Short-term administration of the glucagon receptor antagonist LY2409021 lowers blood glucose in healthy people and in those with type 2 diabetes.

AIM: To describe the clinical effects of single and multiple doses of a potent, selective, orally administered, small-molecule antagonist of the human glucagon receptor, LY2409021, in healthy subjects and in patients with type 2 diabetes. METHODS: LY2409021 was administered in dose-escalation studies to healthy subjects (n = 23) and patients with type 2 diabetes (n = 9) as single doses (Study 1) and daily to patients with type 2 diabetes (n = 47) for 28 days (Study 2). Safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) assessments were made after single doses and in patients receiving once-daily doses of LY2409021 (5, 30, 60 or 90 mg) for 28 days. RESULTS: LY2409021 was well tolerated at all dose levels in both studies. Fasting and postprandial glucose were reduced and glucagon levels increased after single and multiple dosing, with reductions in fasting serum glucose of up to ∼1.25 mmol/l on day 28. Serum aminotransferases increased in a dose-dependent manner with multiple dosing and reversed after cessation of dosing. Significant glucose-lowering was observed with LY2409021 at dose levels associated with only minor aminotransferase increases. CONCLUSION: Blockade of glucagon signalling in patients with type 2 diabetes is well tolerated and results in substantial reduction of fasting and postprandial glucose with minimal hypoglycaemia, but with reversible increases in aminotransferases. Inhibition of glucagon signalling by LY2409021 is a promising potential treatment for patients with type 2 diabetes and should be evaluated in longer clinical trials to better evaluate benefits and risks.

Gender-related differences in the central arterial pressure waveform.

OBJECTIVES: This study investigated the effect of age and gender on central arterial hemodynamic variables derived from noninvasive tonometric carotid pressure waveforms. BACKGROUND: Women have a greater age-related increase in left ventricular (LV) mass than do men and are more likely to experience symptomatic heart failure after infarction despite their higher ejection fraction. In studies of these changes, ventricular afterload is incompletely defined by brachial blood pressure (BP) measurements. We hypothesized that there exist gender differences in pulsatile vascular load, as revealed by pressure waveform analysis, which may produce suboptimal afterload conditions in women. METHODS: Data from 350 healthy normotensive subjects (187 female) aged 2 to 81 years were analyzed in decade groups. Augmentation index (AIx, the difference between early and late pressure peaks divided by pulse pressure) was used as an index of pulsatile afterload, and the ratio of diastolic to systolic pressure-time integral gave a subendocardial viability index. Heart rate, BP, ejection duration and maximal rate of pressure rise (dP/dt(max)) were also determined. RESULTS: Male subjects had a slightly higher systolic pressure until age 50. Female subjects had higher systolic pressure augmentation after the 1st decade, a difference that was significant after age 30 (p < 0.005 for each decade). In both males and females there was a strong age dependence for AIx (r = 0.77, p < 0.001 for females, r = 0.66, p < 0.001 for males). Although males had a larger body size and higher systolic pressure, systolic pressure-time integral was similar in males and females across all age groups. Diastolic pressure-time integral was consistently lower in females because of their shorter diastolic period. Subendocardial viability index was lower in females across the entire group. Differences in stature and heart rate may contribute to these findings. CONCLUSIONS: These new data may help to explain previous findings in women of an age-related increase in LV mass and excess symptomatic heart failure that are not explained by differences in brachial BP.

Relations between left atrial appendage blood flow velocity, spontaneous echocardiographic contrast and thromboembolic risk in vivo.

