Hybrid convergent ablation versus endocardial catheter ablation for atrial fibrillation: A systematic review and meta-analysis.

INTRODUCTION: Endocardial catheter ablation (ECA) for atrial fibrillation (AF) has limited efficacy. Hybrid convergent procedure (HCP) with both epicardial and endocardial ablation is a novel strategy for AF treatment. In this meta-analysis, we aimed to evaluate the efficacy and safety of HCP in AF ablation. METHOD: We performed a comprehensive literature search for studies that evaluated the efficacy and safety of HCP compared with ECA for AF. The primary outcome was freedom of atrial arrhythmia (AA). The secondary outcome was the periprocedural complication rate. Pooled relative risk (RR) and corresponding 95% confidence intervals (CIs) were calculated using the random effects model. RESULTS: A total of eight studies, including 797 AF patients (mean age: 60.7 ± 9.8 years, 366 patients with HCP vs. 431 patients with ECA alone), were included. HCP showed a higher rate of freedom of AA compared with ECA (RR: 1.48, 95% CI: 1.13-1.94, p = .004). However, HCP was associated with higher rates of periprocedural complications (RR: 3.64, 95% CI: 2.06-6.43; p = .00001). Moreover, the HCP had a longer procedure time and postprocedural hospital stay. CONCLUSIONS: Although hybrid ablation was associated with a higher success rate, this should be judged for increased periprocedural adverse events and extended hospital stay. Prospective large-scale randomized trials are needed to validate these results.

Hypoxic preconditioning induces epigenetic changes and modifies swine mesenchymal stem cell angiogenesis and senescence in experimental atherosclerotic renal artery stenosis.

BACKGROUND: Atherosclerotic renal artery stenosis (ARAS) is a risk factor for ischemic and hypertensive kidney disease (HKD) for which autologous mesenchymal stem cell (MSC) appears to be a promising therapy. However, MSCs from ARAS patients exhibit impaired function, senescence, and DNA damage, possibly due to epigenetic mechanisms. Hypoxia preconditioning (HPC) exerts beneficial effects on cellular proliferation, differentiation, and gene and protein expression. We hypothesized that HPC could influence MSC function and senescence in ARAS by epigenetic mechanisms and modulating gene expression of chromatin-modifying enzymes. METHODS: Adipose-derived MSC harvested from healthy control (N = 8) and ARAS (N = 8) pigs were cultured under normoxia (20%O2) or hypoxia (1%O2) conditions. MSC function was assessed by migration, proliferation, and cytokine release in conditioned media. MSC senescence was evaluated by SA-ß-gal activity. Specific pro-angiogenic and senescence genes were assessed by reverse transcription polymerase chain reaction (RT-PCR). Dot blotting was used to measure global genome 5-hydroxymethylcytosine (5hmC) levels on DNA and Western blotting of modified histone 3 (H3) proteins to quantify tri-methylated lysine-4 (H3K4me3), lysine-9 (H3K9me3), and lysine-27 (H3K27me3) residues. RESULTS: Specific pro-angiogenic genes in ARAS assessed by RT-PCR were lower at baseline but increased under HPC, while pro-senescence genes were higher in ARAS at baseline as compared healthy MSCs. ARAS MSCs under basal conditions, displayed higher H3K4me3, H3K27me3, and 5hmC levels compared to healthy MSCs. During HPC, global 5hmC levels were decreased while no appreciable changes occurred in histone H3 tri-methylation. ARAS MSCs cultured under HPC had higher migratory and proliferative capacity as well as increased vascular endothelial growth factor and epidermal growth factor expression compared to normoxia, and SA-ß-gal activity decreased in both animal groups. CONCLUSIONS: These data demonstrate that swine ARAS MSCs have decreased angiogenesis and increased senescence compared to healthy MSCs and that HPC mitigates MSC dysfunction, senescence, and DNA hydroxymethylation in ARAS MSC. Thus, HPC for MSCs may be considered for their optimization to improve autologous cell therapy in patients with nephropathies.

Increased cellular senescence in the murine and human stenotic kidney: Effect of mesenchymal stem cells.

