Medical Optimization of Patients with Symptomatic Peripheral Arterial Disease.

Peripheral artery disease (PAD) is a progressive disease associated with the occurrence of major adverse cardiovascular and limb events and elevated mortality rates. Symptoms of PAD, including claudication and chronic limb-threatening ischemia, impair functional capacity and lead to lower quality of life. The focus of current therapies is to minimize symptoms, improve quality of life, and reduce adverse cardiovascular and limb events. Among the medical therapies are antiplatelets, anticoagulants, antihypertensives, lipid lowering therapies, cilostazol and pentoxifylline, and novel blood sugar-lowering therapies, plus exercise therapy and smoking cessation. In this review, we discuss these evidence-based medical therapies that are available for patients with symptomatic PAD.

Perioperative outcomes of hypertrophic cardiomyopathy: An insight from the National Readmission Database.

BACKGROUND: Data regarding hypertrophic obstructive cardiomyopathy (HOCM) patients undergoing noncardiac surgery is lacking. We sought to examine the perioperative outcomes of HOCM patients undergoing noncardiac surgery using a national database. METHODS: We used the National readmission database from 2016 to 2019. We identified HOCM, heart undergoing noncardiac surgery using ICD 10 codes. We examined hospital outcomes as well as 90 days readmission outcomes. RESULTS: We identified 16,098 HOCM patients and 21,895,699 non-HOCM patients undergoing noncardiac surgery. The HOCM group had more comorbidities at baseline. After adjustment for major clinical predictors, the HOCM group experienced more in-hospital death, odds ratio (OR) 1.33 (1.216-1.47), P < 0.001, acute myocardial infarction (AMI), OR 1.18 (1.077-1.292), P < 0.001, acute heart failure odds ratio OR 1.3 to (1.220-1.431), P < 0.001, 90 days readmission OR 1.237 (1.069-1.432), P < 0.01, cardiogenic shock OR 2.094 (1.855-2.363), P < 0.001. Cardiac arrhythmia was the most common cause of readmission, out of the arrhythmias atrial fibrillation was the most prevalent. Acute heart failure was the most common complication of readmission. There was no difference in major adverse cardiovascular events (MACE), and AMI between both groups and readmission. CONCLUSION: HOCM patients undergoing noncardiac surgery may be at increased risk of in-hospital and readmission events. Acute heart failure was the most common complication during index admission, while cardiac arrhythmias were the most common complication during readmission. More research is needed to address this patient population further.

Safety and outcomes of hip and knee replacement surgery in liver transplant recipients.

BACKGROUND: Liver transplant (LT) is becoming increasingly common with improved life expectancy. Joint replacement is usually a safe procedure; however, its safety in LT recipients remains understudied. AIM: To evaluate the mortality, outcome, and 90-d readmission rate in LT patients undergoing hip and knee replacement surgery. METHODS: Patients with history of LT who underwent hip and knee replacement surgery between 2016 and 2019 were identified using the National Readmission Database. RESULTS: A total of 5046119 hip and knee replacement surgeries were identified. 3219 patients had prior LT. Mean age of patients with no history of LT was 67.51 [95% confidence interval (CI): 67.44-67.58], while it was 64.05 (95%CI: 63.55-64.54) in patients with LT. Patients with history of LT were more likely to have prolonged length of hospital stay (17.1% vs 8.4%, P < 0.001). The mortality rate for patients with no history of LT was 0.22%, while it was 0.24% for patients with LT (P = 0.792). Patients with history of LT were more likely to have re-admissions within 90 d of initial hospitalization: 11.4% as compared to 6.2% in patients without history of LT (P < 0.001). The mortality rate between both groups during readmission was not statistically different (1.9% vs 2%, P = 0.871) respectively. CONCLUSION: Hip and knee replacements in patients with history of LT are not associated with increased mortality; increased re-admissions were more frequent in this cohort of patients. Chronic kidney disease and congestive heart failure appear to predict higher risk of readmission.

Outcomes of Transcatheter Aortic Valve Implant Among Patients With A Previous Coronary Artery Bypass Graft: A Nationwide Analysis.

