Pathophysiologic mechanisms of lupus-induced myocardial injury elucidated by cardiovascular magnetic resonance imaging.

Various pathophysiologic mechanisms may account for lupus-induced myocardial injury. Understanding the distinctions in the underlying disease process helps recognize variable clinical presentations and implement appropriate therapies. This report describes lupus-induced myocardial injury in three men less than 40 years old with diverse pathophysiologic mechanisms and presentations including acute myopericarditis with microvascular obstruction, acute coronary syndrome (ACS) and chronic myocarditis with systolic heart failure. Cardiovascular magnetic resonance (CMR) helped define the mechanism of disease, which included evidence of coronary microvascular obstruction in a patient without epicardial coronary artery disease. These findings highlight the cardiovascular effects of lupus, reveal coronary microvascular obstruction as potential consequence of acute myocarditis, and demonstrate the application of CMR in assessing the extent of disease.

Updates on Baroreflex Activation Therapy and Vagus Nerve Stimulation for Treatment of Heart Failure With Reduced Ejection Fraction.

In the last decade, neuromodulation via baroreflex activation therapy (BAT) and vagus nerve stimulation (VNS) has emerged as an innovative approach for the treatment of heart failure with reduced ejection fraction (HFrEF). A review of the literature was conducted to examine the latest efficacy and safety data on neuromodulation for the treatment of HFrEF. Two independent researchers searched the PubMed, clinicaltrials.org, and the Cochrane databases for the most recent data on BAT and VNS published between 2013 and 2019. A total of nine studies were identified. BAT and VNS therapy consistently improved subjective heart failure parameters including New York Heart Association class and Minnesota Living with Heart Failure Questionnaire. Improvements in objective cardiac parameters such as left ventricular ejection fraction (LVEF) were less consistently seen; however, where present, ranged from +3% to +6%, in line with improvements seen after other guideline directed therapy such as left ventricular assist device (LVAD). Benefits of BAT showed a predilection for patients without cardiac resynchronization therapy (CRT) and efficacy of VNS therapy varied with device type. The clinical application of BAT and VNS was found to be limited due to low-powered data, inconsistencies in study design, short-term follow-up and lack of diversity in patient recruitment. Well-powered studies with consistent design, longer follow-up and diverse populations are warranted before BAT and VNS can be incorporated into heart failure guidelines and clinical practice.

An Evaluation of Lysyl Oxidase-Derived Cross-Linking in Keratoconus by Liquid Chromatography/Mass Spectrometry.

PURPOSE: Current literature contains scant information regarding the extent of enzymatic collagen cross-linking in the keratoconus (KC) cornea. The aim of the present study was to examine levels of enzymatic lysyl oxidase-derived cross-links in stromal collagen in KC tissue, and to correlate the cross-link levels with collagen fibril stability as determined by thermal denaturation temperature (Tm). METHODS: Surgical KC samples (n = 17) and Eye-Bank control (n = 11) corneas of age 18 to 68 years were analyzed. The samples were defatted, reduced (NaBH4), hydrolyzed (6N HCl at 110°C for 18 hours), and cellulose enriched before analysis by C8 high-performance liquid chromatography equipped with parallel fluorescent and mass detectors in selective ion monitoring mode (20 mM heptafluorobutyric acid/methanol 70:30 isocratic at 1 mL/min). Nine different cross-links were measured, and the cross-link density was determined relative to collagen content (determined colorimetrically). The Tm was determined by differential scanning calorimetry. RESULTS: Cross-links detected were dihydroxylysinonorleucine (DHLNL), hydroxylysinonorleucine, lysinonorleucine (LNL), and histidinohydroxylysinonorleucine in both control and KC samples. Higher DHLNL levels were detected in KC, whereas the dominant cross-link, LNL, was decreased in KC samples. Decreased LNL levels were observed among KC ≤ 40 corneas. There was no difference in total cross-link density between KC samples and the controls. Pyridinolines, desmosines, and pentosidine were not detected. There was no notable correlation between cross-link levels with fibril instability as determined by Tm. CONCLUSIONS: Lower levels of LNL in the KC cornea suggest that there might be a cross-linking defect either in fibrillar collagen or the microfibrillar elastic network composed of fibrillin.