Cell stress may give rise to insuperable growth arrest, which is defined as cellular senescence. Stenotic kidney (STK) ischemia and injury induced by renal artery stenosis (RAS) may be associated with cellular senescence. Mesenchymal stem cells (MSCs) decrease some forms of STK injury, but their ability to reverse senescence in RAS remains unknown. We hypothesized that RAS evokes STK senescence, which would be ameliorated by MSCs. Mice were studied after 4 weeks of RAS, RAS treated with adipose tissue-derived MSCs 2 weeks earlier, or sham. STK senescence-associated ß-galactosidase (SA-ß-Gal) activity was measured. Protein and gene expression was used to assess senescence and the senescence-associated secretory phenotype (SASP), and staining for renal fibrosis, inflammation, and capillary density. In addition, senescence was assessed as p16+ and p21+ urinary exosomes in patients with renovascular hypertension (RVH) without or 3 months after autologous adipose tissue-derived MSC delivery, and in healthy volunteers (HV). In RAS mice, STK SA-ß-Gal activity increased, and senescence and SASP marker expression was markedly elevated. MSCs improved renal function, fibrosis, inflammation, and capillary density, and attenuated SA-ß-Gal activity, but most senescence and SASP levels remained unchanged. Congruently, in human RVH, p21+ urinary exosomes were elevated compared to HV, and only slightly improved by MSC, whereas p16+ exosomes remained unchanged. Therefore, RAS triggers renal senescence in both mice and human subjects. MSCs decrease renal injury, but only partly mitigate renal senescence. These observations support exploration of targeted senolytic therapy in RAS.

Senescent Kidney Cells in Hypertensive Patients Release Urinary Extracellular Vesicles.

Background Hypertension may be associated with renal cellular injury. Cells in distress release extracellular vesicles (EVs), and their numbers in urine may reflect renal injury. Cellular senescence, an irreversible growth arrest in response to a noxious milieu, is characterized by release of proinflammatory cytokines. We hypothesized that EVs released by senescent nephron cells can be identified in urine of patients with hypertension. Methods and Results We recruited patients with essential hypertension (EH) or renovascular hypertension and healthy volunteers (n=14 each). Renal oxygenation was assessed using magnetic resonance imaging and blood samples collected from both renal veins for cytokine-level measurements. EVs isolated from urine samples were characterized by imaging flow cytometry based on specific markers, including p16 (senescence marker), calyxin (podocytes), urate transporter 1 (proximal tubules), uromodulin (ascending limb of Henle's loop), and prominin-2 (distal tubules). Overall percentage of urinary p16+ EVs was elevated in EH and renovascular hypertension patients compared with healthy volunteers and correlated inversely with renal function and directly with renal vein cytokine levels. Urinary levels of p16+/urate transporter 1+ were elevated in all hypertensive subjects compared with healthy volunteers, whereas p16+/prominin-2+ levels were elevated only in EH versus healthy volunteers and p16+/uromodulin+ in renovascular hypertension versus EH. Conclusions Levels of p16+ EVs are elevated in urine of hypertensive patients and may reflect increased proximal tubular cellular senescence. In EH, EVs originate also from distal tubules and in renovascular hypertension from Henle's loop. Hence, urinary EVs levels may be useful to identify intrarenal sites of cellular senescence.

Renal Adiposity Does not Preclude Quantitative Assessment of Renal Function Using Dual-Energy Multidetector CT in Mildly Obese Human Subjects.

RATIONALE AND OBJECTIVES: Multidetector computed tomography (MDCT) is useful for measuring in the research setting single-kidney perfusion and function using iodinated contrast time-attenuation curves. Obesity promotes deposition of intrarenal fat, which might decrease tissue attenuation and thereby interfere with quantification of renal function using MDCT. The purpose of this study was to test the hypothesis that background subtraction adequately accounts for intrarenal fat deposition in mildly obese human subjects during renal contrast enhanced dynamic CT. MATERIALS AND METHODS: We prospectively recruited seventeen human subjects stratified as lean or mildly obese based on body mass index below or over 30 kg/m2, respectively. Renal perfusion was quantified from CT-derived indicator-dilution curves after background subtraction. Dual-energy MDCT images were postprocessed to generate iodine and virtual-noncontrast datasets, and the ratios between kidney/aorta CT numbers and iodine values calculated as surrogates of renal function. RESULTS: Subcutaneous adipose tissue was increased in obese subjects. Virtual-noncontrast maps revealed in obese patients a decrease in basal cortical and medullary attenuation. Overall, basal attenuation inversely correlated with body mass index, in line with renal fat deposition. Contrarily, the kidney/aorta CT attenuation (after background subtraction) and kidney/aorta iodine ratios were similar between lean and obese subjects and correlated directly. These observations show that following background subtraction, the CT number reliably reflects basal tissue attenuation. CONCLUSION: Therefore, our findings support our hypothesis that background subtraction enables reliable assessment of kidney function in mildly obese subjects using MDCT, despite decreased basal attenuation due to renal adiposity.