RNA Profiling in Human and Murine Transplanted Hearts: Identification and Validation of Therapeutic Targets for Acute Cardiac and Renal Allograft Rejection.

Acute cellular rejection (ACR) is the adverse response of the recipient's immune system against the allogeneic graft. Using human surveillance endomyocardial biopsies (EMBs) manifesting ACR and murine allogeneic grafts, we profiled implicated microRNAs (miRs) and mRNAs. MiR profiling showed that miR-21, -142-3p, -142-5p, -146a, -146b, -155, -222, -223, and -494 increased during ACR in humans and mice, whereas miR-149-5p decreased. mRNA profiling revealed 70 common differentially regulated transcripts, all involved in immune signaling and immune-related diseases. Interestingly, 33 of 70 transcripts function downstream of IL-6 and its transcription factor spleen focus forming virus proviral integration oncogene (SPI1), an established target of miR-155, the most upregulated miR in human EMBs manifesting rejection. In a mouse model of cardiac transplantation, miR-155 absence and pharmacological inhibition attenuated ACR, demonstrating the causal involvement and therapeutic potential of miRs. Finally, we corroborated our miR signature in acute cellular renal allograft rejection, suggesting a nonorgan specific signature of acute rejection. We concluded that miR and mRNA profiling in human and murine ACR revealed the shared significant dysregulation of immune genes. Inflammatory miRs, for example miR-155, and transcripts, in particular those related to the IL-6 pathway, are promising therapeutic targets to prevent acute allograft rejection.

Effectiveness and safety of collagenase Clostridium histolyticum in Dupuytren's disease : an observational study in Belgium.

Dupuytren's disease is a connective tissue disorder leading to contractures. It can be treated surgically or through injections of collagenase Clostridium histolyticum (CCH). Patients with Dupuytren's contracture (> 20°) and a palpable cord were included in this observational study, aiming to characterise the Belgian patient population and to assess the effectiveness and safety of CCH. Overall, 108 patients (114 joints) received at least one injection of CCH, and 104 patients completed the study. The percentages of joints achieving a degree of contracture of 5° or less, or a relative contracture reduction of at least 50% after the extension procedure were 64.9% and 90.1%, respectively. The mean number of injections per cord was 1.0. The Unité Rhumatologique des Affections de la Main score decreased from 29.4 ±â€ˆ11.0 to 12.9 ±â€ˆ6.3 (mean ±â€ˆSD ; p < 0.0001). CCH was demonstrated to be effective, safe and able to increase quality of life.

Cronobacter sakazakii bacteremia in a heart transplant patient with polycystic kidney disease.

Infections with Cronobacter sakazakii are mainly described among neonates and infants, with contaminated powdered infant formulas most often incriminated as the cause. We describe here a case of C. sakazakii bacteremia secondary to a suspected cyst infection in a heart-and-kidney transplant patient with polycystic kidney disease.

Lower incidence of cytomegalovirus infection with everolimus versus mycophenolate mofetil in de novo cardiac transplant recipients: a randomized, multicenter study.

Cytomegalovirus (CMV) is a major cause of infectious complications following cardiac transplantation, severely affecting short- and long-term outcomes. A 12-month, multicenter, randomized, open-label study in de novo cardiac transplant patients was undertaken to compare the efficacy, renal function, and safety of everolimus plus reduced cyclosporine versus mycophenolate mofetil (MMF) plus standard cyclosporine (ClinicalTrials.gov NCT00150046). CMV-specific data was prospectively collected on infections, laboratory evidence, CMV syndrome, and CMV disease. In total, 176 patients were randomized (everolimus 92; MMF 84). Use of CMV prophylaxis was similar between groups (everolimus 20.8%; MMF 24.0%). Patients in the everolimus arm had a significantly lower incidence of any CMV event (8.8% versus 32.5% with MMF, P<0.001), CMV infection as an adverse event (4.4% versus 16.9%, P=0.011), laboratory evidence of CMV (antigenemia 7.7% versus 27.7%, P<0.001; polymerase chain reaction assay 2.2% versus 12.0%, P=0.015), and CMV syndrome (1.1% versus 8.4%, P=0.028). In the donor (D)+/recipient (R)+and D-/R+ subgroups, even after adjusting for use of prophylaxis, the CMV event rate remained significantly lower with everolimus than with MMF (P=0.0015 and P=0.0381, respectively). In conclusion, de novo cardiac transplant recipients experienced lower rates of CMV infection, CMV syndrome, or organ involvement on an everolimus-based immunosuppressant regimen compared with MMF.

