Journal of Cardiovascular Pharmacology and Therapeutics recent issues

Clinical Review: Is the Perioperative Use of {beta}-Blockers Still Recommended? A Critical Review of Recent Controversies

Domanski, D., Schwarz, E. R. — Tue, 10 Nov 2009 18:11:41 PST

The optimal role of β-adrenergic receptor blockade in the perioperative period remains unclear in patients at risk for cardiovascular events. Cardiovascular complications continue to be the most common cause of perioperative morbidity and mortality, and cardioprotective properties of β-blockers are widely recognized, yet the results of the clinical trials investigating the use of different β-blockers in the perioperative period are controversial. The discrepancy might be related to differences in the design of studies, use of different agents, administration by different routes, and continuation for different time intervals. Evidently, perioperative mortality and morbidity seem to be related to heart rate, and the majority of complications are related to β-blockers’ side effects. Based on the observations from different studies, we propose an algorithm for perioperative β blockade.

What Is the Optimal Postconditioning Algorithm?

Iliodromitis, E. K., Downey, J. M., Heusch, G., Kremastinos, D. T. — Tue, 10 Nov 2009 18:11:41 PST

Ischemic postconditioning has emerged as a clinically feasible intervention for limiting infarction in the setting of percutaneous intervention. In ischemic postconditioning, a number of cycles of a brief period of reperfusion followed by a brief period of occlusion are applied immediately upon reperfusion of the ischemic heart. Although ischemic postconditioning is protective in both animals and man, the animal studies reveal that the algorithm used in selecting the duration of the occlusion and reperfusion periods is critical to the degree of protection realized and it varies with species. The question then arises what is the best algorithm for man? The available animal and clinical data are examined in an attempt to shed light on this perplexing problem.

Efficacy and Safety of Ezetimibe Plus Orlistat or Rimonabant in Statin-Intolerant Nondiabetic Overweight/Obese Patients With Dyslipidemia

Florentin, M., Kostapanos, M. S., Nakou, E. S., Elisaf, M., Liberopoulos, E. N. — Tue, 10 Nov 2009 18:11:41 PST

Aims: To compare the effects of ezetimibe plus orlistat or rimonabant on anthropometric and lipid parameters in nondiabetic statin-intolerant overweight/obese patients with dyslipidemia.

Methods and results: Thirty participants received a hypocaloric diet and were randomized to open-label combination of ezetimibe (10 mg/day) with orlistat (120 mg, 3 times a day with meals; ezetimibe/orlistat [EO], n = 15) or rimonabant (20 mg/day; ezetimibe/ rimonabant [ER], n = 15). Anthropometric and metabolic variables were assessed at baseline and 3 months posttreatment. Similar reductions in body weight, body mass index, and waist circumference were recorded in both groups (—8.3%, —8.6%, and —5.2% in the EO group and —7.3%, —7.2%, and —7.0% in the ER group, P < .01 vs baseline for all). Low-density lipoprotein cholesterol (LDL-C) levels decreased in both treatment groups, but this reduction tended to be more pronounced in the EO group (28.4% vs 15.3%, respectively; P < .01 vs baseline for both). Triglycerides tended to decrease more in the ER compared with the EO group (—20.4% vs —14.1%, P < .01 vs baseline for both). High-density lipoprotein cholesterol (HDL-C) levels tended to decrease in EO group, but remained unaltered with ER treatment. Apolipoprotein B levels were equally reduced in both treatment groups. Conclusion: For similar body weight reduction, the combination of ezetimibe with orlistat may be more efficient in LDL-C lowering, whereas the combination of ezetimibe with rimonabant may be more potent in terms of improving HDL-C and triglycerides.

Rosuvastatin Attenuates Ang II--Mediated Cardiomyocyte Hypertrophy via Inhibition of LOX-1

Kang, B.-Y., Mehta, J. L. — Tue, 10 Nov 2009 18:11:41 PST

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, also known as statins, have been shown to reduce cardiac remodeling. Angiotensin II (Ang II) type 1 receptor (AT1R) and oxidized low-density lipoprotein (ox-LDL) via its lectin-like ox-LDL receptor (LOX-1) are major stimuli for cardiomyocyte growth. We postulated that rosuvastatin, a potent HMG-CoA reductase inhibitor, may reduce Ang II—mediated cardiomyocyte growth via AT1R and LOX-1 inhibition. HL-1 adult mouse cardiomyocytes were incubated overnight in serum-free medium, and then treated with rosuvastatin, the AT1R inhibitor losartan or anti-LOX-1 antibody for 3 hours. The cells were then stimulated with Ang II. We measured cardiomyocyte growth, and associated intracellular redox signals using reverse transcription— polymerase chain reaction (RT-PCR) and real-time quantitative PCR. Losartan and anti-LOX-1 antibody markedly attenuated Ang II—mediated oxidant stress, and the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p40^{pho x} and gp91^phox subunits) and nuclear factor-B (NF-B). Rosuvastatin attenuated the Ang II—mediated upregulation of both subunits of NAPDH oxidase as well as NF-B. Rosuvastatin also reduced Ang II—mediated upregulation of AT1R and LOX-1. In other experiments, LOX-1 was upregulated in cardiomyocytes by transfection with pCI-neo/LOX-1, which also enhanced the expression AT1R messenger RNA (mRNA), and rosuvastatin pretreatment reduced the expression of both LOX-1 and AT1R in this system. Thus, rosuvastatin attenuates Ang II—mediated cardiomyocyte growth by inhibiting LOX-1 and AT1R expression and suppressing the heightened intracellular redox state.

MMP-2 and MMP-9 Alteration in Response to Collaring in Rabbits: The Effects of Endothelin Receptor Antagonism

Tue, 10 Nov 2009 18:11:41 PST

Matrix metalloproteinases (MMPs), and, in particular, gelatinases (MMP-2 and MMP-9), have been implicated in vascular cell proliferation and/or migration, contributing to intimal thickening, an essential stage in the development of atherosclerosis and restenosis following balloon angioplasty. Endothelin, a strong chemoatractant and mitogen, has been shown to promote smooth muscle cell proliferation and migration by activating MMPs via endothelin-A (ETA) receptors. The positioning of a soft silicon collar around the left carotid artery in rabbits results in intimal thickening. In this study, we investigate the possible role of gelatinases and the effect of a nonselective ETA/ETB receptor antagonist, TAK-044 (5 mg/kg body weight/day, subcutaneously [sc]), on these enzymes. Our results demonstrated that both MMP-2 and MMP-9 activities increased in response to collaring in placebo group, while treatment with TAK-044 significantly suppressed both gelatinase activities and proMMP-2 levels, and inhibited intimal thickening in collared arteries. These results suggest that either enhanced MMP expression or endothelin receptor antagonism may be involved in the formation of intimal thickening in this model.

