Preoperative methylprednisolone increases plasma Pentraxin 3 early after total knee arthroplasty: a randomized, double-blind, placebo-controlled trial.

Preoperative glucocorticoid administration reduces the systemic inflammatory response. Pentraxin 3 (PTX3) is a novel inflammatory marker belonging to the humoral arm of innate immunity exerting a potentially protective host response. This study evaluated PTX3 and other complement marker changes after preoperative methylprednisolone (MP) early after total knee arthroplasty (TKA). Seventy patients were randomized (1 : 1) to preoperative intravenous (i.v.) MP 125 mg (group MP) or isotonic saline i.v. (group C). The outcomes included change in plasma PTX3, mannose-binding lectin (MBL), ficolins (ficolin-1, -2 and -3), complement components (C4 and C3), terminal complement complex (TCC) and C-reactive protein (CRP) concentrations. Blood samples were analysed at baseline and 2, 6, 24 and 48 h after surgery with complete sampling from 63 patients for analyses. MP resulted in an increase in circulating PTX3 compared to saline from baseline to 24 h postoperatively (P < 0·001), while MP reduced the systemic inflammatory response (CRP) 24 and 48 h postoperatively (P < 0·001). However, the small postoperative changes in MBL, ficolin-1, -2 and -3, C4, C3 and TCC concentrations did not differ between groups (P > 0·05). In conclusion, preoperative MP 125 mg increased circulating PTX3 and reduced the general inflammatory response (CRP) early after TKA, but did not affect other complement markers.

Impaired beta cell sensitivity to incretins in type 2 diabetes is insufficiently compensated by higher incretin response.

BACKGROUND AND AIMS: The incretin effect is impaired in type 2 diabetes (T2D), but the underlying mechanisms are only partially understood. We investigated the relationships between the time course of the incretin effect and that of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) during oral glucose tolerance tests (OGTTs), thereby estimating incretin sensitivity of the beta cell, and its associated factors. METHODS AND RESULTS: Eight patients with T2D and eight matched subjects with normal glucose tolerance (NGT) received 25, 75, and 125 g OGTTs and corresponding isoglycemic glucose infusions (IIGI). The time course of the incretin effect, representing potentiation of insulin secretion by incretins (PINCR), was determined by mathematical modelling as the time-dependent fold increase in insulin secretion during OGTT compared to IIGI. The time course of PINCR was correlated with that of both GIP and GLP-1 in each subject (median r = 0.67 in NGT and 0.45 in T2D). We calculated an individual beta cell sensitivity to incretins (SINCR) using a weighted average of GIP and GLP-1 (pooled incretin concentration, PIC), as the slope of the relationship between PINCR and PIC. SINCR was reduced in T2D (p < 0.01). In the whole group, mean PIC, GIP and GLP-1 concentrations during the OGTT were inversely correlated with SINCR, but T2D had lower PIC, GIP and GLP-1 levels at the same SINCR (p < 0.05). CONCLUSION: Relative incretin insensitivity is partly compensated for by higher incretin secretory responses. However, T2D shows both impairment in incretin sensitivity and abnormal compensation by incretin secretion.

Reduced postprandial GLP-1 responses in women with gestational diabetes mellitus.

