Biomedical subjects

Jordi Soler-Soler

Publications and source records attributed to Jordi Soler-Soler.

At least 19 recordsLinked to original sources

PubMed2006

Ischemic preconditioning prevents calpain-mediated impairment of Na+/K+-ATPase activity during early reperfusion.

OBJECTIVES: We previously demonstrated that ischemic preconditioning (IPC) attenuates calpain activation during reperfusion. Herein, we tested the hypothesis that enhancement of Na+/K+-ATPase activity during early reperfusion as a result of calpain inhibition is involved in the protection afforded by myocardial IPC. METHODS: Intracellular Na+ concentration ([Na+]i) measured using 23Na-magnetic resonance spectroscopy, Na+/K+-ATPase activity, detachment of Na+/K+-ATPase alpha subunits from the membrane cytoskeleton, degradation of fodrin and ankyrin, and calpain activation were analysed in isolated rat hearts reperfused after 60 min of ischemia with or without previous IPC and different treatments aimed to mimic or blunt the effects of IPC. RESULTS: In non-treated hearts subjected to ischemia (control hearts), reperfusion for 5 min severely reduced Na+/K+-ATPase activity and dissociated alpha1 and alpha2 subunits of Na+/K+-ATPase from the membrane-cytoskeleton complex in parallel with proteolysis of alpha-fodrin and ankyrin-B and calpain activation. IPC accelerated the recovery of [Na+]i, increased Na+/K+-ATPase activity, and prevented dissociation of Na+/K+-ATPase from the membrane-cytoskeleton complex. IPC also prevented alpha-fodrin and ankyrin-B loss and calpain activation, effects that were associated with attenuated lactate dehydrogenase (LDH) release and infarct size and improved contractile recovery. These effects of IPC were reproduced by perfusing the hearts with the calpain inhibitor MDL-28170 and by transient stimulation of cAMP-dependent protein kinase (PKA) with CPT-cAMP, and they were reverted by perfusing with the PKA inhibitor H89. CONCLUSION: The results of the present study are consistent with the hypothesis that enhanced recovery of Na+/K+-ATPase activity during reperfusion as a result of attenuated calpain-mediated detachment of the protein from the membrane-cytoskeleton complex contributes to the protection afforded by IPC.

Animals↗

PubMed2006

Effects of hypoxia, glucose deprivation and acidosis on phosphatidylcholine synthesis in HL-1 cardiomyocytes. CTP:phosphocholine cytidylyltransferase activity correlates with sarcolemmal disruption.

A decrease in [3H]Cho (choline) incorporation in to PtdCho (phos-phatidylcholine) preceded the onset of LDH (lactate dehydrogenase) release in HL-1 cardiomyocytes submitted to simulated ischaemia. This observation led us to examine the role of PtdCho synthesis in sarcolemmal disruption in HL-1 cardiomyocytes. To address this objective we analysed the individual effects of hypoxia, glucose deprivation and acidosis, three prominent components of ischaemia, on the different steps of the Kennedy pathway for the synthesis of PtdCho. Pulse and pulse-chase experiments with [3H]Cho, performed in whole HL-1 cells submitted to hypoxia or normoxia, in the presence or absence of glucose at different pHs indicated first, that CK (choline kinase) was inhibited by hypoxia and acidosis, whereas glucose deprivation exacerbated the inhibition caused by hypoxia. Second, the rate-limiting reaction in PtdCho synthesis, catalysed by CCT (CTP:phosphocholine cytidylyltransferase), was inhibited by hypoxia and glucose deprivation, but unexpectedly activated by acidosis. In cellfree system assays, acidosis inhibited both CK and CCT. In experiments performed in whole cells, the effect of acidosis was likely to be direct on CK, but indirect or intact-cell-dependent on CCT. Since hypoxia and glucose deprivation favoured membrane disruption, but acidosis prevented it, we hypothesized that the modulation of CCT could be an important determinant of cell survival. Supporting this hypothesis, we show that CCT activity in whole-cell experiments clearly correlated with LDH release, but not with ATP concentration. Altogether our results suggest a significant role for CCT activity in sarcolemmal disruption during ischaemia.