Sodium Ferulate Modified Gene Expression Profile of Oxidized Low-Density Lipoprotein-Stimulated Human Umbilical Vein Endothelial Cells

Zhang, D., Bi, Z., Li, Y., Zheng, H., Li, L., Ouyang, J., Wang, B., Bi, Y. — Tue, 10 Nov 2009 18:11:41 PST

Oxidized low-density lipoprotein (ox-LDL) is known to trigger vascular injury in atherosclerosis development. Sodium ferulate is an effective component from Chinese medicines with various beneficial cardiovascular pharmacological activities. Here, we investigated the effects of sodium ferulate on the gene expression profile of ox-LDL-stimulated endothelial cells. Cultured human umbilical vein endothelial cells (HUVECs) were treated with ox-LDL (50 µg/mL) in the absence or presence of sodium ferulate (5 µmol/L). Sodium ferulate significantly reduced ox-LDL-induced endothelial cell death as evaluated by cell viability assay. Human oligonucleotide microarray analysis demonstrated that a total of 32 ox-LDL-induced genes were significantly downregulated to control levels by sodium ferulate. These genes included members from families of chemokine, inflammatory factor, growth factor, and nuclear receptor. These data provided an overview of the gene expression profile of endothelial cells in response to ox-LDL and sodium ferulate, and demonstrated that sodium ferulate could regulate the expression of inflammation-related genes in endothelial cells and has the potential to benefit endothelial function in the setting of atherosclerosis.

Astaxanthin Reduces Oxidative Stress, but not Aortic Damage in Atherosclerotic Rabbits

Tue, 10 Nov 2009 18:11:41 PST

We evaluated whether carotenoid astaxanthin (ASX) could prevent oxidative and atherosclerotic damage in rabbits. Rabbits received regular chow (control) or an atherogenic diet (1% cholesterol) alone or supplemented with 50, 100, and 500 mg% ASX for 60 days (n = 5-9 per group). The atherogenic diet increased the serum cholesterol levels and the ratio of the intima/media area in the aortic arch. These changes were not prevented by ASX. Atherosclerotic rabbits showed increased aortic lipid peroxidation and nonprotein thiol group (NPSH) levels along with inhibition of glutathione peroxidase (GSH-Px). All ASX doses attenuated lipid peroxidation and the increase in NPSH but not the inhibition of GSH-Px. Aortic superoxide dismutase (SOD), catalase (CAT), and thioredoxin reductase (TrxR) activities were enhanced in atherosclerotic rabbits. Although all ASX doses prevented the increase in SOD activity, only 100 and 500 mg% ASX prevented the increase in CAT activity. Furthermore, these same doses partially prevented the increase in TrxR activity, while 50 mg% ASX completely prevented the effects of the atherogenic diet on this enzyme. However, ASX did not attenuate the hypercholesterolemia or the atherosclerotic lesions caused by the atherogenic diet at any of the doses evaluated. Our results indicate that although ASX did not prevent hypercholesterolemia or atherosclerotic lesions, it could play a beneficial role by preventing lipid peroxidation and changes in antioxidant enzyme activities.

Differential Effects of Oral {beta} Blockade on Cardiovascular and Sympathetic Regulation

Beloka, S.P., Gouveia, S., Gujic, M., Naeije, R., Rocha, A.P., van de Borne, P. — Tue, 10 Nov 2009 18:11:41 PST

In patients with hypertension, β blockade decreases muscle sympathetic nerve activity (MSNA; micrographic technique) expressed in burst frequency (burst/min) but does not affect MSNA expressed in burst incidence (burst/100 heart beats), because reductions in blood pressure (BP) upon each diastole continue to deactivate the arterial baroreceptors, but at a slower heart rate (HR). We studied the effects of oral β blockade on MSNA and baroreflex sensitivity (BRS) in normal participants. Bisoprolol (5 mg, 1 week) was administered in 10 healthy young adults, using a double-blind, placebo-controlled, randomized cross-over study design. The beat-to-beat mean RR interval (RR) and systolic blood pressure (SBP) series were analyzed by power spectral analysis and power computation over the very low frequency (VLF), low frequency, and high frequency (HF) bands. Baroreflex sensitivity was computed from SBP and RR cross-analysis, using time and frequency domain methods.

Bisoprolol increased RR (P < .0005), decreased mean SBP and diastolic blood pressure values (P < .01), did not change the SBP and RR powers, except for RR power in VLF (P < .02) and SBP power in HF (P < .03). The MSNA variability (P > .13) and respiratory pattern (P = .84) did not change from placebo to bisoprolol condition. The bisoprolol-induced bradycardia was associated with higher burst/100 heart beats (P < .05) and bisoprolol did not affect burst/min (P = .80). Time domain BRS estimates were increased after bisoprolol (P < .05), while frequency domain ones did not change (P > .1).

Oral bisoprolol induces differential effects on sympathetic burst frequency and incidence in normal participants. Peripheral sympathetic outflow over time is preserved as a result of an increased burst incidence, in the presence of a slower HR. Unchanged BP and HR and MSNA variability suggests that the larger burst incidence is not due to sympathetic activation.

Neither K + Channels Nor PI3K/Akt Mediates the Vasodilative Effect of Nebivolol on Different Types of Rat Arteries

Wang, Y., Zhang, M., Liu, Y., Li, J., Song, E., Niu, L., Cheng, N. — Tue, 10 Nov 2009 18:11:41 PST

Purpose: Nebivolol is a highly selective β₁-adrenoceptor blocker with additional vasodilating properties. It has been shown that the nebivolol-induced vasorelaxation is nitric oxide (NO) dependent. The serine/ threonine protein kinase Akt phosphorylates endothelial cell NO synthase (eNOS) and enhances the ability of eNOS to generate NO. Previous studies have shown that the release of NO from the endothelium may be ascribed to the modulation of different types of K⁺ channels. The current study was designed to determine whether K⁺ channels or phosphatidylinositol-3-kinase (PI3K)/Akt may affect vasorelaxation induced by nebivolol in different rat arteries.

Methods: Rings of the rat aorta, carotid artery, femoral artery, and renal artery were suspended for isometric force recording. During contraction by KCl (60 mmol/L) or phenylephrine (PE; 10^—6 mol/L; femoral artery and renal artery were precontracted by 10^—5 mol/L), the effect of nebivolol (10^—7-10^{— 5} mol/L) was obtained in the presence of different potassium channel, PI3K/Akt, or NOS inhibitors. Results: Nebivolol (10^{— 7}-10^—5 mol/L) relaxed precontractions induced by KCl and PE in different rat arteries, which was inhibited by the presence of the NOS inhibitor N^G-nitro-L-arginine methyl ester (L-NAME; 100 µmol/ L). The effect of nebivolol was concentration dependent. The exposure of the vessel rings to a selective inhibitor of PI3K wortmannin (5 x 10^—7 mol/L) or a selective inhibitor of Akt (1L-6-hydroxymethyl-chiro-inositol 2-(R)-2-Omethyl-3-O-octadecylcarbonate, 10^—5 mol/L) did not influence nebivolol-induced vasorelaxation. Similarly, K⁺ channels blockers, iberiotoxin (100 nmol/L), glibenclamide (0.1 mmol/L), 4-aminopyridine (1 mmol/L), or BaCl₂ (1 mmol/L) had no influence on the relaxation of nebivolol in arteries precontracted by PE. Conclusion: Nebivolol produced a concentration-dependent vasodilation in different rat arteries precontracted by PE or KCl. In the isolated rat aorta, carotid artery, femoral artery, and renal artery, neither K⁺ channels nor PI3K/Akt pathway was involved in the relaxation induced by nebivolol.

