Effects of RIPC on the Metabolome in Patients Undergoing Vascular Surgery: A Randomized Controlled Trial.

BACKGROUND: remote ischemic preconditioning (RIPC) is a phenomenon in which short episodes of ischemia are applied to distant organs to prepare target organs for more prolonged ischemia and to induce protection against ischemia-reperfusion injury. This study aims to evaluate whether preoperatively performed RIPC affects the metabolome and to assess whether metabolomic changes correlate with heart and kidney injury markers after vascular surgery. METHODS: a randomized sham-controlled, double-blinded trial was conducted at Tartu University Hospital. Patients undergoing elective open vascular surgery were recruited and RIPC was applied before operation. Blood was collected preoperatively and 24 h postoperatively. The metabolome was analyzed using the AbsoluteIDQ p180 Kit. RESULTS: final analysis included 45 patients from the RIPC group and 47 from the sham group. RIPC did not significantly alter metabolites 24 h postoperatively. There was positive correlation of change in the kynurenine/tryptophan ratio with change in hs-troponin T (r = 0.570, p < 0.001), NT-proBNP (r = 0.552, p < 0.001), cystatin C (r = 0.534, p < 0.001) and beta-2-microglobulin (r = 0.504, p < 0.001) only in the RIPC group. CONCLUSIONS: preoperative RIPC did not significantly affect the metabolome 24 h after vascular surgery. The positive linear correlation of kynurenine/tryptophan ratio with heart and kidney injury markers suggests that the kynurenine-tryptophan pathway can play a role in RIPC-associated cardio- and nephroprotective effects.

Differences in characteristics, treatments and outcomes in patients with non-ST-elevation myocardial infarction: novel insights from four national European continuous real-world registries.

AIMS: To study baseline characteristics, in-hospital managements and mortality of non-ST-elevation myocardial infarction (NSTEMI) patients in different European countries. METHODS AND RESULTS: NSTEMI patients enrolled in the national myocardial infarction (MI) registries [EMIR; n = 5817 (Estonia), HUMIR; n = 30 787 (Hungary), NORMI; n = 33 054 (Norway), and SWEDEHEART; n = 49 533 (Sweden)] from 2014 to 2017 were included and presented as aggregated data. The median age at admission ranged from 70 to 75 years. Current smoking status was numerically higher in Norway (24%), Estonia (22%), and Hungary (19%), as compared to Sweden (17%). Patients in Hungary had a high rate of diabetes mellitus (37%) and hypertension (84%). The proportion of performed coronary angiographies (58% vs. 75%) and percutaneous coronary interventions (38% vs. 56%), differed most between Norway and Hungary. Prescription of dual antiplatelet therapy at hospital discharge ranged from 60% (Estonia) to 81% (Hungary). In-hospital death ranged from 3.5% (Sweden) to 9% (Estonia). The crude mortality rate at 1 month was 12% in Norway and 5% in Sweden (5%), whereas the 1-year mortality rates were similar (20-23%) in Hungary, Estonia, and Norway and 15% in Sweden. CONCLUSION: Cross-comparisons of four national European MI registries provide important data on differences in risk factors and treatment regiments that may explain some of the observed differences in death rates. A unified European continuous MI registry could be an option to better understand how implementation of guideline-recommended therapy can be used to reduce the burden of cardiovascular disease.

The Role of RIPC in Preventing Organ Damage, Inflammation, and Oxidative Stress during Lower Limb DSA: A Randomised Controlled Trial.

