Effects of spironolactone on exercise blood pressure in patients at increased risk of developing heart failure: report from the HOMAGE trial.

None of the spironolactone trials in heart failure (HF) assessed the blood pressure (BP) responses to exercise, while conflicting results were reported for exercise capacity. In the HOMAGE trial, 527 patients at increased HF risk were randomized to usual treatment with or without spironolactone (25-50 mg/day). The current substudy included 113 controls and 114 patients assigned spironolactone, who all completed the incremental shuttle walk test at baseline and months 1 and 9. Quality of life (QoL) was assessed by EQ5D questionnaire. Between-group differences (spironolactone minus control [Δs]) were analyzed by repeated measures ANOVA with adjustment for baseline and, if appropriate, additionally for sex, age and body mass index. Δs in the pre-exercise systolic/diastolic BP were -8.00 mm Hg (95% CI, -11.6 to -4.43)/-0.85 mm Hg (-2.96 to 1.26) at month 1 and -9.58 mm Hg (-14.0 to -5.19)/-3.84 mm Hg (-6.22 to -1.47) at month 9. Δs in the post-exercise systolic/diastolic BP were -8.08 mm Hg (-14.2 to -2.01)/-2.07 mm Hg (-5.79 to 1.65) and -13.3 mm Hg (-19.9 to -6.75)/-4.62 mm Hg (-8.07 to -1.17), respectively. For completed shuttles, Δs at months 1 and 9 were 2.15 (-0.10 to 4.40) and 2.49 (-0.79 to 5.67), respectively. Δs in QoL were not significant. The correlations between the exercise-induced BP increases and the number of completed shuttles were similar in both groups. In conclusion, in patients at increased risk of developing HF, spironolactone reduced the pre- and post-exercise BP, but did not improve exercise capacity or QoL.

Diabetes mellitus is associated with low exercise capacity and impaired peripheral vasodilation in patients with heart failure - a propensity score-matched study.

AIMS: Diabetes mellitus (DM) and heart failure (HF) share vascular, skeletal and metabolic abnormalities that can reduce exercise capacity. We investigated whether exercise capacity differ in patients with type 2 DM compared to those without DM with HF of similar severity. METHODS AND RESULTS: The Studies Investigating Co-morbidities Aggravating HF (SICA-HF) prospectively enrolled 615 patients with chronic HF, 259 (42.1 %) of whom had DM. We assembled a propensity score-matched cohort of 231 pairs of patients with HF with or without DM who were balanced on age, sex and variables reflecting HF severity. Patients with DM had lower median peak VO2 (15.7 [13.0-19.1] vs. 17.3 [14.1-21.0] ml/min/kg; p = 0.005). Forearm blood flow reserve (per 1 ml/min/100 ml increase) was associated with lower exercise capacity (peak VO2 ≤ 16.6 ml/min/kg) in patients with DM (OR, 0.92; 95 % CI, (0.85-0.98; p = 0.014), but not in those without DM (OR, 0.98; 95 % CI, 0.93-1.02). A similar heterogeneity was also observed for HDL cholesterol. CONCLUSIONS: Diabetes is associated with a reduced exercise capacity in patients with HF. Most predictors of lower exercise capacity in HF are similar regardless of DM except impaired vascular function and lower HDL cholesterol which predict lower exercise capacity only in those with DM.

Disease progression in chronic heart failure is linear: Insights from multistate modelling.

AIMS: Understanding the pattern of disease progression in chronic heart failure (HF) may inform patient care and healthcare system design. We used a four-state Markov model to describe the disease trajectory of patients with HF. METHODS AND RESULTS: Consecutive patients (n = 4918) were enrolled (median age 75 [67-81] years, 61.3% men, 44% with HF and reduced ejection fraction). We generated a model by observing events during the first 2 years of follow-up. The model yielded surprisingly accurate predictions of how a population with HF will behave during subsequent years. As examples, the predicted transition probability from hospitalization to death was 0.11; the observed probabilities were 0.13, 0.14, and 0.16 at 3, 4, and 5 years, respectively. Similarly, the predicted transition intensity for rehospitalization was 0.35; the observed probabilities were 0.38, 0.34, and 0.35 at 3, 4, and 5 years, respectively. A multivariable model including covariates thought to influence outcome did not improve accuracy. Predicted average life expectancy was approximately 10 years for the unadjusted model and 13 years for the multivariable model, consistent with the observed mortality of 41% at 5 years. CONCLUSIONS: A multistate Markov chain model for patients with chronic HF suggests that the proportion of patients transitioning each year from a given state to another remains constant. This finding suggests that the course of HF at a population level is more linear than is commonly supposed and predictable based on current patient status.

