Association of endothelial function and lower extremity perfusion in peripheral artery disease.

Background: The current study aims to investigate the association between endothelial function and lower extremity perfusion in patients with peripheral artery disease (PAD). Patients and methods: In total 229 patients with PAD (Rutherford stage 0-3) were enrolled in the current study. Endothelial function was assessed by measuring flow-mediated dilation (FMD) and endothelial cell proliferation capacity (ECPC). Lower extremity perfusion was assessed by measuring oscillometry-based ankle brachial index (oABI) and pulse wave index (PWI). In addition, carotid intima-media-thickness (cIMT) was also measured as a surrogate marker for atherosclerosis. Correlations between FMD, ECPC, oABI, PWI, and cIMT were analysed using Pearson correlation coefficient. The relationship between the above variables and the severity of PAD was investigated using ordinal logistic regression analysis. Results: Correlation analysis showed that FMD negatively associated with PWI (r = -0.183, p = 0.005), ECPC positively associated with oABI (r = 0.162, p = 0.014), and oABI negatively associated with PWI (r = -0.264, p < 0.001). Ordinal logistic regression analysis showed that ECPC (ß = -0.009, p = 0.048), oABI (ß = -5.290, p < 0.001), and age (ß = -0.058, p = 0.002) negatively associated with the PAD Rutherford stages. In addition, PWI (ß = 0.006, p < 0.001), cIMT (ß = 18.363, p = 0.043) positively associated with the PAD Rutherford stages. Conclusions: Endothelial function significantly associates with lower extremity perfusion in patients with PAD, and both are related to the severity of PAD.

Autophagy-related genes analysis reveals potential biomarkers for prediction of the impaired walking capacity of peripheral arterial disease.

BACKGROUND: The role of autophagy and autophagy-related genes in peripheral arterial disease (PAD) remains unknown and may be of diagnostic and prognostic value. The aim of this study is to investigate the relationship between autophagy and PAD, and identify potential diagnostic or prognostic biomarkers for medical practice. METHODS: Differentially expressed autophagy-related genes in PAD were explored from GSE57691 and validated in our WalkByLab registry participants by quantitative real-time polymerase chain reaction (qRT-PCR). The level of autophagy in peripheral blood mononuclear cells (PBMCs) of WalkByLab participants was assessed by analyzing autophagic marker proteins (beclin-1, P62, LC3B). Single sample gene set enrichment analysis (ssGSEA) was used to evaluate the immune microenvironment within the artery wall of PAD patients and healthy persons. Chemokine antibody array and enzyme-linked immunosorbent assay were used to assess the chemokines in participants' plasma. Treadmill testing with Gardner protocol was used to evaluate participants' walking capacity. Pain-free walking distance, maximum walking distance, and walking time were recorded. Finally, a nomogram model based on logistic regression was built to predict impaired walking performance. RESULTS: A total of 20 relevant autophagy-related genes were identified, and these genes were confirmed to be expressed at low levels in our PAD participants. Western blotting demonstrated that the expression of autophagic marker proteins beclin-1 and LC3BII were significantly reduced in PAD patients' PBMCs. ssGSEA revealed that most of the autophagy-related genes were strongly correlated with immune function, with the largest number of associated genes showing interaction between cytokine-and-cytokine receptors (CCR). In this context, the chemokines growth-related oncogene (GRO) and neutrophil activating protein2 (NAP2) are highly expressed in the plasma of WalkByLab PAD patients and were significantly negatively correlated with the walking distance assessed by Gardner treadmill testing. Finally, the plasma NAP2 level (AUC: 0.743) and derived nomogram model (AUC: 0.860) has a strong predictive potential to identify a poor walking capacity. CONCLUSIONS: Overall, these data highlight both the important role of autophagy and autophagy-related genes in PAD and link them to vascular inflammation (expression of chemokines). In particular, chemokine NAP2 emerged as a novel biomarker that can be used to predict the impaired walking capacity in PAD patients.

Guidelines adherence in the prevention and management of chronic kidney disease in patients with diabetes mellitus on the background of recent European recommendations - a registry-based analysis.

