bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacology of the AC AT Inhibitor Avasimibe (CI‐1011)
Authors: Llaverías Gemma , Laguna Juan C. , Alegret Marta
Published: August 2010

Avasimibe is a novel orally bioavailable ACAT inhibitor, currently under clinical development (phase III trials). It was safe when administered to rats, dogs, and humans. In vitro studies in human macrophages demonstrated that avasimibe reduces foam cell formation not only by enhancing free cholesterol efflux, but also by inhibiting the uptake of modified LDL. The concentration‐dependent reduction in cellular cholesteryl ester content in these cells was not accompanied by an increase in intracellular free cholesterol, which is in agreement with a good safety profile for avasimibe. In the liver, avasimibe caused a significant reduction in the secretion of apo B and apo B‐containing lipoproteins into plasma. Avasimibe induced cholesterol 7α‐hydroxylase and increased bile acid synthesis in cultured rat hepatocytes, and its administration to rats did not produce an increase in lithogenicity index of the bile. The hypolipidemic efficacy of the compound was demonstrated in cholesterol‐fed as well as in non‐cholesterol‐fed animals. In these models, plasma cholesterol levels were reduced, mainly due to the decrease in the non‐HDL cholesterol fraction. Clinical data are scarce, but in a study performed in 130 men and women with combined hyperlipidemia and hypoalphalipoproteinemia, avasimibe, 50–500 mg/day, significantly reduced plasma total triglyceride and VLDL‐cholesterol. Although total cholesterol, LDL‐cholesterol, and HDL‐cholesterol were unchanged, it must be stressed that animal data suggest that avasimibe may have direct antiatherosclerotic activity in addition to its cholesterol‐lowering effect. Avasimibe treatment can also contribute to increase plaque stability, as it reduces the accumulation of lipids in the arterial wall, inhibits macrophage infiltration into the media and reduces matrix metalloproteinase expression and activity. Moreover, avasimibe and statins have been shown to have synergistic effects, and the combination therapy may not only inhibit atherosclerotic lesion progression but also induce lesion regression, independently of changes in plasma cholesterol.
The P2Y1Receptor as a Target for New Antithrombotic Drugs: A Review of the P2Y1Antagonist MRS‐2179
Authors: Baurand Anthony , Gachet Christian
Published: August 2010

MRS‐2179 is a selective P2Y1receptor antagonist, a strong inhibitor of ADP‐induced platelet aggregationin vitroandex vivo.By i.v. administration to mice MRS‐2179 increases resistance to thromboembolism induced by a mixture of collagen and epinephrine or by a tissue factor. Likewise, it significantly increases the time to thrombus formation in a ferric chloride‐induced model of localized arterial thrombosis. MRS‐2179 also confers resistance to localized venous thrombosis, which is dependent on thrombin generation and in which platelets play a relatively minor role as compared to stasis or activation of coagulation. These data provide considerable encouragement for the development of new P2Y1receptor antagonists. Nevertheless, the properties of MRS‐2179 indicate that new compounds should be optimized in order to increase the half‐life of the moleculein vivoand its selectivity and potency at the P2Y1receptor. Further directions include the synthesis of molecules with modifications of the nucleotide structure which replace the fragile moiety by a stable bond and should lead to a non‐hydrolysable structure. In conclusion, P2Y1antagonists have been shown to be efficient antithrombotic agents. MRS‐2179 is the first P2Y1antagonist with antithrombotic action. Its effectiveness demonstrates that the P2Y1receptor is a potentially promising target for drugs designed to treat thrombotic syndromes.
Bucillamine: A Potent Thiol Donor with Multiple Clinical Applications
Authors: Horwitz Lawrence D.
Published: August 2010

Bucillamine has potential to attenuate or prevent damage during myocardial infarction, cardiac surgery and organ transplantation. Bucillamine, a cysteine derivative that contains two donatable thiol groups, is capable of replenishing the thiol group in glutathione, thereby reactivating this endogenous defense against oxidant injury. Bucillamine rapidly enters cells by the same mechanism that normally transports the amino acid cysteine. Bucillamine is a more potent thiol donor than other cysteine derivatives: approximately 16‐fold more potent than N‐acetylcysteine (Mucomyst®) in vivo. In addition bucillamine appears to have additional anti‐inflammatory effects unrelated to its antioxidant effect. Oral bucillamine is used clinically in Asia for treatment of rheumatoid arthritis. There is a strong preclinical evidence that parenteral infusion of this agent is efficacious in acute settings characterized by inflammation and oxidative stress. In an investigator‐blinded, rigorous intact dog model, consisting of 90 min of coronary artery occlusion and 48 h of reperfusion, bucillamine, given i.v. during the first 3 h of reperfusion, substantially reduced myocardial infarct size. Livers exposed to 24 h of cold ischemia were markedly protected by bucillamine in several transplantation models. In Phase I human studies in normal volunteers, bucillamine at doses up to 25 mg/kg/h i.v. for 3 h elicited no serious toxicity. On the basis of pharmacokinetic analyses of blood levels during these studies it was concluded that bucillamine, infused at i.v. doses ≥10 mg/kg/h for 3 h to humans could be expected to be therapeutically effective in myocardial infarction, organ transplantation and other acute inflammatory syndromes.
Calcium Antagonists in Patients with Type 2 Diabetes and Hypertension
Authors: McFarlane Samy I. , Farag Amal , Sowers James
Published: August 2010

Hypertension is twice as common in patients with diabetes compared to those without diabetes. It accounts for up to 75% of cardiovascular disease risk leading to the substantial increase in morbidity and mortality. Control of blood pressure in people with diabetes has been shown in randomized controlled trials to decrease cardiovascular risk and improve outcome especially in preventing stroke.

