The Impact of the COVID-19 Pandemic on Ambulatory Lumbar Spine Decompression Surgery.

Background Only a few studies have examined the impact of the coronavirus disease 2019 pandemic on spine ambulatory surgeries and changes in trends. Therefore, we investigated trends during the pre-pandemic period and three pandemic stages in patients undergoing lumbar decompression procedures in the ambulatory surgery (AMS) setting. Methodology A total of 2,670 adult patients undergoing one- or two-level lumbar decompression surgery were retrospectively reviewed. Patients were categorized into the following four groups: 1: pre-pandemic (before the pandemic from January 1, 2019, to March 16, 2020); 2: restricted period (when elective surgery was canceled from March 17, 2020, to June 30, 2020); 3: post-restricted 2020 (July 1, 2020, to December 31, 2020, before vaccination); and 4: post-restricted 2021 (January 1, 2021 to December 31, 2021 after vaccination). Simple and multivariable logistic regression analyses as well as retrospective interrupted time series (ITS) analysis were conducted comparing AMS patients in the four periods. Results Patients from the restricted pandemic period were younger and healthier, which led to a shorter length of stay (LOS). The ITS analysis demonstrated a significant drop in mean LOS at the beginning of the restricted period and recovered to the pre-pandemic levels in one year. Multivariable logistic regression analyses indicated that the pandemic was an independent factor influencing the LOS in post-restricted phases. Conclusions As the post-restricted 2020 period itself might be independently influenced by the pandemic, these results should be taken into account when interpreting the LOS of the patients undergoing ambulatory spine surgery in post-restricted phases.

Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension.

Hypoxic reprogramming of vasculature relies on genetic, epigenetic, and metabolic circuitry, but the control points are unknown. In pulmonary arterial hypertension (PAH), a disease driven by hypoxia inducible factor (HIF)-dependent vascular dysfunction, HIF-2α promoted expression of neighboring genes, long noncoding RNA (lncRNA) histone lysine N-methyltransferase 2E-antisense 1 (KMT2E-AS1) and histone lysine N-methyltransferase 2E (KMT2E). KMT2E-AS1 stabilized KMT2E protein to increase epigenetic histone 3 lysine 4 trimethylation (H3K4me3), driving HIF-2α-dependent metabolic and pathogenic endothelial activity. This lncRNA axis also increased HIF-2α expression across epigenetic, transcriptional, and posttranscriptional contexts, thus promoting a positive feedback loop to further augment HIF-2α activity. We identified a genetic association between rs73184087, a single-nucleotide variant (SNV) within a KMT2E intron, and disease risk in PAH discovery and replication patient cohorts and in a global meta-analysis. This SNV displayed allele (G)-specific association with HIF-2α, engaged in long-range chromatin interactions, and induced the lncRNA-KMT2E tandem in hypoxic (G/G) cells. In vivo, KMT2E-AS1 deficiency protected against PAH in mice, as did pharmacologic inhibition of histone methylation in rats. Conversely, forced lncRNA expression promoted more severe PH. Thus, the KMT2E-AS1/KMT2E pair orchestrates across convergent multi-ome landscapes to mediate HIF-2α pathobiology and represents a key clinical target in pulmonary hypertension.

Association of Healthy Lifestyle and Incident Polypharmacy.

