Glucose and lipopolysaccharide differentially regulate fibroblast growth factor 21 in healthy male human volunteers - A prospective cross-over trial.

Fibroblast growth factor 21 (FGF21) affects the regulation of metabolism. Additionally, anti-inflammatory properties are attributed to FGF21, and studies in animals and humans show conflicting results. This study aimed to investigate how FGF21 is affected by glucose and lipopolysaccharide (LPS) in humans. Therefore, FGF21 was measured eight times at different time points within 48 h in this prospective cross-over trial after glucose and LPS on two different study days. The study included ten healthy, non-smoking male subjects aged 18-40. Repeated measures analysis of variance and paired t-test as post hoc analysis were applied. The administration of glucose and LPS resulted in a significant difference in regulating FGF21 (p < 0.001). After glucose administration, FGF21 declined sharply at 360 min, with a subsequent steep increase that exceeded baseline levels. LPS induced a drop in FGF21 after 180 min, while the baseline concentrations were not reached. After 180 min and 24 h, a statistically significant difference was demonstrated after adjusting the Bonferroni-Holm method. So, our results support the hypothesis that glucose and LPS differentially affect the human expression of FGF21 over 48 h.

SUBCLINICAL KIDNEY INJURY IS CAUSED BY A MODERATE SINGLE INFLAMMATORY EVENT.

ABSTRACT: Background: Current means of diagnosis of acute kidney injury (AKI) based on serum creatinine have poor sensitivity and may miss possible therapeutic windows in subclinical kidney injury, especially in septic AKI. Kidney injury molecule-1 (KIM-1) may be a valuable biomarker to improve diagnostic algorithms for AKI. The understanding of septic AKI is still insufficient, and knowledge about KIM-1 kinetics in inflammation is scarce. The aim of this study was to investigate the possible effect of lipopolysaccharide (LPS) on KIM-1 as a marker of structural kidney injury in healthy volunteers. Methods: A single-blinded, placebo-controlled cross-over study using the human endotoxin model (LPS administration) was performed in 10 healthy men. Kidney injury molecule-1 and serum creatinine were measured repetitively for 48 hours. Results: We observed a significant elevation of serum KIM-1 levels after the administration of LPS ( P < 0.001). Furthermore, LPS caused a significant elevation of serum creatinine at an early time point ( P = 0.013) as compared with placebo. Conclusion: Even a relatively small inflammatory stimulus is sufficient to cause subclinical structural kidney injury with elevated KIM-1 and serum creatinine in healthy volunteers. This outlines the insufficiency of the current diagnostic approach regarding AKI and the urgency to develop novel diagnostic algorithms including markers of kidney injury. Clinical Trial Registration:www.clinicaltrials.gov . Unique identifier: NCT03392701 (August 1, 2018).

High Anti-CoV2S Antibody Levels at Hospitalization Are Associated with Improved Survival in Patients with COVID-19 Vaccine Breakthrough Infection.

BACKGROUND: Although vaccination against COVID-19 is highly effective, breakthrough infections occur, often leading to severe courses and death. The extent of protection provided by individual antibody levels in breakthrough infections is still unknown and cut-off levels have yet to be determined. METHODS: In 80 consecutive fully vaccinated patients hospitalized between August and December 2021 with COVID-19 breakthrough infection (Delta variant), anti-CoV2S antibody levels were analyzed for the endpoint of death. RESULTS: Ten out of the 12 patients who died (83.3%) had antibody levels < 600 U/mL; 5 (41.7%) of these had antibody levels < 200 U/mL. Only 2 patients with a level of >600 U/mL died from vaccine breakthrough infection. Correction for the number of comorbidities and age revealed that anti-CoV2S antibody levels at the time of hospitalization were a significant predictor for reduced risk of death (OR = 0.402 for every 1000 U/mL, p = 0.018). CONCLUSIONS: In this retrospective data analysis, we show that almost all patients who died from COVID-19 vaccine breakthrough infection had antibody levels < 600 U/mL, most of them below 200 U/mL. In logistic regression corrected for the number of comorbidities and age, anti-CoV2S antibody levels at the time of hospitalization proved to be a significantly protective predictor against death.