Acidosis↗

PubMed2006

Long-term outcome of surgically treated aortic regurgitation: influence of guideline adherence toward early surgery.

OBJECTIVES: The purpose of this study was to compare postoperative outcome in two groups of patients with chronic severe aortic regurgitation (AR): those operated on early and those operated on late according to the guidelines. BACKGROUND: The impact of earlier surgery for chronic severe AR as defined in guidelines has not been evaluated. METHODS: A total of 170 patients with chronic severe AR submitted to aortic valve replacement were prospectively followed up. Patients were divided in two groups depending on the clinical situation at the time of surgery. Group A were 60 patients who were operated on following guidelines advice of earlier surgery, and group B were 110 patients who were operated on late with regard to guideline recommendations. RESULTS: Follow-up was 10 +/- 6 years (1 to 22 years). During follow-up 44 patients died, 7 patients (12%) from group A and 37 (37%) from group B (p = 0.001). The cause of death was non-cardiac in 11 patients, 2 (3%) in group A and 9 (8%) in group B. Cardiac deaths occurred in 33 patients, 5 (9%) from group A and 28 (28%) from group B (p = 0.002). Causes of death differed between groups A and B: heart failure or sudden death were significantly more frequent in group B (20 patients vs. 1 patient, p = 0.001). Overall survival in groups A and B was 90 +/- 4% vs. 75 +/- 8% at 5 years, 86 +/- 5% vs. 64 +/- 5% at 10 years, and 78 +/- 7% vs. 53 +/- 6% at 15 years, respectively (p = 0.009). CONCLUSIONS: Early operation as defined in the guidelines improves long-term survival in patients with chronic AR.

Adolescent↗

PubMed2005

Intracoronary infusion of Gd3+ into ischemic region does not suppress phase Ib ventricular arrhythmias after coronary occlusion in swine.

Increased mechanical tension in the ischemic region during acute coronary occlusion might favor the occurrence of phase Ib ventricular arrhythmias. We aimed to investigate whether intracoronary administration of Gd(3+), a stretch-activated channel blocker, into the ischemic zone reduces the incidence of these arrhythmias. In thiopental-anesthetized, open-chest pigs, the left anterior descending coronary artery (LAD) was ligated for 45 or 48 min. Phosphate-free, HEPES-buffered saline bubbled with 100% N(2) was infused into the ischemic region for 4 min, starting 5 min (series A; n = 16) or 20 min (series B; n = 16) after coronary occlusion, at a rate doubling the baseline blood flow. Animals were blindly allocated to receive 40 muM Gd(3+) or only the buffer during the final 2 min of the infusion. There were no differences between groups with respect to hemodynamic variables, plasma K(+) levels, or size of the ischemic region. In neither series was the number of phase Ib premature ventricular beats reduced by Gd(3+) (46 +/- 20 in untreated vs. 91 +/- 37 in Gd(3+)-treated animals in series A and 19 +/- 7 vs. 22 +/- 13, respectively, in series B; both P = not significant). The occurrence of ventricular tachycardia or fibrillation was significantly associated with the magnitude of early ischemic expansion of the LAD region, as measured by ultrasonic crystals, but was also not prevented by Gd(3+). These results argue against a major role of stretch-activated channels inside the area at risk in the genesis of phase Ib ischemic ventricular arrhythmias.

Animals↗

PubMed2005

Relation of myocardial perfusion defects and nonsignificant coronary lesions by angiography with insights from intravascular ultrasound and coronary pressure measurements.

