Impact of Moderate Altitude on Pro-Inflammatory Cytokines in Healthy Volunteers.

BACKGROUND: The induction of microvascular inflammation and the effects on cytokine production in blood due to hypoxia has been shown in the past. We have previously reported a statistically significant increase of the pro-inflammatory cytokine interleukin-8 (IL-8) in normobaric hypoxia in the setting of a hypoxia-chamber. In the present study, we sought to analyze plasma levels of inflammatory cytokines in a real-life stetting in order to foster our knowledge on hypoxia induced microvascular inflammation at moderate altitude. METHODS: Pro-inflammatory cytokines (IL-8, IL-6, TNF-α) were measured in an experimental field study, exposing 18 healthy volunteers to moderate hypoxia while staying at a mountain lodge in Diavolezza, Switzerland (2978 meters above sea level). Plasma cytokine levels were measured by ELISA. RESULTS: In contradiction to our results in a normobaric hypoxia-chamber, exposure to moderate hypoxia led to a significant decrease of plasma IL-8 levels in a real-life setting (from 2.902 (1.046 - 4.984) pg/mL to 1.395 (0.698 - 3.712) pg/mL, p = 0.034). Concentrations of IL-6 and TNF-α did not show statistically significant changes in comparison to baseline measurements. CONCLUSIONS: The results of this study show a decrease of proinflammatory cytokine IL-8 in a real life setting of moderate altitude in healthy individuals. Initiation of angiogenesis or subliminal stimulus for an altitude-induced inflammatory reaction may be explanations for this unexpected finding.

Preserved right ventricular integrity in a new telemetric rat model of severe pulmonary hypertension.

Telemetric monitoring of hemodynamic parameters has become an established standard in experimental models of pulmonary arterial hypertension (PAH). To that purpose, a dedicated catheter is usually implanted through the right ventricular wall of study animals. Drawbacks of this standard technique are as follows: obtained pressures are from the right ventricle and therefore only surrogates for pulmonary arterial pressures, and furthermore, right ventricular myocardium is always damaged to a certain degree. To overcome shortcomings of standard hemodynamic assessment, we modified an established rat model, where severe PAH is induced by left-sided pneumonectomy plus monocrotaline injection. We describe here a novel telemetry catheter implantation technique, where the device is advanced into the pulmonary artery via the remaining stump and the transmitter is placed in a subcutaneous pocket. A total of 105 rats were operated with a median (range) implantation time of 50 (30-88) min and an excellent perioperative survival of 93%. After monocrotaline induction on day 7, animals developed severe PAH with mean ± SD pressures of 75.9 ± 18.6 (systolic), 55.0 ± 18.0 (mean), and 42.1 ± 21.3 mmHg (diastolic) after 4 wk. Postmortem, the animals showed severe right ventricular hypertrophy, and histological analysis confirmed excessive medial hypertrophy and intimal hyperplasia, both characteristic features of human PAH. Comparison of the new telemetric model with standard microtip catheterization did not show relevant measurement differences. We established the first experimental animal model for PAH with preserved right ventricular integrity that allows direct telemetric monitoring of real-time systolic, mean, and diastolic pressures in the main pulmonary artery of freely moving rats.

Persistent Left Superior Vena Cava Draining Into the Left Atrium Found During Bypass Operation.

We report the case of a 72-year-old woman who underwent urgent coronary bypass grafting (CABG). Intraoperatively a persistent left superior vena cava (PLSVC) draining into the left atrium was detected. Because of the resulting right-to-left shunt volume even after complete drainage and collapse of the right atrium, the heart was still ejecting in the absence of significant aortic insufficiency. Thorough examination revealed a PLSVC draining into the left atrium. After ligation of the PLSVC, the CABG could be performed as planned.

Antiplatelet Usage Impacts Clot Density in Acute Anterior Circulation Ischemic Stroke.