BACKGROUND: Recent European Society of Cardiology (ESC)/European Association for the Study of Diabetes (EASD) guidelines provide recommendations for detecting and treating chronic kidney disease (CKD) in diabetic patients. We compared clinical practice with guidelines to determine areas for improvement. METHODS: German database analysis of 675,628 patients with type 1 or type 2 diabetes, with 134,395 included in this analysis. Data were compared with ESC/EASD recommendations. RESULTS: This analysis included 17,649 and 116,747 patients with type 1 and type 2 diabetes, respectively. The analysis showed that 44.1 and 49.1 % patients with type 1 and type 2 diabetes, respectively, were annually screened for CKD. Despite anti-diabetic treatment, only 27.2 % patients with type 1 and 43.5 % patients with type 2 achieved a target HbA1c of < 7.0 %. Use of sodium-glucose transport protein 2 inhibitors (1.5 % type 1/8.7 % type 2 diabetes) and glucagon-like peptide-1 receptor agonists (0.6 % type 1/5.2 % type 2 diabetes) was limited. Hypertension was controlled according to guidelines in 41.1 and 67.7 % patients aged 18-65 years with type 1 and 2 diabetes, respectively, (62.4 vs. 68.4 % in patients > 65 years). Renin angiotensin aldosterone inhibitors were used in 24.0 and 40.9 % patients with type 1 diabetes (micro- vs. macroalbuminuria) and 39.9 and 47.7 %, respectively, in type 2 diabetes. CONCLUSIONS: Data indicate there is room for improvement in caring for diabetic patients with respect to renal disease diagnosis and treatment. While specific and potentially clinically justified reasons for non-compliance exist, the data may serve well for a critical appraisal of clinical practice decisions.

Impact of chemotherapeutic effects on the pathophysiology of the arterial wall - insights from peripheral arterial disease.

Systemic antineoplastic treatment agents represent one of the fastest developing medical fields. Oncological treatment is becoming increasingly individualized and new targets with corresponding agents, are constantly being developed. In tandem with this progress, new combinations and algorithms have evolved and patient's outcome have improved. Expanding tumors rely on a growing neovascular network to maintain their increased metabolism, which is caused by an accelerated reproduction rate. Accordingly, interrupting this supply mechanism is a major component of antineoplastic pharmaceutics and is a hallmark of cancer treatment. With advances in cancer treatment, long-term side effects have become an important consideration, especially in cases of neoplasia in young patients. While neuropathy and cardiotoxicity are well documented, vascular adverse events remain poorly understood. The mutual risk factors, like smoking and increased age, complicate the association between the vascular pathology and the earlier antineoplastic therapy. A deeper understanding of the effects of chemotherapy on peripheral arterial disease could lead to more detailed pathophysiological insight into both maladies and to new treatment options.

Effect of ACEI and ARB treatment on nitric oxide-dependent endothelial function.

Background: Angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) are widely used as a first-line therapy for the treatment of cardiovascular disease. Here, ACEI modulate the bradykinin receptor (BDKRB1 and BDKRB2) system and NO-dependent endothelial function, thus determining cardiovascular health and regenerative arteriogenesis. The current study aims at evaluating nitric oxide-dependent endothelial function, and gene expression of bradykinin receptors in peripheral blood mononuclear cells (PBMC) from patients with ACEI or ARB treatment. Patients and methods: The WalkByLab has been established to screen cardiovascular patients for peripheral artery disease and coronary artery disease. In total 177 patients from WalkByLab with heterogenous disease and risk status were randomly selected, divided according to their medication history into the following groups: 1. ACEI group, 2. ARB group or 3. non-ACE/ARB group. Total plasma nitrite/nitrate (NO) levels were measured, endothelial function was evaluated by assessing flow meditated dilation (FMD). PBMC were isolated from peripheral whole blood, and gene expression (qRT-PCR) of bradykinin receptors and angiotensin converting enzyme were assessed. Results: Plasma total NO concentration in the ACEI group (24.66±16.28, µmol/l) was increased as compared to the ARB group (18.57±11.58, µmol/l, P=0.0046) and non-ACE/ARB group (16.83±8.64, µmol/l, P=0.0127) in patients between 40 to 90 years of age. However, FMD values (%) in the ACEI group (7.07±2.40, %) were similar as compared to the ARB (6.35±2.13, %) and non-ACE/ARB group (6.51±2.15, %), but significantly negatively correlated with age. Interestingly, BDKRB1 mRNA level was significantly higher and BDKRB2 mRNA level lower in the ACEI group (BDKRB1 3.88-fold±1.05, BDKRB2 0.22-fold±0.04) as compared to the non-ACE/ARB group (BDKRB1 1.00-fold±0.39, P<0.0001, BDKRB2 1.00-fold±0.45, P=0.0136). Conclusions: ACEI treatment enhances total nitrite/nitrate concentration, furthermore, upregulates BDKRB1 in PBMC, but downregulates BDKRB2 mRNA expression. FMD is a strong determinant of vascular aging and is sensitive to underlying heterogenous cardiovascular diseases.