Several studies have demonstrated a correlation between myocardial ischemia and severity of coronary lesions as determined by intravascular ultrasound (IVUS) and fractional flow reserve (FFR) measurements. However, their value for the assessment of mild coronary stenoses that are associated with myocardial perfusion abnormalities has not been well studied. The objective of this study was to prospectively compare the results of myocardial perfusion as determined by exercise/dipyridamole myocardial single-photon emission computed tomography with IVUS and FFR measurements in patients who had angiographically mild coronary stenosis (< 50% diameter stenosis by quantitative coronary angiography). Forty-eight patients who had stable coronary disease (61 +/- 11 years of age; 6 women) were included. All had mild coronary stenosis in the proximal/middle segment of > or = 1 coronary artery and had undergone maximal exercise myocardial technetium-99m tetrofosmin single-photon emission computed tomography within 48 hours before coronary angiography. IVUS measurements included lesion lumen area, external elastic membrane area, lesion plaque burden (calculated as external elastic membrane minus lumen area, divided by external elastic membrane, and multiplied by 100), and lumen area stenosis (calculated as reference lumen area minus lesion lumen area, divided by reference lumen area, multiplied by 100). Fifty-three coronary lesions were studied, with a mean percent diameter stenosis of 34.9 +/- 7.9% on angiography. Myocardial perfusion defects were demonstrated by single-photon emission computed tomography in 11 patients (12 myocardial regions) with no differences in lesion percent diameter stenosis compared with those without perfusion defects. The presence of reversible perfusion defects was associated with a higher lesion plaque burden as evaluated by IVUS (67.4 +/- 8.1% vs 60.2 +/- 9.3%, p = 0.01). FFR values did not differ in the presence or absence of perfusion defects (0.90 +/- 0.06 vs 0.92 +/- 0.07, respectively; p = NS). In conclusion, plaque burden as determined by IVUS may partly explain the presence of myocardial perfusion defects in cases of angiographically nonsignificant coronary lesions. However, the high FFR values associated with these lesions suggest that other mechanisms, such as endothelial/microvascular dysfunction, might also account for perfusion abnormalities in these patients.

Blood Pressure↗

PubMed2005

Membrane association of nitric oxide-sensitive guanylyl cyclase in cardiomyocytes.

OBJECTIVE: Although the importance of the cyclic GMP (cGMP) signaling pathway in cardiac myocytes is well established, little is known about its regulation. Ca2+-dependent translocation of nitric oxide (NO) sensitive guanylyl cyclase (GCNO) to the cell membrane has been recently proposed to play a role. The aim of this study was to determine the possible functional relevance of GCNO bound to the cardiomyocyte membrane. METHODS: Cytosolic and particulate fractions of adult rat cardiomyocytes were isolated and blotted, and their GCNO activity was assayed in parallel experiments. RESULTS: In untreated cardiomyocytes, approximately 30% of beta1-and alpha1-subunits of GCNO and a similar proportion of GCNO activity were found in the particulate fraction. The dependence of GCNO activity on pH, Ca2+, GTP and NO donor concentrations was similar in particulate and cytosolic fractions. Treatment of cardiomyocytes with the ionophore A23187 caused GCNO to translocate to the sarcolemma, increased GCNO activity in this fraction, and potentiated NO-mediated cGMP synthesis. These effects appeared to be mediated by Ca2+-dependent changes on the phosphorylation status of GCNO, since they were enhanced by the non-selective inhibitor staurosporine and by the selective inhibitor of Ca2+/calmodulin-dependent protein kinase KN-93. The effect of drugs increasing intracellular Ca2+ on cGMP synthesis was clearly correlated with their effects on membrane-associated GCNO activity but not with their effects on cytosol-associated GCNO. CONCLUSION: These results are the first evidence that 1) GCNO is associated with the cell membrane in cardiomyocytes, 2) the regulation of membrane-associated GCNO differs from that of cytosolic GCNO, and 3) membrane association may have a crucial role in determining the response of cells to NO.

1-Methyl-3-isobutylxanthine↗

PubMed2005

Long-term vasodilator therapy in patients with severe aortic regurgitation.

