Effects of RIPC on the Metabolomical Profile during Lower Limb Digital Subtraction Angiography: A Randomized Controlled Trial.

Remote ischemic preconditioning (RIPC) has demonstrated protective effects in patients with lower extremity arterial disease (LEAD) undergoing digital subtraction angiography (DSA) and/or percutaneous transluminal angioplasty (PTA). This study aimed to investigate the impact of RIPC on the metabolomical profile of LEAD patients undergoing these procedures and to elucidate its potential underlying mechanisms. A total of 100 LEAD patients were enrolled and randomly assigned to either the RIPC group (n = 46) or the sham group (n = 54). Blood samples were drawn before and 24 h after intervention. Targeted metabolomics analysis was performed using the AbsoluteIDQ p180 Kit, and changes in metabolite concentrations were compared between the groups. The RIPC group demonstrated significantly different dynamics in nine metabolites compared to the sham group, which generally showed a decrease in metabolite concentrations. The impacted metabolites included glutamate, taurine, the arginine-dimethyl-amide-to-arginine ratio, lysoPC a C24:0, lysoPC a C28:0, lysoPC a C26:1, PC aa C38:1, PC ae C30:2, and PC ae C44:3. RIPC exhibited a 'stabilization' effect, maintaining metabolite levels amidst ischemia-reperfusion injuries, suggesting its role in enhancing metabolic control. This may improve outcomes for LEAD patients. However, additional studies are needed to definitively establish causal relationships among these metabolic changes.

Metabolomics of Arterial Stiffness.

Arterial stiffness (AS) is one of the earliest detectable signs of structural and functional alterations of the vessel wall and an independent predictor of cardiovascular events and death. The emerging field of metabolomics can be utilized to detect a wide spectrum of intermediates and products of metabolism in body fluids that can be involved in the pathogenesis of AS. Research over the past decade has reinforced this idea by linking AS to circulating acylcarnitines, glycerophospholipids, sphingolipids, and amino acids, among other metabolite species. Some of these metabolites influence AS through traditional cardiovascular risk factors (e.g., high blood pressure, high blood cholesterol, diabetes, smoking), while others seem to act independently through both known and unknown pathophysiological mechanisms. We propose the term 'arteriometabolomics' to indicate the research that applies metabolomics methods to study AS. The 'arteriometabolomics' approach has the potential to allow more personalized cardiovascular risk stratification, disease monitoring, and treatment selection. One of its major goals is to uncover the causal metabolic pathways of AS. Such pathways could represent valuable treatment targets in vascular ageing.

Five-year survival after elective open and endovascular aortic aneurysm repair.

BACKGROUND AND OBJECTIVE: Current evidence suggests short-term survival benefit from endovascular aneurysm repair (EVAR) versus open surgical repair (OSR) in elective abdominal aortic aneurysm (AAA) procedures, but this benefit is lost during long-term follow-up. The aim of this study was to compare short- and mid-term all-cause mortality in patients with non-ruptured aneurysm treated by OSR and EVAR; and to assess the rate of complications and reinterventions, as well as to evaluate their impact on survival. METHODS: The medical records of the non-ruptured AAA patients undergoing OSR or EVAR between 1 January 2011 and 31 December 2019 at Tartu University Hospital, Estonia, were retrospectively reviewed. We gathered survival data from the national registry (mean follow-up period was 3.7 ± 2.3 years). RESULTS: A total of 225 non-ruptured AAA patients were treated operatively out of whom 95 (42.2%) were EVAR and 130 (57.8%) were OSR procedures. The difference in estimated all-cause mortality between the OSR and EVAR groups at day 30 was statistically irrelevant (2.3% vs 0%; p = 0.140), but OSR patients showed statistically significantly higher 5 year survival compared with EVAR patients (75.3% vs 50.0%, p = 0.002). Complication and reintervention rates for the EVAR and OSR groups did not differ statistically (26.3% vs 16.9%, p = 0.122; 10.5% vs 11.5%, p = 0.981, respectively). Multivariate analysis revealed that greater aneurysm diameter (p = 0.012), EVAR procedure (p = 0.016), male gender (p = 0.023), and cerebrovascular diseases (p = 0.028) were independently positively associated with 5-year mortality. CONCLUSIONS: Thirty-day mortality, and complication and reintervention rates for EVAR and OSR after elective AAA repair were similar. Although the EVAR procedure is an independent risk factor for 5-year mortality, higher age and greater proportion of comorbidities among EVAR patients may influence not only the choice of treatment modality, but also prognosis.

