The adverse impact of pre-operative anaemia on survival following major lower limb amputation.

INTRODUCTION: Approximately 5000 major lower-limb amputations (MLLA) for PAD occur per-annum in the UK with clinical outcomes being poor for this high-risk cohort of patients. Existing evidence suggests that anaemic surgical patients have an increased 30-day mortality, but this has not been explored in the context of MLLA. Recent prioritization processes suggested that MLLAs are a target area for research into outcome improvement. This cohort study evaluates the impact of anaemia on the outcome of MLLA to understand if optimization might improve outcomes. METHODS: All PAD patients undergoing MLLA during 2015-2018 at a tertiary vascular centre were reviewed. Patients were stratified into groups; non-anaemia (>12 g/dL), mild-anaemia (12-10 g/dL) and severe-anaemia (<10 g/dL) by pre-operative haemoglobin (Hb). Primary outcome was overall survival by Kaplan-Meier. Secondary outcomes included length of stay (LOS), post-operative blood-transfusion, surgical-site infection (SSI) and myocardial infarction (MI). Cox-proportional-hazard and receiver-operator characteristics (ROC) analyses were conducted. RESULTS: 345 patients were followed up over (mean) 23 months. 105 were non-anaemic, 111 mildly anaemic and 129 severely anaemic. Patients with severe-anaemia had a higher incidence of heart and renal failure (p = 0.003) than those with non- or mild-anaemia. Overall survival worsened significantly with increasing anaemia (p = 0.001). LOS was significantly longer in mild-anaemia which is 26 (16-43) days, (p = 0.006) and severe-anaemia of 28 days (17-40), (p < 0.001) compared to non-anaemia of 18 (10-30) days. Post-operative blood-transfusion (RBC) was required more frequently in 70.5% of severely anaemic patients (p < 0.001), compared to mildly anaemic (24.3%) and non-anaemic (7.6%) patients, with those receiving RBCs having a significantly worse survival. There was no difference in MI, SSI or wound dehiscence. Anaemia was significantly associated with mortality; (HR 1.7 (1.04-2.78), p = 0.03). A minimum-Hb of 10.4 g/L (by ROC) was identified as a cutoff Hb for an increased risk of mortality. CONCLUSION: Pre-operative anaemia is associated with worse outcome following MLLA, with increasing severity of anaemia associated with increasing mortality and RBC transfusion being potentially detrimental. More work is required to prospectively evaluate this relationship in this complex and multi-morbid cohort of patients.

A study of outcomes in conservatively managed patients with large abdominal aortic aneurysms deemed unfit for surgical repair.

BACKGROUND: The current advancement and increasing use of diagnostic imaging has led to increased detection of abdominal aortic aneurysms (AAA). Many of these patients are unfit for elective AAA surgery. AIM: To investigate the outcome of conservative management of unfit patients with large AAA (>5.5 cm) who are turned down for elective surgical intervention. PATIENTS AND METHODS: Between January 2006 and April 2017, 457 patients presented with AAA >5.5 cm. Seventy-six patients (M: F 54:22) were deemed unfit for elective repair. Mean age was 79.8 years (range 64-96). Mean AAA size was 60.22 mm (55-83). RESULTS: Forty-nine of the 76 patients (64%) had died by April 2017. Fifteen (19.7%) patients died directly because of their aneurysm rupture. A further 34 (44.7%) patients died from non-aneurysm-related causes. CONCLUSION: Patients with large AAA deemed unfit for elective surgery have an overall poor prognosis and die mainly from other causes than AAA. Surgical intervention when rupture occurs results in poor survival.

Snuffbox Versus Wrist Radiocephalic Arteriovenous Fistulas: 10 Years Experience.

