Mathias Burgmaier

Cardiovascular effects of GLP‐1 and GLP‐1‐based therapies: implications for the cardiovascular continuum in diabetes?

Diabet. Med. 30, 289–299 (2013)

Glucagon-like peptide-1(1-37) inhibits chemokine-induced migration of human CD4-positive lymphocytes

The present study examined the effect of GLP-1(1-37) on chemokine-induced CD4-positive lymphocyte migration as an early and critical step in atherogenesis. Pretreatment with GLP-1(1-37) reduced the SDF-induced migration of isolated human CD4-positive lymphocytes in a concentration-dependent manner. Similar effects were seen when RANTES was used as a chemokine. GLP-1(1-37)’s effect on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced PI-3 kinase activity. Downstream, GLP-1(1-37) inhibited SDF-induced phosphorylation of MLC and cofilin and limited f-actin formation as well as ICAM3 translocation. Furthermore, exendin-4 inhibited SDF-induced migration of CD4-positive lymphocytes similarly to GLP-1(1-37), and transfection of these cells with GLP-1 receptor siRNA abolished GLP-1(1-37)’s action on chemokine-induced ICAM3 translocation, suggesting an effect mediated via the GLP-1 receptor. Thus, GLP-1(1-37) inhibits chemokine-induced CD4-positive lymphocyte migration by inhibition of the PI3-kinase pathway and via the GLP-1 receptor. This effect provides a potential novel mechanism for how GLP-1(1-37) may modulate vascular disease.

Relationship between optical coherence tomography derived intraluminal and intramural criteria and haemodynamic relevance as determined by fractional flow reserve in intermediate coronary stenoses of patients with type 2 diabetes

Background The relationship between functional relevance and optical coherence tomography (OCT)-derived measurements of coronary lesions is incompletely understood and of critical importance, particularly in cardiovascular high-risk patients with type 2 diabetes. Objective To investigate the association between functional relevance of intermediate grade coronary stenoses as assessed by fractional flow reserve (FFR) and OCT-derived lesion parameters in patients with diabetes. Methods In 46 diabetic patients with stable coronary artery disease, FFR and OCT were performed in 62 coronary lesions with intermediate severity as determined by quantitative coronary angiography. Among lesions haemodynamic relevance was defined as FFR≤0.8. Results There was a significant association between FFR and OCT-derived minimal lumen area (r2=0.379) and minimal lumen diameter (r2=0.268), all p<0.001. Receiver operating curve (ROC)-analysis demonstrated an OCT-derived minimal lumen area <1.59 mm2 and minimal lumen diameter <1.31 mm to be optimal cut-off values to predict FFR≤0.8. Furthermore, in lipid-rich plaques FFR was significantly associated with minimal fibrous cap thickness (FCT, r2=0.399). Minimal FCT in lesions with FFR≤0.8 was significantly smaller (60.7±15.0 µm) compared with those lesions with FFR>0.8 (106.0±13.0 µm, p<0.001). ROC-analysis revealed that 0.81 is the ideal FFR cut-off to identify lesions with a minimal FCT≤80 µm (accuracy 97.3%, sensitivity 100%, specificity 93.8%, area under the curve 0.943 (95% CI 0.836 to 1.000)). Conclusions Haemodynamic relevance of intermediate grade lesions in patients with type 2 diabetes is closely related to (1) intraluminal measurements, which are smaller than previously described in non-diabetic cohorts and to (2) minimal FCT. Furthermore, FFR may be useful to identify vulnerable (minimal FCT≤80 µm) lesions among those with intermediate severity in lipid-rich plaques.

Glucagon-like peptide-1 (GLP-1) and its split products GLP-1(9-37) and GLP-1(28-37) stabilize atherosclerotic lesions in apoe−/− mice

