bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elevated Baseline Triglyceride Levels Modulate Effects of HMGCoA Reductase Inhibitors on Plasma Lipoproteins
Authors: Drmanac S. , Heilbron D. C. , Pullinger C.R. , Jafari M. , Gietzen D. , Ukrainczyk T. , Cho M. H. , Frost P. H. , Siradze K. , Drmanac R. T. , Kane J. P. , Malloy M. J. 
Published: June 2007

Background: The response in levels of very-low-density (VLDL) and low-density (LDL) lipoproteins varies substantially among hyperlipidemic patients during treatment with HMGCoA reductase inhibitors. Apolipoprotein E genotype and gender are known to contribute to the regulation of steady state levels of plasma lipoproteins. This study explores the effect of these and other potential determinants of the response of VLDL and LDL to treatment with reductase inhibitors. Methods: Using mixed linear statistical models, the response of lipoprotein lipid values was studied in 142 hyperlipidemic individuals who were treated with reductase inhibitors. Patients received one or more of the following drugs individually for a total of 623 treatment observations: lovastatin, pravastatin, simvastatin, or atorvastatin. For evaluation of the effects of treatment in the aggregate, actual doses were expressed as equivalent doses of atorvastatin, using factors based on random assignment comparisons in 16 reported studies. The analysis factors considered were apolipoprotein E genotype, baseline average triglycerides >170 mg/dL (vs less), and gender. Results: Presence of an apo e4 allele was associated with a trend toward greater reduction of triglyceride levels and a diminished ability of the reductase inhibitors to reduce LDL cholesterol levels. Gender had only minimal effect on the response of either LDL cholesterol or triglycerides. However, the effect of elevated baseline triglycerides on the response of both triglycerides and LDL cholesterol was striking and was exerted in opposite directions. The triglyceride-lowering effect of reductase inhibitors was greater in patients with initial triglyceride levels above 170 mg/dL (P=0.0001). The effect was even greater in patients with initial triglyceride levels over 250 mg/dL (P=0.015). Conversely, for LDL cholesterol levels, elevated baseline triglycerides were associated with a significantly decreased response to the drugs (P=0.0015). Conclusions: These findings indicate that baseline triglyceride levels are an important predictor of response of plasma lipoproteins to HMGCoA reductase inhibitors, perhaps reflecting fundamental differences in mechanism underlying the hyperlipidemic phenotype.
L-Arginine Improves Post-Ischemic Vasodilation in Coronary Heart Disease Patients Taking Vasodilating Drugs
Authors: lannuzzi Arcangelo , Jannuzzo Gabriella , Sapio Cecilia , Pauciullo Paolo , Jorio Domenico , Spampinato Nicola , Mancini Mario , Rubba Paolo 
Published: June 2007

Background: The hypothesis that intravenous L-arginine infusion improves the vasodilatory response to ischemia in the resistance vessels of human lower limbs in relatively young coronary heart disease patients taking vasodilating drugs was tested. Methods: Twenty patients with onset of symptoms of coronary artery disease before age 50, operated for aortocoronary bypass and taking vasodilating drugs, were compared with 20 control subjects of comparable age and gender; neither group included heavy smokers (>10 cigarettes/day). Blood flow in the lower limbs was measured noninvasively with strain-gauge plethysmography, both at rest and during a reactive hyperemia test. Intravenous infusion of L-arginine was performed in nine coronary heart disease patients and in nine control subjects. Results: Resting blood flow to the lower limbs was 2.3 mI,/minIlO0 mL in control subjects vs 3.4 mL/minIlO0 mL in patients (difference not statistically significant). Peak blood flow measured after a 3-minute arterial occlusion was 24.0 mL/min/lO0 mL in control subjects vs 20.3 mL/min/lO0 mL in coronary heart disease patients (P<0.05). Peripheral minimal vascular resistances were 4.28 and 5.46 peripheral resistances units (p.r.u.) in control subjects and patients, respectively (P<0.05). Intravenous infusion of L-arginine was followed by increased resting blood flow in cases and controls (P=0.009), with a parallel reduction in peripheral resting vascular resistances (P=0.009). Coronary heart disease patients showed increased peak blood flow (P=0.04) and reduced minimal vascular resistances (P=0.02), whereas no statistically significant changes in these parameters were detectable in control subjects. Intravenous glucose infusion, leading to increased serum insulin concentration, did not modify any hemodynamic parameter. Conclusions: Hemodynamic responses in the skeletal muscle are impaired during a reactive hyperemia test in relatively young coronary heart disease patients taking vasodilating drugs. Intravenous L-arginine infusion corrects the impaired vasodilatory response of the lower limbs to an acute increase in flow following a cuff thigh occlusion.
The Relationship Between Low-Density Lipoprotein Cholesterol Goal Attainment and Prevention of Coronary Heart Disease-Related Events
Authors: Ito Matthew K. , Delucca Gina M. , Aldridge Martha A. 
Published: June 2007