Background The wrist radiocephalic arteriovenous fistula (RCAVF) is the initial suggested procedure for establishing hemodialysis vascular access (HVA) in the most distal site of the upper limb. The anatomical snuffbox arteriovenous fistula (SBAVF) is barely utilised, despite its remote location. In this study, we aimed to analyse and compare the results of SBAVF and RCAVF in terms of their maturity, patency, and failure rates. Methodology This descriptive, retrospective study compared outcomes between SBAVF and RCAVF in terms of maturation, patency, and failure. All patients with chronic kidney disease who attended and underwent either procedure at Betsi Cadwaladr University Health Board between 2013 and 2023 were studied. Results In a period of 10 years, 179 patients were included. Overall, 102 (57%) were male and 77 (43%) were female, with a male-to-female ratio of 1.3:1. Wrist radiocephalic fistula was the dominant type of surgery done in 76% (n = 136), while the snuffbox radiocephalic fistula was done in fewer than 24% (n = 43) of patients. Most patients underwent a successful arteriovenous (AV) fistula (n = 105, 58.7%), in contrast to 67 patients whose fistulas failed. There was a significant relationship between fistula failure and complications (p = 0.000). There was no significant effect of the fistula site, hypertension, diabetes, cardiac diseases, smoking, peripheral vascular disease, or central vein stenosis on the failure of the AV fistula (p = 0.127, 0.534, 0.510, 0.397, 0.017, 0.68, and 0.371, respectively). Conclusions The snuffbox AV fistula is a suitable and feasible first choice for patients on hemodynamic therapy.

Carotid Endarterectomy in the Very Elderly: Short-, Medium-, and Long-Term Outcomes.

Purpose: : Carotid endarterectomy (CEA) has an established effect on stroke-free survival in patients with carotid artery stenosis. Most landmark trials excluded patients ≥80 years of age due to their perceived high risk and uncertainty regarding the benefits of CEA. Despite the ongoing global increase in life expectancy, guidelines have not changed. The current study aimed to assess CEA outcomes in patients ≥80 years of age. Materials and Methods: : Data from patients ≥80 years of age, who underwent CEA between April 2016 and April 2022, were collected. Demographic information, comorbidities, surgical details, operative details, outcomes, and post-CEA survival were reviewed, and long-term data up to April 2023 were collected. Results: : Over the 6-year study period, 258 CEA procedures were recorded, of which 70 (27.1%) were performed in patients ≥80 years of age; the mean age was 84 years (range, 80-96 years), 47 (67.1%) were males, and 69 (98.6%) were symptomatic. Twenty-three (32.9%) patients were American Society of Anesthesiologists (ASA) grade 2, and 47 (67.1%) were grade 3. The 30-day stroke and mortality rates were 4.3% and 1.4%, respectively. At 1, 3, and 5 years, the cumulative freedom-from-stroke rates were 95.7%, 92.9%, and 91.4%, respectively, and the cumulative survival rates were 94.3%, 75.7%, and 61.4%, respectively. No risk factors affected early or late stroke or early mortality rates. Patients with ASA grade 3 had significantly lower cumulative survival than those with grade 2 (HR, 5.29; 95% CI, 1.590-17.603; P<0.01). Conclusion: : CEA was safe and effective in average-risk, elderly patients. Higher risk patients (i.e., ASA 3) showed no increased 30-day risk for stroke or mortality but exhibited significantly worse long-term survival. Hence, careful consideration of the benefits before performing CEA is crucial.

Assessment of Pregabalin-Induced Cardiotoxicity in Rats: Mechanistic Role of Angiotensin 1-7.