OBJECTIVES: The aim of this study was to determine the relations between spontaneous echo contrast, left atrial appendage blood flow velocity and thromboembolism. BACKGROUND: Left atrial thrombus and spontaneous echo contrast, a putative marker of thromboembolic risk, are frequently located in the left atrial appendage. Measurement of left atrial appendage outflow Doppler velocity by transesophageal echocardiography is a recent technique for assessment of left atrial appendage function, which may be important in thrombus formation. METHODS: Transthoracic and transesophageal echocardiographic studies were performed in 140 patients with atrial fibrillation (chronic in 80 patients, paroxysmal in 50 patients, first episode < 2 weeks in 10 patients). The left atrium and appendage were inspected for thrombus and spontaneous echo contrast, which was graded from 0 (none) to 4+ (severe). Outflow velocity profiles were obtained by pulsed wave Doppler at the orifice of the left atrial appendage. RESULTS: Left atrial spontaneous echo contrast was present in 78 patients (56%). In multivariate logistic regression analysis, spontaneous echo contrast was the only significant correlate of left atrial thrombus and was present in 14 (93%) of 15 patients. Spontaneous echo contrast and age were associated positively, and anticoagulant therapy was associated negatively, with previous thromboembolic events. Increasing grades of spontaneous echo contrast were associated with decreasing left atrial appendage blood velocity. The velocity in patients with thrombus was not significantly different from that in patients with 4+ spontaneous echo contrast. In multivariate linear regression analysis, the grade of spontaneous echo contrast was significantly and negatively associated with left atrial appendage velocity (p = -0.0001) and mitral regurgitation (p = -0.0002) and significantly and positively associated with left atrial area (p = 0.0005). The odds ratio for spontaneous echo contrast was 28:1 for low left atrial appendage blood flow velocity (< 35 cm/s) and 96:1 for low velocity and the absence of mitral regurgitation. CONCLUSIONS: Spontaneous echo contrast is the cardiac factor most strongly associated with left atrial appendage thrombus and embolic events. Spontaneous echo contrast formation is promoted by reduced blood flow velocity and increased left atrial size but is diminished by mitral regurgitation.

Effect of inhaled nitric oxide on normal human left ventricular function.

OBJECTIVES: This study determined the effects of inhaled nitric oxide (NO) on load-independent indexes of normal human left ventricular (LV) function. BACKGROUND: Inhaled NO is a potent and selective pulmonary vasodilator. However, when it is used in patients with congestive heart failure, the decrease in pulmonary vascular resistance (PVR) is often associated with an increase in pulmonary capillary wedge pressure. NO has been shown to have a negative inotropic action, but it is not known whether it affects LV chamber function when delivered by inhalation. METHODS: Eleven subjects (51 to 69 years old) with normal LV function (mean ejection fraction 72% [range 60% to 80%]) were studied. Four patients had concomitant coronary artery disease. Pressure-volume loop recordings were used to determine end-systolic and end-diastolic pressure-volume and preload recruitable stroke work relations. NO was delivered at 20 ppm for 10 min. In an additional group of patients with normal LV function, PVR (n = 5) and NO metabolites (n = 9) were measured. RESULTS: There was no effect of inhaled NO on steady state LV pressures, volumes, contractility, contraction duration, active relaxation (time constant of relaxation, peak negative first derivative of left ventricular pressure), diastolic compliance or PVR. NO metabolites (methemoglobin and nitrate) were present in the LV cavity at the same concentration as right atrial venous blood, suggesting inactivation of free NO before arrival in the LV chamber. This study had a power of 0.995 to detect a 5% change in contractility (slope of preload recruitable stroke work relation) for alpha = 0.05, based on the multiple linear regression model used. CONCLUSIONS: These results indicate that 20 ppm of inhaled NO does not have significant effects on normal LV function. This lack of effect may be due in part to rapid inactivation of free NO in transit to the heart.

Photoplethysmographic assessment of pulse wave reflection: blunted response to endothelium-dependent beta2-adrenergic vasodilation in type II diabetes mellitus.