A target blood pressure goal of <130/80 mm Hg is currently recommended for patients with diabetes. However, less than 1/3 of these patients achieve such a goal. This is in part due to the inherent difficulty in controlling blood pressure in these patients where hypertension is usually associated with increased salt sensitivity, volume expansion and isolated systolic hypertension. Therefore, patients with diabetes usually require multiple medications for optimal blood pressure control. Calcium channel antagonists have been shown in large clinical trials to be both safe and effective in controlling blood pressure in diabetic patients and will continue to play a major role in the management of hypertension in this population, particularly in the combination therapy that these patients usually require.
Pharmacology of KB‐R7943: A Na+–Ca2+exchange inhibitor
Authors: Amran Md. Shah , Homma Nobuo , Hashimoto Keitaro
Published: August 2010

The Na+–Ca2+exchange (NCX) system plays a pivotal role in regulating intracellular Ca2+concentration in cardiomyocytes, neuronal cells, kidney and a variety of other cells. It performs a particularly important function in regulating cardiac contractility and electrical activity. One of the leading NCX inhibitors is KB‐R9743 (KBR) that appears to exhibit selectivity for Ca2+‐influx‐mode NCX activity (reverse mode of NCX). In this article we reviewed pharmacology of KBR and provide a brief summary of studies with other NCX inhibitors, such as SEA0400 (SEA) and SN‐6 (SN). Potential clinical usefulness of KBR and other NCX inhibitors is still controversial but the reviewed findings may be helpful in designing more selective and clinically useful NCX inhibitors for the treatment of cardiac, neuronal and kidney diseases.
Phosphomannopentaose Sulfate (PI‐88): Heparan Sulfate Mimetic with Clinical Potential in Multiple Vascular Pathologies
Authors: Khachigian Levon M. , Parish Christopher R.
Published: August 2010

The sulfated oligosaccharide PI‐88 is a potent antiangiogenic, antitumor and anti‐metastatic agent derived from yeast. It is primarily composed of sulfated phosphomannopentaose and phosphomannotetraose oligosaccharide units and is presently under evaluation in Phase II clinical trials for anticancer efficacy. PI‐88 inhibits the heparan sulfate‐degrading enzyme heparanase, exhibits antiangiogenic activity and has anticoagulant properties mediated by heparin cofactor II. It also inhibits vascular smooth muscle cell proliferation, kinase signalling and arterial intimal thickening following balloon injury. Many heparan sulfate‐binding growth factors require heparan sulfate as a co‐receptor in order to effectively deliver growth signals to cells. Thus, the antiangiogenic and antirestenotic activity of PI‐88 may be at least partially due to this highly sulfated oligosaccharide competing with the interaction of growth factors, such as FGF‐2 and VEGF, with cell surface heparan sulfate. This heparan sulfate mimetic has, therefore, multiple functions and therapeutic potential in a variety of vascular disorders.
Agmatine Signaling: Odds and Threads
Authors: Berkels Reinhard , Taubert Dirk , Gründemann Dirk , Schömig Edgar
Published: August 2010

Agmatine is a metabolite of L‐arginine. It is formed by the decarboxylation of L‐arginine via arginine decarboxylase in bacteria, plants and mammals. It is becoming clear that it has multiple physiological functions as a potential transmitter. Agmatine binds to α2‐adrenoceptors and to imidazoline binding sites. It blocks NMDA receptors and other ligand‐gated cation channels. It also inhibits nitric oxide synthase, induces release of peptide hormones and antizyme and plays a role during cell proliferation by interacting with the generation and transport of polyamines. Although the precise function of endogenously released agmatine is presently still unclear, this review will summarize several aspects concerning the biological function of agmatine.
Therapeutic Potentials of Sarpogrelate in Cardiovascular Disease*
Authors: Saini Harjot K. , Takeda Nobuakira , Goyal Ramesh K. , Kumamoto Hideo , Arneja Amarjit S. , Dhalla Naranjan S.
Published: August 2010

In view of the pivotal role of serotonin (5‐HT) in a wide variety of cardiovascular disorders, extensive effort has been made to develop different types of 5‐HT receptor antagonists for therapeutic use. On the basis of experimental studies, this article is focused on the potentials of sarpogrelate, a specific 5‐HT2Areceptor antagonist as an antiplatelet, antithrombotic, antiatherosclerotic and antianginal agent. The major effects of sarpogrelate are due to the inhibition of 5‐HT‐induced platelet aggregation and smooth muscle cell proliferation. This agent was found to attenuate the 5‐HT‐mediated increase in intracellular Ca2+and ischemia‐reperfusion injury in the heart. Sarpogrelate has been found to have beneficial effects in peripheral vascular disease, restenosis after coronary stenting, pulmonary hypertension, acute and chronic myocardial infarction.
Low‐Molecular‐Weight Heparins in Thrombosis and Cancer: Emerging Links
Authors: Mousa Shaker A.
Published: August 2010

