David García Dorado

University Hospital Vall d'Hebron, Barcino, Catalonia, Spain

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Publications (6)19.6 Total impact

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    ABSTRACT: Microtubules play a major role in the transmission of mechanical forces within the myocardium and in maintenance of organelle function. However, this intracellular network is disrupted during myocardial ischaemia-reperfusion. We assessed the effects of prevention of microtubule disruption with paclitaxel on ischaemia-reperfusion injury in isolated rat cardiomyocytes and hearts. Isolated rat cardiomyocytes were submitted to normoxia (1 h) or 45 min of simulated ischaemia (pH 6.4, 0% O2, 37°C) and reoxygenation, without or with treatment with the microtubule stabilizer, paclitaxel (10(-5) m), or the inhibitor of microtubule polymerization, colchicine (5 × 10(-6) m). Simulated ischaemia leads to microtubule disruption before the onset of ischaemic contracture. Paclitaxel attenuated both microtubule disruption and the incidence of hypercontracture, whereas treatment with colchicine mimicked the effects of simulated ischaemia and reoxygenation. In isolated normoxic rat hearts, treatment with paclitaxel induced concentration-dependent decreases in heart rate and left ventricular developed pressure and increases in perfusion pressure. Despite protection against hypercontracture, paclitaxel pretreatment did not modify infarct size (60.37 ± 2.27% in control hearts versus 58.75 ± 10.25, 55.44 ± 10.32 and 50.06 ± 10.14% after treatment with 10(-6), 3 × 10(-6) and 10(-5) m of paclitaxel) after 60 min of global ischaemia and reperfusion in isolated rat hearts. Lack of protection was correlated with a higher increase in cytosolic calcium levels during simulated ischaemia in cardiomyocytes treated with paclitaxel (2.32 ± 0.15 versus 1.13 ± 0.16 a.u. in the presence or absence of 10(-6) m paclitaxel, respectively, P < 0.05), but not with changes in aortic reactivity. In conclusion, microtubule stabilization with paclitaxel reduces hypercontracture in isolated rat cardiomyocytes but does not protect against infarction in isolated rat hearts.
    Experimental physiology 11/2014; 100(1). DOI:10.1113/expphysiol.2014.082925 · 2.67 Impact Factor
  • Javier Inserte · David Garcia‐Dorado
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    ABSTRACT: Cardiomyocyte cell death occurring during myocardial reperfusion (reperfusion injury) contributes to final infarct size after transient coronary occlusion. Different interrelated mechanisms of reperfusion injury have been identified, including alterations in cytosolic Ca2+ handling, sarcoplasmic reticulum-mediated Ca2+ oscillations and hypercontracture, proteolysis secondary to calpain activation, and mitochondrial permeability transition. All these mechanisms occur during the initial minutes of reperfusion and are inhibited by intracellular acidosis. The cGMP/PKG pathway modulates the rate of recovery of intracellular pH, but has also direct effect on Ca2+ oscillations and mitochondrial permeability transition. The cGMP/PKG pathway is depressed in cardiomyocytes by ischemia/reperfusion, and preserved by ischemic postconditioning, which importantly contributes to postconditioning protection. The present article reviews the mechanisms and consequences of the effect of ischemic postconditioning on the cGMP/PKG pathway, the different pharmacological strategies aimed to stimulate it during myocardial reperfusion, and the evidence, limitations and promise of translation of these strategies to the clinical practice. Overall, the preclinical and clinical evidence suggests that modulation of the cGMP/PKG pathway may be a therapeutic target in the context of myocardial infarction.
    British Journal of Pharmacology 10/2014; 172(8). DOI:10.1111/bph.12959 · 4.84 Impact Factor
