Continuous infusion versus bolus injection of loop diuretics for acute heart failure.

BACKGROUND: Acute heart failure (AHF) is new onset of, or a sudden worsening of, chronic heart failure characterised by congestion in about 95% of cases or end-organ hypoperfusion in 5% of cases. Treatment often requires urgent escalation of diuretic therapy, mainly through hospitalisation. This Cochrane review evaluated the efficacy of intravenous loop diuretics strategies in treating AHF in individuals with New York Heart Association (NYHA) classification III or IV and fluid overload. OBJECTIVES: To assess the effects of intravenous continuous infusion versus bolus injection of loop diuretics for the initial treatment of acute heart failure in adults. SEARCH METHODS: We identified trials through systematic searches of bibliographic databases and in clinical trials registers including CENTRAL, MEDLINE, Embase, CPCI-S on the Web of Science, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry platform (ICTRP), and the European Union Trials register. We conducted reference checking and citation searching, and contacted study authors to identify additional studies. The latest search was performed on 29 February 2024. SELECTION CRITERIA: We included randomised controlled trials (RCTs) involving adults with AHF, NYHA classification III or IV, regardless of aetiology or ejection fraction, where trials compared intravenous continuous infusion of loop diuretics with intermittent bolus injection in AHF. We excluded trials with chronic stable heart failure, cardiogenic shock, renal artery stenosis, or end-stage renal disease. Additionally, we excluded studies combining loop diuretics with hypertonic saline, inotropes, vasoactive medications, or renal replacement therapy and trials where diuretic dosing was protocol-driven to achieve a target urine output, due to confounding factors. DATA COLLECTION AND ANALYSIS: Two review authors independently screened papers for inclusion and reviewed full-texts. Outcomes included weight loss, all-cause mortality, length of hospital stay, readmission following discharge, and occurrence of acute kidney injury. We performed risk of bias assessment and meta-analysis where data permitted and assessed certainty of the evidence. MAIN RESULTS: The review included seven RCTs, spanning 32 hospitals in seven countries in North America, Europe, and Asia. Data collection ranged from eight months to six years. Following exclusion of participants in subgroups with confounding treatments and different clinical settings, 681 participants were eligible for review. These additional study characteristics, coupled with our strict inclusion and exclusion criteria, improve the applicability of the body of the evidence as they reflect real-world clinical practice. Meta-analysis was feasible for net weight loss, all-cause mortality, length of hospital stay, readmission, and acute kidney injury. Literature review and narrative analysis explored daily fluid balance; cardiovascular mortality; B-type natriuretic peptide (BNP) change; N-terminal-proBNP change; and adverse incidents such as ototoxicity, hypotension, and electrolyte imbalances. Risk of bias assessment revealed two studies with low overall risk, four with some concerns, and one with high risk. All sensitivity analyses excluded trials at high risk of bias. Only narrative analysis was conducted for 'daily fluid balance' due to diverse data presentation methods across two studies (169 participants, the evidence was very uncertain about the effect). Results of narrative analysis varied. For instance, one study reported higher daily fluid balance within the first 24 hours in the continuous infusion group compared to the bolus injection group, whereas there was no difference in fluid balance beyond this time point. Continuous intravenous infusion of loop diuretics may result in mean net weight loss of 0.86 kg more than bolus injection of loop diuretics, but the evidence is very uncertain (mean difference (MD) 0.86 kg, 95% confidence interval (CI) 0.44 to 1.28; 5 trials, 497 participants; P < 0.001, I2 = 21%; very low-certainty evidence). Importantly, sensitivity analysis excluding trials with high risk of bias showed there was insufficient evidence for a difference in bodyweight loss between groups (MD 0.70 kg, 95% CI -0.06 to 1.46; 3 trials, 378 participants; P = 0.07, I2 = 0%). There may be little to no difference in all-cause mortality between continuous infusion and bolus injection (risk ratio (RR) 1.53, 95% CI 0.81 to 2.90; 5 trials, 530 participants; P = 0.19, I2 = 4%; low-certainty evidence). Despite sensitivity analysis, the direction of the evidence remained unchanged. No trials measured cardiovascular mortality. There may be little to no difference in the length of hospital stay between continuous infusion and bolus injection of loop diuretics, but the evidence is very uncertain (MD -1.10 days, 95% CI -4.84 to 2.64; 4 trials, 211 participants; P = 0.57, I2 = 88%; very low-certainty evidence). Sensitivity analysis improved heterogeneity; however, the direction of the evidence remained unchanged. There may be little to no difference in the readmission to hospital between continuous infusion and bolus injection of loop diuretics (RR 0.85, 95% CI 0.63 to 1.16; 3 trials, 400 participants; P = 0.31, I2 = 0%; low-certainty evidence). Sensitivity analysis continued to show insufficient evidence for a difference in the readmission to hospital between groups. There may be little to no difference in the occurrence of acute kidney injury as an adverse event between continuous infusion and bolus injection of intravenous loop diuretics (RR 1.02, 95% CI 0.70 to 1.49; 3 trials, 491 participants; P = 0.92, I2 = 0%; low-certainty evidence). Sensitivity analysis continued to show that continuous infusion may make little to no difference on the occurrence of acute kidney injury as an adverse events compared to the bolus injection of intravenous loop diuretics. AUTHORS' CONCLUSIONS: Analysis of available data comparing two delivery methods of diuretics in acute heart failure found that the current data are insufficient to show superiority of one strategy intervention over the other. Our findings were based on trials meeting stringent inclusion and exclusion criteria to ensure validity. Despite previous reviews suggesting advantages of continuous infusion over bolus injections, our review found insufficient evidence to support or refute this. However, our review, which excluded trials with clinical confounders and RCTs with high risk of bias, offers the most robust conclusion to date.

