Showing papers by "John G.F. Cleland published in 2023"

Intravenous iron in patients with heart failure and iron deficiency: an updated meta‐analysis

Abstract: For patients with heart failure (HF) and iron deficiency (ID), randomized trials suggest that intravenous (IV) iron reduces hospitalizations for heart failure (HHF), but uncertainty exists about the effects in subgroups and the impact on mortality. We conducted a meta‐analysis of randomized trials investigating the effect of IV iron on clinical outcomes in patients with HF.

The incremental value of multi-organ assessment of congestion using ultrasound in outpatients with heart failure.

Abstract: AIMS We investigated the prevalence and clinical value of assessing multi-organ congestion by ultrasound in heart failure (HF) outpatients. METHODS AND RESULTS Ultrasound congestion was defined as inferior vena cava of ≥21 mm, highest tertile of lung B-lines, or discontinuous renal venous flow. Associations with clinical characteristics and prognosis were explored. We enrolled 310 HF patients [median age: 77 years, median NT-proBNP: 1037 ng/L, 51% with a left ventricular ejection fraction (LVEF) <50%], and 101 patients without HF. There were no clinical signs of congestion in 224 (72%) patients with HF, of whom 95 (42%) had at least one sign of congestion by ultrasound (P < 0.0001). HF patients with ≥2 ultrasound signs were older, and had greater neurohormonal activation, lower urinary sodium concentration, and larger left atria despite similar LVEF. During a median follow-up of 13 (interquartile range: 6-15) months, 77 patients (19%) died or were hospitalized for HF. HF patients without ultrasound evidence of congestion had a similar outcome to patients without HF [reference; hazard ratio (HR) 1.02, 95% confidence interval (CI) 0.86-1.35], while those with ≥2 ultrasound signs had the worst outcome (HR 26.7, 95% CI 12.4-63.6), even after adjusting for multiple clinical variables and NT-proBNP. Adding multi-organ assessment of congestion by ultrasound to a clinical model, including NT-proBNP, provided a net reclassification improvement of 28% (P = 0.03). CONCLUSION Simultaneous assessment of pulmonary, venous, and kidney congestion by ultrasound is feasible, fast, and identifies a high prevalence of sub-clinical congestion associated with poor outcomes.

Efficacy of omecamtiv mecarbil in heart failure with reduced ejection fraction according to N‐terminal pro‐B‐type natriuretic peptide level: insights from the GALACTIC‐HF trial

Abstract: N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) is predictive of both outcomes and response to treatment in patients with heart failure with reduced ejection fraction (HFrEF). The aim of this study was to examine the effect of the cardiac myosin activator omecamtiv mecarbil according to baseline NT‐proBNP level in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure trial (GALACTIC‐HF).

Home-based cardiac rehabilitation for people with heart failure and their caregivers: a mixed-methods analysis of the roll out an evidence-based programme in Scotland (SCOT:REACH-HF study).

Abstract: AIMS Alternative models of cardiac rehabilitation (CR) are required to improve CR access and uptake. Rehabilitation EnAblement in CHronic Heart Failure (REACH-HF) is a comprehensive home-based rehabilitation and self-management programme, facilitated by trained health professionals, for people with heart failure (HF) and their caregivers. REACH-HF was shown to be clinically effective and cost-effective in a multicentre randomised trial. The SCOT:REACH-HF study assessed implementation of REACH-HF in routine clinical practice in NHS Scotland. METHODS & RESULTS A mixed-method implementation study was conducted across six regional Health Boards. Of 136 people with HF and 56 caregivers recruited, 101 people with HF and 26 caregivers provided four-month follow-up data, after participating in the 12-week programme. Compared with baseline, REACH-HF participation resulted in substantial gains in the primary outcome of health-related quality of life, as assessed by the Minnesota Living with Heart Failure Questionnaire (mean difference: -9.8, 95% CI: -13.2 to -6.4, P < 0.001). Improvements were also seen in secondary outcomes (PROM-CR+; EQ-5D-5L; Self-Care of Heart Failure Index (SCHFI) domains of maintenance and symptom perception; Caregiver Contribution to Self-Care (CC-SCHFI) domains of symptom perception and management).Twenty qualitative interviews were conducted with 11 REACH-HF facilitators, five supporting clinicians, and four national stakeholders. Interviewees were largely positive about REACH-HF, considering it to have 'filled a gap' where centre-based CR was not an option. Key issues to support future roll-out were also identified. CONCLUSION Our findings support wider roll-out of REACH-HF as an alternative to centre-based models, to improve CR access and uptake for people with HF.

Impact of left ventricular ejection fraction phenotypes on healthcare resource utilization in hospitalized heart failure: a secondary analysis of REPORT‐HF

Abstract: Evidence on healthcare resource utilization (HCRU) for hospitalized patients with heart failure (HF) and reduced (HFrEF), mildly reduced (HFmrEF) and preserved (HFpEF) ejection fraction is limited.

