ECM-mimetic, NSAIDs loaded thermo-responsive, immunomodulatory hydrogel for rheumatoid arthritis treatment.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, and it leads to irreversible inflammation in intra-articular joints. Current treatment approaches for RA include non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), corticosteroids, and biological agents. To overcome the drug-associated toxicity of conventional therapy and transdermal tissue barrier, an injectable NSAID-loaded hydrogel system was developed and explored its efficacy. RESULTS: The surface morphology and porosity of the hydrogels indicate that they mimic the natural ECM, which is greatly beneficial for tissue healing. Further, NSAIDs, i.e., diclofenac sodium, were loaded into the hydrogel, and the in vitro drug release pattern was found to be burst release for 24 h and subsequently sustainable release of 50% drug up to 10 days. The DPPH assay revealed that the hydrogels have good radical scavenging activity. The biocompatibility study carried out by MTT assay proved good biocompatibility and anti-inflammatory activity of the hydrogels was carried out by gene expression study in RAW 264.7 cells, which indicate the downregulation of several key inflammatory genes such as COX-2, TNF-α & 18s. CONCLUSION: In summary, the proposed ECM-mimetic, thermo-sensitive in situ hydrogels may be utilized for intra-articular inflammation modulation and can be beneficial by reducing the frequency of medication and providing optimum lubrication at intra-articular joints.

Perioperative mortality is the Achilles heel for cardiac transplantation in adults with congenital heart disease: Evidence from analysis of the UNOS registry.

BACKGROUND: Adults with congenital heart disease may present with end-stage heart failure necessitating orthotopic heart transplant (OHT). We sought to review the United Network for Organ Sharing (UNOS) experience with this unique cohort focusing on surgical outcomes and survival. METHODS: From the UNOS registry, 737 adult congenital heart disease recipients (ACHDR) out of 26,993 OHT patients (2.7%) who underwent OHT were studied to analyze early and late outcomes and compared to non-congenital recipients (NCR) over a 15-year period (2000-2014). RESULTS: More ACHDR underwent OHT in the recent-era (3.1%; 2010-2014) as compared to the initial-era (2.5%; 2000-2004; p = 0.03). ACHDR were more likely female (40% vs. 24%; p < 0.01), younger (35 vs. 53 years; p < 0.01), less likely to have ventricular assist devices (4.2% vs. 19.3%; p < 0.01), more likely to have class-II panel-reactive antibody >10%; p < 0.01, and were listed for a longer time (249 vs. 181 days; p < 0.01). When compared to the NCR in the same period, the ACHDR cohort had longer postoperative length of stay (27 vs. 20 days; p < 0.01), higher operative mortality (11.5% vs. 4.6% p < 0.001), higher incidence of primary graft dysfunction (4.3% vs. 2.6%; p < 0.01), and higher need for dialysis (20% vs. 9%; p < 0.01). Primary graft dysfunction is the most common cause of death in (5.8%) ACHDR. Although short-term survival is poorer, long-term survival of ACHDR was found to be equivalent or better than NCR in long term. CONCLUSIONS: Perioperative morbidity and mortality adversely affects short-term survival in ACHDR. ACHDR who survive the first post-transplant year have equivalent or better long-term survival than NCR.

Replacement of the infected composite aortic root prosthesis.

BACKGROUND: We sought to evaluate freedom from reinfection after surgery for infected aortic root replacement (ARR) and the impact of use of synthetic material at reoperation. METHODS: Adult patients (aged more than 18 years) undergoing surgery for infected composite aortic root prosthesis at our institution were identified and their perioperative outcomes and late survival evaluated. RESULTS: Between January 1, 1993, and December 31, 2009, 15 patients (male, 87%; mean [SD] age, 57 [16] years) underwent surgery. All but 1 patient (6.7%) underwent reconstruction with a homograft. Eight patients (53.3%) required synthetic material to complete the repair, including 4 patients who underwent hemiarch reconstruction. Ten patients (66.7%) had circulatory arrest (mean [SD] time, 23.3 [11.0] minutes) and 3 (20.0%) underwent concomitant coronary artery bypass grafting. The 30-day mortality rate was 13.3% (n = 2). Three patients (20.0%)-2 of whom had positive blood cultures in hospital after redo ARR-had reinfection, for which 2 underwent re-replacement of the aortic root. Survival was 86.7%, 65.0%, and 50.6%, and freedom from reinfection was 90.9%, 79.5%, and 79.5% at 3, 6, and 12 months, respectively. Freedom from reinfection was less for the patients who had positive blood cultures within 2 weeks of redo ARR (p < 0.03) and for patients who had multiple previous sternotomies (p = 0.006). Use of synthetic graft material had no adverse impact. CONCLUSIONS: Infected ARR prostheses can be replaced with a homograft with favorable outcomes. Use of synthetic material to complete the repair does not adversely impact outcome.

