Indirect comparison of capmatinib treatment from GEOMETRY mono-1 trial to SOC in German patients with locally advanced or metastatic NSCLC harboring METex14 skipping mutations.

BACKGROUND: This study provides comparative evidence of the selective MET inhibitor capmatinib versus standard of care (SOC) in first-line (1 L) and second-line (2 L) non-small cell lung cancer (NSCLC) patients with METex14 mutations in German routine care. METHODS: SOC data were collected from German routine care via retrospective chart review. Analyses were conducted as naive and propensity score adjusted (PSA) comparisons to capmatinib-treated patients within the GEOMETRY mono-1 trial. Effectiveness endpoints included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), time to CNS progression (CNSprog), and exploratory safety endpoints. RESULTS: The SOC arm included 119 patients in 1 L and 46 in 2 L versus 60 patients in 1 L and 81 in 2 L treated with capmatinib, with balanced baseline characteristics after PSA. In 1 L, the naive comparison showed a significant benefit of capmatinib versus SOC for OS (median: 25.49 vs 14.59 months; HR 0.58; 95 % CI 0.39-0.87; P = 0.011), PFS (median: 12.45 vs 5.03 months; HR: 0.44; 95 % CI: 0.31-0.63; P < 0.001), and ORR (event rate: 68.3 vs 26.9 %; RR 2.54; 95 % CI 1.80-3.58; P < 0.001). In 2 L, OS, PFS, and ORR showed positive trends favoring capmatinib over SOC. Capmatinib treatment in the 1 L and 2 L led to significant benefit in CNSprog. PSA analyses showed consistent results to naive analysis. Exploratory safety endpoints indicated a manageable safety profile for capmatinib. CONCLUSIONS: The present study demonstrates the important role of capmatinib in providing robust clinically meaningful benefit to patients with NSCLC harboring METex14 mutations and its significant role in preventing the development of brain metastases.

[Acute dyspnea]. / Akute Dyspnoe.

ACUTE DYSPNEA: The leading symptom "acute dyspnea" and the causal underlying diseases have a high risk potential for an unfavorable course of treatment with a high letality. This overview of possible causes, diagnostic procedures and guideline-based therapy is intended to help implement a targeted and structured emergency medical care in the emergency department. The leading symptom "acute dyspnea" is present in 10% of prehospital and 4-7% of patients in the emergency department. The most common conditions in the emergency department with the leading symptom "acute dyspnea" are heart failure in 25%, COPD in 15%, pneumonia in 13%, respiratory disorders in 8%, and pulmonary embolism in 4%. In 18% of cases, the leading symptom "acute dyspnea" is sepsis. The in-hospital letality is high and amounts to 9%. In critically ill patients in the non-traumatologic resuscitation room, respiratory disorders (B-problems) are present in 26-29%. In addition to cardiovascular disease, noncardiovascular disease may underlie "acute dyspnea" and requires differential diagnostic consideration. A structured approach can contribute to a high degree of certainty in the clarification of the leading symptom "acute dyspnea".

[Do we need Respiratory Care Units or Respiratory Emergency Centers?] / Brauchen wir Respiratory Care Units oder Atemnotfallzentren?

Although lung and heart diseases often occur together, the focus in acute medical emergency care frequently lies on the treatment of the cardiological symptoms only. This leads to a repeated patient visit and an impaired quality of life. How can this treatment gap be closed?

Patients with severe aortic stenosis and coexisting pulmonary hypertension treated by transapical transcatheter aortic valve replacement-Is there a need for increased attention?

