Nanoparticle-Mediated Mucosal Vaccination: Harnessing Nucleic Acids for Immune Enhancement.

Recent advancements in in vitro transcribed mRNA (IVT-mRNA) vaccine manufacturing have attracted considerable interest as advanced methods for combating viral infections. The respiratory mucosa is a primary target for pathogen attack, but traditional intramuscular vaccines are not effective in generating protective ion mucosal surfaces. Mucosal immunization can induce both systemic and mucosal immunity by effectively eliminating microorganisms before their growth and development. However, there are several biological and physical obstacles to the administration of genetic payloads, such as IVT-mRNA and DNA, to the pulmonary and nasal mucosa. Nucleic acid vaccine nanocarriers should effectively protect and load genetic payloads to overcome barriers i.e., biological and physical, at the mucosal sites. This may aid in the transfection of specific antigens, epithelial cells, and incorporation of adjuvants. In this review, we address strategies for delivering genetic payloads, such as nucleic acid vaccines, that have been studied in the past and their potential applications.

Variation in optimal hemodynamic atrio-ventricular delay of biventricular pacing with different endocardial left ventricular lead locations using precision hemodynamics.

INTRODUCTION: It is not known whether the optimal atrioventricular (AVopt ) delay varies between left ventricular (LV) pacing site during endocardial biventricular pacing (BiVP) and may therefore needs consideration. METHODS: We assessed the hemodynamic AVopt in patients with chronic heart failure undergoing endocardial LV lead implantation. AVopt was assessed during atrio-BiVP with a "roving LV lead." Up to four locations were studied: mid-lateral wall, mid-septum (or a close alternative), site of greatest hemodynamic improvement, and LV lead implant site. The AVopt was compared to a fixed AV delay of 180 ms. RESULTS: Seventeen patients were included (12 male, aged 66.5 ± 12.8 years, ejection fraction 26 ± 7%, 16 left bundle branch block or high percentage of right ventricular pacing [RVP], QRS duration 167 ± 27 ms). In most locations (62/63), AVopt increased systolic blood pressure during BiVP compared with RVP (relative improvement 6 mmHg, interquartile range [IQR] 4-9 mmHg). Compared to a fixed AV delay, the hemodynamic improvement at AVopt was higher (1 mmHg, IQR 0.2-2.6 mmHg, p < .001). Within most patients (16/17), we observed a difference in AVopt between pacing sites (median paced AVopt 209 ms, IQR 117-250). Within this range, the hemodynamic impact of these differences was small (median loss 0.6 mmHg, IQR 0.1-2.6 mmHg). CONCLUSION: Within a patient, different endocardial LV lead locations have slightly different hemodynamic AVopt which are superior to a fixed AV delay. The hemodynamic consequence of applying an optimum from a different lead location is small.

Functionalization of ampicillin and gentamicin with biogenic copper nanoparticles (CuNPs) remodel antimicrobial and cytotoxic outcome against MDR clinical isolates.

The present study reports the functionalization of antibiotic-conjugated Alternanthera pungens and Trichodesma indicum copper nanoparticles (CuNPs). Initially, antibiotic profiling of multi-drug resistant (MDR) clinical isolates against five antibiotics was verified and then gentamicin and ampicillin conjugates of CuNPs were prepared. Biosynthesized nanostructures were characterized through UV-visible spectroscopy, Fourier-transformed infrared spectroscopy, X-ray diffraction and scanning electron microscope. Biogenic synthesized CuNPs displayed highest antibacterial activity (24.0-31.3 mm inhibition zones) when capped with gentamicin as compared to the ampicillin-conjugated NPs which showed resistance against most of the bacterial species. A. pungens-derived conjugates of gentamicin (CuAp-GNT) along with the vehicle revealed 4.86 ± 0.20% and 4.25 ± 2.96% hemolytic potential and highest MDA production in S. typhimurium (3.18 ± 1.52 µg/mL and 6.31 ± 3.49 µg/mL) and K. pneumoniae (2.99 ± 0.90 µg/mL and 4.06 ± 1.20 µg/mL). Similarly, CuAp-GNT also showed highest DNA protection ability by displaying 1342.99 ± 11.87 band intensity. All-inclusive, CuAp showed more promising effects when conjugated with gentamicin indicating that capping of gentamicin with the active components of the plant-based copper nanostructures increases the antibacterial capacity of the drug. Hence, conjugation of antibiotics with bio-based sources offers great potential for identifying potent drug leads.