Heart Failure Specialist Care and Long-Term Outcomes for Patients Admitted With Acute Heart Failure.

BACKGROUND: For patients with acute heart failure (HF), specialist HF care during admission improves diagnosis and treatments. OBJECTIVES: The authors aimed to investigate the association of HF specialist care with in-hospital and longer term prognosis. METHODS: The authors used data from the National Heart Failure Audit from January 1, 2018, to December 31, 2022, linked to electronic records for hospitalization and deaths. All-cause mortality was the primary outcome measure and in-hospital mortality the secondary outcome measure. RESULTS: Data for 227,170 patients admitted to hospital with HF (median age: 81 years; IQR: 72-88 years), were analyzed. Approximately 80% of acute HF admissions received support from HF specialists. Thirty-nine percent of patients (n = 70,720) were seen by a multidisciplinary team (HF physicians and HF specialist nurses [HFSNd]), 22% (n = 40,330) were seen by HFSNs alone, and the remaining 39% (n = 71,700) were seen exclusively by specialist HF physicians. At discharge, more patients who received HF specialist care were prescribed medical therapy for HF and had specialized follow-up. Conversely, diuretic agents were prescribed to fewer patients. HF specialist care was independently associated with a higher rate of prescribing HF therapies at discharge and a lower likelihood of receiving diuretic therapy (OR: 0.90 [95% CI: 0.86-0.95]; P < 0.001). HF specialist care was associated with better long-term survival (HR: 0.89 [95% CI: 0.87-0.90]; P < 0.001) and lower in-hospital mortality (OR: 0.92 [95% CI: 0.0.88-0.97]; P < 0.001). CONCLUSIONS: Receiving HF specialist care during admission for HF is associated with a higher rate of implementation of medical therapy, fewer discharges on diuretic therapy, and lower in-hospital and long-term mortality across the left ventricular ejection fraction spectrum, especially for patients with heart failure with reduced ejection fraction.

Heart rate reactivity, recovery, and endurance of the incremental shuttle walk test in patients prone to heart failure.

AIMS: Few randomized trials assessed the changes over time in the chronotropic heart rate (HR) reactivity (CHR), HR recovery (HRR) and exercise endurance (EE) in response to the incremental shuttle walk test (ISWT). We addressed this issue by analysing the open HOMAGE (Heart OMics in Aging) trial. METHODS: In HOMAGE, 527 patients prone to heart failure were randomized to usual treatment with or without spironolactone (25-50 mg/day). The current sub-study included 113 controls and 114 patients assigned spironolactone (~70% on beta-blockers), who all completed the ISWT at baseline and at Months 1 and 9. Within-group changes over time (follow-up minus baseline) and between-group differences at each time point (spironolactone minus control) were analysed by repeated measures ANOVA, unadjusted or adjusted for sex, age and body mass index, and additionally for baseline for testing 1 and 9 month data. RESULTS: Irrespective of randomization, the resting HR and CHR did not change from baseline to follow-up, with the exception of a small decrease in the HR immediately post-exercise (-3.11 b.p.m.) in controls at Month 9. In within-group analyses, HR decline over the 5 min post-exercise followed a slightly lower course at the 1 month visit in controls and at the 9 month visits in both groups, but not at the 1 month visit in the spironolactone group. Compared with baseline, EE increased by two to three shuttles at Months 1 and 9 in the spironolactone group but remained unchanged in the control group. In the between-group analyses, irrespective of adjustment, there were no HR differences at any time point from rest up to 5 min post-exercise or in EE. Subgroup analyses by sex or categorized by the medians of age, left ventricular ejection fraction or glomerular filtration rate were confirmatory. Combining baseline and Months 1 and 9 data in both treatment groups, the resting HR, CHR and HRR at 1 and 5 min averaged 61.5, 20.0, 9.07 and 13.8 b.p.m. and EE 48.3 shuttles. CONCLUSIONS: Spironolactone on top of usual treatment compared with usual treatment alone did not change resting HR, CHR, HRR and EE in response to ISWT. Beta-blockade might have concealed the effects of spironolactone. The current findings demonstrate that the ISWT, already used in a wide variety of pathological conditions, is a practical instrument to measure symptom-limited exercise capacity in patients prone to developing heart failure because of coronary heart disease.

