Vacuum assisted closure in vascular surgery.

BACKGROUND: Vacuum assisted closure (VAC-therapy) is a well established method in nearly all surgical disciplines. The aim is to present the efficiency of vacuum assisted closure in the treatment of acute and chronic wounds in patients admitted in the department of vascular surgery. METHODS: Within the year 2008 there were 59 patients (44 men, 15 women) treated with VAC therapy in our Department of Vascular surgery (Landshut, Germany). VAC was used 22x (37.28 %) in therapy of ulcus cruris (venous, arterial, mixed genesis), 15x (25.42%) in patients with diabetic foot syndrome, 12x (20.33%) in secondary healing wounds and infected wounds, 5x (8.47%) in wounds after several injuries and soft skin tissue infections and 5x (8.47%) in wound infections connected with vascular graft infections after vascular revascularization. RESULTS: VAC therapy seems to be very effective in the management of patients with venous ulcers, especially after a proper surgical treatment (100%), patients with soft skin tissue infections (100%) and secondary healing wounds (100%) especially in combination with MESH-Grafting. In patients with diabetic foot syndrome (80%) and peripheral arterial occlusive disease (72.7%), an evaluation of peripheral blood perfusion and revascularization prior to VAC therapy is often necessary. Although VAC was used 5x in the therapy of infected vascular grafts, successful preservation of infected graft material was observed in only one case (infection of PTFE femoro-popliteal bypass graft). CONCLUSION: Vacuum assisted closure in vascular surgery proved to be simple and efficient method in therapy of acute and chronic wounds. The efficiency of VAC systems in therapy of infected graft material after revascularization needs further studies (Tab. 3, Ref. 10).

How can we improve our understanding of cardiovascular safety liabilities to develop safer medicines?

Given that cardiovascular safety liabilities remain a major cause of drug attrition during preclinical and clinical development, adverse drug reactions, and post-approval withdrawal of medicines, the Medical Research Council Centre for Drug Safety Science hosted a workshop to discuss current challenges in determining, understanding and addressing 'Cardiovascular Toxicity of Medicines'. This article summarizes the key discussions from the workshop that aimed to address three major questions: (i) what are the key cardiovascular safety liabilities in drug discovery, drug development and clinical practice? (ii) how good are preclinical and clinical strategies for detecting cardiovascular liabilities? and (iii) do we have a mechanistic understanding of these liabilities? It was concluded that in order to understand, address and ultimately reduce cardiovascular safety liabilities of new therapeutic agents there is an urgent need to: • Fully characterize the incidence, prevalence and impact of drug-induced cardiovascular issues at all stages of the drug development process. • Ascertain the predictive value of existing non-clinical models and assays towards the clinical outcome. • Understand the mechanistic basis of cardiovascular liabilities; by addressing areas where it is currently not possible to predict clinical outcome based on preclinical safety data. • Provide scientists in all disciplines with additional skills to enable them to better integrate preclinical and clinical data and to better understand the biological and clinical significance of observed changes. • Develop more appropriate, highly relevant and predictive tools and assays to identify and wherever feasible to eliminate cardiovascular safety liabilities from molecules and wherever appropriate to develop clinically relevant and reliable safety biomarkers.

[Rupture of the common illiac artery isolated aneurysm in a high risk patient--a case review]. / Ruptúra izolovanej aneuryzmy a. iliaca communis u vysoko rizikového pacienta--kazuistika.

Rupture of isolated aneurysm of common iliac artery is a relative seldom finding in vascular surgery. Nowadays are in therapy of this severe conditions used conventional as well as endovascular procedures. Our case report document, that in high risk patients with convenient anatomical conditions endovascular therapy is a safe and effective therapy, that can reduce mortality of these patients.

International Life Sciences Institute (Health and Environmental Sciences Institute, HESI) initiative on moving towards better predictors of drug-induced torsades de pointes.