AIM: We investigated postprandial glucagon-like peptide-1 (GLP-1) responses in pregnant women with and without gestational diabetes mellitus (GDM) and again following delivery when normal glucose tolerance (NGT) was re-established. METHODS: Eleven women with GDM [plasma glucose (PG) concentration at 120 min after a 75-g oral glucose tolerance test (OGTT): 10.0 ± 0.9 mM (mean ± SD); age: 31 ± 6 years; body mass index (BMI): 31.6 ± 6.4 kg/m(2) ; haemoglobin A1c (HbA1c): 5.6 ± 0.5%] and eight pregnant women with NGT (PG(120 min), OGTT : 5.7 ± 0.7 mM; age: 28 ± 3 years; BMI: 29.7 ± 5.4 kg/m(2) ; HbA1c: 5.4 ± 0.3%) were investigated with a 4-h liquid meal test during third trimester (TT) and 3-4 months postpartum (PP). All patients with GDM re-established NGT following delivery. RESULTS: Pregnancy was associated with low postprandial GLP-1 responses. Patients with GDM exhibited reduced postprandial GLP-1 responses compared to their PP levels [area under curve (AUC): 5.5 ± 1.3 vs. 8.4 ± 3.2 nM × min, p=0.005], but the difference among NGT women (7.3 ± 2.8 vs. 8.8 ± 2.0 nM × min, p=0.066) was not statistically significant. Pregnancy did not influence postprandial responses of the other incretin hormone glucose-dependent insulinotropic polypeptide (GIP) in any of the groups, but GDM patients were characterized by greater postprandial GIP responses during both TT and PP compared to NGT subjects. CONCLUSIONS: Pregnancy is associated with reduced postprandial GLP-1 responses (most pronounced in patients with GDM) that normalize after delivery. In contrast, postprandial GIP responses seem unaffected by pregnancy but is increased in GDM patients.

Glucagon antagonism as a potential therapeutic target in type 2 diabetes.

Glucagon is a hormone secreted from the alpha cells of the pancreatic islets. Through its effect on hepatic glucose production (HGP), glucagon plays a central role in the regulation of glucose homeostasis. In patients with type 2 diabetes mellitus (T2DM), abnormal regulation of glucagon secretion has been implicated in the development of fasting and postprandial hyperglycaemia. Therefore, new therapeutic agents based on antagonizing glucagon action, and hence blockade of glucagon-induced HGP, could be effective in lowering both fasting and postprandial hyperglycaemia in patients with T2DM. This review focuses on the mechanism of action, safety and efficacy of glucagon antagonists in the treatment of T2DM and discusses the challenges associated with this new potential antidiabetic treatment modality.

The novel Mechanical Ventilator Milano for the COVID-19 pandemic.

This paper presents the Mechanical Ventilator Milano (MVM), a novel intensive therapy mechanical ventilator designed for rapid, large-scale, low-cost production for the COVID-19 pandemic. Free of moving mechanical parts and requiring only a source of compressed oxygen and medical air to operate, the MVM is designed to support the long-term invasive ventilation often required for COVID-19 patients and operates in pressure-regulated ventilation modes, which minimize the risk of furthering lung trauma. The MVM was extensively tested against ISO standards in the laboratory using a breathing simulator, with good agreement between input and measured breathing parameters and performing correctly in response to fault conditions and stability tests. The MVM has obtained Emergency Use Authorization by U.S. Food and Drug Administration (FDA) for use in healthcare settings during the COVID-19 pandemic and Health Canada Medical Device Authorization for Importation or Sale, under Interim Order for Use in Relation to COVID-19. Following these certifications, mass production is ongoing and distribution is under way in several countries. The MVM was designed, tested, prepared for certification, and mass produced in the space of a few months by a unique collaboration of respiratory healthcare professionals and experimental physicists, working with industrial partners, and is an excellent ventilator candidate for this pandemic anywhere in the world.

Myocardial insulin resistance in patients with syndrome X.

Insulin resistance is common in patients with angina pectoris, a positive exercise electrocardiogram, and normal coronary angiograms (syndrome X). It is still not known whether insulin resistance affects the cardiac muscle itself and, if so, whether insulin resistance involves myocardial hemodynamics and energy metabolism. We investigated hemodynamics as well as metabolite exchanges across the heart and the forearm in eight patients with syndrome X and eight control subjects during a baseline period after an overnight fast and during a hyperinsulinemic-euglycemic clamp. Myocardial hemodynamics and metabolism were studied at rest, during pace stress, and in the recovery period after pacing. Neither coronary sinus blood flow nor forearm blood flow differed between the groups before and during the clamp. Whole body insulin-stimulated glucose uptake was decreased in the patients (15.6+/-2.1 vs. 23.1+/-2.0 micromol x kg-1 x min-1). Insulin-stimulated glucose uptake in the forearm and the cardiac muscle was equally reduced in the patients (46+/-5 and 48+/-5%). Myocardial glucose uptake correlated with total arterial delivery in the control subjects (r = 0.63, P < 0.01), but not in patients (r = 0.22, P = 0.13). Carbohydrate and lipid oxidation was similar in the two groups at rest, and changes during the clamp were not different in control subjects and patients either at rest, during pacing, or in the recovery period. Patients with syndrome X exhibit myocardial insulin resistance, but cardiac energy metabolism remains unaffected. In patients with syndrome X, insulin-stimulated glucose uptake is independent from myocardial blood flow.

