bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and Safety of Sitosterol in the Management of Blood Cholesterol Levels
Authors: Luz Fernandez Maria , Vega‐López Sonia
Published: August 2010

Elevated levels of plasma LDL cholesterol (LDL‐C) represent a major risk factor for cardiovascular disease. Treatments aimed at reducing levels of circulating LDL are regarded, therefore, as cardioprotective. The cholesterol lowering properties of plant sterols have been known for some time and many clinical studies have confirmed the efficacy of sitosterol in lowering plasma LDL‐C concentrations. Animal studies have also shown reductions in LDL by sitosterol. The use of animal models has been useful in facilitating the elucidation of specific mechanisms by which this sterol exerts its hypocholesterolemic action. It is well known that plant sterols compete with cholesterol for space within bile salt micelles in the intestinal lumen thereby reducing cholesterol absorption. The understanding of the function of plant sterols in impeding cholesterol absorption has been clarified with the discovery of the adenosine binding cassette transporters, ABCG5/8, involved in the regulation of sterol absorption and secretion into the enterocyte and hepatocyte. Compared to cholesterol and other sterols, sitosterol is preferentially pumped out to the intestinal lumen by the ABCG5/8 transporters. This selective binding of sitosterol to the transporters ultimately results in significant lowering of plasma cholesterol. However, some findings support the hypothesis that plant sterols might be an additional risk factor for coronary heart disease. From the review of these studies, it is apparent that sitosterol is a useful dietary supplement for the lowering of plasma cholesterol. Nevertheless, this plant sterol should be used with caution in certain individuals who have a higher absorption rate of sitosterol.
Pharmacological Mechanisms Contributing to the Clinical Efficacy of Levosimendan
Authors: Papp Zoltán , Csapó Kálmán , Pollesello Piero , Haikala Heimo , Édes István
Published: August 2010

Acute decompensation of chronic heart failure is a direct life‐threatening situation with short‐term mortality approaching 30%. A number of maladaptive changes are amplified within the cardiovascular system during the progression of chronic heart failure that makes the decompensation phase difficult to handle. Levosimendan is a new Ca2+‐sensitizer for the treatment of acutely decompensated heart failure that has proved to be effective during the decompensation of chronic heart failure and acute myocardial infarction. Levosimendan differs from other cardiotonic agents that are used for acute heart failure in that it utilizes a unique dual mechanism of action: Ca2+‐sensitization through binding to troponin C in the myocardium, and the opening of ATP‐sensitive K+channels in vascular smooth muscle. In general, these mechanisms evoke positive inotropy and vasodilation. Clinical studies suggested long‐term benefits on mortality following short‐term administration. It may, therefore, be inferred that levosimendan has additional effects on the cardiovascular system that are responsible for the prolongation of survival. Results of pre‐clinical and clinical investigations suggest that the combination of levosimendan‐induced cardiac and vascular changes has favorable effects on the coronary, pulmonary and peripheral circulations. Redistribution of the circulating blood offers an improved hemodynamic context for the development of a positive inotropic effect through Ca2+‐sensitization of the contractile filaments, without a proportionate increase in myocardial oxygen consumption or the development of arrhythmias. Activation of ATP‐sensitive K+channels, both on sarcolemma and mitochondria, may protect against myocardial ischemia, and decreased levels of cytokines may prevent the development of further myocardial remodeling. Collectively, these effects of levosimendan shift the disturbed cardiovascular parameters towards normalization, thereby halting the perpetuation of the vicious cycle of heart failure progression. This may contribute to stabilization of the circulation and improved life expectancy of patients with chronic heart failure.
Oleamide: A Fatty Acid Amide Signaling Molecule in the Cardiovascular System?
Authors: Hiley C. Robin , Hoi Pui Man
Published: August 2010

Oleamide (cis‐9,10‐octadecenoamide), a fatty acid primary amide discovered in the cerebrospinal fluid of sleep‐deprived cats, has a variety of actions that give it potential as a signaling molecule, although these actions have not been extensively investigated in the cardiovascular system. The synthetic pathway probably involves synthesis of oleoylglycine and then conversion to oleamide by peptidylglycine α−amidating monooxygenase (PAM); breakdown of oleamide is by fatty acid amide hydrolase (FAAH). Oleamide interacts with voltage‐gated Na+channels and allosterically with GABAAand 5‐HT7receptors as well as having cannabinoid‐like actions. The latter have been suggested to be due to potentiation of the effects of endocannabinoids such as anandamide by inhibiting FAAH‐mediated hydrolysis. This might underlie an “entourage effect” whereby co‐released endogenous nonagonist congeners of endocannabinoids protect the active molecule from hydrolysis by FAAH. However, oleamide has direct agonist actions at CB1cannabinoid receptors and also activates the TRPV1 vanilloid receptor. Other actions include inhibition of gap‐junctional communication, and this might give oleamide a role in myocardial development. Many of these actions are absent from thetransisomer of 9,10‐octadecenoamide. One of the most potent actions of oleamide is vasodilation. In rat small mesenteric artery the response does not involve CB1cannabinoid receptors but another pertussis toxin‐sensitive, G protein–coupled receptor, as yet unidentified. This receptor is sensitive to rimonabant and O‐1918, an antagonist at the putative “abnormal‐cannabidiol” or endothelial “anandamide” receptors. Vasodilation is mediated by endothelium‐derived nitric oxide, endothelium‐dependent hyperpolarization, and also through activation of TRPV1 receptors. A physiological role for oleamide in the heart and circulation has yet to be demonstrated, as has production by cells of the cardiovascular system, but this molecule has a range of actions that could give it considerable modulatory power.
N‐(p‐Amylcinnamoyl)anthranilic Acid (ACA): A Phospholipase A2Inhibitor and TRP Channel Blocker
Authors: Harteneck Christian , Frenzel Henning , Kraft Robert
Published: August 2010

