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Candida albicans infections and their resistance to clinically approved azole drugs are major concerns for human. The azole antifungal drugs inhibit the ergosterol synthesis by targeting lanosterol 14α-demethylase of cytochrome P450 family. The lack of high-resolution structural information of fungal pathogens has been a barrier for the design of modified azole drugs. Thus, a preliminary theoretical molecular dynamic study is carried out to develop and validate a simple homologous model using crystallographic structure of the lanosterol 14α-demethylase of Mycobacterium tuberculosis (PDB ID-1EA1) in which the active site residues are substituted with that of C. albicans (taxid 5476). Further, novel designed pyrazole analogs (SGS1-16) docked on chimeric 1EA1 and revealed that SGS-16 show good binding affinity through non-bonding interaction with the heme, which is different from the leading azole antifungals. The ADME-T results showed these analogs can be further explored in design of more safe and effective antifungal agents.

Background Unexpected serious adverse drug reactions (sADRs) affecting patients with chronic kidney disease (CKD) who received erythropoiesis-stimulating agents were identified by study co-authors. These included pure red cell aplasia (PRCA) after administration of the Eprex formulation of epoetin or the epoetin biosimilar HX575 and fatal anaphylaxis associated with peginesatide, an erythropoietin receptor agonist. We developed and applied a structured framework to describe these sADRs, including root cause analyses and eradication efforts. Methods A 10-step framework termed "ANTICIPATE," focusing on signal identification, incidence, causality, and eradication guided our evaluations. Results Initial cases were identified by a hematologist (Eprex), clinical study monitors (HX575), and 4 nurses (peginesatide). The number of persons with individual ADRs was 13 PRCA cases for epoetin, 2 antibody-mediated PRCA cases for HX575, and 5 fatal anaphylaxis cases for peginesatide. Initial incidence estimates per 1000 treated persons were 0.27 for Eprex-associated PRCA, 11 for HX575-associated PRCA, and 0.38 for peginesatide fatalities. Likely causes were subcutaneous administration of epoetin formulated with polysorbate 80 (Eprex), tungsten leaching from pins included in product syringes (HX575), and inclusion of a phenol stabilizer (peginesatide). Eradication strategies included restricting Eprex administration to the intravenous route, excluding tungsten from HX575 syringes, and for peginesatide, proposed eradication was to return to single-dose vials without preservatives. Conclusion Although the number of cases of each sADR was small, eradication was successful for 2 sADRs, and a proposed eradication was developed for a third sADR. The structured framework used to describe the above 3 sADRs in patients with CKD can also be used in other clinical settings.

Azithromycin and levofloxacin have been shown to be efficacious in treating infections. The adverse drug events associated with azithromycin and levofloxacin were considered rare. However, the US FDA released warnings regarding the possible risk of QT prolongation with azithromycin and levofloxacin.Case reports/case series, observational studies and clinical trials assessing cardiovascular risks associated with azithromycin and levofloxacin were critically reviewed, including 15 case reports/series, 5 observational studies and 5 clinical trials that investigated the cardiac risks associated azithromycin and levofloxacin.Results are discordant. Two retrospective studies utilizing large databases demonstrated an increased risk of cardiovascular death with azithromycin, when azithromycin was compared with amoxicillin. Two other retrospective studies found no difference in cardiovascular death associated with azithromycin and other antibiotics. For levofloxacin, the increased risk of cardiovascular death was only found in one retrospective study. Therefore, the risks and benefits of antibacterial therapies should be considered when making prescription decisions. This study should not preclude clinicians from avoiding azithromycin and levofloxacin. If a patient has an indication to receive an antibiotic and if azithromycin or levofloxacin is needed, it may be used, but the potential risks must be understood.

Calsequestrin-2 (CSQ2) is a resident glycoprotein of junctional sarcoplasmic reticulum that functions in the regulation of SR Ca(2+) release. CSQ2 is biosynthesized in rough ER around cardiomyocyte nuclei and then traffics transversely across SR subcompartments. During biosynthesis, CSQ2 undergoes N-linked glycosylation and phosphorylation by protein kinase CK2. In mammalian heart, CSQ2 molecules subsequently undergo extensive mannose trimming by ER mannosidase(s), a posttranslational process that often regulates protein breakdown. We analyzed the intact purified CSQ2 from mongrel canine heart tissue by electrospray mass spectrometry. The average molecular mass of CSQ2 in normal mongrel dogs was 46,306 ± 41 Da, corresponding to glycan trimming of 3-5 mannoses, depending upon the phosphate content. We tested whether CSQ2 glycan structures would be altered in heart tissue from mongrel dogs induced into heart failure (HF) by two very different experimental treatments, rapid ventricular pacing or repeated coronary microembolizations. Similarly dramatic changes in mannose trimming were found in both types of induced HF, despite the different cardiomyopathies producing the failure. Unique to all samples analyzed from HF dog hearts, 20-40 % of all CSQ2 contained glycans that had minimal mannose trimming (Man9,8). Analyses of tissue samples showed decreases in CSQ2 protein levels per unit levels of mRNA for tachypaced heart tissue, also indicative of altered turnover. Quantitative immunofluorescence microscopy of frozen tissue sections suggested that no changes in CSQ2 levels occurred across the width of the cell. We conclude that altered processing of CSQ2 may be an adaptive response to the myocardium under stresses that are capable of inducing heart failure.

Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year of marketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrel-associated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ.