Evaluating the Toxicity/Fixation Balance for Corneal Cross-Linking With Sodium Hydroxymethylglycinate (SMG) and Riboflavin-UVA (CXL) in an Ex Vivo Rabbit Model Using Confocal Laser Scanning Fluorescence Microscopy.

PURPOSE: To develop methods to delineate the relationship between endothelial cell toxicity and tissue fixation (toxicity/fixation) using sodium hydroxymethylglycinate (SMG), a formaldehyde releaser, and riboflavin-UVA photochemical corneal cross-linking (CXL) for therapeutic tissue cross-linking of the cornea. METHODS: Eleven fresh cadaveric rabbit heads were used for ex vivo corneal cross-linking simulation. After epithelial debridement, the tissue was exposed to 1/4 max (9.8 mM) or 1/3 max (13 mM) SMG at pH 8.5 for 30 minutes or riboflavin-UVA (CXL). The contralateral cornea served as a paired control. Postexposure, cross-linking efficacy was determined by thermal denaturation temperature (Tm) and endothelial damage was assessed using calcein AM and ethidium homodimer staining (The Live/Dead Kit). Confocal laser scanning fluorescence microscopy was used to generate live/dead cell counts using a standardized algorithm. RESULTS: The ΔTm after CXL, 1/3 SMG, and 1/4 SMG was 2.2 ± 0.9°C, 1.3 ± 0.5°C, and 1.1 ± 0.5°C, respectively. Endothelial cell damage was expressed as the percent of dead cells/live + dead cells counted per high-power field. The values were 3 ± 1.7% (control) and 8.9 ± 11.1% (CXL) (P = 0.390); 1 ± 0.2% (control) and 19.5 ± 32.2% (1/3 max SMG) (P = 0.426); and 2.7 ± 2.4% (control) and 2.8 ± 2.2% (1/4 max SMG) (P = 0.938). The values for endothelial toxicity were then indexed over the shift in Tm to yield a toxicity/fixation index. The values were as follows: 2.7 for CXL, 14 for 1/3 max, and 0.1 for 1/4 max. CONCLUSIONS: Quarter max (1/4 max = 9.8 mM) SMG effectively cross-linked tissue and was nontoxic to endothelial cells. Thus, SMG is potentially a compound that could achieve both desired effects.

Cosmetic preservatives as therapeutic corneal and scleral tissue cross-linking agents.

PURPOSE: Previously, aliphatic ß-nitroalcohols (BNAs) have been studied as a means to chemically induce tissue cross-linking (TXL) of cornea and sclera. There are a number of related and possibly more potent agents, known as formaldehyde releasers (FARs), that are in commercial use as preservatives in cosmetics and other personal care products. The present study was undertaken in order to screen such compounds for potential clinical utility as therapeutic TXL agents. METHODS: A chemical registry of 62 FARs was created from a literature review and included characteristics relevant to TXL such as molecular weight, carcinogenicity/mutagenicity, toxicity, hydrophobicity, and commercial availability. From this registry, five compounds [diazolidinyl urea (DAU), imidazolidinyl urea (IMU), sodium hydroxymethylglycinate (SMG), DMDM hydantoin (DMDM), 5-Ethyl-3,7-dioxa-1-azabicyclo [3.3.0] octane (OCT)] were selected for efficacy screening using two independent systems, an ex vivo rabbit corneal cross-linking simulation setup and incubation of cut scleral tissue pieces. Treatments were conducted at pH 7.4 or 8.5 for 30 minutes. Efficacy was evaluated using thermal denaturation temperature (Tm), and cell toxicity was studied using the trypan blue exclusion method. RESULTS: Cross-linking effects in the five selected FARs were pH and concentration dependent. Overall, the Tm shifts were in agreement with both cornea and sclera. By comparison with BNAs previously reported upon, the FARs identified in this study were significantly more potent but with similar or better cytotoxicity. CONCLUSIONS: The FARs, a class of compounds well known to the cosmetic industry, may have utility as therapeutic TXL agents. The compounds studied thus far show promise and will be further tested.