Worsening of chronic heart failure: definition, epidemiology, management and prevention. A clinical consensus statement by the Heart Failure Association of the European Society of Cardiology

Abstract: Episodes of worsening symptoms and signs characterize the clinical course of patients with chronic heart failure (HF). These events are associated with poorer quality of life, increased risks of hospitalization and death and are a major burden on healthcare resources. They usually require diuretic therapy, either administered intravenously or by escalation of oral doses or with combinations of different diuretic classes. Additional treatments may also have a major role, including initiation of guideline‐recommended medical therapy (GRMT). Hospital admission is often necessary but treatment in the emergency service or in outpatient clinics or by primary care physicians has become increasingly used. Prevention of first and recurring episodes of worsening HF is an essential component of HF treatment and this may be achieved through early and rapid administration of GRMT. The aim of the present clinical consensus statement by the Heart Failure Association of the European Society of Cardiology is to provide an update on the definition, clinical characteristics, management and prevention of worsening HF in clinical practice.

Cardiac Resynchronization Therapy Improves Outcomes in Patients With Intraventricular Conduction Delay But Not Right Bundle Branch Block: A Patient-Level Meta-Analysis of Randomized Controlled Trials

Abstract: Background: Benefit from cardiac resynchronization therapy (CRT) varies by QRS characteristics; individual randomized trials are underpowered to assess benefit for relatively small subgroups. Methods: The authors analyzed patient-level data from pivotal CRT trials (MIRACLE [Multicenter InSync Randomized Clinical Evaluation], MIRACLE-ICD [Multicenter InSync ICD Randomized Clinical Evaluation], MIRACLE-ICD II [Multicenter InSync ICD Randomized Clinical Evaluation II], REVERSE [Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction], RAFT [Resynchronization-Defibrillation for Ambulatory Heart Failure], BLOCK-HF [Biventricular Versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block], COMPANION [Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure], and MADIT-CRT [Multicenter Automatic Defibrillator Implantation Trial – Cardiac Resynchronization Therapy]) using Bayesian Hierarchical Weibull survival regression models to assess CRT benefit by QRS morphology (left bundle branch block [LBBB], n=4549; right bundle branch block [RBBB], n=691; and intraventricular conduction delay [IVCD], n=1024) and duration (with 150-ms partition). The continuous relationship between QRS duration and CRT benefit was also examined within subgroups defined by QRS morphology. The primary end point was time to heart failure hospitalization (HFH) or death; a secondary end point was time to all-cause death. Results: Of 6264 patients included, 25% were women, the median age was 66 [interquartile range, 58 to 73] years, and 61% received CRT (with or without an implantable cardioverter defibrillator). CRT was associated with an overall lower risk of HFH or death (hazard ratio [HR], 0.73 [credible interval (CrI), 0.65 to 0.84]), and in subgroups of patients with QRS ≥150 ms and either LBBB (HR, 0.56 [CrI, 0.48 to 0.66]) or IVCD (HR, 0.59 [CrI, 0.39 to 0.89]), but not RBBB (HR 0.97 [CrI, 0.68 to 1.34]; Pinteraction <0.001). No significant association for CRT with HFH or death was observed when QRS was <150 ms (regardless of QRS morphology) or in the presence of RBBB. Similar relationships were observed for all-cause death. Conclusions: CRT is associated with reduced HFH or death in patients with QRS ≥150 ms and LBBB or IVCD, but not for those with RBBB. Aggregating RBBB and IVCD into a single “non-LBBB” category when selecting patients for CRT should be reconsidered. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00271154, NCT00251251, NCT00267098, and NCT00180271.

Estimating nuclear scanning capacity requirements for patients with suspected cardiac transthyretin amyloidosis