Renal function deterioration in adult patients with type-2 diabetes.

BACKGROUND: To explore, in a large group of patients with type-2 diabetes (T2DM), renal function decline in terms of the slope of the estimated glomerular filtration rate (eGFR) over time, and to find out how classical risk factors, such as the presence of hypertension, dyslipidemia and microalbuminuria, affect the renal function. METHODS: The analysis included 32,492 adult T2DM patients from the DIVE/DPV registries who had serial eGFR determinations and information on the presence of microalbuminuria, hypertension and dyslipidemia available. RESULTS: Patients had a mean age of 66.3 years, 52.6% were male with a mean BMI of 31.7 kg/m2. The mean eGFR was 78.4 ± 21.4 mL/min/1.73m2. The results showed that the prevalence of renal function impairment understood as chronic kidney disease (CKD) is considerable (53.0%) in a population of patients with T2DM and has a high incidence rate of 6.6% within a year. Serial determinations of the eGFR are, however, infrequent (7.8% of all patients) and these patients are characterised by the presence of a high-risk profile for CKD, such as hypertension (88.1%) and dyslipidemia (66.1%). Over a three-year time period, 30.9% of the patients had an eGFR slope of -12 mL/min/1.73m2 or more; and more than a doubled proportion of patients with an eGFR < 30 mL/min/1.73 m2 (3.8% vs. 1.8%; p < 0.001). Hypertension and albuminuria contributed to renal function decline while dyslipidemia did not negatively affect the slope. CONCLUSION: CKD is highly prevalent in patients with T2DM. Serial surveillance of the glomerular filtration rate is, however, not established in clinical practice, which would be necessary as indicated by a doubling of patients with an eGFR < 30 mL/min/1.73 m2 within 3 years. Moreover, the use of renin-angiotensin blocking agents was low, pointing at considerable room for improvement. Taken together we conclude that a closer surveillance of patients with diabetes based on the presence of further risk factors is mandatory combined with a mandatory prescription of RAS blocking agents once microalbuminuria and / or renal function deterioration develops.

Loop Diuretics in Acute Kidney Injury Prevention, Therapy, and Risk Stratification.

BACKGROUND: Loop diuretics (LD) are widely used in emergency and intensive care medicine. SUMMARY: The substances increase the clearance of electrolytes and water; thus, they allow us to control hypervolemia and to prevent patients from pulmonary edema. LD are also frequently applied to patients with an acute decrease in glomerular filtration rate, namely, acute kidney injury (AKI). Nevertheless, volume depletion may be associated with reduced renal perfusion and possibly slower restitution or even aggravation of kidney dysfunction. Several trials on the preventive or therapeutic efficacy of LD have been published since the early 1970s. Our review article is intended to summarize the most important references related to this topic. In addition, we discuss the diagnostic value of the so-called furosemide stress test. The currently available data indicate that LD may act in a beneficial manner as long as euvolemia is maintained (matched hydration). Key Massages: LD are not beneficial for AKI treatment if kidney-related endpoints are considered. In certain situations, AKI prevention with LD can be associated with favorable outcomes as long as euvolemia is maintained. LD can help to identify AKI subjects at a higher risk of AKI progression, but the exact clinical consequences need to be determined.

Cell-Based Therapies in Acute Kidney Injury (AKI).

Acute kidney injury frequently occurs in hospitalized patients all over the world. The prognosis remains poor since specific therapies for promoting kidney regeneration/repair are still missing. In recent years cell-based strategies have improved AKI outcomes under experimental circumstances. Four groups of cells, each of them displaying certain biological and functional characteristics have been evaluated in AKI, induced Pluripotent Stem Cells (iPSCs), Spermatagonial Stem Cells (SSCs), Proangiogenic Cells (PACs) and Endothelial Colony Forming Cells (ECFCs), and Mesenchymal Stem Cells (MSCs). All of these have been documented to stabilize either parameters of kidney excretory dysfunction and/or certain morphological parameters. The mechanisms responsible for AKI protection include direct (cell incorporation) and indirect processes, the latter being mediated by humoral factors and particularly by the production of so-called extracellular vesicles. Cell-derived vesicular organelles have been shown to carry pro-regenerative micro-RNA molecules which stabilize the vascular and tubular function. The first trials in humans have been initiated, the majority of such trials employs MSCs. However, any transfer of cell-based strategies in the clinical practice is potentially associated with significant difficulties. These include cell availability, tolerance and competence. The article intends to summarize essential informations about all of the four populations mentioned above and to discuss implications for the management of human AKI.