Heparin as well as low‐molecular‐weight heparins (LMWHs) have polypharmacological actions at various levels. Earlier studies focused on the plasma anti‐Xa and anti‐IIa pharmacodynamics (PD) for the different LMWHs. Other important PD parameters for heparin and LMWHs might explain the diverse clinical impacts of this class of agents in thrombosis and beyond: the release of the vascular tissue factor pathway inhibitor (TFPI), inhibition of key matrix‐degrading enzymes, and other mechanisms. There is much evidence for the key role of LMWHs in hypercoagulation in thrombosis and cancer, angiogenesis, and inflammatory disorders. Many cancer patients reportedly have a hypercoaguable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Studies have demonstrated that unfractionated heparin (UFH) or its low molecular weight fractions interfere with various processes involved in tumor growth and metastasis. Clinical trials have suggested a clinically relevant and improved efficacy of LMWHs, as compared to UFH, on the survival of cancer patients with deep vein thrombosis. Our laboratory has demonstrated a significant role for LMWHs and for LMWH‐releasable TFPI on the regulation of angiogenesis, tumor growth, and tumor metastasis; we have also seen potent inhibition of matrix‐degrading enzymes by LMWHs but not by TFPI. The antiangiogenesis effect of LMWHs or non‐anticoagulant LMWH derivatives was shown to be reversed by anti‐TFPI. Thus, modulation of tissue factor/Vila noncoagulant activities by LMWH‐releasable TFPI and the inhibitory effects on matrix‐degrading enzymes beside the anticoagulant efficacy have provided an expanded clinical utility for LMWHs in angiogenesis‐associated disorders, including human tumor growth and metastasis.
Cardiovascular Protective Effects of Resveratrol
Authors: Bradamante Silvia , Barenghi Livia , Villa Alessandro
Published: August 2010

Resveratrol (3,4′,5‐trihydroxy‐trans‐stilbene), a phytoalexin found in grape skins, peanuts, and red wine, has been reported to have a wide range of biological and pharmacological properties. It has been speculated that at low doses (such as consumed in the common diet) resveratrol may have cardioprotective activity. In this article we describe recent in vitro and in vivo studies in animal models. The results of these studies suggest that resveratrol modulates vascular cell function, inhibits LDL oxidation, suppresses platelet aggregation and reduces myocardial damage during ischemia‐reperfusion. Although the reported biological data indicate that resveratrol is a highly promising cardiovascular protective agent, more studies are needed to establish its bioavailability and in vivo cardioprotective effects, particularly in humans.
Pharmacological and Clinical Studies with Temocapril, an Angiotensin Converting Enzyme Inhibitor that is Excreted in the Bile
Authors: Yasunari Kenichi , Maeda Kensaku , Nakamura Munehiro , Watanabe Takanori , Yoshikawa Junichi , Asada Akira
Published: August 2010

Temocapril is an angiotensin converting enzyme inhibitor (ACEI), a prodrug with a thiazepine ring. Its active form, temocaprilat, is slightly more potent than enalaprilat in inhibiting ACE isolated from rabbit lung. The inhibitory potency of temocaprilat on isolated rat aorta is 3 times that of enalaprilat. Temocapril is excreted in the bile and urine and can be used in patients with renal insufficiency. It reduces blood pressure without causing any significant change in heart rate or cardiac output. Temocapril has been reported to improve endothelial dysfunction in vitro by suppressing increased oxidative stress. In vivo it improves reactive hyperemia in patients with essential hypertension. It has been reported to prevent coronary vascular remodeling in vivo by suppressing local ACE and increased oxidative stress. In humans temocapril has been found to improve insulin resistance partly by increasing adiponectin levels. Cardiac remodeling was improved by temocapril not only in experiment animals but also in humans. It improves renal function and decreases urinary albumin excretion in diabetics as well as in hypertensive patients. Temocapril is currently marketed only in Japan. Considering its beneficial effects and unique pharmaco‐kinetics, temocapril, is likely to be introduced in other countries as well.
Clinical and Experimental Aspects of Olmesartan Medoxomil, a New Angiotensin II Receptor Antagonist
Authors: Yoshida Kazunori , Kohzuki Masahiro
Published: August 2010

Olmesartan medoxomil is a new orally active angiotensin II (Ang II) type 1 receptor antagonist. It is a prodrug and is rapidly de‐esterified during absorption to form olmesartan, the active metabolite. Olmesartan is a potent, competitive and selective Ang II type 1 receptor antagonist. Olmesartan is not metabolized by the cytochrome P‐450 and has a dual route of elimination, by kidneys and liver.

In patients with essential hypertension olmesartan medoxomil administered once daily at doses of 10–80 mg dose‐dependently reduced diastolic blood pressure (DBP). Troughto‐peak ratios for both DBP and systolic blood pressure (SBP) were above 50%. At the recommended once‐daily starting doses, olmesartan medoxomil (20 mg) was more effective than losartan (50 mg), valsartan (80 mg) or irbesartan (150 mg) in reducing cuff DBP in patients with essential hypertension. The results of cuff SBP and mean 24‐h DBP and SBP were similar to those of cuff DBP measurement. In mild‐to‐moderate hypertensive patients the recommended starting dose of olmesartan medoxomil was as effective as that of amlodipine besylate (5 mg/day) in reducing both cuff and 24‐h blood pressure. In lowering DBP olmesartan medoxomil, at 10–20 mg/day, was as effective as atenolol at 50–100 mg/day. In mild‐to‐moderate hypertensive patients, olmesartan medoxomil, at 5–20 mg once daily, was more effective than captopril at 12.5–50 mg twice daily. At 20–40 mg once daily olmesartan medoxomil was as effective as felodipine, at 5–10 mg once daily. Olmesartan medoxomil has minimal adverse effects with no clinically important drug interactions.