Pregabalin (PRG) possesses great therapeutic benefits in the treatment of epilepsy, neuropathic pain, and fibromyalgia. However, clinical data have reported incidence or exacerbation of heart failure following PRG administration. Experimental data exploring cardiac alterations and its underlying mechanisms are quite scarce. The aim of the present work was to investigate the effect of PRG on morphometric, echocardiographic, neurohumoral, and histopathological parameters in rats. It was hypothesized that alterations in cardiac renin angiotensin system (RAS) might be involved in PRG-induced cardiotoxicity. To further emphasize the role of RAS in the mechanism of PRG-induced cardiotoxicity, the protective potential of diminazene aceturate (DIZE), an ACE2 activator, was investigated. Results showed 44% decrease in ejection fraction and sevenfold increase in plasma N-terminal pro-brain natriuretic peptide. Histopathological examination also showed prominent vacuolar changes and edema in cardiomyocytes. In addition, PRG significantly increased angiotensin II (Ang II), angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) levels, while decreased angiotensin 1-7 (Ang 1-7), angiotensin converting enzyme 2 (ACE2), and Mas receptor (MasR) cardiac levels. DIZE co-administration showed prominent protection against PRG-induced echocardiographic, neurohumoral, and histopathological alterations in rats. In addition, downregulation of ACE/Ang II/AT1R and upregulation of ACE2/Ang 1-7/MasR axes were noted in DIZE co-treated rats. These findings showed, for the first time, the detailed cardiac deleterious effects of PRG in rats. The underlying pathophysiological mechanism is probably mediated via altered balance between the RAS axes in favor to the ACE/Ang II/AT1R pathway. Accordingly, ACE2 activators might represent promising therapeutic agents for PRG-induced cardiotoxicity.

Telmisartan and captopril ameliorate pregabalin-induced heart failure in rats.

Pregabalin (PRG) is highly effective in the treatment of epilepsy, neuropathic pain and anxiety disorders. Despite its potential benefits, PRG administration has been reported to induce or exacerbate heart failure (HF). It has been previously documented that overactivation of the renin angiotensin system (RAS) is involved in HF pathophysiological mechanism. The target of the current study was to examine the possible cardioprotective effect of telmisartan (Tel), an angiotensin II type 1 receptor (AT1R) blocker, compared with that of captopril (Cap), an angiotensin converting enzyme (ACE) inhibitor, in ameliorating PRG-induced HF in rats by assessing morphometric, echocardiographic and histopathological parameters. Furthermore, to investigate the role of RAS blockade by the two drugs in guarding against PRG-induced changes in cardiac angiotensin 1-7 (Ang 1-7) and angiotensin II (Ang II) levels, in addition to myocardial expression of ACE2, ACE, Mas receptor (MasR) and AT1R. Results showed that PRG administration induced morphometric, echocardiographic and histopathological deleterious alterations and significantly elevated cardiac Ang II, ACE and AT1R levels, while reduced Ang 1-7, ACE2 and MasR cardiac levels. Concurrent treatment with either Tel or Cap reversed PRG-induced morphometric, echocardiographic and histopathological abnormalities and revealed prominent protection against PRG-induced HF via downregulation of ACE/Ang II/AT1R and upregulation of ACE2/Ang 1-7/MasR axes. These are the first findings to demonstrate that the potential benefits of Tel and Cap are mediated by counteracting the altered balance between the RAS axes induced by PRG. Hence; Tel and Cap may attenuate PRG-induced HF partially through stimulation of ACE2/Ang 1-7/MasR pathway.

Do statins really cause diabetes? A meta-analysis of major randomized controlled clinical trials.

OBJECTIVES: To investigate and establish the relationship between the use of statin therapy and the risk of development of diabetes.  METHODS: PubMed and the Cochrane Central Register of Controlled Trials was searched for randomized controlled end-point trials of statins, with more than 1000 subjects and a minimum of one-year follow-up period, published until August 2015. The odds ratio (OR) of diabetes incidence with overall statin therapy as well as with different statins in question was calculated through random effect meta-analysis model.  RESULTS: Fourteen studies were included in the analysis with a total of 94,943 participants. Of these, 2392 subjects developed incident diabetes in the statin and 2167 in the placebo groups during a 4-year follow-up. The OR of diabetes incidence with statin therapy was significantly higher as compared with the placebo group (OR=1.11; 95% confidence interval = 1.0 to 1.2; p=0.007). There was an insignificant level of heterogeneity between the included trials (Cochran Q= 19.463, p=0.109, I2=33.20). Subgroup analysis showed that only 2 statins namely, atorvastatin (OR= 1.29; p=0.042) and rosuvastatin (OR = 1.17; p=0.01) were significantly associated.   CONCLUSION: Statin therapy can slightly increase risk of incident diabetes in subjects with hypercholesterolemia.