Porcine arteriogenesis based on vasa vasorum in a novel semi-acute occlusion model using high-resolution imaging.

Bridging collaterals (BC) develop in several chronic total artery occlusion diseases, and can prevent extensive myocardial necrosis. Yet, their origin, growth process, and histo-morphology are still unclear. Since vasa vasorum (VV) may take part in collateralization, we hypothesized that VV are the basis for BCs. To comprehensively investigate this arteriogenesis process, we used high-resolution imaging, including corrosion casts, post-mortem angiography with stereoscopy, micro-CT, and immunohistology, in combination with a novel semi-acute vessel occlusion model. This porcine model was produced by implanting a copper stent minimally invasively into the left anterior descending coronary artery. To define the kinetics of arteriogenesis, pigs (n = 11) were assigned to one of the five euthanasia timepoints: day 0.5 (D0.5, n = 2), D3 (n = 2), D5 (n = 1), D7 (n = 3), or D12 (n = 3) after stent implantation. We found that (1) BCs originate from longitudinally running type 1 VV, mainly VV interna, partially also from VV externa; (2) the growth of VV to BC is rapid, occurring within 7 days; and (3) porcine BCs are likely functionally relevant, considering an observed 102% increase in the number of smooth muscle cell layers in their vascular wall. High-resolution imaging in a minimally invasive non-acute vessel occlusion model is an innovative technique that allowed us to provide direct evidence that porcine BCs develop from the VV. These data may be crucial for further studies on the treatment of angina pectoris and thromboangiitis obliterans through therapeutic stimulation of BC development.

Long-term individual shear rate therapy counterpulsation enhances plasma nitrite release in patients with PAD.

BACKGROUND: Individual shear rate therapy (ISRT) has been designed as a novel non-invasive treatment option for peripheral artery disease (PAD) patients and has been shown to improve endothelial function and walking distance. The aim of this study was to elucidate the impact of ISRT on the level of nitric oxide in patient blood plasma and the expression of related molecular markers in peripheral blood mononuclear cells (PBMCs). Molecular diagnostic tests were performed for two ISRT trials. PATIENTS AND METHODS: In ISRT-1 26 healthy subjects underwent one session of treadmill training and one session of ISRT respectively in a cross-over design. In ISRT-2 14 PAD patients with a stable intermittent claudication underwent a 30 hours long-term treatment. Plasma nitrite release as well as the mRNA expression of NOS2 and key regulators of the kallikrein-kinin system were measured in PBMCs at different time points. RESULTS: Short-term ISRT revealed significantly decreased NOS2 expression in PBMCs of healthy volunteers and PAD patients. Long-term ISRT, in turn, demonstrated a significant plasma nitrite increase in PAD patients. CONCLUSIONS: We verified that long-term ISRT stimulates the vascular system and exerts a comparable effect to physical exercise in regards to NO release, which coincide with recent findings regarding an improvement of endothelial function. However, further studies are necessary to investigate the role for circulating leukocytes.
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Adaptation of external counterpulsation based on individual shear rate therapy improves endothelial function and claudication distance in peripheral artery disease.

BACKGROUND: External counterpulsation therapy enhances blood flow and was shown to improve endothelial function and quality of life in coronary artery disease patients. However, high pressures of up to 300 mmHg may lead to malperfusion of the ischaemic limb. To improve the clinical outcome of patients with peripheral artery disease (PAD), we adjusted external counterpulsation and developed a novel non-invasive approach termed individual shear rate therapy (ISRT). PATIENTS AND METHODS: In the present study, 14 patients with a Fontaine stage IIb and femoral-popliteal PAD underwent 30 hours of ISRT over 5 weeks. For ISRT, individual treatment pressures that do not exceed 160 mmHg were assessed by Doppler flow parameters during counterpulsation (individual shear rate diagnosis) in order to enhance and maximise peripheral perfusion. The study aimed to enhance peripheral perfusion and evaluate the primary clinical endpoint endothelial function, as well as to perform preliminary analysis of the ankle brachial index (ABI) and walking distance. RESULTS: Doppler flow measurements in the lower limb (ankle) validated that maximum blood flow velocity during systole and acceleration doubled during ISRT. Study results demonstrated that long-term ISRT significantly increased flow-mediated dilation (FMD) in the brachial artery (0.13+/- 0.09 mm to 0.38+/- 0.05 mm; p < 0.05), while nitromediated dilation (0.36+/- 0.10 mm to 0.45+/- 0.08 mm) remained and common femoral artery FMD did not reach statistical significance (0.38+/- 0.08 mm to 0.67+/- 0.19 mm; p<0.05). Initial claudication distance considerably improved for all patients after 30 hours of ISRT (92.6 +/- 8.2 metres to 280+/- 101.3 metres, p<0.05), just like the absolute claudication distance, which showed a more than 2.5-fold increase (167.8+/- 18.1 metres to 446.7+/- 133.3 metres; p<0.05). The ABI did not improve (0.58+/- 0.03 to 0.65+/- 0.04). CONCLUSIONS: Our data demonstrate that long-term ISRT is a potential novel non-invasive treatment to improve endothelial function and absolute pain-free walking distance for PAD patients.

