Baseline characteristics of patients with heart failure with mildly reduced or preserved ejection fraction: The FINEARTS-HF trial.

AIMS: To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF. METHODS AND RESULTS: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials. CONCLUSIONS: FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population.

Optimising Transitional Care Following a Heart Failure Hospitalisation in Australia.

Hospitalisations for heart failure (HF) are associated with high rates of readmission and death, the most vulnerable period being within the first few weeks post-hospital discharge. Effective transition of care from hospital to community settings for patients with HF can help reduce readmission and mortality over the vulnerable period, and improve long-term outcomes for patients, their family or carers, and the healthcare system. Planning and communication underpin a seamless transition of care, by ensuring that the changes to patients' management initiated in hospital continue to be implemented following discharge and in the long term. This evidence-based guide, developed by a multidisciplinary group of Australian experts in HF, discusses best practice for achieving appropriate and effective transition of patients hospitalised with HF to community care in the Australian setting. It provides guidance on key factors to address before and after hospital discharge, as well as practical tools that can be used to facilitate a smooth transition of care.

Clinical to Population Prevalence of Hypertrophic Cardiomyopathy Phenotype: Insights From the National Echo Database Australia.

BACKGROUND: There is a paucity of data describing the underlying prevalence of hypertrophic cardiomyopathy (HCM), a primary genetic disorder characterised by progressive left ventricular (LV) hypertrophy and sudden death, from both a clinical and a population perspective. METHODS: We screened the echocardiographic reports of 155,668 men and 147,880 women within the multicentre National Echo Database Australia (NEDA) (2001-2019). End-diastolic wall thickness ≥15 mm anywhere in the left ventricle was identified as a characteristic of an HCM phenotype according to current guideline recommendations. Applying a septal-to-posterior wall thickness ratio >1.3 and LV outflow tract obstruction ≥30 mmHg (when documented), we further identified asymmetric septal hypertrophy and obstructive HCM (oHCM), respectively. The observed pattern of phenotypical HCM within the overall NEDA cohort (>650,000 cases) was then extrapolated to the ∼539,000 (5.7% of adult population) and ∼474,000 (4.8%) Australian men and women, respectively, who were investigated with echocardiography in 2021 on an age-specific basis. RESULTS: Overall, 15,380 cases (mean age 71.1±14.6 years, 10,138 men [65.9%]) with the characteristic HCM phenotype within the NEDA cohort were identified. Of these 15,380 cases, 5,552 (36.1%) had asymmetric septal hypertrophy, and 2,276 of the 10,290 cases with LV outflow tract obstruction profiling data (22.1%) had obstructive HCM. A further 3,389 of 13,715 cases (24.7%) had evidence of LV systolic dysfunction (LV ejection fraction <55%). Within the entire NEDA cohort (including those without LV profiling), HCM was found in 10,138 of 342,161 men (2.96%; 95% confidence interval [CI] 2.91%-3.02%) and 5,242 of 308,539 women (1.70%; 95% CI 1.65%-1.75%). When extrapolated to the Australian population, we estimate that a minimum of 15,971 men and 8,057 women presented with echocardiographic features of phenotypical HCM in 2021. This translates into a minimum caseload/prevalence of ∼17 adult men (∼2.5 in those aged ≤50 years) and eight adult women (∼1 in those aged ≤50 years) per 10,000 population meeting phenotypical HCM criteria. CONCLUSIONS: Using contemporary Australian echocardiographic and population data, we estimate that a minimum of 15,971 (17.5 cases/10,000) men and 8,057 women (8.2 cases/10,000) had echocardiographic evidence of phenotypical HCM in 2021. These disease burden data are particularly relevant as new treatment options are emerging.

Prognostic utility of serum NT-proBNP (fragments 1-76aa and 13-71aa) and galectin-3 in predicting death and re-hospitalisation due to cardiovascular events in patients with heart failure.

Patients with heart failure (HF) are at a higher risk of rehospitalisation. In this study, we investigated the prognostic utility of galectin-3 (Gal-3) and NT-proBNP fragments (1-76aa and 13-71aa) as biomarkers to predict outcomes for patients with HF. We collected blood samples from patients with HF (n = 101). Gal-3 and NT-proBNP fragments (1-76aa and 13-71aa) concentrations were measured by immunoassay. Survival analysis and Cox proportional regression models were used to determine the prognostic utility of Gal-3 and NT-proBNP fragments. In patients with increased baseline levels of NT-proBNP1-76 the time to primary endpoint (cardiovascular death or re-hospitalisation) was significantly shorter (p = 0.0058), but not in patient with increased baseline levels of Gal-3 or NTproBNP13-71. Patients with increased levels of NT-proBNP13-71aa at 1 month showed reduced time to the primary endpoint (p = 0.0123). Our findings demonstrated that Gal-3 and NT-proBNP can be used as prognostic biomarkers to stratify patients with HF.