BACKGROUND: Vasodilator therapy can reduce the left ventricular volume and mass and improve left ventricular performance in patients with aortic regurgitation. Accordingly, it has been suggested that such therapy may reduce or delay the need for aortic-valve replacement. METHODS: We randomly assigned 95 patients with asymptomatic severe aortic regurgitation and normal left ventricular function to receive open-label nifedipine (20 mg every 12 hours), open-label enalapril (20 mg per day), or no treatment (control group) to identify the possible beneficial effects of vasodilator therapy on left ventricular function and the need for aortic-valve replacement. RESULTS: After a mean of seven years of follow-up, the rate of aortic-valve replacement was similar among the groups: 39 percent in the control group, 50 percent in the enalapril group, and 41 percent in the nifedipine group (P=0.62). In addition, there were no significant differences among the groups in aortic regurgitant volume, left ventricular size, left ventricular mass, mean wall stress, or ejection fraction. One year after valve replacement, the left ventricular end-diastolic diameter and end-systolic diameter had decreased to a similar degree among the patients who underwent surgery in each of the three groups, and all the patients had a normal ejection fraction. CONCLUSIONS: Long-term vasodilator therapy with nifedipine or enalapril did not reduce or delay the need for aortic-valve replacement in patients with asymptomatic severe aortic regurgitation and normal left ventricular systolic function. Furthermore, such therapy did not reduce the aortic regurgitant volume, decrease the size of the left ventricle, or improve left ventricular function.

Actuarial Analysis↗

PubMed2005

Correspondence between left ventricular 17 myocardial segments and coronary arteries.

AIMS: The last guidelines recommend a standardized 17-segment model for tomographic imaging of the left ventricle. The aim of this study is to analyse the correspondence of the 17 left ventricular segments with each coronary artery by myocardial perfusion SPECT studies. METHODS AND RESULTS: Fifty patients selected for percutaneous revascularization of one coronary artery [24 left anterior descending (LAD), 15 right coronary artery (RCA), and 11 left circumflex (LCX)] were included. The (99m)Tc-labelled compound was injected immediately after the inflation of the balloon during percutaneous coronary angioplasty. At least 90 s of complete occlusion time was required. Maximal contour of regions of hypoperfusion corresponding to each coronary artery occlusion were delineated over the polar map of 17 segments. Nine segments corresponded to only one coronary artery: eight to LAD (basal anterior, basal anteroseptal, mid-anterior, mid-anteroseptal, apical anterior, apical septal, apical lateral, and apex) and one to LCX (basal anterolateral). Basal inferoseptal, mid-inferoseptal, and apical inferior segments could correspond to LAD or RCA. Basal inferior, basal inferolateral, mid-inferior, and mid-inferolateral segments could correspond to RCA or LCX, whereas the mid-anterolateral segment could correspond to LAD or LCX. CONCLUSION: The most specific segments (anterior, anteroseptal, and all apical segments except the infero-apical) correspond to LAD but no segment can be exclusively attributed to the RCA. Inferoseptal segments can be attributed to LAD or RCA, inferior and inferolateral segments to RCA or LCX, and mid-anterolateral segment to LAD or LCX.

Angioplasty, Balloon, Coronary↗

PubMed2005

Protective effect of gap junction uncouplers given during hypoxia against reoxygenation injury in isolated rat hearts.

It has been shown that cell-to-cell chemical coupling may persist during severe myocardial hypoxia or ischemia. We aimed to analyze the effects of different, chemically unrelated gap junction uncouplers on the progression of ischemic injury in hypoxic myocardium. First, we analyzed the effects of heptanol, 18alpha-glycyrrhetinic acid, and palmitoleic acid on intracellular Ca2+ concentration during simulated hypoxia (2 mM NaCN) in isolated cardiomyocytes. Next, we analyzed their effects on developed and diastolic tension and electrical impedance in 47 isolated rat hearts submitted to 40 min of hypoxia and reoxygenation. All treatments were applied only during the hypoxic period. Cell injury was determined by lactate dehydrogenase (LDH) release. Heptanol, but not 18alpha-glycyrrhetinic acid nor palmitoleic acid, attenuated the increase in cytosolic Ca2+ concentration induced by simulated ischemia in cardiomyocytes and delayed rigor development (rigor onset at 7.31 +/- 0.71 min in controls vs. 14.76 +/- 1.44 in heptanol-treated hearts, P < 0.001) and the onset of the marked changes in electrical impedance (tissue resistivity: 4.02 +/- 0.29 vs. 7.75 +/- 1.84 min, P = 0.016) in hypoxic rat hearts. LDH release from hypoxic hearts was minimal and was not significantly modified by drugs. However, all gap junction uncouplers, given during hypoxia, attenuated LDH release during subsequent reoxygenation. Dose-response analysis showed that increasing heptanol concentration beyond the level associated with maximal effects on cell coupling resulted in further protection against hypoxic injury. In conclusion, gap junction uncoupling during hypoxia has a protective effect on cell death occurring upon subsequent reoxygenation, and heptanol has, in addition, a marked protective effect independent of its uncoupling actions.