OBJECTIVES: Aim of this study is to elucidate the impact of pulmonary hypertension on patients treated with a transapical aortic valve replacement. BACKGROUND: In patients with aortic stenosis (AS) the coexistence of pulmonary hypertension (PH) is associated with increased peri-operative risk for surgical aortic valve replacement. For transcatheter aortic valve replacement (TAVR), it is unknown whether transapical TAVR (TA-TAVR) is associated with increased peri-interventional risk in PH patients. METHODS: We performed a single center analysis in 189 patients with severe AS with (AS + PH) or without PH (AS - PH) undergoing TA-TAVR. PH was defined by mean pulmonary artery pressure ≥25 mmHg assessed by right heart catheterization (exclusion of 64 patients due to missing results). As the primary endpoint a combination of 30-day mortality or cardiopulmonary resuscitation (CPR) was analyzed. RESULTS: Seventy three patients (58.4%) had PH. Increased peri-interventional risk in AS + PH patients was reflected by an increased rate of the primary endpoint in comparison to AS - PH patients (24.7 vs. 3.8%; p = .002). A higher proportion of acute kidney injury (34.2 vs. 15.7%; p = .025) was found in AS + PH patients while AS - PH patients showed a higher rate of bleeding in comparison AS + PH patients (18.5 vs. 6.8% p = .050). CONCLUSION: Patients with AS + PH treated by TA-TAVR are at increased peri-interventional risk for severe complications in comparison to AS - PH patients. Therefore, the identification of preventive therapeutic strategies is needed. CLASSIFICATIONS: TAVR, transapical, pulmonary hypertension, aortic stenosis.

Reduction of sleep-disordered breathing following effective percutaneous mitral valve repair with the MitraClip system.

PURPOSE: This study tested the hypothesis that a reduction of pulmonary congestion achieved by a reduction of mitral regurgitation (MR) severity in heart failure (HF) patients is associated with reduced event lengths of sleep-disordered breathing (SDB). METHODS: We prospectively enrolled 20 consecutive HF patients who underwent MitraClip implantation. Patients underwent cardiorespiratory polygraphic recording prior to and after percutaneous mitral valve repair (PMVR). Beyond routinely established indicators of apneas and hypopneas per hour (respiratory event index), we manually analyzed apnea event lengths. RESULTS: MitraClip implantation led to marked reduction of MR severity and a reduction in left atrial pressure. These hemodynamic changes were accompanied by changes in SDB: the subtype of SDB switched from CSA to OSA in 4 patients. Likewise, quantitative indicators of SDB were altered in both forms of SDB with a reduction in circulatory delay (CSA 38 ± 14 vs. 33 ± 15 s.; p = 0.002 and OSA 34 ± 9 vs. 28 ± 6 s.; p = 0.02) and a corresponding reduction in ventilation lengths in CSA patients (42 ± 15 vs. 37 ± 13 s.; p = 0.05). CONCLUSION: A reduction of pulmonary congestion as achieved by a decrease of left atrial pressure through successful MitraClip implantation is associated with a reduction in respiratory event lengths, further pointing towards a relation between SDB and HF.

Oxygen dependence of endothelium-dependent vasodilation: importance in chronic obstructive pulmonary disease.

INTRODUCTION: Epidemiological studies have shown increased morbidity and mortality in patients with coronary artery disease (CAD) and chronic obstructive pulmonary disease (COPD). We aimed to characterize the oxygen dependence of endothelial function in patients with CAD and coexisting COPD. MATERIAL AND METHODS: In CAD patients with and without COPD (n = 33), we non-invasively measured flow-mediated dilation (FMD) and intima-media thickness (IMT) of the brachial artery (BA), forearm blood flow (FBF), and perfusion of the cutaneous microcirculation with laser Doppler perfusion imaging (LDPI). In an experimental setup, vascular function was assessed in healthy volunteers (n = 5) breathing 12% oxygen or 100% oxygen in comparison to room air. RESULTS: COPD was associated with impaired FMD (3.4 ±0.5 vs. 4.2 ±0.6%; p < 0.001) and increased IMT (0.49 ±0.04 vs. 0.44 ±0.04 mm; p <0.01), indicating functional and structural alterations of the BA in COPD. Forearm blood flow and LDPI were comparable between the groups. Flow-mediated dilation correlated with capillary oxygen pressure (pO2, r = 0.608). Subgroup analysis in COPD patients with pO2 > 65 mm Hg and pO2 ≤ 65 mm Hg revealed even lower FMD in patients with lower pO2 (3.0 ±0.5 vs. 3.7 ±0.4%; p < 0.01). Multivariate analysis showed that pO2 was a predictor of FMD independent of the forced expiratory volume and pack years. Exposure to hypoxic air led to an acute decrease in FMD, whereby exposure to 100% oxygen did not change vascular function. CONCLUSIONS: Our data suggest that in CAD patients with COPD, decreased systemic oxygen levels lead to endothelial dysfunction, underlining the relevance of cardiopulmonary interaction and the potential importance of pulmonary treatment in secondary prevention of vascular disease.