Phospholipase A2enzymes display a superfamily of structurally different enzymes classified in at least nine subfamilies by biochemical and structural properties.N‐(p‐amylcinnamoyl)anthranilic acid commonly referred to as ACA is often used as a broad‐spectrum inhibitor for the characterization of phospholipase A2–mediated pathways. Compounds like ACA and ACA‐like structures have been described to block the receptor‐induced release of arachidonic acid and subsequent signaling cascades in the pancreas and the cardiovascular system. We showed that ACA directly blocks several transient receptor potential (TRP) channels (TRPC6, TRPM2, TRP and TRPM8). With respect to the published data of ACA in the phospholipase A2field, the finding that ACA blocks diacylglycerol‐activated TRP channels is of specific interest as it offers the opportunity to interfere with receptor‐induced calcium‐dependent signaling processes in platelets and vascular smooth muscle cells. Overall,N‐phenylcinnamides, as a new pharmaceutical lead structure, form the first class of synthetic TRP channel blockers and represent a promising start for the development of small organic TRP channel–specific blockers.
Perhexiline
Authors: Ashrafian Houman , Horowitz John D. , Frenneaux Michael P.
Published: August 2010

Perhexiline, 2‐(2,2‐dicyclohexylethyl)piperidine, was originally developed as an anti‐anginal drug in the 1970s. Despite its success, its use diminished due to the occurrence of poorly understood side effects including neurotoxicity and hepatotoxicity in a small proportion of patients. Recently, perhexiline's mechanism of action and the molecular basis of its toxicity have been elucidated. Perhexiline reduces fatty acid metabolism through the inhibition of carnitine palmitoyltransferase, the enzyme responsible for mitochondrial uptake of long‐chain fatty acids. The corresponding shift to greater carbohydrate utilization increases myocardial efficiency (work done per unit oxygen consumption) and this oxygen‐sparing effect explains its antianginal efficacy. Perhexiline's side effects are attributable to high plasma concentrations occurring with standard doses in patients with impaired metabolism due to CYP2D6 mutations. Accordingly, dose modification in these poorly metabolizing patients identified through therapeutic plasma monitoring can eliminate any significant side effects. Herein we detail perhexiline's pharmacology with particular emphasis on its mechanism of action and its side effects. We discuss how therapeutic plasma monitoring has led to perhexiline's safe reintroduction into clinical practice and how recent clinical data attesting to its safety and remarkable efficacy led to a renaissance in its use in both refractory angina and chronic heart failure. Finally, we discuss the application of pharmacogenetics in combination with therapeutic plasma monitoring to potentially broaden perhexiline's use in heart failure, aortic stenosis, and other cardiac conditions.
A Multiple Ion Channel Blocker, NIP‐142, for the Treatment of Atrial Fibrillation
Authors: Tanaka Hikaru , Hashimoto Norio
Published: August 2010

Atrial fibrillation (AF) is one of the most frequent cardiac arrhythmia and is associated with increased cardiovascular morbidity and mortality, and the risk of stroke. Although currently available antiarrhythmic drugs are moderately effective in restoring normal sinus rhythm in patients with AF, excessive delay of ventricular repolarization by these agents may be associated with increased risk of proarrhythmia. Therefore, selective blockers of cardiac ion channel(s) that are exclusively present in the atria are highly desirable.

NIP‐142 is a novel benzopyrane derivative, which blocks potassium, calcium, and sodium channels and shows atrial specific action potential duration prolongation. NIP‐142 preferentially blocks the ultrarapid delayed rectifier potassium current (IKur) and the acetylcholine‐activated potassium current (IKACh). Since IKurand IKAChhave been shown to be expressed more abundantly in the atrial than in the ventricular myocardium, the atrial‐specific repolarization prolonging effect of NIP‐142 is considered to be due to the blockade of these potassium currents. In canine models, NIP‐142 was shown to terminate the microreentry type AF induced by vagal nerve stimulation and the macroreentry type atrial flutter induced by an intercaval crush. These effects of NIP‐142 have been attributed to the prolongation of atrial effective refractory period (ERP), because this compound prolonged atrial ERP without affecting intraatrial and interatrial conduction times in these models. The ERP prolongation by NIP‐142 was greater in the atrium than in the ventricle. NIP‐142 also terminated the focal activity type AF induced by aconitine. In addition, NIP‐142 reversed the atrial ERP shortening and the loss of rate adaptation induced by short‐term rapid atrial pacing in anesthetized dogs. Thus, although clinical trials are required to provide evidence for its efficacy and safety, the novel multiple ion channel blocker, NIP‐142, appears to be a useful agent for the treatment of several types of AF with a low risk of proarrhythmic activity.
Use of Antihypertensive Drugs during Pregnancy and Lactation
Authors: Ghanem Firas A , Movahed Assad
Published: August 2010

