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.
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.
Piezo1 forms mechanically activated nonselective cation channels that contribute to endothelial response to fluid flow. Here we reveal an important role in the control of capillary density. ...Conditional endothelial cell-specific deletion of Piezo1 in adult mice depressed physical performance. Muscle microvascular endothelial cell apoptosis and capillary rarefaction were evident and sufficient to account for the effect on performance. There was selective upregulation of thrombospondin-2 (TSP2), an inducer of endothelial cell apoptosis, with no effect on TSP1, a related important player in muscle physiology. TSP2 was poorly expressed in muscle endothelial cells but robustly expressed in muscle pericytes, in which nitric oxide (NO) repressed the Tsp2 gene without an effect on Tsp1. In endothelial cells, Piezo1 was required for normal expression of endothelial NO synthase. The data suggest an endothelial cell-pericyte partnership of muscle in which endothelial Piezo1 senses blood flow to sustain capillary density and thereby maintain physical capability.
Insulin-like growth factor (IGF)-binding proteins (IGFBPs) confer temporospatial regulation to IGF bioactivity. Both stimulatory and inhibitory effects of IGFBPs on IGF actions have been described, ...and IGF-independent effects of several IGFBPs are emerging. Accumulating evidence indicates important roles for members of the IGFBP family in metabolic homeostasis. For example, IGFBP-1 concentrations fluctuate inversely in response to changes in plasma insulin levels, implicating IGFBP-1 in glucoregulation, and fasting levels of IGFBP-1 predict insulin sensitivity at the population level. IGFBP-2 concentrations reflect long-term insulin sensitivity and are reduced in the presence of obesity. Here, we review the evolving roles of IGFBP-1 and IGFBP-2 in metabolic homeostasis, summarize their effects on IGF bioactivity and explore putative mechanisms by which they might exert IGF-independent cellular actions.
To characterise the association between socioeconomic deprivation and adverse outcomes in patients with chronic heart failure (CHF).
We prospectively observed 1802 patients with CHF and left ...ventricular ejection fraction (LVEF) ≤45%, recruited in four UK hospitals between 2006 and 2014. We assessed the association between deprivation defined by the UK Index of Multiple Deprivation (IMD) and: mode-specific mortality (mean follow-up 4 years); mode-specific hospitalisation; and the cumulative duration of hospitalisation (after 1 year).
A 45-point difference in mean IMD score was noted between patients residing in the least and most deprived quintiles of geographical regions. Deprivation was associated with age, sex and comorbidity, but not CHF symptoms, LVEF or prescribed drug therapy. IMD score was associated with the risk of age-sex adjusted all-cause mortality (6% higher risk per 10-unit increase in IMD score; 95% CI 2% to 10%; P=0.004), and non-cardiovascular mortality (9% higher risk per 10-unit increase in IMD score; 95% CI 3% to 16%; P=0.003), but not cardiovascular mortality. All-cause, but not heart failure-specific, hospitalisation was also more common in the most deprived patients. Overall, patients spent a cumulative 3.3 days in hospital during 1 year of follow-up, with IMD score being associated with the age-sex adjusted cumulative duration of hospitalisations (4% increase in duration per 10-unit increase in IMD score; 95% CI 3% to 6%; P<0.0005).
Socioeconomic deprivation in people with CHF is linked to increased risk of death and hospitalisation due to an excess of non-cardiovascular events.
The mechanisms by which physical forces regulate endothelial cells to determine the complexities of vascular structure and function are enigmatic. Studies of sensory neurons have suggested Piezo ...proteins as subunits of Ca(2+)-permeable non-selective cationic channels for detection of noxious mechanical impact. Here we show Piezo1 (Fam38a) channels as sensors of frictional force (shear stress) and determinants of vascular structure in both development and adult physiology. Global or endothelial-specific disruption of mouse Piezo1 profoundly disturbed the developing vasculature and was embryonic lethal within days of the heart beating. Haploinsufficiency was not lethal but endothelial abnormality was detected in mature vessels. The importance of Piezo1 channels as sensors of blood flow was shown by Piezo1 dependence of shear-stress-evoked ionic current and calcium influx in endothelial cells and the ability of exogenous Piezo1 to confer sensitivity to shear stress on otherwise resistant cells. Downstream of this calcium influx there was protease activation and spatial reorganization of endothelial cells to the polarity of the applied force. The data suggest that Piezo1 channels function as pivotal integrators in vascular biology.
