Remnant Cholesterol, Not LDL Cholesterol, Explains Peripheral Artery Disease Risk Conferred by apoB: A Cohort Study.

BACKGROUND: Elevated apoB-containing lipoproteins (=remnants+LDLs [low-density lipoproteins]) are a major risk factor for atherosclerotic cardiovascular disease, including peripheral artery disease (PAD) and myocardial infarction. We tested the hypothesis that remnants and LDL both explain part of the increased risk of PAD conferred by elevated apoB-containing lipoproteins. For comparison, we also studied the risk of chronic limb-threatening ischemia and myocardial infarction. METHODS: apoB, remnant cholesterol, and LDL cholesterol were measured in 93 461 individuals without statin use at baseline from the Copenhagen General Population Study (2003-2015). During up to 15 years of follow-up, 1207 had PAD, 552 had chronic limb-threatening ischemia, and 2022 had myocardial infarction in the Danish National Patient Registry. Remnant and LDL cholesterol were calculated from a standard lipid profile. Remnant and LDL particle counts were additionally measured with nuclear magnetic resonance spectroscopy in 25 347 of the individuals. Results were replicated in 302 167 individuals without statin use from the UK Biobank (2004-2010). RESULTS: In the Copenhagen General Population Study, multivariable adjusted hazard ratios for risk of PAD per 1 mmol/L (39 mg/dL) increment in remnant and LDL cholesterol were 1.9 (95% CI, 1.5-2.4) and 1.1 (95% CI, 1.0-1.2), respectively; corresponding results in the UK Biobank were 1.7 (95% CI, 1.4-2.1) and 0.9 (95% CI, 0.9-1.0), respectively. In the association from elevated apoB to increased risk of PAD, remnant and LDL cholesterol explained 73% (32%-100%) and 8% (0%-46%), respectively; corresponding results were 63% (30%-100%) and 0% (0%-33%) for risk of chronic limb-threatening ischemia and 41% (27%-55%) and 54% (38%-70%) for risk of myocardial infarction; results for remnant and LDL particle counts corroborated these findings. CONCLUSIONS: PAD risk conferred by elevated apoB-containing lipoproteins was explained mainly by elevated remnants, while myocardial infarction risk was explained by both elevated remnants and LDL.

Vascular Endothelial Dysfunction in the Thoracic Aorta of Rats with Ischemic Acute Kidney Injury: Contribution of Indoxyl Sulfate.

Chronic kidney disease (CKD) and cardiovascular disease are known to be linked, and the involvement of indoxyl sulfate (IS), a type of uremic toxin, has been suggested as one of the causes. It is known that IS induces vascular dysfunction through overproduction of reactive oxygen species (ROS). On the other hand, the involvement of IS in the vascular dysfunction associated with acute kidney injury (AKI) is not fully understood. Therefore, we investigated this issue using the thoracic aorta of rats with ischemic AKI. Ischemic AKI was induced by occlusion of the left renal artery and vein for 45 min, followed by reperfusion 2 weeks after contralateral nephrectomy. One day after reperfusion, there was marked deterioration in renal function evidenced by an increase in plasma creatinine. Furthermore, blood IS levels increased markedly due to worsening renal function. Seven days and 28 days after reperfusion, blood IS levels decreased with the improvement in renal function. Of note, acetylcholine-induced vasorelaxation deteriorated over time after reperfusion, contradicting the recovery of renal function. In addition, 28 days after reperfusion, we observed a significant increase in ROS production in the vascular tissue. Next, we administered AST-120, a spherical adsorbent charcoal, after reperfusion to assess whether the vascular endothelial dysfunction associated with the ischemic AKI was due to a temporary increase in blood IS levels. AST-120 reduced the temporary increase in blood IS levels after reperfusion without influencing renal function, but did not restore the impaired vascular reactivity. Thus, in ischemic AKI, we confirmed that the vascular endothelial function of the thoracic aorta is impaired even after the recovery of kidney injury, probably with excessive ROS production. IS, which increases from ischemia to early after reperfusion, may not be a major contributor to the vascular dysfunction associated with ischemic AKI.

Post-ischemic skin peak oxygen saturation is associated with cardiovascular risk factors: a Swedish cohort study.