The decision to treat elevated arterial pressure in pregnancy depends on the risk and benefits imposed on the mother and the fetus. Treatment for mild‐to‐moderate hypertension during pregnancy may not reduce maternal or fetal risk. Severe hypertension, on the other hand, should be treated to decrease maternal risk. Methyldopa and β‐adrenoceptor antagonists have been used most extensively. In acute severe hypertension, intravenous labetalol or oral nifedipine are reasonable choices.
Granulocyte–colony‐stimulatory factor: a strong inhibitor of natural killer cell function
Authors: Schlahsa Laura , Jaimes Yarúa , Blasczyk Rainer , Figueiredo Constança
Published: August 2010

BACKGROUND: The human cytokine granulocyte–colony stimulatory factor (G‐CSF) has found widespread application in the medical treatment of neutropenia and to mobilize hematopoietic stem cells used for transplantation. So far, the effect of G‐CSF on natural killer (NK) cells has not been fully investigated.

STUDY DESIGN AND METHODS: The effect of G‐CSF on the phenotype, cytokine secretion profile, and cytotoxicity of NK cells was assessed. NK cells incubated in vitro in presence of G‐CSF for 48 hours as well as NK cells isolated from peripheral blood of G‐CSF–mobilized stem cell donors (in vivo) were used.

RESULTS: In vitro, G‐CSF caused a strongly altered phenotype in NK cells with 49% down regulation of NKp44 frequency. Furthermore, the expression of the activating receptors NKp46 and NKG2D decreased 40 and 64%, respectively. The expression of KIR2DL1 and KIR2DL2 decreased by 46% each. In cytotoxicity assays, the lytic capacity of G‐CSF–exposed NK cells is reduced by up to 68% in vitro and up to 83% in vivo. Accordingly, granzyme B levels of in vivo G‐CSF–exposed NK cells were reduced by up to 87% in comparison to nonstimulated NK cells. Cytokine production of in vitro and in vivo incubated NK cells was strongly decreased for interferon‐γ, tumor necrosis factor‐α, and granulocyte macrophage colony‐stimulating factor as well as interleukin (IL)‐6 and IL‐8. Furthermore, we observed a reduction in proliferation and a positive feedback loop that increased the expression of the G‐CSF receptor.

CONCLUSION: G‐CSF was demonstrated to be a strong inhibitor of NK cells activity and may prevent their graft‐versus‐leukemia effect after transplantation.
Hemostatic function of buffy coat platelets in additive solution treated with pathogen reduction technology
Authors: Ostrowski Sisse R. , Bochsen Louise , Windeløv Nis A. , Salado‐Jimena José A. , Reynaerts Inge , Goodrich Raymond P. , Johansson Pär I.
Published: August 2010

BACKGROUND: Pathogen reduction technologies (PRTs) may influence the hemostatic potential of stored platelet (PLT) concentrates. To investigate this, buffy coat PLTs (BCPs) stored in PLT additive solution (SSP+) with or without Mirasol PRT treatment (CaridianBCT Biotechnologies) were compared by functional hemostatic assays.

STUDY DESIGN AND METHODS: We performed in vitro comparison of PRT (PRT‐BCP) and control pooled‐and‐split BCPs (CON‐BCP) after 2, 3, 6, 7, and 8 days' storage. Hemostatic function was evaluated with thrombelastography (TEG) and impedance aggregometry (Multiplate), the latter also in a sample matrix (Day 2) with or without addition of red blood cells (RBCs), control plasma, and/or PRT‐treated plasma.

RESULTS: PRT treatment of 8‐day‐stored BCPs influenced clot formation (TEG) minimally, with reductions in maximum clot strength (maximum amplitude, p = 0.014) but unchanged initial fibrin formation (R), clot growth rate (α), and fibrinolysis resistance. In the absence of RBCs and plasma, PRT impaired aggregation (Multiplate) in stored BCPs, with reduced aggregation against thrombin receptor activating peptide‐6 (p < 0.001), collagen (p = 0.014), adenosine 5′‐diphosphate (p = 0.007), and arachidonic acid (p = 0.070). Addition of RBCs and PRT‐treated or untreated plasma to PRT‐BCP and CON‐BCP, respectively, enhanced aggregation in both groups.

CONCLUSIONS: Mirasol PRT treatment of BCPs had a minimal influence on clot formation, whereas aggregation in the absence of RBCs and plasma was significantly reduced. Addition of RBCs and plasma increased agonist‐induced responses resulting in comparable aggregation between PRT‐BCP and CON‐BCP. The clinical relevance for PLT function in vivo of these findings will be investigated in a clinical trial.
Factors affecting banking quality of umbilical cord blood for transplantation
Authors: Yang Hongyou , Loutfy Mona R. , Mayerhofer Stephanie , Shuen Paul
Published: August 2010

BACKGROUND: The most important objective for cord blood banks is to store cord blood units of high quality, which is determined by total nucleated cells (TNCs) and CD34+ cells. Determining the factors affecting the stored life‐saving cells would be beneficial to the field.

STUDY DESIGN AND METHODS: A total of 4930 cord blood units were collected between January 2007 and October 2009 and processed using a double extraction technique to sediment red blood cells with variable centrifugation time determined by the formula CT = KL – M, where CT is centrifuge time, K is 7.7227, M is 29.742, and L is ln (volume of cord blood with anticoagulant). The recovery rate of TNCs and other relevant factors affecting banking quality were analyzed.