Knowledge of the cardiac safety of emerging new drugs is an important aspect of assuring the expeditious advancement of the best candidates targeted at unmet medical needs while also assuring the safety of clinical trial subjects or patients. Present methodologies for assessing drug-induced torsades de pointes (TdP) are woefully inadequate in terms of their specificity to select pharmaceutical agents, which are human arrhythmia toxicants. Thus, the critical challenge in the pharmaceutical industry today is to identify experimental models, composite strategies, or biomarkers of cardiac risk that can distinguish a drug, which prolongs cardiac ventricular repolarization, but is not proarrhythmic, from one that prolongs the QT interval and leads to TdP. To that end, the HESI Proarrhythmia Models Project Committee recognized that there was little practical understanding of the relationship between drug effects on cardiac ventricular repolarization and the rare clinical event of TdP. It was on that basis that a workshop was convened in Virginia, USA at which four topics were introduced by invited subject matter experts in the following fields: Molecular and Cellular Biology Underlying TdP, Dynamics of Periodicity, Models of TdP Proarrhythmia, and Key Considerations for Demonstrating Utility of Pre-Clinical Models. Contained in this special issue of the British Journal of Pharmacology are reports from each of the presenters that set out the background and key areas of discussion in each of these topic areas. Based on this information, the scientific community is encouraged to consider the ideas advanced in this workshop and to contribute to these important areas of investigations over the next several years.

Key clinical considerations for demonstrating the utility of preclinical models to predict clinical drug-induced torsades de pointes.

While the QT/QTc interval is currently the best available clinical surrogate for the development of drug-induced torsades de pointes, it is overall an imperfect biomarker. In addition to low specificity for predicting arrhythmias, other issues relevant to using QT as a biomarker include (1) an apparent dissociation, for some drugs (for example, amiodarone, sodium pentobarbital, ranolazine) between QT/QTc interval prolongation and TdP risk, (2) Lack of clarity regarding what determines the relationship between QTc prolongation and TdP risk for an individual drug, (3) QT measurement issues, including effects of heart rate and autonomic perturbations, (4) the significant circadian changes to the QT/QTc interval and (5) concerns that the development, regulatory and commercial implications of finding even a mild QT prolongation effect during clinical development has significant impact the pharmaceutical discovery pipeline. These issues would be significantly reduced, clinical development simplified and marketing approval for some drugs might be accelerated if there were a battery of preclinical tests that could reliably predict a drug's propensity to cause TdP in humans, even in the presence of QTc interval prolongation. This approach is challenging and for it to be acceptable to pharmaceutical developers, the scientific community and regulators, it would need to be scientifically well validated. A very high-negative predictive value demonstrated in a wide range of drugs with different ionic effects would be critical. This manuscript explores the issues surrounding the use of QT as a clinical biomarker and potential approaches for validating preclinical assays for this purpose against clinical data sets.

Moving towards better predictors of drug-induced torsades de pointes.

Drug-induced torsades de pointes (TdP) remains a significant public health concern that has challenged scientists who have the responsibility of advancing new medicines through development to the patient, while assuring public safety. As a result, from the point of discovering a new molecule to the time of its registration, significant efforts are made to recognize potential liabilities, including the potential for TdP. With this background, the ILSI (HESI) Proarrhythmia Models Project Committee recognized that there was little practical understanding of the relationship between drug effects on cardiac ventricular repolarization and the rare clinical event of TdP. A workshop was therefore convened at which four topics were considered including: Molecular and Cellular Biology Underlying TdP, Dynamics of Periodicity, Models of TdP Proarrhythmia and Key Considerations for Demonstrating Utility of Pre-Clinical Models. The series of publications in this special edition has established the background, areas of debate and those that deserve scientific pursuit. This is intented to encourage the research community to contribute to these important areas of investigation in advancing the science and our understanding of drug-induced proarrhythmia.

A prototypical process for creating evidentiary standards for biomarkers and diagnostics.

A framework for developing evidentiary standards for qualification of biomarkers is a key need identified in the Food and Drug Administration's Critical Path Initiative. This article describes a systematic framework that was developed by Pharmaceutical Research and Manufacturers of America (PhRMA) committees and tested at a workshop in collaboration with the Food and Drug Administration and academia. With some necessary refinements, this could be applied to create an appropriately individualized evidentiary standard for any biomarker purpose.

Efficacy and safety of ezetimibe coadministered with statins: randomised, placebo-controlled, blinded experience in 2382 patients with primary hypercholesterolemia.