Effect of Targeting Mitogen-Activated Protein Kinase on Cardiac Remodeling in Rats

Baraka, A., Mikhail, M., Guemei, A., El Ghotny, S. — Tue, 10 Nov 2009 18:11:41 PST

Background: Increasing evidence suggests that the activation of p38 mitogen-activated protein kinase (p38MAPK) plays a role in cardiac remodeling. Targeting p38MAPK using drugs reported to interfere with its phosphorylation, namely statins and all-trans retinoic acid (atRA), might play a role in ameliorating this remodeling. Methods and Results: Cardiac remodeling was induced in male albino rats by chronic inhibition of nitric oxide (NO) synthesis by N-nitro L-arginine methyl ester (L-NAME). Daily oral administration of L-NAME for 4 weeks resulted in the elevation of mean arterial blood pressure (MABP) together with cardiac remodeling evidenced by an increase in left ventricular-body weight ratio together with an increase in cardiac hydroxyproline concentration and a decrease in left ventricular papillary muscle-developed tension. An elevation in cardiac phosphorylated p38MAPK concentration, tumor necrosis factor alpha concentration and in cardiac caspase 3 activity was also observed. Administration of either rosuvastatin or all-trans retinoic acid (atRA), starting 4 weeks after L-NAME administration, ameliorated remodeling and improved all studied parameters. Conclusions: Targeting MAPK might represent a useful therapeutic avenue to ameliorate cardiac remodeling and support the notion that atRA and statins are potential candidates for the prevention and therapy of cardiac remodeling.

A Salute to Our Founding Editor-in-Chief Bramah N. Singh, MD, DPhil, DSc, FRCP

Kloner, R. A. — Mon, 31 Aug 2009 16:36:06 PDT

Review: Platelet Function Testing and Implications for Clinical Practice

Collet, J.-P., Montalescot, G. — Mon, 31 Aug 2009 16:36:06 PDT

Platelets are key mediators in the pathophysiology of atherothrombotic disease. Inappropriate platelet activation can lead to thrombosis and ischemic events. Platelet function testing has been used to monitor patient response to antiplatelet therapy. Variability in response to antiplatelet therapy may be due in part to incomplete inhibition of targeted pathways (thromboxane A₂ and adenosine diphosphate [ADP]) by currently available agents (aspirin and P2Y₁₂ ADP receptor antagonists). Low responsiveness to antiplatelet therapy (as measured in various platelet function assays) correlates with a high rate of ischemic events. However, tailoring treatment based on platelet response remains to be definitively proven in clinical trials, correlations between assays are modest, and concordance in defining suboptimal response is poor. Additional studies are needed to determine whether changes in therapy based on results of platelet function testing improve clinical outcomes, and thus will determine whether broader use of platelet function testing in clinical practice is warranted.

Lack of Association of Tegaserod With Adverse Cardiovascular Outcomes in a Matched Case-Control Study

Mon, 31 Aug 2009 16:36:06 PDT

Tegaserod is a first-in class selective serotonin 4 receptor agonist approved for the treatment of irritable bowel syndrome. In March 2007, the US Food and Drug Administration (FDA) suspended its use citing increased cardiovascular (CV) events in clinical trials. However, there is no known mechanistic basis for an adverse CV effect. To reassess the CV safety of tegaserod, teagaserod-treated patients (pts) in the Intermountain Healthcare database were identified (n = 2603), matched 1:6 with untreated (n = 15,618) patients by age, sex, and date of tegaserod initiation, and followed for an average of 2.5 years. Age averaged 38.6 ± 13.5 years, and 94% were female. Cardiovascular event rates were low and similar in patients treated with tegaserod and matched untreated patients. For the primary composite CV endpoint, 54 (0.35%) untreated and 12 (0.46%) treated pts had an event (treated OR = 1.27, 95% CI: 0.68-2.38, P =.46), with 7 and 0 events, respectively, occurring within 3 months. A total of 12 (0.1%) untreated and 1 (<0.1%) treated pts were hospitalized for a myocardial infarction (MI). 36 (0.2%) untreated and 10 (0.4%) treated pts for a cardiovascular accident, and 1 pt in each group for unstable angina. A total of 6 (<0.1%) untreated and no treated pts died from cardiac causes. Event rates were comparable to expected rates in this population of mostly premenopausal women. This large epidemiologic study failed to confirm a reported large event differential for tegaserod that was noted incidentally in a clinical trials database, suggesting that the prior observation may have been due to chance.

Statins Reduce Appropriate Cardioverter-Defibrillator Shocks and Mortality in Patients With Heart Failure and Combined Cardiac Resynchronization and Implantable Cardioverter-Defibrillator Therapy

Mon, 31 Aug 2009 16:36:06 PDT

Of 209 patients with heart failure treated with combined cardiac resynchronization therapy and implantable cardioverter-defibrillator therapy, appropriate cardioverter-defibrillator shocks occurred at 34-month follow-up in 22 of 121 patients (18%) on statins and in 30 of 88 patients (34%) not on statins (P = .009). Deaths occurred in 3 of 121 patients (2%) on statins and in 9 of 88 patients (10%) not on statins (P = .017). Stepwise Cox regression analysis showed that significant independent prognostic factors for appropriate shocks were use of statins (risk ratio = 0.46), smoking (risk ratio = 3.5), and diabetes (risk ratio = 0.34). Significant independent prognostic factors for the time to mortality were use of statins (risk ratio = 0.05), use of digoxin (risk ratio = 4.2), systemic hypertension (risk ratio = 14.2), diabetes (risk ratio = 4.3), and left ventricular ejection fraction (risk ratio = 1.1).