Association between natriuretic peptides and C-reactive protein with frailty in heart failure: a systematic review and meta-analysis.

BACKGROUND: Heart failure (HF) and frailty are accompanied by a bidirectional relationship, sharing common risk factors including elevated levels of natriuretic peptides and inflammation. The aim of this study was to compare biomarkers associated with poor clinical outcomes, that is, plasma brain natriuretic peptide (BNP), N-terminal-pro B-type natriuretic peptide (NT-proBNP), and C-reactive protein (CRP) in patients with HF and frailty vs. patients with HF without frailty. METHODS: From inception until July 2023, PubMed, Scopus, Web of Science, and Cochrane Library a systematic literature search was conducted. To evaluate whether frailty is linked with greater levels of BNP, NT-proBNP, and CRP, a meta-analysis using a random-effects model was used to calculate the pooled effects (CRD42023446607). RESULTS: Fifty-three studies were included in this systematic review and meta-analysis. Patients with HF and frailty displayed significantly higher levels of BNP (k = 11; SMD: 0.53, 95%CI 0.30-0.76, I2 = 86%, P < 0.01), NT-proBNP (k = 23; SMD: 0.33, 95%CI 0.25-0.40, I2 = 72%, P < 0.01), and CRP (k = 8; SMD: 0.30, 95%CI 0.12-0.48, I2 = 62%, P < 0.01) vs. patients with HF without frailty. Using meta-regression, body mass index (BMI) and age were deemed potential moderators of these findings. CONCLUSIONS: Frailty in HF is linked to increased concentrations of BNP, NT-proBNP, and CRP, which have been epidemiologically associated with adverse outcomes. The increased risk of NYHA III/IV classification further emphasizes the clinical impact of frailty in this population.

Effects of whey and soy protein supplementation on inflammatory cytokines in older adults: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Low-grade inflammation is a mediator of muscle proteostasis. This study aimed to investigate the effects of isolated whey and soy proteins on inflammatory markers. METHODS: We conducted a systematic literature search of randomised controlled trials (RCT) through MEDLINE, Web of Science, Scopus and Cochrane Library databases from inception until September 2021. To determine the effectiveness of isolated proteins on circulating levels of C-reactive protein (CRP), IL-6 and TNF-α, a meta-analysis using a random-effects model was used to calculate the pooled effects (CRD42021252603). RESULTS: Thirty-one RCT met the inclusion criteria and were included in the systematic review and meta-analysis. A significant reduction of circulating IL-6 levels following whey protein [Mean Difference (MD): -0·79, 95 % CI: -1·15, -0·42, I2 = 96 %] and TNF-α levels following soy protein supplementation (MD: -0·16, 95 % CI: -0·26, -0·05, I2 = 68 %) was observed. The addition of soy isoflavones exerted a further decline in circulating TNF-α levels (MD: -0·20, 95 % CI: -0·31, -0·08, I2 = 34 %). According to subgroup analysis, whey protein led to a statistically significant decrease in circulating IL-6 levels in individuals with sarcopenia and pre-frailty (MD: -0·98, 95 % CI: -1·56, -0·39, I2 = 0 %). These findings may be dependent on participant characteristics and treatment duration. CONCLUSIONS: These data support that whey and soy protein supplementation elicit anti-inflammatory effects by reducing circulating IL-6 and TNF-α levels, respectively. This effect may be enhanced by soy isoflavones and may be more prominent in individuals with sarcopenia.

