & derivados , Transdução de Sinais , Animais , Circulação Coronária/efeitos dos fármacos , Cães , Coração/efeitos dos fármacos , Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Óxido Nítrico/fisiologia , Ramipril/farmacologiaRESUMO
Positive inotropic substances which enhance the myocardial cAMP level or inhibit the Na+/K(+)-ATPase are known for their proarrhythmic side-effects. This study was performed to investigate the inotropic and arrhythmogenic action of the Na(+)-channel activator BDF 9148 (racemate) in comparison to its S-enantiomer BDF 9196, its congener DPI 201-106 (racemate), to norepinephrine, and to ouabain. In 30 open-chest dogs, the effects of these substances on the first derivative of left ventricular pressure (dP/dt, Millar-tip catheter) and anterior systolic wall thickening (AWT, sonomicrometry) were studied. Concomitantly, myocardial excitability, conduction times, and refractory period were assessed with a transmural, three-dimensional, 16-electrode array in the anterior wall. For the study of the Na(+)-channel activators, alpha- and beta-adrenergic and muscarinic receptors were blocked. A first set of measurements was performed during normoperfusion with administration of BDF 9148 (1 mg/kg, n = 8), BDF 9196 (0.5 mg/kg, n = 8), and DPI 201-106 (1 mg/kg, n = 8), respectively. A second set of measurements was performed with administration of the threefold dosage of either substance. With a severe stenosis on the left anterior descending coronary artery, a final set of measurements was performed, again using the higher dosage of either substance. For the study of norepinephrine (0.5 micrograms/kg/min i.v., n = 6) and ouabain (40 micrograms/kg i.v., n = 4), measurements were performed during normoperfusion in additional animals. Under normal conditions, either Na(+)-channel activator induced increases in dP/dtmax (lower dosage: 45-84%, higher dosage: by 93-117%) and AWT (lower dosage: by 24-37%, higher dosage: by 19-56%). Under ischemic conditions, either drug increased dP/dtmax by 60-98% and AWT by 45-102%. Excitability, conduction times, and refractory period did not change significantly in response to the Na(+)-channel activators, neither under normal nor under ischemic conditions. There was no significant difference in the incidence of spontaneous ventricular extrasystoles before and after administration of either Na(+)-channel activator. In contrast, an equi-inotropic dosage of norepinephrine (increases in dP/dtmax by 148% and AWT by 42%) increased excitability, decreased conduction times and refractory period, and increased the incidence of spontaneous ventricular extrasystoles. Ouabain induced only a moderate increase in dP/dtmax by 56% and AWT by 24%, but elicited sustained and complex ventricular arrhythmias. Excitability was markedly increased, whereas conduction times and refractory period changed only little.(ABSTRACT TRUNCATED AT 400 WORDS)
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Azetidinas/farmacologia , Cardiotônicos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Piperazinas/farmacologia , Canais de Sódio/fisiologia , Análise de Variância , Animais , Aorta/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Cães , Estimulação Elétrica , Eletrocardiografia/efeitos dos fármacos , Isomerismo , Norepinefrina/farmacologia , Ouabaína/farmacologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Canais de Sódio/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
Increased heart rate and left ventricular pressure during humoral and neuronal adrenergic activation act to restrict blood flow preferentially in the subendocardium. The hypothesis was advanced that alpha-adrenergic coronary vasoconstriction preferentially in the subepicardium may counterbalance the enhanced extravascular compression in the subendocardium and serve to maintain blood flow transmurally uniform. In 40 anesthetized dogs, regional myocardial blood flow was determined with colored microspheres; wall function, with sonomicrometry. Humoral adrenergic activation (HAA) was induced by a combination of intravenous atropine, intravenous norepinephrine, and atrial pacing during baseline coronary vasomotor tone (group 1, n = 6) and in the presence of maximal coronary vasodilation with intravenous dipyridamole (group 2, n = 6). In an additional group, HAA was induced by intravenous norepinephrine in the presence of dipyridamole but without atropine and atrial pacing in order to increase end-diastolic left ventricular pressure (group 3, n = 6). Measurements were performed at rest, during HAA, and during ongoing HAA with the intracoronary infusion of the alpha-antagonist phentolamine (Phen). At unchanged mean aortic pressure, Phen improved blood flow particularly to the inner layers as follows: from 1.42 +/- 0.40 (mean +/- SD) to 1.90 +/- 0.40 mL/(min.g) (group 1, P < .05), from 4.99 +/- 2.31 to 5.53 +/- 2.56 mL/(min.g) (group 2, P < .05), and from 6.01 +/- 1.41 to 6.29 +/- 1.27 mL/(min.g) (group 3, P < .05), associated with a decrease in outer layer blood flow in groups 2 and 3. In 16 additional dogs, beta-adrenoceptors were blocked by propranolol and muscarinic receptors by atropine. Neuronal adrenergic activation (NAA) was induced by cardiac sympathetic nerve stimulation (CSNS) during baseline coronary vasomotor tone (group 4, n = 8) and in the presence of maximal vasodilation (group 5, n = 8). Measurements were performed at rest, during a first CSNS, and 20 minutes later during a second CSNS+Phen. The reproducibility of two consecutive episodes of CSNS 20 minutes apart was demonstrated in a separate set of experiments (n = 6). At matched mean aortic pressures, Phen improved blood flow to all myocardial layers in group 4, whereas in group 5, Phen induced a redistribution of myocardial blood flow toward subepicardial layers [from 4.44 +/- 0.96 to 4.81 +/- 0.83 mL/(min.g), P < .05] at the expense of inner layers. With the addition of Phen, there was no change in regional wall function in any group of dogs studied. Thus, during HAA, alpha-adrenergic coronary vasoconstriction does not exert a beneficial effect on transmural blood flow distribution. During NAA, a beneficial effect of alpha-adrenergic coronary vasoconstriction becomes apparent only under conditions of maximal coronary vasodilation.