The Effect of Intracoronary Nicorandil on Coronary Myocardial Bridging

Mon, 31 Aug 2009 16:36:06 PDT

Medical treatments of coronary myocardial bridging (CMB) generally include β-blockers and calcium channel blockers. Nitrates are avoided because symptoms may worsen. Nicorandil is a hybrid of a nitrate and a potassium channel opener. However, the effect of nicorandil on CMB is unknown. We analyzed nicorandil reactivity at the site with CMB in 51 patients. Maximal and minimal diameters of CMB were measured by quantitative angiography at baseline and at 60 seconds after intracoronary administration of 200 mg nicorandil. The maximal diameter during diastole increased from 2.15 + 0.42 mm to 2.34 + 0.44 mm after administration of nicorandil (P < .001), and the minimal diameter during systole increased from 1.24 + 0.63 mm to 1.67 + 0.64 mm (P < .001). Thus, nicorandil reduced the percentage vessel narrowing from 44.0 + 26.1% to 30.3 + 21.2% (P < .001). In 22 patients, we also evaluated the effect of nitroglycerin. The maximal diameter during diastole increased from 2.25 + 0.47 mm to 2.51 + 0.44 mm after administration of nitroglycerin (P < .019), and the minimal diameter during systole decreased from 1.28 + 0.64 mm to 1.14 + 0.60 mm (P = .276). Thus, nitroglycerin augmented the percentage vessel narrowing from 44.9% + 25.0% to 56.0% + 23.5% (P = .023). These results indicate that intracoronary administration of nicorandil could dilate coronary arteries during diastole as well as systole in patients with CMB during coronary angiography.

The Effect of Angiotensin-Converting Enzyme Inhibitor on Hemodynamic Instability in Patients Undergoing Cardiopulmonary Bypass: Results of a Dose-Comparison Study

Mon, 31 Aug 2009 16:36:06 PDT

Background: Recently, hemodynamic instability including hypotension and its effect on the clinical outcome in patients treated with angiotensin-converting enzyme inhibitors (ACEIs) during coronary artery bypass graft (CABG) has been described. However, no analysis has examined the dose of ACEIs and its risk of hypotension. In this study, we tested the hypothesis that a higher dose of ACEIs could lead to increased episodes of hypotension.

Methods: A total of 300 patients scheduled for CABG were studied prospectively. They were divided into 3 groups according to their preoperative use of different doses of ACEIs. The demographic and medical characteristics were compared between these 3 groups. During CABG and throughout the intensive care unit (ICU), vasoconstrictors were infused in patients undergoing hypotension (mean arterial pressure [MAP] < 65 mm Hg or >30% below baseline). The predictive factors responsible for hypotension were investigated separately using univariate and multivariate logistic regression models.

Results: The 3 groups were similar with regard to the patients’ demographic and medical characteristics. The patients treated with ACEIs were more likely to develop hypotension (73% of high dose and 47% of low dose) in the operating room than those without ACEIs (30%). However, in the ICU, there was no significant association between hemodynamic changes and ACEIstreated patients. Other independent risk factors identified for hypotension were ejection fraction, history of myocardial infarction, coronary grafting count, and pump time during surgery and/or ICU admission. Conclusions: Hemodynamic changes during CABG were observed to be directly proportional to the dosage of ACEIs prescribed preoperatively.

Heart Rate Variability Increases With Reductions in Cigarette Smoke Exposure After 3 Days

Mon, 31 Aug 2009 16:36:06 PDT

Background: Smoking has been shown to influence the tone of the autonomic nervous system as reflected by heart rate variability (HRV). To date, no information is available as to whether 24-hour HRV might differentiate users of different tobacco products. Objective: To assess the differences in HRV derived from the 24-hour electrocardiogram (ECG) following the use of 2 tobacco products of potentially different exposures. Methods: Thirty adult Caucasian male smokers (mean age: 42.8 + 5.7 years) smoking 20 to 40 cigarettes/ day were randomized in a 3-way crossover study design to either smoke a conventional cigarette (CC, tar: 11 mg, Nic: 0.8 mg), to use the Electrically Heated Cigarette Smoking System (EHCSS: tar: 5 mg, Nic: 0.3 mg, according to the Federal Trade Commission [FTC]), or to stop smoking (NS) for 3 days each. The 24 hours ECGs were recorded during the last 24 hours of each exposure period. Results: A 24-hour ECG showed highest mean values for standard deviation of all normal-to-normal heart beat (NN) intervals (SDNN), standard deviation of all 5-minute averaged NN intervals in a 24-hour period (SDANN), mean of the standard deviations of the NN intervals calculated from all 5-minute segments in a 24-hour period (SDNNI), percentage (P) of all NN intervals that differ by 50 milliseconds of all NN (PNN50%), the square root of the mean of all squared differences between adjacent NN intervals in 24-hour period (RMSSD), and total number of all NN intervals divided by the height of the histogram of all NN intervals measured on a discrete scale with bins of 7 x 8125 ms (1/128 seconds; HRVTI) when participants stopped smoking followed by the use of the reduced exposure product and CC. Conclusion: Heart rate variability tended to increase with reduced smoke exposure.

Partial Hindlimb Occlusion Reduced the Susceptibility to Sustained Ventricular Tachycardia in Conscious Rats

Lujan, H. L., DiCarlo, S. E. — Mon, 31 Aug 2009 16:36:06 PDT

Remote conditioning induced by ischemia in distant organs protects the heart from ischemia/reperfusion injury; however, its effect on ischemia-induced ventricular arrhythmias is unknown. Therefore, we tested the hypothesis that partial hindlimb occlusion during coronary artery occlusion increases the ventricular arrhythmia threshold (VAT) induced by coronary artery occlusion. Rats (n = 7) were instrumented with a radio-telemetry device for recording arterial pressure, electrocardiogram (ECG), and body temperature. A Doppler ultrasonic flow probe and vascular occluder were placed around the terminal aorta. Finally, a snare was placed around the left main coronary artery. The VAT was determined without and, on an alternate day, during partial hindlimb occlusion (remote conditioning) in conscious rats. Without remote conditioning, the VAT was 4.56 + 0.15 minutes. Importantly, remote conditioning significantly increased the VAT (6.29 + 0.49 minutes), suggesting that ischemia in a distant organ may delay the development of ischemia-induced ventricular arrhythmias.

GAP-134 ([2S,4R]-1-[2-Aminoacetyl]4-Benzamidopyrrolidine-2-Carboxylic Acid) Prevents Spontaneous Ventricular Arrhythmias and Reduces Infarct Size During Myocardial Ischemia/Reperfusion Injury in Open-Chest Dogs

Mon, 31 Aug 2009 16:36:06 PDT

The antiarrhythmic dipeptide, GAP-134, ([2S,4R]-1[2-aminoacetyl]-4-benzamido-pyrrolidine-2-carboxylic acid) was evaluated in canine ischemia/reperfusion model. In dogs subjected to 60-minute ischemia and 4-hour reperfusion, GAP-134 was administered 10 minutes before reperfusion as a bolus + intravenous (IV) infusion. The doses administered were 0.25 µg/kg bolus + 0.19 µg/kg per hour infusion; 2.5 µg/kg + 1.9 µg/kg per hour; 25 mg/kg + 19 mg/kg per hour; 75 mg/kg + 57 mg/kg per hour. Ventricular ectopy was quantified during reperfusion, including premature ventricular contractions (PVC) and ventricular tachycardia (VT). Total incidence of VT was reduced significantly with the 2 highest doses of GAP-134 (1.7 + 0.8; 2.2 + 1.4 events; P < .05) compared to controls (23.0 + 6.1). Total PVCs were reduced significantly from 11.1 + 1.6% in control animals to 2.0% + 0.7% and 1.8% + 0.8% after the 2 highest doses of GAP-134. Infarct size, expressed as percentage of left ventricle, was reduced significantly from 19.0% + 3.5% in controls to 7.9% + 1.5% and 7.1% + 0.8% (P < .05) at the 2 highest doses of GAP-134. GAP-134 is an effective antiarrhythmic agent with potential to reduce ischemia/reperfusion injury.