The objective of this study was to explore the associations between skin microcirculatory function and established cardiovascular risk factors in a large Swedish cohort. As part of the Swedish CArdioPulmonary bioImage Study (SCAPIS), microcirculatory data were acquired at Linköping University hospital, Linköping, Sweden during 2016-2017. The subjects, aged 50-64 years, were randomly selected from the national population register. Microcirculatory reactivity was assessed using a 5-min arterial occlusion-release protocol. Comprehensive skin microcirculatory data were continuously acquired by using a fiberoptic probe placed on the lower right arm. After exclusion of missing data (208), 1557 subjects were remaining. Among the parameters, skin microcirculatory peak oxygen saturation after occlusion release, had the strongest relationship to the cardiovascular risk factors. The linear associations between peak oxygen saturation and cardiovascular risk factors were analyzed adjusted for age and sex. We found a negative association with peak oxygen saturation (standardized regression coefficient) for blood pressure (systolic -0.05 (95% CI: -0.10;-0.003) and diastolic -0.05 (-0.10; -0.003)), BMI -0.18 (-0.23; -0.13), waist circumference (males -0.20 (-0.32; -0.16), females -0.18 (-0.25; -0.11)), prevalent diabetes -0.31 (-0.49; -0.12), hypertension -0.30 (-0.42; -0.18), dyslipidemia -0.24 (-0.40; -0.09), fasting glucose level -0.06 (-0.12; -0.01), HbA1c -0.07 (-0.12; -0.02), triglyceride level -0.09 (-0.14; -0.04), hsCRP -0.12 (-0.17; -0.07), and current smoker versus never smoked -0.50 (-0.67; -0.34). A positive association with peak oxygen saturation was found for cholesterol level 0.05 (0.005; 0.11) and HDL 0.11 (0.06; 0.17). This is the first study showing that post-ischemic skin microvascular peak oxygen saturation is associated with virtually all established cardiovascular risk factors in a population-based middle-aged cohort.

Placental Ischemia Says "NO" to Proper NOS-Mediated Control of Vascular Tone and Blood Pressure in Preeclampsia.

In this review, we first provide a brief overview of the nitric oxide synthase (NOS) isoforms and biochemistry. This is followed by describing what is known about NOS-mediated blood pressure control during normal pregnancy. Circulating nitric oxide (NO) bioavailability has been assessed by measuring its metabolites, nitrite (NO2) and/or nitrate (NO3), and shown to rise throughout normal pregnancy in humans and rats and decline postpartum. In contrast, placental malperfusion/ischemia leads to systemic reductions in NO bioavailability leading to maternal endothelial and vascular dysfunction with subsequent development of hypertension in PE. We end this article by describing emergent risk factors for placental malperfusion and ischemic disease and discussing strategies to target the NOS system therapeutically to increase NO bioavailability in preeclamptic patients. Throughout this discussion, we highlight the critical importance that experimental animal studies have played in our current understanding of NOS biology in normal pregnancy and their use in finding novel ways to preserve this signaling pathway to prevent the development, treat symptoms, or reduce the severity of PE.

Low Dose of IL-2 Normalizes Hypertension and Mitochondrial Function in the RUPP Rat Model of Placental Ischemia.

IL-2 is a cytokine released from CD4+T cells with dual actions and can either potentiate the inflammatory response or quell a chronic inflammatory response depending on its circulating concentration. IL-2 is elevated in many chronic inflammatory conditions and is increased during preeclampsia (PE). PE is characterized by new-onset hypertension during pregnancy and organ dysfunction and increasing evidence indicates that proinflammatory cytokines cause hypertension and mitochondrial (mt) dysfunction during pregnancy. The reduced uterine perfusion pressure (RUPP) model of placental ischemia is a rat model of PE that we commonly use in our laboratory and we have previously shown that low doses of recombinant IL-2 can decrease blood pressure in RUPP rats. The objective of this study was to determine the effects of a low dose of recombinant IL-2 on multi-organ mt dysfunction in the RUPP rat model of PE. We tested our hypothesis by infusing recombinant IL-2 (0.05 ng/mL) into RUPP rats on GD14 and examined mean arterial pressure (MAP), renal, placental and endothelial cell mt function compared to control RUPP. MAP was elevated in RUPP rats (n = 6) compared to controls (n = 5) (122 ± 5 vs. 102 ± 3 mmHg, p < 0.05), but was reduced by administration of LD recombinant IL-2 (107 ± 1 vs. 122 ± 5 mmHg, n = 9, p < 0.05). Renal, placental and endothelial mt ROS were significantly increased in RUPP rats compared to RUPP+ IL-2 and controls. Placental and renal respiration rates were reduced in RUPP rats compared to control rats but were normalized with IL-2 administration to RUPPs. These data indicate that low-dose IL-2 normalized multi-organ mt function and hypertension in response to placental ischemia.

