Citations

Injection of A-MSC-derived EVs harvested from patients who are lean can resolve myocardial injury in mice with experimental renovascular hypertension more effectively than A-MSC-derived EVs from patients with obesity. These observations underscore and might have important ramifications for the self-healing capacity of patients with obesity and for the use of autologous EVs as a regenerative tool.

Objective: Electro-Hydraulic Acoustic Therapy (eHAT), using ∼10% of the energy used in shockwave lithotripsy, is a promising technique to ameliorate ischemia and regenerate tissues. eHAT has been demonstrated to enhance healing in tissues such as bone, muscle, and myocardium, via several mechanisms, particularly by promoting neovascularization. Furthermore, previous animal studies demonstrated that eHAT reduces blood pressure (BP) and preserves renal function after ischemic kidney injury. The present pilot study explored the clinical safety and efficacy of eHAT and tested the hypothesis that eHAT would reduce BP and preserve renal function in patients with medically-treated hypertension and CKD. Design and method: So far, a total of 15 patients with HTN and Stage III a/b CKD were enrolled in this prospective, single-arm study. The patients were treated with six sessions of eHAT during a 3-week period. At each session, 2400 shockwaves were applied to each kidney with 0.09 mJ/mm2 at 2.66Hz (NephrospecTM by Curespec LTD, Yehud, Israel). Follow-up (FU) visits were performed at 1, 3, and 6 months. Results: The treatment was well tolerated with no major adverse events or need for analgesic treatment. Average Automated Office BP (AOBP) showed a strong tendency for a decrease in diastolic BP from baseline to the Primary Efficacy Objective at FU II (3 months post-last treatment), which progressively decreased further at FU III (6 months) (Table 1). Similarly, average Office BP (OBP) detected a strong trend for a progressive decrease in systolic BP from baseline to the Primary Efficacy Objective (Table 1). Levels of eGFR appeared to slightly rise throughout the study, but this change has not reached statistical significance levels (Table 1). Conclusions: The current study demonstrates that the eHAT procedure is tolerable and safe in this cohort. Moreover, a 3-week regimen tended to reduce BP and preserve eGFR in patients with controlled HTN and CKD. Therefore, electro-Hydraulic Acoustic Therapy may emerge as a novel, safe, and non-invasive alternative therapeutic approach in the management of HTN in the context of CKD.

Autologous mesenchymal stem/stromal cells (MSCs) have demonstrated important therapeutic effects in several diseases. Cardiovascular risk factors may impair MSC mitochondrial structure and function, but the underlying mechanisms remain unknown. We hypothesized that metabolic syndrome (MetS) induces epigenetic alterations in mitochondria-related genes in swine MSCs. Pigs were fed a Lean or MetS diet (n = 6 each) for 16 weeks. MSCs were collected from subcutaneous abdominal fat, and DNA hydroxymethylation (5 hmC) profiles of mitochondria-related genes (MitoCarta-2.0) were analyzed by hydroxymethylated DNA immunoprecipitation and next-generation sequencing (hMeDIP-seq) in Lean- and MetS-MSCs untreated or treated with the epigenetic modulator vitamin (Vit)-C (n = 3 each). Functional analysis of genes with differential 5 hmC regions was performed using DAVID6.8. Mitochondrial structure (electron microscopy), oxidative stress, and membrane potential were assessed. hMeDIP-seq identified 172 peaks (associated with 103 mitochondrial genes) with higher and 416 peaks (associated with 165 mitochondrial genes) with lower 5 hmC levels in MetS-MSCs versus Lean-MSCs (≥2-fold, p < 0.05). Genes with higher 5 hmC levels in MetS + MSCs were primarily implicated in fatty acid metabolism, whereas those with lower 5 hmC levels were associated with electron transport chain activity. Vit-C increased 5 hmC levels in mitochondrial antioxidant genes, improved mitochondrial structure and membrane potential, and decreased oxidative stress. MetS alters 5 hmC levels of mitochondria-related genes in swine MSCs. Vit-C modulated 5 hmC levels in these genes and preserved mitochondrial structure and function in MetS-MSCs. These observations may contribute to development of strategies to overcome the deleterious effects of MetS on MSCs.