Metabolomic Signature of Amino Acids, Biogenic Amines and Lipids in Blood Serum of Patients with Severe Osteoarthritis.

Metabolomic analysis is an emerging new diagnostic tool, which holds great potential for improving the understanding of osteoarthritis (OA)-caused metabolomic shifts associated with systemic inflammation and oxidative stress. The main aim of the study was to map the changes of amino acid, biogenic amine and complex lipid profiles in severe OA, where the shifts should be more eminent compared with early stages. The fasting serum of 70 knee and hip OA patients and 82 controls was assessed via a targeted approach using the AbsoluteIDQ™ p180 kit. Changes in the serum levels of amino acids, sphingomyelins, phoshatidylcholines and lysophosphatidylcholines of the OA patients compared with controls suggest systemic inflammation in severe OA patients. Furthermore, the decreased spermine to spermidine ratio indicates excessive oxidative stress to be associated with OA. Serum arginine level was positively correlated with radiographic severity of OA, potentially linking inflammation through NO synthesis to OA. Further, the level of glycine was negatively associated with the severity of OA, which might refer to glycine deficiency in severe OA. The current study demonstrates significant changes in the amino acid, biogenic amine and low-molecular weight lipid profiles of severe OA and provides new insights into the complex interplay between chronic inflammation, oxidative stress and OA.

Effect of kidney donation on bone mineral metabolism.

Kidney donation results in reductions in kidney function and lasting perturbations in phosphate homeostasis, which may lead to adverse cardiovascular sequelae. However, the acute effects of kidney donation on bone mineral parameters including regulators of calcium and phosphate metabolism are unknown. We conducted a prospective observational controlled study to determine the acute effects of kidney donation on mineral metabolism and skeletal health. Biochemical endpoints were determined before and after donation on days 1, 2 and 3, 6 weeks and 12 months in donors and at baseline, 6 weeks and 12 months in controls. Baseline characteristic of donors (n = 34) and controls (n = 34) were similar: age (53±10 vs 50±14 years, p = 0.33), BMI (26.3±2.89 vs 25.9±3.65, p = 0.59), systolic BP (128±13 vs 130±6 mmHg, p = 0.59), diastolic BP (80±9 vs 81±9 mmHg, p = 0.68) and baseline GFR (84.4±20.2 vs 83.6±25.2 ml/min/1.73m2, p = 0.89). eGFR reduced from 84.4±20.2 to 52.3±17.5 ml/min/1.73m2 (p<0.001) by day 1 with incomplete recovery by 12 months (67.7±22.6; p = 0.002). Phosphate increased by day 1 (1.1(0.9-1.2) to 1.3(1.1-1.4) mmol/L, p <0.001) but declined to 0.8(0.8-1.0) mmol/L (p<0.001) before normalizing by 6 weeks. Calcium declined on day 1 (p = 0.003) but recovered at 6 weeks or 12 months. PTH and FGF-23 remained unchanged, but α-Klotho reduced by day 1 (p = 0.001) and remained low at 6 weeks (p = 0.02) and 1 year (p = 0.04). In this study, we conclude that kidney donation results in acute disturbances in mineral metabolism characterised by a reduced phosphate and circulating α-Klotho concentration without acute changes in the phosphaturic hormones FGF23 and PTH.

Atenolol's Inferior Ability to Reduce Central vs Peripheral Blood Pressure Can Be Explained by the Combination of Its Heart Rate-Dependent and Heart Rate-Independent Effects.

OBJECTIVE: Whether the inferior ability of atenolol to reduce central (aortic) compared to peripheral (brachial) blood pressure (BP) is related to its heart rate (HR)-dependent or -independent effects, or their combination, remains unclear. To provide further mechanistic insight into this topic, we studied the acute effects of atenolol versus nebivolol and ivabradine on systolic blood pressure amplification (SBPA; peripheral systolic BP minus central systolic BP) in a model of sick sinus syndrome patients with a permanent dual-chamber cardiac pacemaker in a nonrandomized single-blind single-group clinical trial. METHODS: We determined hemodynamic indices noninvasively (Sphygmocor XCEL) before and at least 3 h after administration of oral atenolol 50 or 100 mg, nebivolol 5 mg, or ivabradine 5 or 7.5 mg during atrial pacing at a low (40 bpm), middle (60 bpm), and high (90 bpm) HR level in 25 participants (mean age 65.5 years, 12 men). RESULTS: At the low HR level, i.e., when the drugs could exert their HR-dependent and HR-independent effects on central BP, only atenolol produced a significant decrease in SBPA (mean change 0.74 ± 1.58 mmHg (95% CI, 0.09-1.40; P = 0.028)), indicating inferior central vs peripheral systolic BP change. However, we observed no significant change in SBPA with atenolol at the middle and high HR levels, i.e., when HR-dependent mechanisms had been eliminated by pacing. CONCLUSION: The findings of our trial with a mechanistic approach to the topic imply that the inferior ability of atenolol to reduce central vs peripheral BP can be explained by the combination of its heart rate-dependent and -independent effects. This trial is registered with NCT03245996.