Effect of creatine supplementation as a potential adjuvant therapy to exercise training in cardiac patients: a randomized controlled trial.

OBJECTIVE: To investigate the effect of oral creatine supplementation in conjunction with an exercise programme on physical fitness in patients with coronary artery disease or chronic heart failure. DESIGN: Single centre double-blind randomized placebo controlled trial. SETTING: Cardiac rehabilitation centre. SUBJECTS AND INTERVENTION: 70 (4 women) cardiac patients (age 57.5 (8.4) years) were randomized to a placebo (n = 37) or creatine (n = 33) treatment for three months. Combined aerobic endurance and resistance training (three sessions/ week) was performed during supplementation. MAIN MEASURES: Aerobic power was determined during graded bicycle testing, knee extensor peak isometric and isokinetic strength, endurance and recovery were assessed by an isokinetic dynamometer, and health related quality of life was evaluated with the SF-36 and MacNew Heart Disease questionnaires. In addition, blood samples were taken after an overnight fast and 24 hour urinary collection was performed. RESULTS: At baseline there were no significant differences between both groups. We observed main time effects for aerobic power, muscle performance, health related quality of life, high density lipoprotein cholesterol and triglycerides (pre vs post; P<0.05 for all). However, changes after training were similar between placebo group and creatine group (P>0.05). Further, no detrimental effect on renal or liver function was observed nor were there any reports of side effects. CONCLUSION: Oral creatine supplementation in combination with exercise training does not exert any additional effect on the improvement in physical performance, health related quality of life, lipid profile in patients with coronary artery disease or chronic heart failure than exercise training alone.

Change in donor profile influenced the percentage of organs transplanted from multiple organ donors.

We hypothesized that the change in donor profile over the years influenced the percentage of transplantations. We reviewed medical records for all multiple-organ donors (MODs) within our network. The percentage of transplanted organs was compared between 1991-1992 (A) and 2006-2007 (B). In period A, 156 potential MODs were identified compared with 278 in period B. Fifteen potential donors (10%) in period A and 114 (41%) in period B were rejected because they were medically not suitable (40% vs 75%) or there was no family consent (60% vs 25%). Of the remaining effective MODs (141 in period A and 164 in period B), mean (standard deviation = SD) age was 34 (5) years vs 49 (17) years (P < .001). Brain death resulted from craniocerebral trauma in 69% vs 39%, cerebrovascular disease in 24% vs 46%, hypoxia in 4% vs 15%, and brain tumor in 2% vs 0.6% (P < .001). Chest trauma was present in 19% vs 9% (P < .01). The percentage of MODs who received mechanical ventilation for more than 5 days was 8% vs 24% (P < .001). The percentage of organs transplanted in periods A vs B was kidneys, 97% vs 79%; livers, 64% vs 85%; hearts, 60% vs 26%; lungs, 7% vs 35%; and pancreas, 6% vs 13% (P < .001). The number of referred potential MODs increased by 80%, resulting in a small increase in effective MOD organs (17%), mainly because of medical contraindications. The MOD profile changed to older age, fewer traumatic brain deaths, and longer ventilation time. We transplanted more livers, lungs, and pancreases but fewer kidneys and hearts.

Coronary thrombolysis and infarct size reduction after intravenous infusion of recombinant tissue-type plasminogen activator in nonhuman primates.