Facilitation by the renin-angiotensin system of cyclosporine-evoked hypertension in rats: Role of arterial baroreflexes and vasoreactivity.

AIMS: Cyclosporine (CSA) elevates blood pressure (BP) and alters arterial baroreflex sensitivity (BRS) and vasoreactivity. In this study we determined whether the renin-angiotensin system (RAS) interplays with other vasopressor pathways in mediating the CSA actions. MATERIALS AND METHODS: Whole animal and isolated vascular preparations were employed to determine the effects of pharmacologic interruption of angiotensin II (Ang II), endothelin (ET), or thromboxane (TXA2) signaling on the adverse cardiovascular effects of CSA. KEY FINDINGS: CSA (25mg/kg/day i.p. for 7days) caused significant increases in BP that were paralleled with (i) reduced BRS measured by phenylephrine (BRSPE) or sodium nitroprusside (BRSSNP), (ii) enhanced aortic contractile responses to Ang II and U-46619 (thromboxane analogue), and (iii) reduced aortic eNOS expression and acetylcholine, but not SNP, vasorelaxations. Except for the reduced BRSSNP, the CSA effects disappeared upon concurrent administration of losartan (angiotensin AT1 receptor antagonist), captopril (angiotensin converting enzyme inhibitor), or their combination. Moreover, CSA augmentation of Ang II contractions was abolished after cyclooxygenase inhibition (indomethacin) or endothelin ETA/ETB receptor blockade (atrasentan/BQ788). By contrast, the blockade of thromboxane receptors (terutroban) failed to alter the CSA-evoked facilitation of Ang II responsiveness. SIGNIFICANCE: The facilitation of baroreflex control and inhibition of vascular responsiveness to Ang II and thromboxane contribute to the BP lowering effect of RAS inhibitors in CSA-treated rats. Further, endothelin receptors and vasoconstrictor prostanoids contribute to the CSA-evoked exaggeration of Ang II vascular responsiveness and hypertension.

Blockade of endothelin ET(A), but not thromboxane, receptors offsets the cyclosporine-evoked hypertension and interrelated baroreflex and vascular dysfunctions.

The impairment of arterial baroreceptor and vasodilator functions are two major contributors to the hypertensive action of cyclosporine (CSA). In this study, in vivo and in vitro pharmacological studies were performed to investigate whether these effects of CSA are differentially modulated by endothelin and thromboxane signaling. The treatment of rats with CSA (25mg/kg/day i.p.) for 7 consecutive days caused significant increases in blood pressure (BP), attenuated reflex heart rate (HR) responses to vasopressor (phenylephrine, PE) and vasodepressor (sodium nitroprusside, SNP) agents, and reduced cumulative vasorelaxant responses elicited by acetylcholine (Ach, 1×10(-9)-1×10(-5)M) in PE-precontracted isolated aortas. These effects of CSA were blunted after concurrent i.p. administration of atrasentan (selective ETA blocker, 10mg/kg/day), but not terutroban (thromboxane receptor blocker, 10mg/kg/day). Moreover, atrasentan reversed the reductions in aortic protein expression of eNOS caused by CSA whereas terutroban was without effect. We also report that the favorable effect of atrasentan on CSA-evoked impairment in aortic Ach responsiveness disappeared in rats treated simultaneously with L-NAME (NOS inhibitor, 10mg/kg/day) but not BQ 788 (ETB receptor blocker, 0.1mg/kg/day) or indomethacin (cycloxygenase inhibitor, 5mg/kg/day). Together, the data implicate endothelin ETA receptors in baroreflex and vascular derangements which predispose to the hypertensive effect of CSA. Moreover, the facilitation of NOS, but not ETB receptors or cycloxygenase-derived prostanoids, signaling is pivotal for advantageous effect of atrasentan on the aortic CSA-Ach interaction.