Application of Zinc-bis-(DL-Hydrogensaspartate) Does Not Reduce Apoptotic Cell Death in Myocardial Infarction in the Rat Heart

Mon, 31 Aug 2009 16:36:06 PDT

Background: Early studies in different stress models have shown potential beneficial effects of exogenous zinc application with reduction in the rate of apoptotic cell death. This has not been shown in models of myocardial infarction. Methods: Rats were exposed to either brief episodes of acute ischemia followed by reperfusion (phase 1) or chronic coronary occlusion (phase 2). Animals were either treated with zinc or vehicle. Groups 1 and 3 received zinc-bis-(DL-hydrogenaspartate) 10 mg/kg body weight as a single 5-mL bolus administered intraperitoneally 24 hours prior to coronary occlusion, groups 2 and 4 received saline. The infarct sizes were determined by triphenyltetrazolium chloride staining and expressed at relative areas to areas of ischemia. Histological slices of the rat’s myocardium at the border zones of the infarcts were stained with the TUNEL method to assess for apoptosis. Animals in groups 5, 7, and 9 received zinc, given once before and then repeated every 4 days after coronary occlusion, whereas groups 6, 8, and 10 received saline. Animals were observed for observation periods of 13 (groups 9 and 10), 16 (groups 7 and 8), or 19 weeks (groups 5 and 6), respectively. Two-dimensional echocardiography was performed to measure ejection fraction (EF) at baseline and at the end of the observation periods. TUNEL staining was used to detect and quantify apoptosis rate in the border zones of infarcts after the hearts were excised. Results: Infarct sizes were 49% + 22% in group 1 (zinc + 30 minutes ischemia + 30 minutes reperfusion); 48% + 10% in group 2 (vehicle + 30 minutes ischemia + 30 minutes reperfusion); 42% + 11% in group 3 (zinc + 60 minutes ischemia + 30 minutes reperfusion); and 41% + 23% in group 4 (vehicle + 60 minutes ischemia + 60 minutes reperfusion). In group 1, 11% + 6% of cells were apoptotic compared to 12% + 4% in group 2, 16% + 9% in group 3, and 17% + 7% in group 4 (P > .05). In phase 2, echocardiography revealed a significant reduction in EF in all groups after coronary occlusion. There were no significant differences in EF between the 5 groups at baseline and at follow-up. TUNEL staining did not reveal any significant apoptosis after 13 to 19 weeks. Conclusion: Application of zinc failed to result in reduction of infarct size after temporary coronary occlusion followed by reperfusion and did not demonstrate any reduction in apoptotic cell death. In chronic coronary occlusion, zinc also did not improve EF compared to controls in the presented model in rats. The mechanisms involved in antiapoptotic effects seem to be more complex and might not be inducible by simple zinc injections.

Dose-Related Shortening of Ventricular Tachycardia Cycle Length After Administration of the KATP Channel Opener Bimakalim in a 4-Day-Old Chronic Infarct Anesthetized Pig Model

Mon, 31 Aug 2009 16:36:06 PDT

Potassium channel openers are known to act on potassium ATP-dependent channels in cardiac tissue. Such agents may exacerbate acceleration of acute ischemia-induced ventricular repolarization and aggravate arrhythmias. To test whether activation of K_ATP channels during the healing period of myocardial infarction (MI) can still influence the electrophysiologic properties and the type of inducible arrhythmias, we investigated the effects of bimakalim (BIM) on sustained ventricular tachycardia (VT) 4 days after ligation of the left anterior descending (LAD) coronary artery in pigs. Programmed stimulation was performed to elicit VT prior to and after intravenous (IV) BIM. Combination monophasic action potential (MAP)/PACING catheters were used to enable simultaneous ventricular MAP recording and pacing. Ventricular effective refractory period (ERP) and MAP duration determined at 50% and 90% repolarization were measured prior to and after BIM. After completion of baseline measurements, BIM was consecutively given at 0.5, 1, and 3 mg/kg bolus followed by 0.025, 0.05, and 0.1 mg/kg per minute maintenance infusion, respectively. From a total of 23 pigs subjected to LAD ligation, 4 animals succumbed to infarction and the remaining 19 animals were studied by programmed stimulation. Only animals that exhibited reproducible and hemodynamically stable monomorphic VTs during control stimulation were selected for evaluation (n = 14). After the first, second, and third dose of BIM, the mean VT rate was increased by 6%, 14% (P <. 01), and 47% (P < .001) compared to control values, respectively. Ventricular ERP and repolarization were significantly shortened only by the second and third dose of BIM. Of 14 pigs receiving the highest BIM dosage, 3 revealed polymorphic VTs degenerating into ventricular fibrillation (VF). Our data suggest that high BIM doses may lead to faster and more aggressive pacing-induced reentrant VTs after subacute MI. This is consistent with the drug-induced acceleration of ventricular repolarization with shortening of MAP duration and refractoriness.

Vitamin E Does Not Regress Hypercholesterolemic Atherosclerosis

Prasad, K. — Mon, 31 Aug 2009 16:36:06 PDT

Background: Suppression of hypercholesterolemic atherosclerosis with vitamin E is associated with reductions in oxidative stress without reductions in serum lipids. The objectives of this study were to determine if (1) vitamin E regresses hypercholesterolemic atherosclerosis; and (2) regression is associated with reductions in serum lipids and aortic oxidative stress. Methods and Results: The studies were conducted in 4 groups of rabbits: group I, control, regular diet (2 months); group II, 0.25% cholesterol diet (2 months); group III, 0.25% cholesterol diet (2 months) followed by regular diet (2 months); and group IV, 0.25% cholesterol diet (2 months) followed by regular diet with vitamin E (40 mg/kg body weight/day) (2 months). Blood samples were collected monthly for the measurement of serum lipids and oxidative stress (chemiluminescent activity of white blood cells [WBC-CL]). Aortas were removed at the end of the protocol for assessment of atherosclerotic lesions, and oxidative stress (malondialdehyde [MDA] and CL). Increases in serum lipids in group II were associated with an increase in oxidative stress and development of atherosclerosis. Serum lipids decreased to a similar extent in groups III and IV but the atherosclerotic lesions increased by 63% and 141% compared to group II. Acceleration of atherosclerosis in the rabbits on regular diet with or without vitamin E was associated with practically no change in the oxidative stress. Conclusion: These results suggest that (1) regular diet following a high-cholesterol diet decreased oxidative stress but did not induce regression of atherosclerosis; (2) vitamin E did not produce regression; and (3) regular diet with vitamin E following a high-cholesterol diet was not associated with an increase in oxidative stress but produced acceleration of atherosclerosis.