We explored whether clot density in middle cerebral artery (MCA) occlusion is related to clinical variables, stroke etiology, blood constituents, and prestroke medication. We performed a retrospective chart review of patients with acute ischemic stroke of the anterior circulation admitted to two Central European stroke centers. The acquisition of non-contrast enhanced CT (NECT) and CT angiography (CTA) within 4.5 h of symptom onset was obligatory. We assessed the site of MCA occlusion as well as density, area, and length of the clot in 150 patients. The Hounsfield unit values for the clot were divided with contralateral MCA segment to yield relative Hounsfield Unit ratio (rHU). The site of the vessel occlusion (M1 vs. M2) and antiplatelet usage, but not stroke etiology, significantly influenced rHU. We found an inverse correlation of rHU with erythrocyte count (p < 0.001). The multivariate analysis revealed that a higher rHU (i.e., clot being more hyperdense) was more likely with the use of antiplatelets (OR 4.24, CI 1.10-16.31, p = 0.036). Erythrocyte (OR 0.18, CI 0.05-0.55, p = 0.003), and thrombocyte counts (OR 0.99, CI 0.98-0.99, p = 0.029) were associated with odds for more hypodense clots (lower rHU). Our study disclosed that antiplatelet therapy impacts the composition of intracranial clots of the anterior circulation.

Global research trends in the medical therapy of pulmonary arterial hypertension 2000-2014.

BACKGROUND: Pulmonary arterial hypertension is a progressive disease of the pulmonary vasculature that affects more than 200.000 patients worldwide. Without medical treatment it leads to right heart failure and death. Extensive fundamental and clinical research has been performed throughout the globe to modify the disease and improve survival. METHODS: We performed a bibliometric study on medical treatment for pulmonary arterial hypertension to identify study characteristics, impact factors and the countries of origin of basic and clinical studies that were published between 2000 and 2014. For visualization of the obtained data density equalizing maps were prepared. RESULTS: A total of 681 studies were eligible, of these 56% were clinical studies that have included a total of 30960 patients. Most studies were performed on endothelin receptor antagonists, followed by prostacyclins and phosphodiesterase type 5 inhibitors. Impact factors did not differ between clinical and basic science studies. The United States for clinical studies, and China for basic science studies were identified as main contributors to the global scientific output. CONCLUSIONS: This first bibliometric study in the field of pulmonary arterial hypertension shows that a significant amount of scientific research was performed within the last 14 years mainly in North America, Asia and Europe. As current trends in this field of research we identified combination therapies and Asian countries being a new hatchery for emerging experimental and clinical studies.

Urinary Output Predicts Survival in Patients Undergoing Extracorporeal Membrane Oxygenation Following Cardiovascular Surgery.

OBJECTIVES: Extracorporeal membrane oxygenation represents a valuable and rapidly evolving therapeutic option in patients with severe heart or lung failure following cardiovascular surgery. However, survival remains poor and accurate risk stratification challenging. Therefore, we evaluated the predictive value of urinary output within 24 hours after extracorporeal membrane oxygenation initiation on mortality in patients undergoing venoarterial extracorporeal membrane oxygenation support following cardiovascular surgery and aimed to improve established risk prediction models. DESIGN: Single-center, observational registry. SETTING: University-affiliated tertiary care center. PATIENTS: We included 205 patients undergoing veno-arterial extracorporeal membrane oxygenation therapy following cardiovascular surgery at a university-affiliated tertiary-care center into our single-centre registry. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During a median follow-up time of 35 months (interquartile range, 19-69), 64% of patients died. Twenty-four-hour urinary output was the strongest predictor of outcome among renal function variables with an adjusted hazard ratio per 1 SD of 0.55 (95% CI, 0.40-0.76; p < 0.001) for 30-day mortality and of 0.65 (95% CI, 0.53-0.86; p = 0.002) for 2-year long-term mortality. Most remarkably, 24-hour urinary output showed additional prognostic value beyond that achievable with the simplified acute physiology score-3 and sequential organ failure assessment score indicated by improvements in the category-free net reclassification index for 30-day mortality (simplified acute physiology score-3: 36%, p = 0.015; sequential organ failure assessment score: 36%, p = 0.02), as well as for 2-year mortality (simplified acute physiology score-3: 33%, p = 0.02; sequential organ failure assessment score: 43%, p = 0.005). CONCLUSIONS: We identified 24-hour urinary output as a strong and easily available predictor of mortality in patients undergoing extracorporeal membrane oxygenation therapy following cardiovascular surgery. Implementation of 24-hour urinary output leads to a substantial improvement of established risk prediction models in this vulnerable patient population. These results are particularly compelling because measurement of urinary output is inexpensive and routinely performed in all critical care units.

Stem Cell Therapy for Myocardial Infarction 2001-2013 Revisited.