Impact of Formulation and Processing Parameters on Silicone Extraction from Cyclic Olefin Copolymer (COC) Syringes.

The effect of various formulation and process parameters on the extraction of silicone from siliconized cyclic olefin copolymer (COC) syringes is reported. The impact of proprietary silicone curing process on COC syringe barrels was evaluated with respect to the rate and extent of silicone extraction. Similarly, the impact of formulation parameters such as pH, ionic species, and cosolvents on silicone extraction was also evaluated. The rate and extent of silicone extraction into contact solutions was inversely related to the degree of completion of the silicone curing process. The rate and extent of silicone extraction in solution were highest upon exposure to extreme pH solutions. The silicone extraction data indicate that the silicone curing process and formulation parameters have a profound effect on the rate and extent of silicone extraction into solutions. LAY ABSTRACT: Silicone oils are used in medical syringes to provide lubrication. Prefilled medical syringes contain solutions into which silicone oil components may migrate. This study examined the degree to which silicone components migrated into different solution matrices. The impact of different levels of proprietary silicone curing processes on the migration of silicone components in contact solutions was also examined. This study also examined the impact of various formulation parameters (pHionic strength and cosolvents) on the degree to which silicone components migrated into solutions. Solution pH had the greatest effect on silicone migration with higher levels of silicone measured in solutions at the pH extremes. Curing of the silicone (reaction of the silicone with the syringe materials) also had significant impact. High curing levels resulted in less silicone migrating into solution as compared to levels seen with syringes with low curing levels. Thus it was demonstrated that both the nature of the solution stored in the syringe and the degree of silicone curing on the syringe barrel had substantial impact on the amount of silicone that migrated from the syringe components into the solution contained within the syringe.

Echocardiographic predictors of adverse outcomes after continuous left ventricular assist device implantation.

OBJECTIVES: The purpose of the study was to identify echocardiographic predictors of adverse outcome in patients implanted with continuous-flow left ventricular assist devices (LVAD). BACKGROUND: Continuous flow LVAD have become part of the standard of care for the treatment of advanced heart failure. However, knowledge of echocardiographic predictors of outcome after LVAD are lacking. METHODS: Overall, 83 patients received continuous-flow LVAD (HeartMate II, Thoratec Corporation, Pleasanton, California) from February 2007 to June 2010. The LVAD database, containing various echocardiographic parameters, was examined to analyze their influence on in-hospital mortality, a compound cardiac event (in-hospital mortality or acute right ventricular [RV] dysfunction), and long-term mortality. RESULTS: Eight patients died before discharge (operative mortality 9.6%), and another 15 patients were considered to have acute RV dysfunction immediately after surgery. Patients with relatively small left ventricular end-diastolic diameters (<63 mm) had significantly higher risk for in-hospital mortality (odds ratio [OR]: 0.9; 95% confidence interval [CI]: 0.83 to 0.99; p = 0.04) or occurrence of the compound cardiac event (OR: 0.89; 95% CI: 0.84 to 0.95; p < 0.001). The most significant predictor of outcome was the decreased timing interval between the onset and the cessation of tricuspid regurgitation flow corrected for heart rate (TRDc), a surrogate for early systolic equalization of RV and right atrial pressure. Short TRDc predicted in-hospital mortality (OR: 0.85; 95% CI: 0.74 to 0.97; p = 0.01) and the compound cardiac event (OR: 0.83; 95% CI: 0.74 to 0.91; p < 0.0001). Multivariate analysis based on a logistic regression model demonstrated that the accuracy of predicting the 30-day compound adverse outcome was improved with the addition of echocardiographic variables when added to the commonly used hemodynamic or clinical scores. TRDc predicted long-term survival, with adjusted risk ratios of 0.89 for death from any cause (95% CI: 0.83 to 0.96; p = 0.003) and 0.88 for cardiac-related death (95% CI: 0.77 to 0.98; p = 0.03). CONCLUSIONS: The presence of either a relatively small left ventricle (<63 mm) or early systolic equalization of RV and right atrial pressure (short TRDc) demonstrated by echocardiography is associated with increased 30-day morbidity and mortality. Prediction of early adverse outcomes by echocardiographic parameters is additive to laboratory or hemodynamic variables.

