Effect of Sacubitril/Valsartan on Exercise-Induced Lipid Metabolism in Patients With Obesity and Hypertension.

Sacubitril/valsartan (LCZ696), a novel angiotensin receptor-neprilysin inhibitor, was recently approved for the treatment of heart failure with reduced ejection fraction. Neprilysin degrades several peptides that modulate lipid metabolism, including natriuretic peptides. In this study, we investigated the effects of 8 weeks' treatment with sacubitril/valsartan on whole-body and adipose tissue lipolysis and lipid oxidation during defined physical exercise compared with the metabolically neutral comparator amlodipine. This was a multicenter, randomized, double-blind, active-controlled, parallel-group study enrolling subjects with abdominal obesity and moderate hypertension (mean sitting systolic blood pressure ≥130-180 mm Hg). Lipolysis during rest and exercise was assessed by microdialysis and [1,1,2,3,3-2H]-glycerol tracer kinetics. Energy expenditure and substrate oxidation were measured simultaneously using indirect calorimetry. Plasma nonesterified fatty acids, glycerol, insulin, glucose, adrenaline and noradrenaline concentrations, blood pressure, and heart rate were also determined. Exercise elevated plasma glycerol, free fatty acids, and interstitial glycerol concentrations and increased the rate of glycerol appearance. However, exercise-induced stimulation of lipolysis was not augmented on sacubitril/valsartan treatment compared with amlodipine treatment. Furthermore, sacubitril/valsartan did not alter energy expenditure and substrate oxidation during exercise compared with amlodipine treatment. In conclusion, sacubitril/valsartan treatment for 8 weeks did not elicit clinically relevant changes in exercise-induced lipolysis or substrate oxidation in obese patients with hypertension, implying that its beneficial cardiovascular effects cannot be explained by changes in lipid metabolism during exercise. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01631864.

A randomised, active- and placebo-controlled, three-period crossover trial to investigate short-term effects of the dipeptidyl peptidase-4 inhibitor linagliptin on macro- and microvascular endothelial function in type 2 diabetes.

BACKGROUND: Studies of dipeptidyl peptidase (DPP)-4 inhibitors report heterogeneous effects on endothelial function in patients with type 2 diabetes (T2D). This study assessed the effects of the DPP-4 inhibitor linagliptin versus the sulphonylurea glimepiride and placebo on measures of macro- and microvascular endothelial function in patients with T2D who represented a primary cardiovascular disease prevention population. METHODS: This crossover study randomised T2D patients (n = 42) with glycated haemoglobin (HbA1c) ≤7.5%, no diagnosed macro- or microvascular disease and on stable metformin background to linagliptin 5 mg qd, glimepiride 1-4 mg qd or placebo for 28 days. Fasting and postprandial macrovascular endothelial function, measured using brachial flow-mediated vasodilation, and microvascular function, measured using laser-Doppler on the dorsal thenar site of the right hand, were analysed after 28 days. RESULTS: Baseline mean (standard deviation) age, body mass index and HbA1c were 60.3 (6.0) years, 30.3 (3.0) kg/m2 and 7.41 (0.61)%, respectively. After 28 days, changes in fasting flow-mediated vasodilation were similar between the three study arms (treatment ratio, gMean [90% confidence interval]: linagliptin vs glimepiride, 0.884 [0.633-1.235]; linagliptin vs placebo, 0.884 [0.632-1.235]; glimepiride vs placebo, 1.000 [0.715-1.397]; P = not significant for all comparisons). Similarly, no differences were seen in postprandial flow-mediated vasodilation. However, under fasting conditions, linagliptin significantly improved microvascular function as shown by a 34% increase in hyperaemia area (P = 0.045 vs glimepiride), a 34% increase in resting blow flow (P = 0.011 vs glimepiride, P = 0.003 vs placebo), and a 25% increase in peak blood flow (P = 0.009 vs glimepiride, P = 0.003 vs placebo). There were no significant differences between treatments in postprandial changes. Linagliptin had no effect on heart rate or blood pressure. Rates of overall adverse events with linagliptin, glimepiride and placebo were 27.5, 61.0 and 35.0%, respectively. Fewer hypoglycaemic events were seen with linagliptin (5.0%) and placebo (2.5%) than with glimepiride (39.0%). CONCLUSIONS: Linagliptin had no effect on macrovascular function in T2D, but significantly improved microvascular function in the fasting state. Trial registration ClinicalTrials.gov identifier-NCT01703286; registered October 1, 2012.

