Three-Dimensional Echocardiographic Left Atrial Appendage Volumetric Analysis.

BACKGROUND: Left atrial appendage (LAA) echocardiographic assessment is difficult because of the complex shape and relatively small size of the LAA. Three-dimensional (3D) echocardiographic imaging can overcome the limitations of two-dimensional imaging. Pulsed-wave Doppler is the only currently standard LAA functional parameter. The aim of this study was to test a new approach for 3D echocardiographic volumetric analysis to obtain LAA ejection fraction (EF), its size and shape. METHODS: Transesophageal two-dimensional and 3D LAA images were prospectively obtained in 159 consecutive patients. LAA volumes were measured from 3D echocardiographic images using available software. Pulsed-wave Doppler was considered the reference value for LAA function and was used for comparison with LAA EF. Comparison with cardiac computed tomography was performed in a subgroup of 32 patients. Comparisons included linear regression and Bland-Altman analyses. Repeated measurements were performed to assess measurement variability. RESULTS: Nine patients were excluded because of suboptimal image quality (94% feasibility). Three-dimensional LAA calculated EF was in good agreement with LAA pulsed-wave measurements. Three-dimensional morphologic evaluation showed that 43% of the patients had "chicken wing," 33% "cactus," 19% "windsock," and 5% cauliflower shapes. At the time of data acquisition, patients with atrial fibrillation had nonsignificantly larger LAA end-systolic and end-diastolic volumes, leading to lower calculated EFs. Three-dimensional echocardiographic LAA end-systolic volumes were in good agreement with cardiac computed tomography (r = 0.75), with small biases (mean, -2.5 ± 3.9 ml). Reproducibility was better for larger LAA volumes. CONCLUSIONS: A novel 3D echocardiographic approach can determine the geometry, size, and function of the LAA. A new parameter, LAA EF, provides functional quantitation.

Hybrid Convergent Procedure for the Treatment of Persistent and Long-Standing Persistent Atrial Fibrillation: Results of CONVERGE Clinical Trial.

BACKGROUND: The limited effectiveness of endocardial catheter ablation (CA) for persistent and long-standing persistent atrial fibrillation (AF) treatment led to the development of a minimally invasive epicardial/endocardial ablation approach (Hybrid Convergent) to achieve a more comprehensive lesion set with durable transmural lesions. The multicenter randomized controlled CONVERGE trial (Convergence of Epicardial and Endocardial Ablation for the Treatment of Symptomatic Persistent AF) evaluated the safety of Hybrid Convergent and compared its effectiveness to CA for persistent and long-standing persistent AF treatment. METHODS: One-hundred fifty-three patients were randomized 2:1 to Hybrid Convergent versus CA. Primary effectiveness was freedom from AF/atrial flutter/atrial tachycardia absent new/increased dosage of previously failed/intolerant class I/III antiarrhythmic drugs through 12 months. Primary safety was major adverse events through 30 days. CONVERGE permitted left atrium size up to 6 cm and imposed no limits on AF duration, making it the only ablation trial to substantially include long-standing persistent-AF, that is, 42% patients with long-standing persistent-AF. RESULTS: Of 149 evaluable patients at 12 months, primary effectiveness was achieved in 67.7% (67/99) patients with Hybrid Convergent and 50.0% (25/50) with CA (P=0.036) on/off previously failed antiarrhythmic drugs and in 53.5% (53/99) versus 32.0% (16/50; P=0.0128) respectively off antiarrhythmic drugs. At 18 months using 7-day Holter, 74.0% (53/72) Hybrid Convergent and 55% (23/42) CA patients experienced ≥90% AF burden reduction. A total of 2.9% (3/102) patients had primary safety events within 7 days, and 4.9% (5/102) between 8 and 30 days postprocedure. No deaths, cardiac perforations, or atrioesophageal fistulas occurred. All but one primary safety event resolved. CONCLUSIONS: The Hybrid Convergent procedure has superior effectiveness compared to the CA for the treatment of persistent and long-standing persistent atrial fibrillation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01984346.