Occlusive thrombus was produced by thrombin-induced coagulation in the left anterior descending coronary artery (LAD) of 16 open-chest baboons. In six control animals, occlusive thrombosis persisting over a period of 4 h as evidenced by coronary arteriography resulted in large transmural infarction (63.1 +/- 3.5% of the perfusion area). In 10 animals, tissue-type plasminogen activator obtained by recombinant DNA technology (rt-PA) was infused systemically at a rate of 1,000 IU (10 micrograms)/kg per min for 30 min after 30-80 min of coronary thrombosis. Reperfusion occurred within 30 min in nine animals. In one animal, intravenous infusion was followed by an intracoronary infusion at the same rate, which resulted in thrombolysis within 8 min. In the rt-PA group, mean duration of occlusion before reperfusion was 77 +/- 24 min. Reocclusion occurred in one animal. Recanalization resulted in an overall reduction of infarct size (37.8 +/- 5.9%, P less than 0.05 versus controls). Residual infarction was related to the duration of occlusion (r = 0.80, P less than 0.01). Reperfusion was associated with reduced reflow. Myocardial blood flow in the perfusion area of the LAD was only 70% of normal after 4 h despite perfect angiographic refilling. The infusion of rt-PA was not associated with systemic activation of the fibrinolytic system, fibrinogen breakdown, or clinically evident bleeding. It is concluded that intravenous infusion of rt-PA may recanalize thrombosed coronary vessels without inducing systemic lysis. The extent of residual infarction is closely related to the duration of coronary artery occlusion before thrombolysis.

Cancer After Heart Transplantation: A 25-year Single-center Perspective.

BACKGROUND: Cancer is a major cause of morbidity and mortality after heart transplantation. METHODS: We studied 541 heart transplant patients from a single center over a period of 25 years, with a mean follow-up of 10.7 years. We determined incidence, type, risk factors, and prognosis for cancer after heart transplantation. RESULTS: Cancer was diagnosed in 181 patients, at a mean of 7.7 years after transplantation. Cumulative incidence of cancer at 5, 10, and 20 years was 14%, 29%, and 60%, respectively. The most frequent cancers were spinocellular skin cancer (22%), basocellular skin cancer (19%), lung cancer (16%), lymphoma (11%) and prostate cancer (10%). Age at transplantation > 50 years (hazard ratio, 2.9; P < .001) and male recipient gender (hazard ratio, 1.7; P = .038) were significant risk factors for posttransplant malignancy on multivariate Cox proportional hazards analysis. Median patient survival after diagnosis of cancer was 2.9 years for patients with noncutaneous cancer, versus 13.1 years for patients with only skin cancer (P < .001).

Peak oxygen uptake better predicts outcome than submaximal respiratory data in heart transplant candidates.

BACKGROUND: Many studies have focused on the prognostic power of peak oxygen uptake VO(2) in patients with chronic heart failure, but maximal exercise testing is not without risk. The purpose of the present study was, therefore, to assess the prognostic significance of the steepness of changes in ventilation and carbon dioxide output VO(2) during submaximal exercise in comparison with VO(2). METHODS AND RESULTS: The study population consisted of 284 adult heart transplant candidates who performed a graded maximal bicycle ergometer test with respiratory gas analysis. Using the respiratory data up to a gas exchange ratio of 1.0, 3 submaximal slopes were calculated in each patient. During follow-up (median, 1.33 years), 57 patients died and 149 had >/=1 cardiovascular event. When using Cox proportional hazards analysis, both peak VO(2) and submaximal respiratory slopes predicted outcome before and after accounting for age, sex, and body mass index. However, whereas the prognostic power of peak VO(2) was independent of submaximal respiratory data, the prognostic significance of the slopes was lost after controlling for peak VO(2). Stepwise regression analysis even selected peak VO(2) as an independent prognostic index among the following factors: cause of heart failure, ejection fraction, pulmonary vascular resistance, natremia, and the forced expiratory volume in 1 s. CONCLUSIONS: Respiratory data during submaximal exercise are significant predictors of outcome in patients with chronic heart failure, but their prognostic power is inferior to that of peak VO(2). However, these data may be useful when maximal exercise is contraindicated or not achievable.

Coronary reperfusion by thrombolysis and early beta-adrenergic blockade in acute experimental myocardial infarction.

