The Effect of Weight Loss Through Lifestyle Interventions in Patients With Heart Failure With Preserved Ejection Fraction-A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) accounts for >50% of heart failure cases and is associated with significant morbidity and health system burden. To date, there have been limited treatment options proven to improve outcomes in these patients, with sodium glucose co-transporter 2 (SGLT2) inhibitors the first class of drug to demonstrate significant clinical benefits, including reductions in heart failure hospitalisation. Obesity is associated with all forms of heart failure and has been linked with worse clinical outcomes. Numerous reviews support the benefits of weight loss in heart failure, more specifically in patients with heart failure with reduced ejection fraction. However, the evidence in HFpEF patients is less clear. With limited pharmacotherapy options and growing support for weight loss in patients with HFpEF, this systematic review and meta-analysis aims to examine the effects of lifestyle interventions on weight loss and other health outcomes in patients with HFpEF. METHODS: Web of Science, Embase, Scopus, and PubMed databases were searched to identify relevant studies up to February 2023. Included studies were randomised controlled trials (with a duration of four weeks or more) of lifestyle interventions conducted in adults with HFpEF that reported weight loss. Outcomes of interest were body weight, body mass index (BMI), blood pressure (systolic and diastolic), aerobic capacity (6-minute walk distance), New York Heart Association (NYHA) Functional Classification, self-reported health quality of life (Minnesota Living with Heart Failure Questionnaire; MLHFQ), and N-terminal pro B-Type Natriuretic Peptide (NT-proBNP) levels. Review Manager software was used to conduct random effect meta-analyses, forest plots were generated for each outcome, and between-study heterogeneity was estimated using the I2 test statistic. Risk-of-bias assessment used the Cochrane risk-of-bias tool, and the certainty of the evidence was assessed using GRADE. RESULTS: From 2,282 records identified, six studies with a total of 375 participants, between three to six months in duration, were included in this systematic review and meta-analysis. Lifestyle interventions consisted of diet only, exercise only, combination of diet and exercise, and education and exercise. Over a mean follow-up of 4.5 months, pooled effects of the interventions were associated with a reduction in body weight of >5kg (weight mean difference (WMD): -5.30 kg; 95% CI: -8.72 to -1.87; p=0.002), and a reduction in resting systolic (WMD: -2.98 mmHg; 95% CI: -4.20 to -1.76; p<0.001) and diastolic blood pressure (WMD: -4.51 mmHg; 95% CI: -8.39 to -0.64; p=0.02) compared with those who received usual care. Interventions also improved 6-minute walk distance (WMD: 43.63 m; 95% CI: 22.28 to 64.97; p<0.001), NYHA class (WMD: -0.54; 95% CI: -0.75 to -0.33; p<0.001), and MLHFQ score (WMD: -17.77; 95% CL: -19.00 to -16.53; p<0.001). CONCLUSION: In patients with HFpEF, lifestyle intervention was associated with a significant reduction in body weight and had favourable effects on blood pressure, aerobic capacity, NYHA class, and health-related quality of life. Further research is needed in this population to examine the feasibility and durability of weight loss interventions and to examine the potential impact on hard clinical endpoints.

Canagliflozin and atrial fibrillation in type 2 diabetes mellitus: A secondary analysis from the CANVAS Program and CREDENCE trial and meta-analysis.

AIM: To assess the effects of canagliflozin on the incidence of atrial fibrillation/atrial flutter (AF/AFL) and other key cardiorenal outcomes in a pooled analysis of the CANVAS and CREDENCE trials. MATERIALS AND METHODS: Participants with type 2 diabetes and high risk of cardiovascular disease or chronic kidney disease were included and randomly assigned to canagliflozin or placebo. We explored the effects of canagliflozin on the incidence of first AF/AFL events and AF/AFL-related complications (ischaemic stroke/transient ischaemic attack/hospitalization for heart failure). Major adverse cardiovascular events and a renal-specific outcome by baseline AF/AFL status were analysed using Cox regression models. RESULTS: Overall, 354 participants experienced a first AF/AFL event. Canagliflozin had no detectable effect on AF/AFL (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.67-1.02) compared with placebo. Subgroup analysis, however, suggested a possible reduction in AF/AFL in those with no AF/AFL history (HR 0.78, 95% CI 0.62-0.99). Canagliflozin was also associated with a reduction in AF/AFL-related complications (HR 0.74, 95% CI 0.65-0.86). There was no evidence of treatment heterogeneity by baseline AF/AFL history for other key cardiorenal outcomes (all Pinteraction > 0.14). Meta-analysis of five sodium-glucose cotransporter-2 (SGLT2) inhibitor trials demonstrated a 19% reduction in AF/AFL events with active treatment (HR 0.81, 95% CI 0.72-0.92). CONCLUSIONS: Overall, a significant effect of canagliflozin on the incidence of AF/AFL events could not be shown, however, a possible reduction in AF/AFL events in those with no prior history requires further investigation. Meta-analysis suggests SGLT2 inhibition reduces AF/AFL incidence.