The Antiarrhythmic Effect and Possible Ionic Mechanisms of Pilocarpine on Animal Models

Mon, 31 Aug 2009 16:36:06 PDT

This study was designed to evaluate the effects of pilocarpine and explore the underlying ionic mechanism, using both aconitine-induced rat and ouabain-induced guinea pig arrhythmia models. Confocal microscopy was used to measure intracellular free-calcium concentrations ([Ca²⁺]_i) in isolated myocytes. The current data showed that pilocarpine significantly delayed onset of arrhythmias, decreased the time course of ventricular tachycardia and fibrillation, reduced arrhythmia score, and increased the survival time of arrhythmic rats and guinea pigs. [Ca²⁺]_i overload induced by aconitine or ouabain was reduced in isolated myocytes pretreated with pilocarpine. Moreover, M₃-muscarinic acetylcholine receptor (mAChR) antagonist 4-DAMP (4-diphenylacetoxy-N-methylpiperidine-methiodide) partially abolished the beneficial effects of pilocarpine. These data suggest that pilocarpine produced antiarrhythmic actions on arrhythmic rat and guinea pig models induced by aconitine or ouabain via stimulating the cardiac M₃-mAChR. The mechanism may be related to the improvement of Ca²⁺ handling.

Modest Dietary Reductions in Blood Cholesterol Have Important Public Health Benefits

Hennekens, C. H., Schneider, W. R., Barice, E. J., Hebert, P. R. — Wed, 20 May 2009 10:17:20 PDT

Large reductions in blood cholesterol produce major clinical and public health benefits. Based on extrapolations from randomized evidence, assuming no threshold, a 3% to 4% reduction in blood cholesterol would decrease risk of coronary heart disease (CHD) by 12%. If so, treating larger numbers of people at lower risk would yield greater reductions in CHD than treating smaller numbers at higher risk. High- and moderate-risk patients require evidence-based doses of high-potency statins, as adjuncts to dietary management and benefits to individuals are large and easily quantifiable in randomized trials. In low-risk patients, however, dietary modifications contribute to a public health benefit while that benefit to any individual is small. Thus, the hypothesis that modest dietary reductions in blood cholesterol have important public health benefits is easily quantifiable by extrapolation from existing data but impossible to test among randomized individuals, as the sample sizes and costs are prohibitively large.

p130 Crk-Associated Substrate (CAS) in Vascular Smooth Muscle

Tang, D. D. — Wed, 20 May 2009 10:17:20 PDT

Vascular smooth muscle is a key effector in the wall of blood vessels during the pathogenesis of hypertension. Various factors directly elicit smooth muscle cell contraction, migration, growth, and hypertrophy, which lead to the progression of hypertension. Crk-associated substrate (CAS), the first discovered member of the adapter protein CAS family, has recently emerged as a critical cellular component that regulates smooth muscle functions. In this review, the molecular structure and protein interactions of the CAS family members are summarized. Evidence for the role of CAS in the regulation of vascular smooth muscle contractility, cell migration, hypertrophy, and growth is presented. Regulation of CAS by novel tyrosine kinases/phosphatases and unique downstream signaling partners of CAS are also discussed. These new findings establish the important role for CAS in regulating vascular smooth muscle functions. The CAS-associated processes may be new biological targets for the development of new treatment of cardiovascular diseases such as hypertension.

The Mechanism by Which Ischemic Postconditioning Reduces Reperfusion Arrhythmias in Rats Remains Elusive

Dow, J., Bhandari, A., Kloner, R. A. — Wed, 20 May 2009 10:17:20 PDT

We have observed that ischemic postconditioning markedly reduces reperfusion-induced ventricular arrhythmias, but whether the mechanism is related to previously described pathways of preconditioning or postconditioning for infarct size reduction is unknown. The purpose of this study was to determine whether known pathways were involved in postconditioning's protective effect on arrhythmias.

Anesthetized female rats were subjected to 5 minutes of proximal coronary artery occlusion and 5 minutes of reperfusion. They were either not postconditioned or subjected to 4 cycles of 20 seconds reperfusion, 20 seconds reocclusion before final reperfusion (postconditioned). Electrocardiogram and blood pressure were monitored throughout. Alleged agonists and antagonists to postconditioning representing a number of mechanisms were evaluated.

Nonpostconditioned rats treated with the suppressor of the mitochondrial permeability transition pore, cyclosporine A, did not show a reduction in

reperfusion-induced ventricular arrhythmias compared to control nonpostconditioned rats. Neither Wortmannin (p13-kinase inhibitor), 5 hydroxydecanoate (selective inhibitor of mitochondrial K_ATP channel), nor 8-sulfophenyl theophylline (blocker of adenosine receptors) blocked the reduction in ventricular tachycardia of postconditioning.

The mechanism by which postconditioning reduces reperfusion-induced ventricular arrhythmias may be independent of known pathways that have been implicated in the infarct sparing effects of preconditioning and postconditioning—including adenosine, mitochondrial K_ATP channel, mitochondrial permeability transition pore, and p13-kinase-pAKt pathways. Alternative protective pathways may exist to explain the antiarrhythmic effect of postconditioning.

Time Courses of Subcellular Signal Transduction and Cellular Apoptosis in Remote Viable Myocardium of Rat Left Ventricles Following Acute Myocardial Infarction: Role of Pharmacomodulation

Wed, 20 May 2009 10:17:20 PDT

We tested hypothesis that acute myocardial infarction (AMI) induces cellular apoptosis and serial changes of protein kinase C epsilon (PKC-e) and p38 mitogen-activated protein kinase (p38 MAPK), and tested cardio-protective effect of losartan in this condition. The rats were assigned to group A (sacrificed on day 2), group B (sacrificed on day 5), and group C (sacrificed on day 14). Rats in each group were further randomized into the following groups: AMI (ligation of left coronary artery) without losartan (AMI-L0); AMI with losartan 20 mg/ kg/d (AMI-L1); and sham groups (L0 and L1). The PKC-e expression in membrane compartment was increased in AMI-L1 group than in other groups on day 5 and in AMI groups than in sham groups on day 14 (P < .01). Phosphorylated form of cytosolic p38 MAPK level was increased in AMI-L1 than in other groups on day 14 (P < .05). Furthermore, 14-day left ventricular ejection fraction was higher and cellular apoptosis was lower in AMI-L1 group than in AMI-L0 group (P < .0001).