A nationwide, population-based study on specialized care for acute heart failure throughout the COVID-19 pandemic.

AIMS: The COVID-19 pandemic disrupted the delivery of care for patients with heart failure (HF), leading to fewer HF hospitalizations and increased mortality. However, nationwide data on quality of care and long-term outcomes across the pandemic are scarce. METHODS AND RESULTS: We used data from the National Heart Failure Audit (NHFA) linked to national records for hospitalization and deaths. We compared pre-COVID (2018-2019), COVID (2020), and late/post-COVID (2021-2022) periods. Data for 227 250 patients admitted to hospital with HF were analysed and grouped according to the admission year and the presence of HF with (HFrEF) or without reduced ejection fraction (non-HFrEF). The median age at admission was 81 years (interquartile range 72-88), 55% were men (n = 125 975), 87% were of white ethnicity (n = 102 805), and 51% had HFrEF (n = 116 990). In-hospital management and specialized cardiology care were maintained throughout the pandemic with an increasing percentage of patients discharged on disease-modifying medications over time (p < 0.001). Long-term outcomes improved over time (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.90-0.95, p < 0.001), mainly driven by a reduction in cardiovascular death. Receiving specialized cardiology care was associated with better long-term outcomes both for those who had HFrEF (HR 0.79, 95% CI 0.77-0.82, p < 0.001) and for those who had non-HFrEF (HR 0.87, 95% CI 0.85-0.90, p < 0.001). CONCLUSIONS: Despite the disruption of healthcare systems, the clinical characteristics of patients admitted with HF were similar and the overall standard of care was maintained throughout the pandemic. Long-term survival of patients hospitalized with HF continued to improve after COVID-19, especially for HFrEF.

Urinary proteomic signature of mineralocorticoid receptor antagonism by spironolactone: evidence from the HOMAGE trial.

OBJECTIVE: Heart failure (HF) is characterised by collagen deposition. Urinary proteomic profiling (UPP) followed by peptide sequencing identifies parental proteins, for over 70% derived from collagens. This study aimed to refine understanding of the antifibrotic action of spironolactone. METHODS: In this substudy (n=290) to the Heart 'Omics' in Ageing Study trial, patients were randomised to usual therapy combined or not with spironolactone 25-50 mg/day and followed for 9 months. The analysis included 1498 sequenced urinary peptides detectable in ≥30% of patients and carboxyterminal propeptide of procollagen I (PICP) and PICP/carboxyterminal telopeptide of collagen I (CITP) as serum biomarkers of COL1A1 synthesis. After rank normalisation of biomarker distributions, between-group differences in their changes were assessed by multivariable-adjusted mixed model analysis of variance. Correlations between the changes in urinary peptides and in serum PICP and PICP/CITP were compared between groups using Fisher's Z transform. RESULTS: Multivariable-adjusted between-group differences in the urinary peptides with error 1 rate correction were limited to 27 collagen fragments, of which 16 were upregulated (7 COL1A1 fragments) on spironolactone and 11 downregulated (4 COL1A1 fragments). Over 9 months of follow-up, spironolactone decreased serum PICP from 81 (IQR 66-95) to 75 (61-90) µg/L and PICP/CITP from 22 (17-28) to 18 (13-26), whereas no changes occurred in the control group, resulting in a difference (spironolactone minus control) expressed in standardised units of -0.321 (95% CI 0.0007). Spironolactone did not affect the correlations between changes in urinary COL1A1 fragments and in PICP or the PICP/CITP ratio. CONCLUSIONS: Spironolactone decreased serum markers of collagen synthesis and predominantly downregulated urinary collagen-derived peptides, but upregulated others. The interpretation of these opposite UPP trends might be due to shrinking the body-wide pool of collagens, explaining downregulation, while some degree of collagen synthesis must be maintained to sustain vital organ functions, explaining upregulation. Combining urinary and serum fibrosis markers opens new avenues for the understanding of the action of antifibrotic drugs. TRIAL REGISTRATION NUMBER: NCT02556450.

Outcomes in patients treated with loop diuretics without a diagnosis of heart failure: a retrospective cohort study.