Physical activity and acute exercise benefit influenza vaccination response: A systematic review with individual participant data meta-analysis.

Whether the vaccine adjuvant potential of acute exercise is uniform among different populations, e.g., inactive persons, is unknown. This meta-analysis examines influenza vaccine antibody responses and the effect of physical activity, acute exercise, and their interaction. Inclusion criteria comprised randomized controlled trials with acute exercise intervention and influenza vaccination antibody measurements at baseline and 4-6 weeks, and participant baseline physical activity measurement; there were no exclusion criteria. Searching via six databases (Medline, Embase, CINAHL, Scopus, Web of Science, and Physiotherapy Evidence) and two clinical registries (WHO and NIH), nine studies were identified and assessed with the Cochrane revised risk-of-bias tool. Data analysis comprised one-stage random-effects generalized linear mixed-effects models with random intercept. Seven of nine identified studies, all of high risk of bias, provided data for 550 included participants. Clinical measures of antibody response tended to be higher in the acute-exercised participants compared to rested controls and physically active compared to inactive. Physical activity significantly increased H1 strain seroconversion (adjusted odds ratio (aOR) 1.69, 95%CI: 1.02-2.82) among all participants and titer response (aOR 1.20, 95%CI: 1.03-1.39) among the acute exercise group. Increasing age frequently reduced immunogenic responses whereas body mass index and sex had little-to-no effect. Adjuvant effects were more pronounced with interventions exercising the same arm in which the vaccination was administered. H1 response was increased by both physical activity and the acute exercise-physical activity interaction. Given the observed modifications by age and the subset analysis suggesting the benefit is more pronounced in older populations, future attention is due for acute exercise-PA interactions to impact vaccination response in the at-risk population of older adults. Further, we identify localized exercise as the likely most-effective protocol and encourage its use to augment the available evidence.

Analgesic and adjuvant properties of exercise with vaccinations in healthy young population.

Introduction: Exercise holds the potential to be beneficial if used during vaccination processes by 1)exercise-induced analgesia to reduce pain associated with vaccination, 2)immune-enhancing effects, improving antibody responses to the vaccine, and 3)reducing local and systemic adverse reactions to the vaccine. This study examines whether analgesic responses could be enhanced locally in the exercising limb to further benefit the use of exercise during influenza vaccination processes to minimize vaccine-related pain and improve antibody response to inactivated influenza vaccines.Methods: 57 participants (22.6 ± 3.2 years, 33 females) randomized into a control (n = 19) or one of two exercise groups: pre-vaccine arm (n = 19) or pre-vaccine leg (n = 19). Intervention groups performed exercise (15 minutes), prior to administration of the vaccine. Vaccine-related pain and pressure pain threshold (PPT) were measured at baseline and post-vaccination for all groups. Blood samples were taken on the day of vaccination and one month later to measure serum antibody titers to influenza.Results: No significant difference in vaccine-related pain or change in PPT was found with exercise, however, there was a trend in higher reports of vaccine-related pain in females compared to males(p = .06). Significantly higher fold increase (p = .02) of the B/Brisbane/60/2008 strain was found in the exercise group compared to the control group.Conclusion: The current study failed to observe an analgesic effect of exercise to improve vaccine-related pain in young adults. However, immune-enhancing effects in one of four strains suggest potential adjuvant effects of exercise. Importantly, the sex difference in pain sensitivity suggests the need for separate analysis, especially when examining pain perception.Australian New Zealand Clinical Trial Registry (ACTRN:12617000374369).

Diurnal Variations in Vascular Endothelial Vasodilation Are Influenced by Chronotype in Healthy Humans.