Exaggerated myocardial torsion may contribute to dynamic left ventricular outflow tract obstruction in hypertrophic cardiomyopathy.

Aims: Dynamic left ventricular (LV) outflow tract obstruction (LVOTO) is associated with symptoms and increased risk of developing heart failure in hypertrophic cardiomyopathy (HCM). The association of LVOTO and LV twist mechanics has not been well studied in HCM. The aim of the study was to compare the pattern of LV twist in patients with HCM associated with asymmetrical septal hypertrophy with and without LVOTO. Methods and results: Echocardiography (including speckle tracking) was performed in 212 patients with HCM, divided according to the absence (n = 130) or presence (n = 82) of LVOTO (defined as peak pressure gradient ≥30 mmHg either at rest and/or with Valsalva manoeuvre). Patients with LVOTO were older, had smaller LV dimensions, a higher LV ejection fraction (LVEF), a longer anterior mitral valve leaflet length, and a higher early transmitral pulsed wave to septal tissue Doppler velocity ratio (E/E'). A univariate analysis showed that peak twist was significantly higher in patients with LVOTO compared with patients without LVOTO (19.7 ± 7.3 vs. 15.7 ± 6.0, P = 0.00015). Peak twist was similarly enhanced in patients with LVOTO, manifesting only during Valsalva (19.2 ± 5.6, P = 0.007) and patients with resting LVOTO (19.9 ± 8.0, P = 0.00004) compared with patients without LVOTO (15.7 ± 6.0). A stepwise forward logistic regression analysis showed that LVEF, LV end-systolic dimension indexed to body surface area, anterior mitral valve leaflet length, E/E', and peak twist were all independently associated with LVOTO. Conclusion: This study demonstrates that increased peak LV twist is independently associated with LVOTO in patients with HCM. Peak twist was similarly exaggerated in patients with only latent LVOTO, suggesting that it may play a contributory role to LVOTO in HCM.

Primary care Adherence To Heart Failure guidelines IN Diagnosis, Evaluation and Routine management (PATHFINDER): a randomised controlled trial protocol.

INTRODUCTION: General practitioners (GPs) routinely provide care for patients with heart failure (HF); however, adherence to management guidelines, including titrating medication to optimal dose, can be challenging in this setting. This study will evaluate the effectiveness of a multifaceted intervention to support adherence to HF management guidelines in primary care. METHODS AND ANALYSIS: We will undertake a multicentre, parallel-group, randomised controlled trial of 200 participants with HF with reduced ejection fraction. Participants will be recruited during a hospital admission due to HF. Following hospital discharge, the intervention group will have follow-up with their GP scheduled at 1 week, 4 weeks and 3 months with the provision of a medication titration plan approved by a specialist HF cardiologist. The control group will receive usual care. The primary endpoint, assessed at 6 months, will be the difference between groups in the proportion of participants being prescribed five guideline-recommended treatments; (1) ACE inhibitor/angiotensin receptor blocker/angiotensin receptor neprilysin inhibitor at least 50% of target dose, (2) beta-blocker at least 50% of target dose, (3) mineralocorticoid receptor antagonist at any dose, (4) anticoagulation for patients diagnosed with atrial fibrillation, (5) referral to cardiac rehabilitation. Secondary outcomes will include functional capacity (6-minute walk test); quality of life (Kansas City Cardiomyopathy Questionnaire); depressive symptoms (Patient Health Questionnaire-2); self-care behaviour (Self-Care of Heart Failure Index). Resource utilisation will also be assessed. ETHICS AND DISSEMINATION: Ethical approval was granted by the South Metropolitan Health Service Ethics Committee (RGS3531), with reciprocal approval at Curtin University (HRE2020-0322). Results will be disseminated via peer-reviewed publications and conferences. TRIAL REGISTRATION NUMBER: ACTRN12620001069943.

Urinary sodium concentration predicts time to major adverse coronary events and all-cause mortality in men with heart failure over a 28-33-year period: a prospective cohort study.

