Atrial fibrillation and risk of adverse outcomes in heart failure with reduced, mildly reduced, and preserved ejection fraction: A systematic review and meta-analysis.

INTRODUCTION: Heart failure (HF) and atrial fibrillation (AF) frequently co-exist. Contemporary classification of HF categorizes it into HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF). Aggregate data comparing the risk profile of AF between these three HF categories are lacking. METHODS: We conducted a systematic review and meta-analysis aimed at determining any significant differences in AF-associated all-cause mortality, HF hospitalizations, cardiovascular mortality (CV), and stroke between HFrEF, HFmrEF, and HFpEF. A systematic search of PubMed, EMBASE, and Cochrane Library databases until February 28, 2023. Data were combined using DerSimonian-Laird random effects model. RESULTS: A total of 22 studies comprising 248 323 patients were retained: HFrEF 123 331 (49.7%), HFmrEF 40 995 (16.5%), and HFpEF 83 997 (33.8%). Pooled baseline AF prevalence was 36% total population, 30% HFrEF, 36% HFmrEF, and 42% HFpEF. AF was associated with a higher risk of all-cause mortality in the total population with pooled hazard ratio (HR) = 1.13 (95% confidence interval [CI] = 1.07-1.21), HFmrEF (HR = 1.25, 95% CI = 1.05-1.50) and HFpEF (HR = 1.16, 95% CI = 1.09-1.24), but not HFrEF (HR = 1.03, 95% CI = 0.93-1.14). AF was associated with a higher risk of HF hospitalizations in the total population (HR = 1.29, 95% CI = 1.14-1.46), HFmrEF (HR = 1.64, 95% CI = 1.20-2.24), and HFpEF (HR = 1.46, 95% CI = 1.17-1.83), but not HFrEF (HR = 1.01, 95% CI = 0.87-1.18). AF was only associated with CV in the HFpEF subcategory but was associated with stroke in all three HF subtypes. CONCLUSIONS: AF appears to be associated with a higher risk of all-cause mortality and HF hospitalization in HFmrEF and HFpEF. With these findings, the paucity of data and treatment guidelines on AF in the HFmrEF subgroup becomes even more significant and warrant further investigations.

Persistence of significant secondary mitral regurgitation post-cardiac resynchronization therapy and survival: a systematic review and meta-analysis : Mitral regurgitation and mortality post-CRT.

Cardiac resynchronization therapy (CRT) significantly reduces secondary mitral regurgitation (MR) in patients with severe left ventricular systolic dysfunction. However, uncertainty remains as to whether improvement in secondary MR correlates with improvement with mortality seen in CRT. We conducted a meta-analysis to determine the association of persistent unimproved significant secondary MR (defined as moderate or moderate-to-severe or severe MR) compared to improved MR (no MR or mild MR) post-CRT with all-cause mortality, cardiovascular mortality, and heart failure hospitalization. A systematic search of PubMed, EMBASE, and Cochrane Library databases till July 31, 2022 identified studies reporting clinical outcomes by post-CRT secondary MR status. In 12 prospective studies of 4954 patients (weighted mean age 66.8 years, men 77.8%), the median duration of follow-up post-CRT at which patients were re-evaluated for significant secondary MR was 6 months and showed significant relative risk reduction of 30% compared to pre-CRT. The median duration of follow-up post-CRT for ascertainment of main clinical outcomes was 38 months. The random effects pooled hazard ratio (95% confidence interval) of all-cause mortality in patients with unimproved secondary MR compared to improved secondary MR was 2.00 (1.57-2.55); p < 0.001). There was insufficient data to evaluate secondary outcomes in a meta-analysis, but limited data that examined the relationship showed significant association of unimproved secondary MR with increased cardiovascular mortality and heart failure hospitalization. The findings of this meta-analysis suggest that lack of improvement in secondary MR post-CRT is associated with significantly elevated risk of all-cause mortality and possibly cardiovascular mortality and heart failure hospitalization. Future studies may investigate approaches to address persistent secondary MR post-CRT to help improved outcome in this population.

Evolution and prognosis of tricuspid and mitral regurgitation following cardiac implantable electronic devices: a systematic review and meta-analysis.