BACKGROUND: Polypharmacy, commonly defined as taking ≥5 medications, is an undesirable state associated with lower quality of life. Strategies to prevent polypharmacy may be an important priority for patients. We sought to examine the association of healthy lifestyle, a modifiable risk factor, with incident polypharmacy. METHODS: We performed a secondary analysis of the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort study, including 15,478 adults aged ≥45 years without polypharmacy at baseline. The primary exposure was healthy lifestyle at baseline as measured by the Healthy Behavior Score (HBS), a cumulative assessment of diet, exercise frequency, tobacco smoking, and sedentary time. HBS ranges from 0-8, whereby 0-2 indicates low HBS, 3-5 indicates moderate HBS, and 6-8 indicates high HBS. We used multinomial logistic regression to examine the association between HBS and incident polypharmacy, survival without polypharmacy, and death. RESULTS: Higher HBS (i.e., healthier lifestyle) was inversely associated with incident polypharmacy after adjusting for sociodemographic and baseline health variables. Compared with participants with low HBS, those with moderate HBS had lower odds of incident polypharmacy (odds ratio [OR] 0.85; 95% confidence interval [CI], 0.73-0.98) and lower odds of dying (OR 0.74; 95% CI, 0.65-0.83). Participants with high HBS had even lower odds of both incident polypharmacy (OR 0.75; 95% CI, 0.64-0.88) and death (OR 0.62; 95% CI, 0.54-0.70). There was an interaction for age, where the association between HBS and incident polypharmacy was most pronounced for participants aged ≤65 years. CONCLUSIONS: Healthier lifestyle was associated with lower risk for incident polypharmacy.

Distinct receptor binding domain IgG thresholds predict protective host immunity across SARS-CoV-2 variants and time.

SARS-CoV-2 neutralising antibodies provide protection against COVID-19. Evidence from early vaccine trials suggested binding antibody thresholds could serve as surrogate markers of neutralising capacity, but whether these thresholds predict sufficient neutralising capacity against variants of concern (VOCs), and whether this is impacted by vaccine or infection history remains unclear. Here we analyse individuals recovered from, vaccinated or with hybrid immunity against SARS-CoV-2. An NT50 ≥ 100 IU confers protection in vaccine trials, however, as VOC induce a reduction in NT50, we use NT50 ≥ 1000 IU as a cut off for WT NT50 that would retain neutralisation against VOC. In unvaccinated convalescent participants, a receptor binding domain (RBD) IgG of 456 BAU/mL predicts an NT50 against WT of 1000 IU with an accuracy of 80% (95%CI 73-86%). This threshold maintains accuracy in determining loss of protective immunity against VOC in two vaccinated cohorts. It predicts an NT50 < 100 IU against Beta with an accuracy of 80% (95%CI 67-89%) in 2 vaccine dose recipients. In booster vaccine recipients with a history of COVID-19 (hybrid immunity), accuracy is 87% (95%CI 77-94%) in determining an NT50 of <100 IU against BA.5. This analysis provides a discrete threshold that could be used in future clinical studies.

Omics and Extreme Phenotyping Reveal Longitudinal Association Between Left Atrial Size and Pulmonary Vascular Resistance in Group 2 Pulmonary Hypertension.

BACKGROUND: Left heart disease is the most common cause of pulmonary hypertension (PH) and is frequently accompanied by increases in pulmonary vascular resistance. However, the distinction between phenotypes of PH due to left heart disease with a normal or elevated pulmonary vascular resistance-isolated postcapillary PH (IpcPH) and combined pre- and postcapillary PH (CpcPH), respectively-has been incompletely defined using unbiased methods. METHODS AND RESULTS: Patients with extremes of IpcPH versus CpcPH were identified from a single-center record of those who underwent right heart catheterization. Individuals with left ventricular ejection fraction <40% or with potential causes of PH beyond left heart disease were excluded. Medication usage in IpcPH and CpcPH was compared across Anatomical Therapeutic Chemical classes and identified vitamin K antagonists as the only medication with pharmacome-wide significance, being more commonly used in CpcPH and for an indication of atrial fibrillation in ≈90% of instances. Accordingly, atrial fibrillation prevalence was significantly higher in CpcPH in a phenome-wide analysis. Review of echocardiographic data most proximal to right heart catheterization revealed that left atrial diameter indexed to body surface area-known to be associated with atrial fibrillation-was increased in CpcPH regardless of the presence of atrial fibrillation. An independent cohort with serial right heart catheterizations and PH-left heart disease showed a significant positive correlation between change in left atrial diameter indexed to body surface area and change in pulmonary vascular resistance. CONCLUSIONS: Guided by pharmacomic and phenomic screens in a rigorously phenotyped cohort, we identify a longitudinal association between left atrial diameter indexed to body surface area and pulmonary vascular resistance with implications for the future development of diagnostic, prognostic, and therapeutic tools.