Background: According to the National Cholesterol Education Program (NCEP) treatment guidelines, patients with preexisting coronary heart disease (CHD) or other atherosclerotic vascular disease should lower low-density lipoprotein (LDL) cholesterol to < 100 mg/dL. Recent statin trials document the benefit of cholesterol lowering on CHD events but do not address the optimal goal of LDL cholesterol. Methods: The pravastatin to simvastatin conversion-lipid optimization program (PSCOP) at the VA San Diego Healthcare System (VASDHS) was a formulary-conversion program designed to increase the percentage of patients who meet their recommended NCEP LDL cholesterol goal. We compared the incidence of clinical outcome and mortality between CHD patients from the original PSCOP cohort with postconversion LDL cholesterol greater than and < 100 mg/dL. A total of 524 patients were stratified by postconversion LDL cholesterol levels (greater than [N=183]) or < 100 mg/dL [N=341]) and observed for a mean duration of 27.7 months. Patients' VASDHS records were reviewed for postconversion mortality from any cause and CHD-related events. Patients were mailed a questionnaire to capture similar events that may have occurred outside of VASDHS, which might not be present in the patient's VASDHS record. Results: Lipid-lowering therapy ≤ 100 mg/dL was associated with a significantly lower percentage of total deaths and CHD-related events (40% vs 61%, P=0.008). In patients with LDL cholesterol >100 mg/dL, the relative risk of unstable angina (relative risk, 2.2; 95% confidence interval, 1.3 to 3.8; P=0.004) and stroke (relative risk, 3.0; 95% confidence interval, 1.04 to 8.6; P=0.04) were significantly greater compared to patients meeting their LDL cholesterol goal. Conclusions: Our study results support reducing LDL cholesterol to at least 100 mg/dL in the patient with CHD.
Identification of a Cardiac Sodium Channel Insensitive to Synthetic Modulators
Authors: Mevissen Meike , Denac Helena , Schaad Andreas , Portier Christopher J. , Scholtysik Guenter 
Published: June 2007

Background: DPI 201-106 (DPI) was the first synthetic compound showing cardioselective modulation of voltage-gated sodium channels (VGSCs) resulting in a positive inotropic effect. Currently, the exact mode of action for this class of compounds is not known. Methods: Effects of different natural and synthetic sodium channel modulators were investigated in cardiac tissue of several species with conventional electrophysiologic methods. Results: In electrically driven cardiac tissues, all compounds investigated increased force of contraction (FC) and action potential duration (APD) with increasing concentrations except for DPI in cattle trabecular muscle, which demonstrated no effect. Interestingly, calculation of EC50 levels at 30% repolarization demonstrates that natural VGSC-ligands were highly potent in prolonging the APD in cattle whereas no positive trends could be obtained for DPI and SDZ 211-939 (SDZ) in cattle. Conclusions: These results demonstrate that the binding site for DPI and SDZ is distinct from sites 2 or 3 of the VGSC ox-subunit. Moreover, this is the first time that these compounds show no effect or even shortening of APD. This finding will enable the characterization of the mode of action and probably the binding site for synthetic VGSC-modulators.
Pimozide (Orap®) Prolongs Cardiac Repolarization by Blocking the Rapid Component of the Delayed Rectifier Potassium Current in Native Cardiac Myocytes
Authors: Drolet Benoit , Rousseau Guy , Daleau Pascal , Cardinal René , Simard Chantale , Turgeon Jacques 
Published: June 2007