RESULTS: The mean recovery rate of TNCs was 97.7 ± 2.5% with 0.04% (2/4930) units below 80% and 10.8% (532/4930) units below 95%. The TNCs per unit was affected by gestation duration (p < 0.01), sex of infant (p < 0.01), mode of delivery (p < 0.01), collection method (p < 0.01), and ethnicity (p < 0.001). The number of postprocessing CD34+ cells was affected only by sex of the infant (p < 0.05). The viability of nucleated cells after processing was 94.8 ± 4.8% and was affected by the number of hours between collection and processing (p < 0.01). In contrast, the viability of CD34+ cells was 99.5 ± 1.0% (n = 30) when samples with low viability of TNCs were assessed. The results did not reveal a significant correlation (r = 0.07, p = 0.38).

CONCLUSION: The double extraction technique provides a high and consistent recovery of TNCs, which ensures that more life‐saving cells will be banked for transplants.
Diagnosing Unforeseeable Uncertainty in a New Venture*
Authors: Loch Christoph H. , Solt Michael E. , Bailey Elaine M.
Published: August 2010

New ventures often do not correctly foresee real market opportunities or the best way to address them. How to cope with unforeseen, unpredictable factors, also referred to as unknown unknowns, is critical for new ventures. Findings in the fields of innovation and project management have shown that dealing with the unpredictable requires management approaches different from those used for classical plan‐and‐achieve‐the‐target projects. Management approaches for novel initiatives include a combination of trial‐and‐error learning (i.e., flexible redefinition of the new venture business model as new information emerges) and selectionism (i.e., running multiple parallel trials and choosing the best performing approach ex post). The management approach must be chosen when the venture is set up. This requires a venture management team to diagnose at the outset whether unknown unknowns are present (or possible), although unknown unknowns cannot be identified initially by definition because they emerge over time. Anecdotal testimony from experienced venture managers and project managers suggests they have a feeling for where their knowledge is limited. However, such a claim is controversial. Some researchers think the concept of diagnosing unforeseeable influence factors is an oxymoron. Thus, the research question in this article is this: How can unforeseeable influence factors in a new venture be diagnosed at the outset? Research to date has insufficiently addressed the a priori identification of the type of uncertainty faced by a new venture. Based on models from decision theory, this article suggests dividing the overall problem of structuring the venture into subproblems for which the management team can identify knowledge gaps. Using a case study, the article describes how knowledge gaps were identified for the subareas of a new venture in a real situation and how this diagnosis was used to correctly identify the areas where unknown unknowns lurk. These areas were managed in a different way (i.e., with learning and experimentation) than the other subproblems (i.e., with targets and deadlines). As a result, the venture could successfully respond to unforeseeable events. The results of this study suggest that a decomposition of the overall venture management problem into subproblems is feasible and natural to managers, that a qualitative assessment of knowledge gaps and vulnerability to unknown unknowns is possible, and that a structured, process‐like approach can be used to identify subproblems, to determine their uncertainty profiles, and to update the uncertainty profiles. These results are immediately useful to venture management and venture capitalists in setting up the venture's structure for effective response to uncertainty. The results advance research about uncertainty management by offering a systematic set of questions for the diagnosis of unknown unknowns before they can be formally described. The usefulness of this process can be tested further in more formal empirical research.
Comparing Academic and Corporate Technology Development Processes*
Authors: Golish Bradley L. , Besterfield‐Sacre Mary E. , Shuman Larry J.
Published: August 2010

There is a growing concern that a large portion of innovation, one area in which the United States has excelled, may soon follow manufacturing to less costly, more efficient countries overseas. Although U.S. innovators collectively still have more patentable technologies granted by the U.S. Patent and Trademark Office (PTO) than all other countries, offshore competitors have made substantial gains with recent year‐to‐year percent increases much larger than the United States. Of concern is the relatively low number of patents granted to academic innovators. In spite of the Bayh‐Dole Act of 1980, success in this area has been limited with the proportion of patents from academia being less than 2 percent of the total patents awarded in the United States in the years since the act. Consequently, this article examines the U.S. technology development process in a descriptive study to determine exactly how and where academic and corporate inventors differ in their approaches. A series of structured interviews with academic and corporate innovators was conducted as part of a larger study investigating the technology development processes of academic and corporate inventors. Each inventor developed a concept map describing the particular process followed. To do this, a comprehensive set of possible development process elements was compiled. Inventors were then asked to select and then to arrange the elements they actually used to reflect their individual process. The resultant maps were examined using five different approaches—three quantitative and two qualitative. These analyses clearly documented that, on average, academic inventors used significantly less elements in their process (maps) than did their corporate counterparts, and further, that there was little commonality among elements on the academic maps. Overall, the corporate maps were viewed as being more complete, correct, and organized than the academic maps. This article reveals that for a small number of academic inventors and for a single technology scope, activities such as defining the market and IT growth potential, actual versus planned cost evaluation, and determination of changing customer needs/market requirements are not being conducted by the inventor. If such activities were performed either by the academic inventor or more logically by the PTO, more licensures and patents may occur.
Network Strategies of Small Chinese High‐Technology Firms: A Qualitative Study
Authors: Siu Wai‐sum , Bao Qiong
Published: August 2010