Mechanism-Based Modeling of Gastric Emptying Rate and Gallbladder Emptying in Response to Caloric Intake.

Bile acids released postprandially modify the rate and extent of absorption of lipophilic compounds. The present study aimed to predict gastric emptying (GE) rate and gallbladder emptying (GBE) patterns in response to caloric intake. A mechanism-based model for GE, cholecystokinin plasma concentrations, and GBE was developed on data from 33 patients with type 2 diabetes and 33 matched nondiabetic individuals who were administered various test drinks. A feedback action of the caloric content entering the proximal small intestine was identified for the rate of GE. The cholecystokinin concentrations were not predictive of GBE, and an alternative model linking the nutrients amount in the upper intestine to GBE was preferred. Relative to fats, the potency on GBE was 68% for proteins and 2.3% for carbohydrates. The model predictions were robust across a broad range of nutritional content and may potentially be used to predict postprandial changes in drug absorption.

Cardiac metabolic and hemodynamic effects of insulin in patients with coronary artery disease.

To assess the effects of insulin in stable coronary artery disease (CAD), 2 U i.v. insulin was given to 9 control and 10 CAD patients during coronary sinus catheterization. Hemodynamic and metabolic data were obtained before and for 90 min after insulin injection. Insulin induced no changes in heart rate, mean aortic pressure, rate-pressure product, coronary sinus flow, or coronary resistance. Metabolic changes were similar in both groups and included 1) 30% decrease of arterial glucose (P less than .001) and 3-fold increase of myocardial glucose uptake (P less than .001), 2) 1.5- to 2.5-fold elevation of arterial lactate (P less than .001) and myocardial lactate usage (P less than .001), respectively, 3) 50-70% suppression of arterial levels (P less than .001) and myocardial uptake of free fatty acids (P less than .01), and 4) 10% reduction of myocardial net oxygen consumption (P less than .05). Myocardial citrate efflux increased in the CAD patients (P less than .05), whereas alanine release rose only in control patients (P less than .01), suggesting that glucose enters glycogen production in the CAD patients and pyruvate production in the control patients to a high degree. Myocardial glutamate uptake remained unchanged. In conclusion, insulin sensitivity was not altered in CAD. The insulin-induced shift from myocardial free fatty acid to carbohydrate usage may be beneficial to the ischemic heart by increasing glycogen stores, saving oxygen, and inhibiting an excess free-fatty acid concentration, which may be toxic during ischemia.

Functional significance of recruitable collaterals during temporary coronary occlusion evaluated by 99mTc-sestamibi single-photon emission computerized tomography.

OBJECTIVES: The present study evaluated the impact of recruitable collaterals on regional myocardial perfusion measured by 99mtechnetium (Tc)-sestamibi single-photon emission computerized tomography (SPECT) during temporary coronary occlusion and related these estimates to the coronary wedge pressure and electrocardiographic (ECG) ST-segment changes. BACKGROUND: Clinical variables (angina and ECG changes) and intracoronary flow and pressure recordings have indicated a protective role of recruitable collaterals on myocardial perfusion during percutaneous transluminal coronary angioplasty (PTCA). METHODS: Thirty patients (mean age 55 years, SD 9; 20 men) with stable angina pectoris and proximal nonocluding single-vessel left anterior descending coronary artery (LAD)-stenosis scheduled for PTCA were included. Visualization of recruitable collaterals by ipsilateral and contralateral contrast injection, registration of coronary wedge pressure and injection of 99mTc-sestamibi during 90-s LAD occlusions were undertaken. A rest perfusion study was performed within four days before PTCA. As an estimate of the severity of regional hypoperfusion during occlusion, an occlusion/rest count ratio was calculated (mean defect pixel count during occlusion divided by mean pixel count in identical regions at rest). RESULTS: The scintigraphic occlusion/rest count ratio was higher in patients with recruitable collaterals (n = 16), 67 +/- 11%, compared to patients without collaterals (n = 14), 60 +/- 6% (p < 0.05). The occlusion/rest count ratio correlated with the coronary wedge pressure (R2 = 0.34; p < 0.001). The occlusion/rest count ratio was lower, 61 +/- 6%, in patients with ST-segment elevation (n = 23) versus 74 +/- 9% in patients without ST-segment elevation (n = 7) (p < 0.0001). CONCLUSIONS: Using 99mTc-sestamibi SPECT imaging during brief episodes of coronary occlusion, the severity of regional myocardial hypoperfusion was reduced by the presence of recruitable collaterals in a selected patient population with proximal LAD stenoses. Our results demonstrate a protective effect of recruitable collaterals on myocardial perfusion during temporary coronary occlusion.