AIMS: Significant changes in tricuspid regurgitation (TR) and mitral regurgitation (MR) post-cardiac implantable electronic devices (CIEDs) are increasingly recognized. However, uncertainty remains as to whether the risk of CIED-associated TR and MR differs with right ventricular pacing (RVP) via CIED with trans-tricuspid RV leads, compared with cardiac resynchronization therapy (CRT), conduction system pacing (CSP), and leadless pacing (LP). The study aims to synthesize extant data on risk and prognosis of significant post-CIED TR and MR across pacing strategies. METHODS AND RESULTS: We searched PubMed, EMBASE, and Cochrane Library databases published until 31 October 2023. Significant post-CIED TR and MR were defined as ≥ moderate. Fifty-seven TR studies (n = 13 723 patients) and 90 MR studies (n = 14 387 patients) were included. For all CIED, the risk of post-CIED TR increased [pooled odds ratio (OR) = 2.46 and 95% CI = 1.88-3.22], while the risk of post-CIED MR reduced (OR = 0.74, 95% CI = 0.58-0.94) after 12 and 6 months of median follow-up, respectively. Right ventricular pacing via CIED with trans-tricuspid RV leads was associated with increased risk of post-CIED TR (OR = 4.54, 95% CI = 3.14-6.57) and post-CIED MR (OR = 2.24, 95% CI = 1.18-4.26). Binarily, CSP did not alter TR risk (OR = 0.37, 95% CI = 0.13-1.02), but significantly reduced MR (OR = 0.15, 95% CI = 0.03-0.62). Cardiac resynchronization therapy did not significantly change TR risk (OR = 1.09, 95% CI = 0.55-2.17), but significantly reduced MR with prevalence pre-CRT of 43%, decreasing post-CRT to 22% (OR = 0.49, 95% CI = 0.40-0.61). There was no significant association of LP with post-CIED TR (OR = 1.15, 95% CI = 0.83-1.59) or MR (OR = 1.31, 95% CI = 0.72-2.39). Cardiac implantable electronic device-associated TR was independently predictive of all-cause mortality [pooled hazard ratio (HR) = 1.64, 95% CI = 1.40-1.90] after median of 53 months. Mitral regurgitation persisting post-CRT independently predicted all-cause mortality (HR = 2.00, 95% CI = 1.57-2.55) after 38 months. CONCLUSION: Our findings suggest that, when possible, adoption of pacing strategies that avoid isolated trans-tricuspid RV leads may be beneficial in preventing incident or deteriorating atrioventricular valvular regurgitation and might reduce mortality.

Risk of ventricular arrhythmia in cardiac resynchronization therapy responders and super-responders: a systematic review and meta-analysis.

AIMS: Response to cardiac resynchronization therapy (CRT) is associated with improved survival, and reduction in heart failure hospitalization, and ventricular arrhythmia (VA) risk. However, the impact of CRT super-response [CRT-SR, increase in left ventricular ejection fraction (LVEF) to ≥ 50%] on VA remains unclear. METHODS AND RESULTS: We undertook a meta-analysis aimed at determining the impact of CRT response and CRT-SR on risk of VA and all-cause mortality. Systematic search of PubMed, EMBASE, and Cochrane databases, identifying all relevant English articles published until 31 December 2019. A total of 34 studies (7605 patients for VA and 5874 patients for all-cause mortality) were retained for the meta-analysis. The pooled cumulative incidence of appropriate implantable cardioverter-defibrillator therapy for VA was significantly lower at 13.0% (4.5% per annum) in CRT-responders, vs. 29.0% (annualized rate of 10.0%) in CRT non-responders, relative risk (RR) 0.47 [95% confidence interval (CI) 0.39-0.56, P < 0.0001]; all-cause mortality 3.5% vs. 9.1% per annum, RR of 0.38 (95% CI 0.30-0.49, P < 0.0001). The pooled incidence of VA was significantly lower in CRT-SR compared with CRT non-super-responders (non-responders + responders) at 0.9% vs. 3.8% per annum, respectively, RR 0.22 (95% CI 0.12-0.40, P < 0.0001); as well as all-cause mortality at 2.0% vs. 4.3%, respectively, RR 0.47 (95% CI 0.33-0.66, P < 0.0001). CONCLUSIONS: Cardiac resynchronization therapy super-responders have low absolute risk of VA and all-cause mortality. However, there remains a non-trivial residual absolute risk of these adverse outcomes in CRT responders. These findings suggest that among CRT responders, there may be a continued clinical benefit of defibrillators.