Animals↗

PubMed2005

Calpain-mediated impairment of Na+/K+-ATPase activity during early reperfusion contributes to cell death after myocardial ischemia.

Na+ overload and secondary Ca2+ influx via Na+/Ca2+ exchanger are key mechanisms in cardiomyocyte contracture and necrosis during reperfusion. Impaired Na+/K+-ATPase activity contributes to Na+ overload, but the mechanism has not been established. Because Na+/K+-ATPase is connected to the cytoskeleton protein fodrin through ankyrin, which are substrates of calpains, we tested the hypothesis that calpain mediates Na+/K+-ATPase impairment in reperfused cardiomyocytes. In isolated rat hearts reperfused for 5 minutes after 60 minutes of ischemia, Na+/K+-ATPase activity was reduced by 80%, in parallel with loss of alpha-fodrin and ankyrin-B and detachment of alpha1 and alpha2 subunits of Na+/K+-ATPase from the membrane-cytoskeleton complex. Calpain inhibition with MDL-7943 during reperfusion prevented the loss of these proteins, increased Na+/K+-ATPase activity, attenuated lactate dehydrogenase release, and improved contractile recovery, and these beneficial effects of MDL-7943 were reverted by ouabain. The impairment of Na+/K+-ATPase was not a mere consequence of cell death because it was not altered in hearts in which contracture and cell death had been prevented by contractile blockade with 2,3-butanedione monoxime. In these hearts, concomitant calpain inhibition preserved Na+/K+-ATPase content and function and attenuated cell death occurring on withdrawal of 2,3-butanedione monoxime. In vitro assay showed no detectable degradation of Na+/K+-ATPase subunits after 10 minutes of incubation with activated calpain. Thus, we conclude that calpain activation contributes to the impairment of Na+/K+-ATPase during early reperfusion and that this effect is mainly mediated by degradation of the anchorage of Na+/K+-ATPase to the membrane cytoskeleton.

Animals↗

PubMed2005

Antagonism of selectin function attenuates microvascular platelet deposition and platelet-mediated myocardial injury after transient ischemia.

OBJECTIVES: The goal of this study was to assess whether selectin blockade reduces myocardial platelet deposition and platelet-mediated injury after transient ischemia. BACKGROUND: Selectins participate in platelet adhesion to reperfused endothelium. METHODS: Thiopental-anesthetized, open-chest pigs were subjected to mechanical injury of the left anterior descending coronary artery followed by a 48-min occlusion and 2 (n = 20) or 4 (n = 16) h of reperfusion. Fifteen minutes before occlusion, animals were blindly allocated to receive a continuous intravenous infusion of the selectin blocker fucoidan (30 microg/kg/min, plus a 1-mg/kg bolus in the latter group) or saline. In isolated rat hearts infused with thrombin-activated platelets, the effects of fucoidan (30 microg/ml) administered during reperfusion after 40 min of global ischemia were also analyzed. RESULTS: Fucoidan did not prevent the development of cyclic reductions in coronary flow, but reduced the content of (99m)Tc-labeled platelets in reperfused myocardium after 2 h of reperfusion (23.4 +/- 3.3 vs. 42.1 +/- 8.3 x 10(6) platelets/g in treated and untreated animals, p = 0.03) and attenuated the impairment in the coronary flow reserve and reduced infarct size after 4 h (53 +/- 2% vs. 73 +/- 5% of the ischemic region, respectively, p = 0.003). Treated animals showed a trend toward less neutrophil infiltration early after reperfusion, but not after 4 h. In isolated hearts, fucoidan improved functional recovery and reduced coronary resistance and lactate dehydrogenase release, lacking any beneficial effects if given in the absence of platelets. CONCLUSIONS: The results suggest that selectin-dependent adhesion is a prominent mechanism of platelet deposition in reperfused cardiac microvessels and highlight its potential as a therapeutic target in patients with acute myocardial infarction.