BACKGROUND: Loop diuretics are commonly prescribed in the community, not always to patients with a recorded diagnosis of heart failure (HF). The rate of HF events in patients prescribed loop diuretics without a diagnosis of HF is unknown. METHODS: This was a propensity-matched cohort study using data from the Clinical Practice Research Datalink, Hospital Episode Statistics and Office of National Statistics in the UK. Patients prescribed a loop diuretic without a diagnosis of HF (loop diuretic group) between 1 January 2010 and 31 December 2015 were compared with patients with HF (HF group)-analysis A, and patients with risk factors for HF (either ischaemic heart disease, or diabetes and hypertension-at-risk group)-analysis B. The primary endpoint was an HF event (a composite of presentation with HF symptoms, HF hospitalisation, HF diagnosis (analysis B only) and all-cause mortality). RESULTS: From a total population of 180 384 patients (78 968 in the loop diuretic group, 28 177 in the HF group and 73 239 in the at-risk group), there were 59 694 patients, 22 352 patients and 57 219 patients in the loop diuretic, HF and at-risk groups, respectively, after exclusion criteria were applied. After propensity matching for age, sex and comorbidities, patients in the loop diuretic group had a similar rate of HF events as those in the HF group (71.9% vs 72.1%; HR=0.92 (95% CI 0.90 to 0.94); p<0.001), and twice as those in the at-risk group (59.2% vs 35.7%; HR=2.04 (95% CI 2.00 to 2.08); p<0.001). CONCLUSIONS: Patients prescribed a loop diuretic without a recorded diagnosis of HF experience HF events at a rate comparable with that of patients with a recorded diagnosis of HF; many of these patients may have undiagnosed HF.

Proteomic profiles of left atrial volume and its influence on response to spironolactone: Findings from the HOMAGE trial and STANISLAS cohort.

AIMS: High left ventricular filling pressure increases left atrial volume and causes myocardial fibrosis, which may decrease with spironolactone. We studied clinical and proteomic characteristics associated with left atrial volume indexed by body surface area (LAVi), and whether LAVi influences the response to spironolactone on biomarker expression and clinical variables. METHODS AND RESULTS: In the HOMAGE trial, where people at risk of heart failure were randomized to spironolactone or control, we analysed 421 participants with available LAVi and 276 proteomic measurements (Olink) at baseline, month 1 and 9 (mean age 73 ± 6 years; women 26%; LAVi 32 ± 9 ml/m2). Circulating proteins associated with LAVi were also assessed in asymptomatic individuals from a population-based cohort (STANISLAS; n = 1640; mean age 49 ± 14 years; women 51%; LAVi 23 ± 7 ml/m2). In both studies, greater LAVi was significantly associated with greater left ventricular masses and volumes. In HOMAGE, after adjustment and correction for multiple testing, greater LAVi was associated with higher concentrations of matrix metallopeptidase-2 (MMP-2), insulin-like growth factor binding protein-2 (IGFBP-2) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (false discovery rates [FDR] <0.05). These associations were externally replicated in STANISLAS (all FDR <0.05). Among these biomarkers, spironolactone decreased concentrations of MMP-2 and NT-proBNP, regardless of baseline LAVi (pinteraction > 0.10). Spironolactone also significantly reduced LAVi, improved left ventricular ejection fraction, lowered E/e', blood pressure and serum procollagen type I C-terminal propeptide (PICP) concentration, a collagen synthesis marker, regardless of baseline LAVi (pinteraction > 0.10). CONCLUSION: In individuals without heart failure, LAVi was associated with MMP-2, IGFBP-2 and NT-proBNP. Spironolactone reduced these biomarker concentrations as well as LAVi and PICP, irrespective of left atrial size.

Intravenous iron for heart failure, iron deficiency definitions, and clinical response: the IRONMAN trial.

