The Effect of Renal Denervation on T Cells in Patients with Resistant Hypertension.

(1) Background: Sympathetic overactivity is a major contributor to resistant hypertension (RH). According to animal studies, sympathetic overactivity increases immune responses, thereby aggravating hypertension and cardiovascular outcomes. Renal denervation (RDN) reduces sympathetic nerve activity in RH. Here, we investigate the effect of RDN on T-cell signatures in RH. (2) Methods: Systemic inflammation and T-cell subsets were analyzed in 17 healthy individuals and 30 patients with RH at baseline and 6 months after RDN. (3) Results: The patients with RH demonstrated higher levels of pro-inflammatory cytokines and higher frequencies of CD4+ effector memory (TEM), CD4+ effector memory residential (TEMRA) and CD8+ central memory (TCM) cells than the controls. After RDN, systolic automated office blood pressure (BP) decreased by -17.6 ± 18.9 mmHg. Greater BP reductions were associated with higher CD4+ TEM (r -0.421, p = 0.02) and CD8+ TCM (r -0.424, p = 0.02) frequencies at baseline. The RDN responders, that is, the patients with ≥10mmHg systolic BP reduction, showed reduced pro-inflammatory cytokine levels, whereas the non-responders had unchanged inflammatory activity and higher CD8+ TEMRA frequencies with increased cellular cytokine production. (4) Conclusions: The pro-inflammatory state of patients with RH is characterized by altered T-cell signatures, especially in non-responders. A detailed analysis of T cells might be useful in selecting patients for RDN.

Hospital-acquired pneumonia pattern in the intensive care units of a governmental hospital: A prospective longitudinal study.

Background: Epidemiological data on Hospital-Acquired Pneumonia (HAP) are scarce inside Intensive Care Units (ICUs). Aim: This study aims to quantify the incidence of HAP, determine the predictors of HAP, calculate HAP-related mortality risk ratio as well as pinpoint the different risk factors contributing to mortality. Subjects and Methods: A prospective longitudinal study was conducted at a governmental hospital's general ICUs over 12 months. We included adult patients admitted for at least 72 h before signs appear. We utilized a logistic regression model for fatality outcome and cox proportional hazard model for HAP outcome. Results: Of 356 patients, 133 patients developed Ventilated-Acquired Pneumonia (VAP), 76 patients with Non-Ventilated HAP (NV-HAP), as well as 147 patients did not acquire HAP. The incidence of HAP was 28 cases of HAP per 1000 person-days, as well as the mortality rate was 74 per 100 days, while the Attributable Risk Percentage (ARP) was 85%. This high fatality rate was clarified by independent predictors as reintubation (odds ratio [OR] = 8.99, P < 0.001), ICU duration ≥5 days (OR = 7.29, P = 0.02), HAP outcome (OR = 6.49, P = 0.001), diabetes mellitus (DM) (OR = 2.98, P = 0.004), APACHE II ≥17 (OR = 2.76, P = 0.004), as well as neurological diseases (OR = 2.20, P = 0.03). The most common independent HAP predictors were Pseudomonas aeruginosa (Hazard Ratio [HR] = 2.27, P < 0.001), Klebsiella pneumoniae (HR = 1.81, P = 0.003), tracheostomy (HR = 1.72, P = 0.04), and APACHE II ≥17 (HR = 1.54, P = 0.04). Conclusion: High incidence rate of HAP was linked with P. aeruginosa, K. pneumoniae, tracheostomy, and APACHE II ≥17. Furthermore, a high mortality rate was strongly correlated with reintubation, duration in ICU ≥5 days, HAP outcome, DM, APACHE II ≥17, and neurological diseases.