Stem cell therapy for ischemic heart disease was an emerging concept in the early 2000s. First hopes were largely overshadowed by rather inconsistent results in human trials conducted in the middle of the decade. We aimed at investigating how the field of stem cell research expanded worldwide over the years using scientometric methods. We performed a PubMed inquiry and screened a total of 2609 publications dealing with stem cell therapy for myocardial infarction in the years 2001-2013. Density equalizing maps were used to visualize important centres of stem cell research worldwide. This systematic bibliometric study revealed an increasing research interest in the field of stem cell research in the context of ischemic heart disease over the last decade. Though some of the large human trials failed to show significant effects of stem cell therapy, especially basic science represents an ever growing field that evolved promising new concepts over the last couple of years. The scientific principle of protective paracrine mediators released from transplanted stem cells seems to bear great potential for future cell-free therapeutic use. However, further mechanistic insights are needed before transition from bench to bedside should be attempted, taking the lessons learned from previous studies into account.

Concomitant femoro-femoral bypass graft during surgery for acute type A dissection to treat lower limb malperfusion.

We report the case of a 69-year-old male patient who was admitted to our department with an acute type A dissection complicated by ischemia of the left lower limb. During surgery for acute type A dissection, the patient underwent concomitant femoro-femoral crossover bypass graft placement to ensure blood supply of the left lower limb during surgery and minimize ischemia-reperfusion injury. The patient underwent supracoronary replacement of the ascending aorta while in deep circulatory arrest with a deepest core temperature of 25°C. Postoperative computed tomography showed antegrade perfusion and patency of the crossover bypass. Postoperative course was eventless without sequelae, especially of the left lower limb. We conclude that concomitant crossover bypass graft reduces the risk of ischemia-reperfusion injury in lower limb ischemia in patients undergoing surgery for acute type A dissection.

Biodegradable, thermoplastic polyurethane grafts for small diameter vascular replacements.

Biodegradable vascular grafts with sufficient in vivo performance would be more advantageous than permanent non-degradable prostheses. These constructs would be continuously replaced by host tissue, leading to an endogenous functional implant which would adapt to the need of the patient and exhibit only limited risk of microbiological graft contamination. Adequate biomechanical strength and a wall structure which promotes rapid host remodeling are prerequisites for biodegradable approaches. Current approaches often reveal limited tensile strength and therefore require thicker or reinforced graft walls. In this study we investigated the in vitro and in vivo biocompatibility of thin host-vessel-matched grafts (n=34) formed from hard-block biodegradable thermoplastic polyurethane (TPU). Expanded polytetrafluoroethylene (ePTFE) conduits (n=34) served as control grafts. Grafts were analyzed by various techniques after retrieval at different time points (1 week; 1, 6, 12 months). TPU grafts showed significantly increased endothelial cell proliferation in vitro (P<0.001). Population by host cells increased significantly in the TPU conduits within 1 month of implantation (P=0.01). After long-term implantation, TPU implants showed 100% patency (ePTFE: 93%) with no signs of aneurysmal dilatation. Substantial remodeling of the degradable grafts was observed but varied between subjects. Intimal hyperplasia was limited to ePTFE conduits (29%). Thin-walled TPU grafts offer a new and desirable form of biodegradable vascular implant. Degradable grafts showed equivalent long-term performance characteristics compared to the clinically used, non-degradable material with improvements in intimal hyperplasia and ingrowth of host cells.

Myocardial infarct size measurement using geometric angle calculation.

BACKGROUND: In basic cardiovascular research focusing on animal models of myocardial infarction (MI), the measurement of infarct size is performed by planimetry of histological sections of the heart. However, in the setting of chronic MI with ongoing changes in ventricular geometry caused by wall thinning and hypertrophy, the scar area tends to become smaller. MATERIALS AND METHODS: Here, in this study we compared infarct measurements in tissue sections (of rat and porcine hearts) based on three different calculation approaches, that is, infarct area, infarct lengths and infarct angles utilizing the centroid of the left ventricle using a newly developed calculation approach. RESULTS: Infarct sizes from all three measurement approaches showed significant correlation with parameters of cardiac function. However, results derived from area measurements were significantly smaller than those obtained using the other two measurement approaches due to scar thinning (infarct size area: 14·81% ± 1·27 SEM, length: 23·94% ± 2·04 SEM, angle: 24·75% ± 2·13 SEM, P < 0·0001, n = 30). Moreover, results from angle measurements evidenced a much better correlation with parameters of cardiac function in a small animal model of chronic MI (e.g. ejection fraction, angle: r = -0·73; length: r = -0·64; area: r = -0·59, n = 30) as well as in a large animal model of acute MI (angle: r = -0·82; area: r = -0·67, n = 10). CONCLUSIONS: We concluded that area-, length- and angle-based measurements can be used to determine the relative infarct size in acute MI models, although an area-based measurement might be less accurate in the setting of chronic MI. Our new method of infarct angle measurement is a reliable and simple way to calculate infarct size compared with conventional measurement approaches.