Animal studies have shown that olmesartan medoxomil provides a wide range of organ protection. Olmesartan medoxomil ameliorated atherosclerosis in hyperlipidemic animals and ameliorated cardiac remodeling and improved survival in rats with myocardial infarction. Olmesartan medoxomil has renoprotective effects in a remnant kidney model and type 2 diabetes models. Future investigation should reveal whether these beneficial effects of olmesartan medoxomil are applicable to human diseases.
Therapeutic Potential of Monteplase in Acute Myocardial Infarction as a Powerful Thrombolytic Agent for Pretreatment of Coronary Intervention
Authors: Inoue Teruo , Nishiki Ryoichi , Kageyama Manabu , Node Koichi
Published: August 2010

Thrombolysis with conventional thrombolytic agents followed by percutaneous coronary intervention (PCI) had no impact on the treatment of acute myocardial infarction (AMI). However, the development of mutant type plasminogen activator (mt‐PA) has prompted us to reassess the combination of thrombolysis and PCI. Monteplase (Eisai, Co. Ltd., Tokyo, Japan) is a newly developed mt‐PA that can be administrated as a single intravenous bolus injection. We initiated a clinical trial [Combining Monteplase with Angioplasty (COMA)] to evaluate the effectiveness of monteplase followed by PCI. The AMI patients were randomly assigned to receive PCI following pretreatment with a single bolus intravenous injection of monteplase or direct PCI without monteplase. The initial coronary angiography prior to PCI showed that 36.2% of patients in the monteplase group achieved Thrombolysis in Myocardial Infarction (TIMI) 3 flow in the infarct‐related artery, compared with in only 7.9% of patients in the direct PCI group (P < 0.0001). During 24 months following PCI, major cardiac events occurred in 27.7% of patients in the monteplase + PCI group, and in 46.7% of patients in the direct PCI group without monteplase (P < 0.05). Thus, the ideal strategy for the treatment of AMI is the administration of monteplase upon arrival at a community hospital with a prompt transfer to a tertiary center for PCI.
Serofendic Acid, a Substance Extracted from Fetal Calf Serum, as a Novel Drug for Cardioprotection
Authors: Akao Masaharu , Takeda Toshihiro , Kita Toru , Kume Toshiaki , Akaike Akinori
Published: August 2010

We previously identified a novel endogenous substance, serofendic acid, from a lipophilic extract of fetal calf serum. The compound, a low‐molecular‐weight sulfur‐containing atisane‐type diterpenoid, exhibited potent protective action against neurotoxicity induced by glutamate, nitric oxide, and oxidant stress. We investigated whether this substance has a cardioprotective effect. Primary cultures of neonatal rat cardiac myocytes were exposed to oxidant stress (H2O2) to induce cell death. Pretreatment with serofendic acid significantly suppressed cell death induced by H2O2, and the cytoprotective effect was closely associated with the preservation of mitochondrial function. Serofendic acid inhibited H2O2‐induced loss of mitochondrial membrane potential in a concentration‐dependent manner (with saturation by 100 μM), by attenuating matrix calcium overload and intracellular accumulation of reactive oxygen species. The protective effect of serofendic acid was comparable to that of a mitochondrial ATP‐sensitive potassium (mitoKATP) channel opener, diazoxide. Furthermore, mitoKATP channel blocker, 5‐hydroxydecanoate, abolished the protective effect of serofendic acid. Serofendic acid and diazoxide, administered together, at 100 μM each, had no additive effects. Thus, serofendic acid inhibited the oxidant‐induced mitochondrial death pathway, presumably through activation of the mitoKATP channel. In conclusion, serofendic acid appears to protect cardiac myocytes from oxidant‐induced cell death by preserving the functional integrity of mitochondria. Our findings suggest that serofendic acid may represent a novel candidate for cardioprotective therapy in ischemia/reperfusion injury.
The Role of Urate and Xanthine Oxidase Inhibitors in Cardiovascular Disease
Authors: George Jacob , Struthers Allan D.
Published: August 2010

Many studies have shown a strong correlation between urate levels and cardiovascular disease. The formation of urate is complex as the same enzyme that produces urate, xanthine oxidase (XO) also catalyzes the formation of reactive oxygen species (ROS). There is some evidence that the urate molecule has free radical scavenging properties in vitro and acute infusions of urate improve endothelial function in at‐risk populations. High levels of ROS are clearly linked to worse outcome in a variety of conditions. Allopurinol has been the archetypal XO inhibitor for over 40 years. Small studies have demonstrated its beneficial effects, mainly in heart failure but also in a variety of other cohorts of patients with cardiovascular risk. It is a safe agent, provided suitable patients are chosen and monitored carefully. Newer promising agents like oxypurinol have not shown the expected benefits in larger multicentered studies. This review looks at the biology of urate, its role in cardiovascular disease, the possible mechanisms by which XO inhibitors exert their beneficial effect on endothelial dysfunction, and examines the possible causes for the failure of newer agents to live up to expectations.
Inhibition of Acyl‐CoA Cholesterol Acyltransferase by F12511 (Eflucimibe): Could it be a New Antiatherosclerotic Therapeutic?
Authors: López‐Farré Antonio José , Sacristán Daniel , Zamorano‐León José J. , San‐Martín Nuria , Macaya Carlos
Published: August 2010

Lipid‐lowering strategies, particularly with statins, have been extremely useful in the prevention of cardiovascular disease. However, many patients who receive statin monotherapy do not achieve the desired cardiovascular benefits. Accumulation of cholesteryl esters within macrophages constitutes the hallmark of foam cells during atherogenesis. The action of acyl‐coenzyme A (CoA): cholesterol acyltransferase (ACAT) leads to formation of cholesterol esters. There are two different ACAT isoforms: ACAT1 and ACAT2. A considerable interest to develop ACAT inhibitors has been emerging. This review has been focused on the current knowledge about a new ACAT inhibitor, F12511 or eflucimibe, and more particularly on its antiatherosclerotic properties.
Tolerability of High Doses of Lercanidipine versus High Doses of Other Dihydropyridines in Daily Clinical Practice: The TOLERANCE Study
Authors: Barrios Vivencio , Escobar Carlos , De La Figuera Mariano , Llisterri Jose Luis , Honorato Jesus , Segura Julián , Calderón Alberto
Published: August 2010