Catheter ablation for atrial fibrillation in patients with significant mitral regurgitation: A systematic review and meta-analysis.

BACKGROUND: Atrial fibrillation (AF) is commonly associated with cardiac structural abnormalities including mitral regurgitation (MR). Contemporary guidelines recommend consideration of early rhythm control strategies including catheter ablation (CA) for AF. However, the long-term efficacy of CA is highly variable across studies and patient populations, and the effect of coexisting MR on AF recurrence remains unclear. OBJECTIVE: A systematic review and meta-analysis was performed to determine the impact of significant MR (defined as ≥moderate) on AF recurrence rate after CA and whether CA for AF is associated with significant changes in the severity of MR. METHODS: A systematic search of PubMed, Embase, Web of Science, and Cochrane databases for all English-language studies published to December 31, 2023, was performed. RESULTS: A total of 17 studies (N = 2624 patients) were retained for meta-analysis. The pooled recurrence proportion of AF after CA in patients with baseline significant MR was 36% (95% CI, 27%-46%) compared with 27% (14%-41%) in patients without. The pooled hazard ratio (95% CI) for AF recurrence after CA in the presence of significant MR was 2.47 (1.52-4.01; P < .001; Egger test P value, .0583). The pooled proportion of patients who witnessed MR improvement to nonsignificant (ie,

Intravascular ultrasound-assisted coronary sinus lead implant in patient with contrast anaphylaxis.

Ultrasound imaging has been used in a range of cardiac interventions. We describe the use of intravascular ultrasound to assist in coronary sinus lead implantation in a patient where contrast venography was contraindicated.

Pacing system malfunction is a rare cause of hospital admission for syncope in patients with a permanent pacemaker.

BACKGROUND: Few studies have examined the prevalence of permanent pacemaker (PPM) malfunction among patients with a previously implanted pacemaker admitted to the hospital with syncope. OBJECTIVE: This study sought to examine causes of syncope in patients with a previously implanted pacemaker admitted to our hospital with syncope. METHODS: We retrospectively reviewed our hospital admission database for patients who had both keywords "syncope" and "pacemaker" as their diagnoses from January 1, 1995 until June 1, 2012. One hundred and sixty-two patients who were admitted to the hospital because of syncope and had a PPM implanted prior to the index syncopal episode were included. All patients had pacemakers interrogated during the admission. Two independent physicians examined the discharge summary of each patient and determined the cause of syncope in each case. RESULTS: Of the 162 patients studied, eight (4.9%) were found to have pacemaker system malfunction as a cause of syncope. In 96 patients (59.2%), the cause of syncope could not be determined prior to hospital discharge. Among the identifiable causes of syncope, orthostatic hypotension was most prevalent (16%) followed by vasovagal (6%), severe aortic stenosis (4.3%), atrial arrhythmia (3.1%), acute and subacute infection (3.1%), and other less prevalent causes (3.1%). CONCLUSION: In this study, PPM system malfunction was rarely a cause of syncope in patients admitted to the hospital with a previously implanted device.

T-wave inversion and diastolic dysfunction in patients with electrocardiographic left ventricular hypertrophy.