Résumé Contexte: Les données épidémiologiques sur la pneumonie acquise dans les hôpitaux (HAP) sont rares dans les unités de soins intensifs (ICUs). Objectif: ce L'étude vise à quantifier l'incidence du HAP, à déterminer les facteurs prédictifs du HAP, à calculer le ratio de risque de mortalité lié au HAP ainsi qu'à identifier les différents facteurs de risque contribuant à la mortalité. Sujets et méthodes: Une étude longitudinale prospective a été menée à les unités de soins intensifs générales d'un hôpital gouvernemental sur 12 mois. Nous avons inclus les patients adultes admis depuis au moins 72 h avant l'apparition des signes. Nous ont utilisé un modèle de régression logistique pour les résultats en matière de décès et un modèle de risque proportionnel de Cox pour les résultats HAP. Résultats: Sur 356 patients, 133 patients ont développé une Pneumonie Acquise sous Ventilation (VAP), 76 patients avec une NV-HAP, ainsi que 147 patients n'a pas acquis HAP. L'incidence du HAP était de 28 cas de HAP pour 1000 jours-personnes, ainsi que le taux de mortalité, de 74 pour 100 jours, alors que le pourcentage de risque attribuable (ARP) était de 85 %. Ce taux de mortalité élevé a été clarifié par des prédicteurs indépendants comme réintubation (odds ratio [OR] = 8,99, P < 0,001), durée de ICU ≥ 5 jours (OR = 7,29, P = 0,02), résultat HAP (OR = 6,49, P = 0,001), le diabète sucré (DM) (OR = 2,98, P = 0,004), APACHE II ≥17 (OR = 2,76, P = 0,004), ainsi que les maladies neurologiques (OR = 2,20, P = 0,03). Les prédicteurs indépendants de HAP les plus courants étaient Pseudomonas aeruginosa (Hazard Ratio [HR] = 2,27, P < 0,001), Klebsiella pneumoniae (HR = 1,81, P = 0,003), trachéotomie (HR = 1,72, P = 0,04) et APACHE II ≥ 17 (HR = 1,54, P = 0,04). Conclusion: Le taux d'incidence élevé de HAP était lié à P. aeruginosa, K. pneumoniae, trachéotomie et APACHE II ≥17. De plus, un taux de mortalité élevé était fortement corrélé à la réintubation, à la durée en ICU ≥ 5 jours, au résultat HAP, au DM, à l'APACHE II ≥17, et maladies neurologiques. Mots-clés: Pneumonie nosocomiale, incidence, unités de soins intensifs, facteurs de risque, trachéotomie.

Circulating tumour cells in patients with lung cancer universally indicate poor prognosis.

BACKGROUND: In lung cancer, the relevance of various circulating tumour cell (CTC) subgroups in different lung cancer subtypes is unclear. We performed a comprehensive meta-analysis to assess the prognostic value of CTCs in the different histological types of lung cancer, with particular respect to CTC subtypes, cut-offs and time points of CTC enumeration. METHODS: We searched MEDLINE, Web of Science and Embase alongside relevant studies evaluating the prognostic value of CTCs in lung cancer patients. A random-effects model was used for meta-analysis, calculating hazard ratios (HRs), 95% confidence intervals and p-values. RESULTS: 27 studies enrolling 2957 patients were included. CTC detection indicates poor prognosis, especially in small cell lung cancer (SCLC) patients (overall survival HR 3.11, 95% CI 2.59-3.73) and predicts a worse outcome compared to nonsmall cell lung cancer patients. Epithelial CTCs predict a worse outcome for lung cancer than mesenchymal CTCs or epithelial-mesenchymal hybrids. CONCLUSION: CTCs indicate poor prognosis in patients with primary lung cancer, with CTCs in SCLC having a more pronounced prognostic effect. The prognostic value of CTCs detected by different markers varies; most evidence is available for the strong negative prognostic effect of epithelial CTCs.

Cell-Cell Interactions Drive Metastasis of Circulating Tumor Microemboli.

Circulating tumor cells are the cellular mediators of distant metastasis in solid malignancies. Their metastatic potential can be augmented by clustering with other tumor cells or nonmalignant cells, forming circulating tumor microemboli (CTM). Cell-cell interactions are key regulators within CTM that convey enhanced metastatic properties, including improved cell survival, immune evasion, and effective extravasation into distant organs. However, the cellular and molecular mechanism of CTM formation, as well as the biology of interactions between tumor cells and immune cells, platelets, and stromal cells in the circulation, remains to be determined. Here, we review the current literature on cell-cell interactions in homotypic and heterotypic CTM and provide perspectives on therapeutic strategies to attenuate CTM-mediated metastasis by targeting cell-cell interactions.

Beyond Vessel Diameters: Non-invasive Monitoring of Flow Patterns and Immune Cell Recruitment in Murine Abdominal Aortic Disorders by Multiparametric MRI.