Sodium-glucose co-transporter-2 inhibitors in the non-diabetic heart failure patient.

Heart failure (HF) with reduced ejection fraction (HFrEF) is a global cause of morbidity and mortality with over 60 million estimated cases worldwide. The burden of HF care is expected to increase with an ageing population as evidenced by the fact that 80% of HF-related hospitalizations occur in those aged above 65. Given the significant morbidity and mortality associated with HFrEF, there is a need for new prognostic therapies that have an impact on morbidity and mortality. In February of 2021, the National institute for Health and Care Excellence (NICE) released new guidance on the utility of Dapagliflozin for the management of heart failure with reduced ejection fraction (HFrEF). NICE advocated that dapagliflozin is a viable treatment option in symptomatic HFrEF patients on optimal medical management. The current list price of dapagliflozin is around £36.59 per 28-tablet pack with an estimated annual cost of £476.98 equating to £6939 per quality-adjusted life year. The guidance was mainly based on evidence produced from the 2019 DAPA-HF trial. This demonstrated that in HFrEF population, the use of dapagliflozin led to a significant reduction in worsening HF events, cardiovascular, and all-cause death. In this article, we summarize the evidence base for sodium-glucose co-transporter-2 inhibitors in the non-diabetic heart failure patient.

Systolic [Ca2+ ]i regulates diastolic levels in rat ventricular myocytes.

KEY POINTS: For the heart to function as a pump, intracellular calcium concentration ([Ca2+ ]i ) must increase during systole to activate contraction and then fall, during diastole, to allow the myofilaments to relax and the heart to refill with blood. The present study investigates the control of diastolic [Ca2+ ]i in rat ventricular myocytes. We show that diastolic [Ca2+ ]i is increased by manoeuvres that decrease sarcoplasmic reticulum function. This is accompanied by a decrease of systolic [Ca2+ ]i such that the time-averaged [Ca2+ ]i remains constant. We report that diastolic [Ca2+ ]i is controlled by the balance between Ca2+ entry and Ca2+ efflux during systole. The results of the present study identify a novel mechanism by which changes of the amplitude of the systolic Ca transient control diastolic [Ca2+ ]i . ABSTRACT: The intracellular Ca concentration ([Ca2+ ]i ) must be sufficently low in diastole so that the ventricle is relaxed and can refill with blood. Interference with this will impair relaxation. The factors responsible for regulation of diastolic [Ca2+ ]i , in particular the relative roles of the sarcoplasmic reticulum (SR) and surface membrane, are unclear. We investigated the effects on diastolic [Ca2+ ]i that result from the changes of Ca cycling known to occur in heart failure. Experiments were performed using Fluo-3 in voltage clamped rat ventricular myocytes. Increasing stimulation frequency increased diastolic [Ca2+ ]i . This increase of [Ca2+ ]i was larger when SR function was impaired either by making the ryanodine receptor leaky (with caffeine or ryanodine) or by decreasing sarco/endoplasmic reticulum Ca-ATPase activity with thapsigargin. The increase of diastolic [Ca2+ ]i produced by interfering with the SR was accompanied by a decrease of the amplitude of the systolic Ca transient, such that there was no change of time-averaged [Ca2+ ]i . Time-averaged [Ca2+ ]i was increased by ß-adrenergic stimulation with isoprenaline and increased in a saturating manner with increased stimulation frequency; average [Ca2+ ]i was a linear function of Ca entry per unit time. Diastolic and time-averaged [Ca2+ ]i were decreased by decreasing the L-type Ca current (with 50 µm cadmium chloride). We conclude that diastolic [Ca2+ ]i is controlled by the balance between Ca entry and efflux during systole. Furthermore, manoeuvres that decrease the amplitude of the Ca transient (without decreasing Ca influx) will therefore increase diastolic [Ca2+ ]i . This identifies a novel mechanism by which changes of the amplitude of the systolic Ca transient control diastolic [Ca2+ ]i .