Impact of Continuous Positive Airway Pressure on Left Ventricular Systolic Loading and Coronary Flow Reserve in Healthy Young Men.

BACKGROUND: Increased augmentation index (AIx) is accompanied by an elevated cardiovascular risk. A reduction of AIx is known for long-term continuous positive airway pressure (CPAP) therapy. We hypothesised that acute preload and left ventricular workload effects AIx and subendocardial viability ratio (SEVR) as a marker of coronary flow reserve. METHODS: Increased augmentation index and central blood pressure parameters were measured by radial artery tonometry in 17 healthy men (32/±6years) at rest and during CPAP ventilation at pressures of 5, 10mbar and after recovery. In a subset of seven individuals, haemodynamic parameters and autonomic function were additionally examined using combined impedance cardiography and continuous noninvasive blood pressure monitoring. RESULTS: Continuous positive airway pressure reduced heart rate corrected (AIx@75) (-2.8±8.1 [rest] to -10.7±11.3 [5mbar], p<0.01, to -12.2±10.5% [10mbar], p<0.01) and systolic time integral as a marker of left ventricular workload (2115±231 [rest] to 1978±290 [5mbar], p=0.02 to 1940±218 [10mbar], p<0.01 to 2013±241mmHg/s per min [recovery], p=0.03), while central systolic pressure did not change during CPAP. Total Peripheral Resistance Index increased reaching level of significance at 10mbar CPAP condition (1701±300 [rest] to 1850±301dyn*s*m2/cm5 [10mbar], p=0.04). There was a reversible increase of SEVR under CPAP conditions. CONCLUSIONS: Continuous positive airway pressure ventilation acutely reduces AIx, heart rate and left ventricular workload in healthy young men. These effects seem to be mediated by left ventricular filling pressure, workload and reflection wave. Furthermore, we found an increase of subendocardial viability ratio as an indication for a rising coronary flow reserve by CPAP.

Transcatheter Aortic Valve Implantation in High-Risk/Inoperable Patients: Repositionable versus Non-Repositionable Self-Expanding Valve.

BACKGROUND AND AIM OF THE STUDY: Although next-generation cardiac prostheses have shown favorable results in transcatheter aortic valve implantation (TAVI), these have mostly been documented in intermediate-risk patients. Whether this could be translated to high-risk patients is not known. Hence, the safety and clinical performance of the new, repositionable CoreValve Evolut R-System (ERS) was evaluated by comparison with a non-repositionable CoreValve-System (CVS), in 96 high-risk/inoperable (HRI) patients. METHODS: The primary safety end points were mortality and stroke, defined by VARC-2 criteria, at 30 days. Clinical performance end points were described by VARC-2 criteria, focusing on: (i) higher-grade atrioventricular conduction blocks with concomitant permanent pacemaker (PM) implantation; (ii) vascular complications (VCs); and (iii) aortic regurgitation (AR). The ERS and CVS patients underwent TAVI in equal proportions. RESULTS: In this study, 63% of patients in the CVS group and 82% in the ERS group were defined as HRI. One in-hospital death was documented after 30 days. With regards to the HRI cohort, no difference in rates of PM use were noted (ERS 20% versus CVS 20%; p >0.9999). ERS patients were characterized by a higher prevalence of peripheral vascular disease (PVD) (46% versus 21%; p <0.05), but fewer VCs (13% versus 41%; p <0.01). Both cohorts showed low rates of moderate-to-severe paravalvular AR (ERS 6% versus CVS 5%; p = 0.8639). However, ERS seemed to offer a favorable hemodynamic performance, with a significantly improved AR index (26.3 versus 22.3; p <0.05). TAVI with the ERS was associated with a higher stroke rate (3% versus 0%; p = 0.1232) after necessary postdilatation processes. CONCLUSIONS: In comparison to last-generation CVS, the repositionable ERS is safe and effective in HRI patients. Similar rates of PM use were noted for each group. together with a favorable hemodynamic performance and fewer vascular complications.

