Vascular endothelial growth factors: biology and current status of clinical applications in cardiovascular medicine.

Members of the vascular endothelial growth factor (VEGF) family are among the most powerful modulators of vascular biology. They regulate vasculogenesis, angiogenesis, and vascular maintenance during embryogenesis and in adults. Because of their profound effects on blood vessels, VEGFs have received much attention regarding their potential therapeutic use in cardiovascular medicine, especially for therapeutic vascular growth in myocardial and peripheral ischemia. However, completed randomized controlled VEGF trials have not provided convincing evidence of clinical efficacy. On the other hand, recent preclinical proangiogenic VEGF studies have given insight, and anti-VEGF studies have shown that the disturbance of vascular homeostasis by blocking VEGF-A may lead to endothelial dysfunction and adverse vascular effects. Excess VEGF-A may contribute to neovascularization of atherosclerotic lesions but, currently, there is no evidence that transient overexpression by gene transfer could lead to plaque destabilization. Here, we review the biology and effects of VEGFs as well as the current status of clinical applications and future perspectives of the therapeutic use of VEGFs in cardiovascular medicine.     

Plasma metabolites associated with type 2 diabetes in a Swedish population: a case–control study nested in a prospective cohort

Aims/hypothesis

The aims of the present work were to identify plasma metabolites that predict future type 2 diabetes, to investigate the changes in identified metabolites among individuals who later did or did not develop type 2 diabetes over time, and to assess the extent to which inclusion of predictive metabolites could improve risk prediction.

Methods

We established a nested case–control study within the Swedish prospective population-based Västerbotten Intervention Programme cohort. Using untargeted liquid chromatography-MS metabolomics, we analysed plasma samples from 503 case–control pairs at baseline (a median time of 7 years prior to diagnosis) and samples from a subset of 187 case–control pairs at 10 years of follow-up. Discriminative metabolites between cases and controls at baseline were optimally selected using a multivariate data analysis pipeline adapted for large-scale metabolomics. Conditional logistic regression was used to assess associations between discriminative metabolites and future type 2 diabetes, adjusting for several known risk factors. Reproducibility of identified metabolites was estimated by intra-class correlation over the 10 year period among the subset of healthy participants; their systematic changes over time in relation to diagnosis among those who developed type 2 diabetes were investigated using mixed models. Risk prediction performance of models made from different predictors was evaluated using area under the receiver operating characteristic curve, discrimination improvement index and net reclassification index.

Results

We identified 46 predictive plasma metabolites of type 2 diabetes. Among novel findings, phosphatidylcholines (PCs) containing odd-chain fatty acids (C19:1 and C17:0) and 2-hydroxyethanesulfonate were associated with the likelihood of developing type 2 diabetes; we also confirmed previously identified predictive biomarkers. Identified metabolites strongly correlated with insulin resistance and/or beta cell dysfunction. Of 46 identified metabolites, 26 showed intermediate to high reproducibility among healthy individuals. Moreover, PCs with odd-chain fatty acids, branched-chain amino acids, 3-methyl-2-oxovaleric acid and glutamate changed over time along with disease progression among diabetes cases. Importantly, we found that a combination of five of the most robustly predictive metabolites significantly improved risk prediction if added to models with an a priori defined set of traditional risk factors, but only a marginal improvement was achieved when using models based on optimally selected traditional risk factors.

Conclusions/interpretation

Predictive metabolites may improve understanding of the pathophysiology of type 2 diabetes and reflect disease progression, but they provide limited incremental value in risk prediction beyond optimal use of traditional risk factors.

     

Co-infection with Chlamydia pneumoniae and Helicobacter pylori results in vascular endothelial dysfunction and enhanced VCAM-1 expression in apoE-knockout mice

BACKGROUND: Upregulation of proinflammatory endothelial cell adhesion molecules and decreased bioactivity of endothelial nitric oxide (NO) are important in the pathogenesis of atherosclerosis. We investigated the effects of co-infection with Chlamydia pneumoniae and Helicobacter pylori on these two events in apoE-KO mice. METHODS: Thirty-two apoE-KO mice, 8 weeks old, were equally divided into 4 groups. The first 2 groups were infected with either C. pneumoniae or H. pylori, while the 3rd group was infected with both C. pneumoniae and H. pylori. Mice from the 4th group and 4 wild-type mice served as controls. Thoracic and abdominal aortas were harvested after 10 weeks, and staining for vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 was analyzed by immunocytochemistry. The endothelial vasomotor responses of thoracic aortas to methacholine were studied in organ chambers in the absence and presence of L-NAME. The plasma levels of nitrate/nitrite were measured. RESULTS: Staining for VCAM-1 was more intense at the branching sites of aortas from mice with co-infection than in mono-infected or noninfected apoE-KO mice. The relaxation responses to methacholine and the plasma levels of nitrate/nitrite were significantly less in the co-infected group than in the other groups (p < 0.05). CONCLUSION: Co-infection of apoE-KO mice with C. pneumoniae and H. pylori seems to be associated with impaired bioactivity of endothelial NO and increased expression of VCAM-1 at branching sites. The findings may suggest an additive interaction of these pathogens in atherogenesis.     