Biphasic decay of the Ca transient results from increased sarcoplasmic reticulum Ca leak.

KEY POINTS: Ca leak from the sarcoplasmic reticulum through the ryanodine receptor (RyR) reduces the amplitude of the Ca transient and slows its rate of decay. In the presence of ß-adrenergic stimulation, RyR-mediated Ca leak produces a biphasic decay of the Ca transient with a fast early phase and a slow late phase. Two forms of Ca leak have been studied, Ca-sensitising (induced by caffeine) and non-sensitising (induced by ryanodine) and both induce biphasic decay of the Ca transient. Only Ca-sensitising leak can be reversed by traditional RyR inhibitors such as tetracaine. Ca leak can also induce Ca waves. At low levels of leak, waves occur. As leak is increased, first biphasic decay and then slowed monophasic decay is seen. The level of leak has major effects on the shape of the Ca transient. In heart failure, a reduction in Ca transient amplitude and contractile dysfunction can by caused by Ca leak through the sarcoplasmic reticulum (SR) Ca channel (ryanodine receptor, RyR) and/or decreased activity of the SR Ca ATPase (SERCA). We have characterised the effects of two forms of Ca leak (Ca-sensitising and non-sensitising) on calcium cycling and compared with those of SERCA inhibition. We measured [Ca(2+)]i with fluo-3 in voltage-clamped rat ventricular myocytes. Increasing SR leak with either caffeine (to sensitise the RyR to Ca activation) or ryanodine (non-sensitising) had similar effects to SERCA inhibition: decreased systolic [Ca(2+)]i , increased diastolic [Ca(2+)]i and slowed decay. However, in the presence of isoproterenol, leak produced a biphasic decay of the Ca transient in the majority of cells while SERCA inhibition produced monophasic decay. Tetracaine reversed the effects of caffeine but not of ryanodine. When caffeine (1 mmol l(-1)) was added to a cell which displayed Ca waves, the wave frequency initially increased before waves disappeared and biphasic decay developed. Eventually (at higher caffeine concentrations), the biphasic decay was replaced by slow decay. We conclude that, in the presence of adrenergic stimulation, Ca leak can produce biphasic decay; the slow phase results from the leak opposing Ca uptake by SERCA. The degree of leak determines whether decay of Ca waves, biphasic or monophasic, occurs.

Is sarcopenia an associated factor of increased administration of specific medications in patients with heart failure? A systematic review and meta-analysis.

Background: There is controversy in relation to commonly used drugs in heart failure (HF) and their impact on muscle function. The aim of this study was to evaluate the odds of receiving specific medications often used in clinical practice by patients with HF and sarcopenia vs. without sarcopenia. Methods: A systematic literature search of cohort studies via databases (PubMed, Web of Science, Scopus, and Cochrane Library) was conducted from inception until March 2023. To determine if sarcopenia is linked to a higher number of specific HF-related medications, a meta-analysis using a random-effects model was used to calculate the pooled effects. Results: Our main analyses showed no significant association of sarcopenia with administration of higher HF-related medication count vs. those without sarcopenia. Those with lower appendicular lean mass (ALM) had significantly lower odds of receiving angiotensin converting enzyme inhibitors (ACE-Is)/angiotensin receptor blockers (ARBs) (OR: 0.68, 95%CI 0.50-0.90, I2 = 12%, P < 0.01) vs. patients with higher ALM for which age could be an important confounder based on meta-regression. No statistically significant differences were found in relation to B-blockers OR: 0.84, 95%CI 0.63-1.12, I2 = 7%, P = 0.24) and loop diuretics (OR: 1.19, 95%CI 0.87-1.63, I2 = 0%, P = 0.27). Regarding handgrip strength, gait speed, and short physical performance battery, our narrative synthesis found mixed results. Conclusion: This systematic review and meta-analysis did not find a relationship of specific medication count in sarcopenia vs. without sarcopenia in patients with HF, although increased odds of ACE-I/ARB was shown in those with higher ALM. Systematic Review Registration: PROSPERO (CRD42023411137).

Sarcopenia is linked to higher levels of B-type natriuretic peptide and its N-terminal fragment in heart failure: a systematic review and meta-analysis.