This article is an investigation of the entrepreneurial network and its strategic implications in a Chinese sociocultural context. It identifies four separate but highly interrelated network dimensions (relationship, governance, structure, and dynamic); it also highlights an important research gap. Entrepreneurs of 12 small Chinese high‐technology firms in Beijing and Shenzhen were interviewed. The interview scripts were analyzed by data reduction. Concepts related to entrepreneurial network strategies of small Chinese high‐technology firms were gradually condensed. Categorical principal component analysis (CATPCA) in SPSS for Windows 12.0 software was applied to group the cases, which in turn confirmed the qualitative data analysis results. A tentative schema is proposed, illustrating four types of entrepreneurial networkers according to network adaptation and external resource dependence. Network adaptation is based on the differentiation of the entrepreneurial efforts in network construction and change: integrative adaptation, cooperation, and coordination. External resource dependence indicates to what extent the entrepreneur relies on external resources—that is, placing emphasis on using external resources or maintaining a balance between internal and external resources. The reliance on external resources is highly related to two factors: the nature of relationship and the extent of commitment. In a transaction‐based, relationship‐dominated network, if the entrepreneur decides to develop his or her own resource competitiveness he or she will rely less on external resources. In a collaboration‐based, relationship‐dominated network, if the entrepreneur tends to have a low commitment to maintaining the relationship, he or she will depend little on external resources. Customer‐oriented networkers value interpersonal relations and strive to establish long‐term customer relationships. Partnership networkers form strategic alliance with suppliers, manufacturers, and subcontractors to access external resources. Value‐oriented networkers have a holistic view of networks and play an active role in network construction and development. Prospecting networkers make a strong commitment to network actors to exploit external resources and to make proactive moves to adapt to environmental changes.
Modulated Ventricular Parasystole and the Effects of Lidocaine in Acute Myocardial Infarction
Authors: CASTELLANOS AGUSTIN , PENA JORGE L. , DE LA HERA ARISTIDES , MYERBURG ROBERT J.
Published: August 2010

A report of modulated ventricular parasystole is described in a patient presenting with acute myocardial infarction and classical (nonmodulated) ventricular parasystole. After infusion of intravenous lidocaine, the pattern of QRS distribution changed to one of modulated parasystole. This observation suggests that lidocaine altered the receptivity to electrotonic depolarizations and changed the slope of phase 4 depolarization.
Demonstration of an Excitable Gap in the Common Form of Atrioventricular Nodal Reentrant Tachycardia
Authors: ROSENTHAL MARK E. , MILLER JOHN M. , JOSEPHSON MARK E.
Published: August 2010

Premature ventricular depolarizations were introduced during sustained atrioventricular nodal reentrant tachycardia (“slow‐fast” type) in a single patient during electrophysiological study. Preexcitation of the atrium with retrograde His bundle capture occurred over an 85 msec range of coupling intervals between the last antegmde His bundle depolarization and the first retrograde His bundle depolarimtion associated luith the premature beat (H1 ‐ H2 interval). The interval between the retrograde His bundle depolarization (H2) and the retrograde atrial depolarization (A2) remained constant over this 85 msec excitable gap as the H1‐H2 interval decreased. This indicates the presence of fully excitable tissue luithin the retrograde fast pathway of the reentrant circuit during the tachycardia and demonstrates the utility of this technique for defining the extent and conduction properties of the excitable gap in reentrant arrhythmias
Prevention of Tachycardia Initiation by Programmed Stimulation
Authors: BEGEMANN MALCOLM J.S. , BENNEKERS JOHAN H. , KINGMA J. HERRE , Lie K.I.
Published: August 2010

A 20‐year‐old female with a left‐sided concealed atrioventricular accessory pathway was studied during programmed stimulation to investigate the mechanisms of prevention of tachycardia by timed stimulation of the ventricle after a tachycardia initiating atrial extrastimulus. After the atrial tachycardia initiation zone was determined, the prvention zone of the ventricular stimulus was determined for each initiating interval. Two different prevention mechanisms were found, one whereby the ventricular depolarization was blocked retrogradely in the accessory pathway and another whereby the ventricular depolarization was conducted over the accessory pathway to the atrium but subsequently blocked anterogradely in the AV node. The preventive zone timed from the last ventricular complex to the ventricular stimulus was always greater than 30 msec whereby the minimum preventive internal was determined by the ventricular refractory period. This could be of value when such a preventive algorithm is incorporated into a dual‐chamber antitachycardia pacemaker. Knowing the exact mechanisms by which the prevention occurs allows one to predict how tachycardia can be prevented when the atrial extra beat originates from a different site and when the parameters of the heart are changed due to changes in antonomic tone or catecholamine level.
Mechanisms of Phrenic Nerve Injury During Radiofrequency Ablation at the Pulmonary Vein Orifice
Authors: BUNCH T. JARED , BRUCE G. KEITH , MAHAPATRA SRIJOY , JOHNSON SUSAN B. , MILLER DYLAN V. , SARABANDA ALVARO V. , MILTON MARK A. , PACKER DOUGLAS L.
Published: August 2010

Background: The phrenic nerve can be injured with radiofrequency energy delivery. Nevertheless, the mechanisms of injury are unknown. This study was undertaken to examine phrenic nerve tissue temperatures during ablation at the pulmonary vein (PV) orifice, assess the temperature dependence of injury, and to delineate the possible mechanisms of untoward nerve effects.

Methods: Ten dogs underwent ablation at the right superior PV (RSPV) orifice. Phrenic nerve temperatures were assessed with implanted thermocouples overlying the endocardial ablation site. Using an 8‐mm ablation catheter tip, energy was titrated to 50°C and incremented by 5°C for 120 seconds.