New insulin glargine 300 Units · mL-1 provides a more even activity profile and prolonged glycemic control at steady state compared with insulin glargine 100 Units · mL-1.

OBJECTIVE: To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of a new insulin glargine comprising 300 units · mL(-1) (Gla-300), compared with insulin glargine 100 units · mL(-1) (Gla-100) at steady state in people with type 1 diabetes. RESEARCH DESIGN AND METHODS: A randomized, double-blind, crossover study (N = 30) was conducted, applying the euglycemic clamp technique over a period of 36 h. In this multiple-dose to steady-state study, participants received once-daily subcutaneous administrations of either 0.4 (cohort 1) or 0.6 units · kg(-1) (cohort 2) Gla-300 for 8 days in one treatment period and 0.4 units · kg(-1) Gla-100 for 8 days in the other. Here we focus on the results of a direct comparison between 0.4 units · kg(-1) of each treatment. PK and PD assessments performed on the last treatment day included serum insulin measurements using a radioimmunoassay and the automated euglycemic glucose clamp technique over 36 h. RESULTS: At steady state, insulin concentration (INS) and glucose infusion rate (GIR) profiles of Gla-300 were more constant and more evenly distributed over 24 h compared with those of Gla-100 and lasted longer, as supported by the later time (∼ 3 h) to 50% of the area under the serum INS and GIR time curves from time zero to 36 h post dosing. Tight blood glucose control (≤ 105 mg · dL(-1)) was maintained for approximately 5 h longer (median of 30 h) with Gla-300 compared with Gla-100. CONCLUSIONS: Gla-300 provides more even steady-state PK and PD profiles and a longer duration of action than Gla-100, extending blood glucose control well beyond 24 h.

Effect of the once-daily human GLP-1 analogue liraglutide on appetite, energy intake, energy expenditure and gastric emptying in type 2 diabetes.

AIMS: Liraglutide reduces bodyweight in patients with type 2 diabetes mellitus (T2DM). This study aimed to investigate the mechanisms underlying this effect. METHODS: The comparative effects of liraglutide, glimepiride and placebo on energy intake, appetite, nausea, gastric emptying, antral distension, bodyweight, gastrointestinal hormones, fasting plasma glucose and resting energy expenditure (REE), were assessed in subjects with T2DM randomised to treatment A (liraglutide-placebo), B (placebo-glimepiride) or C (glimepiride-liraglutide). Assessments were performed at the end of each 4-week treatment period. RESULTS: Energy intake was less (NS) with liraglutide vs placebo and glimepiride, and 24-h REE was higher (NS) with liraglutide vs placebo and glimepiride. Fasting hunger was less (p=0.01) with liraglutide vs placebo and glimepiride, and meal duration was shorter with liraglutide (p=0.002) vs placebo. Paracetamol AUC(0-60 min) and C(max) were less (p<0.01) and fasting peptide YY was lower (p ≤ 0.001) after liraglutide vs placebo and glimepiride. Bodyweight reductions of 1.3 and 2.0 kg were observed with liraglutide vs placebo and glimepiride (p<0.001). There were no differences on antral distension, nausea, or other gastro-intestinal hormones. CONCLUSION: Liraglutide caused decreased gastric emptying and increased reduction in bodyweight. The mechanisms of the liraglutide-induced weight-loss may involve a combined effect on energy intake and energy expenditure.

Automated near-continuous glucose monitoring measured in plasma using mid-infrared spectroscopy.