AIMS: Sarcopenia is linked to impaired physical function and exercise tolerance. The aim of this systematic review and meta-analysis was to examine the association of sarcopenia and low appendicular skeletal muscle (ASM) with biomarkers of cardiac function, B-type natriuretic peptide (BNP) and its N-terminal fragment (NT-proBNP), in patients with heart failure (HF). METHODS AND RESULTS: From inception until May 2023, a systematic literature search of observational studies was undertaken utilizing the PubMed, Web of Science, Scopus, and Cochrane Library databases. A meta-analysis employing a random-effects model was used to compute the pooled effects (CRD42023418465). Overall, 16 studies were included in this systematic review and meta-analysis. Our main analysis showed that sarcopenia in HF was linked to significantly higher levels of BNP (MD: 87.76, 95% CI 20.74-154.78, I2 = 61%, P = 0.01) and NT-proBNP (MD: 947.45, 95% CI 98.97-1795.93, I2 = 35%, P = 0.03). Similarly, low ASM was associated with significantly higher levels of BNP (MD: 118.95, 95% CI 46.91-191.00, I2 = 93%, P < 0.01) and NT-proBNP (MD: 672.01, 95% CI 383.72-960.30, I2 = 2%, P < 0.01). The quality of the included cohort studies was considered moderate, using the binary AXIS checklist and the Cochrane Tool to Assess the Risk of Bias in Cohort Studies. CONCLUSIONS: In patients with HF, sarcopenia and reduced ASM are associated with considerably higher plasma levels of BNP and NT-proBNP. Future research is required to investigate whether sarcopenia may express dysregulated biomarkers of cardiac function.

What is the association of polypharmacy with frailty in heart failure? A systematic review and meta-analysis.

This systematic review and meta-analysis aimed to explore the differences in the number of prescribed medications and polypharmacy risk between patients with heart failure (HF) and frailty vs. those with HF but without frailty. Eligible studies included observational or experimental studies in patients aged ≥50 years. Thirteen studies met the criteria and were included in the final analysis. Patients with frailty and HF exhibited a higher risk of polypharmacy (OR: 1.87, 95% CI 1.72 - 2.04, I2 = 0%, P < 0.01) compared to those without frailty. Results remained significant after adjusting for comorbidity status. Additionally, patients with frailty and HF were prescribed more medications compared to those without (k = 6; MD: 1.43, 95% CI 0.31 - 2.55, I2 = 94%, P = 0.01), with a high degree of heterogeneity. However, results were non-significant after adjustment for comorbidity status. Patients with HF and frailty have a higher need of polypharmacy compared to those without frailty, which may increase the risk of potentially inappropriate medications (PIM). Investigating the real-world prevalence of PIM may support clinicians in their routine assessment as part of a comprehensive management strategy in patients with HF and frailty.

Natriuretic peptides and C-reactive protein in in heart failure and malnutrition: a systematic review and meta-analysis.

BACKGROUND: Heart failure (HF) and malnutrition exhibit overlapping risk factors, characterized by increased levels of natriuretic peptides and an inflammatory profile. The aim of this study was to compare the differences in plasma brain natriuretic peptide (BNP), N-terminal-pro B-type natriuretic peptide (NT-proBNP), and C-reactive protein (CRP) in patients with HF and malnutrition versus normal nutrition. METHODS: From inception until July 2023, the databases, PubMed, Scopus, Web of Science, and Cochrane Library were searched. To examine the association among malnutrition [controlling nutritional status (CONUT) score ≥2; Geriatric Nutritional Risk Index (GNRI) score <92] with BNP, NT-proBNP and CRP in patients with HF, a meta-analysis using a random-effects model was conducted (CRD42023445076). RESULTS: A significant association of GNRI with increased levels of BNP were demonstrated [mean difference (MD): 204.99, 95% confidence interval (CI) (101.02, 308.96, I2 = 88%, P < 0.01)], albeit no statistically significant findings were shown using CONUT [MD: 158.51, 95% CI (-1.78 to 318.79, I2 = 92%, P = 0.05)]. GNRI [MD: 1885.14, 95% CI (1428.76-2341.52, I2 = 0%, P < 0.01)] and CONUT [MD: 1160.05, 95% CI (701.04-1619.07, I2 = 0%, P < 0.01)] were associated with significantly higher levels of NT-proBNP. Patients with normal GNRI scores had significantly lower levels of CRP [MD: 0.50, 95% CI (0.12-0.88, I2 = 87%, P = 0.01)] whereas significantly higher levels of CRP were observed in those with higher CONUT [MD: 0.40, 95% CI (0.08-0.72, I2 = 88%, P = 0.01)]. Employing meta-regression, age was deemed a potential moderator between CRP and GNRI. CONCLUSIONS: Normal nutrition scores in patients with HF are linked to lower BNP, NT-proBNP, and CRP levels compared with malnourished counterparts. Despite the significant link between CRP and malnutrition, their relationship may be influenced in older groups considering the sensitivity of GNRI due to ageing factors.

