Brown and beige adipose tissue are emerging as distinct endocrine organs. These tissues are functionally associated with skeletal muscle, adipose tissue metabolism and systemic energy expenditure, ...suggesting an interorgan signaling network. Using metabolomics, we identify 3-methyl-2-oxovaleric acid, 5-oxoproline, and β-hydroxyisobutyric acid as small molecule metabokines synthesized in browning adipocytes and secreted via monocarboxylate transporters. 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid induce a brown adipocyte-specific phenotype in white adipocytes and mitochondrial oxidative energy metabolism in skeletal myocytes both in vitro and in vivo. 3-methyl-2-oxovaleric acid and 5-oxoproline signal through cAMP-PKA-p38 MAPK and β-hydroxyisobutyric acid via mTOR. In humans, plasma and adipose tissue 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid concentrations correlate with markers of adipose browning and inversely associate with body mass index. These metabolites reduce adiposity, increase energy expenditure and improve glucose and insulin homeostasis in mouse models of obesity and diabetes. Our findings identify beige adipose-brown adipose-muscle physiological metabokine crosstalk.
Non-communicable diseases (NCDs) have been highlighted as important risk factors for COVID-19 mortality. However, insufficient data exist on the wider context of infectious diseases in people with ...NCDs. We aimed to investigate the association between NCDs and the risk of death from any infection before the COVID-19 pandemic (up to Dec 31, 2019).
For this observational study, we used data from the UK Biobank observational cohort study to explore factors associated with infection death. We excluded participants if data were missing for comorbidities, body-mass index, smoking status, ethnicity, and socioeconomic deprivation, and if they were lost to follow-up or withdrew consent. Deaths were censored up to Dec 31, 2019. We used Poisson regression models including NCDs present at recruitment to the UK Biobank (obesity defined by use of body-mass index and self-reported hypertension, chronic heart disease, chronic respiratory disease, diabetes, cancer, chronic liver disease, chronic kidney disease, previous stroke or transient ischaemic attack, other neurological disease, psychiatric disorder, and chronic inflammatory and autoimmune rheumatological disease), age, sex, ethnicity, smoking status, and socioeconomic deprivation. Separate models were constructed with individual NCDs replaced by the total number of prevalent NCDs to define associations with multimorbidity. All analyses were repeated with non-infection-related death as an alternate outcome measure to establish differential associations of infection death and non-infection death. Associations are reported as incidence rate ratios (IRR) accompanied by 95% CIs.
After exclusion of 9210 (1·8%) of the 502 505 participants in the UK Biobank cohort, our study sample comprised 493 295 individuals. During 5 273 731 person-years of follow-up (median 10·9 years IQR 10·1–11·6 per participant), 27 729 deaths occurred, of which 1385 (5%) were related to infection. Advancing age, male sex, smoking, socioeconomic deprivation, and all studied NCDs were independently associated with the rate of both infection death and non-infection death. Compared with White ethnicity, a pooled Black, Asian, and minority ethnicity group was associated with a reduced risk of infection death (IRR 0·64, 95% CI 0·46–0·87) and non-infection death (0·80, 0·75–0·86). Stronger associations with infection death than with non-infection death were observed for advancing age (age 65 years vs 45 years: 7·59, 95% CI 5·92–9·73, for infection death vs 5·21, 4·97–5·48, for non-infection death), current smoking (vs never smoking: 3·69, 3·19–4·26, vs 2·52, 2·44–2·61), socioeconomic deprivation (most vs least deprived quintile: 2·13, 1·78–2·56, vs 1·38, 1·33–1·43), class 3 obesity (vs non-obese: 2·21, 1·74–2·82, vs 1·55, 1·44–1·66), hypertension (1·36, 1·22–1·53, vs 1·15, 1·12–1·18), respiratory disease (2·21, 1·96–2·50, vs 1·28, 1·24–1·32), chronic kidney disease (5·04, 4·28–7·31, vs 2·50, 2·20–2·84), psychiatric disease (1·56, 1·30–1·86, vs 1·23, 1·18–1·29), and chronic inflammatory and autoimmune rheumatological disease (2·45, 1·99–3·02, vs 1·41, 1·32–1·51). Accrual of multimorbidity was also more strongly associated with risk of infection death (five or more comorbidities vs none: 9·53, 6·97–13·03) than of non-infection death (5·26, 4·84–5·72).
Several NCDs are associated with an increased risk of infection death, suggesting that some of the reported associations with COVID-19 mortality might be non-specific. Only a subset of NCDs, together with the accrual of multimorbidity, advancing age, smoking, and socioeconomic deprivation, were associated with a greater IRR for infection death than for other causes of death. Further research is needed to define why these risk factors are more strongly associated with infection death, so that more effective preventive strategies can be targeted to high-risk groups.