Evaluation of inert gas rebreathing for determination of cardiac output: influence of age, gender and body size.

The aim of this study was to evaluate an inert gas rebreathing method (Innocor) for measurement of cardiac output and related haemodynamic variables and to provide robust normative data describing the influence of age, gender and body size on these variables. Four separate studies were conducted: measurement repeatability (study 1, n = 45); postural change (study 2, n = 40); response to submaximal cycling exercise (study 3, n = 20); and the influence of age, gender and body size (study 4, n = 1400). Repeated measurements of cardiac output, stroke volume and heart rate were similar, with low mean (±SD) differences (0.26 ± 0.53 L/min, 0 ± 11 mL and 2 ± 6beats/min, respectively). In addition, cardiac output and stroke volume both declined progressively from supine to seated and standing positions (P < 0.001 for both) and there was a stepwise increase in both parameters moving from rest to submaximal exercise (P < 0.001 for both). In study 4, there was a significant age-related decline in cardiac output and stroke volume in males and females, which remained significant after adjusting for body surface area (BSA, P < 0.001 for all comparisons). Both parameters were also significantly higher in those with high body mass index (BMI; P < 0.01 versus those with normal BMI for all comparisons), although indexing cardiac output and stroke volume to BSA reversed these trends. Inert gas rebreathing using the Innocor device provides repeatable measurements of cardiac output and related indices, which are sensitive to the effects of acute physiological manoeuvres. Moreover, inert gas rebreathing is a suitable technique for examining chronic influences such as age, gender and body size on key haemodynamic components of the arterial blood pressure.

Heart rate reduction decreases central blood pressure in sick sinus syndrome patients with a permanent cardiac pacemaker.

Increased resting heart rate (HR) contributes to higher cardiovascular mortality and morbidity in the healthy as well as in people with cardiovascular diseases, possibly due to elevated blood pressure (BP) among other mechanisms. Data on the relationship between HR and central (aortic) BP remains controversial, however, and concerning ß-blockers, it has been proposed that pharmacological HR lowering is associated with augmentation of central BP. We aimed to study the role of pharmacologically unaffected HR on central BP indices in sick sinus syndrome patients with a permanent cardiac pacemaker in the HR range from 40 to 90 bpm. We included 27 subjects (mean age 65.8 ± 9.5 years, 12 men) with a dual-chamber pacemaker implanted due to sick sinus syndrome. We determined central hemodynamic indices noninvasively during an atrial pacing mode at low (40 bpm), middle (60 bpm), and high (90 bpm) HR levels with an oscillometric cuff-based device (Sphygmocor XCEL). There was no difference in central systolic BP at the middle versus the high HR level (mean 121.2 ± 13.0 and 121.2 ± 12.1 mmHg, respectively, P = 0.9), but at the low HR level, it was significantly lower than at the middle HR level (mean 117.2 ± 13.1 and 121.2 ± 13.0 mmHg, P < 0.01). Our acute study provides evidence to suggest that at a HR of <60 bpm, sick sinus syndrome patients may have a lower central BP than at a higher HR, despite the proposed augmenting effects of low HR on central BP.

Medium- and long-chain acylcarnitines are associated with osteoarthritis severity and arterial stiffness in end-stage osteoarthritis patients: a case-control study.

