Abstract

Background
Heart failure has an estimated global prevalence of 64.3 million cases, with an average age of a person living with heart failure at 75.2 years. Approximately 20% of residents living in nursing homes (a long-term residential care environment for some individuals) report living with heart failure. Residents living with heart failure in nursing home environments are often frail, have reduced quality of life, higher rates of rehospitalisation and mortality, and greater complications in heart failure management. Further, nursing home staff often lack the knowledge and skills required to provide the necessary care for those living with heart failure. Interventions for improving heart failure management in nursing homes have proven effective, yet there is a lack of understanding regarding interventions for optimising care provision. The aim of this review was to synthesise the current evidence on educational interventions to optimise care provided to people with heart failure in nursing homes.

Methods
A scoping review with four databases searched: Medline, CINAHL, Web of Science, and EMBASE. Relevant reference lists were searched manually for additional records. Studies of nursing home staff or resident outcomes associated with changes in care provision (i.e., resident quality of life, staff knowledge of heart failure) were included. Results from the charting data process were collated into themes: intervention outcomes, changes to practice, and implementation and process evaluation.

Results
Seven papers were deemed eligible for inclusion. Most studies (n=6) were comprised of nursing home staff only, with one comprised only of residents. Study aims were to improve heart failure knowledge, interprofessional communication, heart failure assessment and management. Positive changes in staff outcomes were observed, with improvements in knowledge, self-efficacy, and confidence in providing care reported. No difference was reported concerning nursing home resident outcomes. Interprofessional communication and staff ability to conduct heart failure assessments improved post-intervention. Changes to practice were mixed, with issues around sustainability reported. Nursing home staff highlighted their appreciation towards receiving education, recommending that videos, images, and humour could improve the intervention content.

Conclusions
There is a paucity of evidence around educational interventions to support residents living with heart failure in nursing homes. However, available evidence suggests that educational interventions in nursing homes may improve care through improving staff self-efficacy and confidence in providing care, heart failure knowledge and interprofessional communication. The complexity of implementing educational interventions in the nursing home setting must be considered during the development process to improve implementation, effectiveness, and sustainability.

Background

Heart failure, defined as a clinical syndrome characterised by structural and/or functional changes to the heart (Bozkurt et al., 2021), has an estimated prevalence of 64.3 million cases worldwide (Savarese et al., 2022). People living with heart failure often present with three or more comorbidities, such as hypertension, diabetes mellitus and chronic kidney disease, which increases the severity of heart failure symptoms and negatively impacts quality of life and prognosis (Groenewegen et al., 2020). The presence of multi-comorbidities increases the complexity to effectively manage patients with heart failure (Conrad et al., 2018). Consequently, difficulties in management have resulted in higher rates of rehospitalisation (Groenewegen et al., 2020, Komajda, 2015, Wachter and Rommel, 2022), placing a significant demand on hospital facilities and personnel, and incurring substantial healthcare costs (Cleland et al., 2019, Conrad et al., 2018, Lesyuk et al., 2018, Urbich et al., 2020).

Due to an ageing population, improvements in diagnostic testing, and greater survival rates following a cardiovascular event, the incidence of heart failure is expected to continue to rise (Lippi and Sanchis-Gomar, 2020, Savarese et al., 2022). The prevalence of heart failure increases with age, from 1% for those <55 years to 10% for those aged >70 years (McDonagh et al., 2021). In the USA between 2001 and 2014, of the 14.6 million individuals hospitalised due to heart failure, 75.3% were classified as older people (>65 years) (Akintoye et al., 2017). The mean age of this population is 75.2 years (Norhammar et al., 2023).

Conclusions

The findings from this review highlight the potential of interventions implemented in nursing homes for improving care provision to residents with heart failure. However, outcomes reported across the included studies were mostly focused on nursing home staff. Thus, future research is needed to determine whether such interventions are effective in improving outcomes associated with nursing home residents. Also, future research should aim to determine whether such interventions can produce long-term effects and sustainability. Education was a common intervention component employed across the studies, provided face-to-face to nursing home staff. Participant feedback, although limited, indicated that education was well-received and beneficial, improving heart failure knowledge of staff. However, this study reported poor participant attendance at the sessions, with the intervention facilitator indicating that this approach was burdensome. The delivery of a digital intervention may provide greater success, reducing the burden on staff and the need for an intervention facilitator. A digital approach also provides participants with the ability to access the intervention at a time that suits them, potentially improving intervention acceptability, user engagement, and likelihood of success.

Abstract

To determine the efficacy and potential protective mechanism of canagliflozin combined with aerobic exercise in treating chronic heart failure (CHF). Isoproterenol was injected into rats to create CHF models. The rats were then subsequently divided into saline, canagliflozin (3 mg/kg/d), aerobic exercise training, and canagliflozin combined with aerobic exercise training. Compared to the CHF group, the canagliflozin combined with the aerobic exercise group had superior ventricular remodeling and cardiac function. In rats treated with canagliflozin combined with aerobic exercise, the expression of cytochrome P450 (CYP) 4A3, CYP4A8, COL1A1, COL3A1, and FN1 was reduced, while the expression of CYP26B1, ALDH1A2, and CYP1A1 increased significantly. Additionally, canagliflozin combined with aerobic exercise decreased the phosphorylation of AKT and ERK1/2. Canagliflozin combined with aerobic exercise has a positive effect on the development of CHF via the regulation of retinol metabolism and the AKT/ERK signaling pathway.