Effect of repeated bolus and continuous glucose infusion on a panel of circulating biomarkers in healthy volunteers.

HYPOTHESIS: Glycaemic variability (GV) refers to fluctuations in the blood glucose level and may contribute to complications in patients suffering from Diabetes. Several studies show negative effects of GV on the cardiovascular system, however there is still a lack of conclusive evidence. Using an explorative cardiovascular panel, it is possible to simultaneously measure the effects on proteins relevant for cardiovascular processes. The aim of this study was to investigate the effects of rapid glucose excursions on cardiovascular and metabolic parameters in healthy individuals. METHODS: An explorative single-blinded cross-over study was performed in ten healthy men. Subjects received 3 times 20 grams of glucose i.v. over 5 minutes or 60 grams of glucose continuously over 3 hours. Blood was taken for repeated measurements of the cardiovascular panel over the following 6 hours and again after 24 and 48 hours. RESULTS: We observed a significant elevation of 7 cardiovascular biomarkers (BMP6, SLAMF7, LOX-1, ADAMTS13, IL-1RA, IL-4RA, PTX3) at t = 360min after rapid glucose infusion compared to a continuous glucose infusion. CONCLUSIONS: Intraday GV seems to have acute effects on cardiovascular proteins in healthy test persons. Rapid glucose administration compared to continuous administration showed significant changes in BMP6, SLAMF7, ADAMTS13, IL1RA, PTX3, IL-4RA and LOX-1. CLINICAL TRIAL REGISTRATION: NCT04488848.

Storm of Cardiovascular Markers After LPS Administration in Human Volunteers.

Acute infections are associated with an elevated cardiovascular risk. However, little is known about the interactions of acute inflammatory responses and the cardiovascular system. We therefore aimed to evaluate effects of acute inflammatory stimuli mediated by LPS administration on a set of 89 cardiovascular biomarkers. A single-blinded, placebo-controlled cross-over study using the human endotoxin model was performed. Ten healthy men were administered lipopolysaccharide (LPS) or placebo on two different study days after an overnight fast. Eighty-nine different cardiovascular biomarkers were measured repetitively over 48 h. Out of 89 cardiovascular biomarkers, 54 markers were significantly influenced by LPS infusion. The observed biomarker response to inflammation was more pronounced and complex than anticipated. In conclusion, our data show that the cardiovascular system is under enormous distress in response to experimental low-dose inflammation in humans, as demonstrated by a significant effect on 54 of the 89 biomarkers tested.

Elevated levels of serum PCSK9 in male patients with symptomatic peripheral artery disease: The CAVASIC study.

BACKGROUND AND AIMS: Peripheral artery disease (PAD) affects more than 200 million people worldwide. Increased low-density lipoprotein cholesterol (LDL-C)levels are a risk factor for PAD and the concentrations are influenced by proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 regulates the recycling of the LDL receptors to the cell membrane surface. Only a limited number of mostly small studies investigated the association between serum PCSK9 concentrations and PAD of different definition, which revealed contrasting results. METHODS: Serum PCSK9, lipoprotein(a) [Lp(a)] and other lipoprotein concentrations were measured in male participants of the CAVASIC study, a case-control study of 248 patients with intermittent claudication and 251 age and diabetes-matched controls. RESULTS: PAD patients had significantly higher PCSK9 concentrations when compared to controls (250 ± 77 vs. 222 ± 68 ng/mL, p < 0.001). Logistic regression analysis with adjustment for age revealed that an increase in PCSK9 concentrations of 100 ng/mL was associated with a 1.78-fold higher risk for PAD (95%CI 1.38-2.33, p = 1.43 × 10-5). The association attenuated, but was still significant when adjusting additionally for age, Lp(a)-corrected LDL cholesterol, HDL cholesterol, high-sensitivity-CRP, statin treatment, hypertension, diabetes mellitus and smoking (OR = 1.49, 95%CI 1.03-2.18, p = 0.035). The strongest association was observed when both PCSK9 concentrations were above the median and Lp(a) concentrations were above 30 mg/dL (OR = 3.35, 95%CI 1.49-7.71, p = 0.0038). CONCLUSIONS: Our findings suggest an association of higher PCSK9 concentrations with PAD, which was independent of other lipid parameters and classical cardiovascular risk factors.