Abstract: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-shortening disease, caused by the deposition of misfolded transthyretin amyloid fibrils in the extracellular space of the myocardium, leading to increased wall thickness and diastolic dysfunction that can result in heart failure (HF). Among patients with confirmed ATTR-CM, HF with a normal left ventricular ejection fraction (LVEF) is the predominant presentation, and an important clue to the underlying diagnosis is the presence of otherwise unexplained left ventricular hypertrophy. Increased left ventricular wall thickness (LVWT) in patients with HF has been proposed as a red flag for cardiac amyloidosis that should prompt further investigations to confirm or exclude the diagnosis. The prevalence of ATTR-CM is uncertain, and, consequently, so is the number of patients that might be referred to an HF service with suspected ATTR-CM. The Hull LifeLab database, containing 20 years of data for patients who have been referred to a community HF clinic, offers a unique opportunity to investigate this issue. The aim of this analysis was to understand the prevalence and characteristics of patients who should be considered for referral for nuclear scintigraphy to exclude or confirm a diagnosis of ATTR-CM, based on the presence of HF with a normal or mildly reduced ejection fraction and an increased LVWT. Between August 2000 and January 2020, consecutive referrals to a community HF clinic were enrolled in a longitudinal epidemiological study at a single clinic (The Hull LifeLab). Patients consented for the use of their medical information prior to investigation. The study was approved by the Hull and East Yorkshire Local Research Ethics Committee. All patient identifiable information was anonymized before analysis. For the present analysis, we focused only on patients with HF who had at their initial visit (i) a diagnosis of HF, based on symptoms and signs together with a raised N-terminal probrain natriuretic peptide (NT-proBNP) (≥400 ng/L); (ii) LVEF ≥45%, corresponding to mild or no evidence of LVSD, as determined by echocardiography; and (iii) measurements of LVWT. Patients were defined as being suitable for further investigations for a possible diagnosis of ATTR-CM if either the left ventricular posterior wall thickness or interventricular septal wall thickness was increased. An international position statement proposes an LVWT greater than or equal to 12 mm, whereas another study suggests a cut-off of 14 mm. Accordingly, we provide analyses using both criteria. We also present data for those with and without hypertension, defined as systolic blood pressure ≥140 mmHg. Of the original 7378 patients assessed in the clinic, 4788 had data available for NT-proBNP, LVEF, and LVWT, of whom 1735 had HF with normal or mildly reduced LVEF (Figure 1). Of these 1735, 884 (51%) had an LVWT ≥12 mm, and 282 (16%) had a LVWT ≥14 mm (Figure 2), which represents approximately 18% and 6%, respectively, of all patients for whom we had data on left ventricular systolic function, LVWT, and a contemporaneous NT-proBNP. Excluding patients with hypertension reduced the proportion who should be considered for nuclear scintigraphy to 7% those with a LVWT ≥12 mm and 2% of those with a LVWT ≥14 mm (Figure 3). Patients with an LVWT ≥12 mm (Table 1) were more likely to have a history of hypertension or diabetes and a higher systolic blood pressure, were less likely to be treated with a beta blocker, and were more likely to be treated with a loop diuretic. Patients with greater wall thickness also had a longer QRS duration, had a higher NT-proBNP, and were more likely to have severe aortic valve disease. Left atrial size was not different between the two groups, but the left ventricular end-diastolic dimension indexed for body surface area (BSA) was slightly lower in the group with greater wall thickness. Similar findings were observed when comparing those with an LVWT ≥14 mm to those with a LVWT <14 mm (Table 1). Epidemiologically, patients with HF and a normal LVEF are more likely to be women. However, men are more likely to have increased LVWT, which could be due to myocardial hypertrophy or infiltration with ATTR and is consistent with the observation that ATTR-CM is much more common in men than women. LETTER TO THE EDITOR

A machine learning derived echocardiographic algorithm identifies people at risk of heart failure with distinct cardiac structure, function, and response to spironolactone: findings from the HOMAGE trial.

Abstract: BACKGROUND An echocardiographic algorithm derived by machine learning (e'VM) characterizes preclinical individuals with different cardiac structure and function, biomarkers, and long-term risk of heart failure (HF). Our aim was the external validation of the e'VM algorithm and to explore whether it may identify subgroups who benefit from spironolactone. METHODS The HOMAGE (Heart OMics in Aging) trial enrolled participants at high risk of developing HF randomly assigned to spironolactone or placebo over 9 months. The e'VM algorithm was applied to 416 participants (mean age 74±7years, 25% women) with available echocardiographic variables (i.e., e' mean, left ventricular [LV] end-diastolic volume and mass indexed by body surface area [LVMi]). The effects of spironolactone on changes in echocardiographic and biomarker variables were assessed across e'VM phenotypes. RESULTS A majority (>80%) had either "diastolic changes (D)", or "diastolic changes with structural remodeling (D/S)" phenotype. D/S phenotype had the highest LVMi, left atrial volume, E/e', natriuretic peptide and troponin levels (all p<0.05). Spironolactone significantly reduced E/e' and b-type natriuretic peptide (BNP) levels in D/S phenotype (p<0.01), but not in other phenotypes (p>0.10; Pinteraction <0.05 for both). These interactions were not observed when considering guideline-recommended echocardiographic structural and functional abnormalities. The magnitude of effects of spironolactone on LVMi, left atrial volume and a type I collagen marker was numerically higher in D/S phenotype than D phenotype but the interaction test did not reach significance. CONCLUSIONS In the HOMAGE trial, the e'VM algorithm identified echocardiographic phenotypes with distinct responses to spironolactone as assessed by changes in E/e' and BNP. This article is protected by copyright. All rights reserved.

Outcomes of Cardiac Resynchronization Therapy by New York Heart Association Class: A Patient-Level Meta-Analysis

Abstract: Data on the benefits of cardiac resynchronization therapy (CRT) in patients with severe heart failure (HF) symptoms are limited. We investigated the relative effects of CRT in patients with ambulatory NYHA IV vs III functional class at the time of device implantation. In this meta-analysis, we pooled patient-level data from the MIRACLE, MIRACLE-ICD, and COMPANION trials. Outcomes evaluated were time to the composite endpoint of first HF hospitalization (HFH) or all-cause mortality and time to all-cause mortality alone. The association between CRT and outcomes was evaluated using a Bayesian Hierarchical Weibull survival regression model. We assessed if this association differs between NYHA III and IV groups by adding an interaction term between CRT and NYHA class as a random effect. A sensitivity analysis was performed by including data from the RAFT trial. Our pooled analysis included 2309 patients. Overall, CRT was associated with a longer time to HFH or all-cause mortality (adjusted hazard ratio [aHR] 0.79, 95%CI 0.64 ? 0.99, p = 0.044), with a similar association with time to all-cause mortality (aHR 0.78, 95% CI 0.59 ? 1.03, p = 0.083). Associations of CRT with outcomes were not significantly different for those in NYHA III and IV classes (ratio of aHR 0.72, 95% CI 0.30 ? 1.27, p = 0.23 for HFH/mortality; ratio of aHR 0.70, 95% CI 0.35 ? 1.34, p = 0.27 for all-cause mortality alone). The sensitivity analysis, including RAFT data, did not show a significant relative CRT benefit between NYHA III and IV classes. Overall, there was no significant difference in the association of CRT with either outcome for patients in NYHA functional class III compared with functional class IV.

