Effects of Catheter-Based Renal Denervation in Hypertension: A Systematic Review and Meta-Analysis.

BACKGROUND: Several sham-controlled trials have investigated the efficacy and safety of catheter-based renal denervation (RDN) with mixed outcomes. We aimed to perform a comprehensive meta-analysis of all randomized, sham-controlled trials investigating RDN with first- and second-generation devices in hypertension. METHODS: We searched MEDLINE and the Cochrane Library for eligible trials. Outcomes included both efficacy (24-hour and office systolic [SBP] and diastolic blood pressure [DBP]) and safety (all-cause death, vascular complication, renal artery stenosis >70%, hypertensive crisis) of RDN. We performed a study-level, pairwise, random-effects meta-analysis of the summary data. RESULTS: Ten trials comprising 2478 patients with hypertension while being either off or on treatment were included. Compared with sham, RDN reduced 24-hour and office systolic blood pressure by 4.4 mm Hg (95% CI, 2.7 to 6.1; P<0.00001) and 6.6 mm Hg (95% CI, 3.6 to 9.7; P<0.0001), respectively. The 24-hour and office diastolic blood pressure paralleled these findings (-2.6 mm Hg [95% CI, -3.6 to -1.5]; P<0.00001; -3.5 mm Hg [95% CI, -5.4 to -1.6]; P=0.0003). There was no difference in 24-hour and office systolic blood pressure reduction between trials with and without concomitant antihypertensive medication (P for interaction, 0.62 and 0.73, respectively). There was no relevant difference in vascular complications (odds ratio, 1.69 [95% CI, 0.57 to 5.0]; P=0.34), renal artery stenosis (odds ratio, 1.50 [95% CI, 0.06 to 36.97]; P=0.80), hypertensive crisis (odds ratio, 0.65 [95% CI, 0.30 to 1.38]; P=0.26), and all-cause death (odds ratio, 1.76 [95% CI, 0.34 to 9.20]; P=0.50) between RDN and sham groups. Change of renal function based on estimated glomerular filtration rate was comparable between groups (P for interaction, 0.84). There was significant heterogeneity between trials. CONCLUSIONS: RDN safely reduces ambulatory and office systolic blood pressure/diastolic blood pressure versus a sham procedure in the presence and absence of antihypertensive medication.

Single-Cell RNA Sequencing Reveals That Adaptation of Human Aortic Endothelial Cells to Antiproliferative Therapies Is Modulated by Flow-Induced Shear Stress.

BACKGROUND: Endothelial cells (ECs) are capable of quickly responding in a coordinated manner to a wide array of stresses to maintain vascular homeostasis. Loss of EC cellular adaptation may be a potential marker for cardiovascular disease and a predictor of poor response to endovascular pharmacological interventions such as drug-eluting stents. Here, we report single-cell transcriptional profiling of ECs exposed to multiple stimulus classes to evaluate EC adaptation. METHODS: Human aortic ECs were costimulated with both pathophysiological flows mimicking shear stress levels found in the human aorta (laminar and turbulent, ranging from 2.5 to 30 dynes/cm2) and clinically relevant antiproliferative drugs, namely paclitaxel and rapamycin. EC state in response to these stimuli was defined using single-cell RNA sequencing. RESULTS: We identified differentially expressed genes and inferred the TF (transcription factor) landscape modulated by flow shear stress using single-cell RNA sequencing. These flow-sensitive markers differentiated previously identified spatially distinct subpopulations of ECs in the murine aorta. Moreover, distinct transcriptional modules defined flow- and drug-responsive EC adaptation singly and in combination. Flow shear stress was the dominant driver of EC state, altering their response to pharmacological therapies. CONCLUSIONS: We showed that flow shear stress modulates the cellular capacity of ECs to respond to paclitaxel and rapamycin administration, suggesting that while responding to different flow patterns, ECs experience an impairment in their transcriptional adaptation to other stimuli.