Animals↗

PubMed2005

Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS).

AIMS: Large randomized trials have shown that beta-blockers reduce mortality and hospital admissions in patients with heart failure. The effects of beta-blockers in elderly patients with a broad range of left ventricular ejection fraction are uncertain. The SENIORS study was performed to assess effects of the beta-blocker, nebivolol, in patients >/=70 years, regardless of ejection fraction. METHODS AND RESULTS: We randomly assigned 2128 patients aged >/=70 years with a history of heart failure (hospital admission for heart failure within the previous year or known ejection fraction </=35%), 1067 to nebivolol (titrated from 1.25 mg once daily to 10 mg once daily), and 1061 to placebo. The primary outcome was a composite of all cause mortality or cardiovascular hospital admission (time to first event). Analysis was by intention to treat. Mean duration of follow-up was 21 months. Mean age was 76 years (SD 4.7), 37% were female, mean ejection fraction was 36% (with 35% having ejection fraction >35%), and 68% had a prior history of coronary heart disease. The mean maintenance dose of nebivolol was 7.7 mg and of placebo 8.5 mg. The primary outcome occurred in 332 patients (31.1%) on nebivolol compared with 375 (35.3%) on placebo [hazard ratio (HR) 0.86, 95% CI 0.74-0.99; P=0.039]. There was no significant influence of age, gender, or ejection fraction on the effect of nebivolol on the primary outcome. Death (all causes) occurred in 169 (15.8%) on nebivolol and 192 (18.1%) on placebo (HR 0.88, 95% CI 0.71-1.08; P=0.21). CONCLUSION: Nebivolol, a beta-blocker with vasodilating properties, is an effective and well-tolerated treatment for heart failure in the elderly.

Adrenergic beta-Antagonists↗

PubMed2005

Clinical and neurohumoral consequences of diuretic withdrawal in patients with chronic, stabilized heart failure and systolic dysfunction.

BACKGROUND: Loop diuretics are beneficial in heart failure in the short term because they eliminate fluid retention, but in the long-term, they could adversely influence prognosis due to activation of neurohumoral mechanisms. AIMS: To explore the changes induced by diuretic withdrawal in chronic nonadvanced heart failure. METHODS: Diuretics were withdrawn in 26 stabilized heart failure patients with systolic dysfunction (ejection fraction [EF]<45%). Clinical status was evaluated by physical exam, exercise capacity (corridor test) and New York Heart Association (NYHA) class. Biochemical and neurohumoral determinations were performed at baseline and at 3 months. RESULTS: At 3 months, 17 out of 26 patients (65%) were able to tolerate diuretic interruption without a deterioration in exercise capacity or New York Heart Association functional class. Renal function parameters improved (baseline urea 46.2+/-10.8 to 39.2+/-10.1 mg/dl at 3 months, p=0.014; creatinine 1.1+/-0.23 to 0.98+/-0.2 mg/dl, p=0.013). Glucose metabolism also improved (fasting glucose 151+/-91 to 122+/-14 mg/dl, p=0.035). Heart rate and systolic blood pressure did not significantly change, while diastolic blood pressure increased (from 80+/-10 to 87+/-13 mm Hg, p=0.006). Neurohumoral determinations showed a decrease in plasma renin activity (4.19+/-5.96 to 2.88+/-4.98 ng/ml, p=0.026), with no changes in aldosterone, arginine-vasopressin, endothelin-1 and norepinephrine. In contrast, atrial natriuretic peptide significantly increased (115+/-87 to 168+/-155 pg/ml, p=0.004). CONCLUSION: Diuretic withdrawal in stabilized heart failure with systolic dysfunction is associated with an improvement in renal function parameters, glucose metabolism and some neurohumoral parameters, such as plasma renin activity; however, atrial natriuretic peptide levels increased.