BACKGROUND AND AIMS: What is the relationship between blood tests for iron deficiency, including anaemia, and the response to intravenous iron in patients with heart failure? METHODS: In the IRONMAN trial, 1137 patients with heart failure, ejection fraction ≤ 45%, and either serum ferritin < 100 µg/L or transferrin saturation (TSAT) < 20% were randomized to intravenous ferric derisomaltose (FDI) or usual care. Relationships were investigated between baseline anaemia severity, ferritin and TSAT, to changes in haemoglobin from baseline to 4 months, Minnesota Living with Heart Failure (MLwHF) score and 6-minute walk distance achieved at 4 months, and clinical events, including heart failure hospitalization (recurrent) or cardiovascular death. RESULTS: The rise in haemoglobin after administering FDI, adjusted for usual care, was greater for lower baseline TSAT (Pinteraction < .0001) and ferritin (Pinteraction = .028) and more severe anaemia (Pinteraction = .014). MLwHF scores at 4 months were somewhat lower (better) with FDI for more anaemic patients (overall Pinteraction = .14; physical Pinteraction = .085; emotional Pinteraction = .043) but were not related to baseline TSAT or ferritin. Blood tests did not predict difference in achieved walking distance for those randomized to FDI compared to control. The absence of anaemia or a TSAT ≥ 20% was associated with lower event rates and little evidence of benefit from FDI. More severe anaemia or TSAT < 20%, especially when ferritin was ≥100 µg/L, was associated with higher event rates and greater absolute reductions in events with FDI, albeit not statistically significant. CONCLUSIONS: This hypothesis-generating analysis suggests that anaemia or TSAT < 20% with ferritin > 100 µg/L might identify patients with heart failure who obtain greater benefit from intravenous iron. This interpretation requires confirmation.

Diuretic Treatment in Patients with Heart Failure: Current Evidence and Future Directions - Part I: Loop Diuretics.

PURPOSE OF REVIEW: Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF). Despite advances in disease-modifying therapy, the mainstay of treatment for congestion-loop diuretics-has remained largely unchanged for 50 years. In these two articles (part I: loop diuretics and part II: combination therapy), we will review the history of diuretic treatment and the current trial evidence for different diuretic strategies and explore potential future directions of research. RECENT FINDINGS: We will assess recent trials including DOSE, TRANSFORM, ADVOR, CLOROTIC, OSPREY-AHF, and PUSH-AHF amongst others, and assess how these may influence current practice and future research. There are few data on which to base diuretic therapy in clinical practice. The most robust evidence is for high dose loop diuretic treatment over low-dose treatment for patients admitted to hospital with HF, yet this is not reflected in guidelines. There is an urgent need for more and better research on different diuretic strategies in patients with HF.

Medicines optimization prior to discharge in patients admitted to hospital with heart failure.

AIMS: Approximately half of patients with heart failure and a reduced ejection fraction (HeFREF) are discharged from hospital on triple therapy [angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs), beta-blockers (BBs), and mineralocorticoid receptor antagonists (MRAs)]. We investigated what proportion of patients are on optimal doses prior to discharge and how many might be eligible for initiation of sacubitril-valsartan or sodium-glucose co-transporter-2 inhibitors (SGLT2Is). METHODS AND RESULTS: Between 2012 and 2017, 1277 patients admitted with suspected heart failure were enrolled at a single hospital serving a local community around Kingston upon Hull, UK. Eligibility for sacubitril-valsartan or SGLT2I was based on entry criteria for the PIONEER-HF, DAPA-HF, and EMPEROR-Reduced trials. Four hundred fifty-five patients had HeFREF with complete data on renal function, heart rate, and systolic blood pressure (SBP) prior to discharge. Eighty-three per cent of patients were taking an ACE-I or ARB, 85% a BB, and 63% an MRA at discharge. More than 60% of patients were eligible for sacubitril-valsartan and >70% for SGLT2I. Among those not already receiving a prescription, 37%, 28%, and 49% were eligible to start ACE-I or ARB, BB, and MRA, respectively. Low SBP (≤105 mmHg) was the most frequent explanation for failure to initiate or up-titrate therapy. CONCLUSIONS: Most patients admitted for heart failure are eligible for initiation of life-prolonging medications prior to discharge. A hospital admission may be a common missed opportunity to improve treatment for patients with HeFREF.

Hospital admissions in the last year of life of patients with heart failure.

