Platelets regulate ischemia-induced revascularization and angiogenesis by secretion of growth factor-modulating factors.

In ischemic tissue, platelets can modulate angiogenesis. The specific factors influencing this function, however, are poorly understood. Here, we characterized the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) expressed on platelets as a potent regulator of ischemia-driven revascularization. We assessed the relevance of the anaphylatoxin receptor C5aR1 on platelets in patients with coronary artery disease as well as those with peripheral artery disease and used genetic mouse models to characterize its significance for ischemia and growth factor-driven revascularization. The presence of C5aR1-expressing platelets was increased in the hindlimb ischemia model. Ischemia-driven angiogenesis was significantly improved in C5aR1-/- mice but not in C5-/- mice, suggesting a specific role of C5aR1. Experiments using the supernatant of C5a-stimulated platelets suggested a paracrine mechanism of angiogenesis inhibition by platelets by means of antiangiogenic CXC chemokine ligand 4 (CXCL4, PF4). Lineage-specific C5aR1 deletion verified that the secretion of CXCL4 depends on C5aR1 ligation on platelets. Using C5aR1-/-CXCL4-/- mice, we observed no additional effect in the revascularization response, underscoring a strong dependence of CXCL4 secretion on the C5a-C5aR1-axis. We identified a novel mechanism for inhibition of neovascularization via platelet C5aR1, which was mediated by the release of antiangiogenic CXCL4.

PrEdictive value of coMbined pre-test proBability and blOod gas anaLysis In pulmonary emboliSM-the EMBOLISM study.

In patients with suspected pulmonary embolism (PE), the number of unnecessary computed tomography pulmonary angiography (CTPA) scans remains high, especially in patients with low pre-test probability (PTP). So far, no study showed any additional benefit of capillary blood gas analysis (BGA) in diagnostic algorithms for PE. In this retrospective analysis of patients with suspected PE and subsequent CTPA, clinical data, D-dimer levels and BGA parameters (including standardized PaO2) were analyzed. Logistic regression analyses were performed to identify independent predictors for PE and reduce unnecessary CTPA examinations in patients with low PTP according to Wells score. Of 1538 patients, PE was diagnosed in 433 patients (28.2%). The original Wells score (odds ratio: 1.381 [95% CI 1.300-1.467], p < 0.001) and standardized PaO2 (odds ratio: 0.987 [95% CI 0.978-0.996], p = 0.005) were independent predictors for PE. After cohort adjustment for low PTP a D-dimer cut-off < 1.5 mg/L (278 patients (18.1%) with 18 PE (6.5%)) was identified in which a standardized PaO2 > 65 mmHg reduced the number of unnecessary CTPA by 31.9% with a 100% sensitivity. This approach was further validated in additional 53 patients with low PTP. In this validation group CTPA examinations were reduced by 32.7%. No patient with PE was missed. With our novel algorithm combining BGA testing with low PTP according to Wells score, we were able to increase the D-Dimer threshold to 1.5 mg/L and reduce CTPA examinations by approximately 32%.

JUUL™ing and Heating Lead to a Worsening of Arterial Stiffness.

Background: The widespread use of the JUUL™ device ignited a discussion about the effects these products have on harm reduction. Therefore, we conducted a study directly comparing the JUUL™ device with a cigarette, a heated tobacco product, and a nicotine-free e-cigarette to examine the acute effects on arterial stiffness. Methods: This crossover-designed study examines 20 occasional smokers (age 25.2 ± 2.5 years). Study participants used each of the four smoking devices for a duration of 5 min following a protocol. Peripheral blood pressure and parameters of arterial stiffness and endothelial vasodilator function such as the reactive hyperemia index and the augmentation index were measured using the EndoPAT™2000 before and after. Results: In addition to significant peripheral hemodynamic changes after 5 and 10 min (p < 0.05), the reactive hyperemia index showed a significant decrease for all devices 15 min after consumption and remained significantly decreased after 60 min (p < 0.01). The augmentation index adjusted for a heart rate of 75 bpm increased significantly for all devices 15 and 60 min after consumption (p < 0.01). Conclusions: In conclusion, the increases in blood pressure and arterial stiffness are similar after smoking, JUUL™ing, heating, and vaping. These changes may be associated with an increase in cardiovascular risks; however, an evaluation of the long-term effects of JUUL™ing, vaping and heating is needed.