The Electronic Properties of Cadmium Naphthalene Diimide Coordination Complex.

The computational simulations for electronic properties of cadmium (Cd) coordinated L-alanine NDI ligand (H2-l-ala NDI) based complex are the focus of this research. For the first time, the Cd-NDI complex (monomer) has been produced using water as the solvent; this is a new approach to synthesizing the Cd-NDI complex that has not been reported yet. Along with crystallography and Hirsch field analysis, CAM-B3LYP/LANL2DZ and B3LYP/LANL2MB basis sets were used, and in-depth characterisation of the Cd-NDI complex by following DFT and TD-DFT hypothetical simulations. Hyperpolarizabilities, frontier molecular orbitals (FMOs), the density of states (DOS), dipole moment (µ), electron density distribution map (EDDM), transition density matrix (TDM), molecular electrostatic potential (MEP), electron-hole analysis (EHA), and electrical conductivity (σ) have all been studied regarding the Cd-NDI complex. The vibrational frequencies and types of interaction are studied using infrared (IR) and non-covalent interaction (NCI) analysis with iso-surface. In comparison to the Cd-NDI complex with 2.61, 2.42 eV Eg (using CAM-B3LYP/LANL2DZ and B3LYP/LANL2MB basis sets, respectively) and 376 nm λmax, (in case of B3LYP/LANL2MB λmax is higher), H2-l-ala NDI have 3.387 eV Eg and 375 nm λmax, metal-ligand coordination in complex dramatically altered charge transfer properties, such as narrowing band gap (Eg). Based on the electronic properties analysis of Cd-NDI complex, it is predicted that the Cd-NDI complex will have a spectacular (nonlinear optical) NLO response. The Cd-NDI complex is discovered to be advantageous for the creation of future nanoscale devices due to the harmony between the Cd metal and H2-l-ala NDI, in addition to their influences on NLO characteristics.

Invasive fungal disease in critically ill and Immunocompromised patients.

OBJECTIVE: To study the frequency and type of invasive fungal disease in critically ill and immunocompromised patients. Method: The prospective, cross-sectional, descriptive study was conducted at the Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from January 2017 to December 2020, and comprised pathological samples from immunocompromised and critically ill patients for fungal culture. Data regarding demographics, comorbidities, results of direct microscopy and fungal culture was recorded. Data was analysed using SPSS 22. RESULTS: Of the 8285 patients' specimens, 4722(57%) belonged to males and 3563(43%) to females. The mean age of the patients was 48.32±5.42 years (range: 14-98 years). Out of total 8285, 3465(41.82%) were related to blood, 2640(32%) endobronchial washing, 837(10%) sputum, 623(7.5%) tissue, 332(4%) body fluids, 288(3.5%) bronchoalveoar lavage and 100(1.2%) cerebrospinal fluid. Aspergillus flavus (20.7%) and candida albicans (14.5%) were the two most commonly isolated fungal species. CONCLUSIONS: A high index of suspicion for invasive fungal disease should be maintained in immunocompromised and critically ill patients.

Antimicrobial susceptibility pattern and genotypic characterisation of quinolone and ceftriaxone resistant genes among Salmonella typhi from various regions of Pakistan.