The TOLERANCE study was aimed to compare the tolerability of high doses of lercanidipine (20 mg) with that of other frequently used dihydropyridines (amlodipine 10 mg/nifedipine GITS 60 mg) in the treatment of essential hypertension in daily clinical practice. It was an observational, transversal, multicentre study performed in a Primary Care Setting. A total of 650 evaluable patients with essential hypertension and age ≥ 18 years were included. They had been treated with high doses of lercanidipine (n= 446) or amlodipine/nifedipine GITS (n= 204) during at least 1 month and previously with low doses (10 mg, 5 mg, and 30 mg, respectively) of the same drugs. The main objective was to compare the rates of vasodilation‐related adverse events between both groups. Rates of signs and symptoms related to vasodilation were significantly higher (P < 0.001) in the amlodipine/nifedipine GITS group (76.8%, CI 95%[70.7; 82.9]) than in lercanidipine group (60.8%, [56.1;65.5]). Blood pressure control (< 140/90 mmHg or <130/80 for diabetics) and type of concomitant antihypertensive medications were similar in both groups. Treatment compliance was good (around 93%) and fairly comparable in both groups. Most adverse events with lercanidipine were mild (74.5% vs. 64% in amlodipine/nifedipine GITS group, P= 0.035) whereas severe adverse event rates did not differ significantly between groups (2.8% vs. 3.6%). In conclusion, treatment with lercanidipine at high doses is associated with a lower rate of adverse events related to vasodilation compared to high doses of amlodipine or nifedipine GITS in clinical practice.
Sanguinarine
Authors: Mackraj I. , Govender Thirumala , Gathiram Prem
Published: August 2010

Sanguinarine is an alkaloid found in many medicinal plants. It has diverse biological activities, including modulation of nuclear factor‐κB and of several enzymes. It is also known to induce apoptosis, perturb microtubules, and to have antimicrobial effects. This article reviews its cardiovascular properties, including hypotensive, antiplatelet, and positive inotropic effects. Its pharmacokinetics, and toxicology, including its carcinogenic potential, are also discussed. Further pharmacological and toxicological studies with sanguinarine are needed before its therapeutic use can be considered.
Implementing a program to improve compliance with neonatal intensive care unit transfusion guidelines was accompanied by a reduction in transfusion rate: a pre‐post analysis within a multihospital health care system
Authors: Baer Vickie L. , Henry Erick , Lambert Diane K. , Stoddard Ronald A. , Wiedmeier Susan E. , Eggert Larry D. , Ilstrup Sarah , Christensen Robert D.
Published: August 2010

BACKGROUND: We previously reported that in the year 2006, approximately 35% of the transfusions administered in the Intermountain Healthcare neonatal intensive care units (NICU) were noncompliant with our transfusion guidelines. In January 2009 we instituted an electronic NICU transfusion ordering and monitoring system as part of a new program to improve compliance with transfusion guidelines.

STUDY DESIGN AND METHODS: In the four largest NICUs of Intermountain Healthcare, we performed a pre‐post analysis of compliance with transfusion guidelines and transfusion usage.

RESULTS: After beginning the new transfusion compliance program all four NICUs had an increase in compliance from 65% to 90%. Accompanying the improved compliance, all four NICUs had a reduction in transfusions administered. Specifically, compared with 2007 and 2008, there were 984 fewer NICU transfusions given in 2009. This included 554 fewer red blood cell (RBC) transfusions, 174 fewer platelet transfusions, and 256 fewer frozen plasma infusions. We calculate that in 2009, a total of 200 NICU patients who in previous years would have received one or more transfusions instead received none. Applying specific Intermountain Healthcare billing data to the observed transfusion reductions, this new program resulted in an annual decrease of $780,074 in blood bank charges (blood administration charges were not included). During the 3‐year period, January 2007 through December 2009, we detected no change in NICU demographics, major morbidities, length of hospital stay, or mortality rate.

CONCLUSION: Implementing a systemwide NICU program to improve compliance with already‐established transfusion guidelines increased compliance from 65% to 90%. Improved compliance with transfusion guidelines was accompanied by a significant reduction in transfusions given, with no increase in NICU length of stay or mortality rate.
Made to Stick: Why Some Ideas Survive and Others Die by Chip Heath and Dan Heath
Authors: Castellion George
Published: August 2010

Books reviewed in this issue:

Made to Stick: Why Some Ideas Survive and Others Die

Think, Play, Do: Technology, Innovation, and Organization

Results without Authority: Controlling a Project When the Team Doesn't Report to You

The Pursuit of New Product Development: The Business Development Process
The Relationship Between Sinoatrial Conduction Time and Sinus Cycle Length Revisited
Authors: REIFFEL JAMES A. , BIGGER J. THOMAS
Published: August 2010

In 1974 we reported an inverse relationship between sinoatrial conduction time (SACT) and sinus cycle length (SCL) during sinus arrhythmia utilizing the indirect atrial premature stimulation technique for estimating SACT, However, this behavior seemed anomalous try analogy with the AV node. Subsequent to 1974, methodological considerations about and limitations of the indirect techniques for estimating SACT became apparent, making us question our former impression. When the capability to directly record sinus node electrograms was developed and established in the 1980s, we had the means to reevaluate the SACT/SCL relationship. This report presents our findings in 40 patients: the SACT/SCL relationship is direct, not inverse. Moreover, we also show that during the phasic fluctuations of sinus arrhythmia, the P‐P alterations are initiated more frequently by changes in sinoatrial conduction time than by changes in sinus cycle length.
Induction of Life‐threatening Ventricular Tachyarrhythmias by Serial Inappropriate AICD‐pulsing in the Hyperthyroid State
Authors: KALTENBRUNNER WILHELM , FROHNER KLAUS , STEINBACH KONRAD
Published: August 2010