COVID-19 and acute limb ischemia: a systematic review.

INTRODUCTION: The main goal of this systematic review was to analyze the outcomes of acute limb ischemia (ALI) in patients suffering from the novel Coronavirus: COVID-19 (SARS-CoV-2). EVIDENCE ACQUISITION: A systematic review on Medline and Embase was conducted up to May 15, 2021. All papers were sorted by abstract and full text by two independent authors. Systematic reviews, commentaries, and studies that did not distinguish status of COVID-19 infection were excluded from review. Patient demographics were recorded along with modality of treatment (endovascular and/or surgical). We analyzed 30-day outcomes, including mortality. Primary outcome was to evaluate clinical characteristic of ALI in patients affected by SARS-CoV-2 in term of location of ischemia, treatment options and 30-day outcomes. EVINDENCE SYNTHESIS: We selected 36 articles with a total of 194 patients. Most patients were male (80%) with a median age of 60 years old. The treatment most used was thromboembolectomy (31% of all surgical interventions). A total of 32 patients (19%) were not submitted to revascularization due to critical status. The rate of technical success was low (68%), and mortality rate was high (35%). CONCLUSIONS: This review confirms that SARS-CoV-2 is associated with a high risk of ALI. Further studies are needed to investigate the association and elucidate potential mechanisms, which may include a hypercoagulable state and hyperactivation of the immune response. Furthermore, management of ALI is not standardized and depends on patient condition and extension of the thrombosed segment. ALI in COVID-19 patients is associated with high risk of failure of revascularization and perioperative mortality.

Effects of chemerin and homocysteine levels and their associations with occurrence and development of ischemic cerebrovascular disease.

BACKGROUND: The current study was conducted to explore the effects of chemerin and homocysteine (Hcy) levels and their associations with the occurrence and development of ischemic cerebrovascular disease (ICVD). METHODS: There involved a total of 187 patients with ICVD and 190 healthy people for physical examination in Cangzhou Central hospital from January 2020 to April 2021. The participants enrolled were divided into four groups based on the digital subtraction angiography: mild stenosis group (64 cases, stenosis rate 30-49 %), moderate stenosis group (72 cases, stenosis rate 50-69 %), severe stenosis group (51 cases, stenosis rate 70-99 %) and control group (190 cases, in healthy condition). The laboratory indexes of ICVD group and control group were observed and the four groups were further compared. Pearson linear correlation was applied to analyze the link between chemerin and Hcy levels and the degree of cerebral vascular stenosis in ICVD patients, and multivariate logistic regression was used to analyze the influencing factors of ICVD. RESULTS: No significant difference was found in general information including age, gender, body mass index (BMI), heart rate, systolic blood pressure, diastolic blood pressure, smoking and drinking between the two groups (P > 0.05). Moreover, there was no significant difference in fasting blood glucose (FBG), total cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) levels between the two groups (P > 0.05). However, the levels of triglyceride (TG), low density lipoprotein cholesterol (LDL-C), chemerin and Hcy in ICVD group were significantly higher than those in control group (P < 0.05). When comparing the four groups, there was no significant difference in FBG and TC levels (P > 0.05). The levels of TG, LDL-C, chemerin and Hcy in mild, moderate and severe stenosis groups were higher than those in control group, the above levels in moderate and severe stenosis group were higher than those in mild stenosis group, and severe stenosis group higher than moderate stenosis group (P < 0.05). Chemerin and Hcy levels were positively correlated with the degree of cerebral vascular stenosis in ICVD patients (r = 0.612, 0.519, P < 0.001). ICVD was regarded as the dependent variable, and the abovementioned general data as well as significant laboratory indicators, including TG, LDL-C, chemerin and Hcy, as independent variables. The results of multivariate logistic regression analysis revealed that TG, LDL-C, chemerin and Hcy were independent influencing factors of ICVD. CONCLUSIONS: Chemerin and Hcy levels exerted a close link to the occurrence and development of ICVD as independent influencing factors.