Establishment of Extracorporeal Circulation under Local Anesthesia in a Patient with an Acute Type A Aortic Dissection Complicated by Cardiac Tamponade.

We report the case of an 82-year-old female who presented in a hemodynamically unstable condition to the emergency department of our institution. Transthoracic echo showed a hemodynamically relevant pericardial effusion and the suspicion of an intimal flap in the ascending aorta. The subsequent computed tomography scan revealed a Type A dissection that was limited to the ascending aorta. To prevent hemodynamic deterioration the patient was prepped and draped awake and underwent femoral cannulation for extracorporeal circulation under local anesthesia. After commencing extracorporeal circulation the patient was anesthetized and intubated. During this whole time period no relevant drop in mean arterial pressure was observed. The patient underwent routine replacement of the ascending aorta and was extubated the day after surgery without any neurologic sequelae. Awake cannulation and inception of extracorporeal circulation can prevent the hemodynamic deterioration and cardiac arrest often seen during induction of anesthesia in patients with cardiac tamponade.

Cardiac magnetic resonance postcontrast T1 time is associated with outcome in patients with heart failure and preserved ejection fraction.

BACKGROUND: The underlying pathophysiology of heart failure with preserved ejection fraction (HFPEF) is incompletely understood, but myocardial extracellular matrix accumulation is thought to play a major role. Our aims were to estimate myocardial extracellular matrix using cardiac magnetic resonance T1 mapping and to assess the relationship between pathobiology/pathophysiology and prognosis. METHODS AND RESULTS: Patients with suspected HFPEF (n=100) were enrolled in this prospective, observational study. Confirmatory diagnostic tests, cardiac magnetic resonance imaging including T1 mapping, and invasive hemodynamic assessments were performed at baseline. Sixty-one patients with confirmed HFPEF entered a longitudinal outcome-monitoring phase (mean, 22.9±5.0 months), during which 16 had a cardiac event. Cardiac magnetic resonance T1 time (hazard ratio, 0.99; 95% confidence interval, 0.98-0.99; P=0.046), left atrial area (hazard ratio, 1.08; 95% confidence interval, 1.03-1.13; P<0.01), and pulmonary vascular resistance (hazard ratio, 1.01; 95% confidence interval, 1.00-1.01; P=0.03) were significantly associated with cardiac events. Patients with T1 times below the median (<388.3 ms) were at greater risk of cardiac events than the rest of the group (P<0.01). Extracellular matrix of left ventricular biopsies (n=9), quantified by TissueFAXS technology correlated with T1 time (R=0.98; P<0.01). T1 time also correlated with right ventricular-pulmonary arterial coupling (pulmonary vascular resistance: R=-0.36; P<0.01; right ventricular ejection fraction: R=0.28; P=0.01). CONCLUSIONS: In the present preliminary study, cardiac magnetic resonance postcontrast T1 time is associated with prognosis in HFPEF, suggesting postcontrast T1 as possible biomarker for HFPEF.

Exhaled nitric oxide measurement to monitor pulmonary hypertension in a pneumonectomy-monocrotaline rat model.

The use of fractional exhaled nitric oxide (FeNO) has been suggested as a quantitative marker for pulmonary arterial hypertension (PAH) in humans. To further characterize FeNO in PAH we investigated this marker in a rodent model. Since there is no standardized technique for FeNO measurement in animals, we intended to reduce measuring errors and confounders of an existing published method by mathematical modification and tested its applicability in an NO-regulating therapy concept of PAH. Thirty-three male Sprague-Dawley rats underwent unilateral pneumonectomy and monocrotaline (MCT) injection and were observed for 49 days. A telemetric catheter was introduced into the left pulmonary artery to continuously record mean pulmonary arterial pressure (mPAP), and FeNO was assessed. After 35 days, animals were randomized to receive either oral l-arginine (300 mg/kg) in combination with tetrahydrobiopterin (20 mg/kg) therapy (n = 12) or vehicle (n = 11) daily over a period of 14 days. mPAP at baseline was 17.19 ± 9.62 mmHg, which increased to 53.1 ± 10.63 mmHg 28 days after monocrotaline exposure (P < 0.001). Using the modified technique, we found an inverse correlation between exhaled NO and pulmonary pressures before (r = -0.366, P = 0.043) and after MCT (r = -0.363, P = 0.038) as well as after therapy administration (r = -0.657, P = 0.02). Our modified technique proved robust in a rodent model, since valid and reproducible data were gained and showed an inverse correlation between exhaled NO and mPAP, whereas the existing method did not.