Are sarcopenia and its individual components linked to all-cause mortality in heart failure? A systematic review and meta-analysis.

OBJECTIVE: The objective of this systematic review and meta-analysis was to assess sarcopenia and its components as prognostic factors in patients with heart failure (HF). METHODS: From inception to December 2022, a systematic literature search was carried out utilizing PubMed, Web of Science, Scopus, and Cochrane Library databases. A meta-analysis employing a random-effects model was performed to assess the pooled effects. RESULTS: The systematic review and meta-analysis included 32 and 18 longitudinal studies, respectively. The prediction of 1- to 2-year all-cause mortality in sarcopenia was not statistically significant (hazard ratio (HR): 1.35, 95% CI 0.76-2.38, I2 = 54%, P = 0.31). The lowest combined quartile and quantile of the population were used to define low handgrip strength that showed identical results (HR: 1.24, 95% CI 0.94-1.62, I2 = 0%, P = 0.13). Low L3-L4 psoas muscle mass (HR: 2.20, 95% CI 1.26-3.83, I2 = 87%, P < 0.01) and slow gait speed (HR: 1.45, 95% CI 1.20-1.74, I2 = 0%, P < 0.01) were significant contributors to all-cause mortality risk. Additionally, a 0.1 m/s increase in gait speed demonstrated a significant reduction of all-cause mortality (HR: 0.77, 95% CI 0.66-0.90, I2 = 60%, P < 0.01). Our narrative synthesis also described appendicular lean mass (ALM) and short physical performance battery (SPPB) scores as significant prognostic factors. CONCLUSIONS: Compared to patients with higher overall functional performance, those with HF and low ALM, low psoas muscle mass, low SPPB, and slow gait speed are at an increased risk of all-cause mortality. Early prevention and/or treatment of lower limb physical function deterioration may be an essential strategy to reduce the risk of premature death in HF.

Alcohol and Heart Failure.

Alcohol is the most frequently consumed toxic substance in the world and remains a major global public health issue, with one in three adults consuming it worldwide. Alcohol use is a leading risk factor for disease, contributing to over 60 acute and chronic health conditions, with a particularly complex association with cardiovascular disease. Chronic excessive alcohol consumption is associated with a range of cardiac complications, including decreased myocardial contractility, hypertension, arrhythmias, MI and heart failure. However, low-level alcohol consumption is believed to have a protective effect against ischaemic heart disease and diabetes. In most cohort studies, small to moderate amounts of alcohol consumption have not been linked to heart failure, indicating a threshold effect of alcohol with individual (possibly genetic) predisposition rather than a continuous effect of exposure. This review article explores the potential benefits of alcohol on the heart, the association between alcohol use and alcoholic cardiomyopathy and the epidemiology, clinical correlates and management of alcoholic cardiomyopathy.

Frailty alone and interactively with obesity predicts heart failure: Kuopio Ischaemic Heart Disease Risk Factor Study.