Background: Several cases of QT prolongation and ventricular tachyarrhythmia have been reported with pimozide, a potent neuroleptic useful in the management of motor and phonic tics associated with Tourette syndrome. To further elucidate the mechanism underlying these clinical observations, the effects of pimozide on monophasic action potential duration (MAPD9O) and on potassium currents involved in the repolarization of native isolated ventricular myocytes were examined.Methods and Results: Studies were undertaken in eight isolated guinea pig hearts that demonstrated reverse rate-dependent prolongation of cardiac repolarization by pimozide 100 nmol/L. Action potential duration increased 24% from baseline 115 ± 2 to 142 ± 4 msec with pimozide 100 nmol/L during pacing at 250 msec cycle length, while a 10% increase from 97 ± 2 to 107 ± 3 msec was seen with pacing at a cycle length of 150 msec. Experiments in native isolated ventricular myocytes (n = 20) demonstrated concentration-dependent block of the rapid component (I,) of the delayed rectifier potassium current: tail current was decreased by 50% at 15 nmol/L.Conclusions: Pimozide possesses cardiac electrophysiological effects similar to those of class III antiarrhythmic drugs. These effects are concentration-dependent and observed at recommended dosages of the drug. Since pimozide is strongly metabolized by CYP3A4, special care should be taken to avoid potential pharmacokinetic interactions leading to high plasma levels of pimozide and proarrhythmia.
Effects of Tedisamil on Cardiovascular Tissues Isolated from Normoand Hypertensive Rats
Authors: Doggrell Sheila A. , Nand Vinita 
Published: June 2007

Background: This study was undertaken to characterize the effects of tedisamil on isolated rat cardiovascular tissues, and identify actions that could be beneficial or detrimental in the treatment of cardiac disease. Results: Tedisamil prolonged the Wistar Kyoto normotensive rat (WKY) left ventricular action potential and augmented the force of contraction of left ventricle strips. On the 12-month-old SHR model of cardiac hypertrophy, the augmenting effects of tedisamil at 10-6 and 3 x 10-6 M were reduced. On the 21-month-old SHR model of heart failure, the augmenting effects of tedisamil at 10-6 and 3 x 10-6 M were further reduced. The augmenting effect of tedisamil at 10-5 M was reduced to 47%. The rate of the right atrium of 16- to 17-month-old WKY was reduced by tedisamil at 10-5 and 104 M, and tedisamil had a similar effect on the SHR right atrium. Tedisamil at 10-6-3 x 10-5 M contracted the portal veins of WKY and aortae of 12-month-old WKY and SHR. Conclusions: The positive inotropic and negative chronotropic effects of tedisamil in the rat, which are partially or fully maintained in hypertrophied or failing myocardium would be beneficial in the treatment of heart failure. In contrast, the vasoconstrictor action of tedisamil will be detrimental in heart failure.
Myocardial Bradykinin Following Acute Angiotensin-Converting Enzyme Inhibition, AT1 Receptor Blockade, or Combined Inhibition in Congestive Heart Failure
Authors: Multani M. Marlina , Krombach R. Stephen , Goldberg Aron T. , King Mary K. , Hendrick Jennifer W. , Sample Jeff A. , Baicu Simona C. , Joffs Cassandra , deGasparo Marc , Spinale Francis G. 
Published: June 2007

Background: The present study examined the effects of acute angiotensin-converting enzyme inhibition (ACEI), AT, receptor blockade (AT, block), or combined treatment on in vitro and in vivo bradykinin (BK) levels. Methods: BK levels were measured in isolated porcine myocyte preparations (n = 13) in the presence of exogenous BK (10-8 M); with an ACEI (benezaprilat; 0.1 mM) and BK; an AT, block (valsartan; 10-5 M) and BK; and combined treatment and BK. In a second study, myocardial microdialysis was used to measure porcine interstitial BK levels in both normal (n = 14) and pacing-induced congestive heart failure (CHF) (240 beats/min, 3 weeks, n = 16) under the following conditions: baseline, following ACEI (benezaprilat, 0.0625 mg/kg) or AT, block (valsartan, 0. I mg/kg), and a combined treatment (benezaprilat, 0.0625 mg/kg; valsartan, 0.1 mg/kg). Results: In the left ventricular myocyte study, BK levels increased over 93% with all treatments compared to untreated values (P < 0.05). In the in vivo study, basal interstitial BK values were lower in the CHF group than in controls (2.64 ± 0.57 vs 5.91 + 1.4 nM, respectively, P < 0.05). Following acute infusion of the ACEI, BK levels in the CHF state increased from baseline (57% ± 22; P < 0.05). Following combined ACEIIAT, block, BK levels increased from baseline in both control (42% ± 11) and CHF groups (60% ± 22; P < 0.05 for both). Conclusion: These findings suggest that ACEI, or combined ACEI/AT, block increased BK at the level of the myocyte and potentiated BK levels in the CHF myocardial interstitium.
Treatment of Edema and Increased Capillary Filtration in Venous Hypertension with HR (Paroven, Venoruton; 0-(β-hydroxyethyl)-rutosides): A Clinical, Prospective, Placebo-Controlled, Randomized, Dose-Ranging Trial
Authors: Cesarone M. R. , Incandela L. , DeSanctis M. T. , Belcaro G. , Griffin M. , Ippolito E. , Acerbi G. 
Published: June 2007