Moderate intensity exercise in pregnant patients with cardiovascular disease: A pilot study.

BACKGROUND: Exercise in pregnancy has proven health benefits, yet the safety of exercise in patients with pre-existing cardiovascular disease (CVD) has not been established. Our aim was to determine the feasibility and safety profile of moderate intensity exercise during pregnancy in patients with CVD, compared with those without CVD. METHODS: This is a prospective single center pilot study of a moderate intensity exercise regimen, with data collection through wearable fitness trackers and personal exercise logs in pregnant patients with and without pre-existing CVD. The primary outcome was Doppler umbilical artery systolic to diastolic (S/D) ratio measured between 32 and 34 weeks' gestation. The secondary outcomes were adverse maternal and fetal events, trends in wearable fitness tracker data, C-reactive protein levels, and weight changes. RESULTS: At baseline, the CVD group (62% congenital heart disease) took part in more prepregnancy walking, less weightlifting, and had a higher body mass index compared to the control group, and on average walked 539 fewer steps per day during pregnancy than the control group. Resting heart rate (HR) was found to increase in both groups up to 30 weeks' gestation. The cardiovascular disease group displayed an overall lower exercise intensity, as measured by the ability to increase HR with exercise over resting heart rate 1 hour prior to exercise at study baseline (45% vs 59% P < .001). Umbilical artery S/D ratio was normal in both groups. No differences were seen in adverse events between groups. CONCLUSIONS: This pilot study of moderate intensity exercise in pregnant individuals with pre-existing CVD demonstrated that patients with CVD were not able to increase their HR during exercise throughout pregnancy compared to those in the control group. Although a small study group, this data supports the hypothesis that exercise interventions during pregnancy for patients with CVD are feasible without evidence abnormal fetal Doppler profiles. Further studies using wearable fitness trackers may provide the opportunity to understand how to safely tailor exercise programs to pregnant individuals with CVD.

Orphan nuclear receptor COUP-TFII enhances myofibroblast glycolysis leading to kidney fibrosis.

Recent studies demonstrate that metabolic disturbance, such as augmented glycolysis, contributes to fibrosis. The molecular regulation of this metabolic perturbation in fibrosis, however, has been elusive. COUP-TFII (also known as NR2F2) is an important regulator of glucose and lipid metabolism. Its contribution to organ fibrosis is undefined. Here, we found increased COUP-TFII expression in myofibroblasts in human fibrotic kidneys, lungs, kidney organoids, and mouse kidneys after injury. Genetic ablation of COUP-TFII in mice resulted in attenuation of injury-induced kidney fibrosis. A non-biased proteomic study revealed the suppression of fatty acid oxidation and the enhancement of glycolysis pathways in COUP-TFII overexpressing fibroblasts. Overexpression of COUP-TFII in fibroblasts also induced production of alpha-smooth muscle actin (αSMA) and collagen 1. Knockout of COUP-TFII decreased glycolysis and collagen 1 levels in fibroblasts. Chip-qPCR revealed the binding of COUP-TFII on the promoter of PGC1α. Overexpression of COUP-TFII reduced the cellular level of PGC1α. Targeting COUP-TFII serves as a novel treatment approach for mitigating fibrosis in chronic kidney disease and potentially fibrosis in other organs.

Tenofovir prodrugs potently inhibit Epstein-Barr virus lytic DNA replication by targeting the viral DNA polymerase.