BACKGROUND [corrected] Glucagon-like peptide-1 (GLP-1) based therapies are new treatment options for patients with type 2 diabetes. Recent reports suggest vasoprotective actions of GLP-1. Similar beneficial effects might be reached by GLP-1(9-37) and the c-terminal GLP-1 split product (28-37) although both peptides do not activate the GLP-1 receptor. We therefore investigated the actions of GLP-1(7-37), GLP-1(9-37) as well as GLP-1(28-37) on vascular lesion formation in a mouse model of atherosclerosis. METHODS AND RESULTS GLP-1(7-37), GLP-1(9-37) and GLP-1(28-37) and LacZ (control) were overexpressed for a period of 12 weeks in apoe(-/-) mice on high-fat diet (n = 10/group) using an adeno-associated viral vector system. Neither of the constructs changed overall lesion size. However, GLP-1(7-37), GLP-1(9-37) and GLP-1(28-37) significantly reduced plaque macrophage infiltration (GLP-1(7-37): 40.6%, GLP-1(9-37): 47.0%, GLP-1(28-37): 40.1% decrease, p < 0.05) and plaque MMP-9 expression (GLP-1(7-37): 41.6%, GLP-1(9-37): 50.2%, GLP-1(28-37): 44.0% decrease, p < 0.05) compared to LacZ in the aortic arch. Moreover, all GLP-1 constructs increased plaque collagen content (GLP-1(7-37): 49.3%, GLP-1(9-37): 86.0%, GLP-1(28-37): 81.9% increase, p < 0.05) and increased fibrous cap thickness (GLP-1(7-37): 188.0%, GLP-1(9-37): 179.9% GLP-1(28-37): 111.0% increase, p < 0.05). These effects of GLP-1(7-37), GLP-1(9-37) and GLP-1(28-37) on plaque macrophage infiltration, MMP-9 expression and plaque collagen content were confirmed in the aortic root. CONCLUSION GLP-1(7-37), GLP-1(9-37) and GLP-1(28-37) reduce plaque inflammation and increase phenotypic characteristics of plaque stability in a murine model of atherosclerosis. Future studies are needed to determine whether these effects translate into improved plaque stability and less cardiovascular events in high-risk patients with type 2 diabetes.

C-Peptide Levels Are Associated With Mortality and Cardiovascular Mortality in Patients Undergoing Angiography: The LURIC study

OBJECTIVE C-peptide is a proinsulin cleavage product released from the pancreas in amounts equimolar to insulin, and elevated levels of C-peptide have been found in patients with insulin resistance and early type 2 diabetes mellitus. Recent data suggest that C-peptide could play a causal role in the pathophysiology of vascular disease, but nothing is known about the prognostic value of C-peptide concentrations in the circulation. RESEARCH DESIGN AND METHODS We examined whether C-peptide is associated with cardiovascular and total mortality in 2,306 patients from the Ludwigshafen Risk and Cardiovascular Health Study who underwent coronary angiography at baseline (1997–2000). RESULTS During a mean follow-up of 7.6 years, 440 deaths (19.1%) occurred, 252 (10.9%) of which were due to cardiovascular causes. Age- and sex-adjusted hazard ratios (HRs) in the third compared with the first tertile of C-peptide were 1.46 (95% CI 1.15–1.85; P = 0.002) for all cause and 1.58 (1.15–2.18; P = 0.005) for cardiovascular mortality. After further adjustment for common risk factors as well as markers of glucose metabolism, these HRs remained significant at 1.46 (1.10–1.93; P = 0.008) and 1.55 (1.07–2.24; P = 0.022), respectively. Moreover, patients in higher tertiles of C-peptide exhibited higher levels of markers of endothelial dysfunction and atherosclerosis as well as a more severe extent of coronary lesions. CONCLUSIONS In patients undergoing coronary angiography, C-peptide levels are independently associated with all cause and cardiovascular mortality as well as presence and severity of coronary artery disease. Further studies are needed to examine a potential causal role of C-peptide in atherogenesis in humans.

High-Risk Cardiovascular Patients: Clinical Features, Comorbidities, and Interconnecting Mechanisms

Cardiovascular disease is the leading cause of death in the Western world with an increase over the last few decades. Atherosclerosis with its different manifestations in the coronary artery tree, the cerebral, as well as peripheral arteries is the basis for cardiovascular events, such as myocardial infarction, stroke, and cardiovascular death. The pathophysiological understanding of the mechanisms that promote the development of vascular disease has changed over the last few decades, leading to the recognition that inflammation and inflammatory processes in the vessel wall are major contributors in atherogenesis. In addition, a subclinical inflammatory status, e.g., in patients with diabetes or the presence of a chronic inflammatory disease, such as rheumatoid arthritis, have been recognized as strong risk factors for cardiovascular disease. The present review will summarize the different inflammatory processes in the vessel wall leading to atherosclerosis and highlight the role of inflammation in diabetes and chronic inflammatory diseases for cardiovascular morbidity and mortality.