Outcomes of subcutaneous implantable cardioverter-defibrillator in dialysis patients: Results from the S-ICD post-approval study.

BACKGROUND: Patients with chronic renal disease on hemodialysis (HD) have limited vascular access and are at high risk of bacteremia. The subcutaneous implantable cardioverter-defibrillator (S-ICD) avoids vascular access, so it may be advantageous in this patient population. OBJECTIVE: The purpose of this study was to report outcomes of patients with end-stage renal disease enrolled in the multicenter S-ICD post-approval study (PAS). METHODS: S-ICD PAS patients were stratified on the basis of the presence (group 1) or absence (group 2) of HD at the time of implantation. Baseline demographic and clinical characteristics were collected. Perioperative and intermediate-term outcomes 365 days postimplantation were compared between the 2 groups. RESULTS: There were 220 patients on HD (13.4%) at the time of implantation out of 1637 patients enrolled in the S-ICD PAS. Patients on HD (group 1) were older (57.4 ± 13.2 years vs 52.5 ± 15.2 years; P < .0001), more likely to be of African descent (48.6% vs 25.1%; P < .0001), and had lower ejection fraction (28.6% ± 11.3% vs 32.6% ± 14.9%; P < .0001) as compared with patients not on HD (group 2). Group 1 had more comorbidities and mortality was higher (17.4% vs 3.7%) than did group 2. The rate of complications calculated using the Kaplan-Meier estimate did not differ between the 2 groups (overall P = .9169), with a 1-year rate of 7.9% and 7.7% for groups 1 and 2, respectively. The rate of appropriate shocks was significantly higher in group 1 (Kaplan-Meier analysis, P = .0003), as was inappropriate shocks (P = .0137). CONCLUSION: S-ICD is associated with similar adverse event rates but a higher risk of inappropriate and appropriate therapy in dialysis patients than in nondialysis patients.

Effect of early diagnosis and treatment with percutaneous lead extraction on survival in patients with cardiac device infections.

Cardiac device infections (CDIs) represent a serious complication after the implantation of pacemakers and defibrillators. In addition to antimicrobials, complete hardware removal, mostly with percutaneous lead extraction (PLE), is necessary to limit recurrences. However, CDI diagnosis is often difficult and is sometimes delayed, and scarce data exist on how the timing of PLE may affect clinical outcomes. In this study, the in-hospital outcomes of 52 consecutive patients with CDIs who underwent PLE were retrospectively analyze. Co-morbidities such as diabetes mellitus, congestive heart failure, renal insufficiency, and end-stage renal disease were highly prevalent in the study cohort. Patients were divided into group A (bacteremia or device endocarditis) and group B (localized pocket infection). In-hospital mortality was 29% in group A and 5% in group B (p = 0.02) and was due mostly to sepsis. Hospital stays were shorter in group B patients (5.7 vs 21.7 days, p <0.001). Presentation with hypotension was more commonly observed in group A patients and was associated with higher in-hospital mortality, whereas pocket findings correlated with better survival. Postoperative courses after PLE were uneventful in most patients, and no fatal complications were observed. PLE was performed significantly earlier in group B patients (hospitalization day 1.3 vs 7.6, p <0.001). PLE performed within 3 hospitalization days was associated with lower in-hospital mortality (p = 0.01). In conclusion, PLE performed within 3 days from admission is associated with shorter hospitalization and better survival. A timely diagnosis is crucial, particularly in the absence of local findings, because early treatment with PLE is likely to prevent the catastrophic outcomes of unrelenting CDIs.

Ultrastructure and regulation of lateralized connexin43 in the failing heart.