A patient treated with the automatic implantable defibrillator exhibited serial inappropriate shacks during amiodarone‐induced hyperthyroidism. This case illustrates the elective effectiveness of the AICD in the termination of ventricular tachyarrhythmias as well as its potency to induce them by serial erroneous interventions on supraventricular tachyarrhythmias so that external life‐saving efforts are needed.
Muscle Stimulation Caused by a Pacemaker Current Leakage: the Role of the Insulation Failure of a Polyurethane Coating
Authors: CHAUVIN MICHEL , BRECHENMACHER CLAUDE
Published: August 2010

Pectoral or deltoid muscle stimulation generally has been reported as secondary to lead insulation defects, anodal stimulation from the can or current leaks. In this report, a case of muscle stimulation related to partial loss of the polyurethane covering of the pulse generator is described.
Unexpected Discharge from an Implanted Automatic Defibrillator
Authors: CRITELLI GIUSEPPE , GRECO CESARE , AMBROSINI MARIA , SINATRA RICCARDO , MARINO BENEDETTO , REALE ATTILIO
Published: August 2010

The occurrence of inappropriate discharge from an implanted cardioverter‐defibrillator is reported. The device was triggered by an episode of induced nonsustained ventricular tachycardia, and the shock was delivered 10 sec after spontaneous termination of the arrhythmia.

This observation demonstrates that unexpected discharges from an implanted cardiaverter/defibrillator can occur while the patient is asymptomatic. In order to avoid such an adverse effect, improvement of the detection system of the device is advisable.
Effect of Procainamide, Mexiletine, and Propranolol on Ventricular Activation Time Recorded at Cardiac Mapping in Chronic Canine Myocardial Infarction
Authors: DENNISS A. ROBERT , ROSS DAVID L. , WAYWOOD JUDITH A. , COOPER MARK J. , UTHER JOHN B.
Published: August 2010

Delayed potentials detected during sinus rhythm appear to be markers for ventricular tachyarrhyth mias associated with ch ronic myocardial infarction. This study investigated whether intravenous Class I and Class II antiarrhythmic drugs could affect delayed potentials detected at cardiac mapping in dogs studied 1–2 weeks after anterior myocardial infarction.

Procainamide at therapeutic serum levels (17–34 μmol/L) caused prolongation of delayed potentials (first degree block), the mean change in duration of ventricular activation being + 19.4 ± 5.0 msec (n = 4, p <0.05). At serum levels above the therapeutic range, procainamide caused first degree block in delayed potentials in three of six animals tested (50%), second degree block (Wenckebach, 2:1 or 3:1 block) in another two animals, and third degree block (complete abolition of delayed potentials) in the remaining animal.

Mexiletine at therapeutic serum levels (3.5–9.0 μmol/L, caused no significant change in delayed potential duration (+3.1 ± 5.7 msec, n = 4). At serum levels above the therapeutic range, first degree block occurred in four of five animals tested (80%), there being no change in the fifth animal. After propranolol (0.2 mg/kg), there was no significant change in delayed potential duration (−2.5 ± 2.5 msec, n = 4).

In conclusion: (1) at standard doses, mexiletine and propranolol have no effect on delayed potentials, but procainamide causes first degree block; (2) at serum levels above the therapeutic range, mexiletine typically causes first degree block, while procainamide causes either first degree or high grade block; (3) ventricular tachyarrhythmias may still be inducible after drugs if delayed potentials persist unchanged or with first degree block.
Comparison of Electrophysiological Effects of Quinidine and Hydroquinidine in Anesthetized Dogs
Authors: DAVY J.M. , WEISSENBURGER J. , ERTZBISCHOFF O. , POIRIER J.M. , BIOUR M. , GAYET J.L. , CHEYMOU G. , MOTTE G.
Published: August 2010

Cross‐over infusions of quinidine (Q) and hydrvcjuinidine (HQ) ivere perfonned at 8‐day intenmls in 12 pentobarhital‐anesthetized dogs. Three increasing doses were administered each time and the mean plasma concentrations (mg/L) were 2.8, 3.7, and 4.9 with Q and 1.2, 1.9, and 2.8 with HQ. Four electrophysiological studies were perfonned at baseline and after each dose. Both drugs exhibited Class IA effects without qualitative differences: sinus automaticiti/ and nodal conduction parameters were increased only Zi'ith the highest doses of drugs; His Purkinje (HV) and intraventricular (QRS) conduction times were increased consistently but only slightly and, for example, mean values of HV increased from 28 to 33 msec after Q and 30 to 34 msec after HQ. The largest increases were seen for QT interval (227 to 294 msec after Q and 237 to 292 msec after HQ), ventricular effective refractory periods (158 to 182 msec after Q and 161 to 185 msec after HQ), and atrial refractory periods (124 to 178 msec after Q and 120 to 172 msec after HQ). For the later parameter, hydroquinidine appeared significantly more potent with a potenaj ratio relative to quinidine estimated at 1.9 and 2.9 respectively for effective and functional atrial refractory periods. If confirmed, this higher potency of hydroquinidine versus quinidine should be clinicalli/ considered, for example, during drug plasma levels monitoring.
Prognosis in Patients with Left Ventricular Dysfunction and Ventricular Tachycardia Following Programmed Ventricular Stimulation
Authors: FLAKER GREG C. , KROL RYSZARD B. , ATAY A. ERSIN , MUSICK WILLIAM , ALPERT MARTIN A. , ANDERSON SHARON
Published: August 2010