The effects of beta-adrenergic blockade, thrombolysis and their combination on infarct size and left ventricular function were investigated in a canine model of thrombotic occlusion of the left anterior descending coronary artery. Metoprolol was administered intravenously (0.5 mg/kg) over 10 min, starting 15 min after occlusion. Recombinant human tissue-type plasminogen activator (rt-PA) was given intravenously 1 h after occlusion for clot lysis. Anatomic infarct size was measured as a percent of perfusion area and ventricular mass. Left ventricular function was assessed by ejection fraction and the centerline method. Groups 1, 3, 5 and 7 were evaluated after 24 h and received, respectively, metoprolol plus rt-PA, rt-PA, metoprolol and no treatment; groups 2, 4, 6 and 8 were studied after 1 week and treated, respectively, as groups 1, 3, 5 and 7. Metoprolol did not influence infarct size and global or regional ventricular function after 24 h and 1 week. Thrombolysis reduced infarct size from 69.5 +/- 3.4% (24 h) and 76.6 +/- 1.8% (1 week) in the control group to, respectively, 44.1 +/- 11.6% and 39.5 +/- 10.5% (p greater than 0.05), did not influence left ventricular function after 24 h and was accompanied after 1 week by a definite recovery of global and regional left ventricular function when compared with findings in control dogs. Metoprolol plus rt-PA further reduced infarct size (percent perfusion area) to 20.4 +/- 3.7% and 19.9 +/- 8.1% after 24 h and 1 week, respectively (p = NS versus rt-PA).(ABSTRACT TRUNCATED AT 250 WORDS)

Repeated stunning precedes myocardial hibernation in progressive multiple coronary artery obstruction.

OBJECTIVE: The aim of this study was to characterize a regional myocardial flow-function relationship in collateral dependent myocardium produced by multiple coronary artery obstruction. METHODS: Ameroid constrictors were placed around the proximal right (RC) and circumflex (CX) coronary arteries and a silicon tubing cuff around the proximal LAD (left anterior descending artery) (luminal stenosis +/- 77%) in 18 dogs. Weekly two-dimensional echocardiography was performed for regional function (anterior [A], inferoposterior [IP], wall thickening [WT]), and fractional shortening (FS). Colored microspheres injected at baseline and before sacrifice, before and after dipyridamole (0.5 mg/kg) injection, determined resting flow (RF) and coronary reserve (CR), respectively. RESULTS: Coronary angiography performed at four weeks after surgery confirmed occlusion of RC and CX with collateralization and a tight stenosis of LAD. Initially, an episodic reduction in A and IP WT was observed which became persistent later (AWT: 16 +/- 3%; IPWT: 16 +/- 4%, FS: 20 +/- 4%, p < 0.005 vs. baseline [BS]). With dobutamine a biphasic response (improvement in A and IP WT between 5-15 and dysfunction between 20-30 microg/kg/min) was observed. Seven dogs were sacrificed at eight weeks and showed normal RF but reduced transmural CR (A: 75 +/- 18%; IP: 46 +/- 22% of control). Seven dogs underwent PTCA of the LAD at eight weeks and showed gradual improvement in AWT with normalization at 12 weeks (AWT: 30 +/- 5%, p < 0.001 vs. eight weeks). At sacrifice RF and CR in the A wall were normal but there was reduced subendocardial RF in the IP region (64% of BS). Further, biopsy samples showed normal histological findings and high energy phosphate content in all dogs. Radioligand binding assays using 125I-iodocyanopindolol showed downregulation of beta-adrenergic receptor density in the dysfunctional regions compared with control. CONCLUSIONS: In this canine model of viable, collateral dependent and reversibly dysfunctional myocardium, there was early episodic dysfunction followed by persistent dysfunction which was initially associated with normal RF and later with subendocardial hypoperfusion.

Effect of superoxide dismutase on infarct size and postischemic recovery of myocardial contractility and metabolism in dogs.