OBJECTIVE: Diagnostic digital subtraction angiography (DSA) and DSA with percutaneous transluminal angioplasty (DSA-PTA) are common procedures for diagnosing and treating symptomatic lower extremity arterial disease (LEAD). However, organ damage following DSA and DSA-PTA is often underrecognised and hence undiagnosed. To reduce the risk induced by invasive procedures in symptomatic LEAD patients, the method of remote ischemic preconditioning (RIPC) has been suggested. The aim of the current study was to assess the effect of RIPC intervention on the organ damage markers profile, oxidative stress, and inflammation biomarkers in LEAD patients undergoing DSA and DSA-PTA procedure. METHODS: The RIPC intervention was performed by inflating a standard blood pressure cuff on the patient's upper arm to 200 mmHg for 5 minutes four times with 5-minute perfusion between each cycle. The sham intervention was performed similarly, but the cuff was inflated to 20 mmHg. Changes in the cardiac and renal damage biomarkers' profile, oxidative stress, and inflammation biomarkers were recorded before and 24 hours after DSA or DSA-PTA. RESULTS: A total of 111 (RIPC 54, sham 57) patients with symptomatic LEAD scheduled for endovascular procedure were randomised, and 102 patients (RIPC 47, sham 55) completed the study protocol. RIPC significantly limited the increase of adiponectine levels after DSA and DSA-PTA, compared to sham intervention (p = 0.020), but CK-MB levels were markedly lower in the sham group (p = 0.047) after procedure. There was no significant difference between the RIPC and the sham group in mean changes in hs-troponin-T (p = 0.25), NT-proBNP (p = 0.24), creatinine (p = 0.76), eGFR (p = 0.61), urea (p = 0.95), beta-2-microglobuline (p = 0.34), or cystatine C (p = 0.24) levels. CONCLUSION: In this controlled clinical study, RIPC failed to improve the profile of renal and cardiac biomarkers in patients with LEAD periprocedurally. RIPC significantly limits the rise in adiponectin levels and may influence the decrease of CK-MB levels 24 hours after endovascular procedure.

Remote ischaemic preconditioning influences the levels of acylcarnitines in vascular surgery: a randomised clinical trial.

BACKGROUND: Vascular surgery patients have reduced tissues` blood supply, which may lead to mitochondrial dysfunction and accumulation of acylcarnitines (ACs). It has been suggested that remote ischaemic preconditioning (RIPC) has its organ protective effect via promoting mitochondrial function. The aim of this study was to evaluate the effect of RIPC on the profile of ACs in the vascular surgery patients. METHODS: This is a randomised, sham-controlled, double-blinded, single-centre study. Patients undergoing open surgical repair of abdominal aortic aneurysm, surgical lower limb revascularisation surgery or carotid endarterectomy were recruited non-consecutively. The RIPC protocol consisting of 4 cycles of 5 min of ischaemia, followed by 5 min of reperfusion, was applied. A blood pressure cuff was used for RIPC or a sham procedure. Blood was collected preoperatively and approximately 24 h postoperatively. The profile of ACs was analysed using the AbsoluteIDQp180 kit (Biocrates Life Sciences AG, Innsbruck, Austria). RESULTS: Ninety-eight patients were recruited and randomised into the study groups and 45 patients from the RIPC group and 47 patients from the sham group were included in final analysis. There was a statistically significant difference between the groups regarding the changes in C3-OH (p = 0.023)-there was a decrease (- 0.007 µmol/L, ± 0.020 µmol/L, p = 0.0233) in the RIPC group and increase (0.002 µmol/L, ± 0.015 µmol/L, p = 0.481) in the sham group. Additionally, a decrease from baseline to 24 h after surgery (p < 0.05) was detected both in the sham and the RIPC group in the levels of following ACs: C2, C8, C10, C10:1, C12, C12:1, C14:1, C14:2, C16, C16:1, C18, C18:1, C18:2. In the sham group, there was an increase (p < 0.05) in the levels of C0 (carnitine) and a decrease in the level of C18:1-OH. In the RIPC group, a decrease (p < 0.05) was noted in the levels of C3-OH, C3-DC (C4-OH), C6:1, C9, C10:2. CONCLUSIONS: It can be concluded that RIPC may have an effect on the levels of ACs and might therefore have protective effects on mitochondria in the vascular surgery patients. Further larger studies conducted on homogenous populations are needed to make more definite conclusions about the effect of RIPC on the metabolism of ACs. TRIAL REGISTRATION: ClinicalTrials.gov database, NCT02689414. Registered 24 February 2016-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02689414.