Introduction

Chronic heart failure (CHF), the most prevalent form of cardiovascular illness, is a global health issue with a high death and morbidity rate.1 The disease affects about 2% of the adult population worldwide, and the 5-year mortality rate is estimated to be between 45 and 60%.2 CHF is a complex condition characterized by a cardiac muscle’s inability to maintain blood supply to peripheral tissues, resulting in decreased systemic energy metabolism.3 Multiple studies have demonstrated that regulating cardiac energy metabolism is critical for treatment.4,5 The β-oxidation of fatty acids in the mitochondria satisfies the heart’s high energy requirements. Oliveros et al. observed previously observed that a vitamin A deficit paired antioxidant defenses, promoted lipid peroxidation in the adult rat heart, and altered aortic lipid metabolism.6 The peroxisome proliferator-activated receptor (PPAR) is a ligand-activated nuclear transcription factor.7 PPAR modulates fatty acid oxidation (FAO) and mitochondrial bioenergetics, suppresses myocardial remodeling and fibrosis, and improves HF.8 Consequently, we must investigate new techniques for enhancing cardiac function by ameliorating abnormalities of cardiac energy metabolism, preventing cardiac remodeling and fibrosis, and thereby preventing or postponing the advancement of heart failure.

Canagliflozin, an inhibitor of sodium-glucose cotransporter 2 (SGLT-2), has been demonstrated to benefit HF with a lower ejection fraction.9 SGLT-2 inhibitors (canagliflozin, and so forth) for patients with CHF, improve the quality of life, and reduce mortality, morbidity, and readmission rates.10 In diabetic and nondiabetic subjects, canagliflozin treatment significantly reduced the risk of cardiovascular death, myocardial infarction, and hospitalization for hypertension.11 In addition, SGLT-2 inhibitors can improve fatty acid metabolism and utilize ketone bodies to create mitochondrial energy, so enhancing the aerobic metabolism of skeletal muscle, inhibiting anaerobic metabolism, and enhancing aerobic exercise capacity.12 Canagliflozin has been demonstrated to decrease myocardial glucose metabolism, enhance myocardial fatty acid metabolism, and increase the circulation of ketone bodies,13 thereby ameliorating heart failure via modifying myocardial energy metabolism and oxidative stress.14

Results

Canagliflozin combined with aerobic exercise improved isoproterenol-induced cardiac dysfunction
To investigate the effect of canagliflozin combined with aerobic exercise on CHF, cardiac function was assessed using echocardiography. After 10 days of ISO administration, the levels of LVEF (p < 0.001) and LVFS (p < 0.001) in the ISO group were significantly lower than in the control group, indicating that the CHF rat model was successfully established. LVEF and LVFS levels were significantly higher in the ISO+CA group (LVEF, p < 0.05; LVFS, p < 0.05), the ISO+AE group (LVEF, p < 0.05; LVFS, p < 0.05), and the ISO+AE+CA group (LVEF, p < 0.01; LVFS, p < 0.01). Moreover, compared to the ISO group, the levels of LVIDs (p < 0.05) and LVESV (p < 0.05) were significantly reduced in the ISO+AE+CA group but not in the ISO+CA group (LVIDs, p = 0.21; LVESV, p = 0.21). (Figures 1A and 1B, Table 1).

Objective
To investigate the influence of aerobic exercise on myocardial injury, NF-B expression, glucolipid metabolism and inflammatory factors in rats with Coronary Heart Disease (CHD) and explore the possible causative role.

Methods
45 Sprague Dawley® rats were randomized into model, control and experimental groups. A high-fat diet was adopted for generating a rat CHD model, and the experimental group was given a 4-week aerobic exercise intervention. ECG was utilized to evaluate the cardiac function of the rats; HE staining to evaluate the damage of myocardial tissue; TUNEL staining to evaluate cardiomyocyte apoptosis level; ELISA to assay the contents of inflammatory factors and glucolipid metabolism in cardiomyocytes; qPCR to assay IB- and NF-B mRNA expression; Western-blot to assay the apoptosis-related proteins and NF-B signaling pathway-related proteins expressions in myocardial tissue.

Results
In contrast to the model group, aerobic exercise strongly improved the rat’s cardiac function and glucolipid metabolism (p < 0.01), enhanced IL-10 content, Bcl-2/Bax level as well as IB- protein and mRNA expression (p < 0.01), and reduced myocardial injury and cardiomyocyte apoptosis, the contents of IL-6, IL-1 and TNF-, Caspase 3 level, NF-B mRNA and protein expression and p-p38 and p-STAT3 expressions (p < 0.01).

Conclusion
Aerobic exercise can not only effectively reduce myocardial injury, the release of inflammatory factors and NF-B expression in CHD rats, but also improve cardiac function and glucolipid metabolism. Its mechanism is likely to be related to the inhibition of the NF-B signaling pathway.

Introduction

Coronary Heart Disease (CHD) refers to coronary artery lumen stenosis or even blockage caused by atherosclerosis, which causes myocardial ischemia, hypoxia and even necrosis, and is also known as ischemic heart disease. 1 , 2 Physiological, genetic and environmental factors that cause aberrant glucolipid metabolism and inflammatory response disorders are the dominating incentives that induce atherosclerosis and the primary pathophysiological basis of CHD. 3 , 4 With the improvement in living standards, the incidence of CHD is increasing year by year, posing a huge economic burden on families and countries. Reducing the mortality and extending the survival time of CHD patients is a major challenge that cardiovascular disease researchers and clinicians urgently need to solve.