Elevated endothelin concentrations are associated with reduced coronary vasomotor responses in patients with chest pain and normal coronary arteriograms.

OBJECTIVES: The purpose of this study was to investigate the relationship between arterial and coronary sinus endothelin (ET) concentrations and coronary vasomotor responses during rapid atrial pacing in patients with chest pain and normal coronary arteriograms (CPNA). BACKGROUND: Plasma ET concentrations are significantly higher in CPNA patients than in healthy control subjects. METHODS: We investigated 19 carefully characterized CPNA patients (14 women; mean age 53 +/- 9 years) of whom 10 had positive electrocardiographic responses to exercise. The percentage fall in coronary vascular resistance (%d.CVR) after 10 min of rapid atrial pacing was determined using a thermodilution pacing catheter. Plasma ET concentrations were measured by radioimmunoassay on simultaneously drawn arterial and coronary sinus samples. RESULTS: No significant differences in ET concentrations were observed between men and women, but a strong statistical trend suggested that %d.CVR was lower in women than men (27[23 to 31]% vs. 34[29 to 45]%--median[interquartile range]; p = 0.07). Simple regression analysis including only the women (n = 14) suggested a significant relationship between baseline arterial ET concentrations and %d.CVR (R2 = 0.34; p = 0.06). Furthermore, stepwise multivariate regression analysis of the group as a whole indicated that both gender (p = 0.03) and baseline arterial ET concentration (p = 0.02) were independently predictive of %d.CVR (R2 = 0.44; overall p = 0.02); this relationship predicts that women with high ET levels would have the lowest %d.CVR during pacing. CONCLUSIONS: These data support the hypothesis that elevated ET activity may be associated with reduced coronary flow responses during rapid atrial pacing in CPNA patients.

The Coronary Artery Revascularisation in Diabetes (CARDia) trial: background, aims, and design.

BACKGROUND: Patients with diabetes have an increased incidence and severity of ischemic heart disease, which leads to an increased requirement for coronary revascularization. Comparative information regarding mode of revascularization--coronary artery bypass graft surgery surgery (CABG) or percutaneous coronary intervention (PCI)--is limited, mainly confined to a subanalysis of the Bypass Angioplasty Revascularization (BARI) trial, suggesting a mortality benefit of CABG over PCI. No prospective trial has specifically compared these modes of revascularization in patients with diabetes. OBJECTIVE: The Coronary Artery Revascularisation in Diabetes (CARDia) trial is designed to address the hypothesis that optimal PCI is not inferior to modern CABG as a revascularization strategy for diabetics with multivessel or complex single-vessel coronary disease. The primary end point is a composite of death, nonfatal myocardial infarction, and cerebrovascular accident at 1 year. METHOD: A total of 600 patients with diabetes are to be randomized to either PCI or CABG, with few protocol restrictions on operative techniques or use of new technology. This gives a power of 80% to detect non-inferiority of PCI assuming that the PCI 1-year event rate is 9%. A cardiac surgeon and a cardiologist must agree that a patient is suitable for revascularization by either technique prior to recruitment into the study. Twenty-one centers in the United Kingdom and Ireland are recruiting patients. Data on cost effectiveness, quality of life, and neurocognitive function are being collected. Long-term (3-5 year) follow-up data will also be collected.