Epstein-Barr virus (EBV) is a ubiquitous human γ-herpesvirus that establishes life-long infection and increases the risk for the development of several cancers and autoimmune diseases. The mechanisms by which chronic EBV infection leads to subsequent disease remain incompletely understood. Lytic reactivation plays a central role in the development of EBV-driven cancers and may contribute to other EBV-associated diseases. Thus, the clinical use of antivirals as suppressive therapy for EBV lytic reactivation may aid efforts aimed at disease prevention. Current antivirals for EBV have shown limited clinical utility due to low potency or high toxicity, leaving open the need for potent antivirals suitable for long-term prophylaxis. In the present study, we show that tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), drugs with excellent safety profiles used clinically for HIV prevention, inhibit EBV lytic DNA replication, with respective IC50 values of 0.30 µM and 84 nM. In a cell-based assay, TAF was 35- and 24-fold and TDF was 10- and 7-fold more potent than acyclovir and penciclovir, respectively, and TAF was also twice as potent as ganciclovir. The active metabolite of tenofovir prodrugs, tenofovir-diphosphate, inhibited the incorporation of dATP into a primed DNA template by the EBV DNA polymerase in vitro. In contrast to acyclovir, treatment of cells during latency for 24 h with TAF still inhibited EBV lytic DNA replication at 72 h after drug was removed. Our results suggest that tenofovir prodrugs may be particularly effective as inhibitors of EBV lytic reactivation, and that clinical studies to address critical questions about disease prevention are warranted.

Novel Lesional Transcriptional Signature Separates Atherosclerosis With and Without Diabetes in Yorkshire Swine and Humans.

[Figure: see text].

Accelerated neutral atom beam (ANAB) modified polyethylene for decreased wear and reduced bacteria colonization: An in vitro study.

Ultra-high molecular weight polyethylene (UHMWPE) model implants were modified using accelerated neutral atom beam (ANAB) technology and tested for in vitro wear properties and bacteria colonization. Material characterization studies using atomic force microscopy (AFM), surface energy, and in vitro protein adsorption events were also conducted to better understand the mechanism behind such wear properties and bacteria colonization. ANAB modified UHMWPE showed significantly reduced wear properties compared to controls due to nanostructured features, greater surface energy, and improved adsorption of lubricin, a synovial fluid lubricating protein. There was significantly greater adsorption of proteins known to reduce bacteria colonization (specifically, mucin, casein, and lubricin) after 4 h on UHMWPE after ANAB treatment. Such changes in initial protein events led to significantly decreased bacteria (including methicillin resistant Staph. aureus (or MRSA), Staph. aureus, E. coli, multi-drug resistant E. coli, Pseudomonas aeruginosa and Staph. epidermidis) colonization after 24 h without resorting to antibiotic use.

1α,25-Dihydroxyvitamin D3 Encapsulated in Nanoparticles Prevents Venous Neointimal Hyperplasia and Stenosis in Porcine Arteriovenous Fistulas.

BACKGROUND: Few therapies prevent venous neointimal hyperplasia (VNH) and venous stenosis (VS) formation in arteriovenous fistulas (AVF). Expression of the immediate early response gene X-1 (Iex-1), also known as Ier3, is associated with VNH and stenosis in murine AVFs. The study aimed to determine if local release of Ier3 long-acting inhibitor 1α,25(OH)2D3 from poly(lactic-co-glycolic acid) (PLGA) nanoparticles embedded in a thermosensitive Pluronic F127 hydrogel (1,25 NP) could affect VNH/VS formation in a large animal model. METHODS: Immediately after AVF creation in a porcine model of renal failure, 1,25 NP or vehicle control was injected into the adventitia space of AVF outflow veins. Scanning electron microscopy and dynamic light scattering characterized drug and control nanoparticles. Animals were sacrificed 3 and 28 days later for gene expression, immunohistologic, magnetic resonance imaging and angiography, and ultrasound analyses. Whole transcriptome RNA sequencing with differential gene expression analysis was performed on outflow veins of AVF. RESULTS: Encapsulation of 1α,25(OH)2D3 in PLGA nanoparticles formed nanoparticles of uniform size that were similar to nanoparticles without 1α,25(OH)2D3. The 1,25 NP-treated AVFs exhibited lower VNH/VS, Ier3 gene expression, and IER-3, MCP-1, CD68, HIF-1α, and VEGF-A immunostaining, fibrosis, and proliferation. Blood flow and lumen area increased significantly, whereas peak systolic velocity and wall shear stress decreased. Treatment increased Young's modulus and correlated with histologic assessment of fibrosis and with no evidence of vascular calcification. RNA sequencing analysis showed changes in the expression of genes associated with inflammatory, TGFß1, and apoptotic pathways. CONCLUSIONS: Local release of 1,25 NP improves AVF flow and hemodynamics, and reduces stenosis in association with reduction in inflammation, apoptosis, and fibrosis in a porcine model of arteriovenous fistula.