Comparison of the simple red blood cell adhesiveness/aggregation test with the laser-assisted optical rotational cell analyzer: Red blood cell aggregation in patients with coronary artery disease and a healthy control group.

BACKGROUND: Red blood cell (RBC) aggregation influences blood flow properties, impacts blood microcirculation and consequently oxygen delivery. Different methods are established to determine RBC aggregation: under static conditions (i.e. the RBC adhesiveness/aggregation test (EAAT)) or under shear conditions (i.e. the laser-assisted optical rotational cell analyzer (LORCA)). OBJECTIVE: Comparison of these two different methods in detecting the RBC aggregation of patients with coronary artery disease (CAD) and of healthy controls. METHODS: RBC aggregation was quantified in peripheral venous blood of patients with CAD and healthy controls using EAAT and LORCA. RESULTS: Both methods detected an increased RBC aggregation in patients with CAD compared to the healthy control group: the ratio of clot-free area to whole area (rCFA) detected with EAAT (15.65 vs. 11.30%), and aggregation index (66.33 vs. 53.90%), shear rate of disaggregation (SDA) (105.59 vs. 69.21 s-1), and upstroke/ttop (0.03 vs. 0.02 au/s) detected with LORCA device were increased, aggregation half time (detected with LORCA) was decreased (2.11 vs. 3.60 s). rCFA (EAAT) correlated with SDA (LORCA). CONCLUSIONS: Both methods determine an increased RBC aggregation in patients with CAD. However, only one measurement parameter of the LORCA seems to reflect the same RBC aggregation properties as the EAAT.

Reduction of neutrophilic lung inflammation by inhalation of the compatible solute ectoine: a randomized trial with elderly individuals.

BACKGROUND: Compatible solutes are natural substances that are known to stabilize cellular functions. Preliminary ex vivo and in vivo studies demonstrated that the compatible solute ectoine restores natural apoptosis rates of lung neutrophils and contributes to the resolution of lung inflammation. Due to the low toxicity and known compatibility of the substance, an inhalative application as an intervention strategy for humans suffering from diseases caused by neutrophilic inflammation, like COPD, had been suggested. As a first approach to test the feasibility and efficacy of such a treatment, we performed a population-based randomized trial. OBJECTIVE: The objective of the study was to test whether the daily inhalation of the registered ectoine-containing medical device (Ectoin® inhalation solution) leads to a reduction of neutrophilic cells and interleukin-8 (IL-8) levels in the sputum of persons with mild symptoms of airway disease due to lifelong exposure to environmental air pollution. METHODS: A double-blinded placebo-controlled trial was performed to study the efficacy and safety of an ectoine-containing therapeutic. Prior to and after both inhalation periods, lung function, inflammatory parameters in sputum, serum markers, and quality-of-life parameters were determined. RESULTS: While the other outcomes revealed no significant effects, sputum parameters were changed by the intervention. Nitrogen oxides (nitrate and nitrite) were significantly reduced after ectoine inhalation with a mean quotient of 0.65 (95% confidence interval 0.45-0.93). Extended analyses considering period effects revealed that the percentage of neutrophils in sputum was significantly lower after ectoine inhalation than in the placebo group (P=0.035) even after the washout phase. CONCLUSION: The current study is the first human trial in which the effects of inhaled ectoine on neutrophilic lung inflammation were investigated. Besides demonstrating beneficial effects on inflammatory sputum parameters, the study proves the feasibility of the therapeutic approach in an aged study group.

Prevalence of De Novo Aortic Valve Insufficiency in Patients After HeartWare VAD Implantation with an Intermittent Low-Speed Algorithm.

De novo aortic valve insufficiency (AI) is a frequent occurrence in patients supported with left ventricular assist device (LVAD). The European version of the HeartWare LVAD has intermittent low-speed software (lavare cycle) to facilitate intermittent aortic valve opening. We examined aortic valve opening status and prevalence of AI in patients supported with HeartWare LVAD and activated lavare cycle. HeartWare LVAD patients were prospectively monitored using serial echocardiograms at different time points after the LVAD implantation. Inclusion criteria were patients with no > mild AI and/or no aortic valve surgery at the time of LVAD implantation and at least 60 days of support. Three of 37 patients had aortic valve surgery and were excluded from the analysis. A total of 34 patients with mean age of 57 ± 12 years met the inclusion criteria. After median support duration of 408 days (77-1250 days), eight patients had trace/mild AI (24%) and one patient developed moderate AI (3%). An average pump flow, speed, and mean arterial pressure of 4.4 ± 0.6 L/min, 2,585 ± 147 rpm, and 88 ± 11 mmHg were documented, respectively. Aortic valve opening was persistently seen in 22 patients (65%). Aortic valve opening is frequent, and the development of > mild AI seems to be rare in patients supported with HeartWare LVAD.