Measurement of Blood Pressure by Ultrasound-The Applicability of Devices, Algorithms and a View in Local Hemodynamics.

OBJECTIVE: Due to ongoing technical progress, the ultrasonic measurement of blood pressure (BP) as an alternative to oscillometric measurement (NIBP) or the continuous non-invasive arterial pressure method (CNAP) moves further into focus. The US method offers several advantages over NIBP and CNAP, such as deep tissue penetration and the utilization of different arterial locations. APPROACH: Ten healthy subjects (six female, aged 30.9 ± 4.6 years) volunteered in our investigation. In the ultrasonic BP measurement, we differentiated between the directly measured (pulsatile diastolic and systolic vessel diameter) and indirectly calculated variables at three different artery locations on both arms, with two different ultrasound devices in the transversal and longitudinal directions of the transducer. Simultaneously, NIBP monitoring served as reference BP, while CNAP monitored the steady state condition of the arm under investigation. The Moens-Korteweg algorithm (MKE) and the algorithm of the working group of San Diego (SanD) were selected for the indirectly calculated ultrasonic BP data. MAIN RESULTS: With US, we were able to measure the BP at each selected arterial position. Due to the investigation setup, we found small but significant interactions of the main effects. Bland and Altman analysis revealed that US-BP measurement was similar to NIBP, with superior accuracy when compared to the established CNAP method. In addition, US-BP measurement showed that the measurement accuracy of both arms can be regarded as identical. In a detailed comparison of the selected arterial vascular sections, systematic discrepancies between the right and left arm could be observed. CONCLUSION: In our pilot study, we measured BP effectively and accurately by US using two different devices. Our findings suggest that ultrasonic BP measurement is an adequate alternative for live and continuous hemodynamic monitoring.

The C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets.

Platelets contribute to the regulation of tissue neovascularization, although the specific factors underlying this function are unknown. Here, we identified the complement anaphylatoxin C5a-mediated activation of C5a receptor 1 (C5aR1) on platelets as a negative regulatory mechanism of vessel formation. We showed that platelets expressing C5aR1 exert an inhibitory effect on endothelial cell functions such as migration and 2D and 3D tube formation. Growth factor- and hypoxia-driven vascularization was markedly increased in C5ar1-/- mice. Platelet-specific deletion of C5aR1 resulted in a proangiogenic phenotype with increased collateralization, capillarization and improved pericyte coverage. Mechanistically, we found that C5a induced preferential release of CXC chemokine ligand 4 (CXCL4, PF4) from platelets as an important antiangiogenic paracrine effector molecule. Interfering with the C5aR1-CXCL4 axis reversed the antiangiogenic effect of platelets both in vitro and in vivo.In conclusion, we identified a mechanism for the control of tissue neovascularization through C5a/C5aR1 axis activation in platelets and subsequent induction of the antiangiogenic factor CXCL4.

Differential Effects of Angiotensin-II Compared to Phenylephrine on Arterial Stiffness and Hemodynamics: A Placebo-Controlled Study in Healthy Humans.