Considerable evidence shows that vascular endothelial injury will raise the adhesion and permeability of vascular endothelium, and then multiple inflammatory factors will gather and produce an inflammatory fiber proliferation reaction, which eventually gives rise to atherosclerosis. 7 , 8 , 9 Nuclear Factor Kappa B (NF-B) takes part in not only the occurrence but also the development of inflammatory response. NF-B inhibitor protein IB- can accelerate the dissociation of NF-B. The dissociated NF-B can be rapidly transferred to the nucleus, modulating the transcription and translation processes of diverse inflammatory factors and adhesion factors, and is an important cytokine that modulates the activation and cascade amplification of inflammatory factors. 10 , 11 Schiffmann et al. 12 have demonstrated that CHD patients will have apparent glucolipid metabolism disorder. Over-nutrition and sedentary behaviors will strikingly accelerate the accumulation of fat and glucose in the body, which in turn will aggravate the vascular endothelial damage of patients. Substantial evidence indicates that aerobic exercise can efficaciously regulate glucolipid metabolism in the body, reduce the activity of lipoprotein lipase, lower blood lipid and blood sugar levels, and reduce body weight. 13 , 14 Ornish et al. 15 demonstrated that long-term aerobic exercise can apparently reduce blood lipid levels and reduce vascular endothelial damage in patients with cardiovascular disease. At present, there are few studies on the impact of aerobic exercise on myocardial damage, glucolipid metabolism, and inflammation in CHD. This investigation aimed to build a rat CHD model to study the influence of aerobic exercise on myocardial damage, NF-B expression, glucolipid metabolism and inflammatory responses in CHD rats, as well as to further explore its possible causative role.

Abstract

Background
Prenatal urban environmental exposures have been associated with blood pressure in children. The dynamic of these associations across childhood and later ages is unknown.

Objectives
The purpose of this study was to assess associations of prenatal urban environmental exposures with blood pressure trajectories from childhood to early adulthood.

Methods
Repeated measures of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were collected in up to 7,454 participants from a UK birth cohort. Prenatal urban exposures (n = 43) covered measures of noise, air pollution, built environment, natural spaces, traffic, meteorology, and food environment. An exposome-wide association study approach was used. Linear spline mixed-effects models were used to model associations of each exposure with trajectories of blood pressure. Replication was sought in 4 independent European cohorts (up to 9,261).

Results
In discovery analyses, higher humidity was associated with a faster increase (mean yearly change in SBP for an interquartile range increase in humidity: 0.29 mm Hg/y, 95% CI: 0.20-0.39) and higher temperature with a slower increase (mean yearly change in SBP per interquartile range increase in temperature: −0.17 mm Hg/y, 95% CI: −0.28 to −0.07) in SBP in childhood. Higher levels of humidity and air pollution were associated with faster increase in DBP in childhood and slower increase in adolescence. There was little evidence of an association of other exposures with change in SBP or DBP. Results for humidity and temperature, but not for air pollution, were replicated in other cohorts.

Conclusions
Replicated findings suggest that higher prenatal humidity and temperature could modulate blood pressure changes across childhood.

Discussion

We assessed the association of 39 prenatal urban environmental exposures with blood pressure trajectories from childhood to early adulthood in ALSPAC (Central Illustration) and sought replication of the findings in 4 independent European cohorts. After accounting for multiple testing, we found that humidity was associated with faster increase in SBP and DBP in childhood, slower decrease in SBP in adulthood, and slower increase in DBP in adolescence. Temperature was associated with slower increase in SBP and DBP in childhood and faster increase in DBP in adolescence. PM2.5 was associated with faster increase in DBP in childhood and slower increase in adolescence. Little evidence for sex differences in these associations was observed. Analyses in independent cohorts replicated results for associations of humidity and temperature with change in blood pressure in childhood but not for PM2.5.

Many studies have assessed the association of outdoor temperature with blood pressure,7 but less evidence is available for humidity. In adults, humidity has been positively associated with blood pressure levels,35 and a positive association with DBP has also been observed in children.15 We were able to identify only one study which assessed the association of humidity during pregnancy with offspring blood pressure. This study, which included 1,277 European children did not find an association between prenatal humidity and blood pressure in children aged 6 to 11 years (mean difference per IQR increase in humidity: 0.76 mm Hg, 95% CI: 3.3 to 1.77 mm Hg for SBP, and 0.44 mm Hg, 95% CI: 2.79 to 1.92 mm Hg for DBP).13

Conclusions

Using an ExWAS approach to systematically assess a range of prenatal urban environmental exposures, this study showed that prenatal outdoor temperature and humidity potentially modulate blood pressure trajectories, particularly in childhood. Our study contributes to the growing body of evidence on the longitudinal associations of prenatal environmental exposures with blood pressure later in life.

ACKNOWLEDGMENTS The authors are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The Generation R Study is conducted by the Erasmus MC, University Medical Center Rotterdam in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, Rotterdam, the Rotterdam Homecare Foundation, Rotterdam and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR-MDC), Rotterdam. We gratefully acknowledge the contribution of children and Gonçalves Soares et al JACC: ADVANCES, VOL. 3, NO. 2, 2024 Prenatal Urban Environment and Blood Pressure Trajectories FEBRUARY 2024:100808 10 parents, general practitioners, hospitals, midwives, and pharmacies in Rotterdam. The authors thank the EDEN mother-child cohort study group, whose members are I. Annesi-Maesano, J.Y. Bernard, J. Botton, M.A. Charles, P. Dargent-Molina, B. de Lauzon-Guillain, P. Ducimetière, M. de Agostini, B. Foliguet, A. Forhan, X. Fritel, A. Germa, V. Goua, R. Hankard, B. Heude, M. Kaminski, B. Larroquey, N. Lelong, J. Lepeule, G. Magnin, L. Marchand, C. Nabet, F Pierre, R. Slama, M.J. Saurel-Cubizolles, M. Schweitzer, and O. Thiebaugeorges. They are grateful to all children and their parents and caregivers who have participated in the PANIC Study. They are also indebted to all members of the PANIC research team for their invaluable contribution in the acquisition of the data throughout the study. They also thank all NFBC1986 members and researchers who participated in the study. They also wish to acknowledge the work of the NFBC project centre.