There is a paucity of data regarding the temporal trends and outcomes of transcatheter aortic valve implant (TAVI) among patients with a previous coronary artery bypass graft (CABG) surgery. We queried the Nationwide Readmissions Database (2016 to 2019) for hospitalized patients who underwent TAVI using the appropriate International Classification of Diseases, Tenth Revision procedural codes. A multivariable regression analysis was used to adjust for the patients' and hospitals' characteristics in comparing the study groups. The primary outcome was in-hospital mortality. The final analysis included 237,829 patients who underwent TAVI, of whom 42,671 (17.9%) had a previous CABG. During the study period, there was a decrease in the proportion of patients with previous CABG who underwent TAVI (21.0% in 2016 vs 15.5% in 2019, ptrend = 0.01), although there was no change in their in-hospital mortality rate (1.08% in 2016 vs 1.25% in 2019, ptrend = 0.43). Patients with a previous CABG were younger and less likely to be women than those without a previous CABG. TAVI among those with a previous CABG was associated with lower in-hospital mortality (adjusted odds ratio [aOR] 0.79, 95% confidence interval [CI] 0.69 to 0.91), similar rate of ischemic stroke (aOR 0.81, 95% CI 0.71 to 0.93) and permanent pacemaker implant (aOR 1.00, 95% CI 0.93 to 1.05). Patients with a previous CABG had a lower all-cause 90-day readmission (odds ratio 0.95, 95% CI 0.94 to 1.06) but higher readmission for transient ischemic attack. Among those with a previous CABG, female gender and chronic kidney disease stage ≥3 were independently associated with a higher in-hospital mortality, whereas obesity was associated with a lower in-hospital mortality. In conclusion, there was a decrease in the proportion of patients with a previous CABG among those who underwent TAVI. TAVI among those with a previous CABG was not associated with increased in-hospital adverse events or 90-day all-cause readmissions.

A modern day perspective on smoking in peripheral artery disease.

Peripheral artery disease (PAD) is associated with increased risk of cardiovascular morbidity and mortality, poor functional status, and lower quality of life. Cigarette smoking is a major preventable risk factor for PAD and is strongly associated with a higher risk of disease progression, worse post-procedural outcomes, and increased healthcare utilization. The arterial narrowing due to atherosclerotic lesions in PAD leads to decreased perfusion to the limbs and can ultimately cause arterial obstruction and limb ischemia. Endothelial cell dysfunction, oxidative stress, inflammation, and arterial stiffness are among the key events during the development of atherogenesis. In this review, we discuss the benefits of smoking cessation among patients with PAD and the use of smoking cessation methods including pharmacological treatment. Given that smoking cessation interventions remain underutilized, we highlight the importance of incorporating smoking cessation treatments as part of the medical management of patients with PAD. Regulatory approaches to reduce the uptake of tobacco product use and support smoking cessation have the potential to reduce the burden of PAD.

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.

Renal fibrosis detected by diffusion-weighted magnetic resonance imaging remains unchanged despite treatment in subjects with renovascular disease.

Tissue fibrosis is an important index of renal disease progression. Diffusion-weighted magnetic resonance imaging's (DWI-MRI) apparent diffusion coefficient (ADC) reveals water diffusion is unobstructed by microstructural alterations like fibrosis. We hypothesized that ADC may indicate renal injury and response to therapy in patients with renovascular disease (RVD). RVD patients were treated with medical therapy (MT) and percutaneous transluminal renal angioplasty (MT + PTRA) (n = 11, 3 bilaterally, n = 14 kidneys) or MT (n = 9). ADC and renal hypoxia (R2*) by blood-oxygen-level-dependent MRI were studied before (n = 27) and 3 months after (n = 20) treatment. Twelve patients underwent renal biopsies. Baseline ADC values were correlated with changes in eGFR, serum creatinine (SCr), systolic blood pressure (SBP), renal hypoxia, and renal vein levels of pro-inflammatory marker tumor necrosis-factor (TNF)-α. Renal oxygenation, eGFR, and SCr improved after MT + PTRA. ADC inversely correlated with the histological degree of renal fibrosis, but remained unchanged after MT or MT + PTRA. Basal ADC values correlated modestly with change in SBP, but not in renal hypoxia, TNF-α levels, or renal function. Lower ADC potentially reflects renal injury in RVD patients, but does not change in response to medical or interventional therapy over 3 months. Future studies need to pinpoint indices of kidney recovery potential.