AIM: Arterial pathology has been suggested to be involved in osteoarthritis (OA). Metabolic profiling enables the determination of low-molecular-weight molecules, which might further explain the pathogenesis of OA and its relationship with cardiovascular diseases (CVD). The aim of this study was to compare the metabolic profile of lipid metabolism-related compounds and arterial stiffness in OA patients and in controls. METHOD: The serum of 70 end-stage OA patients prior to joint replacement surgery and 82 age-matched controls were analyzed by the AbsoluteIDQ™ p180 kit (BIOCRATES Life Sciences AG, Innsbruck, Austria) using the targeted metabolomic approach. Arterial stiffness was assessed by measuring carotid-femoral and carotid-radial pulse wave velocity. Aortic-brachial pulse wave velocity ratio (PWV-ratio) was used as the measure of arterial stiffness gradient. Principal component analysis was performed to analyze the large number of metabolites. RESULTS: The OA patients had decreased levels of C10:1, C10:2, C12, C12:1, C14, C14:2, C14:1-OH, carnitine palmitoyltransferase 1 (CPT1) ratio and total AC/C0 compared with age-matched controls. There was independent association between acylcarnitines and PWV-ratio in the OA patients. Furthermore, acylcarnitines were associated with OA radiographic severity. The component that resembles acylcarnitines was an independent predictor of the PWV-ratio for OA patients. CONCLUSION: We found decreased levels of acylcarnitines in OA patients. Furthermore, medium-and long-chain acylcarnitines associated independently with arterial stiffness and were related to radiographic severity of OA. Thus, acylcarnities might play an important role in the association between OA and CVD.

Metabolic factors and oxidative stress in osteoarthritis: a case-control study.

Previous studies suggest that metabolic disturbances might be involved in the development of osteoarthritis (OA). Associations have been found between the individual components of metabolic syndrome (MetS) and OA. MetS has been associated with increased oxidative stress (OxS). The study aimed to clarify the role of MetS components in OA and to evaluate the levels of OxS in OA patients and in age-matched controls. Fifty-five patients with end-stage OA (age 63 ± 7 years) prior to hip or knee joint replacement surgery and 55 age-, gender- and body mass index matched controls (61 ± 8 years) were enrolled in the study. Serum levels of glucose, insulin, c-peptide, cholesterols and OxS markers were recorded. Homeostasis model assessment for insulin resistance was used as the proxy measure of insulin resistance. Radiographic severity was assessed using the Kellgren-Lawrence score. The OA patients had higher total peroxide concentration and oxidative stress index [488 (250-612) µmol/L vs. 326 (168-442) µmol/L, p = .011 and 34 (17-51) vs. 20 (11-28), p = .002, respectively] and decreased total antioxidant capacity (1.49 ± 0.27 vs. 1.66 ± 0.27 mmol trolox equivalent/L, p= .008) compared with the controls. In addition, OA group had significantly higher level of C-peptide compared with the controls [1.8 (0.94-2.47) vs. 1.3 (0.46-1.42) ng/mL, p < .001, respectively]. Furthermore, OA radiographic severity was independently associated with LDL-cholesterol (p = .007) and oxidized LDL (p = .022). This study demonstrates that end-stage OA patients have increased levels of OxS and decreased antioxidant capacity. OA is associated with impaired lipid metabolism and dysglycemia. Our results underline the importance OxS and metabolic disturbances in the pathogenesis of OA.

The acute effects of passive heat exposure on arterial stiffness, oxidative stress, and inflammation.

BACKGROUND AND OBJECTIVE: The aim of the study was to determine the acute effect of passive heat exposure (PHE) on arterial stiffness, oxidative stress (OxS) and inflammatory parameters. MATERIALS AND METHODS: Subjects were studied in thermoneutral conditions before and after PHE in a climatic chamber. Pulse wave analysis was used for assessment of central hemodynamic and arterial stiffness parameters. Venous blood samples were obtained to measure OxS and inflammatory parameters. RESULTS: Rectal temperature increased after PHE exposure compared to baseline: 37.01°C±0.19°C and 36.4°C±0.31°C, respectively (P<0.001). There was a 17% (P<0.05) decrease in large artery elasticity index (from 24.68±5.53 to 20.42±2.65mL/mmHg*10), which was predicted upon normothermic value (r=-0.878, P<0.01). However, no significant changes were found in others arterial stiffness parameters. A 30% (P<0.05) increase occurred in blood IL-6 concentration (from 0.43±0.15 to 0.56±0.23pg/mL), but OxS parameters remained significantly unchanged. CONCLUSIONS: This study describes for the first time acute PHE effects on arterial stiffness, inflammation and OxS. PHE significantly decreases large artery elasticity index and increases inflammatory IL-6 level. However, further larger investigations are needed for clarifying acute PHE effects on arterial function and biomarkers.

Increased arterial stiffness in patients with end-stage osteoarthritis: a case-control study.