OBJECTIVES: We sought to determine whether a simple index of pressure wave reflection may be derived from the digital volume pulse (DVP) and used to examine endothelium-dependent vasodilation in patients with type II diabetes mellitus. BACKGROUND: The DVP exhibits a characteristic notch or inflection point that can be expressed as percent maximal DVP amplitude (IP(DVP)). Nitrates lower IP(DVP), possibly by reducing pressure wave reflection. Response of IP(DVP) to endothelium-dependent vasodilators may provide a measure of endothelial function. METHODS: The DVP was recorded by photoplethysmography. Albuterol (salbutamol) and glyceryl trinitrate (GTN) were administered locally by brachial artery infusion or systemically. Aortic pulse wave transit time from the root of the subclavian artery to aortic bifurcation (T(Ao)) was measured by simultaneous Doppler velocimetry. RESULTS: Brachial artery infusion of drugs producing a greater than threefold increase in forearm blood flow within the infused limb was without effect on IP(DVP), whereas systemic administration of albuterol and GTN produced dose-dependent reductions in IP(DVP). The time between the first and second peak of the DVP correlated with T(Ao) (r = 0.75, n = 20, p < 0.0001). The effects of albuterol but not GTN on IP(DVP) were attenuated by N(G)-monomethyl-L-arginine. The IP(DVP) response to albuterol (400 microg by inhalation) was blunted in patients with type II diabetes mellitus as compared with control subjects (fall 5.9 +/- 1.8% vs. 11.8 +/- 1.8%, n = 20, p < 0.02), but that to GTN (500 microg sublingually) was preserved (fall 18.3 +/- 1.2% vs. 18.6 +/- 1.9%, p = 0.88). CONCLUSIONS: The IP(DVP) is influenced by pressure wave reflection. The effects of albuterol on IP(DVP) are mediated in part through the nitric oxide pathway and are impaired in patients with type II diabetes.

Effects of postmenopausal hormone replacement therapy on central abdominal fat, glycemic control, lipid metabolism, and vascular factors in type 2 diabetes: a prospective study.

OBJECTIVE: To examine the effects of hormone replacement therapy (HRT) on lipid metabolism, glycemic control, total body and central abdominal fat, blood pressure (BP), and arterial pulse wave velocity (APWV) in overweight postmenopausal females with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a 12-month prospective study of 14 subjects (mean +/- SD age 57.5+/-5.6 years, BMI 29.5+/-4.8 kg/m2) randomized to 6 months of observation or HRT before crossover. HRT consisted of 2 months of conjugated equine estrogen (CEE) 0.625 mg daily, followed by 4 months CEE and medroxyprogesterone 5 mg daily. Measures included anthropometry, fasting glucose, insulin, HbA1c, total and HDL cholesterol, triglycerides, apolipoprotein B, LDL particle size, nonesterified fatty acids (NEFA), sex hormone-binding globulin, resting energy expenditure (REE), total and central abdominal fat (by dual-energy X-ray absorptiometry), resting BP, APWV (by applanation tonometry), physical activity, well-being, and sexual function. RESULTS: Six months of HRT resulted in significant reductions in waist-to-hip ratio (-0.03+/-0.01 vs. 0.01+/-0.009, P = 0.007), HbA1c (-0.34+/-0.24 vs. 0.6+/-0.4%, P = 0.04), total cholesterol (-0.6+/-0.1 vs. 0.2+/-0.2 mmol/l, P = 0.001), central abdominal fat (-175+/-51 vs. -24+/-56 g, P = 0.05), and improved physical functioning (P = 0.05), compared with observation. There was a minor increase in REE with HRT (33+/-23 vs. -38+/-23 kJ/day, P = 0.04). Total fat mass, fasting glucose, insulin, triglyceride, apolipoprotein B, NEFA, resting BP, APWV, and physical activity were unchanged. CONCLUSIONS: Postmenopausal HRT in these overweight women with type 2 diabetes was associated with a reduction in central adiposity and improvement in lipid metabolism and glycemic control without deterioration in weight status or cardiovascular parameters measured. Whether HRT-induced improvements in these cardiovascular risk factors result in lower long-term cardiovascular morbidity and mortality, as observed in nondiabetic women, awaits further study.

Inhaled nitric oxide in cardiology practice.