OBJECTIVES: The aim of this study was to investigate if T-wave inversion (TWI) in the settings of electrocardiogram (ECG)-left ventricular hypertrophy (LVH) is associated with advanced diastolic dysfunction (DD) in subjects with preserved ejection fraction (EF). BACKGROUND: Animal studies suggested that an abnormal transmural repolarization sequence from endocardium to epicardium may contribute to DD. However, little is known about abnormal repolarization sequence and DD in humans. METHODS: We studied 231 patients with ECG-diagnosed LVH and with an EF of 50% or greater (measured within 6 months of the index ECG). T-wave inversion was assessed on leads I, aVL, V(4), V(5), or V(6). Diastolic dysfunction was defined based on echocardiographic estimation of the left atrial pressure. We used multiple logistic regression to estimate the odds ratio of DD comparing patients with TWI with those without TWI. RESULTS: The average age was 65.0 ± 14.2 years, and 61% were women. The mean EF was 61.8% ± 6.6%. Patients with TWIs were more likely to have coronary artery disease (P = .013) and diabetes (P = .007). There was a 5.6-fold increased odds of DD in patients with TWI compared with those without TWI in a model adjusting for sex, age, relative wall thickness, body mass index, hypertension, coronary artery disease, diabetes, hyperlipidemia, and smoking. When comparing different echocardiographic estimates of the left atrial pressure, patients with TWI displayed higher values for septal and lateral E/e', left atrial volume index, and right ventricular/right atrial peak systolic gradient (P < .01 for each parameter). CONCLUSIONS: T-wave inversion is associated with increased odds of DD in patients with ECG-LVH with preserved systolic function. The reversal of the normal sequence of repolarization manifested on the 12-lead ECG as TWI may be a factor to DD.

On-resin synthesis of an acylated and fluorescence-labeled cyclic integrin ligand for modification of poly(lactic-co-glycolic acid).

Cyclic Arg-Gly-Asp (RGD) peptides show remarkable affinity and specificity to integrin receptors and mediate important physiological effects in tumor angiogenesis. Additionally, they are one of the keyplayers in improving the biocompatibility of biomaterials. The fully biodegradable polymer poly(lactic-co-glycolic acid) (PLGA) is frequently used for biomedical implants and can be applied as nanoparticles for drug delivery. The aim of this work was the generation of a lipidated c[RGDfK] peptide including a second functionality for coating of hydrophobic PLGA. Therefore, we established a general and straightforward strategy for the introduction of two different modifications into the same c[RGDfK] peptide. This allowed the generation of a palmitoylated integrin-binding lipopeptide that shows high affinity to PLGA. Additionally, we coupled 5(6)-carboxyfluorescein to the second site for modification to enable sensitive quantification of the immobilized lipopeptide on PLGA. In conclusion, we present a synthesis protocol that enables the preparation of c[RGDfK] lipopeptides with a strong affinity to PLGA and an additional site for modifications. This will provide the opportunity to introduce a variety of effector molecules site-specifically to the c[RGDfK] lipopeptide, which will enable the introduction of multifunctionality into c[RGDfK]-coated PLGA devices or nanoparticles.

Ongoing Risk of Ventricular Arrhythmias and All-Cause Mortality at Implantable Cardioverter Defibrillator Generator Change: A Systematic Review and Meta-Analysis.

[Figure: see text].

Intramyocardial transplantation of autologous CD34+ stem cells for intractable angina: a phase I/IIa double-blind, randomized controlled trial.

BACKGROUND: A growing population of patients with coronary artery disease experiences angina that is not amenable to revascularization and is refractory to medical therapy. Preclinical studies have indicated that human CD34+ stem cells induce neovascularization in ischemic myocardium, which enhances perfusion and function. METHODS AND RESULTS: Twenty-four patients (19 men and 5 women aged 48 to 84 years) with Canadian Cardiovascular Society class 3 or 4 angina who were undergoing optimal medical treatment and who were not candidates for mechanical revascularization were enrolled in a double-blind, randomized (3:1), placebo-controlled dose-escalating study. Patients received granulocyte colony-stimulating factor 5 microg x kg(-1) x d(-1) for 5 days with leukapheresis on the fifth day. Selection of CD34+ cells was performed with a Food and Drug Administration-approved device. Electromechanical mapping was performed to identify ischemic but viable regions of myocardium for injection of cells (versus saline). The total dose of cells was distributed in 10 intramyocardial, transendocardial injections. Patients were required to have an implantable cardioverter-defibrillator or to temporarily wear a LifeVest wearable defibrillator. No incidence was observed of myocardial infarction induced by mobilization or intramyocardial injection. The intramyocardial injection of cells or saline did not result in cardiac enzyme elevation, perforation, or pericardial effusion. No incidence of ventricular tachycardia or ventricular fibrillation occurred during the administration of granulocyte colony-stimulating factor or intramyocardial injections. One patient with a history of sudden cardiac death/ventricular tachycardia/ventricular fibrillation had catheter-induced ventricular tachycardia during mapping that required cardioversion. Serious adverse events were evenly distributed. Efficacy parameters including angina frequency, nitroglycerine usage, exercise time, and Canadian Cardiovascular Society class showed trends that favored CD34+ cell-treated patients versus control subjects given placebo. CONCLUSIONS: A randomized trial of intramyocardial injection of autologous CD34+ cells in patients with intractable angina was completed that provides evidence for feasibility, safety, and bioactivity. A larger phase IIb study is currently under way to further evaluate this therapy.

