Michel Carrier

Evidence for two components of delayed rectifier K+ current in human ventricular myocytes

Previous voltage-clamp studies have suggested that the delayed rectifier current (IK) is small or absent in the human ventricle and, when present, consists only of the rapid component (IKr); however, molecular studies suggest the presence of functionally important IK in the human heart, specific IKr blockers are known to delay ventricular repolarization and cause the long QT syndrome in humans, and we have shown that the expression of IK is strongly influenced by cell isolation techniques. The present experiments were designed to assess the expression of IK in myocytes obtained by arterial perfusion of right ventricular tissue from explanted human hearts. Of 35 cells from three hearts, 33 (94%) showed time-dependent currents typical of IK. The envelope-of-tails test was not satisfied under control conditions but became satisfied in the presence of the benzenesulfonamide E-4031 (5 micromol/L). E-4031 suppressed a portion of IK in 32 of 33 cells, with properties of the drug-sensitive and -resistant components consistent with previous descriptions of IKr and the slow component (IKs), respectively. Action potential duration to 95% repolarization at 1 Hz was prolonged by E-4031 from 336+/-16 (mean +/- SEM) to 421 +/- 19ms (n = 5, P < .01), indicating a functional role for IK. Indapamide, a diuretic agent previously shown to inhibit IKs selectively, suppressed E-4031-resistant current. The presence of a third type of delayed rectifier, the ultrarapid delayed rectifier current (IKur), was evaluated with the use of depolarizing prepulses and low concentrations (50 micromol/L) of 4-aminopyridine. Although these techniques revealed clear IKur in five of five human atrial cells, no corresponding component was observed in any of five human ventricular myocytes. We conclude that a functionally significant IK, with components corresponding to IKr and IKs, is present in human ventricular cells, whereas IKur appears to be absent. These findings are important for understanding the molecular, physiological, and pharmacological determinants of human ventricular repolarization and arrhythmias.

Transmural heterogeneity of action potentials andIto1 in myocytes isolated from the human right ventricle

Limited information is available about transmural heterogeneity in cardiac electrophysiology in man. The present study was designed to evaluate heterogeneity of cardiac action potential (AP), transient outward K+ current ( I to1) and inwardly rectifying K+ current ( I K1) in human right ventricle. AP and membrane currents were recorded using whole cell current- and voltage-clamp techniques in myocytes isolated from subepicardial, midmyocardial, and subendocardial layers of the right ventricle of explanted failing human hearts. AP morphology differed among the regional cell types. AP duration (APD) at 0.5-2 Hz was longer in midmyocardial cells (M cells) than in subepicardial and subendocardial cells. At room temperature, observed I to1, on step to +60 mV, was significantly greater in subepicardial (6.9 ± 0.8 pA/pF) and M cells (6.0 ± 1.1 pA/pF) than in subendocardial cells (2.2 ± 0.7 pA/pF, P < 0.01). Slower recovery of I to1 was observed in subendocardial cells. The half-inactivation voltage of I to1 was more negative in subendocardial cells than in M and subepicardial cells. At 36°C, the density of I to1 increased, the time-dependent inactivation and reactivation accelerated, and the frequency-dependent reduction attenuated in all regional cell types. No significant difference was observed in I K1 density among the regional cell types. The results indicate that M cells in humans, as in canines, show the greatest APD and that a gradient of I to1 density is present in the transmural ventricular wall. Therefore, the human right ventricle shows significant transmural heterogeneity in AP morphology and I to1properties.