The α1-adrenoceptor agonist phenylephrine (PE) and Angiotensin II (Ang II) are both potent vasoconstrictors at peripheral resistance arteries. PE has pure vasoconstrictive properties. Ang II, additionally, modulates central nervous blood pressure (BP) control via sympathetic baroreflex resetting. However, it is unknown whether Ang II vs. PE mediated vasoconstriction at equipressor dose uniformly or specifically modifies arterial stiffness. We conducted a three-arm randomized placebo-controlled cross-over trial in 30 healthy volunteers (15 female) investigating the effects of Ang II compared to PE at equal systolic pressor dose on pulse wave velocity (PWV), pulse wave reflection (augmentation index normalized to heart rate 75/min, AIx) and non-invasive hemodynamics by Mobil-O-Graph™ and circulating core markers of endothelial (dys-)function. PE but not Ang II-mediated hypertension induced a strong reflex-decrease in cardiac output. Increases in PWV, AIx, total peripheral resistance and pulse pressure, in contrast, were stronger during PE compared to Ang II at equal mean aortic BP. This was accompanied by minute changes in circulating markers of endothelial function. Moreover, we observed differential hemodynamic changes after stopping either vasoactive infusion. Ang II- and PE-mediated BP increase specifically modifies arterial stiffness and hemodynamics with aftereffects lasting beyond mere vasoconstriction. This appears attributable in part to different interactions with central nervous BP control including modified baroreflex function.

Microcirculation in Patients with Takotsubo Syndrome-The Prospective CIRCUS-TTS Study.

The pathophysiology of Takotsubo syndrome (TTS) is incompletely understood. A sympathetic overdrive with coronary microvascular dysfunction might play a central role. The aim of our study was to assess the status of the systemic microcirculation (MC) of patients with TTS, compared to patients with myocardial infarction (MI) and healthy subjects. The systemic microvascular function of 22 TTS patients, 20 patients with MI and 20 healthy subjects was assessed via sublingual sidestream dark-field imaging. In TTS and MI patients, measurements were performed during the acute phase (day 1, 3 and 5) and after 3 months. The measurement in healthy subjects was performed once. The assessed parameters were number of vessel crossings, number of perfused vessel crossings, proportion of perfused vessels, total vessel density and perfused vessel density. The results did not show relevant differences between the investigated groups. Some minor, albeit statistically significant, differences occurred rather randomly. The MC parameters of the TTS group did not show any relevant changes in the temporal course. A systemic microvascular dysfunction could not be identified as a contributing factor in the pathogenesis of TTS. A possible microvascular dysfunction might instead be caused by a local effect restricted to the coronary microvascular bed.

Prognostic Value of Different CMR-Based Techniques to Assess Left Ventricular Myocardial Strain in Takotsubo Syndrome.

Cardiac magnetic resonance (CMR)-derived left ventricular (LV) global longitudinal strain (GLS) provides incremental prognostic information on various cardiovascular diseases but has not yet been investigated comprehensively in patients with Takotsubo syndrome (TS). This study evaluated the prognostic value of feature tracking (FT) GLS, tissue tracking (TT) GLS, and fast manual long axis strain (LAS) in 147 patients with TS, who underwent CMR at a median of 2 days after admission. Long-term mortality was assessed 3 years after the acute event. In contrast to LV ejection fraction and tissue characteristics, impaired FT-GLS, TT-GLS and fast manual LAS were associated with adverse outcome. The best cutoff points for the prediction of long-term mortality were similar with all three approaches: FT-GLS -11.28%, TT-GLS -11.45%, and fast manual LAS -10.86%. Long-term mortality rates were significantly higher in patients with FT-GLS > -11.28% (25.0% versus 9.8%; p = 0.029), TT-GLS > -11.45% (20.0% versus 5.4%; p = 0.016), and LAS > -10.86% (23.3% versus 6.6%; p = 0.014). However, in multivariable analysis, diabetes mellitus (p = 0.001), atrial fibrillation (p = 0.001), malignancy (p = 0.006), and physical triggers (p = 0.006) outperformed measures of myocardial strain and emerged as the strongest, independent predictors of long-term mortality in TS. In conclusion, CMR-based longitudinal strain provides valuable prognostic information in patients with TS, regardless of the utilized technique of assessment. Long-term mortality, however, is mainly determined by comorbidities.

Impact of Morphine Treatment on Infarct Size and Reperfusion Injury in Acute Reperfused ST-Elevation Myocardial Infarction.