Baseline myocardial perfusion predicts response to cardiac resynchronization therapy: a prospective observational study.

PURPOSE: We prospectively determined whether preimplant myocardial perfusion imaging (MPI) predicts outcome with biventricular pacing (BiVP). METHODS: Single-photon emission computed tomography (SPECT) MPI, left ventricular (LV) volumes, ejection fraction (EF), 6-min hall walk (6MW) were assessed at baseline and at 4 months in 19 patients with ischemic cardiomyopathy undergoing BiVP. Clinical and hemodynamic responses were correlated with MPI. RESULTS: Lower global myocardial scar burden predicted hemodynamic response to BiVP, while higher burden was associated with poor response. Clinical improvement with BiVP occurred in 12 (63%) of the patients. Clinical BiVP responders had lower rest/stress MPI score difference. There was a close negative correlation between MPI reversibility and increased 6MW distance. CONCLUSIONS: Baseline MPI is associated with clinical and hemodynamic response to BiVP: greater myocardial scar burden is predictive of poor hemodynamic response, while higher ischemic burden is predictive of poor clinical response. There is a differential response to BiVP by clinical and hemodynamic criteria.

Posttraumatic stress disorder and mortality in VA patients with implantable cardioverter-defibrillators.

BACKGROUND: The association between posttraumatic stress disorder (PTSD) and mortality in patients undergoing implantable cardioverter-defibrillator (ICD) placement has not been evaluated in US veterans. HYPOTHESIS: PTSD in veterans with ICD is associated with increased mortality. METHODS: We studied a retrospective cohort of 25 678 veterans who underwent ICD implantation between September 30, 2002, and December 31, 2011. Of these subjects, 3280 carried the diagnosis of PTSD prior to ICD implantation. Primary outcome was all-cause mortality between date of ICD implantation and end of follow-up (September 30, 2013). We used Cox proportional hazard models to compute multivariable adjusted hazard ratios with corresponding 95% confidence intervals for the relation between PTSD diagnosis and death following ICD placement. RESULTS: During a mean follow-up of 4.21 ± 2.62 years, 11 015 deaths were reported. The crude incidence rate of death was 87.8 and 103.9/1000 person-years for people with and without PTSD, respectively. We did not find an association between presence of PTSD before or after ICD implantation and incident death when adjusted for multiple risk factors (hazard ratio: 1.003, 95% confidence interval: 0.948-1.061). In secondary analysis, no statistically significant association was found. CONCLUSIONS: In this retrospective cohort study among more than 25 000 veterans undergoing ICD implantation, almost 13% had a diagnosis of PTSD. Subjects with PTSD were significantly younger, yet they had a higher incidence of coronary heart disease, major cardiac comorbidities, cancer, and mental health conditions. We found no association between presence of PTSD before or after ICD implantation and incident death when adjusting for all covariates.

Three-dimensional rotational angiography of the left atrium and esophagus--A virtual computed tomography scan in the electrophysiology lab?