Recurrent pulmonary intimal sarcoma involving the right ventricular outflow tract.

Intimal sarcoma of the pulmonary artery is commonly misdiagnosed as chronic pulmonary embolism. Rarely, it can involve the right ventricular outflow tract and the pulmonary valve. We report a patient who was treated surgically for an intimal sarcoma of the pulmonary artery involving the right ventricular outflow tract and the pulmonary valve. The sarcoma recurred in about 8 weeks. It responded favorably to chemoradiation therapy and shows some signs of regression.

Ventricular tachycardia in hypertrophic cardiomyopathy with apical aneurysm.

Midventricular hypertrophic cardiomyopathy is a rare form of cardiomyopathy that may be associated with an apical aneurysm. The mechanism of aneurysm formation is uncertain, but it may be related to subendocardial ischemia. In this report, we describe a 57-year-old man with recurrent ventricular arrhythmias that were refractory to medical treatment because of midventricular hypertrophic cardiomyopathy and apical aneurysm. He was treated successfully with apical aneurysmectomy, myectomy, and subendocardial resection. Six months postoperatively, the patient was free of symptoms and was taken off all anti-arrhythmic medications with one inappropriate discharge from the implantable cardioverter-defibrillator at 4 months.

Echocardiographic findings in stable outpatients with properly functioning HeartMate II left ventricular assist devices.

BACKGROUND: Continuous-flow left ventricular assist devices (LVADs) have become part of the standard of care for the treatment of advanced heart failure. However, knowledge of normal values for transthoracic echocardiographic examination and measurements in these patients are lacking. METHODS: All transthoracic echocardiographic examinations in 63 consecutive patients, performed 90 and 180 days after surgery with the implantation of a HeartMate II continuous-flow LVAD between February 2007 and January 2010, were retrospectively analyzed. All patients had to be outpatients at 3 and 6 months after surgery and considered stable on LVAD therapy (New York Heart Association class I or II and no need for inotropes, intravenous furosemide, or hospitalization). RESULTS: End-diastolic and end-systolic diameters and left ventricular mass decreased considerably compared with baseline measurements before LVAD implantation. Mitral inflow deceleration time increased (188 ± 70 vs 132.5 ± 27 msec, P = .009) and left atrial volume (84.1 ± 33 vs 141.7 ± 62 mL, P = .003) and E/e' ratio decreased (20.3 ± 9 vs 26 ± 11, P = .01), all consistent with decreased left ventricular filling pressure. Estimated right ventricular (RV) and right atrial pressure decreased significantly (34.1 ± 10 vs 51.7 ± 14 mm Hg and 9.5 ± 5 vs 14.4 ± 5 mm Hg, respectively, P < .0001 for both). Quantitatively estimated RV function (P = .02), RV fractional area change (27.9 ± 10% vs 37.4 ± 10.9%, P < .0001), and the RV index of myocardial performance (0.32 ± 0.1 vs 0.65 ± 0.2 vs 0.32 ± .01, P < .0001) improved, suggesting improved RV efficiency. LVAD therapy resulted in significant decreases in the severity of mitral regurgitation. Tricuspid regurgitation improved in patients who had concurrent tricuspid surgical correction and was unchanged otherwise. Aortic regurgitation severity increased 3 months after LVAD implantation. There were no significant differences in any of the echocardiographic parameters in the 6-month evaluation compared with the 3-month evaluation. CONCLUSIONS: This is the first report of selected typical echocardiographic values in a group of stable patients with normally functioning HeartMate II continuous-flow LVADs. A stable functioning continuous LVAD is associated with evidence of efficient unloading of the left ventricle, improved RV function, significant improvement in mitral regurgitation, improvement in tricuspid regurgitation only in patients undergoing repair, and increased aortic regurgitation. These normal data provide a basis for future echocardiographic studies after LVAD implantation.