Results: Phrenic nerve capture was achieved in nine (90%) dogs after thermocouple implantation. A RSPV orifice tissue temperature >60°C occurred in 32 (84%) of energy deliveries with a power of 34 ± 22 W. In three (33%) dogs, this resulted in nerve dysfunction (maximum nerve temperature: 41°C, 41°C, and 91°C) with histology consistent with acute thermal injury. In four additional dogs, 17 energy deliveries were made directly to the phrenic nerve using a novel in situ model. In 5 (29%) energy deliveries, nerve function was impacted immediately by the generated current, with resolution simultaneous with discontinuing radiofrequency. Transient phrenic nerve injury occurred in all dogs at a temperature of 47 ± 3°C (range: 43–53°C) after 38 ± 32 seconds (range: 20–120 seconds). After termination of the energy delivery, nerve function returned in 15(88%) during 30 seconds of postablation pacing. In two (12%) ablation attempts, nerve recovery was delayed (>3 minutes). Permanent injury occurred in all dogs after 92 ± 83 seconds (range: 20–280 seconds) of additional energy delivery at a temperature of 51 ± 6°C (range: 45–65°C).

Conclusion: Phrenic nerve injury can be more common than anticipated with RF ablation at the RSPV orifice. Relatively low tissue temperatures can injure the nerve. Immediate nerve effects suggest a second mechanism of nerve dysfunction related to electrical current. Transient nerve effects occur prior to permanent damage, providing an opportunity to discontinue energy delivery before permanent injury.
Clinical Predictors of Noninducibility of Sustained Atrial Fibrillation After Pulmonary Vein Isolation
Authors: ROTTER MARTIN , JAÏS PIERRE , GARRIGUE STEPHANE , SANDERS PRASHANTHAN , HOCINI MÉLÈZE , HSU LI‐FERN , TAKAHASHI YOSHIHIDE , ROSTOCK THOMAS , SACHER FRÉDERIC , CLEMENTY JACQUES , HAÏSSAGUERRE MICHEL
Published: August 2010

Background: Noninducibility of sustained atrial fibrillation (AF) after pulmonary vein isolation (PVI) has been shown to be associated with a better clinical outcome. We evaluated the role of clinical variables that could predict noninducibility of sustained AF after PVI.

Methods and Results: Data were collected prospectively from 181 patients (153 male; age 54 ± 9 years) referred for ablation of drug‐refractory symptomatic paroxysmal AF (duration ≤7 days). Clinical variables were evaluated with regard to their ability of predicting noninducibility of sustained AF (≤10 minutes) after PVI. Univariate analysis was performed on all collected variables followed by multivariate analysis for variables showing a P value <0.1. After PVI, sustained AF was noninducible in 97 (54%) patients. The following clinical variables showed a significant difference between the groups: body weight, longest AF episode, duration of AF history, presence or absence of structural heart disease, left ventricular (LV) hypertrophy, prior cardioversion, left atrial (LA) parasternal, and longitudinal diameters and LV diameters. On multivariate analysis, three independent predictors of noninducibility were identified: a shorter duration of AF episodes (AF <12 hours: RR 0.01 (0.002–0.06), P < 0.001; AF 12–48 hours: RR 0.07 (0.01–0.37), P = 0.001); LA longitudinal diameter <57 mm (RR 0.33 (0.13–0.82), P = 0.016); and absence of LV hypertrophy (RR 0.15 (0.04–0.63), P = 0.01).

Conclusions: Shorter AF episodes, smaller LA longitudinal diameter, and absence of LV hypertrophy are independent predictors of noninducibility of sustained AF after PVI.
Endocardial Implantation of a Cardioverter Defibrillator in Early Childhood
Authors: GASPARINI MAURIZIO , REGOLI FRANÇOIS , GALIMBERTI PAOLA , PRIORI SILVIA G.
Published: August 2010

Introduction: Experience in endovascular/endocardial techniques for implanting implantable cardioverter defibrillators in early childhood is limited. Potentially, this type of approach could limit the surgical risk, while increasing ICD therapy efficacy. The safety and feasibility of adopting a complete endovascular/endocardial approach for implanting ICDs is assessed by considering the cases of two young children.

Methods and Results: Two boys, aged 3 and 6 years, were implanted with ICD for a history of syncope and documented ventricular tachycardia (VT). A complete endovascular/endocardial approach was adopted consisting of positioning a bipolar pacing and sensing lead in the right ventricular (RV) apex with intravascular redundancy forming a loop in the inferior vena cava (IVC), and a caval coil placed in the IVC. Sensing values (7–8 mV), pacing threshold (0.5–0.6 V/0.5 msec), and defibrillation testing (case 1 = 10 J, case 2 = 20 J) were all acceptable. During follow‐up, in both cases ICD intervened correctly. In one case, 16 months after implantation, because of change in the IVC coil‐active can vector, the IVC coil was effectively repositioned to a more distal position.