BACKGROUND: Three-dimensional (3D) reconstruction of the heart and surrounding structures has been supplementing traditional two-dimensional imaging to guide diagnostic and therapeutic electrophysiologic procedures. Current methods using computed tomography (CT)/magnetic resonance imaging (MRI) reconstruction have certain limitations. OBJECTIVE: We investigated the feasibility of rotational angiography (RA) combined with simultaneous esophagogram to create an intraprocedural 3D reconstruction of the left atrium (LA) and the esophagus. METHODS: Rotational angiography was performed. Contrast was injected via a pigtail catheter positioned in the left or right pulmonary artery to achieve a levophase venous cycle opacification of the ipsilateral pulmonary veins and adjacent LA. Simultaneous administration of oral contrast allowed a 3D reconstruction of the esophagus in the same image. Qualitative and quantitative comparison between the intraprocedural 3D RA and a remote CT scan was performed in 11 consecutive patients undergoing ablation for atrial fibrillation. RESULTS: Adequate visualization of the pulmonary veins, adjacent posterior LA, and esophagus was achieved in 10 patients. Determination of pulmonary transit time to guide the initiation of RA resulted in better-quality imaging. A close correlation between 3D RA and CT was found. Based on close proximity between the LA and esophagus, the ablation procedure was modified in three patients. CONCLUSIONS: Three-dimensional RA of the LA and esophagus is a promising new method allowing intraprocedural 3D reconstruction of these structures comparable in quality to a CT scan. Further studies refining the method are justified because it could eliminate the need for CT/MRI scans before ablation.

Evaluation of left atrial and posterior mediastinal anatomy by multidetector helical computed tomography imaging: relevance to ablation.

INTRODUCTION: Increasing use of catheter ablation in the left atrium (LA) requires understanding of substrate anatomy, especially with regard to potential damage to adjacent structures. METHODS AND RESULTS: We reviewed multidetector helical computed tomography (MDCT) imaging on 42 subjects, 26 imaged before planned LA ablation for atrial fibrillation (AF), and 16 without AF. LA volume and dimensions were larger in patients with AF (p < 0.05) and the spine and aorta (Ao) impressed the LA more frequently in the AF group. The esophagus (Eo) was the predominant feature on the posterior LA wall, contacting it in all patients. The Ao was in contact with the LA body or the left inferior pulmonary vein (PV) in 32 (76%) of 42 cases, and in 10 it ran along an indentation on the posterior aspect of the LA. The coronary sinus was adjacent to LA ablation sites, the azygos vein was rarely adjacent to those sites, and the left bronchus abutted the PV ostium but not the LA. Two patients had findings that directly impacted the ablation procedure: one patient had a dilated fluid filled Eo with esophageal stricture and underwent nasogastric decompression before ablation, and one was discovered to have an anomalous PV and underwent surgical repair. CONCLUSIONS: MDCT imaging identifies structures adjacent to the LA, which could be affected by ablation. Posterior LA topography can be influenced by the position of the Ao or by the proximity of the spine. Preprocedural imaging can characterize anatomic structures that could be vulnerable during ablation, and detect unusual pathology that can affect the treatment plan.

Surface modification of copolymerized films from three-armed biodegradable macromers - An analytical platform for modified tissue engineering scaffolds.

The concept of macromers allows for a broad adjustment of biomaterial properties by macromer chemistry or copolymerization. Copolymerization strategies can also be used to introduce reactive sites for subsequent surface modification. Control over surface features enables adjustment of cellular reactions with regard to site and object of implantation. We designed macromer-derived polymer films which function as non-implantable analytical substrates for the investigation of surface properties of equally composed scaffolds for bone tissue engineering. To this end, a toolbox of nine different biodegradable, three-armed macromers was thermally cross-copolymerized with poly(ethylene glycol)-methacrylate (PEG-MA) to films. Subsequent activation of PEG-hydroxyl groups with succinic anhydride and N-hydroxysuccinimid allowed for covalent surface modification. We quantified the capacity to immobilize analytes of low (amino-functionalized fluorescent dye, Fcad, and RGD-peptides) and high (alkaline phosphatase, ALP) molecular weight. Fcad grafting level was controlled by macromer chemistry, content and molecular weight of PEG-MA, but also the solvent used for film synthesis. Fcad molar amount per surface area was twentyfive times higher on high-swelling compared to low-swelling films, but differences became smaller when large ALP (appr. 2:1) were employed. Similarly, small differences were observed on RGD peptide functionalized films that were investigated by cell adhesion studies. Presentation of PEG-derivatives on surfaces was visualized by atomic force microscopy (AFM) which unraveled composition-dependent domain formation influencing fluorescent dye immobilization. Surface wetting characteristics were investigated via static water contact angle. We conclude that macromer ethoxylation and lactic acid content determined film swelling, PEG domain formation and eventually efficiency of surface decoration. STATEMENT OF SIGNIFICANCE: Surfaces of implantable biomaterials are the site of interaction with a host tissue. Accordingly, modifications in the composition of the surface will determine cellular response towards the material which is crucial for the success of innovations and control of tissue regeneration. We employed a macromer approach which is most flexible for the design of biomaterials with a broad spectrum of physicochemical characteristics. For ideal analytical accessibility of the material platform, we cross-copolymerized films on solid supports. Films allowed for the covalent immobilization of fluorescent labels, peptides and enzymes and thorough analytical characterization revealed that macromer hydrophilicity is the most relevant design parameter for surface analyte presentation in these materials. All analytical results were combined in a model describing PEG linker domain formation and ligand presentation.