OBJECTIVE: There are increasing calls for a precise, automated system to enable tight glycemic control and to avoid hypoglycemia in an intensive care unit setting. OptiScan Biomedical has developed a glucose monitor based on mid-infrared spectroscopy that withdraws blood samples (120 µl) and measures plasma glucose. The goal of this study was to validate the performance of the OptiScan Model 5000 over a wide range of glycemic levels in patients. RESEARCH DESIGN AND METHODS: Sixty people with type 1 (n = 18) or type 2 (n = 42) diabetes who were otherwise healthy were connected to OptiScanners. Their blood glucose concentrations were kept in a euglycemic, hypoglycemic (<75 mg/dl), and hyperglycemic (>180 mg/dl) range by intravenous administrations of insulin and glucose. OptiScanner venous blood samples were automatically withdrawn every 15 minutes. Reference measurements were done using the YSI 2300 glucose analyzer. RESULTS: The aggregate data points (1155 paired readings) were within International Organization for Standardization standards, with 98.6% of the glucose values within ±20% above 75 mg/dl and ±15 mg/dl below this value. A Clarke error grid analysis showed a total of 1139 points (98.6%) in zone A. Points outside of A exceeded the A zone boundary by an average of 4.3%. The r(2) was 0.99. The total coefficient for variance was 6.4%. CONCLUSIONS: These results show that the OptiScanner is highly accurate in healthy patients with diabetes across a wide range of glucose values. Mid-infrared spectroscopy may become the method of choice for highly accurate, high frequency, automated glucose measurements and may thus enable better glycemic control in critically ill patients.

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.

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.

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.

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.

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.

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.

Treatment of patients with diabetes with GLP-1 analogues or DPP-4- inhibitors: a hot topic for cardiologists?

Novel drugs for the treatment of patients with diabetes are of interest for cardiologists if they reduce the risk of cardiovascular events. However, as documented by the current discussion about the potential benefits of glitazones, high hopes can fail. Initial beneficial cardiovascular effects shown in proof-of-concept studies were muted by the apparent higher mortality in the metaanalysis of studies with rosiglitazone. Having this in mind, how should one judge about new, emerging antidiabetic therapies, in particular those influencing the incretin axis? The rapidly increasing use of GLP-1 analogues and DPP-4 inhibitors for the treatment of type 2 diabetes mellitus may be of major interest for the cardiologist. Potential beneficial actions on the cardiovascular system so far shown in animal experiments and small proof of concept studies may provide the rationale for using these drugs specifically in diabetic patients with secondary complications such as macrovascular disease or diabetic cardiomyopathy. Theoretically, these new therapies could also proof beneficial in patients with heart failure, independently of concomittend diabetes mellitus. However, many unanswered questions need to be addressed in the near future to extend the experimental findings to potential benefits of real life patients. In summary a new class of antidiabetic drugs, which could possibly directly influence cardiovascular effects of diabetes mellitus and thus possibly treat or even prevent life threatening complications has become available. Further studies both assessing surrogate parameters as well as hard endpoint studies are needed to support the hypothesis generated from the summarized experimental studies.

Disturbed endothelial function of the internal thoracic artery in patients with coronary artery disease.

OBJECTIVES AND BACKGROUND: The internal thoracic artery is an established arterial graft for myocardial revascularization. It never had been investigated, whether there are functional differences in this vessel between patients with or without coronary artery disease. METHODS: We investigated the left internal thoracic artery of 28 patients (15 with and 13 without coronary artery disease) with a duplex-system at rest and with a handgrip exercise. RESULTS: Concerning the measured flow velocities at rest there was only a significant difference between the diastolic mean and peak velocity between the two groups, the other investigated parameters demonstrate no significant difference. The peak diastolic and the mean diastolic velocity was less in patients with coronary artery disease during the handgrip-test. The flow reserve was decreased in patients with coronary artery disease (12.6+/-24.0% vs. 32.3+/-30.9%, P < 0.05). CONCLUSIONS: We demonstrated, that patients with coronary artery disease have a higher peripheral resistance and a lower diastolic velocity of the internal thoracic artery during stress testing. This corresponds to a disturbed vasomotion and may be an early marker of arteriosclerosis.