Coronary revascularization for heart failure with coronary artery disease: a systematic review and meta-analysis of randomized trials.

Abstract: BACKGROUND AND AIMS Coronary artery disease (CAD) is a common cause of heart failure (HF). Whether coronary revascularisation improves outcomes in patients with HF receiving guideline-recommended pharmacological therapy (GRPT) remains uncertain; therefore, we conducted a systematic review and meta-analysis of relevant randomized controlled trials (RCTs). METHODS We searched in public databases for RCTs published between 1st January 2001 and 22nd November 2022, investigating the effects of coronary revascularisation on morbidity and mortality in patients with chronic HF due to CAD. All-cause mortality was the primary outcome. RESULTS We included five RCTs that enrolled, altogether, 2,842 patients (most aged <65 years; 85% men; 67% with left ventricular ejection fraction ≤35%). Overall, compared to medical therapy alone, coronary revascularisation was associated with a lower risk of all-cause mortality (HR 0.88 [95% CI, 0.79-0.99]; p=0.0278) and cardiovascular mortality (HR 0.80 [95% CI, 0.70-0.93]; p=0.0024) but not the composite of hospitalisation for HF or all-cause mortality (HR 0.87 [95% CI, 0.74-1.01]; p=0.0728). There were insufficient data to show whether the effect of CABG or PCI were similar or differed. CONCLUSIONS For patients with chronic HF and CAD enrolled in RCTs, the effect of coronary revascularization on all-cause mortality was statistically significant but neither substantial (HR 0.88) nor robust (upper 95% CI close to 1.0). RCTs were not blinded, which may bias reporting of the cause-specific reasons for hospitalization and mortality. Further trials are required to determine which patients with HF and CAD obtain a substantial benefit from coronary revascularization by either CABG or PCI. This article is protected by copyright. All rights reserved.

Inferior vena cava diameter is associated with prognosis in patients with chronic heart failure independent of tricuspid regurgitation velocity

Abstract: A high, Doppler-derived, tricuspid regurgitation velocity (TRV) indicates pulmonary hypertension, which may contribute to right ventricular dysfunction and worsening tricuspid regurgitation leading to systemic venous congestion, reflected by an increase in inferior vena cava (IVC) diameter. We hypothesized that venous congestion rather than pulmonary hypertension would be more strongly associated with prognosis.895 patients with chronic heart failure (CHF) (median (25th and 75th centile) age 75 (67-81) years, 69% men, LVEF 44 (34-55)% and NT-proBNP 1133 (423-2465) pg/ml) were enrolled. Compared to patients with normal IVC (< 21 mm) and TRV (≤ 2.8 m/s; n = 504, 56%), those with high TRV but normal IVC (n = 85, 9%) were older, more likely to be women and to have LVEF ≥ 50%, whilst those with dilated IVC but normal TRV (n = 142, 16%) had more signs of congestion and higher NT-proBNP. Patients (n = 164, 19%) with both dilated IVC and high TRV had the most signs of congestion and the highest NT-proBNP. During follow-up of 860 (435-1121) days, 239 patients died. Compared to those with both normal IVC and TRV (reference), patients with high TRV but normal IVC did not have a significantly increased mortality (HR: 1.41; CI: 0.87-2.29; P = 0.16). Risk was higher for patients with a dilated IVC but normal TRV (HR: 2.51; CI: 1.80-3.51; P < 0.001) or both a dilated IVC and elevated TRV (HR: 3.27; CI: 2.40-4.46; P < 0.001).Amongst ambulatory patients with CHF, a dilated IVC is more closely associated with an adverse prognosis than an elevated TRV.

Effect of Spironolactone on QRS Duration in Patients at Risk for Heart Failure (from the HOMAGE Trial).