Lipoprotein(a) as a risk factor for atherosclerotic cardiovascular disease in patients in non-metropolitan areas of Brandenburg, Germany.

Background and aims: In the non-metropolitan region of Brandenburg (Germany), which is characterized by high rates of cardiovascular diseases and underserved medical care, there is a lack of awareness regarding lipoprotein(a) [Lp(a)] as a risk factor. In addition, data from patients with atherosclerotic cardiovascular disease (ASCVD) in diverse regional backgrounds, including the understudied Brandenburg cohort, and various healthcare statuses remain insufficient. Methods: In this WalkByLab study, Lp(a) levels were monitored in a non-metropolitan cohort (n = 850) in Brandenburg, Germany, comprising 533 patients at high cardiovascular risk and 317 healthy controls. Patients underwent a comprehensive angiological screening, which included blood serum analysis, assessment of medical and family history, cardiovascular risk, and disease status, and evaluation of lifestyle and quality of life. All parameters were evaluated with regard to two groups based on Lp(a) levels: low (<50 mg/dl) and high (≥50 mg/dl). Results: Brandenburg patients with cardiovascular diseases showed higher Lp(a) levels than healthy controls (24.2% vs. 14.8%, p = 0.001). Logistic regression analysis with different characteristics revealed that Lp(a) was an independent risk factor significantly associated with ASCVD (OR 2.26, 95% CI 1.32-3.95, p = 0.003). The high-Lp(a) group showed a higher proportion of patients with coronary artery disease, peripheral artery disease, or cerebrovascular disease compared to the low-Lp(a) group (50% vs. 36.8%; 57.7% vs. 45.8%; 17.6% vs. 9.2%; p = 0.004); also, a higher percentage of patients in the high-Lp(a) group had heart failure (72.8% vs. 53.2%, p = 0.014) and myocardial infarction (24.7% vs. 13.9%, p = 0.001). The high-Lp(a) group exhibited higher rates of statins (63.1% vs. 50.4%, p = 0.003), ezetimibe (14.8% vs. 5.5.%, p = 0.001), and beta-blockers (55.7% vs. 40.7%, p = 0.001) use. Lp(a) levels were found to be independent of physical activity or smoking behavior and did not change over time (12 months). Conclusions: Our study highlights the significance of elevated Lp(a) levels in Brandenburg cardiovascular patients and identifies them as an independent risk factor for ASCVD, which has implications for addressing cardiovascular health of non-metropolitan populations.

Oxidized high-density lipoprotein associates with atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common heart arrhythmia and considered to be a progressive chronic disease associated with increased morbidity and mortality. Recent data suggest a link between inflammation, oxidative stress, and AF, although the underlying mechanisms are not fully understood. Because oxidized lipoproteins cause structural damage and electrophysiologic changes in cardiomyocytes, it is feasible that the transformation of atheroprotective high-density lipoprotein (HDL) into dysfunctional HDL contributes to the development of AF. OBJECTIVE: The purpose of this study was to determine whether a reduced antioxidant function of HDL is associated with the presence of AF. METHODS: In this multicenter cross-sectional cohort study, we assessed HDL function in sera of 1206 participants. Patients were divided into groups according to the presence of AF (n = 233) or no AF (n = 973). A validated cell-free biochemical assay was used to determine reduced HDL antioxidant function as assessed by increased normalized HDL lipid peroxide content (nHDLox). RESULTS: Participants with AF had a 9% higher mean relative nHDLox compared to persons without AF (P = .025). nHDLox was strongly associated with AF in all models of logistic regression, including the analysis adjusted for age, sex, and risk factors for AF (all P ≤.01). CONCLUSION: Reduced antioxidant HDL function is associated with the presence of AF, which supports growing evidence that impaired lipoprotein function is linked to electrophysiological changes in cardiomyocytes. nHDLox is one of several contributors to the initiation and perpetuation of AF.