Survival of Escherichia coli and Salmonella Typhimurium in slurry applied to clay soil on a Danish swine farm.

A pilot study was carried out on a Danish swine farm infected with multi-resistant Salmonella Typhimurium DT104 (MRDT104). We aimed to (1) investigate to which degree the decline of Escherichia coli and Salmonella in swine slurry applied to farmland depended on the application method; (2) estimate the survival times of E. coli and Salmonella in the soil surface following deposition of naturally contaminated pig slurry; and (3) simulate survival of Salmonella in different infection levels using E. coli data as input estimates. Slurry was deposited by four different methods: (1) hose applicator on black soil followed by ploughing and harrowing; (2) hose applicator on black soil followed only by harrowing; (3) hose applicator on a field with winter-wheat seedlings without further soil treatment; (4) slurry injector on a field with winter-wheat seedlings without further soil treatment. E. coli and Salmonella could not be detected at all in soil following treatment 1. Following the other treatments, E. coli was not detected in soil samples after day 21 and Salmonella was no longer detected after day 7. Simulation results showed that clinical (4 log CFU g(-1)) and sub-clinical Salmonella levels (2500 CFU g(-1)) would fall below the detection limit within 10 or 5 days, respectively. Analysis of samples from 62 Danish MRDT104-infected swineherds showed that nearly 75% of these herds had low levels of MRDT104 (< 10 CFU g(-1)) in their slurry. Our results show that ploughing and harrowing of soil amended with contaminated pig slurry was an effective means to reduce environmental exposure to E. coli and Salmonella on this clay-soil farm.

Admission plasma glucose: an independent risk factor in nondiabetic women after coronary artery bypass grafting.

OBJECTIVE: To investigate the relationship between admission plasma glucose and 30-day mortality after primary isolated coronary artery bypass grafting (CABG) in nondiabetic patients. RESEARCH DESIGN AND METHODS: All nondiabetic patients with admission plasma glucose measurement undergoing primary isolated CABG from 1993 to 1997 were included in this study. RESULTS: In 878 consecutive patients (155 women), overall mortality was 3.4% (95% CI 2.3-4.8). The mortality rate in women (n = 11; 7.1%, 3.6-12.3) was higher than in men (n = 19; 2.6%, 1.6-4.1) (P = 0.01). There was a positive correlation between plasma glucose and 30-day mortality among women only (P = 0.0001). There was a higher mortality rate in the upper two glucose quartiles (11.7%, 5.5-21.0) compared with the lower two quartiles (2.6%, 3.0-8.9) in the female patients (P = 0.03); a plasma glucose of 6.0 mmol/l separated high- and low-mortality groups. Furthermore, women in the upper two glucose quartiles had a fourfold higher mortality rate than men in the similar quartiles (P = 0.002). Among men, there was no difference in mortality rate across glucose quartiles. In a multivariate analysis, admission plasma glucose, history of thyroid disease, left ventricular ejection fraction <0.35, operation bypass time, and perioperative myocardial infarction were independently associated with mortality. CONCLUSIONS: Women with admission plasma glucose < or =6.0 mmol/l and men across the whole range of glucose values had similar mortality rates after CABG. The surplus female mortality was found only in subjects with plasma glucose >6 mmol/l. Further studies are needed to appraise the possible influence of glucose status on outcome from CABG in nondiabetic subjects.

Coronary sinus blood flow determination by the thermodilution technique: influence of catheter position and respiration.