The anatomical positioning change of retroperitoneal organs in prone and lateral position: an assessment for single-prone position lateral lumbar surgery.

PURPOSE: There are reports that performing lateral lumbar interbody fusion (LLIF) in a prone, single position (single-prone LLIF) can be done safely in the prone position because the retroperitoneal organs reflect anteriorly with gravity. However, only a few study has investigated the safety of single-prone LLIF and retroperitoneal organ positioning in the prone position. We aimed to investigate the positioning of retroperitoneal organs in the prone position and evaluate the safety of single-prone LLIF surgery. METHODS: A total of 94 patients were retrospectively reviewed. The anatomical positioning of the retroperitoneal organs was evaluated by CT in the preoperative supine and intraoperative prone position. The distances from the centre line of the intervertebral body to the organs including aorta, inferior vena cava, ascending and descending colons, and bilateral kidneys were measured for the lumbar spine. An "at risk" zone was defined as distance less than 10 mm anterior from the centre line of the intervertebral body. RESULTS: Compared to supine preoperative CTs, bilateral kidneys at the L2/3 level as well as the bilateral colons at the L3/4 level had statistically significant ventral shift with prone positioning. The proportion of retroperitoneal organs within the at-risk zone ranged from 29.6 to 88.6% in the prone position. CONCLUSIONS: The retroperitoneal organs shifted ventrally with prone positioning. However, the amount of shift was not large enough to avoid risk for organ injuries and substantial proportion of patients had organs within the cage insertion corridor. Careful preoperative planning is warranted when considering single-prone LLIF.

The proliferation of human mucosal-associated invariant T cells requires a MYC-SLC7A5-glycolysis metabolic axis.

Mucosal-associated invariant T (MAIT) cells are an abundant population of innate T cells that recognize bacterial ligands and play a key role in host protection against bacterial and viral pathogens. Upon activation, MAIT cells undergo proliferative expansion and increase their production of effector molecules such as cytokines. In this study, we found that both mRNA and protein abundance of the key metabolism regulator and transcription factor MYC was increased in stimulated MAIT cells. Using quantitative mass spectrometry, we identified the activation of two MYC-controlled metabolic pathways, amino acid transport and glycolysis, both of which were necessary for MAIT cell proliferation. Last, we showed that MAIT cells isolated from people with obesity showed decreased MYC mRNA abundance upon activation, which was associated with defective MAIT cell proliferation and functional responses. Collectively, our data uncover the importance of MYC-regulated metabolism for MAIT cell proliferation and provide additional insight into the molecular basis for the functional defects of MAIT cells in obesity.

Single Nucleotide Polymorphism rs9277336 Controls the Nuclear Alpha Actinin 4-Human Leukocyte Antigen-DPA1 Axis and Pulmonary Endothelial Pathophenotypes in Pulmonary Arterial Hypertension.

Background Pulmonary arterial hypertension (PAH) is a complex, fatal disease where disease severity has been associated with the single nucleotide polymorphism (SNP) rs2856830, located near the human leukocyte antigen DPA1 (HLA-DPA1) gene. We aimed to define the genetic architecture of functional variants associated with PAH disease severity by identifying allele-specific binding transcription factors and downstream targets that control endothelial pathophenotypes and PAH. Methods and Results Electrophoretic mobility shift assays of oligonucleotides containing SNP rs2856830 and 8 SNPs in linkage disequilibrium revealed functional SNPs via allele-imbalanced binding to human pulmonary arterial endothelial cell nuclear proteins. DNA pulldown proteomics identified SNP-binding proteins. SNP genotyping and clinical correlation analysis were performed in 84 patients with PAH at University of Pittsburgh Medical Center and in 679 patients with PAH in the All of Us database. SNP rs9277336 was identified as a functional SNP in linkage disequilibrium (r2>0.8) defined by rs2856830, and the minor allele was associated with decreased hospitalizations and improved cardiac output in patients with PAH, an index of disease severity. SNP pulldown proteomics showed allele-specific binding of nuclear ACTN4 (alpha actinin 4) protein to rs9277336 minor allele. Both ACTN4 and HLA-DPA1 were downregulated in pulmonary endothelium in human patients and rodent models of PAH. Via transcriptomic and phenotypic analyses, knockdown of HLA-DPA1 phenocopied knockdown of ACTN4, both similarly controlling cell structure pathways, immune pathways, and endothelial dysfunction. Conclusions We defined the pathogenic activity of functional SNP rs9277336, entailing the allele-specific binding of ACTN4 and controlling expression of the neighboring HLA-DPA1 gene. Through inflammatory or genetic means, downregulation of this ACTN4-HLA-DPA1 regulatory axis promotes endothelial pathophenotypes, providing a mechanistic explanation for the association between this SNP and PAH outcomes.