The Cyclic GMP Modulators YC-1 and Zaprinast Reduce Vessel Remodeling Through Antiproliferative and Proapoptotic Effects

Keswani, A. N., Peyton, K. J., Durante, W., Schafer, A. I., Tulis, D. A. — Wed, 20 May 2009 10:17:20 PDT

Guanosine-specific cyclic nucleotide signaling is suggested to serve protective actions in the vasculature; however, the influence of selective pharmacologic modulation of cyclic guanosine monophosphate— synthesizing soluble guanylate cyclase or cyclic guanosine monophosphate—degrading phosphodiesterase on vessel remodeling has not been thoroughly examined. In this study, rat carotid artery balloon injury was performed and the growth-modulating effects of the soluble guanylate cyclase stimulator YC-1 or the cyclic guanosine monophosphate—dependent phosphodiesterase-V inhibitor zaprinast were examined. YC-1 or zaprinast elevated vessel cyclic guanosine monophosphate content, reduced medial wall and neointimal cell proliferation, stimulated medial and neointimal cellular apoptosis, and markedly attenuated neointimal remodeling in comparable fashion. Interestingly, soluble guanylate cyclase inhibition by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one failed to noticeably alter neointimal growth, and concomitant zaprinast with YC-1 did not modify any parameter compared to individual treatments. These results provide novel in vivo evidence that YC-1 and zaprinast inhibit injury-induced vascular remodeling through antimitogenic and proapoptotic actions and may offer promising therapeutic approaches against vasoproliferative disorders.

Ranolazine as an Adjunct to Cardioplegia: A Potential New Therapeutic Application

Wed, 20 May 2009 10:17:20 PDT

The purpose of this study was to examine the therapeutic potential of ranolazine, a novel antianginal drug, as an adjunctive therapy to hyperkalemic cardioplegia. Rat hearts were Langendorff-perfused and exposed to 40 minutes of ischemia and 30 minutes of reperfusion without (control) or with cardioplegia or cardioplegia with 50 µmol/L ranolazine. During ischemia, cardioplegia prolonged time to contracture, defined as the time to reach an intraventricular pressure of 20 mm Hg, from 12 + 1 minute (control) to 25 + 2 minutes (P < .05). Ranolazine supplement further lengthened the time to contracture to 34 + 2 minutes (P < .05). Ischemia/reperfusion caused a dramatic elevation in left ventricular end diastolic pressure (LVEDP) during reperfusion. Cardioplegia lessened the LVEDP elevation measured at 30 minutes of reperfusion from 76 + 3 mm Hg (control) to 32 + 3 mm Hg (P < .05). The increase in LVEDP was reduced even further to 17 + 2 mm Hg in hearts receiving cardioplegia plus ranolazine (P < .05). These results suggest that addition of ranolazine during hyperkalemic ischemic cardioplegic arrest is beneficial and provides further protection against contracture.

Modification of Epinephrine-induced Arrhythmias by N-Acetyl-L-Cysteine and Vitamin E

Sethi, R., Adameova, A., Dhalla, K. S., Khan, M., Elimban, V., Dhalla, N. S. — Wed, 20 May 2009 10:17:20 PDT

Sprague-Dawley rats were pretreated for 21 days with N-acetyl-L-cysteine (NAC) or vitamin E to investigate their influence on arrhythmias induced by a bolus injection or by cumulative doses of epinephrine. Electrocardiographic analysis revealed that both NAC and vitamin E decreased the duration and increased the time of onset of epinephrine-induced arrhythmias in a dose-dependent manner. The antiarrhythmic effects of NAC were comparable with those seen in the vitamin E-pretreated animals. The lipid peroxidation due to cumulative doses of epinephrine was reduced in both pretreated groups; however, NAC, unlike vitamin E, failed to decrease the basal level of malondialdehyde. Although the plasma concentrations of both norepinephrine and epinephrine were markedly increased, the level of aminochromes on epinephrine administration was decreased by both NAC and vitamin E pretreatments. The results support the view that antioxidants may prevent the catecholamine-induced heart rhythm disorders by reducing the formation of oxidized catecholamines.

Dose-dependent Effect of Rosuvastatin Treatment on HDL-subfraction Phenotype in Patients With Primary Hyperlipidemia

Wed, 25 Feb 2009 12:48:52 PST

Although the raising effect of rosuvastatin on high-density lipoprotein cholesterol is well-established, there is a paucity of data regarding the effect of this statin on the high-density lipoprotein subfraction phenotype. A total of 150 participants without evidence of cardiovascular disease were randomized to therapeutic lifestyle modification (nonstatin-treated group) or to therapeutic lifestyle modification plus rosuvastatin at 10 mg/d (RSV10 group) or 20 mg/d (RSV20 group). We assessed the effect of rosuvastatin on the cholesterol mass of high-density lipoprotein subfractions at baseline as well as after 12 weeks post-treatment. Rosuvastatin treatment dose-dependently increased the high-density lipoprotein cholesterol (3.4% vs 5.3% in the RSV10 and RSV20 groups, respectively, P = .02). A dose-related rosuvastatin-induced increase in the cholesterol concentration of large high-density lipoprotein particles was also noted (by 11.4% in RSV10 group vs 22.0% in the RSV20 group, P = .01). Rosuvastatin treatment increases the high-density lipoprotein cholesterol by increasing the cholesterol mass only of the larger high-density lipoprotein particles in a dose-dependent manner.

Influence of Short-term Rosuvastatin Therapy on Endothelial Progenitor Cells and Endothelial Function

Wed, 25 Feb 2009 12:48:52 PST

Endothelial progenitor cells maintain endothelium integrity by replacing injured endothelial cells. Cholesterol-lowering promotes either endothelial progenitor cells mobilization or improves endothelial function. It is unknown whether improving endothelial function with statin is associated with a parallel increased endothelial progenitor cells availability. Thirty-two hypercholesterolemic patients were assigned to 4-week rosuvastatin (10 mg daily) and 16 hypercholesterolemic served as controls. Circulating endothelial progenitor cells, brachial artery flow-mediated vasodilatation, an index of endothelial function, and the lipid profile were measured before and after the 4-week statin therapy. At baseline, we found a correlation between circulating endothelial progenitor cells and flow-mediated vasodilatation (r = .31, P = .029). At the end of the 4-week intervention with rosuvastatin there was a 37% reduction in low-density lipoprotein cholesterol (P < .001) and a significant 72% increase in the number of endothelial progenitor cells and flow-mediated vasodilatation (4.7 + 0.7% to 8.8 + 0.4%, P < .001). Endothelial progenitor cells and flow-mediated vasodilatation were unchanged at the end of the study in patients not taking statin. A correlation emerged between endothelial progenitor cells and flow-mediated vasodilatation variations (r = .52, P < .001), this correlation being still significant after controlling for blood cholesterol reduction. In conclusion, short-term rosuvastatin therapy contributes in hyperchoelsterolemic patients to improving endothelial function by lowering cholesterol and increasing the number of circulating endothelial progenitor cells; the latter effect appears to be partly independent from reduction in plasma cholesterol.