We performed programmed ventricular stimulation on 69 patients with left ventricular ejection dysfunction (ejection fraction < 50%) and clinically recognized ventricular tachycardia including 28 patients with sustained ventricular tachycardia and 41 patients with nonsustained ventricular tachycardia. An inducible arrhythmia (> 6 beats ventricular tachycardia) was found in 74% of patients. Patients with clinically sustained arrhythmias were frequently inducible (89%) with a high incidence of inducible monomorphic ventricular tachycardia (82%). Patients with clinically nonsustained ventricular tachycardia had a lower rate of inducibility (63%) including a high incidence of inducible polymorphic ventricular tachycardia (27%). Inducible patients with left ventricular dysfunction and ventricular tachycardia had a low incidence of electrophysiologically demonstrated effective drug therapy (16%). However, if an effective drug was found, the prognosis was good. Empirical drug therapy was associated with a poor prognosis in inducible and noninducible patients. Finally, an unfavorable prognosis was associated with a clinically sustained arrhythmia, a lower ejection fraction, and the presence of a left ventricular aneurysm. An inducible arrhythmia did not predict an unfavorable course. Indeed, patients with noninducible ventricular tachycardia in this group of patients were still at risk for sudden cardiac death.
Prolonged Asymptomatic Torsade de Pointes
Authors: SCHIEMAN GREGORY , BLACKY A. ROBERT , NICOD PASCAL H. , DITTRICH HOWARD C.
Published: August 2010

Torsade de pointer is often associated with syncope, particularly when prolonged. We report a cane of prolonged asymptomatic torsade de pointes in a 68‐year‐old woman being treated with quinidine gluconate for paroxysmal atrial fibrillation. Ambulatory monitoring obtained one week after an increase in the daily qninidine dosage demonstrated one minute of polymorphous ventricular tachycardia. The patient remained entirely asymptomatic throughout the time of the arrhythmia. Therefore, a lack of symptoms in patients at risk for torsade de pointes may not exclude the presence of this arrhythmia.
The Best Rate‐Responsive Pacemaker: Perspective on Ideal Rate‐Responsive Pacing
Authors: ROSSI PAOLO
Published: August 2010

The preferred pacing therapy for symptomatic bradycardia incorporates rate responsiveness. The hemodynamic benefits of rate responsiveness have been established. Factors such as type of sensors, reliability, and ease of utilization play a role in the selection of the best‐suited rate‐responsive system for the individual patient.
Part IV: Class II, Class III, and Class IV Antiarrhythmic Drugs, Comparative Efficacy of Drugs, and Effect of Drugs on Mortality — A Review of Their Pharmaco kinetics, Efficacy, and Toxicity*
Authors: SALERNO DAVID M.
Published: August 2010

Part IV: Class II, Class III, and Class IV antiarrhythmic drugs, comparative efficacy of drugs, and the effect of drugs on mortality — review of their pharmacokinetics, efficacy, and toxicity. This part reviews the Class II antiarrhythmic agents that share the property of beta adrenergic antagonism, but include several drugs with other unique features. Also reviewed are the Class III agents, which prolong the action potential duration, with a focus on amiodarone. The Class IV agents, which antagonize the calcium channel, are reviewed. Finally, this part reviews the comparative efficacy of antiarrhythmic agents for treatment of ventricular ectopic depolarizations and examines their effect on mortality.
Immediate Termination of Fibrillation at 50% Probability of Overall Success Correlates with Defibrillation Dose‐Response Curve Width
Authors: TOVAR OSCAR H. , SNYDER DAVID E. , JONES JANICE L.
Published: August 2010

Introduction: Issues in transthoracic defibrillation, including waveform shape, fixed versus escalating dose protocol, and low‐ versus high‐energy shocks, can be addressed by examining the defibrillation dose‐response curve. We tested the hypothesis that, for commonly used defibrillation waveforms, the steepness of the overall defibrillation dose‐response curve, measured as normalized curve width, correlates with the probability of a successful defibrillation being immediate at the shock intensity producing 50% success.

Methods and Results: We used 16 isolated rabbit hearts to determine probability of overall success as a function of shock intensity and probability that a successful defibrillation is immediate rather than progressive (followed by several extrasystoles) at the shock intensity producing 50% overall defibrillation success. Two waveform pairs were tested—a monophasic damped sine versus a biphasic truncated exponential waveform commonly used for transthoracic defibrillation, and a monophasic/biphasic truncated exponential waveform pair similar to those used in internal cardioverter defibrillators. There was a close correlation between probability of a successful defibrillation being immediate at I50 and normalized curve width for the defibrillation dose‐response curve.

Conclusion: Our findings suggest that a high probability of successful defibrillation being immediate at low shock intensities is correlated with a narrow normalized curve width for the defibrillation dose‐response curve.
Paced Electrogram Fractionation Analysis of Arrhythmogenic Tendency in ΔKPQ Scn5a Mice
Authors: HEAD CATHERINE E. , BALASUBRAMANIAM RICHARD , THOMAS GLYN , GODDARD CATHARINE A. , LEI MING , COLLEDGE WILLIAM H. , GRACE ANDREW A. , HUANG CHRISTOPHER L‐H.
Published: August 2010

Introduction: Gain‐of‐function mutations within Scn5a, including the ΔKPQ 1505‐1507 deletion in the inactivation domain compromising myocardial repolarization, are implicated in human long QT 3 syndrome (LQT3), associated with ventricular arrhythmogenesis and sudden death.