In a Phase 1a escalating clinical trial, autologous mesenchymal stem cell infusion for renovascular disease increases blood flow and the glomerular filtration rate while reducing inflammatory biomarkers and blood pressure.

Atherosclerotic renovascular disease (ARVD) reduces tissue perfusion and eventually leads to loss of kidney function with limited therapeutic options. Here we describe results of Phase 1a escalating dose clinical trial of autologous mesenchymal stem cell infusion for ARVD. Thirty-nine patients with ARVD were studied on two occasions separated by three months. Autologous adipose-derived mesenchymal stem cells were infused through the renal artery in 21 patients at three different dose levels (1, 2.5 and 5.0 × 105 cells/kg) in seven patients each. We measured renal blood flow, glomerular filtration rate (GFR) (iothalamate and estimated GFR), renal vein cytokine levels, blood pressure, and tissue oxygenation before and three months after stem cell delivery. These indices were compared to those of 18 patients with ARVD matched for age, kidney function and blood pressure receiving medical therapy alone that underwent an identical study protocol. Cultured mesenchymal stem cells were also studied in vitro. For the entire stem cell treated-cohort, mean renal blood flow in the treated stenotic kidney significantly increased after stem cell infusion from (164 to 190 ml/min). Hypoxia, renal vein inflammatory cytokines, and angiogenic biomarkers significantly decreased following stem cell infusion. Mean systolic blood pressure significantly fell (144 to 136 mmHg) and the mean two-kidney GFR (Iothalamate) modestly but significantly increased from (53 to 56 ml/min). Changes in GFR and blood pressure were largest in the high dose stem cell treated individuals. No such changes were observed in the cohort receiving medical treatment alone. Thus, our data demonstrate the potential for autologous mesenchymal stem cell to increase blood flow, GFR and attenuate inflammatory injury in post-stenotic kidneys. The observation that some effects are dose-dependent and related to in-vitro properties of mesenchymal stem cell may direct efforts to maximize potential therapeutic efficacy.

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.

Loss of Renal Peritubular Capillaries in Hypertensive Patients Is Detectable by Urinary Endothelial Microparticle Levels.

Hypertension, an important cause of chronic kidney disease, is characterized by peritubular capillary (PTC) loss. Circulating levels of endothelial microparticles (EMPs) reflect systemic endothelial injury. We hypothesized that systemic and urinary PTC-EMPs levels would reflect renal microvascular injury in hypertensive patients. We prospectively measured by flow cytometry renal vein, inferior vena cava, and urinary levels of EMPs in essential (n=14) and renovascular (RVH; n=24) hypertensive patients and compared them with peripheral blood and urinary levels in healthy volunteers (n=14). PTC-EMPs were identified as urinary exosomes positive for the PTC marker plasmalemmal-vesicle-associated protein. In 7 RVH patients, PTC and fibrosis were also quantified in renal biopsy, and in 18 RVH patients, PTC-EMPs were measured again 3 months after continued medical therapy with or without stenting (n=9 each). Renal vein and systemic PTC-EMPs levels were not different among the groups, whereas their urinary levels were elevated in both RVH and essential hypertension versus healthy volunteers (56.8%±12.7% and 62.8%±10.7% versus 34.0%±17.8%; both P≤0.001). Urinary PTC-EMPs levels correlated directly with blood pressure and inversely with estimated glomerular filtration rate. Furthermore, in RVH, urinary PTC-EMPs levels correlated directly with stenotic kidney hypoxia, histological PTC count, and fibrosis and inversely with cortical perfusion. Three months after treatment, the change in urinary PTC-EMPs levels correlated inversely with a change in renal function ( r=-0.582; P=0.011). Therefore, urinary PTC-EMPs levels are increased in hypertensive patients and may reflect renal microcirculation injury, whereas systemic PTC-EMPs levels are unchanged. Urinary PTC-EMPs may be useful as novel biomarkers of intrarenal capillary loss.