We assessed pooled safety and lipid-regulating efficacy data from four similarly designed trials of ezetimibe coadministered with statins in 2382 patients with primary hypercholesterolemia. Patients were randomised to one of the following double-blind treatments for 12 weeks: placebo; ezetimibe 10 mg; statin; or statin + ezetimibe. Statin doses tested were 10, 20, 40 mg/day (atorvastatin, simvastatin, pravastatin or lovastatin) or 80 mg/day (atorvastatin, simvastatin). Treatment with ezetimibe + statin led to significantly greater reductions in low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B and increases in HDL-C, compared to statin alone. At each statin dose, treatment with ezetimibe + statin led to a greater LDL-C reduction compared to the next highest statin monotherapy dose. Ezetimibe + statin had a safety profile similar to statin monotherapy. Coadministration of ezetimibe + statin offers a well-tolerated, highly efficacious new treatment strategy for patients with hypercholesterolemia.

Long-term safety and tolerability profile of ezetimibe and atorvastatin coadministration therapy in patients with primary hypercholesterolaemia.

Long-term safety and tolerability of ezetimibe plus atorvastatin (EZE + ATV) coadministration therapy were compared to those of ATV monotherapy in patients with primary hypercholesterolaemia. Upon completion of a 12 week randomised, double-blind, placebo-controlled study comparing EZE 10 mg; ATV 10, 20, 40 or 80 mg; EZE + ATV 10, 20, 40 or 80 mg or placebo, 246 patients were enrolled in a 12-month extension, with reassignment to double-blind EZE 10 mg (n = 201) or matching placebo (n = 45) coadministered daily with open-label ATV 10 mg. At intervals of 6 weeks, patients not at National Cholesterol Education Program Adult Treatment Panel II LDL-C goals were titrated to the next higher ATV dose. Safety evaluations included adverse event (AE) reports and laboratory test results. EZE + ATV and ATV monotherapy groups were similar with regard to incidence of all AEs (71 vs. 67%), treatment-related AEs (22 vs. 27%) and discontinuations due to AEs (9 vs. 7%) or treatment-related AEs (6 vs. 7%), respectively. Neither clinically significant elevations in hepatic transaminases or creatine kinase nor any cases of myopathy or rhabdomyolysis were observed in either group during the extension study. After 6 weeks, EZE + ATV 10mg produced greater reductions in low-density lipoprotein cholesterol (LDL-C; -53 vs. -37%), total cholesterol (TC; -38.8 vs. -26.0%) and triglycerides (TG; -28 vs. -12%) and similar increases in high-density lipoprotein cholesterol (4.6 vs. 4.5%) compared to ATV 10 mg, respectively, and these changes were maintained and significant at 1 year (p < 0.01 for LDL-C, TC and TG). More EZE + ATV patients achieved LDL-C goal than ATV patients at study endpoint (91 vs. 78%, respectively; p = 0.02). Thus, the coadministration of EZE + ATV for 12 months was well tolerated and more efficacious than ATV monotherapy.

Placement of a defibrillation lead in the left subclavian vein from the right cephalic vein.

This case report highlights the feasibility and stability of transvenous placement of a second defibrillation lead in the left subclavian vein from a right cephalic vein approach. This was undertaken in a right-sided implant of an active can cardioverter defibrillator to lower defibrillation thresholds that would have otherwise precluded implant.

New advances in class III antiarrhythmic drug therapy.

In the past 2 years, significant advances have been made in class III antiarrhythmic drug therapy. In patients with ventricular arrhythmias and implantable cardioverter defibrillators (ICDs), antiarrhythmic agents are increasingly being used as adjunct therapy to decrease the frequency of ICD discharges. Sotalol was recently shown to be effective in reducing tachyarrhythmias in patients with ICDs. Intravenous amiodarone is being used for the acute treatment of unstable ventricular arrhythmia and is being investigated for the treatment of acute out-of-hospital cardiac arrest. Class III agents are increasingly being used for prophylaxis in patients who have atrial fibrillation or atrial flutter, and data point to an important role for these agents in reducing supraventricular tachyarrhythmias after cardiac surgery. Future studies will need to directly compare these agents with pure anti-adrenergic maneuvers in postoperative patients. In addition to terminating atrial fibrillation and atrial flutter, ibutilide significantly reduces human atrial defibrillation thresholds and increases the percentage of patients who can be cardioverted from atrial fibrillation to sinus rhythm. The US Food and Drug Administration is expected to approve dofetilide for clinical use soon, and it is currently reviewing azimilide (which seems to be devoid of frequency-dependent effects on repolarization) for prophylaxis against atrial fibrillation and atrial flutter. Dronedarone, tedisamal, and trecetilide are now under active study intended to determine their usefulness in patients with cardiac arrhythmias. Experimental studies are ongoing to identify pharmacologic agents that will selectively prolong repolarization in the atria without exerting electrophysiologic effects in the ventricles.

