Elevated IL-6 and Tumor Necrosis Factor-α in Immune Checkpoint Inhibitor Myocarditis.

INTRODUCTION: The impact of peripheral cytokine levels on the prognosis and treatment of immune checkpoint inhibitor (ICI) myocarditis has not been well studied. OBJECTIVES: This study aimed to identify cytokines that can prognosticate and direct the treatment of ICI myocarditis. METHODS: This was a single-center, retrospective cohort study of patients with ICI myocarditis who had available peripheral cytokine levels between January 2011 and May 2022. Major adverse cardiovascular events (MACEs) were defined as a composite of heart failure with/without cardiogenic shock, arterial thrombosis, life-threatening arrhythmias, pulmonary embolism, and sudden cardiac death. RESULTS: In total, 65 patients with ICI myocarditis had cytokine data available. Patients were mostly males (70%), with a mean age of 67.8 ± 12.7 years. Interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) were the most common cytokines to be elevated with 48/65 (74%) of patients having a peak IL-6 above normal limits (>5 pg/mL) and 44/65 (68%) of patients with peak TNF-α above normal limits (>22 pg/mL). Patients with elevated peak IL-6 had similar 90-day mortality and MACE outcomes compared to those without (10.4% vs. 11.8%, p = 0.878 and 8.8% vs. 17.7%, p = 0.366, respectively). Similarly, those with elevated peak TNF-α had similar 90-day mortality and MACEs compared to those without (29.6% vs. 14.3%, p = 0.182 and 13.6% vs. 4.8%, p = 0.413, respectively). Kaplan-Meier survival analysis also showed that there was not a significant difference between MACE-free survival when comparing elevated and normal IL-6 and TNF-α levels (p = 0.182 and p = 0.118, respectively). MACEs and overall survival outcomes were similar between those who received infliximab and those who did not among all patients and those with elevated TNF-α (p-value 0.70 and 0.83, respectively). CONCLUSION: Peripheral blood levels of IL-6 and TNF-α are the most commonly elevated cytokines in patients with ICI myocarditis. However, their role in the prognostication and guidance of immunomodulatory treatment is currently limited.

Coastal flooding will disproportionately impact people on river deltas.

Climate change is intensifying tropical cyclones, accelerating sea-level rise, and increasing coastal flooding. River deltas are especially vulnerable to flooding because of their low elevations and densely populated cities. Yet, we do not know how many people live on deltas and their exposure to flooding. Using a new global dataset, we show that 339 million people lived on river deltas in 2017 and 89% of those people live in the same latitudinal zone as most tropical cyclone activity. We calculate that 41% (31 million) of the global population exposed to tropical cyclone flooding live on deltas, with 92% (28 million) in developing or least developed economies. Furthermore, 80% (25 million) live on sediment-starved deltas, which cannot naturally mitigate flooding through sediment deposition. Given that coastal flooding will only worsen, we must reframe this problem as one that will disproportionately impact people on river deltas, particularly in developing and least-developed economies.

The surgically created arteriovenous fistula: a forgotten alternative to venous access.

The care of patients requiring lifelong intravenous access was revolutionized with the development of tunneled catheters and implantable ports. These devices are not without complications, however, and selected patients may benefit from alternative modalities to maintain access for such therapies as parenteral nutrition, phlebotomy, or chemotherapy. Use of surgically created arteriovenous (AV) fistulae as an alternative to central venous access has been described. This report reviews our experience using AV access for central venous access. An AV access database of more than 800 active patients was reviewed and all patients who had autogenous or synthetic AV fistulae created exclusively for central venous access between July 1, 2001, and December 31, 2003, were identified. Outcomes were assessed. A total of 853 new accesses were placed during the time period. Six fistulae in six patients (0.7%) were placed for central access. All patients (5 males, 1 female, mean age, 42.8 years) required access for intermittent parenteral nutrition or intravenous fluids secondary to short-gut syndrome (n = 5) or gastroparesis (n = 1). All patients had failed at least two prior catheter-based accesses before access placement was considered. Procedures were all brachial artery based and included autogenous brachiobasilic vein fistulae with elevation or transposition (n = 3), autogenous brachiocephalic fistula (n = 1), autogenous brachiobasilic graft with transposed greater saphenous vein (n = 1), and a prosthetic brachiobasilic graft with ePTFE (n = 1). There was one perioperative autogenous fistula thrombosis treated with thrombectomy and revision. A total of seven late revisions (thrombectomy, thrombectomy with venous outflow revision, fistula elevation, and 4 percutaneous angioplasties) in four patients were required. All fistulae were patent and functional at the end of the review period (mean follow-up, = 393 days; range, 35-757 days). Daily access was performed by family members (n = 2) or nurses (n = 4). One patient received small bowel transplantation and no longer required use of his patent fistula. One patient died of liver failure 382 days after fistula placement with a patent fistula. These results show that, while often forgotten and infrequently used, AV access can be a durable alternative to catheter-based venous access.

Does a standardization tool to direct invasive therapy for symptomatic lower extremity peripheral arterial disease improve outcomes?