OBJECTIVE: To determine the current antibiotic resistance patterns and identification of quinolone and ceftriaxone resistant genes among Salmonella enterica subspecies serovar Typhi. METHODS: The prospective study was conducted from September 2018 to March 2019 and comprised samples collected from major hospitals and laboratories in Karachi, Quetta, Lahore, Kharia, Rawalpindi, Islamabad and Peshawar after approval from the institutional ethics review board of Hazara University, Mansehra, Pakistan. Antimicrobial susceptibility of isolates collected from the health facilities was checked using the Kirby Bauer disc diffusion method in line with the Clinical and Laboratory Standards Institute guidelines at the Department of Microbiology, Armed Forces Institute of Pathology (AFIP), Rawalpindi, Pakistan. All isolates were subjected for identification of genes responsible for quinolone and ceftriaxone resistance using polymerase chain reaction followed by gel-electrophoresis. RESULTS: Among the 96 isolates, phenotypically, ceftriaxone was found resistant in 31(32.29%) and ciprofloxacin in 95(99%). Genotypically, blaCTX-M-15 (beta lactamase, CTX as its acronym, -M from Munich) gene for ceftriaxone resistance was found in all phenotypically resistant 31(32.29%) isolates, while QnrS (Quinolone resistance, S group), GyrA (DNA gyrase subunit A), and GyrB (DNA gyrase subunit B) genes responsible for ciprofloxacin resistance were found in different frequencies (percentages given in table 2). CONCLUSIONS: The spread of extensively drug-resistant Salmonella enterica subspecies serovar Typhi strain to many big cities calls for urgent preventive measures.

Spectral characterization and impact of stepwise ablation protocol including LAA electrical isolation on persistent AF.

OBJECTIVES: To study how left atrial appendage electrical isolation (LAAEI) impacts atrial dominant frequency (DF) in patients with long-standing persistent atrial fibrillation (LSPAF). BACKGROUND: LAAEI is associated with a high probability of freedom from atrial fibrillation (AF) and spectral analysis may identify high-frequency sources. How LAAEI impacts the AF dynamics and the subgroup of LSPAF patients in whom LAAEI would be most beneficial, is unclear. METHODS: Twenty patients with LSPAF were included in the study. Fast Fourier transforms (FFT) were performed on atrial electrograms recorded from 13 sites in the LA and RA. The highest peak frequency was defined as DF. RESULTS: There was no significant difference in DF between atrial sites except for at the superior vena cava which had the lowest DF at baseline. Stepwise ablation consisting of circumferential pulmonary vein isolation and a linear ablation set of mitral isthmus and roof significantly reduced the DF within the coronary sinus (CS) (5.93 ± 0.98 Hz vs. 5.09 ± 0.72 Hz, p < .05) and the LA posterior wall (LApos) (6.26 ± 0.92 Hz vs. 5.43 ± 0.98 Hz, p < .01). LAAEI preferentially further decreased the DF at the LApos (p < .01), but not at the CS. In cases where there was < 13.6% reduction in the DF of the LApos following the stepwise ablation, the addition of LAAEI was associated with an increased restoration of sinus rhythm (55%, p < .05). CONCLUSION: LAAEI in addition to stepwise ablation results in further reduction of the DF in the LApos, which is associated with acute termination of AF and favorable ablation outcome.

Catheter ablation vs. thoracoscopic surgical ablation in long-standing persistent atrial fibrillation: CASA-AF randomized controlled trial.

AIMS: Long-standing persistent atrial fibrillation (LSPAF) is challenging to treat with suboptimal catheter ablation (CA) outcomes. Thoracoscopic surgical ablation (SA) has shown promising efficacy in atrial fibrillation (AF). This multicentre randomized controlled trial tested whether SA was superior to CA as the first interventional strategy in de novo LSPAF. METHODS AND RESULTS: We randomized 120 LSPAF patients to SA or CA. All patients underwent predetermined lesion sets and implantable loop recorder insertion. Primary outcome was single procedure freedom from AF/atrial tachycardia (AT) ≥30 s without anti-arrhythmic drugs at 12 months. Secondary outcomes included clinical success (≥75% reduction in AF/AT burden); procedure-related serious adverse events; changes in patients' symptoms and quality-of-life scores; and cost-effectiveness. At 12 months, freedom from AF/AT was recorded in 26% (14/54) of patients in SA vs. 28% (17/60) in the CA group [OR 1.128, 95% CI (0.46-2.83), P = 0.83]. Reduction in AF/AT burden ≥75% was recorded in 67% (36/54) vs. 77% (46/60) [OR 1.13, 95% CI (0.67-4.08), P = 0.3] in SA and CA groups, respectively. Procedure-related serious adverse events within 30 days of intervention were reported in 15% (8/55) of patients in SA vs. 10% (6/60) in CA, P = 0.46. One death was reported after SA. Improvements in AF symptoms were greater following CA. Over 12 months, SA was more expensive and provided fewer quality-adjusted life-years (QALYs) compared with CA (0.78 vs. 0.85, P = 0.02). CONCLUSION: Single procedure thoracoscopic SA is not superior to CA in treating LSPAF. Catheter ablation provided greater improvements in symptoms and accrued significantly more QALYs during follow-up than SA. CLINICAL TRIAL REGISTRATION: ISRCTN18250790 and ClinicalTrials.gov: NCT02755688.