BACKGROUND: Lower urinary sodium concentrations (UNa) may be a biomarker for poor prognosis in chronic heart failure (HF). However, no data exist to determine its prognostic association over the long-term. We investigated whether UNa predicted major adverse coronary events (MACE) and all-cause mortality over 28-33 years. METHODS: One hundred and eighty men with chronic HF from the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) were included. Baseline data was collected between 1984 and 1989. MACE and all-cause outcomes were obtained using hospital linkage data (1984-2017) with a follow-up of 28-33 years. Cox proportional hazards models were generated using 24-h UNa tertiles at baseline (1 ≤ 173 mmol/day; 2 = 173-229 mmol/day; 3 = 230-491 mmol/day) as a predictor of time-to-MACE outcomes, adjusted for relevant covariates. RESULTS: Overall, 63% and 83% of participants (n = 114 and n = 150) had a MACE event (median 10 years) and all-cause mortality event (median 19 years), respectively. On multivariable Cox Model, relative to the lowest UNa tertile, no significant difference was noted in MACE outcome for individuals in tertiles 2 and 3 with events rates of 28% (HR:0.72; 95% CI: 0.46-1.12) and 21% (HR 0.79; 95% CI: 0.5-1.25) respectively.. Relative to the lowest UNa tertile, those in tertile 2 and 3 were 39% (HR: 0.61; 95% CIs: 0.41, 0.91) and 10% (HR: 0.90; 95% CIs: 0.62, 1.33) less likely to experience to experience all-cause mortality. The multivariable Cox model had acceptable prediction precision (Harrell's C concordance measure 0.72). CONCLUSION: UNa was a significant predictor of all-cause mortality but not MACE outcomes over 28-33 years with 173-229 mmol/day appearing to be the optimal level. UNa may represent an emerging long-term prognostic biomarker that warrants further investigation.

Sodium-glucose co-transporter 2 inhibitors beyond diabetes.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors lower blood glucose by reducing the reabsorption of glucose in the kidney. They are a second-line therapy for type 2 diabetes. During clinical trials it was noticed that SGLT2 inhibitors had favourable effects on cardiovascular and renal disease. This led to further trials that included patients without diabetes. In studies of heart failure, SGLT2 inhibitors were beneficial in treating patients with a reduced left ventricular ejection fraction. A recent study has also reported benefits in patients with a preserved ejection fraction. In chronic kidney disease, SGLT2 inhibitors may reduce disease progression. However, a decline in the glomerular filtration rate may be seen at the start of treatment. As most experience with SGLT2 inhibitors is in diabetes, patients without diabetes need to be aware of why they are being prescribed these drugs. Some of the potential indications for SGLT2 inhibitors beyond diabetes are not yet approved by regulatory authorities.

Consensus statement on the current pharmacological prevention and management of heart failure.

INTRODUCTION: This consensus statement of Australian clinicians provides new recommendations for the pharmacological management of heart failure based on studies reported since the publication of the 2018 Australian heart failure guidelines. MAIN RECOMMENDATIONS: ▪Use of sodium-glucose cotransporter 2 (SGLT2) inhibitors to prevent hospitalisation for heart failure in type 2 diabetes mellitus can be extended to patients with multiple cardiovascular risk factors, albuminuric chronic kidney disease, or atherosclerotic cardiovascular disease. ▪New evidence supports the use of a mineralocorticoid receptor antagonist (finerenone) to prevent heart failure in type 2 diabetes mellitus associated with albuminuric chronic kidney disease. ▪In addition to renin angiotensin system inhibitors (angiotensin receptor neprilysin inhibitor preferred), beta blockers and mineralocorticoid receptor antagonists, an SGLT2 inhibitor (dapagliflozin or empagliflozin) is recommended in all patients with heart failure with reduced left ventricular ejection fraction (LVEF ≤ 40%) (HFrEF). Lower quality evidence supports these therapies in patients with heart failure with mildly reduced LVEF (41-49%) (HFmrEF). ▪A soluble guanylate cyclase stimulator (vericiguat), selective cardiac myosin activator (omecamtiv mecarbil) and, if iron deficient, intravenous iron (ferric carboxymaltose) provide additional benefits in persistent HFrEF. ▪An SGLT2 inhibitor (empagliflozin) should be considered in patients with heart failure with preserved LVEF (≥ 50%) (HFpEF). Key changes in management from this statement: This document broadens the scope of angiotensin receptor neprilysin inhibitor use in patients with HFrEF and HFmrEF. SGLT2 inhibitor use expands to become a cornerstone therapy in HFrEF, with increasing evidence to support its use in HFmrEF and HFpEF.

The Use of Mobile Apps for Heart Failure Self-management: Systematic Review of Experimental and Qualitative Studies.