The effects of superoxide dismutase treatment on infarct size, postischemic recovery of contractile function and tissue content of high energy phosphates were examined in a canine model of myocardial ischemia and reperfusion. Ischemia was induced by thrombotic occlusion of a coronary artery and reperfusion was achieved by intravenous thrombolysis. Average duration of ischemia was 90 min. Fifty closed chest anesthetized dogs were randomized to receive either superoxide dismutase (34,000 IU/min intravenously) or placebo, starting approximately 30 min before and continuing for 30 min into the reperfusion phase. Left ventricular ejection fraction and regional segmental shortening of the postischemic area were calculated from contrast angiograms after 4 h, 48 h and 1 week of reperfusion. Tissue content of high energy phosphates was determined from transmural biopsy after 4 h and 1 week. Infarct size was measured by planimetry of dye-stained heart slices. In the superoxide dismutase and placebo-treated groups, respectively, the mortality rate was 25% and 16%, collateral flow 20 +/- 10 and 23 +/- 18 ml/min per 100 g, area at risk 25 +/- 6% and 26 +/- 7% of the left ventricle and infarct size 28 +/- 19% and 36 +/- 27% of the area at risk. Multiple regression analysis failed to show any beneficial effect of superoxide dismutase treatment on infarct size. Left ventricular ejection fraction, regional segmental shortening of the postischemic area and tissue content of high energy phosphates recovered to a similar extent and at a similar rate in both treated and placebo groups up to 1 week after reperfusion. Thus, in this model of coronary occlusion and reperfusion superoxide dismutase treatment is of no benefit.

Relation between coronary artery stenosis and myocardial purine metabolism, histology and regional function in humans.

In 54 patients undergoing elective or emergency aortocoronary bypass grafting, angiographic and electrocardiographic changes were studied. Five patients with unstable angina and five patients with evolving myocardial infarction were included. High energy phosphate metabolism and the histologic appearance of the myocardium were analyzed in transmural biopsy specimens acquired at the time of surgery. In patients without anterior infarction on the electrocardiogram, severe stenosis of the left anterior descending coronary artery resulted in a reduction of anterior wall motion that was associated with a partial depletion of the adenylate pool. Mitochondrial function, however, remained intact: the adenosine diphosphate/adenosine triphosphate ratio, the energy charge and the creatine phosphate/adenosine triphosphate ratio were in the normal range. Histologic assessment demonstrated viable myocardium with a high incidence of atrophic cells. In evolving myocardial infarction, 170 minutes of acute coronary artery obstruction resulted in anterior wall akinesia associated with a decrease of the sum of the adenylates to 52% and of creatine phosphate to 16% of their normal value (p less than 0.05). The nucleosides accumulated; their major fraction (91%) was inosine. The adenosine diphosphate/adenosine triphosphate ratio increased from 0.14 +/- 0.04 to 0.49 +/- 0.20 (p less than 0.01) and the energy charge decreased from 0.924 +/- 0.021 to 0.660 +/- 0.169 (p less than 0.01). Ultrastructure examination revealed irreversible cell damage in at least the subendocardial layer. These results suggest that the energetic base of reduced contractility due to severe coronary artery stenosis is different from that in acute coronary obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary thrombolysis with recombinant tissue-type plasminogen activator: patency rate and regional wall motion after 3 months.

In a double-blind, placebo-controlled, randomized trial the long-term (+/- 3 months) effects of intravenous administration of recombinant tissue-type plasminogen activator (rt-PA) versus placebo were compared in relation to left ventricular function, coronary patency rate and antigenicity in 28 patients with a first myocardial infarction. Patency rate of the infarct-related coronary artery at the end of the rt-PA/placebo infusion and after 3 months of medical treatment (including oral anticoagulant agents) was 86 and 71%, respectively, in the rt-PA group, and 21 and 58%, respectively, in the placebo group. Regional wall motion of the infarct-related area was quantitated with digital subtraction angiography. Intrapatient comparisons revealed significant improvement in regional wall motion after 3 months in both the rt-PA and placebo groups. The improvement in the rt-PA group was not significantly greater than that in the placebo group. Thirteen patients (10 with rt-PA and 3 with placebo) with persistent patency (both early and late) of the infarct-related coronary artery showed a significant improvement of both global and regional left ventricular function, while 8 patients (2 with rt-PA and 6 with placebo) with persistent occlusion showed no changes. Antibodies against rt-PA were not detected in serum 2 weeks after the infusion, which is indicative of the lack of antigenicity of rt-PA and allows for its repeated administration.

Early intravenous administration of metoprolol enhances myocardial salvage by thrombolysis with recombinant tissue-type plasminogen activator after thrombotic coronary artery occlusion in the dog by improvement of the collateral blood flow to the area at risk.

