fibrin and Metabolic-Syndrome

While there is indisputable evidence supporting the beneficial role of aerobic exercise in reducing cardiovascular risk factors, there are few dose-response studies of this relationship. Increasingly, it is thought that the cardiovascular benefits of exercise are significantly influenced by adaptations within skeletal muscle and its vasculature. However, little is known about the molecular mechanisms underlying these adaptations. To address this need, we initiated a study utilizing longitudinal, microarray-based gene expression profiling of serial skeletal muscle biopsies obtained from the study of targeted risk reduction intervention through defined exercise (STRRIDE). STRRIDE participants were overweight and exhibited symptoms characteristic of the metabolic syndrome that typically precedes type II diabetes such as insulin resistance, abnormal lipids and glucose intolerance. Expression data were statistically filtered and sorted into exercise training-responsive clusters based on gene product knowledge. One such cluster included genes that promote the degradation of fibrin clots such as tissue plasminogen activator (t-PA), connective tissue activation peptide III (CTAP III) and tetranectin. The fibrinolytic activity and protein levels of tetranectin, and t-PA and its endogenous inhibitor PAI-1, were subsequently shown to change significantly in both skeletal muscle and serum in response to exercise training. Our data show that the rigors of exercise directly induce fibrinolytic genes and protein cascades, both within muscle, and in the systemic circulation. This finding is particularly significant given that the metabolic syndrome is an independent risk factor for peripheral vascular disease and thrombotic events within the heart and brain. We conclude that aerobic exercise training induces both local and systemic changes in fibrinolysis and vascular homeostasis that are probably protective against cardiovascular disease.

Topics: Adaptation, Physiological; Blotting, Western; Enzyme-Linked Immunosorbent Assay; Exercise; Fibrin; Fibrinolysis; Fluorescent Antibody Technique; Gene Expression; Homeostasis; Humans; Lectins, C-Type; Male; Metabolic Syndrome; Middle Aged; Multigene Family; Muscle Proteins; Muscle, Skeletal; Obesity; Physical Fitness; Plasminogen Activator Inhibitor 1; Plasminogen Activators; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; RNA, Messenger

Strokes are commonly preceded by transient ischemic attacks (TIAs). TIA is often associated with metabolic syndrome (causing chronic inflammation), resulting in a proinflammatory- and procoagulant-environment. The aim of this study was to determine whether platelet- and fibrin network-morphology or coagulation profiles of individuals that suffered a TIA in the presence of metabolic syndrome was altered when compared to healthy individuals.. The study consisted of 40 voluntary participants. Twenty individuals that suffered a TIA in the previous 48 h with at least two metabolic syndrome risk factors present and twenty healthy age-matched controls. Scanning electron- and atomic force microscopy was used to study platelet- and fibrin-morphology, atomic force microscopy was used to study platelet- and fibrin fiber-elasticity and thromboelastography for the study of coagulation profiles. Statistical analysis was performed to compare the two groups. In all cases a p-value of less than 0.05 was considered statistically significant.. Platelets of the control group appeared spherical with few pseudopodia present while the platelets of the TIA individuals presented with numerous pseudopodia and spreading, indicating activation. Platelet aggregation was also present. The fibrin networks of the healthy individuals consist of thick and thin fibers that form an organized network of fibers. The fibrin networks of the TIA individuals appeared less organized with less taut fibers. Fibrin fiber thickness was found to be significantly increased in the TIA group (p-value <0.001) when compared to healthy controls. The thicker fibers formed irregular networks with thick masses of fibrin fibers. Platelet and fibrin fiber elasticity was found to be significantly lower in the experimental group (p-value 0.0042 and p-value 0.0007 respectively). The hemostatic profiles of the diseased individuals did not differ significantly (p-value > 0.05) from the healthy controls, indicating a normal functioning coagulation cascade.. The findings indicate that pathological clot formation is not caused by alterations in the coagulation cascade but rather by the premature activation of platelets (as a result of chronic inflammation) that in turn causes altered fibrin formation.

Topics: Adult; Aged; Blood Coagulation; Blood Platelets; Case-Control Studies; Elasticity; Female; Fibrin; Fibrinolysis; Humans; Ischemic Attack, Transient; Male; Metabolic Syndrome; Microscopy, Atomic Force; Microscopy, Electron, Scanning; Middle Aged; Platelet Activation; Platelet Aggregation; Predictive Value of Tests; Risk Factors; Thrombelastography

The clustering of impaired glucose metabolism, elevated triglycerides, low HDL cholesterol, and abdominal obesity is known as the metabolic syndrome. Individuals with this syndrome suffer an excess of cardiovascular disease (CVD) for reasons that are unclear.. We randomly sampled 1276 adults of South Asian, Chinese, European, and Native Indian ancestry from 4 communities in Canada. Participants provided fasting blood samples for glucose, lipids, and fibrinolytic measurements; had an oral glucose tolerance test; and underwent a B-mode carotid ultrasound examination. CVD was determined by history and ECG. The prevalence of the metabolic syndrome was 25.8% (95% CI, 23.5 to 28.2) and varied substantially by ethnic group: 41.6% among Native Indians, 25.9% among South Asians, and 22.0% among Europeans, compared with 11.0% among the Chinese (overall, P=0.0001). People with the metabolic syndrome had more atherosclerosis (maximum intimal medial thickness, 0.78+/-0.18 versus 0.74+/-0.18 mm; P=0.0005), CVD (17.2% versus 7.0%; P=0.0001), and elevated plasminogen activator inhibitor-1 (24.2 versus 14.6 U/mL; P=0.001) compared with levels among people without the metabolic syndrome. For the same amount of atherosclerosis, people with the metabolic syndrome had a greater prevalence of CVD, even among nondiabetic individuals. This difference in CVD prevalence among the groups was attenuated after adjustment for plasminogen activator inhibitor-1 levels, suggesting that fibrinolytic dysfunction mediates the increased risk of CVD in individuals with the metabolic syndrome.. CVD among people with the metabolic syndrome is explained by their excess of atherosclerosis and impaired fibrinolysis. Interventions to prevent atherosclerosis progression and improve fibrinolytic function require evaluation in this high-risk group.

Topics: Adult; Arteriosclerosis; Asia; Asian People; Blood Glucose; Canada; Cardiovascular Diseases; Carotid Arteries; Comorbidity; Electrocardiography; Europe; Female; Fibrin; Fibrinolysis; Glucose Tolerance Test; Humans; Indians, North American; Lipids; Male; Metabolic Syndrome; Middle Aged; Prevalence; Risk Assessment; Risk Factors; Ultrasonography; White People