Risk Factors for Ambulatory Surgery Conversion to Extended Stay Among Patients Undergoing One-level or Two-level Posterior Lumbar Decompression.

STUDY DESIGN: A retrospective observational study. OBJECTIVE: The objective of this study was to investigate the factors associated with the conversion of patient status from ambulatory surgery (AMS) to observation service (OS) (<48 h) or inpatient (>48 h). SUMMARY OF BACKGROUND DATA: AMS is becoming increasingly common in the United States because it is associated with a similar quality of care compared with inpatient surgery, significant costs reduction, and patients' desire to recuperate at home. However, there are instances when AMS patients may be subjected to extended hospital stays. Unanticipated extension of hospitalization stays can be a great burden not only to patients but to medical providers and insurance companies alike. MATERIALS AND METHODS: Data from 1096 patients who underwent one-level or two-level lumbar decompression AMS at an in-hospital, outpatient surgical facility between January 1, 2019, and March 16, 2020, were collected. Patients were categorized into three groups based on length of stay: (1) AMS, (2) OS, or (3) inpatient. Demographics, comorbidities, surgical information, and administrative information were collected. Simple and multivariable logistic regression analyses were conducted comparing AMS patients and OS/inpatient as well as OS and inpatients. RESULTS: Of the 1096 patients, 641 (58%) patients were converted to either OS (n=486) or inpatient (n=155). The multivariable analysis demonstrated that age (more than 80 yr old), high American Society of Anesthesiologists Physical Status (ASA) grade, history of sleep apnea, drain use, high estimated blood loss, long operation, late operation start time, and a high pain score were considered independent risk factors for AMS conversion to OS/inpatient. The risk factors for OS conversion to inpatient were an ASA class 3 or higher, coronary artery disease, diabetes mellitus, hypothyroidism, steroid use, drain use, dural tear, and laminectomy. CONCLUSIONS: Several surgical factors along with patient-specific factors were significantly associated with AMS conversion. Addressing modifiable surgical factors might reduce the AMS conversion rate and be beneficial to patients and facilities.

A p53-TLR3 axis ameliorates pulmonary hypertension by inducing BMPR2 via IRF3.

Pulmonary arterial hypertension (PAH) features pathogenic and abnormal endothelial cells (ECs), and one potential origin is clonal selection. We studied the role of p53 and toll-like receptor 3 (TLR3) in clonal expansion and pulmonary hypertension (PH) via regulation of bone morphogenetic protein (BMPR2) signaling. ECs of PAH patients had reduced p53 expression. EC-specific p53 knockout exaggerated PH, and clonal expansion reduced p53 and TLR3 expression in rat lung CD117+ ECs. Reduced p53 degradation (Nutlin 3a) abolished clonal EC expansion, induced TLR3 and BMPR2, and ameliorated PH. Polyinosinic/polycytidylic acid [Poly(I:C)] increased BMPR2 signaling in ECs via enhanced binding of interferon regulatory factor-3 (IRF3) to the BMPR2 promoter and reduced PH in p53-/- mice but not in mice with impaired TLR3 downstream signaling. Our data show that a p53/TLR3/IRF3 axis regulates BMPR2 expression and signaling in ECs. This link can be exploited for therapy of PH.

