Metabolic memory: a vascular perspective.

Multiple and complex pathways promote the deleterious effects of hyperglycemia in diabetes, ultimately leading to micro- and macrovascular disease. Some of the known mechanisms in diabetic vascular disease may explain the initiation of the "metabolic memory", but fall short if long periods of time are involved.Vascular research has been prolific in the past in finding links between microvascular dysfunction and subsequent macrovascular disease. Thus, this text will extend the current discussion of the "metabolic memory" by including available data from vascular research.The hypothesis proposes that structural and functional changes in the microcirculation interact within the vascular continuum with larger arteries. This interaction may lead to subsequent upstream endothelial dysfunction, atherosclerosis and vascular complications ("Micro/Macro Interaction"). The underlying microvascular structural changes may be more long-term and possibly mediate the "metabolic memory".This hypothesis, that the "not-so new" interaction between micro-and macrovasculature may promote "metabolic memory" effects extends and unifies currently discussed theories.

Relevance of hemostatic risk factors on coronary morphology in patients with diabetes mellitus type 2.

OBJECTIVE: The influence hemostatitc parameters on the morphological extent and severity of coronary artery disease were studied in patients with and without DM type 2. BACKGROUND: It is known that patients with diabetes (DM) have abnormal metabolic and hemostatic parameters METHODS: Of 150 consecutive patients with angiographically proven coronary artery disease 29 presented with DM. Additionally to parameters of lipid-metabolism fibrinogen, tissue-plasminogenactivator (t-PA), plasminogen-activator-inhibitor (PAI), plasmin-a-antiplasmin (PAP), prothrombin-fragment 1+2 (F1+2), thrombin-antithrombin (TAT), von-willebrand-factor (vWF), platelet factor 4 (PF4), glykomembranproteine 140 (GMP140) and the rheologic parameters plasma viscosity and red blood cell aggregation were evaluated. The extent and severity of CAD was evaluated according to the criteria of the American Heart Association. RESULTS: Patients with DM presented with a higher number of conventional risk factors as compared to non-diabetic patients. Additionally there were significant differences for F1+2, red blood cell aggregation and PAI. Diabetic patients showed a more severe extent of coronary arteriosclerosis, which also could be found more distally. A significant relationship between blood-glucose, thrombocyte-activation (vWF), endogenous fibrinolysis (PAI) and the severity of CAD and a more distal location of stenoses could be found (r = 0.6, p < 0.001). CONCLUSION: Patients with coronary artery disease and DM type 2 showed marked alterations of metabolic, hemostatic, fibrinolytic and rheologic parameters, which can produce a prothrombogenic state. A direct association of thrombogenic factors on coronary morphology could be shown. This can be the pathophysiologic mechanism of more severe and distal pronounced coronary atherosclerosis in these patients.

Hemostatic risk factors in patients with coronary artery disease and type 2 diabetes - a two year follow-up of 243 patients.

BACKGROUND: Thrombosis is regarded to be a key factor in the development of acute coronary syndromes in patients with coronary artery disease (CAD). We hypothesize, that hemostatic and rheological risk factors may be of major relevance for the incidence and the risk stratification of these patients. METHODS: In 243 patients with coronary artery disease and stable angina pectoris parameters of metabolism, hemostasis, blood rheology and endogenous fibrinolysis were assessed. Patients were prospectively followed for 2 years in respect to elective revascularizations and acute coronary syndromes. RESULTS: During follow-up 88 patients presented with cardiac events, 22 of those were admitted to the hospital because of acute events, 5 Patients were excluded due to non- cardiac death. Patients with clinical events were found to be more frequently diabetic and presented with a more progressed coronary atherosclerosis. Even though patients with diabetes mellitus demonstrated a comparable level of multivessel disease (71% vs. 70%) the rate of elective revascularization was higher (41% vs. 28%, p < 0.05). The results were also unfavorable for the incidence of acute cardiovascular events (18% vs. 8%, p < 0.01). In comparison to non-diabetic patients diabetics demonstrated significantly elevated levels of fibrinogen (352 +/- 76 vs. 312 +/- 64 mg/dl, p < 0.01), plasma viscosity (1.38 +/- 0.23 vs. 1.31 +/- 0.16 mPas, p < 0.01), red blood cell aggregation (13.2 +/- 2.5 vs. 12.1 +/- 3.1 E, p < 0.05) and plasmin-activator-inhibitor (6.11 +/- 3.4 vs. 4.7 +/- 2.7 U/l, p < 0.05). CONCLUSION: Pathological alterations of fibrinogen, blood rheology and plasminogen-activator-inhibitor as indicators of a procoagulant state are of major relevance for the short-term incidence of cardiac events, especially in patients with diabetes mellitus type 2, and may be used to stratify patients to specific therapies.

Percutaneous coronary revascularization in patients with formerly "refractory angina pectoris in end-stage coronary artery disease" - not "end-stage" after all.