Assuntos
Circulação Coronária , Vasos Coronários/fisiologia , Receptores Adrenérgicos alfa/fisiologia , Vasoconstrição , Animais , Cães , Coração/inervação , Miocárdio/metabolismo , Consumo de Oxigênio , Fentolamina/farmacologiaRESUMO
OBJECTIVE: The calcium antagonist nisoldipine has recently been reported to induce rather than to attenuate ischaemia in some patients with stable angina. The aim of the study was to investigate the mechanisms underlying this proischaemic effect. METHODS: In 20 anaesthetised dogs systemic haemodynamic variables, regional myocardial blood flow (coloured microspheres), and systolic wall thickening (sonomicrometry) were measured during control conditions and following severe stenosis on the left circumflex coronary artery, before and after intravenous administration of equihypotensive doses of either nisoldipine (group I, n = 10) or dipyridamole (group II, n = 10). Finally, measurements were performed while the drug induced decreases in mean aortic pressure--18 (SD 6) mmHg in group I and 14(6) mm Hg in group II--were reversed by inflation of an intra-aortic balloon. RESULTS: The stenosis decreased posterior wall thickening to 50% of control, and posterior subendocardial blood flow from 1.48(0.27) to 0.61(0.19) ml.min-1.g-1 in group I and from 1.49(0.23) to 0.62(0.18) ml.min-1.g-1 in group II. Subendocardial blood flow was further decreased after administration of either nisoldipine [0.37(0.20) ml.min-1.g-1, p < 0.05 v stenosis] or dipyridamole [0.22(0.11) ml.min-1.g-1, p < 0.05 v stenosis]. Regional myocardial blood flow in the anterior region was increased. The drug induced reduction of subendocardial blood flow decreased posterior wall thickening further from 9.3(2.1) to 6.2(3.9)% (p < 0.05 v stenosis, group I) and from 9.1(1.7) to 4.3(2.4)% (p < 0.05 v stenosis, group II). When the drug induced decrease in aortic pressure was reversed, subendocardial blood flow again increased in group I [0.63(0.19) ml.min-1.g-1, p < 0.05 v stenosis and nisoldipine] whereas in group II it remained decreased [0.40(0.29) ml.min-1.g-1, NS v stenosis and dipyridamole]. There was restoration of posterior wall thickening in group I [10.4(3.8)%, p < 0.05 v stenosis and nisoldipine], but not in group II [5.2(3.5)%, NS v stenosis and dipyridamole]. CONCLUSIONS: Nisoldipine and dipyridamole decrease subendocardial blood flow and contractile function distal to a severe stenosis when aortic pressure is decreased. No aggravation of ischaemia by nisoldipine is seen when hypotension is prevented. In contrast, dipyridamole in the absence of hypotension still induces a redistribution of flow at the expense of the ischaemic region.