Risk stratification and mortality prediction in octo- and nonagenarians with peripheral artery disease: a retrospective analysis.

OBJECTIVES: Among changes in demographics, aging is the most relevant cardiovascular risk factor. The prevalence of peripheral artery disease (PAD) is high in elderly patients and is associated with a worse prognosis. Despite optimal treatments, mortality in the high-risk population of octo- and nonagenarians with PAD remains excessive, and predictive factors need to be identified. The objective of this study was to investigate predictors of mortality in octo- and nonagenarians with PAD. METHODS: Cases of treated octo- and nonagenarians, including the clinical characteristics and markers of myocardial injury and heart failure, were studied retrospectively with respect to all-cause mortality. Hazard ratios [HR] were calculated and survival was analyzed by Kaplan-Meyer curves and receiver operating characteristic curved were assessed for troponin-ultra and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and chronic limb-threatening ischemia (CLTI). RESULTS: A total of 123 octo- and nonagenarians admitted for PAD were eligible. The troponin level was the major predictor of all-cause mortality (HR: 4.6, 95% confidence interval [CI]: 1.4-15.3), followed by the NT-proBNP level (HR: 3.9, 95% CI 1.8-8.8) and CLTI (HR: 3.1, 95% CI 1.6-5.9). Multivariate regression revealed that each increment of 1 standard deviation in log troponin and log NT-proBNP was associated with a 2.7-fold (95% CI 1.8-4.1) and a 1.9-fold (95% CI 1.2-2.9) increased risk of all-cause death. Receiver operating characteristic curve analysis using a combination of all predictors yielded an improved area under the curve of 0.888. In a control group of an equal number of younger individuals, only NT-proBNP (HR: 4.2, 95% CI 1.2-14.1) and CLTI (HR: 6.1, 95% CI 1.6-23.4) were predictive of mortality. CONCLUSION: Our study demonstrates that cardiovascular biomarkers and CLTI are the primary predictors of increased mortality in elderly PAD patients. Further risk stratification through biomarkers in this high-risk population of octo- and nonagenarians with PAD is necessary.

Hypoxic preconditioning protects against ischemic kidney injury through the IDO1/kynurenine pathway.

Prolonged cellular hypoxia leads to energetic failure and death. However, sublethal hypoxia can trigger an adaptive response called hypoxic preconditioning. While prolyl-hydroxylase (PHD) enzymes and hypoxia-inducible factors (HIFs) have been identified as key elements of oxygen-sensing machinery, the mechanisms by which hypoxic preconditioning protects against insults remain unclear. Here, we perform serum metabolomic profiling to assess alterations induced by two potent cytoprotective approaches, hypoxic preconditioning and pharmacologic PHD inhibition. We discover that both approaches increase serum kynurenine levels and enhance kynurenine biotransformation, leading to preservation of NAD+ in the post-ischemic kidney. Furthermore, we show that indoleamine 2,3-dioxygenase 1 (Ido1) deficiency abolishes the systemic increase of kynurenine and the subsequent renoprotection generated by hypoxic preconditioning and PHD inhibition. Importantly, exogenous administration of kynurenine restores the hypoxic preconditioning in the context of Ido1 deficiency. Collectively, our findings demonstrate a critical role of the IDO1-kynurenine axis in mediating hypoxic preconditioning.

Adverse Effect of Circadian Rhythm Disorder on Reparative Angiogenesis in Hind Limb Ischemia.