Adult↗

PubMed2005

Practical recommendations for the use of ACE inhibitors, beta-blockers, aldosterone antagonists and angiotensin receptor blockers in heart failure: putting guidelines into practice.

Surveys of prescribing patterns in both hospitals and primary care have usually shown delays in translating the evidence from clinical trials of pharmacological agents into clinical practice, thereby denying patients with heart failure (HF) the benefits of drug treatments proven to improve well-being and prolong life. This may be due to unfamiliarity with the evidence-base for these therapies, the clinical guidelines recommending the use of these treatments or both, as well as concerns regarding adverse events. ACE inhibitors have long been the cornerstone of therapy for systolic HF irrespective of aetiology. Recent trials have now shown that treatment with beta-blockers, aldosterone antagonists and angiotensin receptor blockers also leads to substantial improvements in outcome. In order to accelerate the safe uptake of these treatments and to ensure that all eligible patients receive the most appropriate medications, a clear and concise set of clinical recommendations has been prepared by a group of clinicians with practical expertise in the management of HF. The objective of these recommendations is to provide practical guidance for non-specialists, in order to increase the use of evidenced based therapy for HF. These practical recommendations are meant to serve as a supplement to, rather than replacement of, existing HF guidelines.

Adrenergic beta-Antagonists↗

PubMed2005

Assessment of the markers of platelet and coagulation activation following transcatheter closure of atrial septal defects.

BACKGROUND: Aspirin has been routinely prescribed following transcatheter closure of secundum atrial septal defects (ASDs) but its rationale has not been clinically or biologically evaluated; and despite aspirin, thrombotic complications occur following transcatheter ASD closure. We therefore evaluated the presence, degree and timing of the activation of the coagulation and platelet systems following transcatheter closure of ASDs. METHODS AND RESULTS: Fourteen consecutive patients (9 females, mean age 41+/-22 years) who underwent successful transcatheter closure of an ASD defect with the Amplatzer septal occluder were prospectively studied. Measurements of the prothrombin fragment 1+2 (F1+2) levels and the percentage of activated platelets (determined by P-selectin expression detected by flow cytometry) were taken at baseline just before the procedure, and at 1, 7, 30 and 90 days following device implantation. F1+2 levels increased from 0.85+/-0.29 nmol/l at baseline to a maximal value of 1.20+/-0.52 nmol/l at 7 days, gradually returning to the baseline levels at 90 days (0.79+/-0.54 nmol/l) (p<0.001). F1+2 levels at 7 days were also significantly higher than those obtained in a control group of 20 healthy subjects (p=0.016). A greater increase in coagulation activation was observed in cases of residual shunt following ASD closure (r=0.53, p=0.050). No significant variations in the percentage of platelets expressing P-selectin were detected at any time. CONCLUSIONS: Transcatheter closure of ASDs with the Amplatzer septal occluder was associated with a significant increase in F1+2 levels during the first week after device implantation, but there was no detectable effect on platelet system activation. These findings raise the question whether the optimal prophylactic approach following transcatheter ASD closure should be anticoagulant instead of antiplatelet therapy.

Adolescent↗

PubMed2005

Thrombin increases cardiomyocyte acute cell death after ischemia and reperfusion.