Assuntos
Dipiridamol/efeitos adversos , Isquemia Miocárdica/induzido quimicamente , Nisoldipino/efeitos adversos , Animais , Pressão Sanguínea/efeitos dos fármacos , Dipiridamol/farmacologia , Cães , Coração/fisiologia , Contração Miocárdica/efeitos dos fármacos , Nisoldipino/farmacologia , Fluxo Sanguíneo Regional/efeitos dos fármacosRESUMO
The prolonged regional contractile failure of reperfused myocardium has usually been characterized in terms of systolic function, while only few reports on its diastolic function are available. None of these studies considered changes in the isovolumic diastole and the subsequent filling phase separately. Therefore, in the present study, the velocities of wall excursion during systole (Vsys), isovolumic diastole (Viso) and filling phase (Vfill) were determined in 12 anesthetized dogs. Additionally, post-ejection thickening (Pejt), a marker of left ventricular asynchrony, was determined. Measurements were performed under control conditions, during a 15 minute left circumflex (LCX) coronary artery occlusion (CAO) and at 10 minutes, 4 and 8 hours reperfusion. Heart rate, left ventricular pressure, and Vsys, Viso, Vfill, and Pejt of the anterior myocardium remained unchanged throughout the experiments. During CAO, systolic wall-thickening of the posterior wall was reversed to systolic wall-thinning. Upon reperfusion, Vsys started to recover (2.5 +/- 3.2 mm/s at 10 minutes) and gradually improved over 8 hours of reperfusion (4.6 +/- 3.2 mm/s at 4 hours, 6.4 +/- 1.5 mm/s at 8 hours). Viso became positive during CAO (9.4 +/- 7.1 mm/s vs. -5.6 +/- 3.9 mm/s under control conditions) and was unchanged at 10 minutes reperfusion (7.9 +/- 5.2 mm/s). After 4 hours and 8 hours of reperfusion, Viso recovered to 1.2 +/- 9.2 mm/s and -0.3 +/- 10.7 mm/s, respectively. Vfill also became positive during CAO (1.5 +/- 6.2 mm/s vs. -18 +/- 8.7 mm/s under control conditions). There was a quick recovery of Vfill (-9.4 +/- 7.5 mm/s) with the onset of reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Diástole/fisiologia , Miocárdio Atordoado/fisiopatologia , Animais , Cães , Feminino , Masculino , Reperfusão Miocárdica , Fatores de Tempo , Função Ventricular Esquerda/fisiologiaRESUMO
It is unclear whether the protective effects of calcium antagonists on reperfused myocardium are secondary to increased blood flow during ischemia (anti-ischemic action) or reperfusion (Gregg phenomenon), or are mediated through altered calcium kinetics in ischemic or reperfused myocardium. To study the effect of the calcium antagonist nisoldipine on the functional recovery of stunned myocardium, 32 enflurane-anesthetized dogs were subjected to 15 min of occlusion of the left circumflex coronary artery and subsequent 4 h of reperfusion. Eight dogs served as placebo controls (group I), and eight dogs received nisoldipine (5 micrograms/kg i.v.) before occlusion (group II), eight dogs at 10 min of occlusion (group III), and eight dogs at 4 min of reperfusion (group IV). The mean aortic pressure was kept constant with an intra-aortic balloon, and the heart rate did not change. In group I, posterior systolic wall thickening (WT, sonomicrometry) decreased from 18.3 +/- 2.4% (mean +/- SD) during control conditions to -3.0 +/- 2.0% at 13 min of occlusion. At 10 min of reperfusion, WT was 1.7 +/- 3.9% and did not recover further (-1.2 +/- 3.7% at 4 h of reperfusion). Posterior transmural blood flow (BF, colored microspheres) decreased from 1.42 +/- 0.43 ml/min/g during control conditions to 0.26 +/- 0.08 ml/min/g at 13 min of occlusion. BF was 2.07 +/- 0.93 ml/min/g at 10 min and 0.95 +/- 0.31 ml/min/g at 4 h of reperfusion. In groups III and IV, the WT and BF were not different from those in group I throughout the experimental protocol. In group II, however, the WT, although similar to the WT of group I before and during ischemia, recovered from 2.7 +/- 4.3% at 10 min to 11.8 +/- 6.0% at 4 h of reperfusion (p less than 0.05 vs. groups I, III, and IV). The BF in group II decreased from 2.52 +/- 0.66 ml/min/g after administration of nisoldipine to 0.22 +/- 0.14 ml/min g at 13 min of occlusion. The BF was 1.31 +/- 0.51 ml/min/g at 10 min and 1.33 +/- 0.43 ml/min/g at 4 h of reperfusion. Nisoldipine exerts no beneficial effect when given immediately before or after the onset of reperfusion. The improved functional recovery of reperfused myocardium in dogs pretreated with nisoldipine cannot be attributed to an increased regional myocardial blood flow during ischemia or reperfusion. The better myocardial recovery, therefore, appears to be related to an attenuated myocardial calcium overload during the first few minutes of ischemia.