A few observational studies have shown the protective effect of statins on preventing ventricular tachycardia/ventricular fibrillation (VT/VF). However, the disparate study results prompt further exploration of this concept. We performed a meta-analysis to assess whether statin therapy is associated with a decrease in the incidence or recurrence of VT/VF in patients with an implantable cardioverter-defibrillator (ICD).The MEDLINE(®) and Cochrane databases were searched from 1980 to July 2009 for studies examining the effect of statins on VT/VF in recipients of ICDs. We retrieved all prospective cohort studies that examined this association. The endpoint was defined as appropriate ICD therapy for VT/VF. The quality of individual studies was assessed using the Newcastle Ottawa Scale.Seven prospective cohort studies met our inclusion criteria with a total of 2278 patients with a mean follow-up of 19.7 months. Pooled analysis of the eligible studies revealed that statin therapy was associated with a 45% reduction in the risk of developing VT/VF in recepients of ICDs [pooled odds ratio (pOR): 0.55; 95% confidence interval: 0.34-0.90; heterogeneity I(2) = 81%, P = 0.02]. In a subgroup analysis, the magnitude of the risk reduction in patients with ischemic cardiomyopathy was 54% (pOR: 0.46, P = 0.05). Sensitivity analysis including studies with higher methodological qualities alone showed a significant protective effect (pOR: 0.48, P = 0.01). There was no evidence of publication bias in the analysis.Our meta-analysis suggests an association between the use of statin and a reduction in the VT/VF occurrence in recipients of ICDs, mainly in patients with ischemic cardiomyopathy.

Almost 50% of patients with congestive heart failure (HF) have preserved ejection fraction (PEF). Data on the effect of HF-PEF on atrial fibrillation outcomes are lacking. We assessed the prognostic significance of HF-PEF in an atrial fibrillation population compared to a systolic heart failure (SHF) population. A post hoc analysis of the National Heart, Lung, and Blood Institute-limited access data set of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial was carried out. The patients with a history of congestive HF and a preserved ejection fraction (EF50%) were classified as having HF-PEF (n = 320). The patients with congestive HF and a qualitatively depressed EF (EF50%) were classified as having SHF (n = 402). Cox proportional hazards analysis was performed. The mean follow-up duration was 1,181 ± 534 days/patient. The patients with HF-PEF had lower all-cause mortality (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.46 to 0.85, p = 0.003) and cardiovascular mortality (HR 0.56, 95% CI 0.38 to 0.84, p = 0.006), with a possible decreased arrhythmic end point (HR 0.39, 95% CI 0.16 to 1.006, p = 0.052) than did the patients with SHF. No differences were observed for ischemic stroke (HR 1.08, 95% CI 0.48 to 2.39, p = 0.86), rehospitalization (HR 0.89, 95% CI 0.75 to 1.07, p = 0.24), or progression to New York Heart Association class III-IV (odds ratio 0.80, 95% CI 0.42 to 1.54, p = 0.522). In conclusion, although patients with HF-PEF have better mortality outcomes than those with SHF, the morbidity appears to be similar.

Although implantable cardioverter defibrillator (ICD) therapy is the standard of care for prevention of sudden cardiac death (SCD), its underutilization is a clinical concern. We performed a retrospective study on patients who underwent cardiac catheterization at a tertiary medical center to identify those who were eligible for ICD therapy as per the guidelines and those who actually received it as a part of treatment. Surprisingly, only 4.4% of eligible patients received ICD for SCD prevention. Assuming that the major cause of this underutilization of ICD therapy was low referral, we performed a structured survey among the referring physicians to assess specialists' availability, primary care physicians' role in ICD referral, patient management concerns, familiarity with ICD guidelines, and economics of ICD implantation. Physician response rate of the survey was 51% (35/68). Survey results showed that the common reasons for underreferral included nonavailability of electrophysiologists (34%), poor quality of life of patients (25.7%), patients not being on optimal therapy (25.7%), and low awareness (22.85%). Subsequently, a Monte Carlo simulation was used to assess a hypothetical survival of the study cohort, which showed that in an "ideal scenario" of ICD implantation, the mortality in the study cohort was decreased by 6.9% and 12.3% at 2- and 5-year follow-up, respectively. This study highlights the underutilization of ICDs and the referring physicians' approach to this therapy.

Introduction A 75-year-old woman with a dual-chamber pacemaker was seen in the cardiology clinic for possible device malfunction. The patient’s device identification card revealed that a pacemaker from “Manufacturer A” was implanted in 2001. However, device interrogation using the corresponding programmer failed to communicate with the device. Given the age of the device, complete depletion of the battery was suspected and the patient was thus referred for pacemaker generator change. On the day of the surgery in the holding area, upon inspection of the pacemaker implantation site, existence of 2 healed scars side by side raised the suspicion of a previous generator change out or revision of leads. However, the patient did not recall any such procedures; therefore all of the 5 major manufacturers were contacted. Manufacturer A confirmed the information in the identification card, whereas the others showed no record of the patient. Nevertheless, the second scar at the device site still remained a question. Although the decision regarding the pacemaker generator change was acceptable, the possibility of a mistaken device manufacturer identity could not be completely ruled out. The patient’s chest X-ray with the pacemaker image was compared with other patients’ X-rays with known pacemakers for possible manufacturer identification. Similarities with one of the other manufacturer’s (“Manufacturer B”) X-ray pacemaker image prompted device in

The growing indications for permanent pacemaker and implantable cardioverter defibrillator (ICD) implantation have increased the number of patients with these cardiac rhythm management devices (CRMDs). Cardiac rhythm management devices occasionally perform inappropriately in response to electromagnetic interference (e.g. surgical electrocautery) or lead noise over-sensing (e.g. lead fracture). Temporary reprogramming of the CRMDs using device programmers can prevent these untoward device responses. However, these programmers are device manufacturer specific and require technically qualified personnel to operate. This could cause delayed patient care and increased use of resources in certain clinical situations. Alternatively, clinical magnets, when appropriately positioned over the device site, can change the pacing to an asynchronous mode in pacemakers and suspend tachycardia therapies in ICDs. Although readily available, clinical magnets have not been widely used for this purpose, perhaps due to the unfamiliarity with the variable responses of CRMDs to magnet application. This article provides a comprehensive overview of the current literature on the mechanism of action and the specific responses of various CRMDs to clinical magnets.

