Surgical management of calcific valvular and coronary disease in a patient with alkaptonuria: a case report.

Background: Alkaptonuria is a rare metabolic disease that causes an increase in homogentisic acid (HGA) due to a lack of enzymatic activity. Commonly, accumulation of HGA presents with dark discoloration of skin and other tissues, also known as ochronosis. Additionally, alkaptonuria can result in other clinical manifestations, including arthritis and cardiac disease. This case highlights alkaptonuria-related cardiac disease and challenges that cardiac surgery teams may face when treating this patient population. Case summary: A 62-year-old male with a history of alkaptonuria, Hodgkin's lymphoma treated with chemoradiation, hypertension, and hyperlipidaemia originally presented with shortness of breath in the setting of known cardiac disease. Cardiac work-up demonstrated aortic stenosis, mitral stenosis, and multivessel coronary artery disease requiring aortic valve replacement, mitral valve replacement, and coronary artery bypass grafting. During the operation, significant discoloration of tissue was observed. This correlated with areas of severe calcification, which was noted throughout both valves. Extensive debridement was required prior to proceeding to valve replacements. Additionally, near-infrared spectroscopy failed to provide accurate measurements of cerebral oxygenation. Discussion: Alkaptonuria is correlated with cardiovascular disease, particularly valvular disease. Intraoperatively, these patients may exhibit noticeable discoloration and severe calcification of various tissues. Additionally, traditional infrared-based methods of cerebral oxygenation monitoring may not be reliable; however, other options of cerebral monitoring may be feasible. With proper pre-operative planning, however, patients with alkaptonuria may safely undergo cardiac surgery.

Intramyocardial cell-based therapy with Lomecel-B during bidirectional cavopulmonary anastomosis for hypoplastic left heart syndrome: the ELPIS phase I trial.

Aims: Hypoplastic left heart syndrome (HLHS) survival relies on surgical reconstruction of the right ventricle (RV) to provide systemic circulation. This substantially increases the RV load, wall stress, maladaptive remodelling, and dysfunction, which in turn increases the risk of death or transplantation. Methods and results: We conducted a phase 1 open-label multicentre trial to assess the safety and feasibility of Lomecel-B as an adjunct to second-stage HLHS surgical palliation. Lomecel-B, an investigational cell therapy consisting of allogeneic medicinal signalling cells (MSCs), was delivered via intramyocardial injections. The primary endpoint was safety, and measures of RV function for potential efficacy were obtained. Ten patients were treated. None experienced major adverse cardiac events. All were alive and transplant-free at 1-year post-treatment, and experienced growth comparable to healthy historical data. Cardiac magnetic resonance imaging (CMR) suggested improved tricuspid regurgitant fraction (TR RF) via qualitative rater assessment, and via significant quantitative improvements from baseline at 6 and 12 months post-treatment (P < 0.05). Global longitudinal strain (GLS) and RV ejection fraction (EF) showed no declines. To understand potential mechanisms of action, circulating exosomes from intramyocardially transplanted MSCs were examined. Computational modelling identified 54 MSC-specific exosome ribonucleic acids (RNAs) corresponding to changes in TR RF, including miR-215-3p, miR-374b-3p, and RNAs related to cell metabolism and MAPK signalling. Conclusion: Intramyocardially delivered Lomecel-B appears safe in HLHS patients and may favourably affect RV performance. Circulating exosomes of transplanted MSC-specific provide novel insight into bioactivity. Conduct of a controlled phase trial is warranted and is underway.Trial registration number NCT03525418.

Cardio-omentopexy requires a cardioprotective innate immune response to promote myocardial angiogenesis in mice.