OBJECTIVES: While decision analysis and treatment algorithms have repeatedly been shown to improve quality of care in many areas of medicine, no such algorithm has emerged for the invasive management of lower extremity peripheral arterial disease. Using the best available evidence-based outcomes data, our group designed a standardization tool, the Lower Extremity Grading System (LEGS) score, which consistently directs limbs to a specific treatment on the basis of presentation. The purpose of this study was to examine whether use of such a tool improves outcomes by directing treatment of lower extremity peripheral arterial disease. METHODS: Over 18 months (July 2001-December 2002) our group intervened in 673 limbs (angioplasty, open surgery, primary limb amputation) with lower extremity peripheral arterial disease. During this time we developed the LEGS score, and implemented its prospective use for the final 362 limbs. For the purpose of this study, all 673 limbs were retrospectively scored with the LEGS score to determine the LEGS recommended best treatment. Of the 673 limbs, 551 (81.9%) received the same treatment as recommended with LEGS and 122 (18.1%) received treatment contrary to LEGS. Limbs treated contrary to LEGS (cases) were then compared with matched control limbs (treated according to LEGS), with similar angiographic findings, clinical presentation, preoperative functional status, comorbid conditions and operative technical factors. Outcomes measured at 6 months included arterial reconstruction patency, limb salvage, survival, and maintenance of ambulatory status and independent living status. Kaplan-Meier curves were used to assess patency, limb salvage, and survival; associated survival curves were compared with the log-rank test. Functional outcomes were compared with the Fisher exact test. RESULTS: After matching case limbs with control limbs, 9 limbs had no control match. Thus 113 limbs in 100 patients treated contrary to LEGS were compared with 113 limbs in 100 patients treated according to LEGS. Limbs treated contrary to LEGS resulted in significantly inferior outcomes at 6 months for measures of primary patency (57.5% vs 84.3%; P < .001), secondary patency (73.2% vs 96.2%; P < .001), limb salvage (89.7% vs 97.2%; P = .04), and maintenance of ambulatory status (78% vs 92%; P = .02). As an additional finding, 29.6% (92 of 311) of interventions performed before implementation of the algorithm were treated contrary to LEGS, and thus contrary to objectively determined best therapy, compared with 8.3% (30 of 362) after LEGS implementation (P < .001). CONCLUSIONS: Limbs treated according to our standardization tool resulted in better outcomes compared with limbs treated contrary to the algorithm. These data suggest that routine use of an appropriately validated treatment standardization algorithm is capable of improving overall results for invasive treatment of lower extremity peripheral arterial disease.

Calcification and proteoglycan accumulation following balloon angioplasty and stenting.

PURPOSE: To examine in a porcine model if a correlation exists between calcification and the hyperplastic response of arteries to balloon angioplasty and stenting. METHODS: Eleven Sinclair miniature swine on an atherogenic diet underwent balloon angioplasty or endovascular stenting in nondiseased external iliac arteries using standard procedures. Ninety days postoperatively, the animals were euthanized, and histological sections of the dilated, stented, and control arteries were examined for evidence of calcification and increased proteoglycan accumulation. RESULTS: An increase in proteoglycan accumulation and the loss of integrity of the internal elastic lamina were observed in both the dilated and stented arteries. Diffuse calcification was seen in the media/neomedia of both groups, and large calcium salt deposits were observed in the dilated arteries at the site of the internal elastic lamina and near the stent struts in stented arteries. CONCLUSIONS: Internal elastic lamina loss of integrity appears to be related to an increase in proteoglycans through the formation of a neointima, and the arterial hyperplastic response to balloon angioplasty and stenting seems to lead to calcification.

Society of Biomaterials Graduate Degree Candidate Student Research Award. Matrix metalloproteinase inhibitor within an absorbable coating for vascular applications: delivery device characterization and reduction of smooth muscle cell proliferation and migration.

Significant occurrences of arterial restenosis remain a complicating factor of endovascular stent implantation. The incorporation of GM6001, a matrix metalloproteinase inhibitor (MMPI), into a poly(lactide-co-glycolide) (PLGA) absorbable coating for 316L stainless steel is proposed as a means to reduce the rate of smooth muscle cell proliferation and migration. Coatings were fabricated using a solvent evaporation technique, and the surfaces were characterized by noncontacting profilometry and scanning electron microscopy. Sufficient degradation of the PLGA determined by gel permeation chromatography occurred to release adequate amounts of the GM6001 from the coating within a 7-day period. A cumulative GM6001 release at day 42 was determined to be 77.8 +/- 1.4% of the actual GM6001 content within the coating. The coating containing the GM6001 reduced the rate of in vitro cell growth of human aortic smooth muscle cell (HASMC) by 30.7 and 37.4% compared to the metallic substrate only after 4 and 7 days, respectively. However, the MMP-2 activity normalized to cell number was not statistically different between the GM6001 releasing coating and the metal substrate. Using a scrape wound injury assay, the migration of HASMCs was shown to be decreased by 21.4% with GM6001 released from the PLGA coating compared to metallic substrate only. These results suggest that releasing a MMPI from an absorbable coating of a metallic substrate provides a reduction of HASMC proliferation and migration rates, while preserving the overall MMP activity in efforts to retain normal cellular regulation.

In vitro evaluation of phosphonylated low-density polyethylene for vascular applications.

The use of catheters for vascular applications is often complicated by the development of friction between the catheter material and the vessel wall, which leads to endothelial cell removal and intimal lesions. Phosphonylation, a chemical surface treatment, has been proposed as a means of increasing the hydrophilicity of low-density polyethylene (LDPE), a commonly used catheter material, in efforts to impart lubricity to the material and reduce vascular tissue damage. In an in vitro tribological study, phosphonylated LDPE produced a lower coefficient of friction and allowed greater retention of endothelial cells on vessels as compared to untreated LDPE when the materials were reciprocated against normal porcine aorta. Chemical characterizations of the LDPE before and after friction testing involving Fourier transform infrared and energy-dispersive X-ray (EDX) confirmed the phosphorus content on phosphonylated LDPE. Election spectroscopy for chemical analysis (ESCA) and atomic force micrscope (AFM) analyses verified that proteins initially adsorb to both the phosphonylated and untreated LDPE surfaces and that the proteins interfere with water to lubricate the surfaces. However, with repeated friction, proteins are removed from the surface and hydrophilicity, as imparted by phosphonylation, becomes a principal factor in the lubrication process.