BACKGROUND: Heart failure self-management is essential to avoid decompensation and readmissions. Mobile apps seem promising in supporting heart failure self-management, and there has been a rapid growth in publications in this area. However, to date, systematic reviews have mostly focused on remote monitoring interventions using nonapp types of mobile technologies to transmit data to health care providers, rarely focusing on supporting patient self-management of heart failure. OBJECTIVE: This study aims to systematically review the evidence on the effect of heart failure self-management apps on health outcomes, patient-reported outcomes, and patient experience. METHODS: Four databases (PubMed, Embase, CINAHL, and PsycINFO) were searched for studies examining interventions that comprised a mobile app targeting heart failure self-management and reported any health-related outcomes or patient-reported outcomes or perspectives published from 2008 to December 2021. The studies were independently screened. The risk of bias was appraised using Cochrane tools. We performed a narrative synthesis of the results. The protocol was registered on PROSPERO (International Prospective Register of Systematic Reviews; CRD42020158041). RESULTS: A total of 28 articles (randomized controlled trials [RCTs]: n=10, 36%), assessing 23 apps, and a total of 1397 participants were included. The most common app features were weight monitoring (19/23, 83%), symptom monitoring (18/23, 78%), and vital sign monitoring (15/23, 65%). Only 26% (6/23) of the apps provided all guideline-defined core components of heart failure self-management programs: education, symptom monitoring, medication support, and physical activity support. RCTs were small, involving altogether 717 participants, had ≤6 months of follow-up, and outcomes were predominantly self-reported. Approximately 20% (2/10) of RCTs reported a significant improvement in their primary outcomes: heart failure knowledge (P=.002) and self-care (P=.004). One of the RCTs found a significant reduction in readmissions (P=.02), and 20% (2/10) of RCTs reported higher unplanned clinic visits. Other experimental studies also found significant improvements in knowledge, self-care, and readmissions, among others. Less than half of the studies involved patients and clinicians in the design of apps. Engagement with the intervention was poorly reported, with only 11% (3/28) of studies quantifying app engagement metrics such as frequency of use over the study duration. The most desirable app features were automated self-monitoring and feedback, personalization, communication with clinicians, and data sharing and integration. CONCLUSIONS: Mobile apps may improve heart failure self-management; however, more robust evaluation studies are needed to analyze key end points for heart failure. On the basis of the results of this review, we provide a road map for future studies in this area.

Composite Echocardiographic Score to Predict Long-Term Survival Following Myocardial Infarction.

BACKGROUND: Whilst the left ventricular ejection fraction (LVEF) remains the primary echocardiographic measure widely utilised for risk stratification following myocardial infarction (MI), it has a number of well recognised limitations. The aim of this study was to compare the prognostic utility of a composite echocardiographic score (EchoScore) composed of prognostically validated measures of left-ventricular (LV) size, geometry and function, to the utility of LVEF alone, for predicting survival following MI. METHODS: Retrospective data on 394 consecutive patients with a first-ever MI were included. Comprehensive echocardiography was performed within 24 hours of admission for all patients. EchoScore consisted of LVEF<50%, left atrial volume index>34 mL/m2, average E/e >14, E/A ratio>2, abnormal LV mass index, and abnormal LV end-systolic volume index. A single point was allocated for each measure to derive a score out of 6. The primary outcome measure was all-cause mortality. RESULTS: At a median follow-up of 24 months there were 33 deaths. On Kaplan-Meier analysis, a high EchoScore (>3) displayed significant association with all-cause mortality (log-rank χ2=74.48 p<0.001), and was a better predictor than LVEF<35% (log-rank χ2=17.01 p<0.001). On Cox proportional-hazards multivariate analysis incorporating significant clinical and echocardiographic predictors, a high EchoScore was the strongest independent predictor of all-cause mortality (HR 6.44 95%CI 2.94-14.01 p<0.001), and the addition of EchoScore resulted in greater increment in model power compared to addition of LVEF (model χ2 56.29 vs 44.71 p<0.001, Harrell's C values 0.83 vs 0.79). CONCLUSIONS: A composite echocardiographic score composed of prognostically validated measures of LV size, geometry, and function is superior to LVEF alone for predicting survival following MI.

Sodium-glucose cotransporter 2 inhibitor effects on heart failure hospitalization and cardiac function: systematic review.