Pulsatile shear and Gja5 modulate arterial identity and remodeling events during flow-driven arteriogenesis.

In the developing chicken embryo yolk sac vasculature, the expression of arterial identity genes requires arterial hemodynamic conditions. We hypothesize that arterial flow must provide a unique signal that is relevant for supporting arterial identity gene expression and is absent in veins. We analyzed factors related to flow, pressure and oxygenation in the chicken embryo vitelline vasculature in vivo. The best discrimination between arteries and veins was obtained by calculating the maximal pulsatile increase in shear rate relative to the time-averaged shear rate in the same vessel: the relative pulse slope index (RPSI). RPSI was significantly higher in arteries than veins. Arterial endothelial cells exposed to pulsatile shear in vitro augmented arterial marker expression as compared with exposure to constant shear. The expression of Gja5 correlated with arterial flow patterns: the redistribution of arterial flow provoked by vitelline artery ligation resulted in flow-driven collateral arterial network formation and was associated with increased expression of Gja5. In situ hybridization in normal and ligation embryos confirmed that Gja5 expression is confined to arteries and regulated by flow. In mice, Gja5 (connexin 40) was also expressed in arteries. In the adult, increased flow drives arteriogenesis and the formation of collateral arterial networks in peripheral occlusive diseases. Genetic ablation of Gja5 function in mice resulted in reduced arteriogenesis in two occlusion models. We conclude that pulsatile shear patterns may be central for supporting arterial identity, and that arterial Gja5 expression plays a functional role in flow-driven arteriogenesis.

Arteriogenesis is modulated by bradykinin receptor signaling.

RATIONALE: Positive outward remodeling of pre-existing collateral arteries into functional conductance arteries, arteriogenesis, is a major endogenous rescue mechanism to prevent cardiovascular ischemia. Collateral arterial growth is accompanied by expression of kinin precursor. However, the role of kinin signaling via the kinin receptors (B1R and B2R) in arteriogenesis is unclear. OBJECTIVE: The purpose of this study was to elucidate the functional role and mechanism of bradykinin receptor signaling in arteriogenesis. METHODS AND RESULTS: Bradykinin receptors positively affected arteriogenesis, with the contribution of B1R being more pronounced than B2R. In mice, arteriogenesis upon femoral artery occlusion was significantly reduced in B1R mutant mice as evidenced by reduced microspheres and laser Doppler flow perfusion measurements. Transplantation of wild-type bone marrow cells into irradiated B1R mutant mice restored arteriogenesis, whereas bone marrow chimeric mice generated by reconstituting wild-type mice with B1R mutant bone marrow showed reduced arteriogenesis after femoral artery occlusion. In the rat brain 3-vessel occlusion arteriogenesis model, pharmacological blockade of B1R inhibited arteriogenesis and stimulation of B1R enhanced arteriogenesis. In the rat, femoral artery ligation combined with arterial venous shunt model resulted in flow-driven arteriogenesis, and treatment with B1R antagonist R715 decreased vascular remodeling and leukocyte invasion (monocytes) into the perivascular tissue. In monocyte migration assays, in vitro B1R agonists enhanced migration of monocytes. CONCLUSIONS: Kinin receptors act as positive modulators of arteriogenesis in mice and rats. B1R can be blocked or therapeutically stimulated by B1R antagonists or agonists, respectively, involving a contribution of peripheral immune cells (monocytes) linking hemodynamic conditions with inflammatory pathways.

Tolerability safety and effectiveness of enhanced external counterpulsation versus individual shear rate therapy in patients with lower extremity atherosclerotic disease: A prospective pilot clinical trial.