Abstract: The QRS duration can be easily obtained from a 12-lead electrocardiogram. Increased QRS duration reflects greater ventricular activation times and often ventricular dyssynchrony. Dyssynchrony causes an impairment of the global cardiac function and adversely affects the prognosis of patients with heart failure (HF). Little is known about the impact of pharmacologic therapies on the QRS duration, particularly for patients with presymptomatic HF with a preserved left ventricular (LV) ejection fraction (i.e., stage B HF with preserved ejection fraction [HFpEF]). The HOMAGE (Heart OMics in AGEing) trial enrolled patients at risk factors for developing HF and assigned them to receive either spironolactone or the usual care for approximately 9 months in a randomized manner. This analysis reports the effect of spironolactone on the QRS duration. A total of 525 patients was included in the analysis. The median (percentile25-75) QRS duration at baseline was 92 (84 to 106) ms. Spironolactone reduced the QRS duration at month 9 by -2.8, 95% confidence interval -4.6 to -1.0 ms, p = 0.003. No significant associations were found between month 9 changes in the QRS duration and corresponding changes in the LV ejection fraction, LV mass, LV end-diastolic volume, blood pressure, N-terminal pro-brain natriuretic peptide, and procollagen type I carboxy-terminal propeptide (all p >0.05). This analysis shows that for patients with stage B HFpEF, therapy with spironolactone for 9 months shortened the QRS duration, an effect that was not associated with reductions in LV mass or volume, supporting the hypothesis that spironolactone has direct beneficial effects to improve myocardial electrical activation in patients with stage B HFpEF.

Defining Heart Failure Based on Imaging the Heart and Beyond

Abstract: Water and salt retention, in other words congestion, are fundamental to the pathophysiology of heart failure and are important therapeutic targets. Echocardiography is the key tool with which to assess cardiac structure and function in the initial diagnostic workup of patients with suspected heart failure and is essential for guiding treatment and stratifying risk. Ultrasound can also be used to identify and quantify congestion in the great veins, kidneys and lungs. More advanced imaging methods might further clarify the aetiology of heart failure and its consequences for the heart and periphery, thereby improving the efficiency and quality of care tailored with greater precision to individual patient need.

Pregnancy risks and contraceptive use among postpartum mothers in Cameroon: implications for improving the coverage of postpartum family planning services

Abstract: Abstract Background The health hazards of short inter-birth intervals are severe in Cameroon. One-quarter of inter-birth intervals are less than 24 months and the probability of death before age 5 for children born after a short interval is double that associated with intervals of 36–47 months. We examine the risk of an unintended pregnancy in the 18 months following childbirth in Cameroon, taking into account the protective effects of lactational amenorrhea, delayed resumption of sex as well as contraceptive use. Methods Data from 3007 postpartum women in the nationally representative 2018 Cameroon Demographic and Health Survey were used. Risk of an unintended pregnancy was defined from current status information on resumption of sex and menses, contraceptive use, desire for another child within 12 months, and, for the minority of pregnant women, whether the conception was intended. Predictors of risk, and of modern method use, were assessed by bivariate and multivariate analysis. Results In the first 6 postpartum months, only 8% of women were fully at risk (i.e., sex and menses resumed but no contraceptive use), rising to 24% at 6–11 postpartum months, and further to 30% at months 12–17. Though 89% wanted to delay the next birth by at least 1 year, only 17% were currently using a modern method. Menstruating women were much more likely to be users than amenorrheic women: 27% versus 15% at months 12–17 postpartum. Urban and better educated women recorded higher contraceptive use but lower protection from other factors than rural, less educated women, with the net result that risk differed little across these population strata. Uptake of maternal and child health (MCH) services was high but only one-third of women had discussed family planning at a facility visit during the preceding 12 months. Conclusions These results underscore the need for improved postpartum family planning services by means of closer integration with mainstream health services. In view of evidence from other sources of heavy workload and weak motivation of health staff, this will require strong leadership. A related priority is to increase the number of staff trained in provision of long-acting methods, such as implants.

Multi-organ sonographic assessment of congestion has incremental prognostic value in outpatients with heart failure irrespective of left ventricular ejection fraction

Abstract: Type of funding sources: None. Congestion is a key driver of symptoms, disease progression and prognosis for patients with heart failure (HF), irrespective of left ventricular ejection fraction (LVEF). However, clinically overt congestion is often undiagnosed unless severe. Recent research has shown that ultrasonographic quantification of systemic venous (i.e. inferior vena cava), renal venous and lung (B-lines) congestion is feasible and identifies HF patients with a worse prognosis. Whether a simultaneous multi-organ evaluation of congestion by ultrasound may improve risk stratification in HF is unknown. In the present study, we assessed signs of ultrasonographic congestion in the inferior vena cava, lungs and kidneys in HF patients across the LVEF spectrum and investigated their association with pathophysiology, clinical characteristics and prognosis. We prospectively enrolled 326 patients with a prior clinical diagnosis of HF attending a routine follow-up visit. We also enrolled 102 consecutive patients with cardiovascular risk factors (including hypertension, type II diabetes mellitus or chronic ischaemic heart disease) and no history of HF; these latter patients had NT-proBNP levels <125 ng/L, LVEF >50%, and were not taking loop diuretics. All patients underwent a complete clinical assessment, blood and urine tests, and an ultrasound evaluation. Ultrasound congestion was defined as inferior vena cava ≥21 mm, highest tertile of lung B-lines or discontinuous renal venous flow. The final population consisted of 310 HF patients (median age 77 years, median NT-proBNP 1037 ng/L, 51% with LVEF <50%), and 101 subjects without HF. Among the 224 HF patients (72%) with no clinical signs of congestion, 95 (42%) had at least one sign of congestion by ultrasound (p<0.0001). HF patients with ≥2 ultrasound signs were older, had greater neurohormonal activation (i.e., higher NT-proBNP; Figure 1), lower urinary sodium concentration, and larger left atria despite similar LVEF. During a median follow-up of 13 (interquartile range 6–15) months, 77 HF patients (19%) died or were hospitalized for HF. HF patients without ultrasonographic evidence of congestion had a similar outcome to subjects without HF (reference; HR 1.02, 95% CI 0.86 – 1.35), while those with ≥2 ultrasound signs had the worst outcome (HR 26.7, 95% CI 12.4–63.6), even after adjusting for multiple clinical variables and NT-proBNP (Figure 2). Adding multi-organ assessment of congestion by ultrasound to a clinical model, including NT-proBNP, provided a 28% net reclassification improvement (p=0.03). Simultaneous assessment of pulmonary, systemic venous and kidney congestion by ultrasound identifies a high prevalence of sub-clinical congestion associated with poor outcomes in HF, irrespective of LVEF. The speed of investigation, along with the widespread availability and relatively low cost of ultrasound, makes this protocol easy to implement for real-time assessment of congestion.