Atrial fibrillation (AF) is one of the most common arrhythmia encountered in clinical practice. Although AF is due to the structural and electrophysiological alterations in the atria, its sustainability is multifactorial, and the actual mechanisms are still not clear. Despite the recent advances in catheter ablation technology and techniques, pharmacotherapy still remains the first-line therapy for the management of AF. Current pharmacotherapy targets ion channel alterations that in fact represent only one aspect of the management of this complex arrhythmia. Successful pharmacological treatment of AF and restoration of sinus rhythm is limited and is in part due to its potential deleterious side effects. Newer agents having diverse mechanisms acting on the recently uncovered pathophysiological processes are on the horizon. These include atrial repolarization delaying agents, newer class III agents, Na(+)-Ca(2+) channel blockers, stretch receptor blockers, I(KACH) blockers, gap junction modifiers, upstream therapies, and agents targeting ischemia-induced AF. Gene- and cell-specific therapies including 'tailored nanopharmacy,' newer rate control medications with minimal side effects and the emergence of novel drugs targeting multiple areas of AF arrhythmogenesis in tandem with electrical therapy may be the future direction in the management of AF.

Fluoroscopically guided minimally invasive diagnostic and therapeutic cardiovascular procedures constitute an essential component of the contemporary practice in medicine. Such procedures are however associated with radiation exposure and its attendant hazards. Given the exponential increase in both the type and number of various cardiovascular procedures over the past few decades, radiation exposure has become a critical parameter mandating periodic evaluation. Although existent data indicate variable but nominal radiation doses associated with cardiovascular interventions, the radiation risk may be significant in certain patient populations and the operators who perform numerous procedures annually. Awareness regarding radiation doses and exposure delivered to both patients as well as operators during interventional procedures is therefore imperative. In this article, we review the current literature regarding radiation exposure, its potential hazards, and the ways to reduce the radiation dose in the current practice of cardiovascular medicine.

Background Comparative data on the prognostic utility of novel lipid parameters vs. conventional lipid parameters in predicting coronary events are scant. Objective We sought to compare the predictive value of various lipid measures for coronary events and to further examine the incremental value of novel lipid parameters over traditional cardiovascular risk factors in estimating cardiac risk. Methods We performed a post-hoc analysis of the National Heart Lung and Blood Institute limited access dataset of Multi-Ethnic Study of Atherosclerosis subjects (n = 6693). The lipid measures considered in the estimation of coronary risk were conventional and novel lipid parameters, the latter included total low-density lipoprotein (LDL), high-density lipoprotein (HDL) and very low-density lipoprotein (VLDL)-particle concentrations (LDL-p, HDL-p and VLDL-p), LDL-p/HDL-p ratio, and LDL-p subfractions. The outcome measured was occurrence of any coronary event (CE) that included myocardial infarction, resuscitated cardiac arrest, cardiac death, and angina. Results During an average follow up of 4.5 years, 228 patients developed coronary events. In the multivariate Cox proportional hazards model, TC/HDL-c (HR: 3.27; 95% CI: 1.95 to 5.47, P Conclusion In our large study cohort, a predictive model for future coronary events incorporating the best-available novel lipid parameter (LDL-p/HDL-p ratio) was comparable with the same model that incorporated conventional lipid ratios such as the TC/HDL-c ratio . The use of LDL-p/HDL-p ratio did not appear to offer incremental value over more traditional risk prediction models.

Background: The use of recreational drugs has been observed to have deleterious effects on the heart. The aim of our study was to evaluate the effect of substance abuse on the defibrillation threshold (DFT) in patients with implantable cardioverter-defibrillators (ICDs). Methods: A retrospective analysis was conducted on patients who had undergone ICD placement at a tertiary university medical center in Detroit, Michigan. Subjects were identified based on self-reported drug use and placed into one of the three groups: controls, cocaine, and other illicit drugs. Due to a disparity in race among groups, the main analysis on DFT value was conducted on African-American patients only. Furthermore, exploratory analyses were conducted to investigate the effects of marijuana use and race on DFT values. Results: A history of cocaine use (n = 17) significantly increases DFT among African Americans (17.3 ± 8 Joule [J] vs 12.5 ± 5 J in cases vs controls, P < 0.05), while previous use of marijuana does not significantly influence DFT. African-American patients with a history of illicit drug use had indications for ICD implantation at an earlier age and that within the control (nondrug using) group; African Americans (n = 73) had higher DFT compared to Caucasians (n = 32), (14.5 ± 0.5 J vs 9.7 ± 0.6 J, P < 0.05). Conclusions: A history of cocaine use in African Americans with ICD is a risk factor for high DFT and race itself (being African American) may be a risk for high DFT. Use of high-energy ICDs and other DFT lowering techniques may be considered for patients who have used or continue to use cocaine or in whom DFT testing cannot be performed at the time of implantation. (PACE 2011; 34:193–199)