AIMS: We aimed to investigate the tolerability, safety, and effectiveness of enhanced external counterpulsation therapy (EECP) versus individual shear rate therapy (ISRT) in patients with lower extremity atherosclerotic disease (LEAD). METHODS: Eighteen patients (age: 73.1 ± 6 years) underwent EECP and ISRT, each daily over five consecutive days in a cross-over design with a 1 week resting period in between the two regimens. A quality-of-life questionnaire was used to assess the therapy experience. Oxygen saturation (SO2 ), relative hemoglobin amount (rHb) and blood flow (Flow) in the capillary-venous-system (microcirculation) of the skin were monitored continuously during all therapy sessions using the micro-lightguide spectrophotometer, also known as oxygen to see (O2C). The effects of EECP and ISRT on the renal function and skeletal muscles were evaluated using serial blood and urine tests. RESULTS: EECP therapy had to be terminated early before the end of the 5th session in 10 patients (55.6%) because of discomfort. Four patients (22.2%) experienced signs of critical limb ischaemia under EECP. The total score of the quality-of-life questionnaire was significantly higher (= better tolerated) post-ISRT compared with EECP. Microcirculation monitoring revealed that ISRT significantly increased the SO2 , blood flow and rHb during the therapy. All three parameters remained significantly increased in the observation period after ISRT. The serum levels of creatin kinase and myoglobin increased significantly under EECP. CONCLUSIONS: ISRT significantly improves tolerability, safety, and effectiveness over EECP in patients with LEAD.

Defibrillator exchange in the elderly.

Background: Implantable cardioverter-defibrillator (ICD) therapy in elderly patients is controversial because survival benefits might be attenuated by nonarrhythmic causes of death. Objective: The purpose of this study was to investigate the outcome of septuagenarians and octogenarians after ICD generator exchange (GE). Methods: A total of 506 patients undergoing elective GE were analyzed to determine the incidence of ICD shocks and/or survival after GE. Patients were divided into a septuagenarian group (age 70-79 years) and an octogenarian group (age ≥80 years). The primary endpoint was death from any cause. Secondary endpoints were survival after appropriate ICD shock and death without experiencing ICD shocks after GE ("prior death"). Results: The association of the ICD with all-cause mortality and arrhythmic death was determined for septuagenarians and octogenarians. Comparing both groups, similar left ventricular ejection fraction (35.6% ± 11.2% vs 32.4% ± 8.9%) and baseline prevalence of New York Heart Association functional class III or IV heart failure (17.1% vs 14.7%) were found. During the entire follow-up period of the study, 42.5% of patients in the septuagenarian group died compared to 79% in the octogenarian group (P <.01). Prior death was significantly more frequent in both age groups than were appropriate ICD shocks. Predictors of mortality were common in both groups and included advanced heart failure, peripheral arterial disease, and renal failure. Conclusion: In clinical practice, decision-making for ICD GE among the elderly should be considered carefully for individual patients.

Leukocyte telomere length and mitochondrial DNA copy number associate with endothelial function in aging-related cardiovascular disease.

Background: We investigated the association between leukocyte telomere length, mitochondrial DNA copy number, and endothelial function in patients with aging-related cardiovascular disease (CVD). Methods: In total 430 patients with CVD and healthy persons were enrolled in the current study. Peripheral blood was drawn by routine venipuncture procedure. Plasma and peripheral blood mononuclear cells (PBMCs) were collected. Cell-free genomic DNA (cfDNA) and leukocytic genomic DNA (leuDNA) were extracted from plasma and PBMCs, respectively. Relative telomere length (TL) and mitochondrial DNA copy number (mtDNA-CN) were analyzed using quantitative polymerase chain reaction. Endothelial function was evaluated by measuring flow-mediated dilation (FMD). The correlation between TL of cfDNA (cf-TL), mtDNA-CN of cfDNA (cf-mtDNA), TL of leuDNA (leu-TL), mtDNA-CN of leuDNA (leu-mtDNA), age, and FMD were analyzed based on Spearman's rank correlation. The association between cf-TL, cf-mtDNA, leu-TL, leu-mtDNA, age, gender, and FMD were explored using multiple linear regression analysis. Results: cf-TL positively correlated with cf-mtDNA (r = 0.1834, P = 0.0273), and leu-TL positively correlated with leu-mtDNA (r = 0.1244, P = 0.0109). In addition, both leu-TL (r = 0.1489, P = 0.0022) and leu-mtDNA (r = 0.1929, P < 0.0001) positively correlated with FMD. In a multiple linear regression analysis model, both leu-TL (ß = 0.229, P = 0.002) and leu-mtDNA (ß = 0.198, P = 0.008) were positively associated with FMD. In contrast, age was inversely associated with FMD (ß = -0.426, P < 0.0001). Conclusion: TL positively correlates mtDNA-CN in both cfDNA and leuDNA. leu-TL and leu-mtDNA can be regarded as novel biomarkers of endothelial dysfunction.

Granulocyte colony-stimulating factor improves cerebrovascular reserve capacity by enhancing collateral growth in the circle of Willis.