OBJECTIVES: We studied the effects of beta 1-adrenergic blockade preceding thrombolysis on hemodynamic variables, myocardial blood flow and infarct size in a canine model of thrombotic occlusion of the left anterior descending coronary artery. BACKGROUND: Previous work suggested a reduction in infarct size and improvement in left ventricular function by intravenous beta-blockade preceding thrombolysis. METHODS: Experiments were conducted in 34 anesthetized dogs; 17 received 0.975 mg/kg body weight of metoprolol intravenously starting 15 min after occlusion, and thrombolysis was initiated 60 min after occlusion. Seventeen dogs received saline solution followed by thrombolysis. Coronary blood flow was measured by radioactive microspheres, infarct size by a dye method, hemodynamic variables by catheter-tipped pressure transducers and cardiac output by the thermodilution method. RESULTS: Infarct size in metoprolol- and placebo-treated dogs was 23.62 +/- 18.04% and 41.50 +/- 16.03% of area at risk, respectively (p < 0.01). Before occlusion, myocardial blood flow and hemodynamic variables were similar. Sixty minutes after occlusion, cardiac output (1.94 +/- 0.41 vs. 2.32 +/- 0.68 liters/min, p < 0.01) was lower in the metoprolol-treated dogs. Collateral flow to the area at risk (17.27 +/- 7.44 vs. 10.25 +/- 5.33) and to its epicardial (21.68 +/- 8.04 vs. 11.5 +/- 6.10), midmyocardial (14.30 +/- 8.63 vs. 7.35 +/- 4.94) and endocardial (13.18 +/- 8.21 vs. 6.26 +/- 5.34 cm3/min per 100 g) layers was higher (p < or = 0.05) in the metoprolol-treated dogs. The ratio of epicardial flow area at risk/circumflex territory was inversely correlated to infarct size (r = -0.69, p < 0.01). After 5 min of occlusion, collateral flow was comparable in the five dogs of each group; over the next 55 min it remained constant in the metoprolol group but decreased in the placebo dogs. CONCLUSIONS: Intravenous metoprolol, administered before thrombolysis, enhances infarct size limitation, partly by improvement of collateral flow to area at risk.

Coronary thrombolysis by intravenous infusion of recombinant single chain urokinase-type plasminogen activator or recombinant urokinase in baboons: effect on regional blood flow, infarct size and hemostasis.

An occlusive thrombus was produced by thrombin-induced coagulation in the left anterior descending coronary artery of 18 open chest baboons. In six control animals, occlusive thrombosis persisting for 4 hours resulted in a large transmural infarct (66 +/- 4% of the perfusion area, mean +/- SEM). In six animals, single chain urokinase-type plasminogen activator, obtained by recombinant deoxyribonucleic acid (DNA) technology, was infused intravenously at a rate of 20 micrograms/kg per min for 60 minutes after approximately 45 minutes of coronary thrombosis. Persistent reperfusion occurred within 21 +/- 4 minutes (mean +/- SD). The mean duration of occlusion before reperfusion was 72 +/- 6 minutes. Recanalization resulted in a reduction of infarct size (42 +/- 4%, p less than 0.01 versus control animals). Myocardial blood flow in the perfusion area of the left anterior descending coronary artery was 107% of normal 2.5 hours after recanalization. The infusion of recombinant single chain urokinase-type plasminogen activator was not associated with systemic activation of the fibrinolytic system, fibrinogen breakdown or evident bleeding. In six baboons recombinant low molecular weight urokinase (molecular weight 33,000) was infused intravenously at a rate of 20 micrograms/kg per min for 60 minutes after approximately 45 minutes of coronary thrombosis. Persistent reperfusion occurred within 14 +/- 5 minutes (p less than 0.05 versus recombinant single chain urokinase-type plasminogen activator). The mean duration of occlusion was 69 +/- 14 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on experimental myocardial infarction: dogs or baboons?