Inhaled nitric oxide allows selective pulmonary vasodilatation with rapidity of action. It is effective in the acute post-operative management of pulmonary hypertension in cardiac surgical patients and is also valuable in assessing the pulmonary vasodilator capacity in patients with chronic pulmonary hypertension. This review examines the current role of inhaled nitric oxide in cardiac medicine, discussing issues concerning its administration and toxicity, as well as a summary of clinical studies in cardiac patients. New roles, as a modifier of platelet and leukocyte function, post-thrombolysis and following lung transplantation are described. New agents and alternative therapies, which prolong pulmonary activity, are also discussed.

Gender-related differences in left ventricular chamber function.

OBJECTIVES: While women have lower rates of atherosclerotic disease than men, they are more likely to suffer cardiac failure following infarction or cardiac surgery, despite typically having a greater left ventricular (LV) ejection fraction. We hypothesised that gender differences in systolic chamber function and ventriculo-vascular coupling may contribute to these clinical findings. METHODS: LV chamber function was determined in a cohort of 30 patients (16 women) aged 48-75 years with normal LV function using pressure-volume loops obtained by simultaneous conductance catheter volumetry and micromanometer pressure. End-systolic and end-diastolic pressure volume (ESPVR, EDPVR) and preload recruitable stroke work relations (PRSWR) were derived. Results were analysed according to gender, and the effects of body size and chamber dimensions were examined. RESULTS: The groups were closely matched for age (60+/-6 vs. 60+/-8 years) and co-morbid conditions. Women had higher end-systolic blood pressure (139.7+/-21.1 vs. 123.6+/-12.6 mmHg, P=0.001), and smaller LV cavity volume (end-diastolic volume 96.4+/-30.6 vs. 139+/-30.7 ml, P=0.001). Women had significantly higher LV end-systolic elastance (Ees, 2.65+/-0.10 vs. 1.96+/-0.09 mmHg ml(-1), P<0.002), arterial elastance (2.41+/-1.13 vs. 1.54+/-0.55 mmHg ml(-1), P=0.01) and lower passive LV diastolic compliance (slope EDPVR, 6.12+/-0.37 vs. 10.0+/-0.50 ml mmHg(-1), P<0.001). While there was a strong relationship between end-systolic elastance and chamber volume (r=0.69, P<0.001), gender differences in chamber function all persisted after indexing to body size. Higher LV systolic function in women was also shown in PRSWR analysis (slope, M(SW); 101.4+/-3.8 vs. 90.4+/-2.8 mmHg, P<0.05), which is independent of chamber size. After normalising volumes to resting diastolic volume, the greater systolic and diastolic elastance in women was accounted for. The ratio of end-systolic to arterial elastance, a measure of ventriculo-vascular coupling, was similar in women and men (1.19+/-0.40 vs. 1.54+/-0.30, respectively, P=0.23). CONCLUSIONS: This study demonstrates greater systolic chamber function and lower diastolic compliance in women. Within the range of chamber dimensions seen in patients with normal LV function, a strong relationship was found between cardiac size and end-systolic elastance. While these differences were not accounted for by indexing to body size, the greater ventricular elastance in women was removed after normalising to chamber size. Despite differences in resting ventricular elastance, appropriate ventriculo-vascular coupling was maintained in both genders as the greater end-systolic elastance in women was matched by similarly elevated arterial elastance.

OCEANOGRAPHY. Contrasting futures for ocean and society from different anthropogenic CO2 emissions scenarios.

The ocean moderates anthropogenic climate change at the cost of profound alterations of its physics, chemistry, ecology, and services. Here, we evaluate and compare the risks of impacts on marine and coastal ecosystems­and the goods and services they provide­for growing cumulative carbon emissions under two contrasting emissions scenarios. The current emissions trajectory would rapidly and significantly alter many ecosystems and the associated services on which humans heavily depend. A reduced emissions scenario­consistent with the Copenhagen Accord's goal of a global temperature increase of less than 2°C­is much more favorable to the ocean but still substantially alters important marine ecosystems and associated goods and services. The management options to address ocean impacts narrow as the ocean warms and acidifies. Consequently, any new climate regime that fails to minimize ocean impacts would be incomplete and inadequate.

The ATP-sensitivity of K+ channels in rat pancreatic B-cells is modulated by ADP.