Background Circadian rhythm disorders, often seen in modern lifestyles, are a major social health concern. The aim of this study was to examine whether circadian rhythm disorders would influence angiogenesis and blood perfusion recovery in a mouse model of hind limb ischemia. Methods and Results A jet-lag model was established in C57BL/6J mice using a light-controlled isolation box. Control mice were kept at a light/dark 12:12 (12-hour light and 12-hour dark) condition. Concentrations of plasma vascular endothelial growth factor and circulating endothelial progenitor cells in control mice formed a circadian rhythm, which was diminished in the jet-lag model (P<0.05). The jet-lag condition deteriorated tissue capillary formation (P<0.001) and tissue blood perfusion recovery (P<0.01) in hind limb ischemia, which was associated with downregulation of vascular endothelial growth factor expression in local ischemic tissue and in the plasma. Although the expression of clock genes (ie, Clock, Bmal1, and Cry) in local tissues was upregulated after ischemic injury, the expression levels of cryptochrome (Cry) 1 and Cry2 were inhibited by the jet-lag condition. Next, Cry1 and Cry2 double-knockout mice were examined for blood perfusion recoveries and a reparative angiogenesis. Cry1 and Cry2 double-knockout mice revealed suppressed capillary density (P<0.001) and suppressed tissue blood perfusion recovery (P<0.05) in the hind limb ischemia model. Moreover, knockdown of CRY1/2 in human umbilical vein endothelial cells was accompanied by increased expression of WEE1 and decreased expression of HOXC5. This was associated with decreased proliferative capacity, migration ability, and tube formation ability of human umbilical vein endothelial cells, respectively, leading to impairment of angiogenesis. Conclusions Our data suggest that circadian rhythm disorder deteriorates reparative ischemia-induced angiogenesis and that maintenance of circadian rhythm plays an important role in angiogenesis.

Hippo-YAP/MCP-1 mediated tubular maladaptive repair promote inflammation in renal failed recovery after ischemic AKI.

Acute kidney injury (AKI) is associated with significant morbidity and its chronic inflammation contributes to subsequent chronic kidney disease (CKD) development. Yes-associated protein (YAP), the major transcriptional coactivator of the Hippo pathway, has been shown associated with chronic inflammation, but its role and mechanism in AKI-CKD transition remain unclear. Here we aimed to investigate the role of YAP in AKI-induced chronic inflammation. Renal ischemia/reperfusion (I/R) was used to induce a mouse model of AKI-CKD transition. We used verteporfin (VP), a pharmacological inhibitor of YAP, to treat post-IRI mice for a period, and evaluated the influence of YAP inhibition on long-term outcomes of AKI. In our results, severe IRI led to maladaptive tubular repair, macrophages infiltration, and progressive fibrosis. Following AKI, the Hippo pathway was found significantly altered with YAP persistent activation. Besides, tubular YAP activation was associated with the maladaptive repair, also correlated with interstitial macrophage infiltration. Monocyte chemoattractant protein 1 (MCP-1) was found notably upregulated with YAP activation. Of note, pharmacological inhibition of YAP in vivo attenuated renal inflammation, including macrophage infiltration and MCP-1 overexpression. Consistently, in vitro oxygen-glucose deprivation and reoxygenation (OGD/R) induced YAP activation and MCP-1 overproduction whereas these could be inhibited by VP. In addition, we modulated YAP activity by RNA interference, which further confirmed YAP activation enhances MCP-1 expression. Together, we concluded tubular YAP activation with maladaptive repair exacerbates renal inflammation probably via promoting MCP-1 production, which contributes to AKI-CKD transition.

Pre-operative Neutrophil to Lymphocyte Ratio is Associated With 30 Day Death or Amputation After Revascularisation for Acute Limb Ischaemia.