BACKGROUND: Patients with refractory angina pectoris in end-stage coronary artery disease represent a severe condition with a higher reduction of life-expectancy and quality of life as compared to patients with stable coronary artery disease. It was the purpose of this study to invasively re-evaluate highly symptomatic patients with formerly diagnosed refractory angina pectoris in end-stage coronary artery disease for feasible options of myocardial revascularization. METHODS: Thirty-four patients formerly characterized as having end stage coronary artery disease with refractory angina pectoris were retrospectively followed for coronary interventions. RESULTS: Of those 34 patients 21 (61.8%) were eventually revascularized with percutaneous interventional revascularization (PCI). Due to complex coronary morphology (angulation, chronic total occlusion) PCI demanded an above-average amount of time (66 +/- 42 minutes, range 25-206 minutes) and materials (contrast media 247 +/- 209 ml, range 50-750 ml; PCI guiding wires 2.0 +/- 1.4, range 1-6 wires). Of PCI patients 7 (33.3%) showed a new lesion as a sign of progression of atherosclerosis. Clinical success rate with a reduction to angina class II or lower was 71.4% at 30 days. Surgery was performed in a total of8 (23.5%) patients with a clinical success rate of 62.5%. Based on an intention-to-treat 2 patients of originally 8 (25%) demonstrated clinical success. Mortality during follow-up (1-18 months) was 4.8% in patients who underwent PCI, 25% in patients treated surgically and 25% in those only treated medically. CONCLUSION: The majority of patients with end-stage coronary artery disease can be treated effectively with conventional invasive treatment modalities. Therefore even though it is challenging and demanding PCI should be considered as a first choice before experimental interventions are considered.

Gene expression analysis of human red blood cells.

Understanding of molecular mechanisms governing the enucleating phenomena of human erythrocytes is of major importance in both fundamental and applied studies. Total RNA (n=7) from human RBCs (purity of erythrocyte preparation >99,99%) was tested using 2100 Bioanalyzer (Agilent, USA), and transcribed to cDNA. Microarray analysis was performed with the Human Genome Focus GeneChip (Affymetrix, USA), containing 8500 transcripts corresponding to 8400 human genes. Here we report that human RBCs contain typical eukaryotic RNA with 28S- and18S-rRNA standard bands. Microarray studies revealed the presence of transcripts of 1019 different genes in erythrocytic RNA. Gene Ontology analysis recognized 859 genes involved in general biological processes: 529 genes for cellular metabolism, 228 genes for signal transduction, 104 genes for development, 107 genes for immune response, 62 genes for protein localization, 53 genes for programmed cell death, and 5 genes for autophagy. A number of genes responsible for transcription, translation, RNA-stabilisation as well as for apoptosis and anti-apoptosis have been identified for the first time in circulating human RBCs. The presented data shed new light on the genetic determination of erythropoiesis, apoptosis and may have implications on the pathophysiology and diagnosis of various diseases involving red blood cells.

Evaluation of early and late postoperative flow capacity of internal thoracic artery bypass by means of stress Doppler echocardiography.

OBJECTIVES: Arterial revascularization with the internal thoracic artery (ITA) has shown exceptional long-term results, even though early hypoperfusion can occur and can cause ischemia and contractile dysfunction. Therefore, it is still controversial as to whether the bypass vessel can guarantee the required demand for blood flow during the early postoperative (EPO) phase or whether this is only possible a long time after the operation. This question is important particular in the early postoperative phase to manage afterload and reduce left ventricular oxygen demand. Therefore, stress Doppler echocardiography was performed to assess EPO and late postoperative (LPO) flow capacity after minimal-invasive coronary artery bypass grafting (MIDCAB) in subjects with single vessel disease. METHODS: Doppler echocardiography was performed after MIDCAB in 15 patients (mean age 65 years+/-12 standard deviation) in the EPO (15 days) and LPO (266 days) at rest and under stress. RESULTS: The mean diastolic velocity (MDV) as a measure for the coronary perfusion in the bypass-graft was comparable (30.9+/-14.5 EPO to 30.8+/-13.9 cm/s LPO, P>0.05) for both settings (early vs. late). In both tests, the stress reactions by means of handgrip maneuver lead to comparable increases in blood flow: MDV 65.0+/-54.4% (EPO) to 62.5+/-53.7% n.s. (LPO). The flow increase in the bypass graft was just as similar [48.2+/-46.2% (EPO) to 51.1+/-41.6% n.s. (LPO)]. CONCLUSION: The stress echocardiography revealed for the first time that the ITA-graft after MIDCAB-operation is able to produce the same flow reserve through the EPO phase as well as the LPO phase. Restrictions to a maximum early flow adaptation are not justified. Thus, particularly a patient with severe comorbidities or higher age should be mobilized in the EPO phase to minimize the postoperative complications without risk of myocardial ischemia caused by impaired early blood flow through recent implanted ITA. This method for assessment of ITA blood flow allows for long-time observations and can detect disturbances in perfusion at an early stage.

Stress Doppler echocardiography of the internal thoracic artery--a new non-invasive approach for functional assessment after minimally invasive coronary bypass grafting.

Minimally invasive surgery for coronary revascularization using the left internal thoracic artery (ITA) has gained increasing interest. For control of graft function the established transcutaneous color-Doppler echocardiography in combination with a stress-test was performed to test the ability of this novel technique. Twenty-one patients having received a single ITA-graft were evaluated early postoperatively at rest and during isometric stress test with a handgrip exercise. Compared to the right internal thoracic artery, the mainly systolic flow is changed to a wide diastolic component when the left ITA is anastomosed to the coronary artery. The peak systolic/peak diastolic velocity ratio changed from 4.5+/-1.9 to 1.4+/-0.47 (P<0.0001). During stress reaction with the isometric handgrip maneuver the grafted ITA showed a significant increase of the mean diastolic flow (29.1+/-13.3 to 44.3+/-14.7 cm/s, P<0.0001) and total blood flow (124.8+/-55.4 ml/min to 176.6+/-71.7 ml/min), which may demonstrate an efficient bypass function. We conclude, that the noninvasive measurement of ITA-graft function with Doppler-ultrasound may be a clinically useful method to assess the functional status after minimally invasive coronary artery bypass grafting. In combination with the hand-grip test it represents a valid new technique with the potential to estimate graft patency.