Patent foramen ovale (PFO) is associated with cryptogenic stroke, migraine headache, decompression sickness, and platypnea-orthodeoxia syndrome. Patients undergoing transesophageal echocardiography are often hypovolemic from preprocedural fasting and might not demonstrate right to left shunting owing to insufficient right atrial pressure generation, despite provocative maneuvers. We hypothesized that volume replenishment with saline loading could potentially unmask a PFO by favorably modulating the interatrial pressure gradient. Our study sought to examine the role of pre- or intraprocedural intravenous fluid replenishment on PFO detection during transesophageal echocardiography. A total of 103 patients were enrolled. An initial series of bubble injections was performed unprovoked and then with provocative maneuvers such as the Valsalva maneuver and coughing. The patients were then given a rapid 500 ml saline bolus, and the same sequence of bubble injections was repeated. The presence, type, and magnitude of the right to left shunts were noted before and after the saline bolus. The detection rate of PFO increased from 10.6% to 26.2% after saline loading without any provocative maneuvers. When combined with provocative maneuvers (Valsalva or cough), saline loading improved the detection rate from 17.4% to 32.0%. Overall, from amongst the 103 enrolled patients, saline bolusing resulted in a de novo diagnosis of PFO in 15 patients, atrial septal aneurysm in 15, PFO coexisting with an atrial septal aneurysm in 10, and pulmonary arteriovenous fistula in 5 patients. In conclusion, saline infusion in appropriately selected patients during transesophageal echocardiography significantly enhances the detection of PFOs and pulmonary arteriovenous fistulas.

The clinical implications of microalbuminuria (MA) in nondiabetic persons with the metabolic syndrome (MS) are largely unknown. The present post hoc analysis of the Multiethnic Study of Atherosclerosis (MESA) included 5,809 nondiabetic persons with no history of cardiovascular disease aged 45 to 84 years. The study population was divided according to the presence or absence of MS and MA into 4 study groups: no MS and no MA, MA only, MS only, and MS plus MA. The measurements included markers of systemic inflammation, subclinical atherosclerosis, left ventricular mass index, composite and individual cardiovascular end points, and all-cause mortality. Prospective and cross-sectional analyses were performed to ascertain the association of study groups with these covariates. The MS plus MA group showed a consistently stronger association with the markers of systemic inflammation, subclinical atherosclerosis, and most clinical end points compared to the other study groups. In conclusion, stratification by MA can help identify a high-risk subset of nondiabetic patients with the MS.

Background Obese patients have favorable outcomes in congestive heart failure, hypertension, peripheral vascular disease, and coronary artery disease. Obesity also has been linked with increased incidence of atrial fibrillation, but its influence on outcomes in atrial fibrillation patients has not been investigated. The objective of this research is to investigate the effect of obesity on outcomes in atrial fibrillation. Methods The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study was one of the largest multicenter trials of atrial fibrillation, with 4060 patients. Subjects were randomized to rate versus rhythm-control strategy. We performed a post hoc analysis of the National Heart, Lung and Blood Institute limited access dataset of atrial fibrillation patients who had body mass index (BMI) data available in the AFFIRM study. BMI data were not available on 1542 patients. Patients with BMI ≥18.5 were split into normal (18.5-25), overweight (25-30), and obese (>30) categories as per BMI (kg/m 2 ). Multivariate Cox proportional hazards regression was used on the eligible 2492 patients. End points were all-cause mortality and cardiovascular mortality. Results Over three fourths of all patients in our cohort were overweight or obese. There were 304 deaths (103 among normal weight, 108 among overweight, and 93 among obese) and 148 cardiovascular deaths (54 among normal weight, 41 among overweight, and 53 among obese) over a mean period of 3 years of patient follow-up. On multivariate analysis, overweight (hazard ratio [HR] 0.64; 95% confidence interval [CI], 0.48-0.84; P =.001) and obese (HR 0.80; 95% CI, 0.68-0.93; P =.005) categories were associated with lower all-cause mortality as compared with normal weight. Overweight (HR 0.40; 95% CI, 0.26-0.60; P P =.01) also had lower cardiovascular mortality as compared with the normal weight patients. Conclusions Although in prior studies, obesity has been associated with increased risk of atrial fibrillation, an obesity paradox exists for outcomes in atrial fibrillation. Obese patients with atrial fibrillation appear to have better long-term outcomes than nonobese patients.

Lipid-lowering therapy (LLT) decreases mortality in select patient populations. LLT has also been shown to have antiarrhythmic effects, thus favorably influencing the incidence and recurrence of atrial fibrillation (AF). However, data are lacking regarding the effect of LLT on mortality in patients with AF. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study was the one of the largest multicenter trials comprising of 4,060 patients with AF at high risk for stroke and death. This is a post hoc analysis of the National Heart, Lung, and Blood Institute limited-access dataset of AFFIRM patients who were on LLT at the time of randomization (n = 913). The control group consisted of AFFIRM patients who were not on LLT (n = 3,147). Cox proportional hazards analysis was performed controlling for baseline differences. The end point was all-cause mortality, cardiovascular mortality, and ischemic stroke. A separate analysis was carried out for the combined end point of death, ventricular tachycardia, ventricular fibrillation, cardiac arrest, ischemic stroke, major bleeding, systemic embolism, pulmonary embolism, and myocardial infarction. Patients on LLT were younger and on more cardioactive medications but also had more cardiovascular morbidities. On multivariate analysis, LLT use was associated with lower all-cause mortality (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.62 to 0.95, p = 0.01), cardiovascular mortality (HR 0.71, 95% CI 0.53 to 0.95, p = 0.02), ischemic stroke (HR 0.56, 95% CI 0.36 to 0.89, p = 0.01), and combined end point (HR 0.81, 95% CI 0.69 to 0.96, p = 0.01). In conclusion, a decrease in mortality and adverse cardiovascular events was observed using LLT in AF.