Conclusion: A complete endovascular/endocardial ICD implantation technique in early childhood is both feasible and safe. This approach avoids thoracotomy and ensures ICD therapy efficacy.
Hemodynamic Effects of Atrial Septal Pacing in Cardiac Resynchronization Therapy Patients
Authors: DI PEDE FRANCESCO , GASPARINI GIANNI , DE PICCOLI BRUNO , YU YINGHONG , CUESTA FRANCISCA , RAVIELE ANTONIO
Published: August 2010

Introduction: Spontaneous or pacing‐induced interatrial conduction delay may affect the outcome of heart failure patients treated with cardiac resynchronization therapy (CRT). The objective of this study was to evaluate the impact of the atrial pacing site (right atrial appendage, RAA; and low interatrial septum, LIS) during biventricular (BV) pacing on the left ventricular (LV) systolic function in candidates for CRT.

Methods and Results: Fifteen heart failure patients with left bundle branch block and LV ejection fraction ≤35% were enrolled. Electrodes were placed at the RAA, LIS, right ventricular apex, and LV free wall. A DDD protocol was tested, which consisted of 50 beats in AAI mode from the RAA followed by 50 beats in BV DDD mode with atrial pacing at the RAA (DDD_RAA) or at the LIS (DDD_LIS) at four AV delays. The average (±SD)%LV+dP/dtmax increase during DDD_RAA and DDD_LIS pacing with respect to baseline was 24 ± 16% and 21 ± 15%, respectively (P < 0.01), and average percentage change in aortic pulse pressure during DDD_RAA and DDD_LIS with respect to baseline (%PP) was 13 ± 8% and 13 ± 7% (ns).

Conclusions: Our results show a significant hemodynamic improvement with both DDD_RAA and DDD_LIS biventricular pacing compared to AAI pacing. However DDD_LIS pacing was not superior to DDD_RAA pacing in acute hemodynamic responses.
Isolation of Pulmonary Veins Using a Transvenous Curvilinear Cryoablation Catheter: Feasibility, Initial Experience, and Analysis of Recurrences
Authors: SKANES ALLAN C. , JENSEN STEEN M. , PAPP ROBERT , LI JULIANA , YEE RAYMOND , KRAHN ANDREW D. , KLEIN GEORGE J.
Published: August 2010

Introduction: Pulmonary vein isolation (PVI) using focal cryothermal catheters is safe and moderately effective, but associated with long procedure times. We hypothesized that a linear freezing segment could shorten fluoroscopic and procedure times. We report our initial experience with a novel circular cryothermal catheter.

Methods and Results: Complete PV isolation (PVI) was achieved in 41 of 45 PVs by cryoablation (91%) in 18 patients who underwent Lasso‐guided cryothermal using a novel 7 F circular catheter (2.5 ± 0.7 veins per patient). A mean of 27.2 ± 11 applications per patient (9.2 ± 4.7 per vein) with a mean temperature −79.8 ± 4°C were delivered. Recorded temperatures did not predict complete or incomplete isolation. Focal cryothermal ablation using a 7 F 4‐mm tip was required in the remainder for isolation. During 14.8 ± 6.2 month follow‐up, 4 (22%) had no recurrence of AF, and 7/18 (39%) had >90% reduction in symptoms without antiarrhythmic agents (AAA). Computed tomography scans at 3 months showed no stenosis (14.1 ± 2.5 mm, 13.9 ± 2.4 mm; P = 0.2). Eight patients underwent repeat ablation. Mapping demonstrated 13 of 14 (93%) previously isolated veins had recovery of over 64 ± 24% of the ostium. All were successfully isolated with RF and 7 of 8 were arrhythmia free 6.0 ± 2.9 months after ablation. Overall, 14 of 18 (78%) patients had their arrhythmia clinically controlled without drugs after one or two procedures.

Conclusions: Our initial experience demonstrates safety and feasibility of circular cryothermal ablation with less fluoroscopic and procedure times as compared to focal cryothermy. As with RF, complete and permanent isolation of the PVs is not easily achieved. Reducing heat load due to PV flow may improve results.
Case Studies with the Experts: Management Decisions in Atrial Fibrillation
Authors: PRYSTOWSKY ERIC N. , JAÏS PIERRE , KOWEY PETER , NATTEL STANLEY , RUSKIN JEREMY N.
Published: August 2010

Atrial fibrillation (AF) is the most common outpatient arrhythmia. The recent ACC/AHA/ESC guidelines outline a variety of approaches to the management of AF, but their implementation into clinical practice requires multi‐faceted patient evaluations and assessments for optimizing patient care. Using a case‐based approach, issues such as rate versus rhythm control, anticoagulation, cardioversion, pharmacological and catheter ablation for maintenance of sinus rhythm, and the pathophysiology of AF are discussed. These data were originally presented at a satellite symposium titled Case Studies with the Experts: Management Decisions in AF, held on May 10, 2007, during the annual Heart Rhythm Society meeting.
Recent Perspective on Coronary Bifurcation Intervention: Statement of the “Bifurcation Club in KOKURA”
Authors: MURASATO YOSHINOBU , HIKICHI YUTAKA , NAKAMURA SUNAO , KAJIYA FUMIHIKO , IWASAKI KIYOTAKA , KINOSHITA YOSHIHISA , YAMAWAKI MASAHIRO , SHINKE TOSHIRO , YAMADA SHNICHIRO , YAMASHITA TAKEHIRO , CHOO GIM‐HOOI , NAM CHANG‐WOOK , KIM YOUNG‐HAK , JEPSON NIGEL , FERENC MIROSLAW
Published: August 2010

The treatment of coronary bifurcation lesion remains a challenging issue even in the drug‐eluting stent era. Frequent restenosis and stent thrombosis have been recently shown to be related not only to geometrical gap or stent structural deformation but also to rheological disturbance. Low wall shear stress at the lateral side of the bifurcation is likely to cause atherosclerotic changes due to easy access of the macrophages that induce chemical mediators. The turbulent flow over stent metal may facilitate accumulation of platelets, which results in thrombosis. The jailed strut and excess metal overlap may increase these risks. Since dramatic changes of the coronary flow pattern at the bifurcation are closely related to the genesis of atherosclerosis, future bifurcation intervention technique should be considered to restore the original physiological state as well as the anatomical structure.