Current evidence regarding the effect of intravenous morphine administration on reperfusion injury and/or cardioprotection in patients with myocardial infarction is conflicting. The aim of this study was to evaluate the impact of morphine administration, on infarct size and reperfusion injury assessed by cardiac magnetic resonance imaging (CMR) in a large multicenter ST-elevation myocardial infarction (STEMI) population. In total, 734 STEMI patients reperfused by primary percutaneous coronary intervention <12 h after symptom onset underwent CMR imaging at eight centers for assessment of myocardial damage. Intravenous morphine administration was recorded in all patients. CMR was completed within one week after infarction using a standardized protocol. The clinical endpoint of the study was the occurrence of major adverse cardiac events (MACE) within 12 months after infarction. Intravenous morphine was administered in 61.8% (n = 454) of all patients. There were no differences in infarct size (17%LV, interquartile range [IQR] 8-25%LV versus 16%LV, IQR 8-26%LV, p = 0.67) and microvascular obstruction (p = 0.92) in patients with versus without morphine administration. In the subgroup of patients with early reperfusion within 120 min and reduced flow of the infarcted vessel (TIMI-flow ≤2 before PCI) morphine administration resulted in significantly smaller infarcts (12%LV, IQR 12-19 versus 19%LV, IQR 10-29, p = 0.035) and reduced microvascular obstruction (p = 0.003). Morphine administration had no effect on hard clinical endpoints (log-rank test p = 0.74) and was not an independent predictor of clinical outcome in Cox regression analysis. In our large multicenter CMR study, morphine administration did not have a negative effect on myocardial damage or clinical prognosis in acute reperfused STEMI. In patients, presenting early ( ≤120 min) morphine may have a cardioprotective effect as reflected by smaller infarcts; but this finding has to be assessed in further well-designed clinical studies.

Angiotensin II-mediated nondipping during sleep in healthy humans: effects on baroreflex function at subsequent daytime.

Blood pressure dipping at night is mediated by sleep-inherent, active downregulation of sympathetic vascular tone. Concomitantly, activity of the renin-angiotensin system is reduced, which might contribute to the beneficial effect of baroreflex downward resetting on daytime blood pressure homeostasis. To evaluate whether experimental nondipping mediated by angiotensin II during sleep would alter blood pressure and baroreflex function the next day in healthy humans, angiotensin-II or placebo (saline) was infused for a 7-h period at night, preventing blood pressure dipping in 11 sleeping normotensive individuals (5 males, balanced, crossover design). Baroreflex function was assessed about 1 h upon awakening and stop of infusion via microneurographic recordings of muscle sympathetic nerve activity (MSNA), showing that resting MSNA was significantly increased following angiotensin II nondipping compared with placebo (P = 0.029), whereas blood pressure and heart rate remained unchanged. Baroreflex sensitivity in response to vasoactive drug challenge was preserved, and neuroendocrine markers of fluid balance and electrolytes did not differ between conditions. Ambulatory blood pressure during subsequent daytime was not altered. Data were compared with analog experiments previously performed within the same subjects during awake daytime (ANCOVA). We conclude that angiotensin-II mediated nocturnal nondipping did not induce blood pressure elevation at subsequent daytime in healthy humans but was linked to increased vasoconstrictive sympathetic activity. This is in contrast to a prolonged increase in blood pressure in corresponding daytime experiments of the same individuals. Evidently, sleep strongly preserves normotensive blood pressure homeostasis in healthy humans.

GHRH-mediated GH release is associated with sympathoactivation and baroreflex resetting: a microneurographic study in healthy humans.