AIMS: We aim to evaluate the association of frailty and high body mass index with risk of incident heart failure. METHODS AND RESULTS: From the Kuopio Ischaemic Heart Disease Risk Factor Study, 408 women and 369 men, aged 61-74 years were included in this study. Frailty was ascertained with the presence of 3-5 and prefrailty 1-2 of the following criteria: weight loss (highest 20% over 7 years), self-reported tiredness, weakness (measured by handgrip strength), slow walking speed (walking pace), and low physical activity (lowest 20%). At the baseline, participants were allocated to frail (n = 36), prefrail (n = 340), and robust (n = 441). HF incidents were obtained by record linkages from the national hospitalization registry in Finland up to 31 December 2019. Multivariate Cox proportional hazards regression estimated the hazard ratio (HR) of incident events, adjusted for potential confounders. Two hundred one HF events were recorded (111 in women and 90 in men) during the 14.2 years follow-up. After adjustment for the age and sex, the risk of HF events was higher among prefrail (HR 1.42, 95% CI 1.08 to 1.79, P = 0.02) and frail (HR 3.39, 95% CI 1.89 to 4.79, P ≤ 0.001) compared with the robust group. After adjusting for multiple confounders result remained significant for HF indecent in prefrail [1.46 (HR 1.46, 95% CI 1.09 to 1.95, P = 0.01] and frail (HR 3.33, 95% CI 1.86 to 5.70, P ≤ 0.001). In the sensitivity analysis, significant interaction between high BMI (≥25 kg/m2 ) and frailty was observed (P for interaction = 0.02). The association of frailty [multivariate-adjusted HR: 2.88 (1.56 to 5.33), P ≤ 0.001)] and prefrailty [multivariate-adjusted HR: 1.40 (1.08 to 1.91), P = 0.03)] with risk of HF indecent was more pronounced in those with high BMI. CONCLUSIONS: Frailty is highly common in older age, and our results indicated the high risk of HF incident in frail and prefrail groups. While frailty is clinically recognized by weight loss phenotype, our finding showed that frailly and high BMI can coexist and worsen the risk of HF incidence. Further research is warranted to substantiate these results in large studies and clinical settings.

Representation of Chronic Kidney Disease in Randomized Controlled Trials Among Patients With Heart failure With Reduced Ejection Fraction: A Systematic Review.

Patients with advanced chronic kidney disease (CKD) have largely been excluded from randomized control trials (RCTs) in heart failure (HF). This creates a paucity of high quality evidence for guideline directed medical therapy (GDMT), particularly in patients with heart failure with reduced ejection fraction (HFrEF) and CKD. This is a systematic review looking at the patterns and rates of inclusion of CKD in RCTs among patients with HFrEF. The search included RCTs from January 2010 to December 2020. A heat map was constructed to reflect the stages of CKD stages. The percentage of studies that included advanced CKD (stages IV-V) was recorded and log transformed, and then fitted into a time regression model. A P value of <0.05 was considered statistically significant. Out of the 3052 screened, 706 studies were included in the analysis. Only 61% of the RCTs reported at least some information on kidney function. There was a trend of increase in percentage of studies that included CKD stages IV-V from years 2010 to 2020. This was confirmed with a statistically significant linear trend P = 0.02 while the percentage of studies that included dialysis and kidney transplant recipients remained consistently low. There is a paucity of high-quality evidence for GDMT in the HFrEF population with CKD, particularly in those with advanced non-dialytic CKD, those on maintenance dialysis and kidney transplant recipients. There is a pressing need for wider inclusion of patients with advanced CKD in RCTs of GDMT in HFrEF.

"Renalism" with Renin Angiotensin Aldosterone System Inhibitor Use in Patients Enrolled in Trials for Heart Failure with Reduced Ejection Fraction and Advanced Chronic Kidney Disease: A Systematic Review.

INTRODUCTION: Angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), angiotensin receptor-neprilysin inhibitor (ARNI), and mineralocorticoid receptor antagonists (MRA) reduce mortality and hospitalizations in heart failure with reduced ejection fraction (HFrEF) but their use is limited in advanced chronic kidney disease (CKD). METHODS: We carried out a systematic review of studies on HFrEF and CKD patients. The mean overall percentage of reported ACEI, ARB, MRA, and ARNI use, and the proportion of trials that included patients with advanced CKD grades 4-5 (estimated glomerular filtration rate (eGFR) <15-30 ml/min/1.73m2) were recorded per year. The proportion of trials with advanced CKD was logtransformed, and then fitted into a time regression model. The interactions between the proportion of trials that included CKD grades 4-5 and the proportion of reported use of ACEI, ARB, and MRAs per year were explored using Pearson's correlation and univariate linear regression. RESULTS: A total of 706 articles were included; 76% reported background ACEI/ARB use, while 51% reported MRA use. ACEI/ARB use averaged 83% and MRA 50%. Of the trials, 57% included CKD grades 4-5. Over 10 years, the proportion of trials with CKD grades 4-5 increased while ACEI/ARB use decreased. MRA use rates remained about the same. There was an inverse association found between the proportion of trials with CKD grades 4-5 and ACEI/ARB use per year. CONCLUSION: In the past 10 years, CKD grades 4-5 patients have been increasingly included in HFrEF clinical trials. Concurrently, ACEI/ARB use has reportedly decreased.