New advances in class III antiarrhythmic drug therapy.

During the past 10 years there has been a major shift in antiarrhythmic drug development from class I to class III antiarrhythmic agents. The first two class III antiarrhythmic drugs that became available, sotalol and amiodarone, also have potent antiadrenergic actions. Newer antiarrhythmic drugs either block a specific ionic current (e.g., dofetilide-induced blockade of the rapidly activating component of the delayed rectifier potassium current) or block multiple ionic channels (e.g., ibutilide and azimilide) in order to prolong atrial and ventricular action potentials without other specific pharmacologic effects. Recent data suggest that these new class III antiarrhythmic drugs are highly effective for treating patients with rhythm disorders with an acceptable degree of proarrhythmia. This manuscript reviews the newer class III agents' effectiveness in treating atrial and ventricular arrhythmias and the recent studies examining drug-induced prolongation of atrial repolarization to prevent or terminate postoperative atrial fibrillation.

Modulation of antiarrhythmic drug effects by beta-adrenergic sympathetic stimulation.

Appreciation has grown for the impact of the autonomic nervous system on the development of clinical cardiac arrhythmias. Antiarrhythmic medications work to significantly prolong cardiac repolarization and slow conduction. The question has arisen whether these pharmacologic actions of antiarrhythmic drugs can be modulated by alterations in the sympathetic nervous system. This article examines the data pertaining to modulation of the class I and class III effects of antiarrhythmic drugs during beta-adrenergic stimulation, the body's natural response to stress. The actions of several antiarrhythmic drugs can be fully reversed during beta-adrenergic sympathetic stimulation. Overall, the data suggest that pure class III drugs are the most susceptible to reversal of their effects on refractoriness, followed by class IA agents, amiodarone (which has partial resistance), and d,l-sotalol (which is highly resistant to reversal). Whereas retrospective analyses of a number of trials suggest that sympathetic-stimulation-induced reversal of the electrophysiologic effects of certain antiarrhythmic drugs can decrease their clinical efficacy, prospective trials examining this issue are needed. At the current time it appears reasonable to administer beta blockers to patients receiving antiarrhythmic agents that do not have intrinsic antiadrenergic effects.

Radiofrequency catheter ablation of ventricular tachycardia after myocardial infarction.

BACKGROUND: Patients with ventricular tachycardia (VT) after myocardial infarction often have multiple morphologies of inducible VT, which complicates mapping and is viewed by some as a relative contraindication to ablation. Attempting to identify and target a single "clinical" VT is often limited by inability to obtain 12-lead ECGs of VTs that are terminated emergently or by defibrillators. This study assesses the feasibility of ablation in patients selected without regard to the presence of multiple VTs by targeting all VTs that allow mapping. METHODS AND RESULTS: Radiofrequency catheter ablation targeting all inducible monomorphic VTs that allowed mapping was performed in 52 patients with prior myocardial infarction. Antiarrhythmic drug therapy had failed in 41 (79%) patients including amiodarone in 36 (69%) patients. An average of 3.6+/-2 morphologies of VT were induced per patient. More than 1 ablation session was required in 16 (31%) patients. Complications occurred in 5 (10%) patients, including 1 (2%) death caused by acute myocardial infarction. During follow-up 59% of patients continued to receive amiodarone; 23 (45%) had implantable defibrillators. During a mean follow-up of 18+/-15 months (range 0 to 51 months) 1 patient died suddenly, 2 died from uncontrollable VT, and 5 died from heart failure. Three-year survival rate was 70+/-10%, and rate for risk of VT recurrence was 33+/-7%. CONCLUSIONS: Radiofrequency catheter ablation controls VT that is sufficiently stable to allow mapping in 67% of patients despite failure of antiarrhythmic drug therapy and multiple inducible VTs. However, ablation was largely adjunctive to amiodarone and defibrillators in this referral population.

Atrial fibrillation: antiarrhythmic therapy versus rate control with antithrombotic therapy.