The fate of patients with intermittent claudication in the 21st century revisited - results from the CAVASIC Study.

Patients with intermittent claudication carry a high risk for cardiovascular complications. The TransAtlantic Inter-Society Consensus (TASC) Group estimated a five-year overall mortality of 30% for these patients, the majority dying from cardiovascular causes. We investigated whether this evaluation is still applicable in nowadays patients. We therefore prospectively followed 255 male patients with intermittent claudication from the CAVASIC Study during 7 years for overall mortality, vascular morbidity and mortality and local PAD outcomes. Overall mortality reached 16.1% (n = 41). Most patients died from cancer (n = 20). Half of patients (n = 22; 8.6%) died within the first five years. Incident cardiovascular events were observed among 70 patients (27.5%), 54 (21.2%) during the first five years. Vascular mortality was low with 5.1% (n = 13) for the entire and 3.1% for the first five years of follow-up. Prevalent coronary artery disease did not increase the risk to die from all or vascular causes. PAD symptoms remained stable or improved in the majority of patients (67%). In summary, compared to TASC, the proportion of cardiovascular events did not markedly decrease over the last two decades. Vascular mortality, however, was low among our population. This indicates that nowadays patients more often survive cardiovascular events and a major number dies from cancer.

Serum concentrations of L-arginine and L-homoarginine in male patients with intermittent claudication: a cross-sectional and prospective investigation in the CAVASIC Study.

BACKGROUND: High serum concentrations of l-arginine and l-homoarginine increase nitric oxide (NO) availability and thereby improve endothelial function. Information about the association of these markers with peripheral arterial disease (PAD) and related outcomes is sparse. METHODS: l-arginine, its metabolites and l-homoarginine were analyzed in the CAVASIC Study including 232 male patients diagnosed with intermittent claudication and 246 age- and diabetes-matched controls. After the baseline investigation PAD patients were prospectively followed (median 7 years). The association of these markers with symptomatic PAD at baseline, incident cardiovascular events and all-cause mortality was assessed. RESULTS: At baseline each increase of ln-l-homoarginine and l-arginine by one standard deviation was associated with symptomatic PAD: OR=0.75, 95%CI 0.59-0.96, P=0.02 and OR=1.36, 95%CI 1.07-1.73, P=0.01, respectively (both models adjusted for ln-CRP, GFR, HDL cholesterol, and current smoking). Only l-arginine remained significant after additional adjustment for ln-NT-proBNP and hs-cTnT: OR=1.49, P=0.002. In the Cox regression analysis elevated ln-l-homoarginine significantly reduced the risk to die (n=38) even independent from ln-NT-proBNP and hs-cTnT: HR=0.59, 95%CI 0.41-0.84, P=0.004. l-arginine was significantly predicting incident cardiovascular events (n=65): HR=1.68, 95%CI 1.35-2.10, P < 0.001. CONCLUSIONS: This study in male patients with intermittent claudication and age- and diabetes-matched controls showed an association of l-homoarginine and l-arginine with PAD. During follow-up, l-arginine was associated with incident cardiovascular events probably due to its primary role in NO metabolism and impact on endothelial integrity. l-homoarginine was related to all-cause mortality implying a broader role in metabolic processes besides endothelial function.