BACKGROUND: Both osteoarthritis (OA) and cardiovascular diseases (CVD) are prevalent conditions which often co-exist. Vascular involvement in the pathogenesis of these diseases, as well as increased cardiovascular risk in OA patients give occasion to investigate arterial stiffness in OA. The aim of this study was to establish associations between OA and arterial stiffness. METHODS: The characteristics of arterial stiffness were measured with Sphygmocor and HDI devices in 48 patients (age 63 ± 7 years (mean ± SD)) with end-stage OA awaiting knee and hip replacement and in 49 age and gender matched controls (61 ± 7 years). Independent Student's t-test or the Mann-Whitney U test was used to compare means between the groups. Correlation between variables was determined using Pearson's or Spearman's correlation analysis and stepwise multiple regression analysis. RESULTS: Carotid-femoral pulse wave velocity (car-fem PWV) was increased in the patients with OA compared to the controls (9.6 ± 2.4 and 8.4 ± 1.9 m/s, p = 0.015 respectively). High-sensitivity C-reactive protein and white blood cells count were significantly higher in the OA patients compared with the controls (1.80 ± 1.10 and 1.48 ± 1.32 mg/l, p = 0.042; 6.5 ± 1.5 and 5.6 ± 1.9 10(9)/l, p = 0.001 respectively). In multiple regression analysis age (p < 0.001), mean arterial blood pressure (p = <0.001) and OA status (p = 0.029) were found to be independent predictors of car-fem PWV. CONCLUSIONS: This study showed that patients with OA had increased aortic stiffness compared to non-OA controls. The potential link between arterial stiffening and OA suggests that vascular alterations are involved in OA pathogenesis and could be responsible for increased cardiovascular risk in end-stage OA patients.

Severity of Osteoarthritis Is Associated with Increased Arterial Stiffness.

Objective. Osteoarthritis (OA) is associated with increased cardiovascular comorbidity and mortality. Evidence is lacking about whether arterial stiffness is involved in OA. The objective of our study was to find out associations between OA, arterial stiffness, and adipokines. Design. Seventy end-stage knee and hip OA patients (age 62 ± 7 years) and 70 asymptomatic controls (age 60 ± 7 years) were investigated using the applanation tonometry to determine their parameters of arterial stiffness. Serum adiponectin, leptin, and matrix metalloproteinase 3 (MMP-3) levels were determined using the ELISA method. Correlation between variables was determined using Spearman's rho. Multiple regression analysis with a stepwise selection procedure was employed. Results. Radiographic OA grade was positively associated with increased carotid-femoral pulse wave velocity (cf-PWV) (r = 0.272, p = 0.023). We found that OA grade was also associated with leptin and MMP-3 levels (rho = -0.246, p = 0.040 and rho = 0.235, p = 0.050, resp.). In addition, serum adiponectin level was positively associated with augmentation index and inversely with large artery elasticity index (rho = 0.293, p = 0.006 and rho = -0.249, p = 0.003, resp.). Conclusions. Our results suggest that OA severity is independently associated with increased arterial stiffness and is correlated with expression of adipokines. Thus, increased arterial stiffness and adipokines might play an important role in elevated cardiovascular risk in end-stage OA.

Early Biomarkers of Renal Damage in Relation to Arterial Stiffness and Inflammation in Male Coronary Artery Disease Patients.

BACKGROUND/AIMS: Plasma neutrophil gelatinase-associated lipocalin (NGAL), urinary liver-type fatty acid-binding protein (L-FABP) and urinary kidney injury molecule-1 (KIM-1) have emerged as promising biomarkers for both acute and chronic kidney injury that also provide prognostic value for cardiovascular morbidity and mortality. Our aim was to evaluate their relationships with arterial stiffness and inflammation in coronary artery disease (CAD) patients and in clinically healthy controls. METHODS: We studied 52 patients with CAD (age 63.2 ± 9.2 years) and 41 healthy controls (age 60.1 ± 7.2 years). Urinary L-FABP and KIM-1 as well as serum NGAL, adiponectin and resistin levels were measured using the enzyme-linked immunosorbent assay method. The technique of applanation tonometry was used for non-invasive pulse wave analysis and pulse wave velocity assessments. RESULTS: Urinary L-FABP and KIM-1 were independent determinants of cf-PWV for the CAD patients (R2=0.584, P<0.001) but not for the controls. Adiponectin correlated with log-KIM-1 (r=0.31, P=0.028) only for the patients, while NGAL correlated with WBC count (rho=0.29, P=0.038; r=0.35, P=0.029) and resistin (rho=0.60, P<0.001; r=0.57, P<0.001) for both the CAD and control groups, respectively. CONCLUSION: Our findings suggest that urinary L-FABP and KIM-1 may be independently associated with aortic stiffness in individuals with CAD.