Introduction: The time of day when cardiovascular events are most likely to occur is thought to be aligned with the circadian rhythm of physiological variables. Chronotype has been shown to influence the time of day when cardiovascular events happen, with early chronotypes reported to be more susceptible in the morning and late chronotypes in the evening. However, no studies have investigated the influence of chronotype on physiological variables responsible for cardiovascular regulation in healthy individuals. Methods: 312 individuals completed the Munich ChronoType Questionnaire to assess chronotype. Twenty participants were randomly selected to continue into the main study. In a repeated-measures experiment, participants were tested between 08:00 and 10:00 h and again between 18:00 and 20:00 h. Measurements of mean arterial pressure, heart rate and vascular endothelial vasodilation via flow-mediated dilatation (FMD) were obtained at each session. Results: Individual diurnal differences in mean arterial pressure and heart rate show no significant relationship with chronotype. Diurnal differences in FMD showed a significant correlation (p = 0.010), driven by a clear significant relationship in the evening and not the morning (p < 0.001). Conclusion: These preliminary data indicate that chronotype influences the diurnal variation of endothelial vasodilation measured using flow-mediated dilatation. Furthermore, we show that the influence of chronotype is much stronger in the evening, highlighting an increased susceptibility for later types. These findings are consistent with the diurnal rhythm in cardiovascular events and uncover potential mechanisms of local mediators that may underpin the influence of chronotype in the onset of these events.

Improving vaccine-related pain, distress or fear in healthy children and adolescents-a systematic search of patient-focused interventions.

OBJECTIVE: The WHO recently highlighted the need for research into potential interventions that can be used to mitigate pain during mass vaccinations, in addition to interventions specific for adolescents. The current review examines the literature on potential interventions that can be used during mass vaccination settings in healthy individuals between the ages of 4 and 15 years old. METHODS: Criteria for inclusion were: 1)participants between the ages of 4-15 years, 2)interventions that were patient-focused, 3)vaccinations in healthy individuals, 4)outcome measures to include self-reported pain, fear or distress. RESULTS: Twenty-seven articles were identified with a total of 31 interventions. Eleven interventions used injection-site specific interventions, 17 used patient-led interventions and three used a combination of both site-specific and patient-led interventions. CONCLUSION: Interventions using coolant and vibration together, as well as a combination of site-specific and patient-led interventions, showed the most consistent effects in reducing self-reported pain, fear or distress.

Bcl-2 family members and functional electron transport chain regulate oxygen deprivation-induced cell death.

The mechanisms underlying cell death during oxygen deprivation are unknown. We report here a model for oxygen deprivation-induced apoptosis. The death observed during oxygen deprivation involves a decrease in the mitochondrial membrane potential, followed by the release of cytochrome c and the activation of caspase-9. Bcl-X(L) prevented oxygen deprivation-induced cell death by inhibiting the release of cytochrome c and caspase-9 activation. The ability of Bcl-X(L) to prevent cell death was dependent on allowing the import of glycolytic ATP into the mitochondria to generate an inner mitochondrial membrane potential through the F(1)F(0)-ATP synthase. In contrast, although activated Akt has been shown to inhibit apoptosis induced by a variety of apoptotic stimuli, it did not prevent cell death during oxygen deprivation. In addition to Bcl-X(L), cells devoid of mitochondrial DNA (rho degrees cells) that lack a functional electron transport chain were resistant to oxygen deprivation. Further, murine embryonic fibroblasts from bax(-/-) bak(-/-) mice did not die in response to oxygen deprivation. These data suggest that when subjected to oxygen deprivation, cells die as a result of an inability to maintain a mitochondrial membrane potential through the import of glycolytic ATP. Proapoptotic Bcl-2 family members and a functional electron transport chain are required to initiate cell death in response to oxygen deprivation.

Proapoptotic Bid is required for pulmonary fibrosis.

The molecular mechanisms of pulmonary fibrosis are poorly understood. Previous reports indicate that activation of TGF-beta1 is essential for the development of pulmonary fibrosis. Here, we report that the proapoptotic Bcl-2 family member Bid is required for the development of pulmonary fibrosis after the intratracheal instillation of bleomycin. Mice lacking Bid exhibited significantly less pulmonary fibrosis in response to bleomycin compared with WT mice. The attenuation in pulmonary fibrosis was observed despite similar levels of inflammation, lung injury, and active TGF-beta1 in bronchoalveolar lavage fluid 5 days after the administration of bleomycin in mice lacking Bid and in WT controls. Bleomycin induced similar levels cell death in vitro in alveolar epithelial cells isolated from WT and bid(-/-) mice. By contrast, alveolar epithelial cells from bid(-/-) mice were resistant to TGF-beta1-induced cell death. These results indicate that Bcl-2 family members are critical regulators for the development of pulmonary fibrosis downstream of TGF-beta1 activation.