Comparison evaluation between gene Xpert Mtb/Rif and multiplex PCR for rapid diagnosis of mycobacterium tuberculosis.

OBJECTIVE: To compare the efficacy of Gene Xpert mycobacterium tuberculosis-rifampicin and multiplex polymerase chain reacton for the detection of mycobacterium tuberculosis and Rifampicin resistance. METHODS: The cross-sectional validation study was conducted at the Department of Microbiology, Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from March to October 2018, and comprised mycobacterium tuberculosis-positive rifampicin-resistant and rifampicin-susceptible samples, with the latter acting as negative controls. Gene Xpert mycobacterium tuberculosis-rifampicin assasy and multiplex polymerase chain reacton were applied simultaneously and compared with gold standard mycobacterium growth indicator tube 960. Data was analysed using SPSS 24. RESULTS: Of the 192 samples, 84(44%) were culture-positive rifampicin-resistant and 108(56%) were culture-positive rifampicin-susceptible. Overall, 84(44%) were found positive. Gene Xpert mycobacterium tuberculosis-rifampicin assay detected all 84(100%) rifampicin-resistant samples, while multiplex polymerase chain reacton detected 44(52.3%) such samples. Sensitivity, specificity, positive predictive value and negative predictive value of Gene Xpert were 100% each respectively, while the corresponding values for multiplex polymerase chain reacton were 52%, 100%, 100% and 72% respectively. CONCLUSIONS: Molecular detection of mycobacterium tuberculosis and resistance by Gene Xpert and multiplex polymerase chain reacton simultaneously was found to be a rapid and cost-effective method.

Evaluation of rapid polymyxin Nordmann Poirel test for detection of polymyxin resistance in clinical isolates of Enterobacteriaceae.

Polymyxins play a significant role against carbapenem-resistant Enterobacteriaceae (CRE). A total of 121 clinical samples yielded growth of CRE that were included in the study. Rapid Polymyxin NP test was performed on all the isolates as described by Nordmann P et al. and results were compared with broth microdilution method. Majority of the isolates were Klebsiella pneumoniae (70.2%) followed by Escherichia coli (17.4%). A total of 71 isolates were found resistant and 50 as susceptible by broth microdilution. Sensitivity and specificity of rapid polymyxin NP test were found to be 97.2% and 100%, respectively. Our study concluded that rapid polymyxin NP test is reliable and can be used as an alternative to broth microdilution in resource limited settings.

Trends of utilization of Complete Blood Count parameters for patient management among doctors in Azad Kashmir.

OBJECTIVE: To determine the trends of utilization of CBC parameters in patient management among doctors in different hospitals in Kashmir, Pakistan. METHODD: A self-administered questionnaire-based survey was carried out amongst doctors working in four hospitals of Kashmir i.e. Combined Military Hospital, Muzaffarabad, Combined Military Hospital, Rawalakot, Abbas Institute of Medical Sciences, Muzaffarabad, and District Hospital, Kotli during August to December 2017. RESULTS: Out of 500 physicians, 217 physicians answered the questionnaire, representing a response rate of 43.4%. Only three of the 11 parameters in the CBC report i.e. hemoglobin, white blood cell count and platelets were selected as frequently or always useful by more than 80% of physicians. Rest of the eight parameters of the CBC were found useful by less than 80% of the physicians. Most agreed that the current format of a CBC report gives adequate information. CONCLUSION: The present study concludes that majority of the physicians utilize only three of the basic parameters on the complete blood count. An educational intervention can be planned for the physicians to increase their knowledge about the utility of other parameters.

Characterising the difference in electrophysiological substrate and outcomes between heart failure and non-heart failure patients with persistent atrial fibrillation.