Methods and Results: Patch clamp studies on isolated ventricular Scn5a+/Δ myocytes from ΔKPQ mice produced by homologous recombination in embryonic stem (ES) cells confirmed such altered electrophysiological properties of the mutant channel. Programmed electrical stimulation (PES) with decremental pacing from the basal right ventricular epicardial surface and paced electrogram fractionation analysis (PEFA) of electrograms recorded from the basal left ventricular epicardial surface of Langendorff‐perfused whole heart preparations demonstrated ventricular tachycardia (VT) in 8 of 9 Scn5a+/Δ mutant (but no Scn5a+/+ (wild‐type (WT)) controls; n = 17), with increased electrogram durations (EGD) and more dispersed conduction curves. Isoproterenol (100 nM) was without effect on tachycardic Scn5a+/Δ hearts (n = 9) yet propranolol (1 μM) prevented VT in all isoproterenol‐infused WT control (n = 4) but no Scn5a+/Δ hearts (n = 4). Furthermore propranolol itself increased EGD and dispersion in Scn5a+/Δ hearts. In contrast, mexiletine (10 μM) suppressed VTs in 4 of 5 Scn5a+/Δ hearts without altering EGD or dispersion.

Conclusion:β‐adrenoreceptor blockade does not confer an antiarrhythmic effect and may even enhance arrhythmogenesis by increasing reentrant substrate in Scn5a+/Δ hearts while mexiletine protects against VT without modifying conduction characteristics. Together these findings permit a scheme where VT in LQT3 is initiated by triggered mechanisms but propagated by reentry.
Comparison Between Anatomical and Integrated Approaches to Atrial Fibrillation Ablation: Adjunctive Role of Electrical Pulmonary Vein Disconnection
Authors: MANTOVAN ROBERTO , VERLATO ROBERTO , CALZOLARI VITTORIO , BACCILLIERI STELLA , DE LEO ALESSANDRO , TURRINI PIETRO , PASTORE GIOVANNI , CROSATO MARTINO , RAMONDO ANGELO , STRITONI PAOLO
Published: August 2010

Introduction: The aim of this study was to compare the outcome of anatomical pulmonary vein (PV) radiofrequency (RF) ablation with that of an integrated approach (anatomical with electrophysiological confirmation of PV disconnection).

Methods: Sixty consecutive patients affected by drug‐refractory paroxysmal (39), persistent (13), and permanent (8) atrial fibrillation (AF) were assigned to an anatomical (group A: 30 patients; 25 male, 5 female, mean age: 55 ± 7 years) or integrated approach (group B: 30 patients; 26 male, 4 female, mean age: 52 ± 9 years). In all cases, RF ablation was performed by means of the Carto system in order to anatomically create circumferential lines around PVs. In group B, the persistence of PV potentials was then assessed with a multipolar circular catheter. If PV potentials persisted, RF pulses targeting the electrophysiological breakthroughs were delivered to disconnect PVs.

Results: Total procedure duration, fluoroscopy time, and RF delivery time were similar in both groups: 227 ± 43, 50 ± 23, and 43 ± 16 minutes (group A); 232 ± 32, 55 ± 15, and 42 ± 10 minutes (group B), respectively (ns). One asymptomatic PV stenosis and one pericardial effusion occurred in group A and B, respectively. After 15.4 ± 7.4 months, 17 (57%) group A patients and 25 (83%) group B patients were in stable sinus rhythm (P = 0.02) (RR 1.78; 95% CI: 1.7–2.9).

Conclusions: PV ablation by means of an integrated anatomical and electrophysiological approach seems more effective than a purely anatomical RF ablation approach. Electrophysiological confirmation of PV disconnection could be a useful marker of successful RF treatment of AF.
Value of Different Follow‐Up Strategies to Assess the Efficacy of Circumferential Pulmonary Vein Ablation for the Curative Treatment of Atrial Fibrillation
Authors: PIORKOWSKI CHRISTOPHER , KOTTKAMP HANS , TANNER HILDEGARD , KOBZA RICHARD , NIELSEN JENS COSEDIS , ARYA ARASH , HINDRICKS GERHARD
Published: August 2010

Background: The objective of this study was to compare transtelephonic ECG every 2 days and serial 7‐day Holter as two methods of follow‐up after atrial fibrillation (AF) catheter ablation for the judgment of ablation success. Patients with highly symptomatic AF are increasingly treated with catheter ablation. Several methods of follow‐up have been described, and judgment on ablation success often relies on patients' symptoms. However, the optimal follow‐up strategy objectively detecting most of the AF recurrences is yet unclear.

Methods: Thirty patients with highly symptomatic AF were selected for circumferential pulmonary vein ablation. During follow‐up, a transtelephonic ECG was transmitted once every 2 days for half a year. Additionally, a 7‐day Holter was recorded preablation, after ablation, after 3 and 6 months, respectively. With both, procedures symptoms and actual rhythm were correlated thoroughly.

Results: A total of 2,600 transtelephonic ECGs were collected with 216 of them showing AF. 25% of those episodes were asymptomatic. On a Kaplan‐Meier analysis 45% of the patients with paroxysmal AF were still in continuous SR after 6 months. Simulating a follow‐up based on symptomatic recurrences only, that number would have increased to 70%. Using serial 7‐day ECG, 113 Holter with over 18,900 hours of ECG recording were acquired. After 6 months the percentage of patients classified as free from AF was 50%. Of the patients with recurrences, 30–40% were completely asymptomatic. The percentage of asymptomatic AF episodes stepwise increased from 11% prior ablation to 53% 6 months after.

Conclusions: The success rate in terms of freedom from AF was 70% on a symptom‐only‐based follow‐up; using serial 7‐day Holter it decreased to 50% and on transtelephonic monitoring to 45%, respectively. Transtelephonic ECG and serial 7‐day Holter were equally effective to objectively determine long‐term success and to detect asymptomatic patients.