The extrapolation to humans of results obtained in experimental studies is a major problem in cardiovascular research. It is generally believed that non-human primates provide a better model for the study of experimental myocardial infarction than the canine or porcine heart. In the present study the transmural distribution of myocardial infarction and collateral flow were compared between dogs and baboons. In the open chest model, the left anterior descending coronary artery was ligated for 4 h. In the subepicardial and subendocardial portions of the left ventricle myocardial blood flow was measured with tracer microspheres, and infarct size and site were determined using triphenyl tetrazolium chloride. In baboons, mean(SD) subendocardial collateral flow was higher than subepicardial collateral flow (41.8(24.6) ml . min-1 X 100 g-1 vs 28.6(21.3) ml . min-1 X 100 g-1 (p less than 0.05)). Subendocardial infarct size (expressed as a percentage of the perfusion area) was smaller than subepicardial infarct size (50.3(8.5)% vs 61.2(9.6)% (p less than 0.001)). In dogs, subendocardial collateral flow was less than subepicardial collateral flow (10.2(6.0) ml . min-1 vs 13.6(4.6) ml . min-1 X 100 g-1 (p less than 0.05)), and subendocardial infarct size was greater than subepicardial infarct size (67.3(12.9)% vs 38.3(18.0)% (p less than 0.01)). When, irrespective of the species or transmural localisation, infarct size is related to collateral flow, expressed as a percentage of normal flow, a weak but significant correlation is obtained (r = 0.61, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Frequency dependence of Ca2+ release from the sarcoplasmic reticulum in human ventricular myocytes from end-stage heart failure.

OBJECTIVES: Human cardiac muscle from failing heart shows a decrease in active tension development and a rise in diastolic tension at stimulation frequencies above 50-60 beats/min due to both systolic and diastolic dysfunction. We have investigated underlying changes in cellular [Ca2+]i regulation. METHODS: Single ventricular myocytes were isolated enzymatically from the explanted hearts of transplant recipients with ischemic cardiomyopathy (nhearts = 5 ncells = 15) or dilated cardiomyopathy (nhearts = 6, ncells = 19). Cells were studied during whole-cell patch clamp with fluo-3 and fura-red as [Ca2+]i indicators (36 +/- 1 degrees C). RESULTS: In current clamp mode (action potential recording), the amplitude of Ca2+ release from the sarcoplasmic reticulum (SR) decreased at stimulation frequencies above 0.5 Hz; this decrease was more pronounced for cells from dilated cardiomyopathy. Diastolic [Ca2+]i increased at 1 and 2 Hz for both groups. Action potential duration (APD90) decreased with frequency in all cells; in addition there was a drop in plateau potential of 10 +/- 1 mV for cells from ischemic cardiomyopathy and of 13 +/- 2 mV for cells from dilated cardiomyopathy. In voltage clamp mode the L-type Ca2+ current showed reversible decrease during stimulation at 1 and 2 Hz. Recovery from inactivation during a double pulse protocol was slow (75 +/- 3% at 500 ms, 89 +/- 3% at 1000 ms) and followed the decay of the [Ca2+]i transient. CONCLUSIONS: The negative force-frequency relation of the failing human heart is due to a decrease in Ca2+ release of the cardiac myocytes at frequencies > or = 0.5 Hz, more pronounced in dilated than in ischemic cardiomyopathy. Inhibition of ICaL at higher frequencies, at least partially related to an increase in diastolic [Ca2+]i, will contribute to this negative staircase because of a decrease in the trigger for Ca2+ release, and of decreased loading of the SR.

Long term spontaneous evolution of left ventricular function after experimental acute coronary occlusion.

In a canine model of acute occlusion of the left anterior descending artery (LAD), left ventriculography was performed before and immediately after occlusion and also one and three weeks later. Regional left ventricular function was evaluated by the centreline method. Global and regional left ventricular function were significantly depressed immediately after occlusion and showed no significant recovery after one and three weeks, except for a decrease in the paradoxical motion of the LAD territory, which was probably due to stiffening of the infarct area.

DVR plating of distal radius fractures.

Volar plating has become the standard of care for most distal radius fractures. When done for the right indication and with adequate mastering of the technique complication ratio is low. The concept of subchondral support is key in this technique. Osteoporotic patients will especially benefit from this type of fixation which allows early immobilization, quick return to activities of daily living and early good outcome.