Aims: Characterizing the differences in substrate and clinical outcome between heart failure (HF) and non-heart failure (non-HF) patients undergoing persistent atrial fibrillation (AF) ablation. Methods and results: Using complex fractionated electrograms (CFE) as a surrogate marker of substrate complexity, we compared the bi-atrial substrate in patients with persistent AF with and without HF, at baseline and after ablation, to determine its impact on clinical outcome. In this retrospective analysis of two prospective studies, 60 patients underwent de-novo step-wise left atrial (LA) ablation, 30 with normal left ventricular ejection fraction (LVEF) ≥ 50% (non-HF group) and 30 with LVEF ≤ 35% (HF group). Multiple high-density bi-atrial CFE maps were acquired along with AF cycle length (AFCL) at each procedural stage. Change in bi-atrial CFE areas, AFCL and outcome data were then compared. In the non-HF group, higher CFE-areas were found at baseline and at each step of the procedure in the LA. In both LA and the right atrium (RA), baseline and final CFE area were also higher in the non-HF group. Single procedure, arrhythmia-free survival at 1 year was higher in the HF group compared with the non-HF group (72% vs. 43%, log rank P = 0.04). Final total bi-atrial CFE area was an independent predictor of arrhythmia recurrence. Conclusions: CFE represents an important surrogate marker of atrial substrate complexity. The atrial substrate in persistent AF differs between HF and non-HF with the latter representing a more complex 'primary' bi-atrial myopathy. LA focussed ablation results in more extensive substrate modification in HF and better clinical outcomes as compared with non-HF.

Resource use and clinical outcomes in patients with atrial fibrillation with ablation versus antiarrhythmic drug treatment.

BACKGROUND: The objective of our study was to compare resource use and clinical outcomes among atrial fibrillation (AF) patients who underwent catheter ablation versus antiarrhythmic drug (AAD) treatment. METHODS: A retrospective cohort design using the Clinical Practice Research Data-Hospital Episode Statistics linkage data from England (2008-2013) was used. Patients undergoing catheter ablation treatment for AF were indexed to the date of first procedure. AAD patients with at least two different AAD drugs were indexed to the first fill of the second AAD. Patients were matched using 1:1 propensity matching. Primary endpoints including inpatient and outpatient visits were compared between ablation and AAD cohorts in the 4 months-1 year period after index. Secondary endpoints including heart failure, stroke, cardioversion, mortality, and a composite outcome were compared for the 4 months-3 years post-index period in the two groups. Cox-proportional hazards models were estimated for clinical outcomes comparison. RESULTS: A total of 558 patients were matched in the two groups for resource utilization comparison. The average number of cardiovascular (CV)-related outpatient visits in the 4-12 months post-index period were significantly lower in the ablation group versus the AAD group (1.76 vs 3.57, p < .0001). There was no significant difference in all-cause and CV-related inpatient visits and all-cause outpatient visits among the two groups. For secondary endpoints comparison, 615 matched patients in each group emerged. Ablation patients had 38% lower risk of heart failure (hazard ratio [HR] 0.62, p = 0.0318), 50% lower risk of mortality (HR 0.50, p = 0.0082), and 43% lower risk of experiencing a composite outcome (HR 0.57, p = 0.0009) as compared to AAD treatment cohort. CONCLUSION: AF ablation was associated with significantly lower CV-related outpatient visits, and lower risk of heart failure and mortality versus AAD therapy.

Safety and mid-term outcome of catheter ablation of ventricular tachycardia in octogenarians.