Assuntos
Circulação Coronária/efeitos dos fármacos , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Nisoldipino/farmacologia , Análise de Variância , Animais , Cálcio/metabolismo , Cães , Isquemia Miocárdica/fisiopatologia , Reperfusão Miocárdica , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Nisoldipino/administração & dosagem , Análise de RegressãoRESUMO
Ventricular arrhythmias are primarily responsible for sudden cardiac death early after the onset of acute myocardial ischemia. We designed an experimental model to simultaneously characterize regional myocardial function, myocardial blood flow, and electrophysiological parameters, and to determine predisposing factors for the development of early ventricular arrhythmias (EVA). The left circumflex coronary artery was occluded in six anesthetized (n = 2 piritramide/N2O, n = 4 chloralose/urethane) mongrel dogs. Systolic wall thickening (%WT) in a control zone and in the central ischemic zone was measured with sonomicrometry and regional myocardial blood flow (RMBF) with colored microspheres. Excitability and relative refractory period at the stimulus electrode and conduction times to all other electrodes were determined with a three-dimensional transmural multi(16)-electrode assay using a computer algorithm. In three of six dogs spontaneous EVA occurred 4 to 6 min after coronary occlusion, degenerating to ventricular fibrillation in two of these dogs. The three dogs developing EVA were not distinguished from those not developing EVA, neither by the kind of anesthesia nor by ischemic % WT (-6.6 +/- 3.8 [SD] vs -7.8 +/- 1.6, ns). Also, dogs with and without EVA did not differ significantly in excitability and relative refractory period. In contrast, dogs with EVA were characterized by a greater mass of severely ischemic myocardium, i.e., exhibiting a RMBF reduction to less than 0.1 ml/(min.g) (18 +/- 3 g vs 7 +/- 4 g, p less than 0.05), and by an increase in subendocardial conduction times of greater than 100% above the respective pre-ischemic values (120 +/- 18% vs 66 +/- 9%, p less than 0.05). Dogs with and without EVA were not as clearly distinguished by the increases in subepicardial (81 +/- 22% vs 46 +/- 15%, ns) and transmural (98 +/- 31% vs 67 +/- 14%, ns) conduction times. The development of EVA is associated with a greater mass of severely ischemic myocardium and a greater increase in subendocardial conduction times.
Assuntos
Arritmias Cardíacas/fisiopatologia , Doença das Coronárias/fisiopatologia , Sistema de Condução Cardíaco/fisiopatologia , Ventrículos do Coração/fisiopatologia , Animais , Arritmias Cardíacas/etiologia , Doença das Coronárias/complicações , Modelos Animais de Doenças , Cães , Eletrofisiologia , Tamanho do Órgão , Fluxo Sanguíneo RegionalRESUMO
In the initial seconds after a sudden reduction in coronary blood flow, a temporary mismatch between myocardial energy demand and supply exists. The mechanisms underlying the rapidly ensuing reduction in contractile function in the ischemic myocardium are still unknown. In the presence of some residual blood flow, a state of "perfusion-contraction matching" develops. The metabolic status of such hypoperfused myocardium improves, since myocardial lactate production is attenuated and creatine phosphate (CP), after an initial reduction, returns toward control values. The hypoperfused myocardium responds to inotropic stimulation by dobutamine. The recruitment of an inotropic reserve implies increased energy utilization. During inotropic stimulation, after partial normalization, lactate production is again increased, and CP is decreased again. Thus, a supply-demand imbalance that had been at least partially corrected by the ischemia-induced decrease in regional contractile function is precipitated again. A situation of chronic contractile failure in viable myocardium that normalizes upon reperfusion has been termed myocardial "hibernation." Myocardial "stunning" is characterized by a reversible postischemic contractile dysfunction despite full restoration of blood flow. The details of the underlying mechanisms are not clear. An inadequate energy supply and impaired sympathetic neurotransmission have been excluded. Potential mechanisms, which are not mutually exclusive, may include (a) damage of membranes by free radicals, (b) an increase in free cytosolic calcium during ischemia and reperfusion, and (c) a decrease in the calcium sensitivity of the myofibrils. The equally pronounced increases in regional contractility in normal and "stunned" myocardium during postextrasystolic potentiation and the infusion of calcium or the calcium-sensitizing agent AR-L-57, however, suggest an unchanged calcium sensitivity of reperfused myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Isquemia Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Cálcio/metabolismo , Circulação Coronária/efeitos dos fármacos , Humanos , Lactatos/metabolismo , Ácido Láctico , Contração Miocárdica/efeitos dos fármacos , Isquemia Miocárdica/fisiopatologia , Reperfusão Miocárdica , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Fosfocreatina/metabolismoRESUMO