Summary

Background
Randomised trials of vitamin D supplementation for cardiovascular disease and all-cause mortality have generally reported null findings. However, generalisability of results to individuals with low vitamin D status is unclear. We aimed to characterise dose-response relationships between 25-hydroxyvitamin D (25[OH]D) concentrations and risk of coronary heart disease, stroke, and all-cause mortality in observational and Mendelian randomisation frameworks.

Methods
Observational analyses were undertaken using data from 33 prospective studies comprising 500 962 individuals with no known history of coronary heart disease or stroke at baseline. Mendelian randomisation analyses were performed in four population-based cohort studies (UK Biobank, EPIC-CVD, and two Copenhagen population-based studies) comprising 386 406 middle-aged individuals of European ancestries, including 33 546 people who developed coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died. Primary outcomes were coronary heart disease, defined as fatal ischaemic heart disease (International Classification of Diseases 10th revision code I20-I25) or non-fatal myocardial infarction (I21-I23); stroke, defined as any cerebrovascular disease (I60-I69); and all-cause mortality.

Findings
Observational analyses suggested inverse associations between incident coronary heart disease, stroke, and all-cause mortality outcomes with 25(OH)D concentration at low 25(OH)D concentrations. In population-wide genetic analyses, there were no associations of genetically predicted 25(OH)D with coronary heart disease (odds ratio [OR] per 10 nmol/L higher genetically-predicted 25(OH)D concentration 0·98, 95% CI 0·95–1·01), stroke (1·01, [0·97–1·05]), or all-cause mortality (0·99, 0·95–1·02). Null findings were also observed in genetic analyses for cause-specific mortality outcomes, and in stratified genetic analyses for all outcomes at all observed levels of 25(OH)D concentrations.

Interpretation
Stratified Mendelian randomisation analyses suggest a lack of causal relationship for 25(OH)D concentrations with both cardiovascular and mortality outcomes for individuals at all levels of 25(OH)D. Our findings suggest that substantial reductions in mortality and cardiovascular morbidity due to long-term low-dose vitamin D supplementation are unlikely even if targeted at individuals with low vitamin D status.

Funding
British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer.

Introduction

Vitamin D is an essential nutrient obtained from sunlight, dietary intake, and supplementation.1 Observational epidemiological studies have consistently found that low concentrations of circulating 25-hydroxyvitamin D (25[OH]D), a metabolite used as a clinical indicator of vitamin D status, are associated with an increased risk of cardiovascular disease and all-cause mortality, as well as other chronic diseases.2,  3 However, several large randomised trials of vitamin D supplementation have reported null results,4,  5,  6 casting doubt on the observational evidence. However, as trials have typically recruited participants irrespective of baseline 25(OH)D concentration, they have had limited power to test supplementation effects in subgroups with low 25(OH)D concentrations.7

An efficient approach for assessing the potential causal effect of vitamin D supplementation is Mendelian randomisation. Mendelian randomisation uses genetic variants specifically related to a particular exposure to compare genetically defined population subgroups with different average levels of the exposure. The independent segregation of alleles at conception means that these genetically defined subgroups should not differ systematically with respect to confounding variables, creating a natural experiment analogous to a randomised trial.8 Therefore, Mendelian randomisation analyses can provide more reliable insights into causal relationships between risk factors and disease outcomes than conventional observational analyses. Previous Mendelian randomisation analyses have reported null associations of genetically predicted 25(OH)D concentrations with coronary heart disease9,  10 and ischaemic stroke.11,  12 An inverse association has been observed between genetically predicted 25(OH)D and all-cause mortality.13 Null findings have been observed for several further outcomes, including other cardiovascular diseases and cancers.14

Results

386 406 participants from the four studies were included in genetic analyses (table 1), including 33 546 people who had coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died, and 500 962 participants were included in observational analyses (appendix 3 pp 11–13). Mean age of participants included in the genetic analysis ranged from 54·8 years (SD 9·4) to 57·5 years (12·9), with similar numbers of men and women in each study, and the mean season-shifted 25(OH)D concentrations (corresponding to an autumn measurement) were 54·5 nmol/L (SD 19·6) in UK Biobank, 46·9 nmol/L (16·4) in EPIC-CVD, and 53·8 nmol/L (25·9) in the Copenhagen studies. Mean 25(OH)D estimates did not notably differ by assay type (appendix 3 p 21). The focused genetic risk score explained 4·7% of the variance in 25(OH)D concentrations in UK Biobank study, 5·8% in EPIC-CVD, and 1·8% in the Copenhagen studies. This genetic risk score was not associated with a range of cardiovascular risk factors in UK Biobank, except for BMI and HDL cholesterol, although these associations were small (appendix 3 p 22). The genome-wide score was strongly associated with LDL cholesterol and triglycerides (appendix 3 p 23), and so Mendelian randomisation estimates using this score are unreliable.

Summary

Background
Randomised trials of vitamin D supplementation for cardiovascular disease and all-cause mortality have generally reported null findings. However, generalisability of results to individuals with low vitamin D status is unclear. We aimed to characterise dose-response relationships between 25-hydroxyvitamin D (25[OH]D) concentrations and risk of coronary heart disease, stroke, and all-cause mortality in observational and Mendelian randomisation frameworks.