AIMS: Radiofrequency (RF) catheter ablation (CA) is superior to standard medical therapy in controlling recurrent ventricular tachycardia (VT). The majority of procedures have been performed in a middle-aged population. The outcome of VT ablation in the elderly has not been described. METHODS AND RESULTS: We retrospectively studied the outcome and safety of CA of VT in octogenarians performed in four European centres. The population consisted of patients presenting with recurrent VT refractory to medical therapy. Patients aged over 80 years were compared with younger patients undergoing CA. Clinical characteristics, procedural data, complications, and outcomes were examined. Implantable cardioverter-defibrillator (ICD) therapy data were collected. A total of 54 consecutive octogenarian patients underwent RF CA of VT and represented the study group (42 males, age 82.8 ± 2.7 years) compared with a control group of 104 younger patients (85 males, age 66.7 ± 8.9 years). Mean follow-up was 33 ± 48 months. Implantable cardioverter-defibrillators were present in 81 and 86% of patients, respectively (P = 0.93). Left ventricular ejection fraction was 29% ± 8.2 in octogenarians vs. 34% ± 10.2 in the younger group (P < 0.01). More major complications occurred in octogenarians (18 vs. 2%, P < 0.01). During follow-up, there were more ICD shocks in the octogenarians (28 vs. 15%, P < 0.01). The Kaplan-Meier curve of survival after VT ablation confirms comparable survival rates at 1 year, but the elderly have poor survival in the mid-term. Survival in the elderly post VT ablation is comparable with that in an age-matched cohort with ICDs but no VT storm. CONCLUSION: Octogenarians undergoing CA of VT have more risk factors, higher risk of complications and ICD shocks, but demonstrate comparable short-term survival rates.

Catheter ablation for AF improves global thrombotic profile and enhances fibrinolysis.

Patients with atrial fibrillation (AF) are at increased risk of thrombotic events despite oral anticoagulation (OAC). Radiofrequency catheter ablation (RFCA) can restore and maintain sinus rhythm (SR) in patients with AF. To assess whether RFCA improves thrombotic status. 80 patients (71% male, 64 ± 12y) with recently diagnosed AF, on OAC and scheduled to undergo RFCA or DC cardioversion (DCCV) were recruited. Thrombotic status was assessed using the point-of-care global thrombosis test (GTT), before, and 4-6 weeks after DCCV and 3 months after RFCA. The GTT first measures the time taken for occlusive thrombus formation (occlusion time, OT), while the second phase of the test measures the time taken to spontaneously dissolve this clot through endogenous thrombolysis (lysis time, LT). 3 months after RFCA, there was a significant reduction in LT (1994s [1560; 2475] vs. 1477s [1015; 1878]) in those who maintained SR, but not in those who reverted to AF. At follow-up, LT was longer in those in AF compared to those in SR (AF 2966s [2038; 3879] vs. SR 1477s [1015; 1878]). RFCA resulted in no change in OT value, irrespective of rhythm outcome. Similarly, there was no change in OT or LT in response to DCCV, irrespective of whether SR was restored. Successful restoration and maintenance of SR following RFCA of AF is associated with improved global thrombotic status with enhanced fibrinolysis. Larger studies are required to confirm these early results and investigate whether improved thrombotic status translates into fewer thromboembolic events.

Outcomes and costs of left atrial appendage closure from randomized controlled trial and real-world experience relative to oral anticoagulation.

AIMS: The aim of this study was to analyse randomized controlled study and real-world outcomes of patients with non-valvular atrial fibrillation (NVAF) undergoing left atrial appendage closure (LAAC) with the Watchman device and to compare costs with available antithrombotic therapies. METHODS AND RESULTS: Registry data of LAAC from two centres were prospectively collected from 110 patients with NVAF at risk of stroke, suitable and unsuitable for long-term anticoagulation (age 71.3 ± 9.2 years, CHADS2 2.8 ± 1.2, CHA2DS2-VASc 4.5 ± 1.6, and HAS-BLED 3.8 ± 1.1). Outcomes from PROTECT AF and registry study LAAC were compared with warfarin, dabigatran, rivaroxaban, apixaban, aspirin, and no treatment using a network meta-analysis. Costs were estimated over a 10-year horizon. Uncertainty was assessed using sensitivity analyses. The procedural success rate was 92% (103/112). Follow-up was 24.1 ± 4.6 months, during which annual rates of stroke, major bleeding, and all-cause mortality were 0.9% (2/223 patient-years), 0.9% (2/223 patient-years), and 1.8% (4/223 patient-years), respectively. Anticoagulant therapy was successfully stopped in 91.2% (93/102) of implanted patients by 12 months. Registry study LAAC stroke and major bleeding rates were significantly lower than PROTECT AF results: mean absolute difference of stroke, 0.89% (P = 0.02) and major bleeding, 5.48% (P < 0.001). Left atrial appendage closure achieved cost parity between 4.9 years vs. dabigatran 110 mg and 8.4 years vs. warfarin. At 10 years, LAAC was cost-saving against all therapies (range £1162-£7194). CONCLUSION: Left atrial appendage closure in NVAF in a real-world setting may result in lower stroke and major bleeding rates than reported in LAAC clinical trials. Left atrial appendage closure in both settings achieves cost parity in a relatively short period of time and may offer substantial savings compared with current therapies. Savings are most pronounced among higher risk patients and those unsuitable for anticoagulation.