Optical coherence tomography derived differences of plaque characteristics in coronary culprit lesions between type 2 diabetic patients with and without acute coronary syndrome

To compare optical coherence tomography (OCT)‐derived plaque characteristics of coronary target lesions between diabetic patients with acute coronary syndrome (ACS) versus stable angina pectoris (SAP).

AnxA5 reduces plaque inflammation of advanced atherosclerotic lesions in apoE(-/-) mice.

Annexin A5 (AnxA5) exerts anti‐inflammatory, anticoagulant and anti‐apoptotic effects through binding cell surface expressed phosphatidylserine. The actions of AnxA5 on atherosclerosis are incompletely understood. We investigated effects of exogenous AnxA5 on plaque morphology and phenotype of advanced atherosclerotic lesions in apoE−/− mice. Advanced atherosclerotic lesions were induced in 12 weeks old Western type diet fed apoE−/− mice using a collar placement around the carotid artery. After 5 weeks mice were injected either with AnxA5 (n = 8) or vehicle for another 4 weeks. AnxA5 reduced plaque macrophage content both in the intima (59% reduction, P < 0.05) and media (73% reduction, P < 0.01) of advanced atherosclerotic lesions of the carotid artery. These findings corroborated with advanced lesions of the aortic arch, where a 67% reduction in plaque macrophage content was observed with AnxA5 compared to controls (P < 0.01). AnxA5 did not change lesion extension, plaque apoptosis, collagen content, smooth muscle cell content or acellular plaque composition after 4 weeks of treatment as determined by immunohistochemistry in advanced carotid lesions. In vitro, AnxA5 exhibited anti‐inflammatory effects in macrophages and a flow chamber based assay demonstrated that AnxA5 significantly inhibited capture, rolling, adhesion as well as transmigration of peripheral blood mononuclear cells on a TNF‐α‐activated endothelial cell layer. In conclusion, short‐term treatment with AnxA5 reduces plaque inflammation of advanced lesions in apoE−/− mice likely through interfering with recruitment and activation of monocytes to the inflamed lesion site. Suppressing chronic inflammation by targeting exposed phosphatidylserine may become a viable strategy to treat patients suffering from advanced atherosclerosis.

Circulating annexin A5 predicts mortality in patients with heart failure

Natriuretic peptides are currently used to predict mortality in patients with heart failure (HF). However, novel independent biomarkers are needed to improve risk stratification in these patients. We hypothesized that annexin A5 (anxA5) would be highly expressed by organs which are generally affected by HF and that circulating anxA5 levels would predict mortality in HF patients.

Dual stack black blood carotid artery CMR at 3T: application to wall thickness visualization.

BackgroundThe increasing understanding of atherosclerosis as an important risk factor for the development of acute ischemic events like ischemic stroke has stimulated increasing interest in non-invasive assessment of the structure, composition and burden of plaque depositions in the carotid artery wall. Vessel wall imaging by means of cardiovascular magnetic resonance (CMR) is conventionally done by 2D dual inversion recovery (DIR) techniques, which often fail in covering large volumes of interest as required in plaque burden assessment. Although the technique has been extended to 2D multislice imaging, its straight extension to 3D protocols is still limited by the prolonged acquisition times and incomplete blood suppression. A novel approach for rapid overview imaging of large sections of the carotid artery wall at isotropic spatial resolutions is presented, which omits excitation of the epiglottis. By the interleaved acquisition of two 3D stacks with the proposed motion sensitized segmented steady-state black-blood gradient echo technique (MSDS) the coverage of the carotid artery trees on both sides in reasonable scan times is enabled.Results10 patients were investigated with the proposed technique and compared to conventional transversal DIR turbo spin and gradient echo approaches centered at the height of the carotid bifurcation. In all MSDS experiments sufficient black-blood contrast could be obtained over the entire covered volumes. The contrast to noise ratio between vessel and suppressed blood was improved by 73% applying the motion sensitizing technique. In all patients the suspicious areas of vessel wall thickening could be clearly identified and validated by the conventional local imaging approach. The average assessable vessel wall segment length was evaluated to be 18 cm. While in 50% of the cases motion artifacts could be appreciated in the conventional images, none were detected for the MSDS technique.ConclusionThe proposed technique enables the time efficient coverage of large areas of the carotid arteries without compromising wall-lumen CNR to get an overview about detrimental alterations of the vessel wall. Thickening of the vessel wall can be identified and the suspicious segments can be targeted for subsequent high-resolution CMR. The exclusion of the epiglottis may further facilitate reduction of swallowing induced motion artifacts.