Myocardial function is impaired by ischaemia, and it remains depressed during reperfusion following short periods of ischaemia (stunned myocardium). We tested whether ischaemic and reperfusion dysfunction, in particular the time course of its recovery, can be distinguished by postextrasystolic potentiation (PESP). In eight open-chest dogs, posterior systolic wall thickening (sonomicrometry) was reduced by graded occlusion of the left circumflex coronary artery (LCX) from 17.4 +/- 6.8% (SD) during control conditions to 10.7 +/- 1.3% (mild ischaemic dysfunction), 7.2 +/- 2.3% (moderate ischaemic dysfunction), 3.6 +/- 1.4% (severe ischaemic dysfunction), and -4.4 +/- 3.6% (complete coronary occlusion). Extrasystoles with constant prematurity and a fully compensated postextrasystolic interval were induced after at least 4 min steady-state ischaemia. After each ischaemic period full recovery of posterior systolic wall thickening was assured. During 8 h of reperfusion following a 15-min LCX occlusion, extrasystoles were induced when posterior systolic wall thickening was comparable to one degree of the preceding ischaemic dysfunction. The increases in posterior systolic wall thickening induced by PESP were 10.5 +/- 5.8% during control conditions, during ischaemia they were 11.5 +/- 3.5% (mild dysfunction), 12.3 +/- 4.6% (moderate dysfunction), 12.6 +/- 4.1% (severe dysfunction) and 10.4 +/- 4.4% (complete coronary occlusion), and during reperfusion they were 12.8 +/- 8.2% (severe dysfunction), 13.0 +/- 9.7% (moderate dysfunction) and 10.7 +/- 2.2% (mild dysfunction).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Doença das Coronárias/diagnóstico , Eletrofisiologia/métodos , Traumatismo por Reperfusão Miocárdica/diagnóstico , Animais , Diagnóstico Diferencial , Diástole , Cães , Feminino , Coração/fisiopatologia , Hemodinâmica , Masculino , Miocárdio/patologia , Necrose , SístoleRESUMO
There is a marked heterogeneity of myocardial wall thickening within the left ventricle and among different individuals. It is therefore difficult to detect regional myocardial dysfunction from absolute values of systolic wall thickening. We tested whether the extent of left ventricular asynchrony during ischemia and reperfusion can be used to quantify the severity of regional myocardial dysfunction when nonischemic baseline function is not known. In six anesthetized, open-chest dogs regional myocardial wall thickness was measured by means of sonomicrometry under control conditions, at three degrees of ischemic dysfunction (mild, moderate, and severe), and after release of a 15-minute occlusion of the left circumflex coronary artery, when degrees of moderate and mild reperfusion dysfunction similar to the preceding ischemic dysfunction were present. Two indexes of left ventricular asynchrony were calculated: (1) postejection thickening (PET) and (2) the phase difference of the first Fourier harmonic of posterior versus anterior myocardial wall motion (PD). Systolic myocardial wall thickening was decreased from 15.3 +/- 3.1 (standard deviation) % (control value) to 9.7 +/- 1.4% (mild ischemia), 4.2 +/- 1.6% (moderate ischemia), and -3.7 +/- 3.1% (severe ischemia). Conversely PET increased from 0.02 +/- 0.04 mm (control value) to 0.15 +/- 0.22 mm (mild ischemia), 0.19 +/- 0.15 mm (moderate ischemia), and 0.50 +/- 0.26 mm (severe ischemia). PD increased from 9 +/- 28 degrees (control value) to 22 +/- 19 degrees (mild ischemia), 54 +/- 18 degrees (moderate ischemia), and 107 +/- 21 degrees (severe ischemia). After release of the 15-minute left circumflex coronary artery occlusion, PET and PD recovered to 0.34 +/- 0.19 mm and 36 +/- 24 degrees (moderate dysfunction) and 0.25 +/- 0.31 mm and 29 +/- 8 degrees (mild dysfunction), respectively. There were inverse linear relationships between systolic wall thickening and PET (r = -0.86, p less than 0.001) and between systolic wall thickening and PD (r = -0.87, p less than 0.001). Inotropic stimulation by postextrasystolic potentiation increased regional systolic myocardial posterior and anterior wall thickening but did not alter the extent of left ventricular asynchrony. Thus, when normal baseline function is not known, the severity of regional myocardial dysfunction at a given inotropic state can be determined by analysis of left ventricular asynchrony. There was no significant correlation between the extent of PET and PD during ischemia and at early reperfusion and the recovery of contractile function at late reperfusion. Thus PET does not provide a prospective marker for the functional outcome of reperfusion.