Biomarkers in Persistent AF and Heart Failure: Impact of Catheter Ablation Compared with Rate Control.

BACKGROUND: To investigate the effects of catheter ablation and rate control strategies on cardiac and inflammatory biomarkers in patients with heart failure and persistent atrial fibrillation (AF). METHODS: Patients were recruited from the ARC-HF trial (catheter Ablation vs Rate Control for management of persistent AF in Heart Failure, NCT00878384), which compared ablation with rate control for persistent AF in heart failure. B-type natriuretic peptide (BNP), midregional proatrial natriuretic peptide (MR-proANP), apelin, and interleukin-6 (IL-6) were assayed at baseline, 3 months, 6 months, and 12 months. The primary end point, analyzed per-protocol, was changed from baseline at 12 months. RESULTS: Of 52 recruited patients, 24 ablation and 25 rate control subjects were followed to 12 months. After 1.2 ± 0.5 procedures, sinus rhythm was present in 22 (92%) ablation patients; under rate control, rate criteria were achieved in 23 (96%) of 24 patients remaining in AF. At 12 months, MR-proANP fell significantly in the ablation arm (-106.0 pmol/L, interquartile range [IQR] -228.2 to -60.6) compared with rate control (-28.7 pmol/L, IQR -69 to +9.5, P = 0.028). BNP showed a similar trend toward reduction (P = 0.051), with no significant difference in apelin (P = 0.13) or IL-6 (P = 0.68). Changes in MR-proANP and BNP correlated with peak VO2 and ejection fraction, and MR-proANP additionally with quality-of-life score. CONCLUSIONS: Catheter ablation, compared with rate control, in patients with heart failure and persistent AF was associated with significant reduction in MR-proANP, which correlated with physiological and symptomatic improvement. Ablation-based rhythm control may induce beneficial cardiac remodeling, unrelated to changes in inflammatory state. This may have prognostic implications, which require confirmation by event end point studies.

Combination therapy with nifedipine GITS 60 mg: subanalysis of a prospective, 12-week observational study (AdADOSE).

BACKGROUND: AdADOSE was a 12-week, international, observational study conducted in the Middle East and Russia where patients received nifedipine gastrointestinal therapeutic system (GITS) at a daily dose of 30, 60, or 90 mg as part of an antihypertensive combination therapy. This subgroup analysis of the AdADOSE study assesses the efficacy and tolerability of nifedipine GITS combination therapy when used specifically at the 60-mg strength. METHODS: Patients with hypertension who received a daily nifedipine GITS dose of 60 mg, either at constant dose (n = 686) or up-titrated from 30 mg (n = 392), were analyzed. Target blood pressure (BP) was <140/90 mmHg (or <130/80 mmHg for those at high/very high cardiovascular risk). RESULTS: Following nifedipine GITS combination therapy, target BP was achieved by 33.7% patients in the 60 mg group (previously untreated, 42.5%; previously treated, 32.0%) and 32.4% patients in the 30-60 mg group (previously untreated, 45.2%; previously treated, 30.7%). Mean systolic BP/diastolic BP changes were -40.3/-20.7 mmHg and -35.6/-18.5 mmHg, respectively, and were similar regardless of previous antihypertensive treatment or the number of concomitant diseases. Incidences of drug-related adverse events (AEs) were low (3.2%, 60 mg; 2.0%, 30-60 mg group), few patients discontinued because of AEs (0.6% and 1.0%, respectively), and there were no serious AEs. CONCLUSION: Combination therapy with nifedipine GITS 60 mg in a real-life observational setting was effective and well tolerated in hypertensive patients, with low rates of treatment-related AEs.

Relationship between contact force sensing technology and medium-term outcome of atrial fibrillation ablation: a multicenter study of 600 patients.