Received December 8, 2009; revision accepted February 9, 2010. A 70-year-old African American female with known history of nonischemic cardiomyopathy (ejection fraction, 15%) was referred for BiVentricular implantable cardioverter-defibrillator (BiV-ICD) implantation for primary prevention. Because of a previous left mastectomy for breast cancer and occlusion of the left subclavian axillary venous system, a right-sided prepectoral implant was chosen for this patient. The procedure included a right-sided prepectoral BiV-ICD implantation, implantation of a right atrial appendage active fixation lead, a single-coil active fixation right ventricular lead, and a left ventricular coronary sinus lead. During the routine testing of the ICD, the defibrillation threshold (DFT) was >35 J, requiring external cardioversion. A second DFT testing performed thereafter with a polarity modification was also >35 J. The patient was subsequently treated with sotalol 80 mg bid for 1 week and the DFT was repeated but was still refractory (>35 J). Hence, alternate options were entertained. Although a left-sided subcutaneous coil array was considered, it was abandoned because the coil extension had to cross the midline of the chest. However, a percutaneous epicardial defibrillation coil implantation was considered (Figure 1A). Figure 1. A, Anteroposterior chest radiograph showing the BiV-ICD generator in the right prepectoral region with the defibrillation coil (halo) in the pericardial space. B, Subxyphoid approach (arrow) to access the pericardial space. Note …

Background: The implantable loop recorder (ILR) is a cost-effective tool with a high diagnostic yield in the evaluation of unexplained recurrent syncope. The Sleuth ILR (Transoma Medical, St. Paul MN, USA) is a new-generation ILR with wireless transmission capability approved by the Food and Drug Administration. We report the feasibility of achieving appropriate sensing over 1-year follow-up at the traditional midclavicular and alternative inframammary implantation sites without preimplant electrocardiogram (ECG) mapping. Methods and Results: We studied 32 patients with unexplained syncope, aged 58.4±18.44 years, with an ILR implanted at the left midclavicular location (n = 17) or the left inframammary site (n = 15) over 1-year post implant. No preimplant electrocardiogram (ECG) mapping was performed. The highest R-wave amplitudes were observed at the inframammary site, but over the entire follow-up period, amplitudes were not significantly different from those at the midclavicular site. At both sites, R-wave amplitudes at the 6-month follow-up were significantly higher than those measured at 1 week. P-waves were visible in 80–90% of the patients. There was no discernible difference in P-waves (amplitude) relative to implant location. Body mass index, left ventricular ejection fraction, and age did not significantly influence the R-wave amplitude or the ability to discern P-waves. Conclusion: Our findings show that the Sleuth ILR implanted at both the midclavicular and inframammary locations without preimplant ECG mapping achieves acceptable “R” waves. This may simplify implantation procedures and improve patient satisfaction. (PACE 2010; 834–840)

Clinical diagnosis of chronic or slowly progressing pericardial effusion with impending tamponade remains a challenge, particularly when classical physical signs are subtle or absent. A high index of suspicion should be entertained in such cases in the appropriate setting even when the clinical signs and symptoms are missing. We present two cases where the pericardial effusion was missed in the emergency department due to subtle clinical features or mistaken for a more familiar "look-a-like" presentation. A review of the literature and an analysis of various clinical parameters of published cases were performed. It is pivotal that physicians should not only be aware of the limitations of the traditional clinical signs, but also be familiar with the use of other subtle findings and the importance of other modalities that may potentially enhance the sensitivity in diagnosing chronic pericardial effusion impending tamponade.

Impaired relaxation of the left ventricle (LV) (diastolic dysfunction) invariably is associated with LV systolic dysfunction.1 Atrial contribution to ventricular filling (second filling phase of diastole) is pivotal in the presence of impaired relaxation where early filling is reduced. Cardiac Resynchronization Therapy (CRT) has been shown to improve diastolic function in patients with heart failure.2,3 Optimization of atrioventricular (AV) synchrony in sinus rhythm for patients with biventricular ICD (BiV ICD) for CRT is crucial in maximizing hemodynamic improvements.4,5

Background— Q waves on a 12-lead ECG are markers of a prior myocardial infarction (MI). However, they may regress or even disappear over time, and there is no specific ECG sign of a non–Q-wave MI. Fragmented QRS complexes (fQRSs), which include various RSR′ patterns, without a typical bundle-branch block are markers of altered ventricular depolarization owing to a prior myocardial scar. We postulated that the presence of an fQRS might improve the ability to detect a prior MI compared with Q waves alone by ECG. Methods and Results— A cohort of 479 consecutive patients (mean±SD age, 58.2±13.2 years; 283 males) who were referred for nuclear stress tests was studied. The fQRS included various morphologies of the QRS (1 R′ (fragmentation) in 2 contiguous leads, corresponding to a major coronary artery territory. The Q wave was present in 71 (14.8%) patients, an fQRS was present in 191 (34.9%) patients, and an fQRS and/or a Q wave was present in 203 (42.3%) patients. Sensitivity, specificity, and the negative predictive value for myocardial scar as detected by single photon emission computed tomography analysis were 36.3%, 99.2%, and 70.8%, respectively, for the Q wave alone; 85.6%, 89%, and 92.7%, respectively, for the fQRS; and 91.4%, 89%, and 94.2%, respectively, for the Q wave and/or fQRS. Conclusions— The fQRS on a 12-lead ECG is a marker of a prior MI, defined by regional perfusion abnormalities, which has a substantially higher sensitivity and negative predictive value compared with the Q wave.