Troponin levels in patients with myocardial infarction after coronary artery bypass grafting

BACKGROUND The objective of this study was to evaluate serum cardiac troponin T and I levels in patients in whom electrocardiogram, myocardial scan, and serum CK-MB levels of the MB isoenzyme of creatine kinase indicated perioperative myocardial infarction (MI) after coronary artery bypass grafting (CABG). METHODS We studied 590 patients who underwent CABG at the Montreal Heart Institute between 1992 and 1996. Postoperative cardiac troponin T levels (493 patients), troponin I levels (97 patients), and activity of the MB isoenzyme of creatine kinase, electrocardiograms, clinical data, and clinical events were recorded prospectively. The diagnosis of perioperative PMI was defined by a new Q wave on the electrocardiogram, by serum levels of the MB isoenzyme of creatine kinase higher than 100 IU/L within 48 hours after operation, or both. RESULTS After CABG, 22 patients in whom troponin T levels (22/493, 4.5%) and 6 patients in whom troponin I levels (6/97, 6.2%) were measured had sustained a perioperative MI according to current diagnostic criteria. In these patients, troponin T levels higher than 3.4 microg/L 48 hours after CABG best detected the presence of perioperative MI, with an area under the receiver operating characteristic curve of 0.95, a sensitivity of 90%, a specificity of 94%, a positive predictive value of 41%, a negative predictive value of 99%, and a likelihood ratio of 15. Serum troponin I levels higher than 3.9 microg/L 24 hours after CABG confirmed the perioperative MI with an area under the receiver operating curve of 0.86, a sensitivity of 80%, a specificity of 85%, a positive predictive value of 24%, a negative predictive value of 99%, and a likelihood ratio of 5. CONCLUSIONS Serum troponin T levels higher than 3.4 microg/L 48 hours after CABG correlated best with the diagnosis of perioperative MI. Serum troponin T levels greater than 3.9 microg/L 24 hours after CABG also correlated with the diagnosis of perioperative MI, although a larger experience is needed to confirm the validity of the chosen cutoff value.

15-year experience with the Carpentier-Edwards pericardial bioprosthesis

BACKGROUND The aim of the study was to evaluate the late results of the Carpentier-Edwards pericardial bioprosthesis, which we have been implanting since 1981. METHODS The 812 patients who underwent heart valve replacement with a Carpentier-Edwards pericardial bioprosthesis between 1981 and 1996 were reviewed. Their clinical, operative, and follow-up data were prospectively recorded in a computerized database. All but 29 patients were available for follow-up (96% completeness), which averaged 58 months and totaled 3,000 patient-years. RESULTS There were 598 aortic valve replacements (74%), 149 mitral valve replacements (18%), and 65 double valve replacements (8%). The mean age at the time of surgery was 65 years (range, 18 to 88 years), with 24% of the patients under the age of 60 years. Preoperatively, 558 patients (69%) were in New York Heart Association functional class III or IV. Associated surgical procedures included coronary artery bypass grafting in 219 patients (27%) and tricuspid or mitral valve repair in 40 (5%). Previous cardiac operations had been performed in 149 patients, including 134 valve-related procedures. There were 49 early deaths overall (6%): 29 after aortic valve replacement (4.8%), 11 after mitral valve replacement (7.4%), and 9 with double valve replacement (13.8%). There were 120 late deaths for a 10-year actuarial survival rates of 69%+/-3%, 58%+/-7%, and 38%+/-10% for aortic, mitral, and double valve replacement, respectively. The 14-year survival rate for aortic valve replacement patients is 68%+/-3%. The 10-year and 14-year actuarial freedom rates from events after aortic valve replacement are 92% +/-2% and 88%+/-4% for thromboembolism, 96%+/-1% and 92%+/-4 for endocarditis, 91%+/-2 and 72%+/-6% for reoperation, and 93%+/-2% and 80%+/-5% for structural dysfunction of the valve. The 10-year actuarial freedom rates from events after mitral and double valve replacement are 93%+/-3% and 89%+/-4% for thromboembolism, 95%+/-3% and 88%+/-5% for endocarditis, 76%+/-7% and 70%+/-14% for reoperation, and 81%+/-7% and 72%+/-15% for structural dysfunction. No primary tissue failure of the prosthesis in any position was observed in the 357 patients aged 70 years or more at the time of valve implantation. CONCLUSIONS The Carpentier-Edwards pericardial valve offers excellent clinical results and durability, particularly in the aortic position and for patients older than 70 years of age.