Atrial fibrillation is a major health problem in the United States, but the best strategies for treating it have not been rigorously determined in clinical studies. Specifically, there is a paucity of data comparing the approach of maintaining sinus rhythm using prophylactic antiarrhythmic drug therapy with the approach of controlling the ventricular response to atrial fibrillation while reducing embolic events with concomitant antithrombotic therapy. Until ongoing randomized trials are completed, which patients benefit most from a specific approach cannot be determined with certainty. In general, the most reasonable strategies include (1) the restoration of sinus rhythm (without prophylactic antiarrhythmic therapy) after the patient's first episode of atrial fibrillation; and (2) the maintenance of sinus rhythm (including the use of prophylactic antiarrhythmic therapy) in patients who remain symptomatic despite adequate rate control, and who are not at high risk for proarrhythmia and/or are unlikely to maintain sinus rhythm. The risks and benefits need to be carefully weighed in patients with truly asymptomatic atrial fibrillation. Many patients may require multiple attempts to maintain sinus rhythm. Current investigative treatment modalities (e.g., ablation techniques, atrial implantable cardioverter-defibrillators, new antiarrhythmic agents) are likely to alter the current approaches to atrial fibrillation.

Exploring postinfarction reentrant ventricular tachycardia with entrainment mapping.

Ventricular tachycardia late after myocardial infarction is usually due to reentry in the infarct region. These reentry circuits can be large, complex and difficult to define, impeding study in the electrophysiology laboratory and making catheter ablation difficult. Pacing through the electrodes of the mapping catheter provides a new approach to mapping. When pacing stimuli capture the effects on the tachycardia depend on the location of the pacing site relative to the reentry circuit. The effects observed allow identification of various portions of the reentry circuit, without the need for locating the entire circuit. Isthmuses where relatively small lesions produced by radiofrequency catheter ablation can interrupt reentry can often be identified. A classification that divides reentry circuits into one or more functional components helps to conceptualize the reentry circuit and predicts the likelihood that heating with radiofrequency current will terminate tachycardia. These methods are helping to define human reentry circuits.

Preferential locations for critical reentry circuit sites causing ventricular tachycardia after inferior wall myocardial infarction.

INTRODUCTION: For relatively slow monomorphic ventricular tachycardia (VT) after myocardial infarction, entrainment can be used to identify reentry circuit "isthmus sites" (exit sites and sites proximal to the exit) where radiofrequency (RF) catheter ablation has the greatest likelihood of interrupting reentry. Similarities in coronary and ventricular anatomy may cause such sites to form in preferential locations. The objective of this study is to determine if there are preferential locations for reentry circuit isthmus regions in chronic inferior wall infarctions causing VT. METHODS AND RESULTS: Catheter mapping and RF catheter ablation was performed in 21 patients with an old inferior wall myocardial infarction and VT. The inferior wall was divided into 9 anatomic regions: 3 apical, 3 mid, and 3 basal segments. Of 46 different VTs, an endocardial isthmus site was identified in one or more zones in 28 (61%), with 10 VTs having isthmus sites in two or more adjacent regions. Isthmus zones were found in a basal region of the left ventricle in 24 (86%) of 28 VTs, in a mid segment in 9 (32%) VTs, and in an apical segment in 1 (4%) (P = 0.002). Of 30 RF current applications that terminated VT, 21 (70%) were at basal isthmus sites. CONCLUSION: The high prevalence of endocardial isthmus zones near the base of the left ventricle suggests that the mitral annulus often plays a role in defining the margins of reentry circuits that cause relatively slow VTs after inferior wall myocardial infarction.

Quasiperiodicity and chaos in cardiac fibrillation.

In cardiac fibrillation, disorganized waves of electrical activity meander through the heart, and coherent contractile function is lost. We studied fibrillation in three stationary forms: in human chronic atrial fibrillation, in a stabilized form of canine ventricular fibrillation, and in fibrillation-like activity in thin sheets of canine and human ventricular tissue in vitro. We also created a computer model of fibrillation. In all four studies, evidence indicated that fibrillation arose through a quasiperiodic stage of period and amplitude modulation, thus exemplifying the "quasiperiodic transition to chaos" first suggested by Ruelle and Takens. This suggests that fibrillation is a form of spatio-temporal chaos, a finding that implies new therapeutic approaches.