Tissue Doppler imaging (TDI) patterns from the left atrial appendage (LAA) were evaluated by transesophageal echocardiography. Reproducible, characteristic triphasic or biphasic tissue velocities similar to Doppler flow of the LAA were obtained. Patient peak TDI velocities correlated well with flow and were measurable in atrial fibrillation. Patients with an embolic cerebrovascular accident and in sinus rhythm had higher tissue TDI velocities from the LAA compared with patients without an event, and the groups had similar flow velocities. Hence, Doppler tissue contraction dynamics determined by TDI may complement flow velocities in evaluating LAA function for risk assessment of thromboembolism.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening generalized disorder. The classic TTP ‘pentad’ is thrombocytopenia, microangiopathic hemolytic anemia (MAHA), renal impairment, neurological symptoms, and fever (Amorosi & Ultmann, 1966). Laboratory studies identified deficiency of plasma ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motifs 13) activity (ADAMTS13:AC) among some TTP patients (Furlan et al, 1998; Tsai & Lian, 1998). ADAMTS13 cleaves the peptide bond between Thy1605 and Met1606 in the A2 domain of von Willebrand factor (VWF) subunit. VWF is released into the plasma as unusually large VWF multimers (UL-VWFMs), which are degraded into smaller size VWF multimers by ADAMTS13. In the late 1990's, studies in the United States identified 117 cases of TTP that developed after initiation of the thienopyridine, ticlopidine; although at that time, ADAMTS13 activity levels were not widely available (Bennett et al, 1999; Steinhubl et al, 1999). A study of seven patients in the United States with ticlopidine-associated TTP found that all seven had severe deficiency of ADAMTS13 activity and five had detectable antibodies to ADAMTS13 activity (Tsai et al, 2000). We now report on 22 individuals from Japan with ticlopidine-induced TTP and compare these findings to those from the United States. Ticlopidine was the primary anti-platelet agent in Japan from 1989 to 2006. Since 1998, our laboratory at Nara Medical University has been a nationwide referral centre in Japan for thrombotic microangiopathies (TMAs), including TTP (Fujimura & Matsumoto, 2010). The study protocol was approved by the Ethics Committee of Nara Medical University Hospital. TTP diagnostic criteria were: microangiopathic haemolytic anaemia (haemoglobin ≤ 120 g/l), Coombs test negative, undetectable serum haptoglobin (

e describe the case of a 38-year-old patient, with nown psychiatric illnesses, who had systemic inlammatory response syndrome, acute respiratory istress syndrome (ARDS), and multiple organ dysunction syndrome (MODS) with Clostridium difficile olitis as the only identifiable cause. A syncopal vent from possible dehydration was followed by ymptoms of septic shock and ARDS. The untimely nd aberrant presentation of the C. difficile colitis, articularly with the uncertainty of recent antibiotic se, probably contributed to the severity of the linical course.

Syncope is most often due to temporary and self-terminating global cerebral hypoperfusion with an increased incidence in patients older than 70 years of age [1]. Although the etiopathogenesis of syncope is largely ascribed to neurally mediated, cardiovascular and orthostatic mechanisms, around 18% of patients have multiple potential causes, sometimes overlapping or by hitherto unexplained mechanisms [2]. Herein, we present a case of unexplained syncope and elucidate a mechanism which could plausibly explain the etiopathogenesis in a subset of elderly population presenting with syncope. An 84-year old Caucasian woman was brought to our emergency department (ED) after she passed out while watching and cheering at a baseball game. The patient was apparently pulseless at that time according to a family friend cardiologist who was seated next to her and had performed cardiopulmonary resuscitation. In the ED, her vital signs were stable with no orthostatic intolerance and the physical exam was unremarkable. Her past medical history included hypertension, gastroesophageal reflux disease and two recent episodes of

The human immunodeficiency virus (HIV) is the causative agent of the acquired immunodeficiency syndrome (AIDS) that has been affected 34 million people worldwide. Though an unprecedented growth has been taken place in the development of anti-HIV drugs during the last two decades, there is still no cure for this deadly disease. Cross resistance to anti HIV drugs is also a major concern in the development of anti AIDS pharmaceuticals. Therefore, nowadays studies are being focused mainly on the development of newer drugs capable of inhibiting resistant mutants. HIV-1-RT is one of the major targets for the development of newer molecular entities (NMEs) for the treatment of HIV/AIDS. Inhibitors of HIV-1-RT are classified as nucleoside reverse transcriptase inhibitors (NRTIs) and non nucleoside reverse transcriptase inhibitors (NNRTIs). A compound incorporating the pyrazole structural unit, lersiverine was reported recently, as a NNRTI. The objective of this study was to elucidate the binding mode analysis of novel pyrazole analogs in the non nucleoside inhibitory binding pocket of reverse transcriptase (PDB ID IRT2). Molecular docking studies of 484 novel pyrazole analogs were performed by Glide program in the NNIBP of HIV-1 reverse transcriptase (PDB code 1RT2).The Novel pyrazole analogs bearing different substituted aryl groups were designed The following eight compounds with aryl substituents like R=2,5-2CH3 &R1= m-OCH3 , R=H &R1=m-OCH3,R=H &R1=m-CH3, R=o-Cl &R1=m-OCH3, R=o-Cl &R1=p-OCH3, R=m-CH3 &R1=m-CH3, R=m-Cl &R1=m-Cl, R=m-Cl &R1=2,4-2NO2, exhibited highest docking score in the NNIBP of IRT2 . Thus, it is evident that this kind of scaffold with hydrophobic and electron donating or electron withdrawing groups substituted in the phenyl rings can be exploited for the development of novel HIV-1-RT2 inhibitors which can facilitate better patient adherence and also inhibit the resistant strains of HIV.