The pathophysiology of the initiation and progression of abdominal aortic aneurysms (AAAs) and aortic dissections (AADs) is still unclear. However, there is strong evidence that monocytes and macrophages are of crucial importance in these processes. Here, we utilized a molecular imaging approach based on background-free 19F MRI and employed perfluorocarbon nanoemulsions (PFCs) for in situ 19F labeling of monocytes/macrophages to monitor vascular inflammation and AAA/AAD formation in angiotensin II (angII)-treated apolipoproteinE-deficient (apoE-/-) mice. In parallel, we used conventional 1H MRI for the characterization of aortic flow patterns and morphology. AngII (1 µg/kg/min) was infused into apoE-/- mice via osmotic minipumps for 10 days and mice were monitored by multiparametric 1H/19F MRI. PFCs were intravenously injected directly after pump implantation followed by additional applications on day 2 and 4 to allow an efficient 19F loading of circulating monocytes. The combination of angiographic, hemodynamic, and anatomical measurements allowed an unequivocal classification of mice in groups with developing AAAs, AADs or without any obvious aortic vessel alterations despite the exposure to angII. Maximal luminal and external diameters of the aorta were enlarged in AAAs, whereas AADs showed either a slight decrease of the luminal diameter or no alteration. 1H/19F MRI after intravenous PFC application demonstrated significantly higher 19F signals in aortae of mice that developed AAAs or AADs as compared to mice in which no aortic disorders were detected. High resolution 1H/19F MRI of excised aortae revealed a patchy pattern of the 19F signals predominantly in the adventitia of the aorta. Histological analysis confirmed the presence of macrophages in this area and flow cytometry revealed higher numbers of immune cells in aortae of mice that have developed AAA/AAD. Importantly, there was a linear correlation of the 19F signal with the total number of infiltrated macrophages. In conclusion, our approach enables a precise differentiation between AAA and AAD as well as visualization and quantitative assessment of inflammatory active vascular lesions, and therefore may help to unravel the complex interplay between macrophage accumulation, vascular inflammation, and the development and progression of AAAs and AADs.

α2A-Adrenoceptors Modulate Renal Sympathetic Neurotransmission and Protect against Hypertensive Kidney Disease.

BACKGROUND: Increased nerve activity causes hypertension and kidney disease. Recent studies suggest that renal denervation reduces BP in patients with hypertension. Renal NE release is regulated by prejunctional α2A-adrenoceptors on sympathetic nerves, and α2A-adrenoceptors act as autoreceptors by binding endogenous NE to inhibit its own release. However, the role of α2A-adrenoceptors in the pathogenesis of hypertensive kidney disease is unknown. METHODS: We investigated effects of α2A-adrenoceptor-regulated renal NE release on the development of angiotensin II-dependent hypertension and kidney disease. In uninephrectomized wild-type and α2A-adrenoceptor-knockout mice, we induced hypertensive kidney disease by infusing AngII for 28 days. RESULTS: Urinary NE excretion and BP did not differ between normotensive α2A-adrenoceptor-knockout mice and wild-type mice at baseline. However, NE excretion increased during AngII treatment, with the knockout mice displaying NE levels that were significantly higher than those of wild-type mice. Accordingly, the α2A-adrenoceptor-knockout mice exhibited a systolic BP increase, which was about 40 mm Hg higher than that found in wild-type mice, and more extensive kidney damage. In isolated kidneys, AngII-enhanced renal nerve stimulation induced NE release and pressor responses to a greater extent in kidneys from α2A-adrenoceptor-knockout mice. Activation of specific sodium transporters accompanied the exaggerated hypertensive BP response in α2A-adrenoceptor-deficient kidneys. These effects depend on renal nerves, as demonstrated by reduced severity of AngII-mediated hypertension and improved kidney function observed in α2A-adrenoceptor-knockout mice after renal denervation. CONCLUSIONS: Our findings reveal a protective role of prejunctional inhibitory α2A-adrenoceptors in pathophysiologic conditions with an activated renin-angiotensin system, such as hypertensive kidney disease, and support the concept of sympatholytic therapy as a treatment.

Short-Chain Fatty Acid Propionate Protects From Hypertensive Cardiovascular Damage.

BACKGROUND: Arterial hypertension and its organ sequelae show characteristics of T cell-mediated inflammatory diseases. Experimental anti-inflammatory therapies have been shown to ameliorate hypertensive end-organ damage. Recently, the CANTOS study (Canakinumab Antiinflammatory Thrombosis Outcome Study) targeting interleukin-1ß demonstrated that anti-inflammatory therapy reduces cardiovascular risk. The gut microbiome plays a pivotal role in immune homeostasis and cardiovascular health. Short-chain fatty acids (SCFAs) are produced from dietary fiber by gut bacteria and affect host immune homeostasis. Here, we investigated effects of the SCFA propionate in 2 different mouse models of hypertensive cardiovascular damage. METHODS: To investigate the effect of SCFAs on hypertensive cardiac damage and atherosclerosis, wild-type NMRI or apolipoprotein E knockout-deficient mice received propionate (200 mmol/L) or control in the drinking water. To induce hypertension, wild-type NMRI mice were infused with angiotensin II (1.44 mg·kg-1·d-1 subcutaneous) for 14 days. To accelerate the development of atherosclerosis, apolipoprotein E knockout mice were infused with angiotensin II (0.72 mg·kg-1·d-1 subcutaneous) for 28 days. Cardiac damage and atherosclerosis were assessed using histology, echocardiography, in vivo electrophysiology, immunofluorescence, and flow cytometry. Blood pressure was measured by radiotelemetry. Regulatory T cell depletion using PC61 antibody was used to examine the mode of action of propionate. RESULTS: Propionate significantly attenuated cardiac hypertrophy, fibrosis, vascular dysfunction, and hypertension in both models. Susceptibility to cardiac ventricular arrhythmias was significantly reduced in propionate-treated angiotensin II-infused wild-type NMRI mice. Aortic atherosclerotic lesion area was significantly decreased in propionate-treated apolipoprotein E knockout-deficient mice. Systemic inflammation was mitigated by propionate treatment, quantified as a reduction in splenic effector memory T cell frequencies and splenic T helper 17 cells in both models, and a decrease in local cardiac immune cell infiltration in wild-type NMRI mice. Cardioprotective effects of propionate were abrogated in regulatory T cell-depleted angiotensin II-infused mice, suggesting the effect is regulatory T cell-dependent. CONCLUSIONS: Our data emphasize an immune-modulatory role of SCFAs and their importance for cardiovascular health. The data suggest that lifestyle modifications leading to augmented SCFA production could be a beneficial nonpharmacological preventive strategy for patients with hypertensive cardiovascular disease.