BACKGROUND AND PURPOSE: Restoration of cerebrovascular reserve capacity (CVRC) depends on the recruitment and positive outward remodeling of preexistent collaterals (arteriogenesis). With this study, we provide functional evidence that granulocyte colony-stimulating factor (G-CSF) augments therapeutic arteriogenesis in two animal models of cerebral hypoperfusion. We identified an effective dosing regimen that improved CVRC and stimulated collateral growth, thereby improving the outcome after experimentally induced stroke. METHODS: We used two established animal models of (a) cerebral hypoperfusion (mouse, common carotid artery ligation) and (b) cerebral arteriogenesis (rat, 3-vessel occlusion). Following therapeutic dose determination, both models received either G-CSF, 40 µg/kg every other day, or vehicle for 1 week. Collateral vessel diameters were measured following latex angiography. Cerebrovascular reserve capacities were assessed after acetazolamide stimulation. Mice with left common carotid artery occlusion (CCAO) were additionally subjected to middle cerebral artery occlusion, and stroke volumes were assessed after triphenyltetrazolium chloride staining. Given the vital role of monocytes in arteriogenesis, we assessed (a) the influence of G-CSF on monocyte migration in vitro and (b) monocyte counts in the adventitial tissues of the growing collaterals in vivo. RESULTS: CVRC was impaired in both animal models 1 week after induction of hypoperfusion. While G-CSF, 40 µg/kg every other day, significantly augmented cerebral arteriogenesis in the rat model, 50 or 150 µg/kg every day did not show any noticeable therapeutic impact. G-CSF restored CVRC in mice (5 ± 2 to 12 ± 6%) and rats (3 ± 4 to 19 ± 12%). Vessel diameters changed accordingly: in rats, the diameters of posterior cerebral arteries (ipsilateral: 209 ± 7-271 ± 57 µm; contralateral: 208 ± 11-252 ± 28 µm) and in mice the diameter of anterior cerebral arteries (185 ± 15-222 ± 12 µm) significantly increased in the G-CSF groups compared to controls. Stroke volume in mice (10 ± 2%) was diminished following CCAO (7 ± 4%) and G-CSF treatment (4 ± 2%). G-CSF significantly increased monocyte migration in vitro and perivascular monocyte numbers in vivo. CONCLUSION: G-CSF augments cerebral collateral artery growth, increases CVRC and protects from experimentally induced ischemic stroke. When comparing three different dosing regimens, a relatively low dosage of G-CSF was most effective, indicating that the common side effects of this cytokine might be significantly reduced or possibly even avoided in this indication.

MISAGO 2: one-year outcomes after implantation of the Misago self-expanding nitinol stent in the superficial femoral and popliteal arteries of 744 patients.

PURPOSE: To evaluate the safety and efficacy of the Misago self-expanding rapid-exchange nitinol stent system for the treatment of femoropopliteal occlusive disease in a prospective multicenter observational trial (ClinicalTrials.gov; identifier NCT01118117). METHODS: Between April and October 2008, the registry enrolled 744 patients (496 men; 69 ± 10 years) who had symptomatic ≥ 70% stenosis or occlusion of the superficial femoral or popliteal arteries treated with the Misago stent. Mean length of the 750 lesions was 63.9 mm; 282 (37.6%) vessels were completely occluded. Primary study endpoints were the need for target lesion revascularization (TLR) and event-free survival rates for the assessment of efficacy and safety, respectively. At 6 and 12 months post intervention, clinical symptoms of recurrent ischemia and/or claudication, Rutherford category, and ankle-brachial index (ABI) at rest were assessed. RESULTS: In the study period, 945 stents were successfully deployed in the 750 lesions. The overall TLR rate was 10.1% among 671 (90.3%) patients evaluated at 1 year [3.1% among 709 (95.3%) patients at 6 months]. Event-free survival at 12 months was 84.9%. Mean ABIs improved by ≥ 0.1 in three quarters of the patients (76.0%) over 12 months. The Rutherford grade improved or remained stable in the majority of patients (95.5%) after 1 year. Stent fractures (13 grade 1, 2 grade 2) in 3.1% of stents examined radiographically (n=484) at 1 year were not related to any clinical events. Primary patency was recorded in 574 (87.6%) patients evaluated at 1 year post procedure. CONCLUSION: The Misago rapid-exchange nitinol stent showed promising efficacy and safety results, with a low stent fracture rate, in patients with femoropopliteal disease, making it a safe and reliable treatment option.