Currying the Heart: Curcumin and Cardioprotection

Srivastava, G., Mehta, J. L. — Wed, 25 Feb 2009 12:48:52 PST

Curcumin (diferuoylmethane) is the active ingredient of turmeric (curcuma longa). There has been a surge of research in its anti-inflammatory and antioxidative properties, and its cardiovascular effects. A host of studies in in vitro and in vivo models of cardiac injury show that curcumin treatment reduces reactive oxygen species generation, monocyte adhesion to activated endothelial cells, and phosphorylation of c-Jun N-terminal kinase, p38 mitogen activated protein kinase and signal transducer and activator of transcription-3, and subsequent downstream signals. These alterations lead to preservation of myocardial function following ischemic or biochemical insult to the heart. Recent studies in models of pressure overload show that curcumin can reduce cardiac remodeling by altering reninangiotensin-system—transforming growth factor β1 and collagen axis. Studies need to be done in humans to define the potential of curcumin in limitation of cardiac injury and preservation of cardiac function following ischemia.

Gender-related Differences in Drug-induced Prolongation of Cardiac Repolarization in Prepubertal Guinea Pigs

Hreiche, R., Morissette, P., Zakrzewski-Jakubiak, H., Turgeon, J. — Wed, 25 Feb 2009 12:48:52 PST

Underlying mechanisms of drug-induced long QT syndrome are not fully understood. Our objective was to evaluate gender-related differences for block of the rapid (I_Kr ) or/and the slow (I_Ks) components of the delayed rectifier potassium current in prepubertal male and female guinea pigs (n = 120) treated with or without verapamil. Indapamide (I_Ks blocker) prolonged the monophasic action potential duration at 90% repolarisation (MAPD₉₀) in females more than in males (15.1 + 0.5 vs 9.7 + 1.3 msec; P < .05) in verapamil treated animals. In contrast, MAPD₉₀ prolongation induced by domperidone or dofetilide (I_Kr blockers) was not different between genders. Verapamil treatment augmented prolongation of MAPD₉₀ caused by dofetilide or domperidone (P < .01). In conclusion, 1) females exhibited greater prolongation of MAPD₉₀ when exposed to indapamide, 2) no gender-related differences were observed for I_Kr blockers, and 3) verapamil treatment did not uncover gender-related differences in I_Kr or I_Ks block, although it augmented prolongation of cardiac repolarization by I_Kr blockers.

Flax Lignan Complex Slows Down the Progression of Atherosclerosis in Hyperlipidemic Rabbits

Prasad, K. — Wed, 25 Feb 2009 12:48:52 PST

Flax lignan complex suppresses the development of hypercholesterolemic atherosclerosis. However, it is not known whether flax lignan complex would slow down the progression of hypercholesterolemic atherosclerosis. This study was carried out to determine whether flax lignan complex slows down the progression of already developed atherosclerosis, and whether this effect is associated with reductions in serum lipids and oxidative stress. The studies were conducted in 4 groups of rabbits: group I, regular diet (2 months); group II, 0.25% cholesterol diet (2 months); group III, 0.25% cholesterol diet (4 months); group IV, 0.25% cholesterol diet (2 months) followed by 0.25% cholesterol diet plus flax lignan complex (2 months). Serum lipids and oxidative stress parameters (malondialdehyde, antioxidant reserve, white blood cell chemiluminescence) were measured before and at monthly intervals thereafter on their respective diets. Aortas were removed at the end of the protocol for assessment of atherosclerosis and oxidative stress. Atherosclerosis in group II was associated with hyperlipidemia and increased oxidative stress. Significant areas of the aortic intimal surfaces from group II (37.76% + 7.96%), group III (76.6% + 9.04%), and group IV (52.95% + 10.29%) were covered with atherosclerotic plaques. Group IV rabbits had 40% more atherosclerotic lesions than group II but 31% fewer lesions than group III. The flax lignan complex—induced reduction in the progression of atherosclerosis was associated with reductions in oxidative stress. In conclusion, flax lignan complex was effective in slowing down the progression of atherosclerosis by 31%, and this effect was associated with a reduction in oxidative stress.

Management of Hyperlipidemia in Older Adults

Wed, 25 Feb 2009 12:48:52 PST

Cardiovascular disease is the leading cause of death in men and women older than 65 years; therefore, its prevention is an important public health priority. Although cardiovascular risk is multifactorial, elevated low-density lipoprotein cholesterol levels contribute to risk even in old age. Despite the importance of lowering low-density lipoprotein cholesterol with statins to reduce cardiovascular events, specific evidence and recommendations for older populations are limited. Where evidence supports lipid lowering in older adults, provider and patient adherence to statins remains suboptimal. Paradoxically, risk is an inverse driver of statin use regardless of age, with those most likely to benefit being least likely to receive them. Reconsidering evidence around, use of statins as well as ways to optimize the prescription of statins and adherence in appropriately selected older adults is warranted.

Anandamide Preserves Cardiac Function and Geometry in an Acute Doxorubicin Cardiotoxicity Rat Model

Hydock, D. S., Lien, C.-Y., Hayward, R. — Wed, 25 Feb 2009 12:48:52 PST

We investigated the use of the endocannabinoid anandamide as a means of cardioprotection against doxorubicin-induced cardiac dysfunction. Male rats received doxorubicin with or without anandamide pretreatment. Cardiac function was assessed in vivo using transthoracic echocardiography and ex vivo using the isolated working heart 5 days posttreatment. Doxorubicin administration without anandamide pretreatment resulted in a decline in fractional shortening (P < .05) and left ventricular wall thickness when compared to controls (P < .05). Ex vivo cardiac function analysis revealed a reduction in left ventricular developed pressure in hearts from animals receiving doxorubicin without anandamide pretreatment when compared to controls (P < .05). Left ventricles from animals receiving anandamide pretreatment before doxorubicin administration did not exhibit depressed fractional shortening, ventricular wall thickness, or developed pressure when compared to controls (P > .05). These results suggest that a potential therapy for doxorubicin-induced cardiotoxicity involves targeting the endogenous cannabinoid system.

Macrophage Depletion in Hypertensive Rats Accelerates Development of Cardiomyopathy

Wed, 25 Feb 2009 12:48:52 PST

Inflammation contributes to the process of ventricular remodeling after acute myocardial injury. To investigate the role of macrophages in the chronic process of cardiac remodeling, they were selectively depleted by intravenous administration of liposomal clodronate in heart failure—prone hypertensive Ren-2 rats from the age of 7 until 13 weeks. Plain liposomes were used for comparison. Liposomal clodronate treatment reduced the number of blood monocytes and decreased the number of macrophages in the myocardium. Compared to plain liposomes, liposomal clodronate treatment rapidly worsened left ventricular ejection function in hypertensive rats. Liposomal clodronate— treated Ren-2 rat hearts showed areas of myocyte loss with abundant inflammatory cell infiltration, predominantly comprising CD4 positive T lymphocytes. The current study showed that lack of macrophages was associated with earlier development of myocardial dysfunction in hypertensive rats. Modulation of macrophage function may be of value in the evolution of cardiomyopathy.