Mortality and Paclitaxel-Coated Devices: An Individual Patient Data Meta-Analysis.

BACKGROUND: Paclitaxel-containing devices (PTXDs) significantly reduce reintervention in patients with symptomatic femoropopliteal peripheral artery disease. A recent aggregate-data meta-analysis reported increased late mortality in patients with peripheral artery disease treated with PTXDs. We performed an individual patient data meta-analysis to evaluate mortality. METHODS: Manufacturers of US Food and Drug Administration-approved and commercially available devices in the United States provided deidentified individual patient data for independent analysis. Cox proportional hazards 1-stage meta-analysis models using intention-to-treat methods were used for the primary analysis. A secondary analysis of recovered missing vital status data was performed. The impact of control crossover to PTXDs, cause-specific mortality, and drug dose mortality were assessed. RESULTS: A total of 2185 subjects and 386 deaths from 8 PTXD trials with 4-year median follow-up were identified. The primary analysis indicated a 38% (95% CI, 6% to 80%) increased relative mortality risk, corresponding to 4.6% absolute increase, at 5 years associated with PTXD use. Control and treatment arm loss to follow-up and withdrawal were 24% and 23%, respectively. With inclusion of recovered vital status data, the excess relative mortality risk was 27% (95% CI, 3%-58%). This observation was consistent across various scenarios, including as-treated analyses, with no evidence of increased risk over time with PTXDs. Mortality risk tended to be increased for all major causes of death. There were no subgroup differences. No drug dose-mortality association was identified. CONCLUSIONS: This individual patient data meta-analysis, based on the most complete available data set of mortality events from PTXD randomized controlled trials, identified an absolute 4.6% increased mortality risk associated with PTXD use.

Noninvasive quantification of cerebrovascular pressure changes using 4D Flow MRI.

PURPOSE: Hemodynamic alterations are indicative of cerebrovascular disease. However, the narrow and tortuous cerebrovasculature complicates image-based assessment, especially when quantifying relative pressure. Here, we present a systematic evaluation of image-based cerebrovascular relative pressure mapping, investigating the accuracy of the routinely used reduced Bernoulli (RB), the extended unsteady Bernoulli (UB), and the full-field virtual work-energy relative pressure ( ν WERP) method. METHODS: Patient-specific in silico models were used to generate synthetic cerebrovascular 4D Flow MRI, with RB, UB, and ν WERP performance quantified as a function of spatiotemporal sampling and image noise. Cerebrovascular relative pressures were also derived in 4D Flow MRI from healthy volunteers ( n=8 ), acquired at two spatial resolutions (dx = 1.1 and 0.8 mm). RESULTS: The in silico analysis indicate that accurate relative pressure estimations are inherently coupled to spatial sampling: at dx = 1.0 mm high errors are reported for all methods; at dx = 0.5 mm ν WERP recovers relative pressures at a mean error of 0.02 ± 0.25 mm Hg, while errors remain higher for RB and UB (mean error of -2.18 ± 1.91 and -2.18 ± 1.87 mm Hg, respectively). The dependence on spatial sampling is also indicated in vivo, albeit with higher correlative dependence between resolutions using ν WERP (k = 0.64, R2 = 0.81 for dx = 1.1 vs. 0.8 mm) than with RB or UB (k = 0.04, R2 = 0.03, and k = 0.07, R2 = 0.07, respectively). CONCLUSION: Image-based full-field methods such as ν WERP enable cerebrovascular relative pressure mapping; however, accuracy is directly dependent on utilized spatial resolution.