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    ABSTRACT: Occurrence of moderate-to-severe pericardial effusion (PE; ≥10 mm), cardiac tamponade (CT), and sudden electromechanical dissociation (EMD) was investigated in 4,361 patients with ST-elevation myocardial infarction from 1993 to 2011 in 3 different periods: 1993 to 2000 (n: 1,488); 2001 to 2008 (n: 1,844); and 2009 to 2011 (n: 1,014). Their predictors, including the use of no reperfusion therapy (n: 1,186), thrombolysis (n: 1,607), or primary percutaneous coronary intervention (PPCI, n: 1,562), were also evaluated. Incidence of PE (8.7%, 6.8%, and 5.0%), CT (5.0%, 2.9%, and 1.9%), and EMD (3.7%, 1.7%, and 1.0%), declined over the 3 periods as did mortality (12.0% 8.2%, and 5.9%) with different rates of thrombolytic therapy (52%, 37%, and 14%) and PPCI (7%, 38%, and 76%; all p <0.001). In patients treated without reperfusion therapy, thrombolysis, and PPCI, incidence of PE (12.0%, 5.7%, and 4.3%), CT (6.0%, 3.0%, and 2.2%), and EMD (4.1%, 2.2%, and 0.8%) was different as was mortality (14.4%, 8.3%, and 5.9%; all p <0.001). Independent predictors of PE were lateral infarction (odds ratio [OR] 4.09, 95% confidence interval [CI] 2.57 to 6.49), increasing age (OR 1.05, 95% CI 1.04 to 1.07), number of electrocardiographic leads involved (OR 1.34, 95% CI 1.23 to 1.45), and admission delay (OR 1.01, 95% CI 1.01 to 1.02). Increasing ejection fraction (OR 0.97, 95% CI 0.96 to 0.98), thrombolysis (OR 0.53, 95% CI 0.37 to 0.75), and PPCI (OR 0.35, 95% CI 0.25 to 0.50), however, were protectors (all p <0.001). Lateral infarction, age, number of leads involved, ejection fraction, thrombolytic therapy, and PPCI were also predictors/protectors of CT and EMD. In conclusion, PE, CT, and EMD rates in patients with ST-elevation myocardial infarction have objectively fallen in the last 2 decades, and their predictors are lateral site, increasing age, number of leads involved, and lack of reperfusion therapy. Late hospital admission is also a relevant predictor of PE.
    The American journal of cardiology 01/2014; 113(8). DOI:10.1016/j.amjcard.2013.11.071 · 3.28 Impact Factor
  • International journal of cardiology 12/2011; 154(3):370-2. DOI:10.1016/j.ijcard.2011.11.064 · 4.04 Impact Factor
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    ABSTRACT: Among patients with acute cardiac syndromes without coronary stenosis, the clinical, electrocardiographic, echocardiographic, and angiographic features of those with a first acute myocardial infarction (AMI) were compared with those with apical-ballooning syndrome (ABS). Data of consecutive patients admitted with a first AMI (n=30) or ABS (n=45) were reviewed. Patients with ABS were older (72 vs. 56 years; P=0.001) and presented a higher frequency of female sex (91 vs. 43%; P=0.001), triggering emotional or physical stress (47 vs. 17%; P=0.003) and a lower rate of tobacco smoking (27 vs. 50%; P=0.051) than those with the first AMI. They also presented a greater number of leads (5.5 vs. 3.6; P=0.01) and more anterior or anterior+inferior involvement (96 vs. 40%; P<0.001), more depressed ejection fraction (45 vs. 57%; P=0.001), more proportion of akinesia or diskinesia (89 vs. 27%; P=0.001) that extended beyond the boundaries of a single-vessel territory, and a greater rate of left ventricular outflow obstruction (29 vs. 0%; P=0.001) and heart failure (38 vs. 10%; P=0.015). Frequency of nonsignificant coronary stenosis or smooth vessels, however, was similar in both groups. Patients with ABS were older and more frequently were women than those with first AMI without significant coronary stenosis and had larger hypocontractile areas. The preponderance of tobacco smoking, pain without triggers, and hypocontractility limited to one-vessel territory in the latter, however, may suggest a transient thrombotic/vasospastic event as their underlying mechanism as opposed to patients with ABS.
    Coronary artery disease 06/2011; 22(6):435-41. DOI:10.1097/MCA.0b013e328348f502 · 1.50 Impact Factor
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    ABSTRACT: Patients with variant angina pectoris showed greater serotonin plasma levels than did control subjects and patients with healed myocardial infarction. The levels also tended to be greater in those with > 1 episode/month than in those with fewer episodes. Moreover, patients with variant angina pectoris also had greater levels of nitrite and nitrate plasma levels than did control subjects or patients with healed myocardial infarction, partly, perhaps, as a compensatory mechanism. (c) 2005 Elsevier Inc. All rights reserved.
    The American Journal of Cardiology 07/2005; 96(2):204-7. DOI:10.1016/j.amjcard.2005.03.044 · 3.28 Impact Factor