Methods
Observational analyses were undertaken using data from 33 prospective studies comprising 500 962 individuals with no known history of coronary heart disease or stroke at baseline. Mendelian randomisation analyses were performed in four population-based cohort studies (UK Biobank, EPIC-CVD, and two Copenhagen population-based studies) comprising 386 406 middle-aged individuals of European ancestries, including 33 546 people who developed coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died. Primary outcomes were coronary heart disease, defined as fatal ischaemic heart disease (International Classification of Diseases 10th revision code I20-I25) or non-fatal myocardial infarction (I21-I23); stroke, defined as any cerebrovascular disease (I60-I69); and all-cause mortality.

Findings
Observational analyses suggested inverse associations between incident coronary heart disease, stroke, and all-cause mortality outcomes with 25(OH)D concentration at low 25(OH)D concentrations. In population-wide genetic analyses, there were no associations of genetically predicted 25(OH)D with coronary heart disease (odds ratio [OR] per 10 nmol/L higher genetically-predicted 25(OH)D concentration 0·98, 95% CI 0·95–1·01), stroke (1·01, [0·97–1·05]), or all-cause mortality (0·99, 0·95–1·02). Null findings were also observed in genetic analyses for cause-specific mortality outcomes, and in stratified genetic analyses for all outcomes at all observed levels of 25(OH)D concentrations.

Interpretation
Stratified Mendelian randomisation analyses suggest a lack of causal relationship for 25(OH)D concentrations with both cardiovascular and mortality outcomes for individuals at all levels of 25(OH)D. Our findings suggest that substantial reductions in mortality and cardiovascular morbidity due to long-term low-dose vitamin D supplementation are unlikely even if targeted at individuals with low vitamin D status.

Funding
British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer.

Introduction

Vitamin D is an essential nutrient obtained from sunlight, dietary intake, and supplementation.1 Observational epidemiological studies have consistently found that low concentrations of circulating 25-hydroxyvitamin D (25[OH]D), a metabolite used as a clinical indicator of vitamin D status, are associated with an increased risk of cardiovascular disease and all-cause mortality, as well as other chronic diseases.2,  3 However, several large randomised trials of vitamin D supplementation have reported null results,4,  5,  6 casting doubt on the observational evidence. However, as trials have typically recruited participants irrespective of baseline 25(OH)D concentration, they have had limited power to test supplementation effects in subgroups with low 25(OH)D concentrations.7

An efficient approach for assessing the potential causal effect of vitamin D supplementation is Mendelian randomisation. Mendelian randomisation uses genetic variants specifically related to a particular exposure to compare genetically defined population subgroups with different average levels of the exposure. The independent segregation of alleles at conception means that these genetically defined subgroups should not differ systematically with respect to confounding variables, creating a natural experiment analogous to a randomised trial.8 Therefore, Mendelian randomisation analyses can provide more reliable insights into causal relationships between risk factors and disease outcomes than conventional observational analyses. Previous Mendelian randomisation analyses have reported null associations of genetically predicted 25(OH)D concentrations with coronary heart disease9,  10 and ischaemic stroke.11,  12 An inverse association has been observed between genetically predicted 25(OH)D and all-cause mortality.13 Null findings have been observed for several further outcomes, including other cardiovascular diseases and cancers.14

Results

386 406 participants from the four studies were included in genetic analyses (table 1), including 33 546 people who had coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died, and 500 962 participants were included in observational analyses (appendix 3 pp 11–13). Mean age of participants included in the genetic analysis ranged from 54·8 years (SD 9·4) to 57·5 years (12·9), with similar numbers of men and women in each study, and the mean season-shifted 25(OH)D concentrations (corresponding to an autumn measurement) were 54·5 nmol/L (SD 19·6) in UK Biobank, 46·9 nmol/L (16·4) in EPIC-CVD, and 53·8 nmol/L (25·9) in the Copenhagen studies. Mean 25(OH)D estimates did not notably differ by assay type (appendix 3 p 21). The focused genetic risk score explained 4·7% of the variance in 25(OH)D concentrations in UK Biobank study, 5·8% in EPIC-CVD, and 1·8% in the Copenhagen studies. This genetic risk score was not associated with a range of cardiovascular risk factors in UK Biobank, except for BMI and HDL cholesterol, although these associations were small (appendix 3 p 22). The genome-wide score was strongly associated with LDL cholesterol and triglycerides (appendix 3 p 23), and so Mendelian randomisation estimates using this score are unreliable.

Abstract

Objective

     To characterize distinct comorbidities, outcomes, and treatment patterns in children with Down syndrome and pulmonary hypertension in a large, multicenter pediatric pulmonary hypertension registry.

Study design

     We analyzed data from the Pediatric Pulmonary Hypertension Network (PPHNet) Registry, comparing demographic and clinical characteristics of children with Down syndrome and children without Down syndrome. We examined factors associated with pulmonary hypertension resolution and a composite outcome of pulmonary hypertension severity in the cohort with Down syndrome.

Results

     Of 1475 pediatric patients with pulmonary hypertension, 158 (11%) had Down syndrome. The median age at diagnosis of pulmonary hypertension in patients with Down syndrome was 0.49 year (IQR, 0.21-1.77 years), similar to that in patients without Down syndrome. There was no difference in rates of cardiac catheterization and prescribed pulmonary hypertension medications in children with Down syndrome and those without Down syndrome. Comorbidities in Down syndrome included congenital heart disease (95%; repaired in 68%), sleep apnea (56%), prematurity (49%), recurrent respiratory exacerbations (35%), gastroesophageal reflux (38%), and aspiration (31%). Pulmonary hypertension resolved in 43% after 3 years, associated with a diagnosis of pulmonary hypertension at age <6 months (54% vs 29%; P = .002) and a pretricuspid shunt (65% vs 38%; P = .02). Five-year transplantation-free survival was 88% (95% CI, 80%-97%). Tracheostomy (hazard ratio [HR], 3.29; 95% CI, 1.61-6.69) and reflux medication use (HR, 2.08; 95% CI, 1.11-3.90) were independently associated with a composite outcome of severe pulmonary hypertension.