Clinical and prognostic associations of autoantibodies recognizing adrenergic/muscarinic receptors in patients with heart failure

Abstract: Abstract Aims The importance of autoantibodies (AABs) against adrenergic/muscarinic receptors in heart failure (HF) is not well-understood. We investigated the prevalence and clinical/prognostic associations of four AABs recognizing the M2-muscarinic receptor or the β1-, β2-, or β3-adrenergic receptor in a large and well-characterized cohort of patients with HF. Methods and results Serum samples from 2256 patients with HF from the BIOSTAT-CHF cohort and 299 healthy controls were analysed using newly established chemiluminescence immunoassays. The primary outcome was a composite of all-cause mortality and HF rehospitalization at 2-year follow-up, and each outcome was also separately investigated. Collectively, 382 (16.9%) patients and 37 (12.4%) controls were seropositive for ≥1 AAB (P = 0.045). Seropositivity occurred more frequently only for anti-M2 AABs (P = 0.025). Amongst patients with HF, seropositivity was associated with the presence of comorbidities (renal disease, chronic obstructive pulmonary disease, stroke, and atrial fibrillation) and with medication use. Only anti-β1 AAB seropositivity was associated with the primary outcome [hazard ratio (95% confidence interval): 1.37 (1.04–1.81), P = 0.024] and HF rehospitalization [1.57 (1.13–2.19), P = 0.010] in univariable analyses but remained associated only with HF rehospitalization after multivariable adjustment for the BIOSTAT-CHF risk model [1.47 (1.05–2.07), P = 0.030]. Principal component analyses showed considerable overlap in B-lymphocyte activity between seropositive and seronegative patients, based on 31 circulating biomarkers related to B-lymphocyte function. Conclusions AAB seropositivity was not strongly associated with adverse outcomes in HF and was mostly related to the presence of comorbidities and medication use. Only anti-β1 AABs were independently associated with HF rehospitalization. The exact clinical value of AABs remains to be elucidated.

Protein Biomarkers of New-Onset Heart Failure: Insights From the Heart Omics and Ageing Cohort, the Atherosclerosis Risk in Communities Study, and the Framingham Heart Study

Abstract: Background: We sought to identify protein biomarkers of new-onset heart failure (HF) in 3 independent cohorts (HOMAGE cohort [Heart Omics and Ageing], ARIC study [Atherosclerosis Risk in Communities], and FHS [Framingham Heart Study]) and assess if and to what extent they improve HF risk prediction compared to clinical risk factors alone. Methods: A nested case-control design was used with cases (incident HF) and controls (without HF) matched on age and sex within each cohort. Plasma concentrations of 276 proteins were measured at baseline in ARIC (250 cases/250 controls), FHS (191/191), and HOMAGE cohort (562/871). Results: In single protein analysis, after adjusting for matching variables and clinical risk factors (and correcting for multiple testing), 62 proteins were associated with incident HF in ARIC, 16 in FHS, and 116 in HOMAGE cohort. Proteins associated with incident HF in all cohorts were BNP (brain natriuretic peptide), NT-proBNP (N-terminal pro-B-type natriuretic peptide), eukaryotic translation initiation factor 4E-BP1 (4E-binding protein 1), hepatocyte growth factor (HGF), Gal-9 (galectin-9), TGF-alpha (transforming growth factor alpha), THBS2 (thrombospondin-2), and U-PAR (urokinase plasminogen activator surface receptor). The increment in C-index for incident HF based on a multiprotein biomarker approach, in addition to clinical risk factors and NT-proBNP, was 11.1% (7.5%–14.7%) in ARIC, 5.9% (2.6%–9.2%) in FHS, and 7.5% (5.4%–9.5%) in HOMAGE cohort, all P<0.001), each of which was a larger increase than that for NT-proBNP on top of clinical risk factors. Complex network analysis revealed a number of overrepresented pathways related to inflammation (eg, tumor necrosis factor and interleukin) and remodeling (eg, extracellular matrix and apoptosis). Conclusions: A multiprotein biomarker approach improves prediction of incident HF when added to natriuretic peptides and clinical risk factors.