Objective: The pedicled greater omentum, when applied onto stressed hearts using omentopexy, has been shown to be protective in humans and animals. The mechanisms underlying cardioprotection using omentopexy remain elusive. This study examined whether macrophage-mediated angiogenesis accounts for the cardioprotective effect of omentopexy in mice. Methods: C57BL/6 mice were subjected to minimally invasive transverse aortic constriction for 6 weeks and subsequent cardio-omentopexy for 8 weeks. Control mice underwent the same surgical procedures without aortic constriction or cardio-omentopexy. Results: Transverse aortic constriction led to left ventricular concentric hypertrophy, reduced mitral E/A ratio, increased cardiomyocyte size, and myocardial fibrosis in the mice that underwent sham cardio-omentopexy surgery. The negative effects of transverse aortic constriction were prevented by cardio-omentopexy. Myocardial microvessel density was elevated in the mice that underwent aortic constriction and sham cardio-omentopexy surgery, and cardio-omentopexy further enhanced angiogenesis. Nanostring gene array analysis uncovered the activation of angiogenesis gene networks by cardio-omentopexy. Flow cytometric analysis revealed that cardio-omentopexy triggered the accumulation of cardiac MHCIIloLyve1+TimD4+ (Major histocompatibility complex class IIlow lymphatic vessel endothelial hyaluronan receptor 1+ T cell immunoglobulin and mucin domain conataining 4+) resident macrophages at the omental-cardiac interface. Intriguingly, the depletion of macrophages with clodronate-liposome resulted in the failure of cardio-omentopexy to protect the heart and promote angiogenesis. Conclusions: Cardio-omentopexy protects the heart from pressure overload-elicited left ventricular hypertrophy and dysfunction by promoting myocardial angiogenesis. Cardiac MHCIIloLyve1+TimD4+ resident macrophages play a critical role in the cardioprotective effect and angiogenesis of cardio-omentopexy.

Autologous Cardiac Stem Cell Injection in Patients with Hypoplastic Left Heart Syndrome (CHILD Study).

Mortality in infants with hypoplastic left heart syndrome (HLHS) is strongly correlated with right ventricle (RV) dysfunction. Cell therapy has demonstrated potential improvements of RV dysfunction in animal models related to HLHS, and neonatal human derived c-kit+ cardiac-derived progenitor cells (CPCs) show superior efficacy when compared to adult human cardiac-derived CPCs (aCPCs). Neonatal CPCs (nCPCs) have yet to be investigated in humans. The CHILD trial (Autologous Cardiac Stem Cell Injection in Patients with Hypoplastic Left Heart Syndrome) is a Phase I/II trial aimed at investigating intramyocardial administration of autologous nCPCs in HLHS infants by assessing the feasibility, safety, and potential efficacy of CPC therapy. Using an open-label, multicenter design, CHILD investigates nCPC safety and feasibility in the first enrollment group (Group A/Phase I). In the second enrollment group, CHILD uses a randomized, double-blinded, multicenter design (Group B/Phase II), to assess nCPC efficacy based on RV functional and structural characteristics. The study plans to enroll 32 patients across 4 institutions: Group A will enroll 10 patients, and Group B will enroll 22 patients. CHILD will provide important insights into the therapeutic potential of nCPCs in patients with HLHS.Clinical Trial Registration https://clinicaltrials.gov/ct2/home NCT03406884, First posted January 23, 2018.

Representation of African American Patients in Social Media for Breast Reconstruction.

BACKGROUND: Social media use by plastic surgeons may contribute to the overall increase in breast reconstruction in the United States. However, recent data show a concerning decrease in breast reconstruction in African American women. The purpose of this study was to analyze the inclusion of African American women in social media posts for breast reconstruction, with the premise that this may be a possible contributing factor to decreasing rates of breast reconstruction in this population. METHODS: Data from several social media platforms were obtained manually on December 1, 2019. Each image was analyzed using the Fitzpatrick scale as a guide. RESULTS: A total of 2580 photographs were included that met the authors' criteria. Only 172 photographs (6.7 percent) were nonwhite. This study surveyed 543 surgeons, 5 percent of whom were nonwhite. The analysis of the results from the random sample of the top plastic surgery social media influencers showed that only 22 (5 percent) of the photographs uploaded were nonwhite patients. Furthermore, 30 percent of surgeons did not have any photographs of nonwhite patients uploaded. CONCLUSIONS: Numerous factors can contribute to the disparity between the growing trend of white patients seeking reconstructive surgery compared to the decreasing trend of African American patients, one of which may be the disparity in their representation in social media, particularly among common platforms and social media influencers. This study highlights the evolving factors that may impair African American breast cancer patients' access to safe, effective breast reconstruction, which must be identified and resolved.