Conclusions

     Despite high rates of cardiac and respiratory comorbidities that influence the severity of pulmonary hypertension, children with Down syndrome–associated pulmonary hypertension generally have a survival rate similar to that of children with non–Down syndrome–associated pulmonary hypertension. Resolution of pulmonary hypertension is common but reduced in children with complicated respiratory comorbidities.

Methods

     The PPHNet registry includes comprehensive clinical data from 8 centers in the US and Canada that enrolled patients between October 2014 and February 2018 and includes follow-up data submitted through May 18, 2020.20 The PPHNet registry was supported in part by a National Heart, Lung, and Blood Institute–funded U01 program (U01 HL12118; Data Fusion: A Sustainable, Open Source Registry Advancing Pediatric Pulmonary Vascular Disease Research; S.A. and K.M., principal investigators). The study protocol was approved by the Institutional Review Board of each participating center. Parents and/or guardians provided signed informed consent, and participants gave assent when appropriate, according to institutional guidelines.

Results

     Of the 1475 children enrolled in the PPHNet Registry, 158 (10.7%) were identified as subjects with Down syndrome.20 There was a slight preponderance of males in the Down syndrome group (53.8%). The proportion of patients with pulmonary hypertension with Down syndrome differed by study site, ranging from 6% to 22%. Compared with the non-Down syndrome cohort, patients with Down syndrome were less likely to be White and more likely to be Asian (P < .001). There were 12 deaths and no lung transplants in the Down syndrome cohort, which was followed for a median of 2.9 years. There was no difference in the proportion of patients with death/transplant for the Down syndrome and non-Down syndrome cohorts (Table I).

     The distribution of the primary WSPH classification of pulmonary hypertension differed between the Down syndrome and non-Down syndrome cohorts (P < .001). The Down syndrome cohort was more commonly group 1 (pulmonary arterial hypertension) compared with the non-Down syndrome cohort (69.6% vs 37.3%), and group 3 pulmonary hypertension (related to lung disease) was more common in the nonDown syndrome group (52.2% vs 20.9%) (Table I). Of the 110 patients with Down syndrome categorized as having group 1 pulmonary hypertension (pulmonary arterial hypertension), 109 were further classified: 103 (94.5%) with pulmonary arterial hypertension associated with CHD, 5 (4.6%) with idiopathic pulmonary arterial hypertension, and 1 (0.9%) with pulmonary arterial hypertension induced by drugs and toxins. Relatively few patients were classified as group 10 (pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis), group 100 (PPHN), and group 2 pulmonary hypertension (related to left heart disease), and prevalence was similar in children with Down syndrome and those without Down syndrome. No patients were classified as having chronic thromboembolic pulmonary hypertension (group 4). Group 5 (multifactorial) pulmonary hypertension was uncommon across the registry (Table I).

Abstract

Background
Calcium channel blockers (CCBs) are used for the treatment of cardiovascular disease (CVD), including angina pectoris, and hypertension; however, the effect on survival remains uncertain. CCBs impair fibrinolysis and have been linked to elevated plasma homocysteine (Hcy), a CVD risk marker.

Objective
We explored the association between CCB use and mortality in a large prospective cohort of patients with suspected stable angina pectoris (SAP), and potential effect modifications by Hcy-lowering B-vitamin treatment (folic acid, B12, and/or B6) as 61.8% of the patients participated in a randomized placebo-controlled B-vitamin intervention trial.

Methods
Patient baseline continuous characteristics according to CCB treatment were tested by linear regression. Hazard ratios (HRs) for mortality associated with CCB treatment, also according to B-vitamin intervention, were examined using Cox regression analysis. The multivariable model included CVD risk factors, medical histories, and the use of CVD medications.

Results
A total of 3991 patients (71.5 % men) were included, of whom 907 were prescribed CCBs at discharge. During 10.3 years of median follow-up, 20.6% died and 8.9% from cardiovascular- and 11.7% from non-cardiovascular causes. Patients treated with CCBs had higher plasma Hcy, fibrinogen levels, and erythrocyte sedimentation rate (all P<0.001). Furthermore, CCB use was positively associated with mortality, also after multivariable adjustments (HRs [95% CIs]: 1.34 [1.15,1.57], 1.35 [1.08,1.70], and 1.33 [1.09,1.64] for total, CVD, and non-CVD death, respectively). Numerically stronger associations were observed among patients not treated with B-vitamins (HR [95% CI]: 1.54 [1.25, 1.88], 1.69 [1.25, 2.30], and 1.41 [1.06, 1.86] for total, CVD deaths, and non-CVD deaths, respectively), whereas no association was seen in patients treated with B-vitamins (HR [95% CI]: 1.15 [0.91, 1.46], 1.09 [0.76, 1.57], and 1.20 [0.88, 1.65]).

Conclusions
In patients with suspected SAP, CCB treatment was associated with increased mortality risk primarily among patients not treated with B-vitamins.

Introduction

Calcium channel blockers (CCBs) are widely used in patients with stable angina pectoris (SAP) for symptom relief or blood pressure control [1]. However, there is conflicting evidence that CCBs improve prognosis in the former condition or other clinical manifestations of coronary artery disease (CAD). Notably, while most studies showed no clinical benefit on survival [[2], [3], [4]], some have linked CCB treatment to higher mortality risk [[5], [6], [7]].