Antigen specific T cells in people with obesity at five months following ChAdOx1 COVID-19 vaccination.

BACKGROUND/OBJECTIVES: People with obesity (PWO) face an increased risk of severe outcomes from COVID-19, including hospitalisation, ICU admission and death. Obesity has been seen to impair immune memory following vaccination against influenza, hepatitis B, tetanus, and rabies. Little is known regarding immune memory in PWO following COVID-19 adenovirus vector vaccination. SUBJECTS/METHODS: We investigated SARS-CoV-2 specific T cell responses in 50 subjects, five months following a two-dose primary course of ChAdOx1 nCoV-19 (AZD1222) vaccination. We further divided our cohort into PWO (n = 30) and matched controls (n = 20). T cell (CD4+, CD8+) cytokine responses (IFNγ, TNFα) to SARS-CoV-2 spike peptide pools were determined using multicolour flow cytometry. RESULTS: Circulating T cells specific for SARS-CoV-2 were readily detected across our cohort, with robust responses to spike peptide stimulation across both T cell lines. PWO and controls had comparable levels of both CD4+ and CD8+ SARS-CoV-2 spike specific T cells. Polyfunctional T cells - associated with enhanced protection against viral infection - were detected at similar frequencies in both PWO and controls. CONCLUSIONS: These data indicate that PWO who have completed a primary course of ChAdOx1 COVID-19 vaccination have robust, durable, and functional antigen specific T cell immunity that is comparable to that seen in people without obesity.

Obesity in HIV infection: host-pathogen interaction.

OBJECTIVE: Both obesity and HIV infection are characterized by a state of chronic inflammation associated with increased morbidity and mortality. This review aims to assess the available literature on immune dysregulation in obesity and people with HIV infection (PWH). DESIGN: A systematic review of peer-reviewed literature. METHODS: We conducted a systematic literature search of PubMed, Embase, Scopus, and international conference abstracts for articles on the epidemiology of obesity in the general population and in PWH and the pathogenesis of obesity with a focus on inflammation and immune activation. RESULTS: Of the 631 articles selected after title review, 490 met the inclusion criteria and 90 were included in the final selection. The selected studies highlight the increasing prevalence of obesity in PWH and a substantial role for antiretroviral treatment (ART) in its development. Pathogenesis of obesity and its associated inflammation derives from disturbances in adipose tissue (AT) immune function, focused on T-cell and macrophage function, with a switch to pro-inflammatory immune phenotype and resulting increases in pro-inflammatory chemokines, which contribute to the development of metabolic syndrome. Although dysregulation of these pathways is seen in both obesity and HIV, there remains a lack of human studies on AT inflammation in HIV. CONCLUSION: Obesity is an emerging comorbidity in PWH, with a substantial overlap in immune dysregulation patterns seen in both conditions. How this immune dysfunction impacts on development of metabolic complications for both obesity and HIV infection, and whether targeting of AT-derived inflammation will improve outcomes in PWH requires further study.

Individuals with obesity who survive SARS-CoV-2 infection have preserved antigen-specific T cell frequencies.

OBJECTIVE: Obesity is a major risk factor for severe disease in COVID-19, with increased hospitalization, intensive care unit admission, and mortality. This increased impact of COVID-19 in people with obesity (PWO) is likely driven, in part, by the well-described obesity-induced immune dysregulation. Obesity has also been associated with impaired immune memory in many settings, including weakened responses to hepatitis B, tetanus, rabies, and influenza vaccination. Recently, it was reported that PWO who have COVID-19 have reduced IgG antibody titers with defective neutralizing capabilities. However, it remains unknown whether PWO generate durable T cell immunity to SARS-CoV-2. METHODS: This study investigated SARS-CoV-2-specific T cell responses in a cohort of 40 patients (n = 20 PWO and n = 20 matched control individuals) who had recovered from COVID-19. T cell (CD4+ , CD8+ ) cytokine responses (IFNγ, TNFα) to SARS-CoV-2 peptide pools (spike, membrane) were determined using multicolor flow cytometry. RESULTS: Circulating T cells specific for SARS-CoV-2 were readily detected in the total cohort. PWO displayed comparable levels of SARS-CoV-2 spike- and membrane-specific T cells, with both T cell subsets responding. CONCLUSIONS: These data indicate that PWO who survive COVID-19 generate robust and durable SARS-CoV-2-specific T cell immunity that is equivalent to that seen in those without obesity.