Remote Ischaemic Preconditioning Reduces Kidney Injury Biomarkers in Patients Undergoing Open Surgical Lower Limb Revascularisation: A Randomised Trial.

BACKGROUND AND AIMS: Perioperative kidney injury affects 12.7% of patients undergoing lower limb revascularisation surgery. Remote ischaemic preconditioning (RIPC) is a potentially protective procedure against organ damage and consists of short nonlethal episodes of ischaemia. The main objective of this substudy was to evaluate the effect of RIPC on kidney function, inflammation, and oxidative stress in patients undergoing open surgical lower limb revascularisation. Materials and Methods. This is a subgroup analysis of a randomised, sham-controlled, double-blinded, single-centre study. A RIPC or a sham procedure was performed noninvasively along with preparation for anaesthesia in patients undergoing open surgical lower limb revascularisation. The RIPC protocol consisted of 4 cycles of 5 minutes of ischaemia, with 5 minutes of reperfusion between every episode. Blood was collected for analysis preoperatively, 2, 8, and 24 hours after surgery, and urine was collected preoperatively and 24 hours after surgery. RESULTS: Data of 56 patients were included in the analysis. Serum creatinine, cystatin C, and beta-2 microglobulin increased, and eGFR decreased across all time points significantly more in the sham group than in the RIPC group (p = 0.021, p = 0.021, p = 0.021, p = 0.021, p = 0.021. CONCLUSIONS: Our finding of reduced release of kidney injury biomarkers may indicate the renoprotective effect of RIPC in patients undergoing open surgical lower limb revascularisation. The trial is registered with ClinicalTrials.gov NCT02689414.

Remote Ischaemic Preconditioning Attenuates Cardiac Biomarkers During Vascular Surgery: A Randomised Clinical Trial.

OBJECTIVE: The main aim of this study was to evaluate the effect of remote ischaemic preconditioning (RIPC) on preventing the leakage of cardiac damage biomarkers in patients undergoing vascular surgery. METHODS: This is a randomised, sham-controlled, double-blinded, single-centre study. Patients undergoing open abdominal aortic aneurysm repair, surgical lower limb revascularisation surgery or carotid endarterectomy were recruited non-consecutively. The RIPC protocol consisting of 4 cycles of 5 minutes of ischaemia, followed by 5 minutes of reperfusion, was applied. A RIPC or a sham procedure was performed noninvasively along with preparation for anaesthesia. High sensitivity troponin T level was measured preoperatively and 2, 8 and 24 hours after surgery and pro b-type natriuretic peptide was measured preoperatively and 24 hours after surgery. RESULTS: There was significantly higher leakage of high sensitivity troponin T (peak change median 2 ng/L, IQR 0.9-6.2 ng/L vs 0.6 ng/L, IQR 0.7-2.1 ng/L, p = .0002) and pro b-type natriuretic peptide (change median 144 pg/mL, IQR 17-318 pg/mL vs 51 pg/mL, IQR 12-196 pg/mL, p = .02) in the sham group compared to the RIPC group. CONCLUSION: RIPC reduces the leakage of high sensitivity troponin T and pro b-type natriuretic peptide. Therefore, it may offer cardioprotection in patients undergoing non-cardiac vascular surgery. The clinical significance of RIPC has to be evaluated in larger studies excluding the factors known to influence its effect.

Effects of Remote Ischaemic Preconditioning on Arterial Stiffness in Patients Undergoing Lower Limb Angiographic Procedures: A Randomised Clinical Trial.