INTRODUCTION: Contact force sensing (CFS) technology improves acute pulmonary vein isolation durability; however, its impact on the clinical outcome of ablating atrial fibrillation (AF) is unknown. METHODS AND RESULTS: First time AF ablation procedures employing CFS from 4 centers were matched retrospectively to those without CFS in a 1:2 manner by type of AF. Freedom from atrial tachyarrhythmia was defined as the primary outcome measure, and fluoroscopy time the secondary outcome measure. Nineteen possible explanatory variables were tested in addition to CFS. A total of 600 AF ablation procedures (200 using CFS and 400 using non-CFS catheters) performed between 2010 and 2012 (46% paroxysmal, 36% persistent, 18% long-lasting persistent) were analyzed. The mean follow-up duration was 11.4 ± 4.7 months-paroxysmal AF 11.2 ± 4.1 CFS versus 11.3 ± 3.9 non-CFS (P = 0.745)-nonparoxysmal AF 10.4 ± 4.5 CFS versus 11.9 ± 5.4 non-CFS (P = 0.015). The use of a CFS catheter independently predicted clinical success in ablating paroxysmal AF (HR 2.24 [95% CIs 1.29-3.90]; P = 0.004), but not nonparoxysmal AF (HR 0.73 [0.41-1.30]; P = 0.289) in a multivariate analysis that included follow-up duration. Among all cases, the use of CFS catheters was associated with reduced fluoroscopy time in multivariate analysis (reduction by 7.7 [5.0-10.5] minutes; P < 0.001). Complication rates were similar in both groups. CONCLUSIONS: At medium-term follow-up, CFS catheter technology is associated with significantly improved outcome of first time catheter ablation of paroxysmal AF, but not nonparoxysmal AF. Fluoroscopy time was lower when CFS technology was employed in all types of AF ablation procedures.

Effectiveness of combination therapy with nifedipine GITS: a prospective, 12-week observational study (AdADOSE).

BACKGROUND: Observational studies can provide important information on the efficacy and safety of antihypertensive agents in the real-life clinical setting. AdADOSE was a large observational study to assess the effectiveness of nifedipine GITS in combination with other antihypertensive agent(s). The study was also the first to examine the role of combination therapy with nifedipine GITS in the Middle East, Pakistan and Russia, regions that are associated with particularly high cardiovascular risk. METHODS: AdADOSE was a 12-week, international, multicenter, prospective, observational study. Patients with hypertension (ie, blood pressure [BP] >140/90 mm Hg, or >130/80 mm Hg in patients at high or very high cardiovascular risk) received once-daily nifedipine GITS (30, 60 or 90 mg) in combination with another antihypertensive or as add-on to existing therapy. The primary study endpoint was the proportion of patients who achieved the target BP of <140/90 mm Hg (or <130/80 mm Hg for those at high or very high cardiovascular risk). Study outcomes are reported by descriptive statistics. RESULTS: The study enrolled 4497 patients (n = 4477, safety population; n = 3430, efficacy population). Baseline mean systolic/diastolic BP (SBP/DBP) was 166.4/99.7 mm Hg; 85.2 % of patients had received prior antihypertensive treatment, and 90.6 % had ≥ 1 concomitant diseases. Following combination treatment with nifedipine GITS, target BP was achieved by 64.8% of patients without concomitant diseases, and by 56.5%, 32.3% and 22.6% with 1, 2-3 and >3 concomitant diseases, respectively. The proportion of patients achieving target BP was 51.5% in previously untreated and 33.7% in previously treated patients. Nifedipine GITS combination treatment provided mean SBP/DBP changes of -36.1/-18.8 mm Hg in all patients, -40.2/-21.5 mm Hg in previously untreated patients, and -35.6/-18.4 mm Hg in previously treated patients, with similar BP reductions irrespective of the number of concomitant diseases. Drug-related adverse events (AEs) were reported in 2.6% patients. There were no serious AEs and only 0.8% of patients discontinued due to drug-related AEs. CONCLUSIONS: Combination therapy with nifedipine GITS in a real-life observational setting was highly effective in reducing SBP/DBP in a range of hypertensive patients, with low rates of treatment-related AEs. TRIAL REGISTRATION: at ClinicalTrials.gov registration number NCT01118286 .