This letter describes serious adverse events (three fatal cardiorespiratory arrests and two grade 4 anaphylaxis and hypotension events) related to the administration of peginesatide during surveillance in patients undergoing dialysis. As a result, the drug was removed from the market.

PURPOSE Azithromycin use has been associated with increased risk of death among patients at high baseline risk, but not for younger and middle-aged adults. The Food and Drug Administration issued a public warning on azithro- mycin, including a statement that the risks were similar for levofloxacin. We conducted a retrospective cohort study among US veterans to test the hypothesis that taking azithromycin or levofloxacin would increase the risk of cardiovascular death and cardiac arrhythmia compared with persons taking amoxicillin. METHODS We studied a cohort of US veterans (mean age, 56.8 years) who received an exclusive outpatient dispensation of either amoxicillin (n = 979,380), azithromycin (n = 594,792), or levofloxacin (n = 201,798) at the Department of Veterans Affairs between September 1999 and April 2012. Azithromycin was dis- pensed mostly for 5 days, whereas amoxicillin and levofloxacin were dispensed mostly for at least 10 days. RESULTS During treatment days 1 to 5, patients receiving azithromycin had sig- nificantly increased risk of death (hazard ratio (HR) = 1.48; 95% CI, 1.05-2.09) and serious arrhythmia (HR = 1.77; 95% CI, 1.20-2.62) compared with patients receiving amoxicillin. On treatment days 6 to 10, risks were not statistically differ- ent. Compared with patients receiving amoxicillin, patients receiving levofloxacin for days 1 to 5 had a greater risk of death (HR = 2.49, 95% CI, 1.7-3.64) and serious cardiac arrhythmia (HR = 2.43, 95% CI, 1.56-3.79); this risk remained significantly different for days 6 to 10 for both death (HR = 1.95, 95% CI, 1.32- 2.88) and arrhythmia (HR = 1.75; 95% CI, 1.09-2.82). CONCLUSIONS Compared with amoxicillin, azithromycin resulted in a statistically significant increase in mortality and arrhythmia risks on days 1 to 5, but not 6 to 10. Levofloxacin, which was predominantly dispensed for a minimum of 10 days, resulted in an increased risk throughout the 10-day period.

As of 2013, the Southern Network on Adverse Reactions (SONAR) team described 50 significant adverse drug reactions (sADRs) associated with FDA approved drugs. The team also investigates policy issues surrounding pharmacovigilance. Herein we describe the systematic approach to pharmacovigilance taken by the Southern Network on Adverse Reactions and discuss major findings from the group. By 2015, the team hopes to have identified 20 additional sADRs focusing on biologics, biosimilars, and biobetters. The ultimate goal of SONAR is to decrease the timescale between ADR detection and the dissemination of information regarding the sADR

Bronchocutaneous fistula is a pathologic communication between the bronchus, pleural space, and subcutaneous tissue. It can occur as a complication of positive pressure ventilation and pneumonectomy. Diagnosis is made by imaging studies. Treatment options are endoscopic repair, parietal pleurectomy, and pleurodesis. Our patient is a 53-year-old woman who had a difficult chest-tube placement for complicated parapneumonic effusion. Computed tomography scan revealed a fistulous tract from the bronchus to the skin at the site of the original chest tube, and chest x-ray film revealed a subcutaneous fistulous air tract in the lateral chest. It is usually an acquired condition; congenital bronchocutaneous fistula is rare. We report a case of bronchocutaneous fistula after chest-tube placement.

Objective: The reason for the failure of most of the anti-HIV drugs are their poor pharmacokinetics, the poor risk to benefit ratio and the drug resistance. With the objective of developing newer pyrazole scaffolds for effective treatment of HIV, binding mode analysis of designing ligands with the HIV-1RT protein and prediction of key ADME and toxicity parameters of the compounds was in an area of interest.Methods: In this study, molecular docking studies and ADME-T studies were carried out in designing of some novel pyrazole analogs. The protein (PDB ID: 1RT2) was prepared using the Protein Preparation Wizard (Schrodinger Glide 5.0). ADME parameters calculated by QikProp 3.0v and toxicity of designed analogs checked by using two different online software’s namely Lazar and protox.Results: Most of the designed pyrazole analogs have good oral absorption as well as good binding affinity towards HIV-1 reverse transcriptase.Conclusion: Finally total 5 analogs (SGS-2, 3, 12, 13 and 14) from the 14 designed leads were found to be best on the basis of molecular docking and ADME-T studies.

