Low efficiency of Ca2+ entry through the Na+-Ca2+ exchanger as trigger for Ca2+ release from the sarcoplasmic reticulum - A comparison between L-type Ca2+ current and reverse-mode Na+-Ca2+ exchange

It has been proposed that Ca2+ entry through the Na+-Ca2+ exchanger can contribute significantly to the trigger for Ca2+ release from the sarcoplasmic reticulum (SR). We have compared the characteristics of Ca2+ release triggered by reverse-mode Na+-Ca2+ exchange and by L-type Ca2+ current (I-CaL) during depolarizing steps in single guinea pig ventricular myocytes (whole-cell voltage clamp, flue 3 and fura-red as [Ca2+](i) indicators, 36+/-1 degrees C, K+-based pipette solution with 20 mmol/L [Na+]). Conditioning pulses to +60 mV ensured comparable Ca2+ loading of the SR. In the presence of I-CaL, [Ca2+](i) transients typically have an early and rapid rising phase reflecting Ca2+ release, which has a bell-shaped voltage dependence with a peak at +10 mV. With Ca2+ entry through Na+-Ca2+ exchange only (20 mu mol/L nisoldipine), Ca2+ release flux from the SR is decreased and directly related to the amplitude of the depolarizing step. Ca2+ release is preceded by a significant delay (81+/-21 ms at +20 mV, 24+/-4 ms at +70 mV) related to Ca2+ entry through the exchanger. Triggered release interrupts Ca2+ entry, as evidenced by reversal of the exchanger current. At potentials positive to +40 mV, Ca2+ influx through Na+-Ca2+ exchange, calculated from the outward exchange current, reaches magnitudes comparable to I-CaL, but Ca2+ release due to reverse-mode Na+-Ca2+ exchange still has a significant delay. We calculated trigger efficiency as the ratio between the maximal rate of Ca2+ release and the Ca2+ influx preceding this release; efficiency of reverse-mode Na+-Ca2+ exchange is approximately four times less than that of I-CaL. With both I-CaL and reverse-mode Na+-Ca2+ exchange present, Ca2+ release is triggered by I-CaL, and a contribution of reverse-mode Na+-Ca2+ exchange to the trigger could not be detected at potentials below +60 mV. These characteristics of reverse; mode Na+-Ca2+ exchange predict that its role as a trigger for Ca2+ release during the action potential is likely to be negligible

Randomized coronary patency trial of double-bolus recombinant staphylokinase versus front-loaded alteplase in acute myocardial infarction

One hundred two patients with evolving myocardial infarction of 6 hours' duration were given aspirin and intravenous heparin and randomly allocated to intravenous front-loaded, weight-adjusted rTPA administration over a 90-minute period (52 patients) or to two 15 mg doses of recombinant staphylokinase, 30 minutes apart (50 patients). Thrombolysis in Myocardial Infarction (TIMI) perfusion grade 3 at 90 minutes was achieved in 68% (95% confidence interval, 55% to 81%) of patients treated with staphylokinase versus 57% (95% confidence interval, 43% to 72%) of patients treated with rTPA (p = not significant). Double-bolus stophylokinase was significantly more fibrin-specific than accelerated rTPA with residual fibrinogen at 90 minutes of 105% +/- 4.1% and 68% +/- 75%, respectively (p 5 mu g/ml) and specific anti-staphylokinase IgG developed in 73% of patients after 2 weeks. Thus two 75 mg doses of staphylokinase induce early, complete, and sustained coronary artery patency at least as frequently as accelerated rTPA without associated fibrinogen degradation but with subsequent induction of circulating neutralizing antibodies

Predictors of 30-day Mortality in the Era of Reperfusion for Acute Myocardial-infarction - Results From An International Trial of 41 021 Patients