Pulmonary Arterial Hypertension: Emerging Principles of Precision Medicine across Basic Science to Clinical Practice.

Pulmonary arterial hypertension (PAH) is an enigmatic and deadly vascular disease with no known cure. Recent years have seen rapid advances in our understanding of the molecular underpinnings of PAH, with an expanding knowledge of the molecular, cellular, and systems-level drivers of disease that are being translated into novel therapeutic modalities. Simultaneous advances in clinical technology have led to a growing list of tools with potential application to diagnosis and phenotyping. Guided by fundamental biology, these developments hold the potential to usher in a new era of personalized medicine in PAH with broad implications for patient management and great promise for improved outcomes.

Association of healthy lifestyle and all-cause mortality according to medication burden.

BACKGROUND: Healthy lifestyle is associated with reduced all-cause mortality, but it is not known whether this association persists for individuals with high medication burden. We examined the association between healthy lifestyle behaviors and all-cause mortality across different degrees of polypharmacy. METHODS: This was a secondary analysis of 20,417 adults aged ≥45 years from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort study. The primary exposure was healthy lifestyle (adherence to Mediterranean diet, physical activity, smoking abstinence, sedentary behavior avoidance, and composite healthy behavior score [HBS]). The primary outcome was all-cause mortality. Strata of medication burden were based on the number of medications taken (no polypharmacy: 0-4, polypharmacy: 5-9, hyperpolypharmacy: ≥10). We used Cox proportional hazards regression models to examine the association between healthy lifestyle behaviors and mortality within each medication burden stratum and examined for interactions with age. RESULTS: The healthiest category of each lifestyle behavior, except sedentary behavior avoidance among the hyperpolypharmacy group, was associated with lower all-cause mortality (hazard ratio [HR]) regardless of medication burden: Mediterranean diet (no polypharmacy: HR 0.77, polypharmacy: HR 0.78, hyperpolypharmacy: HR 0.85), physical activity (no polypharmacy: HR 0.87, polypharmacy: HR 0.82, hyperpolypharmacy: HR 0.79), smoking abstinence (no polypharmacy: HR 0.40, polypharmacy: HR 0.45, hyperpolypharmacy: HR 0.52), and sedentary behavior avoidance (no polypharmacy: HR 0.88, polypharmacy: HR 0.86, hyperpolypharmacy: HR 0.95). Higher HBS was inversely associated with all-cause mortality within each medication burden stratum (no polypharmacy: HR 0.52, polypharmacy: HR 0.55, hyperpolypharmacy: HR 0.69). Although there was an interaction with age among those with no polypharmacy and those with polypharmacy, point estimates for HBS followed a graded pattern whereby higher HBS was incrementally associated with improved mortality across all age strata. CONCLUSION: Greater adherence to a healthy lifestyle was associated with lower all-cause mortality irrespective of medication burden and age.

SCUBE1 Controls BMPR2-Relevant Pulmonary Endothelial Function: Implications for Diagnostic Marker Development in Pulmonary Arterial Hypertension.

Utilizing publicly available ribonucleic acid sequencing data, we identified SCUBE1 as a BMPR2-related gene differentially expressed between induced pluripotent stem cell-endothelial cells derived from pulmonary arterial hypertension (PAH) patients carrying pathogenic BMPR2 mutations and control patients without mutations. Endothelial SCUBE1 expression was decreased by known triggers of PAH, and its down-regulation recapitulated known BMPR2-associated endothelial pathophenotypes in vitro. Meanwhile, SCUBE1 concentrations were reduced in plasma obtained from PAH rodent models and patients with PAH, whereas plasma concentrations were tightly correlated with hemodynamic markers of disease severity. Taken together, these data implicate SCUBE1 as a novel contributor to PAH pathogenesis with potential therapeutic, diagnostic, and prognostic applications.