Effect of internal mammary artery dissection on sternal vascularization

Internal mammary artery (IMA) dissection may cause sternal devascularization and ischemia resulting in sternal wound complication. To evaluate the effect of median sternotomy and IMA dissection on sternal vascular supply, sternal bone tomography was performed 7 days and 1 month after cardiac operation in 67 patients. Seventeen nondiabetic patients had single IMA grafts, 18 had double IMA grafts, and 12 had only saphenous vein grafts or valve replacement. Twenty diabetic patients were studied after any one of these operations. Seven patients were restudied 1 month after the operation. Sternal technetium-99m-methylene diphosphate tomography was performed. The sternum was visualized and focal zones of hypoactivity represented sternal hypoperfusion. The ratio of hypoactivity area over total sternal area was calculated for every patient. After median sternotomy without single or double IMA grafts, the averaged hypoperfusion ratio was 4% +/- 1% compared with 13% +/- 3% after single IMA grafts and 24% +/- 6% after double IMA grafts (p less than 0.0001). Diabetic patients without IMA, with single IMA, and with double IMAs showed hypoperfusion areas of 5% +/- 3%, 15% +/- 5%, and 23% +/- 9%, respectively, a result similar to that of nondiabetic patients. One month after operation the hypoperfusion area decreased to 2% +/- 2% (p less than 0.05) in restudied patients. Our results indicate that IMA dissection causes a significant although partial and temporary sternal ischemia, which is more severe after double IMA than single IMA mobilization and which may be incriminated in the development of sternal wound infection. This vascularization defect was not greater among patients with diabetes mellitus.

Cellular senescence in endothelial cells from atherosclerotic patients is accelerated by oxidative stress associated with cardiovascular risk factors.

Risk factors for cardiovascular diseases (CVD) increase oxidative stress, and they are proposed to hasten endothelial cell (EC) damage and dysfunction. Our objective was to elucidate the impact of chronic exposure to risk factors for CVD on senescence of EC isolated and cultured from internal mammary arterial segments of patients with severe coronary artery disease. Senescence induced by serial passages resulted in progressive telomere shortening, and short initial telomeres predicted early appearance of senescence in culture. Neither time course of senescence nor telomere length was age-dependent, suggesting that biological age, rather than chronological age, determined the dynamics. Senescence appeared earlier in patients with longer history of risk factor for CVD, and multivariate analysis suggested that hypertension hastened the onset of senescence. Risk factors for CVD override the effects of chronological aging likely by generating stress-dependent damage: senescent EC exhibited oxidative stress (increase in lipid peroxydation and caveolin-1 gene expression) and cell damage markers (loss of eNOS expression and increase in Cox2 mRNA, lower TRF1 protein level). Thus, cell senescence was triggered both by telomere-dependent and -independent pathways. In conclusion, chronic exposure to risk factors for CVD accelerated the development of endothelial senescence that could contribute to the pathogenesis of CVD.

The stratification of cardiac surgical procedures according to use of blood products: a retrospective analysis of 1480 cases