British Heart Foundation.
Abstract Background Patients with chronic heart failure (CHF) secondary to left ventricular (LV) systolic dysfunction (LVSD) are frequently deficient in vitamin D. Low vitamin D levels are associated ...with a worse prognosis. It is unclear whether vitamin D deficiency is a marker of disease severity or plays a pathophysiological role. Objectives The VitamIN D treatIng patients with Chronic heArT failurE (VINDICATE) study was designed to establish the safety and efficacy of high-dose vitamin D supplementation in patients with CHF due to LVSD. Methods We enrolled 229 patients (179 men) with CHF due to LVSD and vitamin D deficiency ((25(OH) vitamin D3 <50nmol/L (<20ng/mL)) into a randomised, placebo-controlled double-blind trial of vitamin D supplementation. Participants were either allocated to one year of vitamin D3 supplementation (4000IU (100μg) 25(OH)D3 daily) or matching non-calcium-based placebo. The primary endpoint was change in six-minute walk distance from baseline to 12 months. Pre-specified secondary endpoints included change in left ventricular ejection fraction at one year, and safety measures of renal function and serum calcium concentration assessed every three months. Results One year of high-dose vitamin D supplementation did not improve 6-minute walk distance at one year, but was associated with a significant improvement in cardiac function on echocardiography (left ventricular ejection fraction +6.07% (95% CI 3.20, 8.95; p<0.0001); and a reversal of left ventricular remodeling (left ventricular end diastolic diameter -2.49mm (95% CI -4.09, -0.90; p=0.002) and left ventricular end systolic diameter -2.09mm (95% CI -4.11; -0.06 p=0.043). There were no clinically significant effects on calcium levels or renal function. Conclusions One year of 100μg daily 25-OH vitamin D3 supplementation does not improve 6-minute walk distance but has beneficial effects on LV structure and function in patients on contemporary optimal medical therapy. Further studies are necessary to determine whether these translate to improvements in outcomes.
Aims
Left ventricular (LV) thrombus is increasingly detected in patients with and without ischaemic heart disease due to the increased availability of cardiac magnetic resonance imaging. Risk factors ...include anterior ST elevation myocardial infarction, delayed reperfusion therapy, and non‐ischaemic cardiomyopathy with severe LV systolic dysfunction. We aimed to report the characteristics and outcomes of patients with LV thrombus treated with either vitamin K antagonist (VKA) or direct oral anticoagulants (DOAC) with a view to describing differences in efficacy, specifically, subsequent thromboembolic events, thrombus resolution, and also side effects of therapy including clinically significant bleeding.
Methods and results
We conducted a retrospective, observational cohort study of patients diagnosed with LV thrombus between 1 December 2012 and 30 June 2018 and treated with either DOAC or VKA. We recorded patient demographics, past medical history, prescribed medications, and baseline investigations. The primary outcomes were rates of thromboembolism and clinically significant bleeding, with secondary outcomes of thrombus resolution on repeat cardiac imaging, repeat hospitalization, and all‐cause mortality. During the study period, 84 patients were diagnosed with and managed for LV thrombus. Of these, 62 received VKA and 22 DOAC including 13 prescribed rivaroxaban, eight apixaban, and one dabigatran. Most patients 75 (89%) were male with an average age of 62 ± 14 years. Ischaemic heart disease was the cause of LV impairment in 73 (87%) patients. Baseline characteristics were similar between groups at baseline. Most n = 55 (65%) were co‐prescribed a single antiplatelet agent and 32 (38%) received dual‐antiplatelet therapy. During an average follow‐up of 3.0 ± 1.4 years, there were no statistically significant differences between VKA and DOAC in rates of stroke (2% vs. 0%, P = 0.55), other thromboemboli (2% vs. 0%, P = 0.55), or clinically significant bleeding (10% vs. 0%, P = 0.13). The average interval to cardiac imaging follow‐up was 233 ± 251 days and was not different between groups (P = 0.83), and there was no difference in the rate of resolution of thrombus (76% vs. 65% P = 0.33). Rehospitalization (50% vs. 45%: P = 0.53) and all‐cause mortality (10% vs. 14%; P = 0.61) were also similar.
Conclusions
Our data suggest that DOACs are likely to be at least as effective and safe as VKA for stroke prevention in patients with LV thrombus and, despite their lack of a licence for this indication, are therefore likely to represent a reasonable and more convenient option for this setting. The optimal timing and type of anticoagulation for LV thrombus, as well as the role of screening for high‐risk patients, should be tested in prospective, randomized trials.
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