Established Heart Failure Research Articles

Soluble Receptor for Advanced Glycation End Products (sRAGE) Is a Sensitive Biomarker in Human Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive condition with an unmet need for early diagnosis, better monitoring, and risk stratification. The receptor for advanced glycation end products (RAGE) is activated in response to hypoxia and vascular injury, and is associated with inflammation, cell proliferation and migration in PAH. For the adult cohort, we recruited 120 patients with PAH, 83 with idiopathic PAH (IPAH) and 37 with connective tissue disease-associated PAH (CTD-PAH), and 48 controls, and determined potential plasma biomarkers by enzyme-linked immunoassay. The established heart failure marker NTproBNP and IL-6 plasma levels were several-fold higher in both adult IPAH and CTD-PAH patients versus controls. Plasma soluble RAGE (sRAGE) was elevated in IPAH patients (3044 ± 215.2 pg/mL) and was even higher in CTD-PAH patients (3332 ± 321.6 pg/mL) versus controls (1766 ± 121.9 pg/mL; p < 0.01). All three markers were increased in WHO functional class II+III PAH versus controls (p < 0.001). Receiver-operating characteristic analysis revealed that sRAGE has diagnostic accuracy comparable to prognostic NTproBNP, and even outperforms NTproBNP in the distinction of PAH FC I from controls. Lung tissue RAGE expression was increased in IPAH versus controls (mRNA) and was located predominantly in the PA intima, media, and inflammatory cells in the perivascular space (immunohistochemistry). In the pediatric cohort, plasma sRAGE concentrations were higher than in adults, but were similar in PH (n = 10) and non-PH controls (n = 10). Taken together, in the largest adult sRAGE PAH study to date, we identify plasma sRAGE as a sensitive and accurate PAH biomarker with better performance than NTproBNP in the distinction of mild PAH from controls.

Renal, Cardiac, and Autonomic Effects of Catheter-Based Renal Denervation in Ovine Heart Failure.

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Cardiac, renal, and metabolic effects of sodium-glucose co-transporter 2 inhibitors: a position paper from the European Society of Cardiology ad-hoc task force on sodium-glucose co-transporter 2 inhibitors.

In 2015, the first large-scale placebo-controlled trial designed to assess cardiovascular safety of glucose-lowering with sodium-glucose co-transporter 2 (SGLT2) inhibition in type 2 diabetes mellitus raised hypotheses that the class could favourably modify not only risk of atherosclerotic cardiovascular disease, but also hospitalization for heart failure, and the development or worsening of nephropathy. By the start of 2021, results from 10 large SGLT2 inhibitor placebo-controlled clinical outcome trials randomizing ∼71 000 individuals have confirmed that SGLT2 inhibitors can provide clinical benefits for each of these types of outcome in a range of different populations. The cardiovascular and renal benefits of SGLT2 inhibitors appear to be larger than their comparatively modest effect on glycaemic control or glycosuria alone would predict, with three trials recently reporting that clinical benefits extend to individuals without diabetes mellitus who are at risk due to established heart failure, or albuminuric chronic kidney disease. This European Society of Cardiology position paper summarizes reported results from these 10 large clinical outcome trials considering separately each of the different types of cardiorenal benefit, summarizes key molecular and pathophysiological mechanisms, and provides a synopsis of metabolic effects and safety. We also describe ongoing placebo-controlled trials among individuals with heart failure with preserved ejection fraction and among individuals with chronic kidney disease.

Pericardial Adipose Tissue Volume and Left Ventricular Assist Device-Associated Outcomes

Pericardial adipose tissue (PAT) is associated with adverse cardiovascular outcomes in those with and without established heart failure (HF). However, it is not known whether PAT is associated with adverse outcomes in patients with end-stage HF undergoing left ventricular assist device (LVAD) implantation. This study aimed to evaluate the associations between PAT and LVAD-associated outcomes. We retrospectively measured computed tomography-derived PAT volumes in 77 consecutive adults who had available chest CT imaging prior to HeartMate 3 LVAD surgery between October 2015 and March 2019 at Duke University Hospital. Study groups were divided into above-median (≥219 cm3) and below-median (<219 cm3) PAT volume. Those with above-median PAT had a higher proportion of atrial fibrillation, chronic kidney disease and ischemic cardiomyopathy. Groups with above-median vs below-median PAT had similar Kaplan-Meier incidence rates over 2 years for (1) composite all-cause mortality, redo-LVAD surgery and cardiac transplantation (35.9 vs 32.2%; log-rank P = 0.65) and (2) composite incident hospitalizations for HF, gastrointestinal bleeding, LVAD-related infection, and stroke (61.5 vs 60.5%; log-rank P = 0.67). In patients with end-stage HF undergoing LVAD therapy, PAT is not associated with worse 2-year LVAD-related outcomes. The significance of regional adiposity vs obesity in LVAD patients warrants further investigation.