Severe aortic valve stenosis in the elderly: high prevalence of sleep-related breathing disorders.

BACKGROUND: Aortic valve stenosis is common in the elderly, with a prevalence of nearly 3% in patients aged 75 years or older. Despite the fact that sleep-related breathing disorders (SRBD) are thought to be associated with cardiac disease, little is known about their prevalence in this patient cohort. The purpose of this study was to evaluate the prevalence of SRBD in older patients with aortic valve stenosis admitted for transcatheter aortic valve implantation. METHODS: Forty-eight consecutive patients (mean age 81±6 years; 37.5% male) with symptomatic aortic valve stenosis and considered for transcatheter aortic valve replacement were screened for SRBD. Sleep studies were performed by in-hospital unattended cardiorespiratory polygraphy measuring nasal air flow, chest and abdominal efforts, as well as oxygen saturation and body position. The patients were divided in subgroups dependent on the documented apnea-hypopnea index (AHI; no SRBD was defined as an AHI of <5 events/hour; mild SRBD as AHI 5-15 events/hour, and moderate to severe SRBD as AHI ≥15 events/hour). RESULTS: Thirty-seven patients (77%) had SRBD defined as an AHI of ≥5 events/hour. Eleven patients had an unremarkable investigation, with AHI <5 events/hour (mean 3.0±1.3 events/hour). Among patients with sleep apnea, 19 patients had mild SRBD, with an AHI of 5-15 events/hour (mean 9.9±3.4 events/hour) and 18 patients had moderate to severe SRBD (mean 26.6±11.3 events/hour). Mainly, obstructive apneas were found. Subgroups were not different regarding EuroSCORE (European System for Cardiac Operative Risk Evaluation) or aortic valve area. Also, no correlations were found between AHI and the additive or logistic EuroSCORE or aortic valve area. Significant correlations were found for AHI and N-terminal of the prohormone brain natriuretic peptide (r=0.53; P=0.003) and for AHI and glomerular filtration rate (r = -0.39; P=0.007). CONCLUSION: SRBD is common in elderly patients with symptomatic aortic valve stenosis admitted for transcatheter aortic valve replacement. Interestingly, this finding is not reflected by the currently used risk scores. Further randomized studies are needed to evaluate the clinical significance of concomitant SRBD in the management of severe aortic stenosis.

Macrovascular and microvascular function after implantation of left ventricular assist devices in end-stage heart failure: Role of microparticles.

BACKGROUND: The hemodynamic vascular consequences of implanting left ventricular assist devices (LVADs) have not been studied in detail. We investigated the effect of LVAD implantation compared with heart transplant (HTx) on microvascular and macrovascular function in patients with end-stage heart failure and evaluated whether microparticles may play a role in LVAD-related endothelial dysfunction. METHODS: Vascular function was assessed in patients with end-stage heart failure awaiting HTx, patients who had undergone implantation of a continuous-flow centrifugal LVAD, and patients who had already received a HTx. Macrovascular function was measured by flow-mediated vasodilation (FMD) using high-resolution ultrasound of the brachial artery. Microvascular function was assessed in the forearm during reactive hyperemia using laser Doppler perfusion imaging and pulsed wave Doppler. Age-matched patients without heart failure and without coronary artery disease (CAD) (healthy control subjects) and patients with stable CAD served as control subjects. Circulating red blood cell (CD253(+)), leukocyte (CD45(+)), platelet (CD31(+)/CD41(+)), and endothelial cell (CD31(+)/CD41(-), CD62e(+), CD144(+)) microparticles were determined by flow cytometry and free hemoglobin by enzyme-linked immunosorbent assay. RESULTS: FMD and microvascular function were significantly impaired in patients with end-stage heart failure compared with healthy control subjects and patients with stable CAD. LVAD implantation led to recovery of microvascular function, but not FMD. In parallel, increased free hemoglobin was observed along with red and white cell microparticles and endothelial and platelet microparticles. This finding indicates destruction of blood cells with release of hemoglobin and activation of endothelial cells. HTx and LVAD implantation led to similar improvements in microvascular function. FMD increased and microparticle levels decreased in patients with HTx, whereas shear stress during reactive hyperemia was similar in patients with LVADs and patients with HTx. CONCLUSIONS: Our data suggest that LVAD support leads to significant improvements in microvascular perfusion and hemodynamics. However, destruction of blood cells may contribute to residual endothelial dysfunction potentially by increasing nitric oxide scavenging capacity.