Introduction: Moderate alcohol intake has been associated with reduced cardiovascular mortality. Red cell distribution width (RDW) is an emerging cardiovascular risk marker, that is increasingly gaining recognition. No prior study has evaluated the association between alcohol intake and RDW. Methods: We evaluated 6,424 nationally representative individuals participating in the National Health and Nutrition Examination Survey (NHANES) 1999 to 2006, free of cardiovascular co-morbidities (including coronary heart disease, diabetes, congestive heart failure, stroke and myocardial infarction) at baseline. RDW was divided into quartiles [Quartile 1 (Q1) ≤12 (reference category), Q2: 12.1-12.5; Q3: 12.6-13; Q4: >13] and alcohol intake was categorized by number of drinks per day [ Results: Mean RDW levels varied inversely with number of drinks per day (12.9 in reference alcohol category versus 12.5 in ≥3 drinks/day, p Conclusion: Moderate alcohol intake [1 to 2 drinks /day] is associated with more favorable levels of RDW. The association appears to be independent of nutritional deficiencies, inflammatory markers and other conventional cardiovascular risk factors. Table 1: Risk of Higher RDW with Increasing Alcohol Intake RDW Categories Alcohol Categories * ≤12 n=1,612 12.1-12.5 n=2,037 12.6-13 n=1,215 >13 n=1,560 1 OR[95% CI] p-value OR [95% CI] p-value OR [95% CI] p-value * 1 1 1 1 1 1 drink/day n=1,510 Model 1 1 0.93 [0.79-1.09] 0.351 0.97 [0.81-1.16] 0.750 0.72 [0.61-0.88] 0.001 Model 2 1 0.96 [0.82-1.13] 0.657 1.01 [0.84-1.21] 0.931 0.76 [0.62-0.93] 0.008 2 drinks/day n=1,212 Model 1 1 1.00 [0.85-1.17] 0.963 0.81 [0.67-0.99] 0.046 0.67 [0.55-0.82] Model 2 1 1.04 [0.88-1.22] 0.669 0.90 [0.74-1.11] 0.336 0.71 [0.56-0.88] 0.002 ≥3 drinks/day Model 1 1 1.00 [0.86-1.17] 0.995 0.85 [0.70-1.02] 0.082 0.86 [0.71-1.03] 0.105 Model 2 1 0.98 [0.84-1.15] 0.826 0.88 [0.72 -1.07]0.193 0.91 [0.74-1.11] 0.346 Model 1: Alcohol Drinks + Sex, Age, systolic blood pressure, anti-hypertensive medications, High Density Lipoprotein cholesterol, total cholesterol, ever smoking and deficiency of nutritional factors (Iron, folic acid and vitamin B 12 ) Model 2: Age, sex, race + body mass index, estimated Glomerular Filtration Rate, high sensitivity C - Reactive Protein, hypertension, hyperlipidemia, ever smoking, mean corpuscular volume, hemoglobin and deficiency of nutritional factors Abbreviations: OR - odds ratio, CI - Confidence Interval, RDW - Red cell Distribution Width. * RDW ≤12 and ‘Zero’ Alcohol drinks/day serve as reference categories for the comparison

Introduction: Metabolic syndrome (MS) is an adverse predictor of cardiovascular outcomes. Recently, waist height ratio (WHtR) is shown to correlate better with future cardiovascular risk factors than other anthropometric measures. We sought to determine whether replacing waist circumference (WC) with WHtR in metabolic syndrome diagnostic criteria per National Cholesterol Education Program (NCEP) guidelines improves predictive accuracy for future cardiovascular disease (CVD) events. Methods: The study cohort consisted of prospectively evaluated 6,702 healthy adults aged 45-84 years enrolled in the Multi-Ethnic Study of Atherosclerosis [MESA] study [Age-: 62±10 years, 47% males, 1473 Hispanics, 2575 Caucasians, 799 Chinese and 1855 African Americans]. Metabolic syndrome (MSwc), at baseline, was defined by NCEP guidelines (n=2,208). Metabolic syndrome (MSwhtr) was redefined using WHtR (≥ 0.5 in both male and females) in place of WC, keeping rest of the components constant as recommended by NCEP (n=2,590). CVD events were defined as All CVD (CVDa) per MESA protocol (See Table ). Unadjusted and adjusted Cox-proportional hazard analysis was performed. Harrell's C-statistics were calculated for the most adjusted models. Results: Total of 319 CVDa events [n=171 (7.44%) in MSwc group and n=190 (7.34%) in MSwhtr group] were identified during a mean follow up of 4.6 years. Results are displayed in the table . Conclusion: Predictive accuracy of MS re-defined with WHtR and MS defined with WC per NCEP criteria is comparable. Risk of CVDa and Metabolic Syndrome Metabolic Syndrome per NCEP guideline [MSwc] Re-defined Metabolic Syndrome with WHtR [MSwhtr] Models HR (95% CI) p-value Models HR (95% CI) p-value 2.45 (1.97-3.06) 0.000 2.43 (1.95-3.05) 0.000 MSwc + X 2.39 (1.91-2.99) 0.000 MSwhtr + X 2.28 (1.82-2.85) 0.000 MSwc + Y 1.97 (1.56-2.49) 0.000 MSwhtr + Y 1.93 (1.53-2.43) 0.000 MSwc + Z 1.89 (1.47-2.44) 0.000 MSwhtr + Z 1.83 (1.43-2.35) 0.000 Harrell's C (MSwc + Z) -: 0.7517 Harrell's C (MSwhtr + Z) -: 0.7531 Abbreviations: HR - Hazard Ratio; CI - Confidence Interval; CVDa - All Cardiovascular Disease events X = Age, Sex, Race Y = X + Hypertension, Use of Hypertension Medications, Total intentional exercise, Total cholesterol, Use of Statins, Smoking [>100 cigarettes ever in life] Z = Y + C-reactive Protein + Serum Insulin level CVDa includes - Myocardial infarction(MI), Resuscitated Cardiac Arrest (RCA), Definite Angina, Probable Angina (if followed by Revascularization), Stroke, Stroke Death, coronary heart disease (CHD) Death, Other Atherosclerotic Death, Other CVD Death.