AIMS: To systematically review randomized controlled trials assessing effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) on hospitalization for heart failure (HHF) and cardiac structure/function and explore randomized controlled trial (RCT)-derived evidence for SGLT2i efficacy mechanisms in heart failure (HF). METHODS AND RESULTS: Systematic searches of Medline and Embase were performed. In seven trials [3730-17 160 patients; low risk of bias (RoB)], SGLT2is significantly reduced the relative risk of HHF by 27-39% vs. placebo, including in two studies in patients with HF with reduced ejection fraction with or without type-2 diabetes mellitus (T2DM). Improvements in conventional cardiovascular risk factors, including glycaemic levels, cannot account for these effects. Five trials (56-105 patients; low RoB) assessed the effects of 6-12 months of SGLT2i treatment on left ventricular structure/function; four reported significant improvements vs. placebo, and one did not. Five trials (low RoB) assessed SGLT2i treatment effects on serum N-terminal pro B-type natriuretic peptide levels; significant reductions vs. placebo were reported after 8-12 months (two studies; 3730-4744 patients) but not ≤12 weeks (three studies; 80-263 patients). Limited available RCT-derived evidence suggests various possible cardioprotective SGLT2i mechanisms, including improved haemodynamics (natriuresis and reduced interstitial fluid without blood volume contraction/neurohormonal activation) and vascular function, enhanced erythropoiesis, reduced tissue sodium and epicardial fat/inflammation, decreased sympathetic tone, and beneficial changes in cellular energetics. CONCLUSIONS: Sodium-glucose cotransporter 2 inhibitors reduce HHF regardless of T2DM status, and reversal of adverse left ventricular remodelling likely contributes to this efficacy. Hypothesis-driven mechanistic trials remain sparse, although numerous trials are planned or ongoing.

Evolutionary dissection of mtDNA hg H: a susceptibility factor for hypertrophic cardiomyopathy.

Mitochondrial DNA (mtDNA) haplogroup (hg) H has been reported as a susceptibility factor for hypertrophic cardiomyopathy (HCM). This was established in genetic association studies, however, the SNP or SNP's that are associated with the increased risk have not been identified. Hg H is the most frequent European mtDNA hg with greater than 80 subhaplogroups (subhgs) each defined by specific SNPs. We tested the hypothesis that the distribution of H subhgs might differ between HCM patients and controls. The subhg H distribution in 55 HCM index cases was compared to that of two Danish mtDNA hg H control groups (n = 170 and n = 908, respectively). In the HCM group, H and 12 different H subhgs were found. All these, except subhgs H73, were also found in both control groups. The HCM group was also characterized by a higher proportion of H3 compared to H2. In the HCM group the H3/H2 proportion was 1.7, whereas it was 0.45 and 0.54 in the control groups. This tendency was replicated in an independent group of Hg H HCM index cases (n = 39) from Queensland, Australia, where the H3/H2 ratio was 1.5. In conclusion, the H subhgs distribution differs between HCM cases and controls, but the difference is subtle, and the understanding of the pathogenic significance is hampered by the lack of functional studies on the subhgs of H.

Determinants of Diastolic Dysfunction Following Myocardial Infarction: Evidence for Causation Beyond Infarct Size.

BACKGROUND: The determinants of severe diastolic dysfunction (DD) following myocardial infarction (MI) are not well defined. This study sought to define the determinants of severe DD (restrictive mitral inflow pattern on Doppler echocardiography [RFP]) in patients with a first-ever MI, with particular emphasis on the impact of infarct size. METHODS: Retrospective single-centre study including consecutive patients admitted to a tertiary referral centre with a first-ever non-ST-elevation-MI (NSTEMI) or ST-elevation-MI (STEMI) (n=477). Peak troponin-I (Peak-TnI) was used as the principal measure of infarct size, whilst left ventricular ejection fraction (LVEF) and wall motion score index (WMSI) were regarded as surrogate measures. Echocardiography was performed within 24 hours of admission for all patients. RFP was defined as E/A ratio >2.0 or E/A ratio >1.5 and E-wave deceleration time <140 ms. RESULTS: A total of 69 patients (14.5%) had RFP. Peak-TnI levels were higher in the RFP group (32.6±32.7 versus 16.9±25.2 µg/L, p<0.001). In sequential multivariable models incorporating significant clinical, angiographic and left ventricular (LV) size-related variables, Peak-TnI (OR 1.98, p=0.001), WMSI (OR 2.34, p=0.048) and LVEF (OR 0.97, p=0.044) were independent predictors of RFP. Presence of diabetes was also an independent predictor in all the models constructed. When patients were stratified according to an LVEF of 50%, 39% of RFP patients had a preserved LVEF (RFP/preserved EF group), and these patients had lower Peak-TnI levels compared to the RFP/reduced EF group (14.4±18.7 vs 44.5±35.5 µg/L). CONCLUSIONS: Whilst infarct size is a major determinant of severe diastolic dysfunction after MI, a significant subset of patients develop severe diastolic dysfunction despite a small infarct size and preserved LVEF, highlighting that other factors such as pre-existing diastolic dysfunction due to risk factors such as diabetes have an important role in causation.