Stenting as a rescue treatment of a pulmonary artery false aneurysm caused by swan-ganz catheterization.

Pulmonary vascular injury is a rare but life-threatening complication of Swan-Ganz catheterization. We report an 82-year old patient who underwent right heart catheterization by a balloon-tipped catheter because of suspected pulmonary hypertension. After deflation of the catheter in the wedge position, hemoptoe appeared associated with acute respiratory insufficiency requiring respiratory support by intubation and mechanical ventilation. Pulmonary angiography showed the formation of a false aneurysm of a segment artery of the left lower lobe. Immediate interventional therapy was performed by the implantation of two coated coronary stent grafts into the injured pulmonary artery thereby excluding the false aneurysm. Bleeding was stopped by this interventional approach while antegrade blood flow was maintained. Long term follow-up after 3 months showed an effective treatment with a completely thrombotic false aneurysm. However, despite oral anticoagulation and dual antiplatelet therapy, graft patency could not be achieved after 3 months. In summary, implantation of coated stents is a feasible and safe approach for the acute and long term treatment of potentially life-threatening condition of a pulmonary artery false aneurysm while treatment to achieve long term patency of the affected vessel still remains an issue to be resolved.

Recovery of neutrophil apoptosis by ectoine: a new strategy against lung inflammation.

The life span of neutrophilic granulocytes has a determining impact on the intensity and duration of neutrophil driven lung inflammation. Based on the compatible solute ectoine, we aimed to prevent anti-apoptotic reactions in neutrophils triggered by the inflammatory microenvironment in the lung. Neutrophils from chronic obstructive pulmonary disease patients and control individuals were exposed to inflammatory mediators and xenobiotics in the presence or absence of ectoine. The in vivo relevance of this approach was tested in xenobiotic-induced lung inflammation in rats. The reduction of apoptosis rates of ex vivo-exposed neutrophils from all study groups was significantly restored in the presence of ectoine. However, natural apoptosis rates not altered by inflammatory stimuli were not changed by ectoine. Mechanistic analyses demonstrated the preventive effect of ectoine on the induction of anti-apoptotic signalling. Neutrophilic lung inflammation induced by single or multiple expositions of animals to environmental particles was reduced after the therapeutic intervention with ectoine. Analyses of neutrophils from bronchoalveolar lavage indicate that the in vivo effect is due to the restoration of neutrophil apoptosis. Ectoine, a compound of the highly compliant group of compatible solutes, demonstrates a reproducible and robust effect on the resolution of lung inflammation.

Dietary inorganic nitrate mobilizes circulating angiogenic cells.