The variation of capillary filtration rate (CFR) and ankle edema (AE) were evaluated in three groups of patients with venous hypertension with ambulatory venous pressure > 42 mmHg and in healthy subjects before and after treatment for four weeks with HR (Paroven, Venoruton; 0-(P-hydroxyethyl)-rutosides), a venoactive drug acting on the microcirculation and on capillary permeability. Group A (30 patients) was treated with HR 500 mg tid; group B (30 patients) was treated with 1 g tid; group C (30 patients) was treated with placebo; group D (10 healthy subjects) was treated with HR 1 g/day in a randomised study. CFR was assessed by venous occlusion plethysmography. Subjective symptoms of venous hypertension were assessed by an analogue scale line considering four symptoms: swelling sensation, restless lower extremity, pain and cramps, and tiredness. Results: There were no significant differences for sex and age distribution among the groups; no significant differences were found for ambulatory venous pressure and refilling time and parameters of venous hypertension among groups. There was a significant difference between normal subjects and patients. There were no drop-outs and observed intolerance. In group A, there was a significant decrease of CFR (P < 0.01) after treatment. In group B (2 g/day), the decrease was greater than that in group A (P < 0.05). In group C (placebo) there was no significant difference before or after treatment. The variations in analogue score was higher with the higher dosage. The score of group A fell from 7.8 (SD 1.3) to 4 (1). Group B's score fell from 7.9 (2) to 3.1 (1.2). In group C (placebo) there was no change. The decrease in the score in the groups of patients was correlated with the variation in edema and CFR. Conclusion: HR is effective in venous edema and hypertension. Its effects are dose-related.
HR (Venoruton1000, Paroven, 0-[beta-hydroxyethyl]-rutosides) vs. Daflon 500 in Chronic Venous Disease and Microangiopathy: An Independent Prospective, Controlled, Randomized Trial
Authors: Belcaro G. , Cesarone M. R. , Bavera P. , Ricci A. , Renton S. , Leon M. , Ippolito E. , Dugall M. , Acerbi G. 
Published: June 2007

Objectives: The aim of this study was to demonstrate whether and how HR (Venoruton1000, Paroven, 0-[beta-hydroxyethyl]-rutosides) and Daflon (diosmin, 500 mg) were comparatively effective in improving the microcirculation in venous hypertension and microangiopathy. Methods: A group of 90 patients with severe venous hypertension due to chronic venous insufficiency, ankle swelling, and lipodermatosclerosis were included. After informed consent, patients were randomized into a Venoruton and a Daflon (DF) group: patients in the Venoruton group received oral HR (2 g/day for 8 weeks); those in the Daflon group received three 500-mg tablets daily every 8 hours. The two groups were comparable for age and sex distribution. The mean age was 41 years (SD ± 11) in the Venoruton group (46 patients) and 41.3 (SD ± 12) in the DF group (44 patients). Results: There were no differences in microcirculatory parameters between the Venoruton and DF treatment groups at inclusion. There was no significant change between inclusion and measurements at 8 weeks in the DF group. In comparison, a significant decrease ( P < .05) in RF (resting skin flux) and RAS (rate of ankle swelling) was observed in the Venoruton group ( P < .00 1). The decrease in capillary filtration was associated with improvement in signs and symptoms (measured by an analogue scale line) ( P < .05). Symptomatic improvement was clinically and statistically significant and important only in the Venoruton group. No side effects and no drop-outs were observed. Conclusion: Venous microangiopathy was improved by the treatment with Venoruton. The comparison with Daflon indicates that HR is comparatively more effective both on microcirculatory parameters and on signs and symptoms.
The Effect of Isoproterenol on the Class III Effect of Azimilide in Humans
Authors: Dorian Paul , Dunnmon Preston , Elstun Laura , Newman David 
Published: June 2007