Systemic oxidative stress associates with disease severity and outcome in patients with new-onset or worsening heart failure

Abstract: Oxidative stress may be a key pathophysiological mediator in the development and progression of heart failure (HF). The role of serum-free thiol concentrations, as a marker of systemic oxidative stress, in HF remains largely unknown.The purpose of this study was to investigate associations between serum-free thiol concentrations and disease severity and clinical outcome in patients with new-onset or worsening HF.Serum-free thiol concentrations were determined by colorimetric detection in 3802 patients from the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF). Associations between free thiol concentrations and clinical characteristics and outcomes, including all-cause mortality, cardiovascular mortality, and a composite of HF hospitalization and all-cause mortality during a 2-years follow-up, were reported.Lower serum-free thiol concentrations were associated with more advanced HF, as indicated by worse NYHA class, higher plasma NT-proBNP (P < 0.001 for both) and with higher rates of all-cause mortality (hazard ratio (HR) per standard deviation (SD) decrease in free thiols: 1.253, 95% confidence interval (CI): 1.171-1.341, P < 0.001), cardiovascular mortality (HR per SD: 1.182, 95% CI: 1.086-1.288, P < 0.001), and the composite outcome (HR per SD: 1.058, 95% CI: 1.001-1.118, P = 0.046).In patients with new-onset or worsening HF, a lower serum-free thiol concentration, indicative of higher oxidative stress, is associated with increased HF severity and poorer prognosis. Our results do not prove causality, but our findings may be used as rationale for future (mechanistic) studies on serum-free thiol modulation in heart failure. Associations of serum-free thiol concentrations with heart failure severity and outcomes.

Variation in optimal hemodynamic atrio‐ventricular delay of biventricular pacing with different endocardial left ventricular lead locations using precision hemodynamics

Abstract: It is not known whether the optimal atrioventricular (AVopt) delay varies between left ventricular (LV) pacing site during endocardial biventricular pacing (BiVP) and may therefore needs consideration.

Assessment of haemoglobin and serum markers of iron deficiency in people with cardiovascular disease

Abstract: Background The prevalence of anaemia and iron deficiency and their prognostic association with cardiovascular disease have rarely been explored at population level. Methods National Health Service records of the Greater Glasgow region for patients aged ≥50 years with a broad range of cardiovascular diagnoses were obtained. During 2013/14, prevalent disease was identified and results of investigations collated. Anaemia was defined as haemoglobin <13 g/dL for men or <12 g/dL for women. Incident heart failure, cancer and death between 2015 and 2018 were identified. Results The 2013/14 dataset comprised 197 152 patients, including 14 335 (7%) with heart failure. Most (78%) patients had haemoglobin measured, especially those with heart failure (90%). Of those tested, anaemia was common both in patients without (29%) and with heart failure (prevalent cases in 2013/14: 46%; incident cases during 2013/14: 57%). Ferritin was usually measured only when haemoglobin was markedly depressed; transferrin saturation (TSAT) even less often. Incidence rates for heart failure and cancer during 2015–18 were inversely related to nadir haemoglobin in 2013/14. A haemoglobin of 13–15 g/dL for women and 14–16 g/dL for men was associated with the lowest mortality. Low ferritin was associated with a better prognosis and low TSAT with a worse prognosis. Conclusion In patients with a broad range of cardiovascular disorders, haemoglobin is often measured but, unless anaemia is severe, markers of iron deficiency are usually not. Low haemoglobin and TSAT, but not low ferritin, are associated with a worse prognosis. The nadir of risk occurs at haemoglobin 1–3 g/dL above the WHO definition of anaemia.

Mortality, Outcomes, Costs, and Use of Medicines Following a First Heart Failure Hospitalization: EVOLUTION HF.

Abstract: There are few contemporary data on outcomes, costs, and treatment following a hospitalization for heart failure (hHF) in epidemiologically representative cohorts.The study sought to describe rehospitalizations, hospitalization costs, use of guideline-directed medical therapy (GDMT) (renin-angiotensin system inhibitors, sacubitril/valsartan, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors), and mortality after hHF.EVOLUTION HF (Utilization of Dapagliflozin and Other Guideline Directed Medical Therapies in Heart Failure Patients: A Multinational Observational Study Based on Secondary Data) is an observational, longitudinal cohort study using data from electronic health records or claims data sources in Japan, Sweden, the United Kingdom, and the United States. Adults with a first hHF discharge between 2018 and 2022 were included. One-year event rates per 100 patient-years (ERs) for death and rehospitalizations (with a primary diagnosis of heart failure (HF), chronic kidney disease [CKD], myocardial infarction, stroke, or peripheral artery disease) were calculated. Hospital health care costs were cumulatively summarized. Cumulative GDMT use was assessed using Kaplan-Meier estimates.Of 263,525 patients, 28% died within the first year post-hHF (ER: 28.4 [95% CI: 27.0-29.9]). Rehospitalizations were mainly driven by HF (ER: 13.6 [95% CI: 9.8-17.4]) and CKD (ER: 4.5 [95% CI: 3.6-5.3]), whereas the ERs for myocardial infarction, stroke, and peripheral artery disease were lower. Health care costs were predominantly driven by HF and CKD. Between 2020 and 2022, use of renin-angiotensin system inhibitors, sacubitril/valsartan, beta-blockers, and mineralocorticoid receptor antagonists changed little, whereas uptake of sodium-glucose cotransporter-2 inhibitors increased 2- to 7-fold.Incident post-hHF rehospitalization risks and costs were high, and GDMT use changed little in the year following discharge, highlighting the need to consider earlier and greater implementation of GDMT to manage risks and reduce costs.