The B-vitamins folic acid, vitamin B12, and B6 are water-soluble nutrients essential for diverse physiological processes, including homocysteine (Hcy) metabolism [8,9]. A deficiency of these vitamins may lead to elevated circulating total Hcy (tHcy) concentrations [8], which is a risk factor for atherothrombosis [8,9]. Moreover, treatment with these vitamins is reported to have anti-inflammatory [10,11] and anti-coagulant effects [12,13], and vitamin B6 may inhibit sympathetic tone [14]. However, randomized clinical trials (RCTs) failed to reduce cardiovascular disease (CVD) risk with Hcy-lowering B-vitamins [15,16], although treatment effects may have been heterogeneous according to certain subgroup phenotypes. Notably, CCB treatment has been associated with increased systemic Hcy concentrations [[17], [18]]. Moreover, CCBs promote proinflammatory responses [19,20], decrease fibrinolytic function [21,22], and increase sympathetic activation [23], thus potentially increasing CVD risk.

Conclusions

Among patients with suspected SAP, the use of CCBs was associated with increased long-term risk of all-cause, cardiovascular, and noncardiovascular mortality. However, these associations were attenuated in patients receiving B-vitamin treatment, which may explain some of the heterogenic results in prior observational studies.

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Abstract

Purpose of Review
There are several aspects of donor selection for heart transplantation that are particularly challenging. Information about the donor is often limited and relayed through a review of selected chart snippets and tests. The donor heart must work immediately unlike kidney transplantation where delayed function is common and not life-threatening. This review focuses on recent findings in the literature which are distilled for the transplant clinician to be eminently practical to advise teams as they consider which donor factors are important in individual situations.

Recent Findings
Left ventricular dysfunction has many causes and particularly in younger donors may resolve with time. Such donors can be utilized with excellent results. Donor age is still a critically important risk factor for outcome post-transplant though it is additive with other factors such as left ventricular hypertrophy and anticipated ischemic time. Donor size is another important factor and recent work suggests that calculation of predicted heart mass is superior to simple weight, height, and gender in reaching a decision about donor sizing. Recent work suggests that even donors with non-critical coronary lesions (50% or less) may be utilized with similar outcomes, including a similar incidence of progression of vasculopathy. Diabetes appears to be a manageable comorbidity particularly with careful screening. With the increase in drug-related deaths, a recent study looking at more than 23,000 accepted donors found no difference in long-term survival with multiple drugs in the toxicology screen of the donor which may allow increased use of such donors. Finally, we review the details of donation after circulatory determination of death (DCD). Currently, this is confined to certain specialized centers but this is anticipated to become more common worldwide and enhance the number of transplants over time.

Summary
Current evidence is reviewed and summarized to allow the busy transplant clinician to be up to date on the latest information regarding large and smaller important studies in this field. It is hoped that this review helps teams maximize their use of appropriate donors.

Abstract

     Cardiovascular disease is a global leading cause of death, and timely monitoring can determine its extent. Clinicians use these diagnostic indicators to make scientific and reasonable decisions. However, when decision-makers (DMs) encounter risks in complex environments, their limited rationality may affect decision behaviors. Therefore, the paper explores a new three-way multi-attribute decision making method based on regret theory (3W-MADM-R), which uses heart disease data to make decisions in fuzzy environments. There are three main steps in developing 3W-MADM-R, i.e., (i) we propose the notion of relative outcome functions and corresponding aggregated regret-based utility functions of each object; (ii) we estimate the conditional probability via an outranked set defined by an outranking relation based on the Preference Ranking Organization Method for Enrichment Evaluation (PROMETHEE II); (iii) we construct three-way decision rules to solve the problems of clustering and ranking of objects in data analysis. In order to demonstrate the usefulness of 3W-MADM-R, we apply it to analyze heart disease data. By comparing with results of other methods, we show the feasibility, stability and superiority of the presented 3W-MADM-R method.

Introduction

     Multi-attribute decision making (MADM) refers to a decision problem in which the importance of different attributes is considered and the decision scheme is ranked or the optimal one is selected. There are many applications of MADM methods in management, engineering design, economics and other fields. For instance, Churchman et al. [1] first used a simple weighting method to solve the problem of “choosing the investment policy of enterprises”. At present, the classic MADM methods, including the TOPSIS method [2], the ELECTRE method [3], the PROMETHEE-II method [4] and others. Meanwhile, many types of uncertainties have been considered in MADM methods, including randomness [5], fuzziness [6] and roughness [7]. According to the behavior characteristics of a DM, stochastic, fuzzy-set, and rough-set-based MADM models have been proposed and investigated [8], [9], [10], [11], [12].

     With the rise of MADM techniques, their applications in the medical field [13] have become more and more widespread. A case in point is that the MADM method can be applied to solve cardiovascular and cerebrovascular diseases that seriously threaten human health. According to a report released by World Health Organization (WHO), 18 million people die from cardiovascular diseases each year, and 85% of which are due to heart disease and stroke. Data from the National Bureau of Statistics (https://data.stats.gov.cn/) show that the proportion of deaths due to heart disease in the total number of deaths is increasing year by year and has reached 23.65% in 2019. Therefore, the prevention and control of heart disease need joint efforts of all individuals. Early monitoring, diagnosis and treatment can effectively reduce the morbidity and mortality of heart disease and improve the life quality of patients. One of the key problems in the field of life sciences is how to quickly and effectively diagnose heart disease. At present, routine detection items for this disease mainly include blood pressure, electrocardiogram, blood routine, blood lipids, blood glucose, hemorheology, and so forth. These tests will help clinicians to determine the location and extent of cardiovascular diseases. However, in complex environments, facing with limited rationality owned by DMs and different forms of biomedical data, there are two issues that need to be addressed. One is how to effectively and reasonably deal with ambiguities in psychological and medical data along with the bounded rationality of DMs, and the other one is how DMs with limited rationality apply these data to diagnose a variety of diseases. In real world, clinical decision making and other aspects remain to be explored.