RATIONALE: Gap junctions mediate cell-to-cell electric coupling of cardiomyocytes. The primary gap junction protein in the working myocardium, connexin43 (Cx43), exhibits increased localization at the lateral membranes of cardiomyocytes in a variety of heart diseases, although the precise location and function of this population is unknown. OBJECTIVE: To define the subcellular location of lateralized gap junctions at the light and electron microscopic level, and further characterize the biochemical regulation of gap junction turnover. METHODS AND RESULTS: By electron microscopy, we characterized gap junctions formed between cardiomyocyte lateral membranes in failing canine ventricular myocardium. These gap junctions were varied in structure and appeared to be extensively internalizing. Internalized gap junctions were incorporated into multilamellar membrane structures, with features characteristic of autophagosomes. Intracellular Cx43 extensively colocalized with the autophagosome marker GFP-LC3 when both proteins were exogenously expressed in HeLa cells, and endogenous Cx43 colocalized with GFP-LC3 in neonatal rat ventricular myocytes. Furthermore, a distinct phosphorylated form of Cx43, as well as the autophagosome-targeted form of LC3 (microtubule-associated protein light chain 3) targeted to lipid rafts in cardiac tissue, and both were increased in heart failure. CONCLUSIONS: Our data demonstrate a previously unrecognized pathway of gap junction internalization and degradation in the heart and identify a cellular pathway with potential therapeutic implications.

Preparation of multiparticulate vaginal tablet using glyceryl monooleate for sustained progesterone delivery.

Most of the sustained release vaginal formulations are in the form of bioadhesive gels and tablets. Though proved efficient, their presence in the vagina for a longer time as a bulk produces discomfort and interference with body functioning including sexual activities. Hence, they lack complete patient compliance. In this study, multiparticulate vaginal tablets were prepared by utilizing progesterone (PRO) loaded dry powder precursor of cubic phase (DPPCP) of glyceryl monooleate (GMO). DPPCP were obtained by spray drying GMO with magnesium trisilicate (MTS) and have presented PRO sustained release in simulated vaginal fluid (SVF) for 14 hours. The effect of hydrophilic and hydrophobic tableting excipients on compression, phase, bioadhesion and drug release properties of prepared tablets was evaluated. The effervescent hydrophilic tablet (EHT) prepared with hydrophilic excipients showed rapid disintegration but, diminished sustaining ability owing to transformation into lamellar phase whereas the multiparticulate hydrophobic tablet (MHT) obtained from hydrophobic excipients presented both rapid disintegration and sustained release in SVF by virtue of cubic phase retention. During bioadhesivity testing, fast disintegration of MHT with formation of uniform and viscous bioadhesive layer on cow mucosa was observed even with a small volume of SVF. As MHT may not produce discomfort and interference, it will be preferred over bioadhesive gel or tablet.

Effect of HLB of additives on the properties and drug release from the glyceryl monooleate matrices.

Glyceryl monooleate (GMO) is an amphiphilic surfactant, which as such can solubilize hydrophilic, lipophilic and amphiphilic drug molecules in its different polarity regions. Addition of additives with different polarities in GMO leads to change in phase behavior and related properties of GMO. Effect of the additives with different hydrophilic lipophilic balance (HLB; 1.5, 3, 4, 5, 7, 10 and 11) in GMO matrices on its phase transformation, rheological properties, mechanical properties, wetting and release behavior was investigated. Polarizing light microscopy showed that the GMO matrices incorporated with lower HLB additive (1.5, 3, 4 and 5) form cubic phase at higher rate while lamellar phase was prominent for matrices with additive of HLB 7, 10 and 11. The diametrical crushing strength and viscosity was decreased with increased HLB of additive. Lower HLB additives enhanced contact angle as compared to plain matrices and high HLB additives induced change in solid-liquid interface from hydrophobic to hydrophilic leading to decline in contact angle. Percent swelling of matrices was increased linearly with increase in HLB of additives. Tensiometric method was used for determination of bioadhesive strength of hydrated matrices and it was observed that matrices with additives of HLB 10 presented highest bioadhesion due to higher rate of hydration and formation of lamellar phase. As the HLB of additives in matrix increased, release was shifted from anomalous (non-Fickian) diffusion and/or partially erosion-controlled release to Fickian diffusion. Initial lag was observed for drug released from matrices with additive of HLB 1.5, 3, 4 and 5. Thus incorporation of the additives of different HLB changed molecular packing, which significantly affected drug release pattern.