OBJECTIVE: Inflammation is an early feature of acute limb ischaemia (ALI), hence the potential prognostic significance of inflammatory biomarkers. This study aimed to assess the value of pre-operative inflammatory biomarkers, specifically the neutrophil to lymphocyte ratio (NLR) and the platelet to lymphocyte ratio (PLR), for predicting an adverse outcome after revascularisation for ALI. METHODS: All patients submitted to lower limb revascularisation for Rutherford IIa or IIb ALI at the authors' institution between 2009 and 2019 were screened retrospectively. Pre-operative NLR and PLR were analysed, along with other known prognostic factors. Primary outcome was the composite endpoint of 30 day death or amputation. RESULTS: A total of 345 patients were included, 84 of whom suffered the primary outcome (24.3%). The median follow up was 23.1 months (3.1 - 52.2). Higher age (OR 1.05 per year increase, 95% CI 1.01 - 1.09), diabetes (OR 2.63, 95% CI 1.14 - 6.06), Rutherford grade IIb vs. IIa (OR 5.51, 95% CI 2.11 - 14.42), higher NLR (OR 1.28 per unit increase, 95% CI 1.12 - 1.47), and fasciotomy need (OR 3.44, 95% CI 1.14 - 10.34) were independently associated with 30 day death or amputation, whereas pre-operative statin or anticoagulant medication were associated with a risk reduction (OR 0.23, 95% CI 0.53 - 0.96 and OR 0.20, 95% CI 0.05 - 0.84, respectively). PLR did not show an independent effect on this population. Pre-operative NLR presented a good discriminative ability (AUC 0.86, 95% CI 0.82 - 0.90). A cut off NLR level ≥ 5.4 demonstrated a 90.5% sensitivity and 73.6% specificity for 30 day death or amputation. Kaplan-Meier analysis showed that patients with pre-operative NLR ≥ 5.4 had significantly lower 30 day, six month and one year amputation free survival when compared with those with NLR < 5.4 (64.8 ± 4.0%, 44.1 ± 4.1%, and 37.5 ± 4.1% vs. 98.5 ± 0.9%, 91.9 ± 2.0%, and 85.9 ± 2.5%, log rank p < .001). CONCLUSION: In this study, higher pre-operative NLR was associated with 30 day death or amputation following intervention for Rutherford grade IIa or IIb ALI. NLR potentially stands as a simple, widely available and inexpensive biomarker that can refine decision making and possibly contribute to ALI morbidity and mortality reduction.

Ratio of venous-to-arterial PCO2 to arteriovenous oxygen content difference during regional ischemic or hypoxic hypoxia.

The purpose of the study was to evaluate the behavior of the venous-to-arterial CO2 tension difference (ΔPCO2) over the arterial-to-venous oxygen content difference (ΔO2) ratio (ΔPCO2/ΔO2) and the difference between venous-to-arterial CO2 content calculated with the Douglas' equation (ΔCCO2D) over ΔO2 ratio (ΔCCO2D/ΔO2) and their abilities to reflect the occurrence of anaerobic metabolism in two experimental models of tissue hypoxia: ischemic hypoxia (IH) and hypoxic hypoxia (HH). We also aimed to assess the influence of metabolic acidosis and Haldane effects on the PCO2/CO2 content relationship. In a vascularly isolated, innervated dog hindlimb perfused with a pump-membrane oxygenator system, the oxygen delivery (DO2) was lowered in a stepwise manner to decrease it beyond critical DO2 (DO2crit) by lowering either arterial PO2 (HH-model) or flow (IH-model). Twelve anesthetized and mechanically ventilated dogs were studied, 6 in each model. Limb DO2, oxygen consumption ([Formula: see text]), ΔPCO2/ΔO2, and ΔCCO2D/ΔO2 were obtained every 15 min. Beyond DO2crit, [Formula: see text] decreased, indicating dysoxia. ΔPCO2/ΔO2, and ΔCCO2D/ΔO2 increased significantly only after reaching DO2crit in both models. At DO2crit, ΔPCO2/ΔO2 was significantly higher in the HH-model than in the IH-model (1.82 ± 0.09 vs. 1.39 ± 0.06, p = 0.002). At DO2crit, ΔCCO2D/ΔO2 was not significantly different between the two groups (0.87 ± 0.05 for IH vs. 1.01 ± 0.06 for HH, p = 0.09). Below DO2crit, we observed a discrepancy between the behavior of the two indices. In both models, ΔPCO2/ΔO2 continued to increase significantly (higher in the HH-model), whereas ΔCCO2D/ΔO2 tended to decrease to become not significantly different from its baseline in the IH-model. Metabolic acidosis significantly influenced the PCO2/CO2 content relationship, but not the Haldane effect. ΔPCO2/ΔO2 was able to depict the occurrence of anaerobic metabolism in both tissue hypoxia models. However, at very low DO2 values, ΔPCO2/ΔO2 did not only reflect the ongoing anaerobic metabolism; it was confounded by the effects of metabolic acidosis on the CO2-hemoglobin dissociation curve, and then it should be interpreted with caution.

Insulin-Dependent Status Influences Post-Procedural Outcomes in Diabetic Patients Following Lower Extremity Endovascular Intervention for Peripheral Arterial Disease.