ATP-sensitive K+ channels in inside-out membrane patches from dispersed rat pancreatic B-cells were studied using patch-clamp methods. The dose-response curve for ATP-induced channel inhibition was shifted to higher concentrations in the presence of ADP (2 mM). In glucose-free solution, the total intracellular concentration of ATP was 3.8 mM and of ADP 1.5 mM; glucose (20 mM) increased ATP and decreased ADP by approx. 40%. These results suggest that both ADP and ATP may be involved in regulating the activity of the glucose-sensitive K+ channel in intact B-cells.

ATP-sensitive K+ channels in human isolated pancreatic B-cells.

Glucose-stimulated insulin release from rodent pancreatic B-cells is thought to be initiated by the closing of ATP-sensitive K+ channels in the plasma membrane as a consequence of glucose metabolism. We have identified an ATP-sensitive K+ channel in membrane patches excised from human B-cells which is similar to that found in rodent B-cells in conductance, kinetics, ATP sensitivity and its inhibition by sulphonylureas. In man, the ATP-sensitive K+ channel may also have a central role in glucose-stimulated insulin secretion and may be (linked to) the receptor for the hypoglycemic sulphonylureas.

Effect of hormone replacement therapy on non-invasive cardiovascular haemodynamics.

OBJECTIVE: To determine the detailed effects of hormone replacement therapy (HRT) on non-invasive haemodynamics, including an assessment of the effect on the pulsatile afterload assessed in terms of the augmentation index and pulse-wave velocity. DESIGN: A cross-sectional study of healthy postmenopausal women using carotid and radial tonometry and pulse-wave velocity measurements. SETTING: Community-based ambulatory women attending the menopause centre at a tertiary hospital. PATIENTS: Seventy postmenopausal women divided into those not currently being administered HRT (n = 38, aged 46-72 years) and those who were being administered a variety of HRT (n = 32, aged 49-67 years). METHODS: Central arterial pressure waveforms were measured using carotid applanation tonometry to derive the augmentation index and ejection duration. The arterial pulse-wave velocity was assessed using paired carotid, radial and dorsalis tonometry waveforms. RESULTS: Women being administered HRT had a significantly lower augmentation index (20.4 +/- 8.6 versus 27.0 +/- 10.2%, P = 0.005) and shorter ejection times (320 +/- 17 versus 329 +/- 18 ms, P = 0.037). There was no significant difference in brachial blood pressure (131/76 versus 129/77 mmHg). Women being administered HRT exhibited a greater reversal in the age-related loss of amplification which occurs owing to arterial stiffening. This amplification between central and peripheral systolic blood pressures was greater among women being administered HRT (5.3 +/- 6.2 versus 2.2 +/- 4.0 mmHg, P = 0.014). There was no difference in pulse-wave velocity between the two groups. CONCLUSIONS: HRT appears to improve the pulsatile vascular afterload by decreasing the augmentation of the late systolic blood pressure. This effect is not apparent from routine brachial cuff measurements, which, as a result, may underestimate haemodynamic benefits. Such effects may help to explain a portion of the improvement in cardiovascular morbidity found in other trials.

Effects of arterial dilator agents on central aortic systolic pressure and on left ventricular hydraulic load.

Recordings of pressure in the brachial or peripheral arteries fail to disclose the marked increase in systolic pressure that occurs in the proximal aorta and central arteries with increasing age and with hypertension. This systolic pressure boost is caused by wave reflection returning from the periphery of the body while the ventricle is still contracting. Such early wave reflection is caused in turn by increased pulse-wave velocity, attributable to stiffening of the aorta and major conduit arteries. Drugs have little effect on arterial stiffening, whereas wave reflection can be markedly reduced by agents that dilate peripheral arteries. Such reduction in wave reflection causes substantial decrease of systolic pressure in central arteries. Because of differential timing of wave reflection, however, such reduction is not apparent from pressure recordings taken in the brachial or other peripheral arteries. The sphygmomanometer, therefore, fails to show the favorable effects of reduced wave reflection in the proximal aorta and central arteries. Noninvasive tonometric pressure wave recordings can supplement the sphygmomanometer to assess the magnitude of beneficial effect.