Background Despite remarkable advances in the treatment of acute myocardial infarction, substantial early patient mortality remains. Appropriate choices among alternative therapies and the use of clinical resources depend on an estimate of the patient's risk. Individual patients reflect a combination of clinical features that influence prognosis, and these factors must be appropriately weighted to produce an accurate assessment of risk. Prior studies to define prognosis either were performed before widespread use of thrombolysis or were limited in sample size or spectrum of data. Using the large population of the GUSTO-I trial, we performed a comprehensive analysis of relations between baseline clinical data and 30-day mortality and developed a multivariable statistical model for risk assessment in candidates for thrombolytic therapy. Methods and Results For the 41 021 patients enrolled in GUSTO-I, a randomized trial of four thrombolytic strategies, relations between clinical descriptors routinely collected at initial presentation, and death within 30 days (which occurred in 7% of the population) were examined with both univariable and multivariable analyses. Variables studied included demographics, history and risk factors, presenting characteristics, and treatment assignment. Risk modeling was performed with logistic multiple regression and validated with bootstrapping techniques. Multivariable analysis identified age as the most significant factor influencing 30-day mortality, with rates of 1.1% in the youngest decile (75 (adjusted chi(2)=717, P<.0001). Other factors most significantly associated with increased mortality were lower systolic blood pressure (chi(2)=550, P<.0001), higher Killip class (chi(2)=350, P<.0001), elevated heart rate (chi(2)=275, P<.0001), and anterior infarction (chi(2)=143, P<.0001). Together, these five characteristics contained 90% of the prognostic information in the baseline clinical data. Other significant though less important factors included previous myocardial infarction, height, time to treatment, diabetes, weight, smoking status, type of thrombolytic, previous bypass surgery, hypertension, and prior cerebrovascular disease. Combining prognostic variables through logistic regression, we produced a validated model that stratified patient risk and accurately estimated the likelihood of death. Conclusions The clinical determinants of mortality in patients treated with thrombolytic therapy within 6 hours of symptom onset are multifactorial and the relations complex. Although a few variables contain most of the prognostic information, many others contribute additional independent prognostic information. Through consideration of multiple characteristics, including age, medical history, physiological significance of the infarction, and medical treatment, the prognosis of an individual patient can be accurately estimated

Early discharge in the thrombolytic era: An analysis of criteria for uncomplicated infarction from the global utilization of streptokinase and t-PA for occluded coronary arteries (GUSTO) trial

Objectives. This study sought to readdress the definition of uncomplicated myocardial infarction and to apply clinical criteria for early discharge of such patients in the thrombolytic era. Background. Previous studies proposed early hospital discharge at day 7 to 10 after acute myocardial infarction. The potential for earlier discharge of patients with uncomplicated infarction after thrombolysis remains undemonstrated. Methods. We defined ''uncomplicated infarction'' a priori as the absence of death, reinfarction, ischemia, stroke, shock, heart failure (Killip class >1), bypass surgery, balloon pumping, emergency catheterization or cardioversion or defibrillation in the first 4 hospital days. We applied this definition to 41,021 patients in the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO-I) trial. We examined death at 30 days and 1 year and rates of in-hospital reinfarction, heart failure, recurrent ischemia, shock and stroke in the uncomplicated and complicated groups created by application of our definition. We also assessed lengths of hospital and cardiac care unit stay. Results. Application of our clinical criteria yielded 23,497 (57.3%) patients in the uncomplicated group at day 4 with a very low risk of death and in-hospital complications: 30-day mortality 1%, reinfarction 1.7%, heart failure 2.6%, recurrent ischemia 6.7%, shock 0.4% and stroke 0.2%. One-year mortality was 3.6%. The median hospital stay was 9 days (7, 12 [25th, 75th percentiles, respectively]), and the median cardiac care unit stay 3 days (3, 5). Conclusions. Simple clinical characteristics can identify a very low risk post-myocardial infarction population by hospital day 4. Use of these criteria for early discharge planning could substantially reduce length of stay for patients with uncomplicated acute myocardial infarction