Healing characteristics of electrospun polyurethane grafts with various porosities.

Pore size and porosity control the rate and depth of cellular migration in electrospun vascular fabrics and thus have a strong impact on long-term graft success. In this study we investigated the effect of graft porosity on cell migration in vitro and in vivo. Polyurethane (PU) grafts were fabricated by electrospinning as fine-mesh, low-porosity grafts (void fraction (VF) 53%) and coarse-mesh, high-porosity grafts (VF 80%). The fabricated grafts were evaluated in vitro for endothelial cell attachment and proliferation. Prostheses were investigated in a rat model for either 7 days, 1, 3 or 6 months (n=7 per time point) and analyzed after retrieval by biomechanical analysis and various histological techniques. Cell migration was calculated by computer-assisted morphometry. In vitro, fine-pore mesh favored early cell attachment. In vivo, coarse mesh grafts revealed significantly higher cell populations at all time points in all areas of the conduit wall. Biomechanical tests indicated sufficient compliance, tensile and suture retention strength before and after implantation. Increased porosity improves host cell ingrowth and survival in electrospun conduits. These conduits show successful natural host vessel reconstitution without limitation of biomechanical properties.

Electrospun small-diameter polyurethane vascular grafts: ingrowth and differentiation of vascular-specific host cells.

No small-diameter synthetic graft has yet shown comparable performance to autologous vessels. Synthetic conduits fail due to their inherent surface thrombogenicity and the development of intimal hyperplasia. In addressing these shortcomings, electrospinning offers an interesting alternative to other nanostructured, cardiovascular substitutes because of the close match of electrospun materials to the biomechanical and structural properties of native vessels. In this study, we investigated the in vivo behavior of electrospun, small-diameter conduits in a rat model. Vascular grafts composed of polyurethane were fabricated by electrospinning. Prostheses were implanted into the abdominal aorta in 40 rats for either 7 days, 4 weeks, 3 months, or 6 months. Retrieved specimens were evaluated by histology, immunohistochemical staining, confocal laser scanning microscopy, and scanning electron microscopy. At all time points, we found no evidence of foreign body reaction or graft degradation. The overall patency rate of the intravascular implants was 95%. Within 7 days, grafts revealed ingrowth of host cells. CD34+ cells increased significantly from 7 days up to 6 months of implantation (P < 0.05). Myofibroblasts and myocytes showed increasing cell numbers up to 3 months (P < 0.05). Ki67 staining indicated unaltered cell proliferation during the whole follow-up period. Besides biomechanical benefits, electrospun polyurethane grafts exhibit excellent biocompatibility in vivo. Cell immigration and differentiation seems to be promoted by the nanostructured artificial matrix.

Mesenchymal stem cells restore lung function by recruiting resident and nonresident proteins.

Because human lungs are unlikely to repair or regenerate beyond the cellular level, cell therapy has not previously been considered for chronic irreversible obstructive lung diseases. To explore whether cell therapy can restore lung function, we administered allogenic intratracheal mesenchymal stem cells (MSCs) in the trachea of rats with chronic thromboembolic pulmonary hypertension (CTEPH), a disease characterized by single or recurrent pulmonary thromboembolic obliteration and progressive pulmonary vascular remodeling. MSCs were retrieved only in high pressure-exposed lungs recruited via a homing stromal derived factor-1α/CXCR4 pathway. After MSC administration, a marked and long-lasting improvement of all clinical parameters and a significant change of the proteome level were detected. Beside a variation of liver proteome, such as caspase-3, NF-κB, collagen1A1, and α-SMA, we also identified more than 300 resident and nonresident lung proteins [e.g., myosin light chain 3 (P16409) or mitochondrial ATP synthase subunit alpha (P15999)]. These results suggest that cell therapy restores lung function and the therapeutic effects of MSCs may be related to protein-based tissue reconstituting effects.