OBJECTIVES: Remote ischaemic preconditioning (RIPC) is a phenomenon that promotes protection of tissues and organs against ischaemia reperfusion injury. RIPC has been shown to reduce myocardial and renal injury but its effect on arterial stiffness in patients undergoing lower limb digital subtraction angiography (DSA) is unknown. The aim of this study was to evaluate the effect of RIPC on arterial stiffness in patients with peripheral arterial disease (PAD) undergoing lower limb DSA. METHODS: In the RIPC intervention, the blood pressure cuff on the arm was inflated to 200 mmHg or to 20 mmHg above systolic pressure, and in the sham intervention to 20 mmHg. For both, the procedure was repeated for four five minute cycles at five minute intervals between the cycles. Changes in heart rate corrected augmentation index (AIx@75), augmentation index (AIx), carotid femoral pulse wave velocity (PWV), and haemodynamic parameters were measured before and 24 h after DSA. RESULTS: 111 (RIPC 54, sham 57) patients with symptomatic lower limb PAD scheduled for DSA were randomised. 102 patients (RIPC 47, sham 55) were included in final analysis. RIPC significantly improved AIx (-5.46% in RIPC and -1.45% in sham group; p = .05), but not AIx@75 (-4.88% in RIPC and -1.38% in sham group; p = .07) or PWV (-0.41 m/s in RIPC and -0.27 m/s in sham group; p = .74). In the RIPC group a significant reduction in AIx (p = .002) and AIx@75 (p = .003) was noted after stenting when compared with the sham intervention. AIx (p = .001), AIx@75 (p = .002), mean arterial (p = .01), peripheral (p = .02), and central systolic blood pressure (p = .006) were significantly reduced only in the RIPC group 24 h after DSA. CONCLUSION: This study evaluates for the first time the effects of RIPC on arterial stiffness parameters in patients with symptomatic PAD following DSA. RIPC may modulate arterial stiffness following a DSA procedure and is more pronounced in patients after stent placement.

The Effect of Remote Ischaemic Preconditioning on Arterial Stiffness in Patients Undergoing Vascular Surgery: A Randomised Clinical Trial.

OBJECTIVES: The main aim of this study was to evaluate the effect of remote ischaemic preconditioning (RIPC) on arterial stiffness in patients undergoing vascular surgery. METHODS: This was a randomised, sham controlled, double blind, single centre study. Patients undergoing open abdominal aortic aneurysm repair, surgical lower limb revascularisation surgery or carotid endarterectomy were recruited. A RIPC or a sham procedure was performed, using a blood pressure cuff, along with preparation for anaesthesia. The RIPC protocol consisting of four cycles of 5 min of ischaemia, followed by 5 min of reperfusion was applied. Arterial stiffness and haemodynamic parameters were measured pre-operatively and 20-28 h after surgery. Two primary outcomes were selected: augmentation index and pulse wave velocity. RESULTS: Ninety-eight patients were randomised. After dropouts 44 and 46 patients were included in the RIPC and sham groups, respectively. Both groups were comparable. There were no statistically significant differences in augmentation index (p = .8), augmentation index corrected for heart rate of 75 beats per minute (p = .8), pulse wave velocity (p = .7), large artery elasticity indices (p = .8), small artery elasticity indices (p = .6), or mean arterial pressure (p = .7) changes between the RIPC and sham groups. There occurred statistically significant (p ≤ .01) improvement in augmentation index (-5.8% vs. -5.5%), augmentation index corrected for a heart rate of 75 beats per minute (-2.5% vs. -2%), small artery elasticity indices (0.7 mL/mmHg × 100 vs. 0.9 mL/mmHg × 100), and mean arterial pressure post-operatively in both the RIPC and the sham groups (change median values in RIPC and sham groups, respectively). CONCLUSIONS: RIPC had no significant effect on arterial stiffness, but there was significant improvement in arterial stiffness after surgery in both groups. Arterial stiffness and haemodynamics may be influenced by surgery or anaesthesia or oxidative stress or all factors combined. Further studies are needed to clarify these findings. CLINICALTRIALS.GOV: NCT02689414.

Recall by genotype and cascade screening for familial hypercholesterolemia in a population-based biobank from Estonia.