Unexpected Serious Cardiac Arrhythmias in the Setting of Loperamide Abuse.

Loperamide (Imodium) is a non-prescription opioid receptor agonist available over-the-counter for the treatment of diarrhea. When ingested in excessive doses, loperamide can penetrate the blood-brain barrier and is reported to produce euphoria, central nervous system and respiratory depression, and cardiotoxicity. There is an emerging trend in its use among drug abusers for its euphoric effects or for self-treatment of opioid withdrawal. We report a case of ventricular dysrhythmias associated with loperamide abuse in a 28-year-old man who substituted loperamide for the opioids that he used to abuse. [Full article available at http://rimed.org/rimedicaljournal-2017-04.asp].

Artificial extracellular matrices support cell growth and matrix synthesis of human dermal fibroblasts in macroporous 3D scaffolds.

Surface modification of materials designed for regenerative medicine may improve biocompatibility and functionality. The application of glycosaminoglycans (GAGs) and chemically sulphated GAG derivatives is a promising approach for designing functional biomaterials, since GAGs interact with cell-derived growth factors and have been shown to support fibroblast growth in two-dimensional (2D) cultures. Here, coatings with artificial extracellular matrix (aECM), consisting of the structural protein collagen I and the GAG hyaluronan (HA) or sulphated HA derivatives, were investigated for their applicability in a three-dimensional (3D) system. As a model, macroporous poly(lactic-co-glycolic acid) (PLGA) scaffolds were homogeneously coated with aECM. The resulting scaffolds were characterized by compressive moduli of 0.9-1.2 MPa and pore sizes of 40-420 µm. Human dermal fibroblasts (dFbs) colonized these aECM-coated PLGA scaffolds to a depth of 400 µm within 14 days. In aECM-coated scaffolds, collagen I(α1) and collagen III(α1) mRNA expression was reduced, while matrix metalloproteinase-1 (MMP-1) mRNA expression was increased within 7 days, suggesting matrix-degradation processes. Stimulation with TGFß1 generally increased cell density and collagen synthesis, demonstrating the efficiency of bioactive molecules in this 3D model. Thus, aECM with sulphated HA may modulate the effectivity of TGFß1-induced collagen I(α1) expression, as demonstrated previously in 2D systems. Overall, the tested aECM with modified HA is also a suitable material for fibroblast growth under 3D conditions. Copyright © 2015 John Wiley & Sons, Ltd.

ERRATUM: Unexpected Serious Cardiac Arrhythmias in the Setting of Loperamide Abuse.

Loperamide (Imodium) is a non-prescription opioid receptor agonist available over-the-counter for the treatment of diarrhea. When ingested in excessive doses, loperamide can penetrate the blood-brain barrier and is reported to produce euphoria, central nervous system and respiratory depression, and cardiotoxicity. There is an emerging trend in its use among drug abusers for its euphoric effects or for self-treatment of opioid withdrawal. We report a case of ventricular dysrhythmias associated with loperamide abuse in a 28-year-old man who substituted loperamide for the opioids that he used to abuse. [Full article available at http://rimed.org/rimedicaljournal-2017-04.asp, free with no login].