The use of blood products in 1480 consecutive cases of adult cardiac surgical procedures over a period of 15 mth was studied retrospectively using the database of the Department of Anaesthesia of the Institut de Cardiologie de Montreal. Use of blood products was compared in patients having (1) coronary artery bypass grafting, (2) valvular surgery, (3) or a combination of 1 and 2. First operations were compared with reoperations. Overall, the use of homologous blood products was greatest in patients of Group 3, intermediate in patients of Group 2, and smallest in patients of Group I. Reoperations were associated with an increase in inlraoperative transfusion of packed red blood cells, but postoperative chest drainage was similar to first operations. When all blood products (packed red blood cells, fresh frozen plasma and platelets were taken into consideration, patients undergoing primary CABG or valve surgery were the least exposed to homologous blood donors (five and six units transfused respectively). Repeat CABG was associated with an intermediate exposure to homologous blood products (eight units). Finally, primary and repeat combined procedures, and repeat valve surgery were associated with the greatest exposure to foreign blood products (10, 13 and 10 units respectively). The data presented in this study provide a rational basis for stratification of procedures according to the expected use of blood products, particularly in view of future studies which may be planned to examine the efficiency of blood conservation strategies.RésuméCette étude rétrospective rapporte l’utilisation des produits sanguins en chirurgie cardiaque de l’adulte à l’Institut de Cardiologie de Montréal chez 1480 patients opérés sous circulation extracorporelle entre novembre 1988 et avril 1990. Les patients out été regroupés selon l’intervention subie: 1) la revascularisation myocardique, 2) la chirurgie valvulaire, 3) une combinaison de 1 et de 2. Nous avons égalemenl comparé les interventions de premiere intention avec les réinterventions. A u total, les besoins en produits sanguins homologues out été les plus considérables chez les patients du groupe 3, intermédiaires chez les patients du groupe 2, et les plus faibles chez les patients du groupe I. Les réinterventions out été associées à une augmentation des transfusions de culots globulaires durant la chirurgie, mais non à des pertes sanguines postopératoires accrues. Lorsque tous les produits sanguins sont pris en consideration (culots globulaires, plasma, plaquettes), l’exposition (en nombre dunités) aux produits sanguins homologues était la plus faible chez les patients subissant une premiere chirurgie de revascularisation (cinq unités) on une chirurgie valvulaire de premiere intention (six unités). Dans la réintervention pour revascularisation myocardique Vexposition était intermédiaire (huit unités), alors qu’elle était la plus forte dans la chirurgie combinée, qu’elle soit primaire ou de réintervention (10 ou 13 unités). Les données présentées dans cette étude permettent de stratifier les chirurgies en fonction des besoins transfusionnels prévus et devraient nous guider dans la gestion des technologies visant à diminuer les pertes sanguines el l’exposition aux produits sanguins homologues en chirurgie cardiaque de l’adulte.

Comparative study of cyclosporine and tacrolimus vs newer immunosuppressants mycophenolate mofetil and rapamycin on coronary endothelial function

BACKGROUND Endothelial dysfunction contributes to the development of intimal hyperplasia in transplanted hearts by decreasing the protective effects of endothelial-derived nitric oxide. Immunosuppressive drugs may increase the dysfunction caused by rejection and further accelerate the development of graft coronary vasculopathy. This study compares the effect of cyclosporine and tacrolimus vs two newer immunosuppressive drugs, mycophenolate mofetil and rapamycin, on coronary endothelial function. METHODS An in vitro model of drug incubation in Krebs-bicarbonate solution (4(o)C, 48 hours) using porcine epicardial coronary arteries was developed. Coronary endothelial function studies were performed in organ chamber experiments after incubation with cyclosporine (10(-4), 10(-7) mol/liter), tacrolimus (10(-4), 10(-7) mol/liter), mycophenolate mofetil (10(-4), 10(-7) mol/liter), rapamycin (10(-7), 10(-11) mol/liter), and their vehicles to assess effects on G-protein-mediated vasorelaxations leading to the release of nitric oxide. RESULTS Exposure to cyclosporine and mycophenolate mofetil was associated with a dose-dependent decrease in endothelium-dependent relaxations to serotonin (an agonist that binds to 5-HT1D receptors coupled to Gi-protein) but no impairment of relaxations to bradykinin (an agonist that binds to B2 receptors coupled to Gq-proteins). Exposure to tacrolimus and rapamycin caused severe impairment of relaxations to serotonin and a lesser one to bradykinin. We observed alterations of relaxations to the calcium ionophore A23187 after exposure to mycophenolate mofetil and rapamycin. Exposure to rapamycin and mycophenolate mofetil vehicles impaired relaxation to all agonists. CONCLUSIONS These results suggest that cyclosporine and mycophenolate mofetil induce a dysfunction of the vasorelaxing properties of the endothelium that may lead to a decrease in the protective effects of nitric oxide on the vascular wall but that these drugs still have a more favorable vascular profile than do tacrolimus and rapamycin. Decreased endothelial function after mycophenolate mofetil and rapamycin exposure could be caused by their vehicles.