PURPOSE: Large-scale, population-based biobanks integrating health records and genomic profiles may provide a platform to identify individuals with disease-predisposing genetic variants. Here, we recall probands carrying familial hypercholesterolemia (FH)-associated variants, perform cascade screening of family members, and describe health outcomes affected by such a strategy. METHODS: The Estonian Biobank of Estonian Genome Center, University of Tartu, comprises 52,274 individuals. Among 4776 participants with exome or genome sequences, we identified 27 individuals who carried FH-associated variants in the LDLR, APOB, or PCSK9 genes. Cascade screening of 64 family members identified an additional 20 carriers of FH-associated variants. RESULTS: Via genetic counseling and clinical management of carriers, we were able to reclassify 51% of the study participants from having previously established nonspecific hypercholesterolemia to having FH and identify 32% who were completely unaware of harboring a high-risk disease-associated genetic variant. Imaging-based risk stratification targeted 86% of the variant carriers for statin treatment recommendations. CONCLUSION: Genotype-guided recall of probands and subsequent cascade screening for familial hypercholesterolemia is feasible within a population-based biobank and may facilitate more appropriate clinical management.

Benefit-Risk Assessment of Crataegus Extract WS 1442: An Evidence-Based Review.

Preparations from Crataegus (hawthorn) have a long history in the treatment of heart failure. WS 1442 is a dry extract from hawthorn leaves with flowers (4-6.6:1), extraction solvent of ethanol 45% (w/w), adjusted to 17.3-20.1% of oligomeric procyanidins. Nonclinical studies show that WS 1442 has positive inotropic and antiarrhythmic properties and protects the myocardium from ischemic damage, reperfusion injury, and hypertension-related hypertrophy, improves endothelial functions such as NO synthesis, and delays endothelial senescence. Randomized, controlled trials in patients with heart failure have demonstrated that the herbal medicinal product increases functional capacity, alleviates disabling symptoms, and improves health-related quality of life, all of which have become important targets of heart failure therapy according to current disease management guidelines. Clinical trials (including a 2-year mortality study with polypharmacy and > 1300 patients exposed) and post-marketing surveillance studies have shown that WS 1442 has a very favorable safety profile both as monotherapy and as add-on therapy, where no drug interactions have been observed. No specific adverse reactions to WS 1442 are known to date. WS 1442 may thus help to close the therapeutic gap between systolic and diastolic heart failure for which evidence of efficacy for other cardioactive drugs is sparse. Scientific evidence shows that WS 1442 is safe and has a beneficial effect in patients with heart failure corresponding to New York Heart Association classes II or III. The benefit-risk assessment for WS 1442 is therefore positive.

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.

Metabolomic signature of arterial stiffness in male patients with peripheral arterial disease.

Arterial stiffness is an independent determinant of cardiovascular risk and a marker of subclinical organ damage. Metabolomics may facilitate identification of novel low-molecular cardiovascular risk factors. The aim of the present study was to compare metabolic signatures and functional-biochemical characteristics of patients with peripheral arterial disease (PAD) and clinically healthy subjects. We studied 42 men with symptomatic PAD (aged 66±7 years) and 46 healthy men (aged 66±8 years). Aortic pulse wave velocity (aPWV) was assessed by applanation tonometry using the Sphygmocor device. Metabolic profiling was performed with high-performance liquid chromatography and mass spectrometry. Serum oxidized low-density lipoprotein (oxLDL) level was measured by enzyme-linked immunosorbent assay. The aPWV as well as serum levels of lactate, free carnitine and 11 amino acids including tyrosine were higher among the patients with PAD. In contrast, serum levels of pyruvate, citrate, α-ketoglutarate, aconitate and cysteine were higher in the control group. In multiple regression models, aPWV was independently determined by log-tyrosine and log-oxLDL in the patients (R(2)=0.61; P<0.001) and by age, log-pyruvate and log-oxLDL in the controls (R(2)=0.52; P<0.001). Our study describes for the first time significant differences in metabolomic signature of patients with advanced atherosclerosis compared with clinically healthy controls. The aPWV is independently associated with serum levels of tyrosine and oxLDL in the patients with PAD and is related to pyruvate and oxLDL levels in the control group. The measurement of low-molecular metabolites, which are related to changes in vascular phenotypes, may lead to identification of novel vascular risk markers.