By measuring the coronary sinus blood flow using the thermodilution technique the influence of "thermodilution catheter" withdrawal from the great cardiac vein to the ostium of the coronary sinus was investigated in 41 patients. In addition, the influence of normal and forced respiration on coronary sinus blood flow was measured in 16 of the patients. Mean great cardiac vein flow was measured to 54 +/- 25 ml X min-1. Catheter withdrawal revealed coronary sinus blood flows of 80 +/- 32, 103 +/- 35, 145 +/- 39 and 213 +/- 61 ml X min-1 when the catheter was moved by steps of 1 cm towards the coronary sinus ostium. The coronary sinus blood flow changed between 116 +/- 34 ml X min-1 and 128 +/- 41 ml X min-1 on expiration or inspiration during normal respiration, respectively, when the catheter was placed in a mid-coronary sinus position. Forced respiration changed the coronary sinus blood flow from 98 +/- 41 ml X min-1 during expiration to 196 +/- 76 ml X min-1 during inspiration. The data show that coronary sinus blood flow changes from 23 to 68 ml X min-1 per cm catheter movement, the nearer the ostium the greater the change. Therefore comparison of coronary sinus blood flow between groups of patients would be a comparison between different catheter positions. Normal respiration moves, as judged by the coronary sinus blood flow, the thermodilution catheter by less than 0.5 cm while forced respiration moves the catheter up to 2 cm within the coronary sinus.

Verapamil induced increment of oxygen extraction in the arteriosclerotic limb.

The acute effect of intravenously administered verapamil (0.08 mg X kg-1 body weight, mean dose 5.1 +/- 0.7 mg) on oxygen exchange and arterial blood flow (measured electromagnetically) of the lower limb was studied during reconstructive arterial surgery in 17 patients with obliterative arterial disease of the lower limbs. Verapamil increased oxygen extraction in the diseased leg by 12% (from a median value of 28.3 to 31.6 ml X litre-1, p less than 0.01) whereas it had no effect on arterial blood flow. The increment of oxygen extraction after drug administration correlated negatively with the walking distance of the patients (r = 0.69, p less than 0.01). Systolic and diastolic blood pressure decreased significantly by 10% and 6%, respectively, whereas heart rate remained unchanged after the administration of verapamil. The results suggest that verapamil might be beneficial in the treatment of patients with intermittent claudication, despite the fact that no vasodilatation was seen after the drug.

Physics at the [Formula: see text] linear collider.

A comprehensive review of physics at an [Formula: see text] linear collider in the energy range of [Formula: see text] GeV-3 TeV is presented in view of recent and expected LHC results, experiments from low-energy as well as astroparticle physics. The report focusses in particular on Higgs-boson, top-quark and electroweak precision physics, but also discusses several models of beyond the standard model physics such as supersymmetry, little Higgs models and extra gauge bosons. The connection to cosmology has been analysed as well.

Somatostatin enhances insulin-stimulated glucose uptake in the perfused human forearm.

Somatostatin is widely used in experimental metabolic studies to control hormone actions. It has also been suggested that, in addition to its well known suppressive effects, somatostatin per se may increase insulin sensitivity. In order to examine this suggestion, we gave six healthy male volunteers (age 33 +/- 1 yr, mean +/- SEM; body mass index, 24.1 +/- 0.6 kg/m2) either a local intraarterial (brachial artery) or a systemic venous infusion of 25 micrograms/h somatostatin twice. The study consisted of a 1-h basal period and a 2-h systemic hyperinsulinemic (0.4 mU/kg.min) euglycemic clamp. Compared with the systemic control infusion, local forearm perfusion with somatostatin caused a 55% increase in insulin-stimulated forearm glucose uptake (0.74 +/- 0.18 vs. 0.47 +/- 0.19 mmol/L, P < 0.05). Intraarterial somatostatin perfusion did not alter basal forearm glucose uptake (0.14 +/- 0.07 vs. 0.17 +/- 0.12 mmol/L), the amount of glucose administered during the clamp (M-value, 3.2 +/- 0.5 vs. 3.0 +/- 0.6 mg/kg.min), or the levels of insulin, C-peptide, glucagon, or GH. Intermediary metabolite exchange across the forearm, total forearm blood flow, and oxygen saturations also remained stable. Glucose concentrations were slightly higher (0.06 +/- 0.01 mmol/L) in arterial than in arterialized blood, whereas lactate concentrations were comparatively decreased (108 +/- 51 mumol/L) in arterial blood. Our data suggest that somatostatin increases insulin-stimulated muscle utilization of glucose through local mechanisms. Although the nature of this increase remains to be established, it should be taken into consideration in metabolic studies using somatostatin.