AIM: To explore the frequency, causes, and pattern of hospitalisation for patients with chronic heart failure (HF) in the 12 months preceding death. We also investigated cause of death. METHODS: Patients referred to a secondary care HF clinic were routinely consented for follow-up between 2001 and 2020 and classified into three phenotypes: (i) HF with reduced ejection fraction (HFrEF), (ii) HF with preserved ejection fraction (HFpEF) with plasma N-terminal pro B-type natriuretic peptide (NT-proBNP) 125-399 ng L-1, and (iii) HFpEF with NT-proBNP ≥400 ng L-1. Hospital admissions in the last year of life were classified as: HF, other cardiovascular (CV), or non-cardiovascular (non-CV). The cause of death was systematically adjudicated. RESULTS: A total of 4925 patients (38% women; median age at death 81 [75-87] years) had 9127 hospitalisations in the last year of life. The median number of hospitalisations was 2 (1-3) and total days spent in hospital was 12 (2-25). Out of the total, 83% of patients had ≥1 hospitalisation but only 20% had ≥1 HF hospitalisation; 24% had ≥1 CV hospitalisation; 70% had ≥1 non-CV hospitalisation. Heart failure hospitalisations were most common in patients with HFrEF, but in all groups, at least two thirds of admissions were for non-CV causes. There were 788 (16%) deaths due to progressive HF, of which 74% occurred in hospital. CONCLUSION: For patients with chronic HF in the last year of life, most hospitalisations were for non-CV causes regardless of HF phenotype. Most patients had no HF hospitalisations in their last year of life. Most deaths were from causes other than progressive HF.

A novel, small-volume subcutaneous furosemide formulation delivered by an abdominal patch infusor device in patients with heart failure: results of two phase I studies.

AIMS: Subcutaneous (SC) furosemide has potential advantages over intravenous (IV) furosemide by enabling self-administration or administration by a lay caregiver, such as facilitating early discharge, preventing hospitalizations, and in palliative care. A high-concentration, pH-neutral furosemide formulation has been developed for SC administration via a small patch infusor pump. We aimed to compare the bioavailability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of a new SC furosemide formulation with conventional IV furosemide and describe the first use of a bespoke mini-pump to administer this formulation. METHODS AND RESULTS: A novel pH-neutral formulation of SC furosemide containing 80 mg furosemide in ∼2.7 mL (infused over 5 h) was investigated. The first study was a PK/PD study of SC furosemide compared with 80 mg IV furosemide administered as a bolus in ambulatory patients with heart failure (HF). The primary outcome was absolute bioavailability of SC compared with IV furosemide. The second study investigated the same SC furosemide preparation delivered by a patch infusor in patients hospitalized with HF. Primary outcome measures were treatment-emergent adverse events, infusion site pain, device performance, and PK measurements.The absolute bioavailability of SC furosemide in comparison to IV furosemide was 112%, resulting in equivalent diuresis and natriuresis. When SC furosemide was administered via the patch pump, there were no treatment-emergent adverse events and 95% of participants reported no/minor discomfort at the infusion site. CONCLUSION: The novel preparation of SC furosemide had similar bioavailability to IV furosemide. Administration via a patch pump was feasible and well tolerated.

Phenotyping patients with ischaemic heart disease at risk of developing heart failure: an analysis of the HOMAGE trial.

AIMS: We aim to characterize the clinical and proteomic profiles of patients at risk of developing heart failure (HF), with and without coronary artery disease (CAD) or prior myocardial infarction (MI). METHODS AND RESULTS: HOMAGE evaluated the effect of spironolactone on plasma and serum markers of fibrosis over 9 months of follow-up in participants with (or at risk of having) CAD, and raised natriuretic peptides. In this post hoc analysis, patients were classified as (i) neither CAD nor MI; (ii) CAD; or (iii) MI. Proteomic between-group differences were evaluated through logistic regression and narrowed using backward stepwise selection and bootstrapping. Among the 527 participants, 28% had neither CAD or MI, 31% had CAD, and 41% had prior MI. Compared with people with neither CAD nor MI, those with CAD had higher baseline plasma concentrations of matrix metalloproteinase-7 (MMP-7), galectin-4 (GAL4), plasminogen activator inhibitor 1 (PAI-1), and lower plasma peptidoglycan recognition protein 1 (PGLYRP1), whilst those with a history of MI had higher plasma MMP-7, neurotrophin-3 (NT3), pulmonary surfactant-associated protein D (PSPD), and lower plasma tumour necrosis factor-related activation-induced cytokine (TRANCE). Proteomic signatures were similar for patients with CAD or prior MI. Treatment with spironolactone was associated with an increase of MMP7, NT3, and PGLYRP1 at 9 months. CONCLUSIONS: In patients at risk of developing HF, those with CAD or MI had a different proteomic profile regarding inflammatory, immunological, and collagen catabolic processes.

Prognosis and Personalized In Silico Prediction of Treatment Efficacy in Cardiovascular and Chronic Kidney Disease: A Proof-of-Concept Study.