Augmentation of natriuretic peptide (NP) receptor A and B (NPR-A and NPR-B) and cyclic guanosine monophosphate (cGMP) signalling as a therapeutic strategy in heart failure.

INTRODUCTION: Heart failure is a complex, debilitating condition and despite advances in treatment, it remains a significant cause of morbidity and mortality worldwide. Therefore, the need for alternative treatment strategies is essential. In this review, we explore the therapeutic strategies of augmenting natriuretic peptide receptors (NPR-A and NPR-B) and cyclic guanosine monophosphate (cGMP) in heart failure. AREAS COVERED: We aim to provide an overview of the evidence of preclinical and clinical studies on novel heart failure treatment strategies. Papers collected in this review have been filtered and screened following PubMed searches. This includes epigenetics, modulating enzyme activity in natriuretic peptide (NP) synthesis, gene therapy, modulation of downstream signaling by augmenting soluble guanylate cyclase (sGC) and phosphodiesterase (PDE) inhibition, nitrates, c-GMP-dependent protein kinase, synthetic and designer NP and RNA therapy. EXPERT OPINION: The novel treatment strategies mentioned above have shown great potential, however, large randomized controlled trials are still lacking. The biggest challenge is translating the results seen in preclinical trials into clinical trials. We recommend a multi-disciplinary team approach with cardiologists, geneticist, pharmacologists, bioengineers, researchers, regulators, and patients to improve heart failure outcomes. Future management can involve telemedicine, remote monitoring, and artificial intelligence to optimize patient care.

Language matters: representations of 'heart failure' in English discourse-a large-scale linguistic study.

AIMS: Heart failure (HF) has a lower public profile compared with other serious health conditions, notably cancer. This discourse analysis study investigates the extent to which HF is discussed in general contemporary English, UK parliamentary debates and the ways in which HF is framed in discussions, when compared with two other serious health conditions, cancer and dementia. METHODS: The Oxford English Corpus (OEC) of 21st century English-language texts (2 billion words) and the UK Hansard Reports of parliamentary debates from 1945 to early 2021 were used to investigate the relative frequencies, contexts and use of the terms 'heart failure', 'cancer' and 'dementia'. RESULTS: In the OEC, the term 'heart failure' occurs 4.26 times per million words (pmw), 'dementia' occurs 3.68 times pmw and 'cancer' occurs 81.96 times pmw. Cancer is talked about 19 times more often than HF and 22 times more often than dementia. These are disproportionately high in relation to actual incidence: annual cancer incidence is 1.8 times that of the other conditions; annual cancer mortality is two times that caused by coronary heart disease (including HF) or dementia.'Heart failure' is used much less than 'cancer' in UK parliamentary debates (House of Commons and House of Lords) between 1945 and early 2021, and less than 'dementia' from 1990 onwards. Moreover, HF is even mentioned much less than pot-holes in UK roads and pavements. In 2018, for example, 'pot-hole/s' were mentioned over 10 times pmw, 37 times more often than 'heart failure', mentioned 0.28 times pmw. Discussions of HF are comparatively technical and formulaic, lacking survivor narratives that occur in discussions of cancer. CONCLUSIONS: HF is underdiscussed in contemporary English compared with cancer and dementia and underdiscussed in UK parliamentary debates, even compared with the less-obviously life-threatening topic of pot-holes in roads and pavements.

The Impact of Frailty and Comorbidities on Heart Failure Outcomes.

Frailty is a multisystemic process leading to reduction of physiological reserve and a reduction in physical activity. Heart failure (HF) is recognised as a global cause of morbidity and mortality, increasing in prevalence over recent decades. Because of shared phenotypes and comorbidities, there is significant overlap and a bidirectional relationship, with frail patients being at increased risk of developing HF and vice versa. Despite this, frailty is not routinely assessed in patients with HF. Identification of these patients to direct multidisciplinary care is key, and the development of a frailty assessment tool validated in a large HF population is also an unmet need that would be of considerable benefit in directing multidisciplinary-team management. Non-pharmacological treatment should be included, as exercise and physical rehabilitation programmes offer dual benefit in frail HF patients, by treating both conditions simultaneously. The evidence for nutritional supplementation is mixed, but there is evidence that a personalised approach to nutritional support in frail HF patients can improve outcomes.