Previous research suggested substantial interactions of growth hormone (GH) and sympathetic nervous activity. This cross talk can be presumed both during physiological (e.g., slow-wave sleep) and pathological conditions of GH release. However, microneurographic studies of muscle sympathetic nerve activity (MSNA) and assessment of baroreflex function during acute GH-releasing hormone (GHRH)-mediated GH release were not conducted so far. In a balanced, double-blind crossover design, GHRH or placebo (normal saline) were intravenously administered to 11 healthy male volunteers. MSNA was assessed microneurographically and correlated with blood pressure (BP) and heart rate (HR) at rest before (pre-) and 30-45 (post-I) and 105-120 min (post-II) after respective injections. Additionally, baroreflex function was assessed via graded infusion of vasoactive drugs. GHRH increased GH serum levels as intended. Resting MSNA showed significant net increases of both burst rate and total activity from pre- to post-I and post-II following GHRH injections compared with placebo (ANOVA for treatment and time, burst rate: P = 0.028; total activity: P = 0.045), whereas BP and HR were not altered. ANCOVA revealed that the dependent variable MSNA was not affected by the independent variables mean arterial BP (MAP) or HR (MAP: P = 0.006; HR: P = 0.003). Baroreflex sensitivity at baroreflex challenge was not altered. GHRH-mediated GH release is associated with a significant sympathoactivation at central nervous sites superordinate to the simple baroreflex feedback loop because GH induced a baroreflex resetting without altering baroreflex sensitivity.

E-cigarettes and cigarettes worsen peripheral and central hemodynamics as well as arterial stiffness: A randomized, double-blinded pilot study.

The introduction of electronic cigarettes has led to widespread discussion on the cardiovascular risks compared to conventional smoking. We therefore conducted a randomized cross-over study of the acute use of three tobacco products, including a control group using a nicotine-free liquid. Fifteen active smokers were studied during and after smoking either a cigarette or an electronic cigarette with or without nicotine (eGo-T CE4 vaporizer). Subjects were blinded to the nicotine content of the electronic cigarette and were followed up for 2 hours after smoking a cigarette or vaping an electronic cigarette. Peripheral and central blood pressures as well as parameters of arterial stiffness were measured by a Mobil-O-Graph® device. The peripheral systolic blood pressure rose significantly for approximately 45 minutes after vaping nicotine-containing liquid ( p<0.05) and for approximately 15 minutes after smoking a conventional cigarette ( p<0.01), whereas nicotine-free liquids did not lead to significant changes during the first hour of follow-up. Likewise, heart rate remained elevated approximately 45 minutes after vaping an electronic cigarette with nicotine-containing liquid and over the first 30 minutes after smoking a cigarette in contrast to controls. Elevation of pulse wave velocity was independent from mean arterial pressure as well as heart rate in the electronic cigarette and cigarette groups. In this first of its kind trial, we observed changes in peripheral and central blood pressure and also in pulse wave velocity after smoking a cigarette as well as after vaping a nicotine-containing electronic cigarette. These findings may be associated with an increased long-term cardiovascular risk.

Thermoregulatory and Cardiovascular Consequences of a Transient Thyrotoxicosis and Recovery in Male Mice.

Thyroid hormones play a major role in body homeostasis, regulating energy expenditure and cardiovascular function. Given that obese people or athletes might consider rapid weight loss as beneficial, voluntary intoxication with T4 preparations is a growing cause for thyrotoxicosis. However, the long-lasting effects of transient thyrotoxicosis are poorly understood. Here we examined metabolic, thermoregulatory, and cardiovascular function upon induction and recovery from a 2-week thyrotoxicosis in male C57BL/6J mice. Our results showed that T4 treatment caused tachycardia, decreased hepatic glycogen stores, and higher body temperature as expected; however, we did not observe an increase in brown fat thermogenesis or decreased tail heat loss, suggesting that these tissues do not contribute to the hyperthermia induced by thyroid hormone. Most interestingly, when the T4 treatment was ended, a pronounced bradycardia was observed in the animals, which was likely caused by a rapid decline of T3 even below baseline levels. On the molecular level, this was accompanied by an overexpression of cardiac phospholamban and Serca2a mRNA, supporting the hypothesis that the heart depends more on T3 than T4. Our findings therefore demonstrate that a transient thyrotoxicosis can have pathological effects that even persist beyond the recovery of serum T4 levels, and in particular the observed bradycardia could be of clinical relevance when treating hyperthyroid patients.

Prolonged blood pressure elevation following continuous infusion of angiotensin II-a baroreflex study in healthy humans.