(1) Background: Kidney and cardiovascular diseases are responsible for a large fraction of population morbidity and mortality. Early, targeted, personalized intervention represents the ideal approach to cope with this challenge. Proteomic/peptidomic changes are largely responsible for the onset and progression of these diseases and should hold information about the optimal means of treatment and prevention. (2) Methods: We investigated the prediction of renal or cardiovascular events using previously defined urinary peptidomic classifiers CKD273, HF2, and CAD160 in a cohort of 5585 subjects, in a retrospective study. (3) Results: We have demonstrated a highly significant prediction of events, with an HR of 2.59, 1.71, and 4.12 for HF, CAD, and CKD, respectively. We applied in silico treatment, implementing on each patient's urinary profile changes to the classifiers corresponding to exactly defined peptide abundance changes, following commonly used interventions (MRA, SGLT2i, DPP4i, ARB, GLP1RA, olive oil, and exercise), as defined in previous studies. Applying the proteomic classifiers after the in silico treatment indicated the individual benefits of specific interventions on a personalized level. (4) Conclusions: The in silico evaluation may provide information on the future impact of specific drugs and interventions on endpoints, opening the door to a precision-based medicine approach. An investigation into the extent of the benefit of this approach in a prospective clinical trial is warranted.

Glycaemic control and insulin therapy are significant confounders of the obesity paradox in patients with heart failure and diabetes mellitus.

BACKGROUND: A high body mass index (BMI) confers a paradoxical survival benefit in patients with heart failure (HF) or diabetes mellitus (DM). There is, however, controversy whether an obesity paradox is also present in patients with HF and concomitant DM. In addition, the influence of glycaemic control and diabetes treatment on the presence or absence of the obesity paradox in patients with HF and DM is unknown. METHODS: We identified 2936 patients with HF with reduced ejection fraction (HFrEF) in the HF registries of the universities of Heidelberg, Germany, and Hull, UK (general sample). Of these, 598 (20%) were treated for concomitant DM (DM subgroup). The relationship between BMI and all-cause mortality was analysed in both the general sample and the DM subgroup. Patients with concomitant DM were stratified according to HbA1c levels or type of diabetes treatment and analyses were repeated. RESULTS: We found an inverse BMI-mortality relationship in both the general sample and the DM subgroup. However, the obesity paradox was less pronounced in patients with diabetes treated with insulin and it disappeared in those with poor glycaemic control as defined by HbA1c levels > 7.5%. CONCLUSION: In patients with HFrEF, a higher BMI is associated with better survival irrespective of concomitant DM. However, insulin treatment and poor glycaemic control make the relationship much weaker.

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

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.

Dapagliflozin vs. metolazone in heart failure resistant to loop diuretics.

BACKGROUND AND AIMS: To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients hospitalized for heart failure and resistant to treatment with intravenous furosemide. METHODS AND RESULTS: A multi-centre, open-label, randomized, and active-comparator trial. Patients were randomized to dapagliflozin 10 mg once daily or metolazone 5-10 mg once daily for a 3-day treatment period, with follow-up for primary and secondary endpoints until day 5 (96 h). The primary endpoint was a diuretic effect, assessed by change in weight (kg). Secondary endpoints included a change in pulmonary congestion (lung ultrasound), loop diuretic efficiency (weight change per 40 mg of furosemide), and a volume assessment score. 61 patients were randomized. The mean (±standard deviation) cumulative dose of furosemide at 96 h was 977 (±492) mg in the dapagliflozin group and 704 (±428) mg in patients assigned to metolazone. The mean (±standard deviation) decrease in weight at 96 h was 3.0 (2.5) kg with dapagliflozin compared to 3.6 (2.0) kg with metolazone [mean difference 0.65, 95% confidence interval (CI) -0.12,1.41 kg; P = 0.11]. Loop diuretic efficiency was less with dapagliflozin than with metolazone [mean 0.15 (0.12) vs. 0.25 (0.19); difference -0.08, 95% CI -0.17,0.01 kg; P = 0.10]. Changes in pulmonary congestion and volume assessment score were similar between treatments. Decreases in plasma sodium and potassium and increases in urea and creatinine were smaller with dapagliflozin than with metolazone. Serious adverse events were similar between treatments. CONCLUSION: In patients with heart failure and loop diuretic resistance, dapagliflozin was not more effective at relieving congestion than metolazone. Patients assigned to dapagliflozin received a larger cumulative dose of furosemide but experienced less biochemical upset than those assigned to metolazone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04860011.