Conclusions

     In recent years, the researches on MADM problems and 3WD models have become the mainstream. On this basis, we have combined RT with the traditional PROMETHEE-II method to construct a new 3W-MADM-R method to solve the decision making problems with behavioral psychology in real life. The effectiveness and superiority of our proposed method have been verified by an illustrative example and comparative analysis of other methods. In addition, in order to demonstrate the stability and feasibility of the 3W-MADM-R method, parameter analysis has been carried out and another three data sets have been added for further verification. The main contributions of this paper are summarized as follows:

     (1) Based on the net-flow of the traditional PROMETHEE-II method, we have constructed a new outranking relation and objectively given the membership degree of the membership function to calculate the conditional probability, which solves the deficiency of the existing methods [38,39].

Abstract

Introduction

Methods

Results

Discussion

Conclusions

Acknowledgements

Appendix A. Supplementary data

References

Abstract

Aim

     We investigated sex-related differences in the in-hospital management of patients with out-of-hospital cardiac arrest (OHCA).

Methods

     We retrospectively analyzed prospectively collected data from the Korean Cardiac Arrest Resuscitation Consortium (KoCARC) registry, a prospective, multicenter OHCA registry. We enrolled adult patients with OHCA between October 2015 and June 2020. The primary outcomes were coronary angiography (CAG), percutaneous coronary intervention (PCI), targeted temperature management (TTM), and extracorporeal membrane oxygenation (ECMO) performed in the hospital. Propensity score matching (PSM) was performed to minimize differences in baseline demographics and characteristics.

Results

     Among 12,321 patients in the KoCARC registry, we analyzed 8,177 with OHCA. PSM yielded 5,564 matched patients (2,782 women and men, respectively). In the unmatched cohort, women were less likely to undergo CAG, PCI, TTM, and ECMO. In the PSM cohort, women were less likely to undergo CAG and PCI (6.4% vs. 9.1%, p < 0.001 and 1.9% vs. 3.7%, p < 0.001). The duration of cardiopulmonary resuscitation was shorter in women (19 vs. 20 min, p < 0.001). TTM, ECMO use, and survival outcomes did not differ significantly between sexes. The subgroup analysis according to age showed that among patients aged < 65 years, women were less likely than men to undergo CAG and PCI (12.7% vs. 19.2%, p < 0.001 and 2.3% vs. 8.1%, p < 0.001).

Conclusions

     In the PSM cohort, women with OHCA underwent CAG and PCI less frequently than men, regardless of the initial rhythm. However, these sex-related differences narrowed with increasing age. Further studies are needed to confirm the sex-related disparities in the in-hospital management of patients with OHCA.

Introduction

     Annually, approximately 300,000 individuals in the United States and 275,000 in Europe experience out-of-hospital cardiac arrest (OHCA).1.,  2. Although the survival rate of patients with OHCA has increased, the mortality rate remains high.3.,  4.,  5.

     In the past decade, sex disparities in health care systems have been reported, particularly in OHCA characteristics and survival.6.,  7.,  8.,  9.,  10.,  11.,  12.,  13.,  14.,  15.,  16. While men have a higher OHCA incidence than women,1.,  2.,  3.,  4.,  5. women are less likely to experience witnessed cardiac arrest,6.,  7.,  8.,  9. as its occurrence in public places is more common in men.10.,  11. Women experiencing cardiac arrest are less likely to receive bystander cardiopulmonary resuscitation (CPR)5.,  12.,  13.,  14. and less frequently present with a shockable rhythm.15.,  16. Conflicting results regarding sex disparities in survival and prognosis after OHCA were noted.16.,  17.,  18.,  19.,  20.,  21.,  22.,  23.,  24.,  25.,  26.,  27.,  28. However, the extent of sex disparities in OHCA remains unclear.

     Conflicting sex-related differences in the in-hospital management of OHCA patients have been reported.7.,  21.,  22.,  23.,  24.,  25.,  29.,  30.,  31.,  32.,  33. While some studies reported that women with OHCA were less likely to undergo early coronary angiography (CAG),17.,  23.,  24.,  30.,  31. Lindgren et al. did not observe this tendency.32. The findings on sex-related differences in performing percutaneous coronary intervention (PCI) are also conflicting.17.,  30.,  22.,  23.,  24.,  25. Targeted temperature management (TTM) was less frequently performed in women in older studies,17.,  23. whereas more recent studies showed no sex-related differences.22.,  24.,  25.,  30.

Results

Demographics of all eligible patients

     A total of 12,321 patients with OHCA were registered in the KoCARC. Among these, 4,144 patients were excluded due to age < 18 years, unknown covariate data, and missing primary outcomes. Finally, the analysis included 8,177 patients (Fig. 1). The mean age of the total population was 68.1 ± 15.6 years (median age, 71.0 [57.0–80.0] years; 65.8% male, 34.2% female). Of the patients, 60.2% had witnessed arrest, 19.7% experienced cardiac arrest in public places, and 19.9% had a shockable rhythm. Bystander CPR was performed in 54.1% of the patients, defibrillation in 25.2%, and prehospital advanced airway management in 82.6%. CAG, PCI, TTM, and ECMO were performed in 13.3%, 4.9%, 10.2%, and 2.8% of the patients, respectively. Among the patients, 28.8% survived to admission, 13.4% survived to discharge, and 9.2% were discharged with good neurological outcomes (Table 1).