Nitric oxide (NO) was implicated in the regulation of mobilization and function of circulating angiogenic cells (CACs). The supposedly inert anion nitrate, abundant in vegetables, can be stepwise reduced in vivo to form nitrite, and consecutively NO, representing an alternative to endogenous NO formation by NO synthases. This study investigated whether inorganic dietary nitrate influences mobilization of CACs. In a randomized double-blind fashion, healthy volunteers ingested 150 ml water with 0.15 mmol/kg (12.7 mg/kg) of sodium nitrate, an amount corresponding to 100-300 g of a nitrate-rich vegetable, or water alone as control. Mobilization of CACs was determined by the number of CD34(+)/KDR(+) and CD133(+)/KDR(+) cells using flow cytometry and the mobilization markers stem cell factor (SCF) and stromal cell-derived factor-1a (SDF-1α) were determined in plasma via ELISA. Nitrite and nitrate were measured using high-performance liquid chromatography and reductive gas-phase chemiluminescence, respectively. NOS-dependent vasodilation was measured as flow-mediated vasodilation. Further mechanistic studies were performed in mice after intravenous application of nitrite together with an NO scavenger to identify the role of nitrite and NO in CAC mobilization. Nitrate ingestion led to a rise in plasma nitrite together with an acute increase in CD34(+)/KDR(+) and CD133(+)/KDR(+)-CACs along with increased NOS-dependent vasodilation. This was paralleled by an increase in SCF and SDF-1α and the maximal increase in plasma nitrite correlated with CD133(+)/KDR(+)-CACs (r=0.73, P=0.016). In mice, nitrate given per gavage and direct intravenous injection of nitrite led to CAC mobilization, which was abolished by the NO scavenger cPTIO, suggesting that nitrite mediated its effect via formation of NO. Dietary inorganic nitrate acutely mobilizes CACs via serial reduction to nitrite and NO. The nitrate-nitrite-NO pathway could offer a novel nutritional approach for regulation of vascular regenerative processes.

Nitric oxide influences red blood cell velocity independently of changes in the vascular tone.

Nitric oxide (NO) plays a key role in regulation of vascular tone and blood flow. In the microcirculation blood flow is strongly dependent on red blood cells (RBC) deformability. In vitro NO increases RBC deformability. This study hypothesized that NO increases RBC velocity in vivo not only by regulating vascular tone, but also by modifying RBC deformability. The effects of NO on RBC velocity were analysed by intra-vital microscopy in the microcirculation of the chorioallantoic membrane (CAM) of the avian embryo at day 7 post-fertilization, when all vessels lack smooth muscle cells and vascular tone is not affected by NO. It was found that inhibition of enzymatic NO synthesis and NO scavenging decreased intracellular NO levels and avian RBC deformability in vitro. Injection of a NO synthase-inhibitor or a NO scavenger into the microcirculation of the CAM decreased capillary RBC velocity and deformation, while the diameter of the vessels remained constant. The results indicate that scavenging of NO and inhibition of NO synthesis decrease RBC velocity not only by regulating vascular tone but also by decreasing RBC deformability.

Characterization of macro-and microvascular function and structure in patients with type 2 diabetes mellitus.

OBJECTIVE: Diabetes mellitus (DM) leads to accelerated progression of arteriosclerosis with an increased risk of coronary events in comparison to non-diabetic patients with coronary artery disease (CAD). The precise and early detection of DM-induced vascular alterations is crucial to identify patients with high risk for cardiovascular complications. Thus, we aimed at simultaneously characterizing functional, physicomechanical, and structural vascular alterations in diabetic patients using a non-invasive approach. RESEARCH DESIGN AND METHODS: In CAD patients with and without type 2 diabetes mellitus (n=50), we non-invasively measured flow-mediated dilation (FMD) of the brachial artery as a marker for endothelial function, fractional diameter changes (FDC) as a marker for physicomechanical properties, intima-media thickness (IMT) as a marker for structural properties, and forearm blood flow (FBF) as a marker for microvascular function. RESULTS: DM was associated with reduced FMD (2.5±0.2 vs 4.8±0.4%; p≤0.001) indicating impaired macrovascular endothelial function. In parallel, reduced FDC (0.024±0.002 vs 0.034±0.004; p≤0.05) and increased IMT (0.38±0.01 vs 0.31±0.01mm; p≤0.001) indicated increased stiffness and enhanced structural alterations. Furthermore, reduced forearm blood flow during reactive hyperemia (10.7±1.0 vs. 15.3±1.4mL/min*100mL; p≤0.05) was found indicating microvascular dysfunction. Plasma glucose and HbA(1c) correlated with FMD (glucose: r=-0.32; HbA(1c): r=-0.45), IMT (glucose: r=0.54; HbA(1c): r=0.48) and FBF (glucose: r=-0.30) suggesting diabetes-specific effects on vascular properties. CONCLUSION: In patients with CAD, DM leads to functional and structural vascular alterations of the peripheral vasculature which are determined by the control of the disease underlining the relevance of a strict control of the DM to prevent accelerated atherosclerosis.