Influence of serum transferrin concentration on diagnostic criteria for iron deficiency in chronic heart failure.

Abstract: AIMS Transferrin saturation (TSAT), a marker of iron deficiency, reflects both serum concentrations of iron (SIC) and transferrin (STC). TSAT is susceptible to changes in each of these biomarkers. Little is known about determinants of STC and its influence on TSAT and mortality in patients with heart failure. Accordingly, we studied the relationship of STC to clinical characteristics, to markers of iron deficiency and inflammation and to mortality in chronic heart failure (CHF). METHODS AND RESULTS Prospective cohort of patients with CHF attending a clinic serving a large local population. A total of 4422 patients were included (median age 75 (68-82) years; 40% women; 32% with left ventricular ejection fraction ≤40%). STC ≤ 2.3 g/L (lowest quartile) was associated with older age, lower SIC and haemoglobin and higher high-sensitivity C-reactive protein, ferritin and N-terminal pro-brain natriuretic peptide compared with those with STC > 2.3 g/L. In the lowest STC quartile, 624 (52%) patients had SIC ≤13 μmol/L, of whom 38% had TSAT ≥20%. For patients in the highest STC quartile, TSAT was <20% when SIC was >13 μmol/L in 185 (17%) patients. STC correlated inversely with ferritin (r = -0.52) and high-sensitivity C-reactive protein (r = -0.17) and directly with albumin (r = 0.29); all P < 0.001. In models adjusted for age, N-terminal pro-brain natriuretic peptide and haemoglobin, both higher SIC (hazard ratio 0.87 [95% CI: 0.81-0.95]) and STC (hazard ratio 0.82 [95% CI: 0.73-0.91]) were associated with lower mortality. SIC was more strongly associated with both anaemia and mortality than either STC or TSAT. CONCLUSIONS Many patients with CHF and a low STC have low SIC even when TSAT is >20% and serum ferritin >100 μg/L; such patients have a high prevalence of anaemia and a poor prognosis and might have iron deficiency but are currently excluded from clinical trials of iron repletion.

Urinary Proteomic Signature of Mineralocorticoid Receptor Antagonism by Spironolactone: Evidence from the Randomized-Controlled HOMAGE and PRIORITY Trials

Abstract: BACKGROUND: Mineralocorticoid receptor (MR) activation induces fibrosis. Urinary proteomic profiling (UPP) detects thousands of sequenced peptides, mainly derived from collagen. No previous study applied UPP to generate insights in the antifibrotic actions of MR antagonism. METHODS: Based on urine sample availability, subsets of the open HOMAGE trial (n=290; 23.8% women; median age: 73 years) and the double-blind PRIORITY trial (n=110; 21.8% women; 64 years) were analyzed as discovery and replication data sources. In the open HOMAGE trial, patients at risk of heart failure were randomized to usual therapy or usual therapy combined with spironolactone 25-50 mg/d. In the double-blind PRIORITY trial, type 2 diabetic patients with normal renal function were randomized to placebo or spironolactone 25 mg/d, both given on top of usual therapy. UPP relied on capillary electrophoresis coupled with mass spectrometry. In HOMAGE, the PICP/CITP ratio was calculated from serum PICP and serum CITP, which are markers of type-1 collagen synthesis and degradation, respectively. After rank-normalization of the biomarker distributions, between-group differences in the biomarker changes were analyzed by multivariable models. Correlations between the changes in urinary peptides and in serum CITP, derived from mature type-1 collagen, were compared between groups, using Fisher Z transform. RESULTS: In the HOMAGE and PRIORITY analytical subsets, patients had detectable signals of 1498 urinary peptides. Follow-up totaled 9 months in HOMAGE and was 30 months (median) in PRIORITY. All changes in urinary peptides that remained significantly different (P<0.05) between randomization groups after accounting for baseline levels, covariables and multiple testing were collagen fragments. In HOMAGE and PRIORITY spironolactone reduced 16/27 and 10/13 collagen-derived urinary peptides. In HOMAGE, from baseline to 9 months, serum PICP and PICP/CITP decreased from 79.0 to 75.4 {micro}g/L and from 21.3 to 18.3, respectively (P[≤]0.0129). Correlations between changes from baseline to follow-up in urinary type-1 collagen fragments and CITP were positive often reaching significance if fragments increased during follow-up, but were nonsignificant if fragments decreased during follow-up. There were no between-group differences in these correlations. CONCLUSIONS: MR antagonism predominantly reduces collagen-derived urinary peptides. Inhibition of collagen synthesis by lowering the amount available for breakdown may be a contributing mechanism.