Hemodynamic variables and progression of acute kidney injury in critically ill patients with severe sepsis: data from the prospective observational FINNAKI study

Introduction

Knowledge of the association of hemodynamics with progression of septic acute kidney injury (AKI) is limited. However, some recent data suggest that mean arterial pressure (MAP) exceeding current guidelines (60–65 mmHg) may be needed to prevent AKI. We hypothesized that higher MAP during the first 24 hours in the intensive care unit (ICU), would be associated with a lower risk of progression of AKI in patients with severe sepsis.

Methods

We identified 423 patients with severe sepsis and electronically recorded continuous hemodynamic data in the prospective observational FINNAKI study. The primary endpoint was progression of AKI within the first 5 days of ICU admission defined as new onset or worsening of AKI by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. We evaluated the association of hemodynamic variables with this endpoint. We included 53724 10-minute medians of MAP in the analysis. We analysed the ability of time-adjusted MAP to predict progression of AKI by receiver operating characteristic (ROC) analysis.

Results

Of 423 patients, 153 (36.2%) had progression of AKI. Patients with progression of AKI had significantly lower time-adjusted MAP, 74.4 mmHg [68.3-80.8], than those without progression, 78.6 mmHg [72.9-85.4], P < 0.001. A cut-off value of 73 mmHg for time-adjusted MAP best predicted the progression of AKI. Chronic kidney disease, higher lactate, higher dose of furosemide, use of dobutamine and time-adjusted MAP below 73 mmHg were independent predictors of progression of AKI.

Conclusions

The findings of this large prospective multicenter observational study suggest that hypotensive episodes (MAP under 73 mmHg) are associated with progression of AKI in critically ill patients with severe sepsis.     

Evolution of gastritis in patients with gastric erosions

Objective. Gastric erosions are mainly associated with Helicobacter pylori infection and non-steroidal anti-inflammatory drugs (NSAIDs), but there has been no information available on the long-term evolution of gastritis in subjects with erosions. Material and methods. A series of 117 patients with gastric erosions without peptic ulcer disease and matched controls without erosions or ulcers were studied. Available subjects underwent endoscopy and biopsy 17 years later. Parietal cell antibodies were analysed at the first visit. Results. Fifty-two patients and 67 controls were available for follow-up. Since H. pylori was a major determinant of gastritis, only subjects with unchanged H. pylori status were included in the evaluation of gastritis progression. At the follow-up visit, gastric erosions were present in 38% (16/42) of the patients and 11% (5/46) of the controls (p=0.005). In H. pylori-negative subjects, no evolution of histological changes was seen. In H. pylori-positive subjects, body gastritis was initially less active in the erosion group. With time, antral gastritis worsened only in the erosion group. Parietal cell antibodies were more common in the control group (23%; erosion patients 0%; p=0.01), which also showed worsening of gastritis (p=0.003) and aggravation of atrophy (p=0.002) in the body mucosa. Conclusions. Gastritis in H. pylori-positive subjects with gastric erosions shows evolution of antral predominance, body predominance including development of atrophic changes being rare. Accordingly, patients with erosions share the characteristics of gastritis of the duodenal ulcer phenotype. These findings support the importance of H. pylori and acid in the pathogenesis of gastric erosions in H. pylori-positive patients.     

Pregnancy Outcome After Previous Stillbirth Resulting from Causes Other Than Maternal Conditions and Fetal Abnormalities

Background: An adequate fetomaternal circulatory system may be compromised by a variety of disturbances leading to stillbirth. The purpose of this study was to assess subsequent pregnancy outcome in women with a history of stillbirth as a result of causes other than maternal conditions and fetal abnormalities. Methods: Ninety‐two deliveries after stillbirth were identified among 11,910 deliveries of parous women recorded in the birth registry at Kuopio, Finland. Using logistic regression, pregnancy outcome measures were compared with those of a parous healthy obstetric population (n= 11,818). Results: Women with a history of stillbirth as a result of causes other than maternal conditions and fetal abnormalities were older than their unaffected controls (32.4 yr vs 30.3 yr). Stillbirth in an earlier pregnancy was associated with a significantly higher (p < 0.001) frequency of placental abruption in subsequent pregnancy (5.4% vs 0.7%). A history of stillbirth was predictive of preterm delivery (OR = 2.25) and low‐birthweight infants (OR = 2.70). No recurrence was reported. Conclusions: Pregnancy with a history of stillbirth as a result of causes other than maternal conditions and fetal abnormalities is a moderate risk state, with prematurity and low‐birthweight rates somewhat higher than those in the general population. The overall probability of a favorable outcome is good. These findings may be useful in counseling pregnant women with a history of stillbirth.