Spray dried glyceryl monooleate-magnesium trisilicate dry powder as cubic phase precursor.

Glyceryl monooleate (GMO) is a polar amphiphilic lipid, which forms different sequential lyotropic liquid crystals upon hydration. GMO has been utilized for various delivery systems and routes of administrations. Owing to sticky and waxy nature of GMO, preparation of oral solid dosage form utilizing GMO is still a challenge for pharmaceutical researchers. Therefore, the objective of the present work was to fabricate dry powder precursors using GMO, which upon hydration in situ forms cubic phase and can be wisely used for fabrication of oral solid dosage forms. In addition to this, dry powder precursor was evaluated for drug loading, in vitro release behavior and in vivo performance of model drug diclofenac sodium (DiNa). The dry powder precursor was obtained by spray-drying GMO with DiNa using magnesium trisilicate (MTS) as adsorbent. The percent drug entrapment of various batches of powder precursor was in the range of 84-93% indicating high content uniformity. SEM and image analysis showed that as the amount of MTS in powder precursor was increased, the particle size decreased. Furthermore, the viscosity of powder precursor was function of amount of MTS. The rate of water uptake of powder precursor was higher due to uniform layer of GMO on the MTS surface, which led to faster transformation of lamellar phase into cubic phase. The polarizing light microscopy confirmed that cubic phase was formed upon hydration of powder precursor. The drug released from powder precursor was initially governed by the cubic phase formed and in later stage it depends upon dynamic swelling behavior of hexagonally packed cylindrical aggregates. The drug loaded powder precursor was found to have more effective and prolonged anti-inflammatory and analgesic activity as compared to pure drug. Thus the dry powder precursor of cubic phase was prepared in which drug release was entirely governed by the mesophases formed.

Cubic liquid crystalline glyceryl monooleate matrices for oral delivery of enzyme.

In situ cubic phase transforming system of glyceryl monooleate (GMO) has been prepared which offers protection to the metaloenzyme, seratiopeptidase (STP), in gastric environment and provides delayed and controlled release with no initial burst after oral administration. Effect of magnesium trisilicate (MTS) on floating, proteolytic activity and drug release was studied. Gelucire 43/01 was incorporated in the system to provide prolonged lag time. The drug-loaded matrices required 100 mg of MTS to overcome floatability of GMO matrix. Plain GMO matrices showed 85.3% loss of proteolytic activity in acidic medium, whereas matrices containing MTS showed retention of activity (111.6%). The hydrophobic nature of MTS induced formation of cubic phase at faster rate and the existence of cubic phase was confirmed by polarizing light microscopy. Furthermore, MTS provided alkaline microenvironment, which prevented acid-catalyzed hydrolysis and protein unfolding. The magnesium ions restored the activity of STP. The release of STP was decreased with increasing amount of MTS in the matrix. Gelucire did not affect proteolytic activity. The water uptake of matrices with gelucire was decelerated due to formation of hexagonal phase. However, the rate of STP release from these matrices was very slow due to incorporation of gelucire into lipid bilayers, which provided resistance to movement of STP. Thus, microenvironment-controlled in situ cubic phase transforming GMO matrices provided protection to STP and controlled release.

Effect of drug solubility and different excipients on floating behaviour and release from glyceryl monooleate matrices.

Glycerol monooleate (GMO) matrix was found to be a gastro-retentive carrier system suitable for both polar and as well as non-polar drugs. Chlorpheniramine maleate (CPM) and diazepam (DZP) were used as model drugs. Effect of PEG 4000, PEG 10000, and stearic acid on floatability and release profile was studied. Water uptake increased with increase in the loading of polar drug (CPM) and decreased with non-polar drug (DZP). Similar effect was found to occur in case of drug release. PEGs increased the release up to certain concentration and decreased thereafter. Drug release decreased linearly with concentration of stearic acid. The type and extent of mesophases formed were significantly affected by the nature of drug, excipients and their concentration. Thus the selection of suitable excipients depending on polarity of drug, could help to modulate the floatability and release profile from GMO matrices.