Standards and Trends in Lipoabdominoplasty.

BACKGROUND: Lipoabdominoplasty has evolved over the last 6 decades through contributions from numerous luminaries in plastic and reconstructive surgery. METHODS: The authors review historical perspective and provide a contemporary examination of trends in lipoabdominoplasty. RESULTS: In 1967, Pitanguy popularized abdominoplasty (without liposuction) as a technique for augmenting ventral hernias repairs and subsequently for aesthetic improvement of the abdomen. After the introduction of suction assisted lipectomy by Illouz in 1983, abdominoplasty became a central tool in a diverse armamentarium of anterior and lateral abdominal wall contouring procedures. Liposuction was initially utilized with mini-abdominoplasty in order to improve contour. Subsequently, Matarasso advanced the safe combination of liposuction with full abdominoplasty. Additionally, he systematized the variety of cutaneous undermining, excision, and liposuction procedures utilized in abdominal contouring as indicated by the degree of skin laxity and musculofascial diastasis. Lockwood advocated high lateral tension closure of the superficial fascial system of the abdomen to improve the contour of the hips and flanks. Saldanha advanced selective undermining and anterior abdominal wall perforator preservation to minimize wound healing and seroma complications associated with lipoabdominoplasty procedures. CONCLUSION: In abdominal contour surgery, surgeons can rely on classic techniques and algorithms that have withstood the test of time while modifying their approaches with advances backed by compelling and rigorously obtained evidence.

Depletion of Vasohibin 1 Speeds Contraction and Relaxation in Failing Human Cardiomyocytes.

RATIONALE: Impaired myocardial relaxation is an intractable feature of several heart failure (HF) causes. In human HF, detyrosinated microtubules stiffen cardiomyocytes and impair relaxation. Yet the identity of detyrosinating enzymes have remained ambiguous, hindering mechanistic study and therapeutic development. OBJECTIVE: We aimed to determine if the recently identified complex of VASH1/2 (vasohibin 1/2) and SVBP (small vasohibin binding protein) is an active detyrosinase in cardiomyocytes and if genetic inhibition of VASH-SVBP is sufficient to lower stiffness and improve contractility in HF. METHODS AND RESULTS: Transcriptional profiling revealed that VASH1 transcript is >10-fold more abundant than VASH2 in human hearts. Using short hairpin RNAs (shRNAs) against VASH1, VASH2, and SVBP, we showed that both VASH1- and VASH2-SVBP complexes function as tubulin carboxypeptidases in cardiomyocytes, with a predominant role for VASH1. We also generated a catalytically dead version of the tyrosinating enzyme TTL (TTL-E331Q) to separate the microtubule depolymerizing effects of TTL from its enzymatic activity. Assays of microtubule stability revealed that both TTL and TTL-E331Q depolymerize microtubules, while VASH1 and SVBP depletion reduce detyrosination independent of depolymerization. We next probed effects on human cardiomyocyte contractility. Contractile kinetics were slowed in HF, with dramatically slowed relaxation in cardiomyocytes from patients with HF with preserved ejection fraction. Knockdown of VASH1 conferred subtle kinetic improvements in nonfailing cardiomyocytes, while markedly improving kinetics in failing cardiomyocytes. Further, TTL, but not TTL-E331Q, robustly sped relaxation. Simultaneous measurements of calcium transients and contractility demonstrated that VASH1 depletion speeds kinetics independent from alterations to calcium cycling. Finally, atomic force microscopy confirmed that VASH1 depletion reduces the stiffness of failing human cardiomyocytes. CONCLUSIONS: VASH-SVBP complexes are active tubulin carboxypeptidases in cardiomyocytes. Inhibition of VASH1 or activation of TTL is sufficient to lower stiffness and speed relaxation in cardiomyocytes from patients with HF, supporting further pursuit of detyrosination as a therapeutic target for diastolic dysfunction.