ANG II interacts with the sympathetic nervous system at central nervous blood pressure-regulating structures, including the baroreflex. It is unknown whether prolonged BP elevation mediated by high ANG II plasma levels could induce a persistent shift of the central nervous baroreflex setpoint, lasting beyond the short ANG II plasmatic half time of a few seconds, thereby consolidating elevated BP and/or increased SNA in healthy humans. In a blinded crossover design, ANG II or placebo (saline) was infused for a 6-h period in 12 resting normotensive students (6 males, 6 females) raising BP to borderline hypertensive levels. Between 60 and 120 min after the infusion period, muscle sympathetic nerve activity (MSNA) was assessed microneurographically and correlated with oscillometric BP measurements and heart rate at supine rest (baseline) and during pharmacologic baroreceptor challenge. Infusion of ANG II increased BP to borderline-hypertensive levels, as intended, whereas heart rate remained unaltered. At baroreflex assessment (i.e., 60-120 min after end of infusion period), systolic BP was significantly higher compared with placebo (Δ8.4 ± 3.1 mmHg; P < 0.05), whereas diastolic values were nearly equal between conditions. Baseline MSNA was neither decreased nor increased, and baroreflex sensitivity to vasoactive drug challenge was not altered. Our results show that elevation of ANG II plasma levels over 6 h was able to increase systolic, but not diastolic, BP far beyond blood-mediated ANG II effects. MSNA or heart rate did not counter-regulate this BP elevation, indicating that ANG II had sustainably reset the central nervous BP threshold of sympathetic baroreflex function to accept elevated BP input signals without counter-regulatory response.

Quality of life after thyroid surgery in women with benign euthyroid goiter: influencing factors including Hashimoto's thyroiditis.

BACKGROUND: Hashimoto's thyroiditis is associated with decreased quality of life (QoL). Thyroid surgery could hypothetically lead to an increase in QoL. METHODS: In a follow-up analysis of a prospective cohort study that included euthyroid women undergoing thyroid surgery for benign thyroid disease, 248 patients were willing to answer the SF-36 QoL questionnaire. RESULTS: At follow-up after a median of 26 months, only the SF-36 module of "bodily pain" had increased (P = .046). Preoperative anti-thyroid peroxidase antibody levels were positively correlated with increasing QoL in the SF-36 modules "bodily pain" (P < .001) and "role emotional" (P < .001). For the presence of histologically confirmed Hashimoto's thyroiditis, a significant positive correlation (P < .001) was found for all modules apart from "physical functioning." CONCLUSIONS: In women with benign euthyroid goiter, thyroid surgery does not lead to an overall improvement in health-related QoL. It should not be recommended for patients with elevated anti-thyroid peroxidase antibody levels. Patients with histologically confirmed Hashimoto's thyroiditis might benefit in terms of QoL.

The incidence of lymphocytic thyroid infiltration and Hashimoto's thyroiditis increased in patients operated for benign goiter over a 31-year period.

The incidence of Hashimoto's thyroiditis (HT) seems to have increased over the last several decades. Since there is a lack of recent studies in the literature that evaluate this phenomenon on a histological basis, we aimed to assess the incidence of lymphocytic thyroid infiltration (LTI) in our large surgical patient collective over a 31-year period. In our study, a total of 1,050 patients who had undergone uni- or bilateral thyroid surgery for benign goiter were included (150 patients in each group, during 1979 to 2009). The stored histological sections of the removed thyroid specimens were re-analyzed, including routine grading of LTI severity on a scale of 0-4, according to Williams and Doniach. Positive correlations were seen for the incidences of LTI grading (0-4) (r = 0.077, p = 0.013) and HT (r = 0.044, p = 0.078) over the years. Furthermore, when comparing the years 1979-1989 and 1994-2009, i.e., before and after the second iodine prophylaxis had been introduced in Austria, a higher incidence of HT was found for the later years (2 out of 450, 0.4%, vs. 6 out of 600, 1.0%, respectively; p < 0.0001). In conclusion, the data demonstrate that the incidence of LTI and HT has increased substantially over the last 31 years.