The Use of Botulinum Toxin to Prevent Anastomotic Thrombosis and Promote Flap Survival: A Bridge to Developing Clinical Studies.

BACKGROUND: Despite the possibility of using botulinum toxin to improve perfusion and prevent vasospasm, only a few studies have examined the use of botulinum toxin in the setting of flap surgery and thrombosis, and the mechanisms have not been fully explained. OBJECTIVE: The primary objective of this study was to provide a comprehensive review of the effectiveness of botulinum toxin in anastomotic thrombosis prevention and surgical flap survival to determine the value of conducting large-scale human trials. METHODS: Using the SYRCLE and CAMRADES criteria, a systematic review was performed. PubMed, Medline, EmBase, and the Cochrane Library were searched for studies that met our eligibility criteria. RESULTS: Twenty studies were included in the final selection. A total of 397 subjects were included. Eighteen studies used botulinum toxin type A alone, one used botulinum toxin type B alone, and only one used both botulinum toxin type A and botulinum toxin type B. The most commonly used injection technique was a preoperative intradermal injection. The most common procedure performed was a pedicled flap with random pattern skin flaps (65%). The mean injection dose was 28.17 ± 49.21 IU, whereas the mean reported injection time for studies using animal models was 7.4 ± 6.84 days. CONCLUSIONS: Similar mechanisms demonstrated in animal models may be replicable in humans, allowing botulinum toxin to be used to prolong flap survival. However, many factors, such as optimal injection techniques, dosages, and long-term outcomes of botulinum use in flap surgery, need to be further assessed before applying this to clinical practice.

Mitochondrial transcription factor A promotes DNA strand cleavage at abasic sites.

In higher eukaryotic cells, mitochondria are essential subcellular organelles for energy production, cell signaling, and the biosynthesis of biomolecules. The mitochondrial DNA (mtDNA) genome is indispensable for mitochondrial function because it encodes protein subunits of the electron transport chain and a full set of transfer and ribosomal RNAs. MtDNA degradation has emerged as an essential quality control measure to maintain mtDNA and to cope with mtDNA damage resulting from endogenous and environmental factors. Among all types of DNA damage known, abasic (AP) sites, sourced from base excision repair and spontaneous base loss, are the most abundant endogenous DNA lesions in cells. In mitochondria, AP sites trigger rapid DNA loss; however, the mechanism and molecular factors involved in the process remain elusive. Herein, we demonstrate that the stability of AP sites is reduced dramatically upon binding to a major mtDNA packaging protein, mitochondrial transcription factor A (TFAM). The half-life of AP lesions within TFAM-DNA complexes is 2 to 3 orders of magnitude shorter than that in free DNA, depending on their position. The TFAM-catalyzed AP-DNA destabilization occurs with nonspecific DNA or mitochondrial light-strand promoter sequence, yielding DNA single-strand breaks and DNA-TFAM cross-links. TFAM-DNA cross-link intermediates prior to the strand scission were also observed upon treating AP-DNA with mitochondrial extracts of human cells. In situ trapping of the reaction intermediates (DNA-TFAM cross-links) revealed that the reaction proceeds via Schiff base chemistry facilitated by lysine residues. Collectively, our data suggest a novel role of TFAM in facilitating the turnover of abasic DNA.