Left ventricular ejection fraction is associated with prevalent and incident cardiovascular disease in patients with intermittent claudication - results from the CAVASIC Study.

BACKGROUND: Individuals with an impaired ventricular function have a poor prognosis due to underlying heart failure and higher mortality rates. Patients with peripheral arterial disease (PAD) represent a high-risk population for left ventricular systolic dysfunction (LVSD). METHODS: The left ventricular ejection fraction (LVEF) was measured in a subset of the CAVASIC Study, consisting of 180 male patients with intermittent claudication and 226 controls. The patients were prospectively followed for a median time of 7 years. The association of LVEF with PAD and prevalent cardiovascular disease (CVD) as well as with incident CVD and survival rates during follow-up was analyzed. RESULTS: The prevalence of LVSD (LVEF<55%) was 30% among PAD patients and 7% among controls (p < 0.001). The adjusted logistic regression analysis showed that a decrease of LVEF by one standard deviation (SD) and an LVEF below 55% was associated with PAD (OR = 1.72, 95%CI 1.30-2.28 and OR = 5.71, 95%CI 2.52-12.95, both p < 0.001). Similar results were found for prevalent CVD (n = 50) in PAD patients: LVEF per SD: OR 1.60; LVEF <55%: OR 2.81, both p ≤ 0.008. The adjustment for ln-NT-proBNP or hs-cTnT resulted in a borderline significant association. In the adjusted Cox regression analysis a decrease of LVEF by one SD showed a trend for association with all-cause mortality (n = 32) (HR 1.27, p = 0.08). An impaired LVEF significantly increased the risk for incident major CVD events (n = 52): HR 1.56, p < 0.01. CONCLUSIONS: Patients with PAD have significantly lower LVEF values compared to controls. The LVEF can serve as a risk predictor for subsequent cardiovascular disease among this high-risk population.

High-sensitivity cardiac troponin T in patients with intermittent claudication and its relation with cardiovascular events and all-cause mortality--the CAVASIC Study.

BACKGROUND: Serum concentrations of high-sensitivity cardiac troponin T (hs-cTnT) are elevated in various diseases. The role of this marker in peripheral arterial disease (PAD) has not been fully investigated. METHODS: Hs-cTnT was measured in the CAVASIC Study, a male cohort of 235 patients diagnosed with intermittent claudication and 249 age- and diabetes-matched controls. Patients with symptomatic PAD were prospectively followed for a median time of 7 years. The association of hs-cTnT with PAD, cardiovascular disease (CVD) at baseline as well as incident CVD and all-cause mortality during follow-up was analyzed. RESULTS: Detectable hs-cTnT was associated with an 84% higher probability for symptomatic PAD at baseline: OR = 1.84, 95%CI 1.05-3.21, p = 0.03. Inclusion of ln-NT-proBNP or prevalent CVD abolished this association (both OR = 1.22, p = 0.52). However, detectable hs-cTnT was associated with prevalent CVD (n = 69) in PAD patients independent from ln-NT-proBNP: OR = 3.42, p = 0.001. In the adjusted Cox regression analysis detectable (HR = 2.15, p = 0.05) and especially hs-cTnT ≥ 14 ng/L (HR = 5.06, p < 0.001) were predictive for all-cause mortality (n = 39) independent from ln-NT-proBNP. Furthermore, hs-cTnT ≥ 14 ng/L was significantly associated with incident CVD (n = 66): HR = 3.15, 95%CI 1.26-7.89, p = 0.01. CONCLUSIONS: This study in male patients with intermittent claudication and age- and diabetes-matched controls revealed hs-cTnT to be associated with PAD and prevalent CVD. The latter association was even significant after considering NT-proBNP. Prospectively, in PAD patients hs-cTnT was predictive for incident cardiovascular diseases and all-cause mortality. Thus, hs-cTnT could be a surrogate marker for cardiomyocyte damage also in symptomatic PAD patients.