Effect of combination hormone replacement therapy on ambulatory blood pressure and arterial stiffness in diabetic postmenopausal women.

BACKGROUND: Diabetes mellitus negates the premenopausal gender benefit with respect to coronary artery disease. Whether hormone replacement therapy (HRT) offers any cardiovascular advantage to diabetic postmenopausal women is not known. Diabetic subjects have increased vascular load and abnormal 24-h blood pressure (BP) profiles. Hormone replacement therapy has been shown to improve indexes of arterial load in nondiabetic postmenopausal women as well as to restore circadian variation in BP. This aim of this study, therefore, was to determine prospectively whether HRT improved arterial stiffness and 24-h ambulatory BP profile in diabetic postmenopausal women. METHODS: Twelve diabetic postmenopausal women were studied. Six subjects were also hypertensive. Vascular load was characterized by carotid arterial pulse waveform analysis to calculate central augmentation index. All subjects also underwent 24-h BP monitoring. Subjects were studied before commencement of HRT and were then randomized to two groups. The first group was observed for 6 months and then given 2 months of estrogen alone, followed by 4 months of combination estrogen with progestin. The second group received the HRT regimen first, then were restudied after 6 months off HRT. RESULTS: The HRT did not affect either clinic or ambulatory BP. There were no changes in indexes of vascular load or pulse pressure, an indirect measure of arterial stiffness. There was a low rate of circadian variation in 24-h BP at baseline (55%), which was unaltered by HRT. CONCLUSIONS: The HRT was well tolerated. Despite evidence for a beneficial effect of HRT on indexes of arterial load and ambulatory BP previously reported in normal subjects, we found no change in this cohort of diabetic postmenopausal women.

Head injury with subsequent, intermittent, nonschizophrenic, psychotic symptoms and violence.

A young, black, adult woman presented to an outpatient clinic for treatment with a history of intermittent, nonschizophrenic, psychotic symptoms. Blacks, because of their situational sociology, may be more predisposed to severe head injuries, and this acquired biologic factor may be, in part, responsible for the high rates of black-on-black murder. The use of beta blockers is discussed as an adjunct in the treatment of violence occurring in patients with a past history of severe head injury.

Pharmacological potential for reversing the ill effects of ageing and of arterial hypertension on central aortic systolic pressure.

CARDIOVASCULAR RISK: Systolic arterial pressure is an important risk factor for future cardiovascular morbidity and mortality. PULSATILE LOAD: The aortic systolic pressure with which the heart interacts is determined by pulsatile vascular load. In particular, wave reflections from peripheral sites affect peak central aortic systolic pressure but not brachial systolic pressure. DRUG POTENTIAL: Drugs that reduce wave reflection and hence reduce the pulsatile vascular load in addition to reducing peripheral resistance have the potential to reduce target organ damage to a greater extent than drugs that reduce mean pressure and resistance alone.

On-pump coronary artery bypass surgery in vascular Ehlers-Danlos syndrome.

A 58-year-old woman with vascular Ehlers-Danlos syndrome (EDS; type IV) presented to a Canadian tertiary care emergency department with a non-ST elevation myocardial infarction. The patient failed medical therapy and after careful consideration of the options, elected to undergo urgent coronary artery bypass (CABG) surgery. To the best of our knowledge, this is the first reported case of a successful on-pump CABG surgery in a patient with vascular EDS.

A divalent heteroleptic lanthanoid fluoride complex stabilised by the tetraphenylcyclopentadienyl ligand, arising from C-F activation of pentafluorobenzene.

The divalent heteroleptic lanthanoid fluoride complex, [Yb(C5Ph4H)(µ-F)(thf)2]2, as well as [Yb(C5Ph4H)2(thf)] and [Yb(C5Ph4H)(C6F5)(thf)2] were obtained from reactions of ytterbium metal with Hg(C6F5)2 and tetraphenylcyclopentadiene under different conditions, and C-F activation of C6F5H by Yb metal was observed.