PURPOSE: Diabetic patients are at increased risk of developing lower extremity peripheral arterial disease (PAD) requiring revascularization. This study assessed the effect of insulin dependence in diabetics on post-procedural outcomes following infra-inguinal endovascular intervention. MATERIALS AND METHODS: The American College of Surgeon's National Surgical Quality Improvement Program database was used to identify 8022 patients undergoing infra-inguinal endovascular interventions between 2014 and 2017. Thirty-day post-procedural outcomes for patients without diabetes, with non-insulin-dependent diabetes mellitus (NIDDM), and with insulin-dependent diabetes mellitus (IDDM) were compared. RESULTS: At presentation, IDDM patients were more likely to present with critical limb ischemia compared to NIDDM and non-diabetic patients. In propensity score-weighted logistic regression analysis, IDDM status was an independent predictor for increased renal complication (odds ratio [OR] = 3.08, confidence interval [CI] = 1.44-6.65), sepsis (OR = 1.68, CI = 1.13-2.48), wound complication (OR = 1.57, CI = 1.09-2.25, p = 0.006), UTI (OR = 2.07, CI = 1.09-3.94, p = 0.03), and readmission (OR = 1.21, CI = 1.03-1.42). NIDDM status was an independent predictor for increased risk of renal complications (OR = 2.80, CI = 1.18-6.63). CONCLUSIONS: IDDM status is an independent predictor for increased risk of 30-day post-procedural complications and readmission compared to both NIDDM and non-diabetic status in patients undergoing lower extremity endovascular interventions for PAD.

Electrophysiological and inflammatory changes of CA1 area in male rats exposed to acute kidney injury: Neuroprotective effects of erythropoietin.

The high mortality rate associated with acute kidney injury (AKI) is commonly due to progressive, inflammatory multiple organ dysfunction, which often involves neurological complications. The AKI-stimulated mechanisms leading to brain dysfunction are not well understood, which hinders development of new therapeutic avenues to minimize AKI-mediated neural effects. The hippocampal CA1 area is a particularly vulnerable region during AKI but the electrophysiological and inflammatory mechanisms involved in this vulnerability remain largely unknown. Here, we used immunohistochemistry to quantitatively investigate the number of astrocytes expressing glial fibrillary acidic protein (GFAP) as an indicator of inflammation, and whole cell patch clamp to evaluate electrophysiological changes in CA1 at different time points following induction of bilateral renal ischemia (BRI) in male Wistar rats. Further we evaluated the effectiveness of erythropoietin (EPO, 1000 U/kg i.p.) in mitigating BRI-associated changes. Plasma concentrations of blood urea nitrogen (BUN) were significantly enhanced at 24 h, 72 h and 1 week, and creatinine (Cr) was increased at 24 h after reperfusion, which were changes reduced by EPO. BRI led to an increase in CA1 GFAP-positive cells 24 h and 72 h, but not 1 week, after reperfusion, and EPO reversed this effect of BRI at 24 h. Additionally, BRI caused an increase in the peak amplitude and coefficient of variation of CA1 pyramidal neuronal action potentials, which were changes not seen in presence of EPO. When taken together, altered neuronal electrophysiological properties and astrogliosis could contribute to the neurological complications induced by AKI, and EPO offers hope as a potential neuroprotective agent.

Critical limb ischemia patients clinically improving with medical treatment have lower neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios.

OBJECTIVES: Inflammation is a component in the pathogenesis of critical limb ischemia. We aimed to assess how inflammation affects response to treatment in patients treated for critical limb ischemia using neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocytes ratios (PLR) as markers of inflammation. METHODS: Patients in a single tertiary cardiovascular center with critical limb ischemia unsuitable for surgical or interventional revascularization were retrospectively identified. Data were collected on medical history for risk factors, previous surgical or endovascular revascularization, and outcome. A standard regimen of low molecular weight heparin, aspirin, statins, iloprost infusions, and a standard pain medication protocol were applied to each patient per hospital protocol. Patients with improvement in ischemic pain and healed ulcers made up the responders group and cases with no worsening pain or ulcer size or progression to minor or major amputations made up the non-responders group. Responders and Non-responders were compared for risk factors including pretreatment NLR and PLR. RESULTS: 268 included patients who were not candidates for surgical or endovascular revascularization were identified. Responders had significantly lower pretreatment NLR (4.48 vs 8.47, p < 0.001) and PLR (162.19 vs 225.43, p = 0.001) values. After controlling for associated risk factors NLR ≥ 4.63 (p < 0.001) and PLR ≥ 151.24 (p = 0.016) were independently associated with no response to treatment. CONCLUSIONS: Neutrophil-to-lymphocyte ratio and platelet-to-lymphocytes ratio are markers of inflammation that are reduced in patients improving with medical treatment suggesting a decreased state of inflammation before treatment in responding patients.