Plasma nitrite concentrations reflect the degree of endothelial dysfunction in humans.

A reduced nitric oxide availability is a hallmark of endothelial dysfunction occurring early in atherosclerosis. Recently, we have shown that plasma nitrite mirrors acute changes in endothelial nitric oxide synthase activity in various mammals, including humans. Here, we examined the hypothesis that plasma nitrite levels are reduced in humans with endothelial dysfunction and the decrease is correlated with increasing numbers of cardiovascular risk factors (RF). Plasma nitrite concentrations were quantified by flow-injection analysis. The coefficient of variation for repeated measurements of plasma nitrite was <8%, and heart rate and blood pressure at the time of blood sampling had no significant effect on nitrite values measured (n=10). Baseline levels of plasma nitrite followed a normal distribution in each group studied and decreased progressively with increasing numbers of cardiovascular risk factors (n=351, p<0.001): 351+/-13 (0 RF), 261+/-10 (1 RF), 253+/-11 (2 RF), 222+/-18 (3 RF), and 171+/-29 nmol/L (4 RF). Intima media thickness (IMT) and flow-mediated dilation (FMD) were determined via ultrasound. Plasma nitrite and FMD levels were lower, whereas IMT was greater in individuals with endothelial dysfunction (n=12) compared to healthy volunteers (n=12). Nitrite correlated significantly with FMD (r=0.56, p<0.001) and inversely with IMT (r= -0.49, p<0.01). Plasma nitrite levels are reliably measurable in humans, indicate endothelial dysfunction, and correlate with cardiovascular risk factors. Future studies are necessary to identify the prognostic relevance of plasma nitrite determination in patients suffering from cardiovascular disease.

Red blood cells express a functional endothelial nitric oxide synthase.

The synthesis of nitric oxide (NO) in the circulation has been attributed exclusively to the vascular endothelium. Red blood cells (RBCs) have been demonstrated to carry a nonfunctional NO synthase (NOS) and, due to their huge hemoglobin content, have been assumed to metabolize large quantities of NO. More recently, however, RBCs have been identified to reversibly bind, transport, and release NO within the cardiovascular system. We now provide evidence that RBCs from humans express an active and functional endothelial-type NOS (eNOS), which is localized in the plasma membrane and the cytoplasm of RBCs. This NOS is regulated by its substrate L-arginine, by calcium, and by phosphorylation via PI3 kinase. RBC-NOS activity regulates deformability of RBC membrane and inhibits activation of platelets. The NOS-dependent conversion of L-arginine in RBCs is comparable to that of cultured human endothelial cells. RBCs in eNOS-/- mice in contrast to wild-type mice lack NOS protein and activity, strengthening the evidence of an eNOS in RBCs. These data show an eNOS-like protein and activity in RBCs serving regulatory functions in RBCs and platelets, which may stimulate new approaches in the treatment of NO deficiency states inherent to several vascular and hematologic diseases.

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.

Nitric oxide differentially regulates proliferation and mobilization of endothelial progenitor cells but not of hematopoietic stem cells.

To investigate the role of nitric oxide in controlling endothelial progenitor (EPC) and hematopoietic stem cell (HSC) mobilization, wild-type mice, L-NAME treated WT and eNOS-/- mice received either PBS or G-CSF for 5 days. Under unstimulated conditions bone marrow of either L-NAME treated WT and eNOS-/- mice, representing acute and chronic NO-deficiency, showed higher CD34(+)Flk-I+ EPC numbers compared to their WT littermates. Furthermore, CD34(+)Flk-I+ progenitors under NO-deficient conditions showed a higher cell turn over since the proliferation and apoptosis activity under in vivo as well as in vitro conditions were enhanced. In line with this finding bone marrow derived EPC differentiation towards endothelial cells was modulated in an NO-dependent manner. Administration of G-CSF resulted in an increase of EPC within the bone marrow of WT animals with a consecutive release of these cells into the peripheral circulation. Under NO-deficient conditions G-CSF failed to increase EPC numbers. In contrast, the HSC population c-kit(+)Lin- was not influenced by nitric oxide. Thus, NO differentially supports the mobilization of the endothelial committed progenitor subpopulation in bone marrow but does not have an effect on HSC in vivo.