Cardiac energy metabolism in patients with chest pain and normal coronary angiograms.

In 70 patients (94% were a consecutive series) with angina pectoris and normal coronary angiograms, we measured cardiac exchange of lactate, glucose, free fatty acids (FFAs), glutamate, alanine, citrate, and oxygen together with coronary sinus blood flow and blood pressure in response to pacing (150 beats/min). Twelve patients had an abnormal exercise stress test; 26 developed ST depression and 46 had chest pain in response to pacing. Sixteen patients had no ST changes (exercise/ pacing) and no pain during pacing. Pacing induced an increase in cardiac carbohydrate extraction and a decrease in FFA extraction in the entire group of patients. Less than 3% of patients had significant cardiac lactate release in response to pacing, and there were no consistent differences in the cardiac metabolic or hemodynamic responses between patient groups. The pacing-induced shift from FFA to carbohydrate extraction probably reflects the cardiac response to an acute workload. A definite sign of cardiac ischemia (lactate production) was a rare finding in these patients and not confined to the demonstration of electrocardiographic signs of ischemia.

Metabolic and hemodynamic effects of nicardipine during pacing-induced angina pectoris.

During repeat exercise testing in 10 patients with stable angina, individual optimal doses of nicardipine were determined. Hemodynamic values and cardiac metabolism were studied during 2 pacing periods carried out before and after this dose (mean 5.3 mg). Postpacing ST-segment depression diminished (1 mm) after nicardipine administration (p less than 0.05), whereas pacing time to onset of angina did not change. Nicardipine administration increased heart rate 16% (p less than 0.005) and reduced systolic (10%) and diastolic (8%) blood pressures (both p less than 0.005). Coronary blood flow increased 16% (p less than 0.05) and coronary vascular resistance decreased 24% (p less than 0.01). Myocardial oxygen consumption was unchanged despite an 11% decrease in rate-pressure product during pacing (p less than 0.02). In the control state before nicardipine administration, metabolic signs of ischemia included release of lactate across the heart in 7 patients, decreased mean free fatty acid and glutamate uptake and alanine release during pacing, together with increased glucose uptake and citrate release during recovery. After nicardipine lactate release decreased in 5 of the 7 patients, pacing no longer changed free fatty acid, glutamate and alanine uptake/release from the level at rest. During recovery glucose uptake was reduced and citrate release was unaffected. The hemodynamic data indicate that nicardipine is a systemic and coronary vasodilator, increasing oxygen supply to the ischemic myocardium. The metabolic results indicate a change in substrate utilization toward that of normal heart, suggesting improved aerobic energy supply.

Usefulness of ST deviation induced by prolonged hyperventilation as a predictor of cardiac death in angina pectoris.

One hundred ninety patients with chronic angina for an average of 2 years were followed. Forty-seven had at least 1 mm of ST deviation in response to provocation of coronary vasoconstriction by prolonged hyperventilation (group I); 143 had no ST deviation (group II). The angiographic response to this test was studied in 21 patients from group I, and revealed 25 to 100% diameter reduction; in group II 9 patients showed a 5 to 14% diameter reduction. In group I, 15 patients (32%) died (hazard rate = 0.17 deaths/patients X years) vs 18 (13%) in group II (hazard rate = 0.06) (p less than 0.01). Seven patients in group I (15%) and 3 in group 2 (2%) died while waiting for surgery (p less than 0.01). All patients who died had coronary stenoses of at least 70%. A Cox regression analysis, using 24 variables (invasive and noninvasive), showed a positive hyperventilation test (ST deviation at least 1 mm), low ejection fraction and systolic blood pressure of at least 160 mm Hg to be independent predictors of death (p less than 0.05). Considering only deaths in non-operated patients (patients waiting for surgery and patients not planned to undergo operation), a rate-pressure product/100 of 150 or less at exercise stress testing, left ventricular end-diastolic pressure of 15 mm Hg or more and duration of angina less than 1 year were also independent predictors of death. Thus, the hyperventilation test may be useful for identifying angina patients who are at high risk of cardiac death due to dynamic coronary obstructions.