Thrombin exerts multiple actions on cardiomyocytes leading to increased intracellular Na+ and Ca2+ concentrations, and to activation of a Ca2+-independent PLA2, and has been proposed to favor the genesis of arrhythmias and ischemic injury in acute coronary syndromes. However, the influence of thrombin on cardiomyocyte cell death during ischemia-reperfusion has not been studied. A beneficial influence of low thrombin concentrations has been described in other cell types. HL-1 cardiomyocytes were subjected to simulated ischemia (SI) and reperfusion (SR) and cell death was assessed by means of LDH release to the incubation media. Thrombin dose-dependently increased cell death in normoxic cells, in cells subjected to SI, and in cells subjected to SR (by 20+/-8%, 95+/-32% and 35+/-9%, respectively, at 100 U/ml). The effects of thrombin were associated to increased cytosolic Ca2+ overload, mimicked by 100 microM PAR-1 agonist peptide SFLLRNPNDKYEPF, and reversed by the direct thrombin inhibitor lepirudin (IC50=1.3+/-0.2 microg/ml). The presence of thrombin during simulated ischemia-reperfusion increases cardiomyocyte cell death by a mechanism that involves activation of PAR-1 receptors and can be prevented by the direct thrombin inhibitor lepirudin.

Animals↗

PubMed2004

Acute cardiogenic pulmonary edema--relevance of multivessel disease, conduction abnormalities and silent ischemia.

The frequency distribution and severity of the cardiac disease underlying acute cardiogenic pulmonary edema (APE) to define appropriate subsequent diagnostic and management strategies were investigated in 216 consecutive patients. To this effect, the clinical, electrocardiographic, ecocardiographic and angiographic characteristics were analyzed. Coronary artery disease was identified in 185 patients (86%)-146 with acute myocardial infarction-as the underlying cause, isolated valvular disease in 10 (5%) and other causes in 21 (11%). Most patients were elderly (> or =70 years, 72%), hypertensive (71%) and diabetic (44%). Among coronary disease (CAD) patients, however, 105 (57%) showed conduction disturbances in the ECG (QRS>0.10 s) and 84 (45%) had no anginal pain during pulmonary edema. A 2D echocardiogram showed a 30% incidence of moderate-severe mitral regurgitation in coronary disease and non-coronary disease patients, and a 67% incidence of reduced ejection fraction (<50%), particularly in coronary disease patients (73%). A coronary angiography performed in 99 patients with coronary disease showed multivessel disease in 89 (91%) with a 32% incidence of significant left main disease. Therefore, these findings demonstrate that coronary disease is the most common cause of acute pulmonary edema and it is associated with a distinctly high prevalence of multivessel and left main disease. This diagnosis, however, may often be overlooked if no serial enzymatic sampling is performed given the increased frequency of conduction abnormalities and lack of anginal pain.

Acute Disease↗

PubMed2004

Effect of sarcolemmal rupture on myocardial electrical impedance during oxygen deprivation.

Plasma membrane disruption is a characteristic feature of cell death induced by hypoxia or ischemia. Here, we investigated whether analysis of tissue electrical impedance allows detection of ongoing cell membrane rupture and necrotic cell death in hypoxic or ischemic myocardium. Twenty-eight isolated rat hearts were submitted to 5 h of ischemia (n = 8) or hypoxia (n = 20). Myocardial electrical impedance and lactate dehydrogenase (LDH) release were monitored. The time course of hypoxia-induced cell death was modified by altering pH (pH 7.4 or 6.4, 5 h) or by adding 3 or 10 mM glycine. Ischemia and hypoxia induced an increase in electrical impedance, followed by a plateau, and later a reduction. During hypoxia, LDH release started after a prolonged lapse of time (80.00 +/- 8.37 min at pH 7.4 and 122.50 +/- 11.82 min at pH 6.4). The onset of LDH release was followed by the onset of the late reduction in electrical impedance, and both were delayed by acidic pH (P < 0.05) and by glycine (P < 0.05). The times of onset of LDH release and of late electrical changes were significantly correlated (r = 0.752, P < 0.001). In separate experiments, induction of sarcolemmal rupture with Triton X-100 (n = 6) mimicked the late effects of ischemia or hypoxia on tissue impedance. The protective effects of glycine and acidosis on membrane disruption were confirmed (propidium iodide) in energy-deprived HL-1 cardiomyocytes. These results describe for the first time a late fall in electrical impedance in myocardium submitted to prolonged oxygen deprivation and demonstrate that this fall allows detection of ongoing cell necrosis.

Acids↗