Altered blood rheology in obstructive sleep apnea as a mediator of cardiovascular risk.

BACKGROUND: Cardiovascular complications are common in patients with obstructive sleep apnea (OSA). Blood rheology is a major determent of coagulation and an established risk factor for cardiovascular events. Since nocturnal hypoxemia could influence parameters of blood rheology, we hypothesized that OSA alters blood rheology independent of other cardiovascular risk factors. METHODS: One hundred and ten consecutive patients admitted to the sleep laboratory were included. The association of plasma fibrinogen and viscosity (as parameters of blood rheology) with OSA was evaluated. RESULTS: One hundred and ten patients aged 61.4+/-10.1 years (body mass index 28.4+/-4.1 kg/m2) were included. OSA was confirmed in 63 patients (57.2%) with an apnea-hypopnea index (AHI) of 28.7+/-14.9 events/hour. Patients with OSA showed higher levels of plasma viscosity (1.36+/-0.09 vs. 1.31+/-0.08 mPas, p=0.005). Nevertheless, hypertensive apneics have even higher levels of plasma viscosity than nonapneics (1.38+/-0.091 vs. 1.32+/-0.028 mPas, p=0.018). Similar results were found in patients with coronary artery disease, where OSA was associated with elevated plasma viscosity (1.36+/-0.076 vs. 1.31+/-0.081 mPas, p=0.007). Plasma fibrinogen was correlated with nocturnal minimal oxygen saturation (r=-0275, p=0.0036) and AHI (r=0.297, p=0.001). OSA was associated with higher plasma fibrinogen (353+/-83 vs. 317+/-62 mg/dl, p=0.015). These differences persist with control for cardiovascular risk factors. CONCLUSIONS: Patients with OSA have elevated morning fibrinogen levels and a higher plasma viscosity, which correlate positively with indices of sleep apnea severity. These changes in blood rheology are independent of cardiovascular risk factors, and therefore, might be specific mechanisms of OSA. This supports the pathophysiological concept that sleep apnea is a cardiovascular risk factor.

A prospective study on incidence and risk factors of arteriovenous fistulae following transfemoral cardiac catheterization.

BACKGROUND: A potentially harmful complication of cardiac catheterization is the arteriovenous fistula. Precise knowledge of possible factors predisposing for acquisition of iatrogenic AV-fistulae could enable cardiologists to perform a risk stratification for cardiac patients prior to catheterization. METHODS: Over a period of 2 years, 10,271 consecutive patients who underwent cardiac catheterization were included in this study. Auscultation of a new femoral bruit was followed by a duplex scan to confirm the suspected diagnosis of an AVF. Every patient was investigated on the day after catheterization. RESULTS: The incidence of iatrogenic AVF was 0.86%. A multivariate regression analysis revealed five significant and independent risk factors: (1) procedural heparin dosage >or=12,500 IU (Odds Ratio (OR)=2.88), (2) coumadin therapy (OR=2.34), (3) puncture of the left groin (OR=2.21), (4) arterial hypertension (OR=1.86) and (5) female gender (OR=1.84). Coronary angioplasty (instead of diagnostic procedure), size and number of sheaths, age and body mass index did not significantly affect the incidence of AVF. CONCLUSIONS: The overall incidence of AV-fistulae following cardiac catheterization approximates 1%. Determination of significant risk factors will facilitate identification of patients at risk for iatrogenic arteriovenous fistulae prior to cardiac catheterization and thus help to develop strategies to reduce the incidence of AV-fistulae.