This article summarizes the global consensus of the members of the Asian Bifurcation Club and European Bifurcation Club at the KOKURA meeting. It also provides a perspective of basic sciences relating to bifurcation anatomy, physiology, and pathology, in the search for a best strategy for bifurcation intervention. (J Interven Cardiol 2010;23:295–304)
Editorial: At the Bifurcation of the Last Frontiers
Authors: NGUYEN THACH , CHEN SHAO LIANG , XU BO , KWAN TAK , NGUYEN KATRINA , NANJUNDAPPA ARAVINDA , VAN HO BAO , GAO RUN‐LIN
Published: August 2010

The concept of coronary angioplasty percutaneous coronary intervention (PCI) was pioneered by Andreas Gruntzig. Since then, several modifications, innovative devices, techniques, and advances have revolutionized the practice of interventional cardiology. Coronary bifurcation and chronic total occlusion are the last two frontiers that continue to challenge the skills of the interventional cardiologists. Proceedings of the second Bifurcation Summit held from November 26 to 28, 2009 in Nanjing, China are published in this symposium. In a general review, the state of the art in management of bifurcation lesion is summarized in the statement of the “Bifurcation Club in KOKURA.” A new‐presented concept was the “extension distance” between the main vessel and the sidebranch ostia and its association with restenosis. The results of two studies on shear stress (SS) after PCI showed that contradictory lower SS after stenting was associated with lower in‐stent restenosis. There was better fractional flow reserve after double kissing crush technique than provisional one‐stent technique. There was also lower rate of stent thrombosis after bifurcation stenting with excellent final angiographic results. In a negative note, the SYNTAX score had no predictive values on trifurcated left main stenting. In summary, different aspects of percutaneous management for bifurcated lesion are described seen from different perspectives and evidenced by novel techniques and strategies. (J Interven Cardiol 2010;23:293–294)
Incomplete Aneurysm Coverage after Patent Foramen Ovale Closure in Patients with Huge Atrial Septal Aneurysm: Effects on Left Atrial Functional Remodeling
Authors: RIGATELLI GIANLUCA , RONCO FEDERICO , CARDAIOLI PAOLO , DELL’AVVOCATA FABIO , BRAGGION GABRIELE , GIORDAN MASSIMO , AGGIO SILVIO
Published: August 2010

Background: Large devices are often implanted to treat patent foramen ovale (PFO) and atrial septal aneurysm (ASA) with increase risk of erosion and thrombosis. Our study is aimed to assess the impact on left atrium functional remodeling and clinical outcomes of partial coverage of the approach using moderately small Amplatzer ASD Cribriform Occluder in patients with large PFO and ASA.

Methods: We prospectively enrolled 30 consecutive patients with previous stroke (mean age 36 ± 9.5 years, 19 females), significant PFO, and large ASA referred to our center for catheter‐based PFO closure. Left atrium (LA) passive and active emptying, LA conduit function, and LA ejection fraction were computed before and after 6 months from the procedure by echocardiography. The preclosure values were compared to values of a normal healthy population of sex and heart rate matched 30 patients.

Results: Preclosure values demonstrated significantly greater reservoir function as well as passive and active emptying, with significantly reduced conduit function and LA ejection fraction, when compared normal healthy subjects. All patients underwent successful transcatheter closure (25 mm device in 15 patients, 30 mm device in 6 patients, mean ratio device/diameter of the interatrial septum = 0.74). Incomplete ASA coverage in both orthogonal views was observed in 21 patients. Compared to patients with complete coverage, there were no differences in LA functional parameters and occlusion rates.

Conclusions: This study confirmed that large ASAs are associated with LA dysfunction. The use of relatively small Amplatzer ASD Cribriform Occluder devices is probably effective enough to promote functional remodeling of the left atrium. (J Interven Cardiol 2010;23:362–367)
Talent, technology and tolerance in Canadian regional development
Authors: FLORIDA RICHARD , MELLANDER CHARLOTTA P.A. , STOLARICK KEVIN M.
Published: August 2010

This article examines the factors that shape economic development in Canadian regions. It employs path analysis and structural equation models to isolate the effects of technology, human capital and/or the creative class, universities, the diversity of service industries and openness to immigrants, minorities and gay and lesbian populations on regional income. It also examines the effects of several broad occupations groups—business and finance, management, science, arts and culture, education and health care—on regional income. The findings indicate that both human capital and the creative class have a direct effect on regional income. Openness and tolerance also have a significant effect on regional development in Canada. Openness towards the gay and lesbian population has a direct effect on both human capital and the creative class, while tolerance towards immigrants and visible minorities is directly associated with higher regional incomes. The university has a relatively weak effect on regional incomes and on technology as well. Management, business and finance and science occupations have a sizeable effect on regional income; arts and culture occupations have a significant effect on technology; health and education occupations have no effect on regional income.