Renal fibrosis is an important marker in the progression of chronic kidney disease, and renal biopsy is the current reference standard for detecting its presence. Currently, non-invasive methods have only been partially successful in detecting renal fibrosis. Magnetization transfer imaging (MTI) allows estimates of renal fibrosis but may vary with scanning conditions. We hypothesized that MTI-derived renal fibrosis would be reproducible at 1.5T and 3T MRI and over time in fibrotic kidneys. Fifteen pigs with unilateral renal artery stenosis (RAS, n = 9) or age-matched sham controls (n = 6) underwent MTI-MRI at both 1.5T and 3T 6 weeks post-surgery and again 4 weeks later. Magnetization transfer ratio (MTR) measurements of fibrosis in both kidneys were compared between 1.5T and 3T, and the reproducibility of MTI at the two timepoints was evaluated at 1.5T and 3T. MTR at 3T with 600 Hz offset frequency successfully distinguished between normal, stenotic, and contralateral kidneys. There was excellent reproducibility of MTI at 1.5T and 3T over the two timepoints and no significant differences between MTR measurements at 1.5T and 3T. Therefore, MTI is a highly reproducible technique which is sensitive to detect changes in fibrotic compared to normal kidneys in the RAS porcine model at 3T.

Abstract:Coronary artery disease is the leading cause of morbidity and mortality worldwide, espe-cially in developed countries, with an increasing incidence in developing countries. Despite the ad-vances in cardiology, there are yet many unanswered questions about the natural history of coronary atherosclerosis. However, it has not been fully explained why some coronary artery plaques remain quiescent over time, whereas others evolve to a high-risk, “vulnerable” plaque with a predisposition to destabilize and induce a cardiac event. Furthermore, approximately half of the patients with acute coronary syndromes demonstrate no prior symptoms of ischemia or angiographically evident dis-ease. Recent findings have indicated that apart from cardiovascular risk factors, genetics, and other unknown factors, local hemodynamic forces, such as endothelial shear stress, blood flow patterns, and endothelial dysfunction of the epicardial and microvascular coronary arteries, are associated with the progression of coronary plaque and the development of cardiovascular complications with complex interactions. In this review article, we summarize the mechanisms that affect coronary ar-tery plaque progression, indicating the importance of endothelial shear stress, endothelial dysfunc-tion of epicardial and microvascular vessels, inflammation, and their complex associations, underly-ing in parallel the clinical perspectives of these findings.

Background: Clonal hematopoiesis (CH) of indeterminate potential (CHIP) is a risk factor for cardiovascular disease. The relationship between CHIP and coronary microvascular dysfunction (CMD) is unknown. The current study examines the association between CHIP and CH with CMD and the potential relationships in risk for adverse cardiovascular outcomes. Methods: In this retrospective observational study, targeted next-generation sequencing was performed for 177 participants with no coronary artery disease who presented with chest pain and underwent routine coronary functional angiogram. Patients with somatic mutations in leukemia-associated driver genes in hematopoietic stem and progenitor cells were examined; CHIP was considered at a variant allele fraction ≥2%; CH was considered at a variant allele fraction ≥1%. CMD was defined as coronary flow reserve to intracoronary adenosine of ≤2. Major adverse cardiovascular events considered were myocardial infarction, coronary revascularization, or stroke. Results: A total of 177 participants were examined. Mean follow-up was 12±7 years. A total of 17 patients had CHIP and 28 had CH. Cases with CMD (n=19) were compared with controls with no CMD (n=158). Cases were 56±9 years, were 68% women, and had more CHIP (27%; P =0.028) and CH (42%; P =0.001) than controls. CMD was associated with independent risk for major adverse cardiovascular events (hazard ratio, 3.89 [95% CI, 1.21–12.56]; P =0.023), and 32% of this risk was mediated by CH. The risk mediated by CH was ≈0.5× as large as the direct effect of CMD on major adverse cardiovascular events. Conclusions: In humans, we observe patients with CMD are more likely to have CHIP, and nearly one-third of major adverse cardiovascular events in CMD are mediated by CH.

