Hypertension is associated with inflammation and excessive production of catecholamines. Hypertensive patients have reduced plasma levels of CST (catestatin)—a bioactive cleavage product of the prohormone CgA (chromogranin A). In mouse models, hypertension symptoms can be reduced by administration of CST, but the role of CST in the regulation of cardiovascular function is unknown. In this study, we generated mice with KO (knockout) of the region of the CgA gene coding for CST (CST-KO) and found that CST-KO mice are not only hypertensive as predicted but also display left ventricular hypertrophy, have marked macrophage infiltration of the heart and adrenal gland, and have elevated levels of proinflammatory cytokines and catecholamines. Intraperitoneal injection with CST reversed these phenotypes, and ischemic preconditioning-induced cardioprotection was also abolished in CST-KO mice. Experiments with chlodronate depletion of macrophages and bone marrow transfer showed that macrophages produce CST and that the antihypertensive effects of CST are mediated, in part, via CST’s immunosuppression of macrophages as a form of feedback inhibition. The data thus implicate CST as a key autocrine attenuator of the cardiac inflammation in hypertension by reducing macrophage inflammation.

38Objective: Hypertension (HTN) is a global pandemic, affecting more than one billion people. 39Although catestatin (CST), a chromogranin A (CgA)-derived peptide, decreases blood pressure 40 (BP) in rodent models of HTN, the mechanisms underlying its hypotensive action is yet to be 41 established. Here we generated CST knockout (CST-KO) mice to pinpoint the mechanism of the 42 hypotensive action of CST. 44Methods and Results: CST-KO mice were hypertensive; their serum cytokines were elevated, 45 anti-inflammatory genes were downregulated, and their hearts showed marked infiltration with 46 macrophages. CST replenishment reversed all these phenotypes -it normalized BP, reduced 47 serum cytokines, upregulated anti-inflammatory genes, and reduced the cardiac infiltrates by 48 ~30%, as determined by FACS. Pre-conditioning-induced cardioprotection was also abolished in 49 CST-KO mice. We hypothesize that CST's anti-hypertensive and cardioprotective effects may be 50 caused by suppressed trafficking of macrophages to the heart and reduced inflammation. Such 51 cause-and-effect relationship is supported by the fact that CST-KO mice became normotensive 52 when they were depleted of macrophages using chlodronate, or when they received bone marrow 53 transplant from wild-type littermates. Mechanistically, cardiac tissue transcriptomes revealed 54 multiple altered gene expression programs in CST-KO mice that are commonly encountered in 55 human cardiomyopathies. Among others, a prominent reduction of Glo1 gene was seen in CST-56 KO mice; supplementation with CST increased it expression by >7-fold. Because Glo1 in 57 macrophages metabolizes methylglyoxal, an inflammatory agent whose accumulation promotes 58 vascular damage in HTN and T2DM, this could be one of the means by which CST attenuates 59 inflammation and improves cardiovascular health. Repletion of CST also improved glucose 60 metabolism and increased the surface area of mitochondrial cristae and decreased the secretion 61 of catecholamines; the latter explains the anti-hypertensive actions of CST. 63Conclusions: We conclude that the anti-hypertensive effects of CST is mediated at least in part 64 via CST's anti-inflammatory actions; in the absence of CST, macrophages are more reactive, they 65 infiltrate the heart and alter the ultrastructure, physiologic and molecular makeup of the 66 myocardium. These studies implicate CST as a key mediator of the observed crosstalk between 67 systemic and cardiac inflammation in HTN.68 69 70 71 3 Abbreviations 72 2DG: 2-deoxy-glucose 73 Actc1: cardiac muscle actin alpha 74 Atp5j: mitochondrial ATP synthase subunit F6 75 BRS: baroreflex sensitivity 76 Cd36: cluster of differentiation 36 77 Cers2: ceramide synthase 2 78 CgA: chromogranin A 79 CST: catestatin 80 CST-KO: CST knockout Introduction 122 123 Hypertension (HTN) is an important risk factor for cardiovascular disease (CVD) and mortality 1 .124 The burden of HTN and the estimated HTN-associated deaths have increased substantially over 125 the past 25 years 2 .126 The role o...