Background: Many class III antiarrhythmic agents lose efficacy under f-adrenergic stimulation and at high heart rates (reverse rate dependence). This effect is thought to be due to selective blockade of the rapidly (Ij), but not the slowly (IKS, activating component of the delayed inward rectifier potassium current. Azimilide is an investigational class III antiarrhythmic agent that blocks both Ir and 1KS. Methods: We investigated the electrophysiologic effect of azimilide with and without P-adrenergic stimulation in humans. Right ventricular effective refractory period at cycle lengths of 600 and 400 milliseconds and monophasic right ventricular action potential duration at 90% repolarization at cycle lengths of 250, 300, 400, 500 and 600 milliseconds were measured in 13 patients at baseline. Isoproterenol was then infused to increase the heart rate to 125% of baseline, and the pacing protocol was repeated. Patients then received, in a single-blind randomized manner, azimilide dihydrochloride (4.5 mg/kg intravenous loading dose followed by 0.625 mg/kg/h) plus either isoproterenol at the previous dose, or saline. After measurements were taken, treatment groups were crossed over, the azimilide infusion was continued and the procedure repeated. Results: Azimilide significantly (P < 0.05) prolonged monophasic action potential duration compared to baseline at all cycle lengths except for the 250 millisecond cycle length. In the presence of isoproterenol, azimilide maintained its class III effect, prolonging the action potential duration at 90% repolarization by a mean of 8.7 ± 3.9 milliseconds, (3.7 ± 1.7%), whereas isoproterenol alone shortened the action potential duration at 90% repolarization by -2.6 ± 3.2 milliseconds (-1.2 ± 1.4%) (P = 0.0051). Isoproterenol alone shortened the right ventricular effective refractory period by -13.6 ± 3.4 milliseconds, whereas with isoproterenol in the presence of azimilide, the right ventricular effective refractory period was essentially unaffected (-1.4 ± 3.4 milliseconds, P = 0.0085). Conclusions: Azimilide maintained its class III effect in the presence of isoproterenol and at increased heart rates, suggesting that IKS block may be of particular benefit in these circumstances.
Effects of Adrenomedullin on Human Myocyte Contractile Function and β-Adrenergic Response
Authors: Mukherjee Rupak , Multani Marlina M. , Sample Jeffrey A. , Dowdy Kathryn B. , Zellner James L. , Hoover Donald B. , Spinale Francis G. 
Published: June 2007

Background: Adrenomedullin has been demonstrated to cause systemic vasodilation, and increased plasma adrenomedullin levels have been observed in cardiovascular disease states such as heart failure. While adrenomedullin receptors have been localized to the myocardium, the effects of adrenomedullin on human myocyte contractility remained unknown. Methods and Results: Left ventricular myocytes were isolated from myocardial biopsies of patients (n = 16) undergoing elective coronary artery bypass surgery with normal left ventricular ejection fractions (51 ± 1%). A total of 233 left ventricular myocytes were studied by videomicroscopy. Myocyte shortening velocity (,um/s) was measured at baseline and following the addition of either 3 nM, 30 nM, or 60 nM of adrenomedullin. The change in myocyte shortening velocity with increasing concentrations of adrenomedullin was computed. At all concentrations, adrenomedullin reduced myocyte shortening velocity from baseline values (P < 0.05). Next, the potential interaction of adrenomedullin with the P-adrenergic receptor system was examined using 25 nM isoproterenol. The 3-adrenergic receptor-mediated increase in the myocyte shortening velocity was blunted with adrenomedullin (29 ± 7 vs 63 ± 13 tm/s, P < 0.05). Conclusions: These unique findings demonstrate that adrenomedullin reduced contractility in isolated human left ventricular myocytes and exhibited a negative interaction with the fadrenergic receptor system. Past studies have shown that adrenomedullin induces nitric oxide synthesis and that nitric oxide can uncouple myocyte metabolism. Thus, while adrenomedullin causes systemic vasodilation, this peptide can also exert a negative contractile effect in human left ventricular myocytes.