Background Mechanisms underlying bioprosthetic valve deterioration are multifactorial and incompletely elucidated. Reparative circulating progenitor cells, and conversely calcification‐associated osteocalcin expressing circulating progenitor cells, have been linked to native aortic valve deterioration. However, their role in bioprosthetic valve deterioration remains elusive. This study sought to evaluate the contribution of different subpopulations of circulating progenitor cells in bioprosthetic valve deterioration. Methods and Results This single‐center prospective study enrolled 121 patients who had peripheral blood mononuclear cells isolated before bioprosthetic aortic valve replacement and had an echocardiographic follow‐up ≥2 years after the procedure. Using flow cytometry, fresh peripheral blood mononuclear cells were analyzed for the surface markers CD34, CD133, and osteocalcin. Bioprosthetic valve deterioration was evaluated by hemodynamic valve deterioration (HVD) using echocardiography, which was defined as an elevated mean transprosthetic gradient ≥30 mm Hg or at least moderate intraprosthetic regurgitation. Sixteen patients (13.2%) developed HVD during follow‐up for a median of 5.9 years. Patients with HVD showed significantly lower levels of reparative CD34 + CD133 + cells and higher levels of osteocalcin‐positive cells than those without HVD (CD34 + CD133 + cells: 125 [80, 210] versus 270 [130, 420], P =0.002; osteocalcin‐positive cells: 3060 [523, 5528] versus 670 [180, 1930], P =0.005 respectively). Decreased level of CD34 + CD133 + cells was a significant predictor of HVD (hazard ratio, 0.995 [95% CI, 0.990%–0.999%]). Conclusions Circulating levels of CD34 + CD133 + cells and osteocalcin‐positive cells were significantly associated with the subsequent occurrence of HVD in patients undergoing bioprosthetic aortic valve replacement. Circulating progenitor cells might play a vital role in the mechanism, risk stratification, and a potential therapeutic target for patients with bioprosthetic valve deterioration.

To address the ongoing shortage of organs available for replacement, xenotransplantation of hearts, corneas, skin, and kidneys has been attempted. However, a major obstacle facing xenotransplants is rejection due to a cycle of immune reactions to the graft. Both adaptive and innate immune systems contribute to this cycle, in which natural killer cells, macrophages, and T-cells play a significant role. While advancements in the field of genetic editing can circumvent some of these obstacles, biomarkers to identify and predict xenograft rejection remain to be standardized. Several T-cell markers, such as CD3, CD4, and CD8, are useful in both the diagnosis and prediction of xenograft rejection. Furthermore, an increase in the levels of various circulating DNA markers and microRNAs is also predictive of xenograft rejection. In this review, we summarize recent findings on the advancements in xenotransplantation, with a focus on pig-to-human, the role of immunity in xenograft rejection, and its biomarkers.

The inflammatory response is a major pathological feature in most kidney diseases and often evokes compensatory mechanisms. Recent evidence suggests that TSG-6 (tumor necrosis factor-α-stimulated gene/protein-6) plays a pivotal role in anti-inflammation in various renal diseases, including immune-mediated and nonimmune-mediated renal diseases. TSG-6 has a diverse repertoire of anti-inflammatory functions: it potentiates antiplasmin activity of IαI (inter-α-inhibitor) by binding to its light chain, crosslinks hyaluronan to promote its binding to cell surface receptor CD44, and thereby regulate the migration and adhesion of lymphocytes, inhibits chemokine-stimulated transendothelial migration of neutrophils by directly interacting with the glycosaminoglycan binding site of CXCL8 (CXC motif chemokine ligand-8), and upregulates COX-2 (cyclooxygenase-2) to produce anti-inflammatory metabolites. Hopefully, further developments can target this anti-inflammatory molecule to the kidney and harness its remedial properties. This review provides an overview of the emerging role of TSG-6 in blunting renal inflammation.