Complement activation and coagulopathy - an ominous duo in COVID19.

INTRODUCTION: COVID-19 has similarities to the Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) outbreaks, as severe patients and non-survivors have frequently shown abnormal coagulation profiles. Immune-mediated pathology is a key player in this disease; hence, the role of the complement system needs assessment. The complement system and the coagulation cascade share an intricate network, where multiple mediators maintain a balance between both pathways. Coagulopathy in COVID-19, showing mixed features of complement-mediated and consumption coagulopathy, creates a dilemma in diagnosis and management. AREAS COVERED: Pathophysiology of coagulopathy in COVID-19 patients, with a particular focus on D-dimer and its role in predicting the severity of COVID-19 has been discussed. A comprehensive search of the medical literature on PubMed was done till May 30th, 2020 with the keywords 'COVID-19', 'SARS-CoV-2', 'Coronavirus', 'Coagulopathy', and 'D-dimer'. Twenty-two studies were taken for weighted pooled analysis of D-dimer. EXPERT OPINION: A tailored anticoagulant regimen, including intensification of standard prophylactic regimens with low-molecular-weight heparin is advisable for COVID-19 patients. Atypical manifestations and varying D-dimer levels seen in different populations bring forth the futility of uniform recommendations for anticoagulant therapy. Further, direct thrombin inhibitors and platelet inhibitors in a patient-specific manner should also be considered.

Double VEGF/HGF Gene Therapy in Critical Limb Ischemia Complicated by Diabetes Mellitus.

Critical leg ischemia (CLI) complicated by diabetes mellitus (DM), which is a very common and dangerous disease, represents the ultimate stage of peripheral arterial disease. Patients are treated with antiplatelet drugs, statins and limb revascularization, but a significant number of patients are not candidate for revascularization. Literature shows that in such cases, gene therapy could be a perfect therapeutic option. The aim of our study was to evaluate efficacy of double vascular endothelial growth factor/hepatocyte growth factor (VEGF/HGF) gene therapy in patients with CLI complicated by DM. We observed that 90 days after administration, serum level of VEGF and ankle-brachial index increased significantly (p < 0.001) and rest pain decreased significantly compared with the control group (p < 0.002). Moreover considerable improvement in vascularization was observed in computed tomography angiography (P = 0.04). Based on the results of this study, we suggest that the therapy with pIRES/VEGF165/HGF bicistronic plasmid administration is a safe and effective method of treatment of patients with both CLI and DM. Graphical abstract.

A preliminary pilot study investigating the impact of endovascular treatment on leg muscle volume in peripheral artery disease and its relation to baseline glycemic control.

BACKGROUND AND AIMS: Peripheral artery disease (PAD), intermittent claudication, and impaired mobility contribute to the loss of skeletal muscle. This study investigated the impact of endovascular treatment (EVT) in patients suffering from PAD above the knee and its relation to baseline glycemic control. METHODS AND RESULTS: Mid-thigh muscle volume was measured before EVT, 3 months after EVT and 6 months after EVT. Mid-thigh muscle volumes of ipsilateral PAD patients with ischemic and non-ischemic legs were compared. Correlations between total thigh muscle volume and clinical characteristics were analyzed using univariable and multivariable analysis. Overall, thigh muscle volume increased after EVT. The mid-thigh muscle volume was significantly lower in patients with ipsilateral lesions and in those with ischemic lower limbs. The thigh muscle volume of those with ischemic lower limbs increased after EVT. Baseline glycated hemoglobin was the only factor that was negatively correlated with changes in the muscle volume after EVT. Muscle volume significantly increased in normoglycemic HbA1c<6.5% (47 mmol/mol) patients. There was no significant alteration in the muscle volume of hyperglycemic HbA1c ≥ 6.5% patients. CONCLUSION: Ischemic muscle atrophy was ameliorated after EVT in normoglycemic patients. There is a need for a large-scale trial to investigate whether EVT can protect or delay skeletal muscle loss.