Mammalian biology adapts to physical activity but the molecular mechanisms sensing the activity remain enigmatic. Recent studies have revealed how Piezo1 protein senses mechanical force to enable ...vascular development. Here, we address Piezo1 in adult endothelium, the major control site in physical activity. Mice without endothelial Piezo1 lack obvious phenotype but close inspection reveals a specific effect on endothelium-dependent relaxation in mesenteric resistance artery. Strikingly, the Piezo1 is required for elevated blood pressure during whole body physical activity but not blood pressure during inactivity. Piezo1 is responsible for flow-sensitive non-inactivating non-selective cationic channels which depolarize the membrane potential. As fluid flow increases, depolarization increases to activate voltage-gated Ca
channels in the adjacent vascular smooth muscle cells, causing vasoconstriction. Physical performance is compromised in mice which lack endothelial Piezo1 and there is weight loss after sustained activity. The data suggest that Piezo1 channels sense physical activity to advantageously reset vascular control.The mechanisms that regulate the body's response to exercise are poorly understood. Here, Rode et al. show that the mechanically activated cation channel Piezo1 is a molecular sensor of physical exercise in the endothelium that triggers endothelial communication to mesenteric vessel muscle cells, leading to vasoconstriction.
Background Noncardiovascular death is increasingly common in people with chronic heart failure ( CHF ), yet its causes remain poorly characterized. We aimed to define the prevalence of sepsis death ...in people with CHF and to ascertain its risk marker profile. Methods and Results We conducted a prospective cohort study of 1802 patients with CHF and left ventricular ejection fraction ≤45% attending CHF clinics in 4 United Kingdom hospitals between 2006 and 2014. Mode of death was defined over a 10.3-year follow-up period (mean 4 years). Competing risk regression defined mode-specific hazard ratios for sepsis, other noncardiovascular, progressive heart failure, and sudden cardiac death in relation to established heart failure prognostic markers. Of 737 deaths, 173 (23.5%) were due to sepsis; respiratory tract infections accounted for 69.9% (n=121) of these events. Those who died from sepsis were older, had higher platelet counts, and had a higher prevalence of chronic obstructive pulmonary disease than those who died from other causes. Sepsis death was independently associated with older age (hazard ratio=1.05; 95% confidence interval 1.03-1.07), greater prevalence of chronic obstructive pulmonary disease (2.43; 1.74-3.40), male sex (1.73; 1.16-2.60), lower log serum vitamin D (0.68; 0.49-0.95), and higher platelet count (1.002; 1.000-1.005) than nonsepsis death. Established heart failure prognostic markers exhibited different patterns of association with sepsis death, other noncardiovascular death, progressive heart failure death, and sudden cardiac death. Conclusions Sepsis is a major contributor to death in people with CHF and has a different risk marker profile from other modes of death, suggesting that it may be amenable to targeted preventative strategies.
Pacemakers are widely utilised to treat bradycardia, but right ventricular (RV) pacing is associated with heightened risk of left ventricular (LV) systolic dysfunction and heart failure. We aimed to ...compare personalised pacemaker reprogramming to avoid RV pacing with usual care on echocardiographic and patient-orientated outcomes.
A prospective phase II randomised, double-blind, parallel-group trial in 100 patients with a pacemaker implanted for indications other than third degree heart block for ≥2 years. Personalised pacemaker reprogramming was guided by a published protocol. Primary outcome was change in LV ejection fraction on echocardiography after 6 months. Secondary outcomes included LV remodeling, quality of life, and battery longevity.
Clinical and pacemaker variables were similar between groups. The mean age (SD) of participants was 76 (+/-9) years and 71% were male. Nine patients withdrew due to concurrent illness, leaving 91 patients in the intention-to-treat analysis. At 6 months, personalised programming compared to usual care, reduced RV pacing (-6.5±1.8% versus -0.21±1.7%; p<0.01), improved LV function (LV ejection fraction +3.09% 95% confidence interval (CI) 0.48 to 5.70%; p = 0.02) and LV dimensions (LV end systolic volume indexed to body surface area -2.99mL/m2 95% CI -5.69 to -0.29; p = 0.03). Intervention also preserved battery longevity by approximately 5 months (+0.38 years 95% CI 0.14 to 0.62; p<0.01)) with no evidence of an effect on quality of life (+0.19, 95% CI -0.25 to 0.62; p = 0.402).
Personalised programming in patients with pacemakers for bradycardia can improve LV function and size, extend battery longevity, and is safe and acceptable to patients.
ClinicalTrials.gov identifier: NCT03627585.
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