IMPORTANCE Early discussion of end-of-life (EOL) care preferences improves clinical outcomes and goal-concordant care. However, most EOL discussions occur approximately 1 month before death, despite most patients desiring information earlier.OBJECTIVE To describe successful navigation and missed opportunities for EOL discussions (eg, advance care planning, palliative care, discontinuation of disease-directed treatment, hospice care, and after-death wishes) between oncologists and outpatients with advanced cancer. DESIGN, SETTING, AND PARTICIPANTSThis study is a secondary qualitative analysis of outpatient visits audio-recorded between November 2010 and September 2014 for the Studying Communication in Oncologist-Patient Encounters randomized clinical trial. The study was conducted at 2 US academic medical centers. Participants included medical, gynecological, and radiation oncologists and patients with stage IV malignant neoplasm, whom oncologists characterized as being ones whom they "…would not be surprised if they were admitted to an intensive care unit or died within one year." Data were analyzed between January 2018 and August 2020. EXPOSURES The parent study randomized participants to oncologist-and patient-directed interventions to facilitate discussion of emotions. Encounters were sampled across preintervention and postintervention periods and all 4 treatment conditions. MAIN OUTCOMES AND MEASURES Secondary qualitative analysis was done of patient-oncologist dyads with 3 consecutive visits for EOL discussions, and a random sample of 7 to 8 dyads from 4 trial groups was analyzed for missed opportunities. RESULTS The full sample included 141 patients (54 women [38.3%]) and 39 oncologists (8 women [19.5%]) (mean [SD] age for both patients and oncologists, 56.3 [10.0] years). Of 423 encounters, only 21 (5%) included EOL discussions. Oncologists reevaluated treatment options in response to patients' concerns, honored patients as experts on their goals, or used anticipatory guidance to frame treatment reevaluation. In the random sample of 31 dyads and 93 encounters, 35 (38%) included at least 1 missed opportunity. Oncologists responded inadequately to patient concerns over disease progression or dying, used optimistic future talk to address patient concerns, or expressed concern over treatment discontinuation. Only 4 of 23 oncologists (17.4%) had both an EOL discussion and a missed opportunity. CONCLUSIONS AND RELEVANCEOpportunities for EOL discussions were rarely realized, whereas missed opportunities were more common, a trend that mirrored oncologists' treatment style. There (continued) Key Points Question How do oncologists successfully navigate and miss opportunities for discussions about end of life (EOL), including advance care planning, palliative care, discontinuation Author affiliations and article information are listed at the end of this article.

When using a new noninvasive method for measuring the efficiency of pulmonary gas exchange, a key measurement is the oxygen deficit, defined as the difference between the end-tidal alveolar PO2 and the calculated arterial PO2. The end-tidal PO2 is measured using a rapid gas analyzer, and the arterial PO2 is derived from pulse oximetry after allowing for the effect of the PCO2 on the oxygen affinity of hemoglobin. In the present report we show that the values of end-tidal PO2 and PCO2 are highly reproducible providing a solid foundation for the measurement of the oxygen deficit. We compare the oxygen deficit with the classical ideal alveolar-arterial PO2 difference (A-aDO2) as originally proposed by Riley, and now extensively used in clinical practice. This assumes Riley's criteria for ideal alveolar gas, namely no ventilation-perfusion inequality, the same PCO2 as arterial blood, and the same respiratory exchange ratio as the whole lung. It transpires that in normal subjects, the end-tidal PO2 is essentially the same as the ideal value. This conclusion is consistent with the very small oxygen deficit that we have reported in young normal subjects, the significantly higher values seen in older normals, and the much larger values in patients with lung disease. We conclude that this noninvasive measurement of the efficiency of pulmonary exchange is identical in many respects to that based on the ideal alveolar PO2, but that it is easier to obtain.

The oxygen deficit (OD) is the difference between the end-tidal alveolar Po2 and the calculated Po2 of arterial blood based on measured oxygen saturation that acts as a proxy for the alveolar-arterial Po2 difference. Previous work has shown that the alveolar gas meter (AGM100) can measure pulmonary gas exchange, via the OD, in patients with a history of lung disease and in normal subjects breathing 12.5% O2. The present study measured how the OD varied at different values of inspired O2. Healthy subjects were split by age (young 22–31; n = 23; older 42–90; n = 13). Across all inspired O2 levels (12.5, 15, 17.5, and 21%), the OD was higher in the older cohort 10.6 ± 1.0 mmHg compared with the young −0.4 ± 0.6 mmHg ( P < 0.0001, using repeated measures ANOVA), the difference being significant at all O2 levels (all P < 0.0001). The OD difference between age groups and its variance was greater at higher O2 values (age × O2 interaction; P = 0.002). The decrease in OD with lower values of inspired O2 in both cohorts is consistent with the increased accuracy of the calculated arterial Po2 based on the O2-Hb dissociation curve and with the expected decrease in the alveolar-arterial Po2 difference due to a lower arterial saturation. The persisting higher OD seen in older subjects, irrespective of the inspired O2, shows that the measurement of OD remains sensitive to mild gas exchange impairment, even when breathing 21% O2.