Impact of the NO-Sensitive Guanylyl Cyclase 1 and 2 on Renal Blood Flow and Systemic Blood Pressure in Mice.

Nitric oxide (NO) modulates renal blood flow (RBF) and kidney function and is involved in blood pressure (BP) regulation predominantly via stimulation of the NO-sensitive guanylyl cyclase (NO-GC), existing in two isoforms, NO-GC1 and NO-GC2. Here, we used isoform-specific knockout (KO) mice and investigated their contribution to renal hemodynamics under normotensive and angiotensin II-induced hypertensive conditions. Stimulation of the NO-GCs by S-nitrosoglutathione (GSNO) reduced BP in normotensive and hypertensive wildtype (WT) and NO-GC2-KO mice more efficiently than in NO-GC1-KO. NO-induced increase of RBF in normotensive mice did not differ between the genotypes, but the respective increase under hypertensive conditions was impaired in NO-GC1-KO. Similarly, inhibition of endogenous NO increased BP and reduced RBF to a lesser extent in NO-GC1-KO than in NO-GC2-KO. These findings indicate NO-GC1 as a target of NO to normalize RBF in hypertension. As these effects were not completely abolished in NO-GC1-KO and renal cyclic guanosine monophosphate (cGMP) levels were decreased in both NO-GC1-KO and NO-GC2-KO, the results suggest an additional contribution of NO-GC2. Hence, NO-GC1 plays a predominant role in the regulation of BP and RBF, especially in hypertension. However, renal NO-GC2 appears to compensate the loss of NO-GC1, and is able to regulate renal hemodynamics under physiological conditions.

Angiotensin-(1-7)-induced Mas receptor activation attenuates atherosclerosis through a nitric oxide-dependent mechanism in apolipoproteinE-KO mice.

Angiotensin (Ang)-(1-7) ameliorates vascular injury by increasing nitric oxide (NO) bioavailability. Evidence that Ang-(1-7) attenuates the development of atherosclerosis through a NO-dependent mechanism is still missing. Moreover, it has been postulated that Ang-(1-7) may mediate its effects by other mechanisms than Mas receptor activation. To investigate Ang-(1-7)-dependent Mas receptor function, we treated apoE-KO and apoE/Mas-KO mice chronically with Ang-(1-7) (82 µg/kg per hour) or saline for 6 weeks. Flow-mediated dilation (FMD), a measure for NO-dependent vasodilation and the most accepted prognostic marker for the development of atherosclerosis, was measured in vivo. Chronic Ang-(1-7) treatment improved FMD and attenuated the development of atherosclerosis in apolipoproteinE (apoE)-KO but not in apoE/Mas-KO mice. These effects were accompanied by increased aortic nitrite and cGMP levels. To test whether Ang-(1-7) modulates atherosclerosis through a NO-dependent mechanism, apoE-KO mice were treated with the NO synthase inhibitor L-NAME (20 mg/kg/day) in the presence or absence of Ang-(1-7). L-NAME treatment reduced aortic nitrite content and increased blood pressure and exaggerated atherosclerosis compared to untreated apoE-KO mice. In L-NAME-treated apoE-KO mice, chronic Ang-(1-7) treatment did not increase aortic nitrite content and consequently showed no effect on blood pressure and the development of atherosclerosis. The present study proves that Ang-(1-7) mediates its protective vascular effects through Mas receptor activation. Moreover, Ang-(1-7)-mediated NO generation is essential for improving vascular function and prevents atherosclerosis in apoE-KO mice.