Left ventricular assist device therapy in patients with restrictive and hypertrophic cardiomyopathy.

BACKGROUND: Left ventricular assist device (LVAD) is being increasingly used in patients with end-stage dilated and ischemic cardiomyopathy. There have been no clinical trials addressing the use of LVAD therapy in patients with end-stage heart failure caused by restrictive (RCM) or hypertrophic cardiomyopathy (HCM). The purpose of this study was therefore to analyze the outcome of LVAD therapy in these patients. METHODS AND RESULTS: Eighty-three patients received continuous axial flow LVAD (Heart mate II, Thoratec, Pleasanton, CA) from February 2007 to May 2010 at our institution. We analyzed the baseline characteristics and surgical and long-term impact of LVAD therapy in 8 patients with RCM or HCM and compared their outcomes with the 75 patients with dilated and ischemic cardiomyopathy. Compared with patients with ischemic or dilated cardiomyopathy, patients with RCM and HCM have significantly smaller left ventricular end-diastolic dimensions (52.5±6 mm versus 68.6±8 mm; P<0.0001) and increased thickness of septal (16 [12, 19] mm versus 10[8.5, 11] mm, P=0.0003) and higher left ventricular ejection fraction (21 [20, 36]% versus 17 [15, 22]%; P=0.0009). We found no difference in early mortality (12.5% versus 9.3%, P=0.57) or length of hospital stay (11 [8, 45] days versus 18.5 [12.2, 27.7] days; P=0.51) between the 2 groups. The right atrial pressure was higher (18 [15, 20] mm Hg versus 12 [9, 15] mm Hg, P=0.03), and pump flow was lower (4.3 [3.8, 4.5] L versus 5.2 [4.7, 5.5] L, P=0.001) after LVAD implantation in patients with RCM and HCM. Central venous catheter related infections were more common in patients with RCM and HCM (87.5% versus 44.5%, P=0.006). There was no difference in the total number of blood units transfused. Median (min, max) follow-up duration after LVAD implantation was 166 [1, 1044] days. The 1-year actuarial survival rate was not different between the 2 groups (87.5% [95% confidence interval, 52.9% to 97.8%] versus 73.2 [95% confidence interval, 60% to 85%]; P=0.77). CONCLUSIONS: Our preliminary data show that patients with end-stage heart failure caused by RCM or HCM may benefit from continuous axial flow LVAD therapy. This small study suggests that mortality is comparable with those patients who have dilated or ischemic cardiomyopathy, but right heart failure, prolonged inotropic use, and central venous catheter infections are more common in patients with RCM and HCM who were treated with LVAD. Because of the small numbers the differences should be interpreted cautiously, and prospective clinical trials would be required to recommend this therapy for these patients as bridge to transplantation or destination treatment.

Paradoxical embolus caught in transit through a patent foramen ovale.

Diagnosing a paradoxical embolism is challenging, and it can be proven only if the thrombus is identified across the intracardiac defect. Very few cases have been diagnosed as an impending paradoxical embolism. Recently, the diagnosis and management of these entities have greatly improved with the advent of transesophageal echocardiography (compared with transthoracic echocardiography). Pulmonary hypertension may cause right-to-left shunting across a patent foramen ovale and predispose development of a paradoxical embolism. We report a patient with an impending paradoxical embolism that was caught in transit across the patent foramen ovale. The patient was treated successfully with emergent surgery.

Carotid Doppler ultrasound findings in patients with left ventricular assist devices.

Left ventricular assist devices (LVADs) have been used to treat advanced heart failure refractory to medical management, as bridge therapy to myocardial recovery, as bridge therapy to cardiac transplantation, or as destination therapy for patients with unfavorable transplant candidacy. Neurologic complications are some of the most common and devastating complications in these patients. Preoperative carotid ultrasound is, therefore, a standard evaluation in patients at risk for cerebrovascular disease. Postoperative carotid artery Doppler sonography is performed in those patients with neurologic symptoms. It is likely, therefore, that sonographers, radiologists, and other physicians working in a center where LVADs are implanted will likely encounter a carotid artery Doppler study in this patient group. To our knowledge, the carotid Doppler findings in these patients have never been published. We review the Doppler ultrasound findings in 6 patients after LVAD insertion.