Bleomycin induces alveolar epithelial cell death through JNK-dependent activation of the mitochondrial death pathway.

Exposure to bleomycin in rodents induces lung injury and fibrosis. Alveolar epithelial cell death has been hypothesized as an initiating mechanism underlying bleomycin-induced lung injury and fibrosis. In the present study we evaluated the contribution of mitochondrial and receptor-meditated death pathways in bleomycin-induced death of mouse alveolar epithelial cells (MLE-12 cells) and primary rat alveolar type II cells. Control MLE-12 cells and primary rat alveolar type II cells died after 48 h of exposure to bleomycin. Both MLE-12 cells and rat alveolar type II cells overexpressing Bcl-X(L) did not undergo cell death in response to bleomycin. Dominant negative Fas-associating protein with a death domain failed to prevent bleomycin-induced cell death in MLE-12 cells. Caspase-8 inhibitor CrmA did not prevent bleomycin-induced cell death in primary rat alveolar type II cells. Furthermore, fibroblast cells deficient in Bax and Bak, but not Bid, were resistant to bleomycin-induced cell death. To determine whether the stress kinase JNK was an upstream regulator of Bax activation, MLE-12 cells were exposed to bleomycin in the presence of an adenovirus encoding a dominant negative JNK. Bleomycin-induced Bax activation was prevented by the expression of a dominant negative JNK in MLE-12 cells. Dominant negative JNK prevented cell death in MLE-12 cells and in primary rat alveolar type II cells exposed to bleomycin. These data indicate that bleomycin induces cell death through a JNK-dependent mitochondrial death pathway in alveolar epithelial cells.

Anoxia-induced apoptosis occurs through a mitochondria-dependent pathway in lung epithelial cells.

The intracellular signaling pathways that control O(2) deprivation (anoxia)-induced apoptosis have not been fully defined in lung epithelial cells. We show here that the lung epithelial cell line A549 releases cytochrome c and activates caspase-9 followed by DNA fragmentation and plasma membrane breakage in response to anoxia. The antiapoptotic protein Bcl-X(L) prevented the anoxia-induced cell death by inhibiting the release of cytochrome c and caspase-9 activation. A549 cells devoid of mitochondrial DNA (rho(o)-cells) and lacking a functional electron transport chain were resistant to anoxia-induced apoptosis. A549 cells preconditioned with either hypoxia (1.5% O(2)) or tumor necrosis factor-alpha, which activated the transcription factors hypoxia-inducible factor-1 or nuclear factor-kappaB, respectively, did not provide protection from anoxia-induced cell death. These results indicate that A549 cells require a functional electron transport chain and the release of cytochrome c for anoxia-induced apoptosis.

Hypoxia sensitizes cells to nitric oxide-induced apoptosis.

Nitric oxide (NO) can induce apoptosis in a variety of cell types. A non-toxic concentration of nitric oxide under normal oxygen conditions triggered cell death under hypoxic conditions (1.5% O(2)) in fibroblasts. Nitric oxide administered during hypoxia induced the release of cytochrome c, caspase-9 activation, and the loss of mitochondrial membrane potential followed by DNA fragmentation and lactate dehydrogenase release (markers of cell death). Bcl-X(L) protected cells from nitric oxide-induced apoptosis during hypoxia by preventing the release of cytochrome c, caspase-9 activation, and by maintaining a mitochondrial membrane potential. Murine embryonic fibroblasts from bax(-/-) bak(-/-) mice exposed to nitric oxide during hypoxia did not die, indicating that pro-apoptotic Bcl-2 family members are required for NO-induced apoptosis during hypoxia. The nitric oxide-induced cell death during hypoxia was independent of cGMP and peroxynitrite. Cells devoid of mitochondrial DNA (rho secondary-cells) lack a functional electron transport chain and were resistant to nitric oxide-induced cell death during hypoxia, suggesting that a functional electron transport chain is required for nitric oxide-induced apoptosis during hypoxia.