ß2-microglobulin, a novel biomarker of peripheral arterial disease, independently predicts aortic stiffness in these patients.

Arterial stiffness is a prominent feature of vascular ageing and strongly predicts cardiovascular and total mortality. The ß2-microglobulin, (ß2M) a newly identified biomarker of peripheral arterial disease (PAD), is related to renal insufficiency, inflammatory and neoplastic diseases, but may also play a role in vascular dysfunction. However, the relationship between arterial stiffness and ß2M has not been previously studied in patients with atherosclerosis. In the present study we examined a possible association between ß2M and arterial stiffness in patients with PAD and in healthy subjects. Plasma ß2M levels and parameters of arterial stiffness such as aortic pulse wave velocity (aPWV) and augmentation index (AIx) were measured in 66 patients with PAD and in 66 apparently healthy subjects. Plasma levels of ß2M, aPWV and AIx were significantly increased in patients with PAD compared with controls (1858.1 ± 472.8 vs 1554.5 ± 277.9 µg/L, p < 0.001; 9.9 ± 2.2 m/s vs 7.6 ± 1.6 m/s, p < 0.001; 28 ± 8 vs 14 ± 11%, p < 0.001; respectively). There existed significant correlation between aPWV and ß2M for the patient group (R = 0.47; p < 0.001), but not for the controls (R = 0.14; p = 0.26). In multivariate analysis, ß2M remained independently associated with aPWV, fetuin-A, age and glomerular filtration rate in patients (R(2) = 0.5, p < 0.001). We found no relationship between ß2M and AIx in either group. We demonstrated that among patients with PAD elevated plasma ß2M levels were associated with higher aortic stiffness irrespective of cardiovascular disease risk factors. These data suggest that ß2M may influence the pathogenesis of aortic stiffness in atherosclerosis.

Association of osteoprotegerin with aortic stiffness in patients with symptomatic peripheral artery disease and in healthy subjects.

BACKGROUND: Arterial stiffening is an independent predictor for cardiovascular mortality. Preliminary studies have shown that arterial calcification may have an impact on increased vascular stiffness. However, there are limited data about the role of calcification inhibitor osteoprotegerin (OPG) as an independent predictor for arterial stiffness in patients with peripheral arterial disease (PAD) and in healthy subjects. The aim of this study was to evaluate the association between OPG and arterial stiffness parameters in patients with PAD and in healthy subjects. METHODS: We studied 69 men with PAD (age 63 + or - 7 years) and 68 healthy subjects (age 54 + or - 8 years). Serum OPG and oxidized low-density lipoprotein (oxLDL) were measured using the enzyme-linked immunosorbent assay method. Radial and aortic pulse wave velocity (aPWV) and augmentation index (AIx) were determined by applanation tonometry. RESULTS: The OPG (5.4 + or - 1.7 vs. 4.4 + or - 1.1 pmol/l; P < 0.001) and aPWV (10.1 + or - 2.5 vs. 7.6 + or - 1.6 m/s; P < 0.001) were different for the patients and for the controls. There was a linear relationship between OPG and aPWV in patients with PAD (R = 0.37; P = 0.003) and in healthy individuals (R = 0.40; P = 0.001). In multiple regression models after adjustment for potential confounders, OPG was independently associated with aPWV in the patients (R(2) = 0.47; P < 0.0001) and in the controls (R(2) = 0.44; P < 0.0001). The AIx or radial PWV was not correlated with OPG for either group. CONCLUSION: The independent association between OPG and aPWV in patients with PAD and in controls suggests that the calcification inhibitor OPG may influence aortic stiffening in atherosclerosis and in clinically healthy subjects.