Transmembrane ICa contributes to rate-dependent changes of action potentials in human ventricular myocytes.

The mechanism of action potential abbreviation caused by increasing rate in human ventricular myocytes is unknown. The present study was designed to determine the potential role of Ca2+ current ( I Ca) in the rate-dependent changes in action potential duration (APD) in human ventricular cells. Myocytes isolated from the right ventricle of explanted human hearts were studied at 36°C with whole cell voltage and current-clamp techniques. APD at 90% repolarization decreased by 36 ± 4% when frequency increased from 0.5 to 2 Hz. Equimolar substitution of Mg2+ for Ca2+ significantly decreased rate-dependent changes in APD (to 6 ± 3%, P < 0.01). Peak I Ca was decreased by 34 ± 3% from 0.5 to 2 Hz ( P < 0.01), and I Ca had recovery time constants of 65 ± 12 and 683 ± 39 ms at -80 mV. Action potential clamp demonstrated a decreasing contribution of I Ca during the action potential as rate increased. The rate-dependent slow component of the delayed rectifier K+current ( I Ks) was not observed in four cells with an increase in frequency from 0.5 to 3.3 Hz, perhaps because the I Ks is so small that the increase at a high rate could not be seen. These results suggest that reduction of Ca2+influx during the action potential accounts for most of the rate-dependent abbreviation of human ventricular APD.The mechanism of action potential abbreviation caused by increasing rate in human ventricular myocytes is unknown. The present study was designed to determine the potential role of Ca2+ current (ICa) in the rate-dependent changes in action potential duration (APD) in human ventricular cells. Myocytes isolated from the right ventricle of explanted human hearts were studied at 36 degreesC with whole cell voltage and current-clamp techniques. APD at 90% repolarization decreased by 36 +/- 4% when frequency increased from 0.5 to 2 Hz. Equimolar substitution of Mg2+ for Ca2+ significantly decreased rate-dependent changes in APD (to 6 +/- 3%, P < 0.01). Peak ICa was decreased by 34 +/- 3% from 0.5 to 2 Hz (P < 0.01), and ICa had recovery time constants of 65 +/- 12 and 683 +/- 39 ms at -80 mV. Action potential clamp demonstrated a decreasing contribution of ICa during the action potential as rate increased. The rate-dependent slow component of the delayed rectifier K+ current (IKs) was not observed in four cells with an increase in frequency from 0.5 to 3.3 Hz, perhaps because the IKs is so small that the increase at a high rate could not be seen. These results suggest that reduction of Ca2+ influx during the action potential accounts for most of the rate-dependent abbreviation of human ventricular APD.

Postinfarction Ventricular Septal Defects: Towards a New Treatment Algorithm?

BACKGROUND We reviewed our experience at the Montreal Heart Institute with early surgical and percutaneous closure of postinfarction ventricular septal defects (VSD). METHODS Between May 1995 and November 2007, 51 patients with postinfarction VSD were treated. Thirty-nine patients underwent operations, and 12 were treated with percutaneous closure of the VSD. RESULTS Half of the patients were in systemic shock, and 88% were supported with an intraaortic balloon pump before the procedure. Before the procedure, 14% of patients underwent primary percutaneous transluminal coronary angioplasty. The mean left ventricular ejection fraction was 0.44 +/- 0.11, and mean Qp/Qs was 2.3 +/- 1. Time from acute myocardial infarction to VSD diagnosis was 5.4 +/- 5.1 days, and the mean delay from VSD diagnosis to treatment was 4.0 +/- 4.0 days. A moderate to large residual VSD was present in 10% of patients after correction. Early overall mortality was 33%. Residual VSD, time from myocardial infarction to VSD diagnosis, and time from VSD diagnosis to treatment were the strongest predictor of mortality. Twelve patients were treated with a percutaneous occluder device, and the hospital or 30-day mortality in this group was 42%. CONCLUSION Small or medium VSDs can be treated definitively with a ventricular septal occluder or initially to stabilize patients and allow myocardial fibrosis, thus facilitating delayed subsequent surgical correction.