Lockdown, slow down: impact of the COVID-19 pandemic on physical activity—an observational study

AimsIn response to the COVID-19 pandemic, the UK was placed under strict lockdown measures on 23 March 2020. The aim of this study was to quantify the effects on physical...

A Practical Guide for Cardiologists to the Pharmacological Treatment of Patients with Type 2 Diabetes and Cardiovascular Disease.

Patients with type 2 diabetes are at increased cardiovascular risk. Until recently, reductions in HbA1c and the use of specific glucose-lowering agents have not had a clear, reproducible benefit in reducing the incidence of cardiovascular disease. However, over the past 5 years, members of two categories of diabetes medications, sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, have been associated with improved rates of major adverse cardiovascular events when used in high-risk type 2 diabetes patients. Importantly, these effects are not necessarily linked to these agents’ effects on HbA1c. Sodium–glucose cotransporter 2 inhibitors have also been associated with reductions in heart failure hospitalization, a benefit that appears to extend to individuals without diabetes with established heart failure. Cardiovascular specialists should become familiar with these emerging data and be prepared to implement corresponding strategies in their practice to improve the cardiovascular outcomes of their patients. Recent clinical trial data and the changing landscape of corresponding professional guidelines are reviewed. Practical recommendations for safe prescribing of these anti-diabetes drugs are provided.

Ivabradine and Blood Pressure Reduction: Underlying Pleiotropic Mechanisms and Clinical Implications

Elevated heart rate (HR) is a well-recognized but somewhat neglected risk factor among the healthy population and various cardiovascular pathologies (1). High HR is fraught with a spate of detrimental cardiovascular consequences including immense myocardial oxygen demand in reduced diastolic perfusion time (2) and low, oscillatory vascular shear stress with high tensile stress triggering endothelial dysfunction (3). Although beta-blockers (BBs) are considered to be the cornerstone treatment of elevated HR in various cardiovascular pathologies, they are associated with negative inotropy, a number of side effects, and undesirable metabolic actions limiting their usage (4, 5). Thus, new approaches to HR reduction are being continuously sought out. The inhibition of the If current in the sinoatrial node (SAN) seems to offer a promising approach to the reduction of elevated HR. Indeed, the SAN's pacemaker cells are inherently capable of cyclic variations of the resting membrane potential necessary for spontaneous depolarization. The SAN's spontaneous slow diastolic depolarization is administered by a mixed sodium/potassium inward current, known as an If current, through the “funny” (f)-channel (6). Structurally, the f-channel belongs to hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels and is activated by both hyperpolarization in the diastolic voltage range and intracellular cyclic adenosine monophosphate (7). Ivabradine selectively inhibits the If current, thus reducing the steepness of SAN's diastolic depolarization, ensuing diastole prolongation without affecting action potential duration or inducing negative inotropy (7, 8). Several studies have assessed ivabradine's efficacy in clinical settings. In the SHIFT study, the investigation of 6,558 patients with systolic heart failure (HF) during a median 22.9 month follow-up period revealed that the addition of ivabradine to an established HF therapy significantly reduced the primary composite endpoint of hospital admission for worsening HF or cardiovascular death. Considering the results of the SHIFT study, ivabradine is recommended for patients with systolic HF and HR above 70 bpm despite an evidence-based optimal medical therapy (with or without BB) to reduce the composite endpoint of hospitalization and mortality (9, 10). The BEAUTIFUL study comprised 10,917 systolic HF patients with HR above 70 bpm suffering from stable coronary artery disease (CAD), and the primary endpoint was a composite of cardiovascular death and hospital admission for acute myocardial infarction or HF. Although neither the primary endpoint nor the cardiovascular death rate improved, ivabradine reduced the secondary endpoints of hospital admissions for myocardial infarction and coronary revascularization (11). However, in the SIGNIFY study involving 19,102 patients with stable CAD but without HF, ivabradine did not reduce the compound primary endpoint of cardiovascular death and myocardial infarction (12). Hypertension, however, is a substantially different condition, and data regarding ivabradine's effect on peripheral blood pressure (BP) in a hypertensive population are scanty. Yet ivabradine's interference with central BP (CBP) was indicated in several studies. Lopatin and Vitale (13) reviewed five studies analyzing ivabradine's effect on CBP in patients with CAD: two studies reported a neutral effect, while in two other studies and in one study, ivabradine decreased and increased CBP, respectively. In 12 normotensive patients with stable CAD and HR ≥ 70 bmp, a 3 week ivabradine treatment reduced brachial systolic and diastolic BP, while the HR reduction did not increase central aortic BP (14). Moreover, in patients with arterial hypertension and CAD treated with ivabradine, the increase in HR between resting conditions and early recovery post exercise showed a trend toward correlation with the radial augmentation index (15). Besides ivabradine's HR-reducing action, which is considered to be a principal mechanism of its benefit, ivabradine exerts a number of pleiotropic effects, some of which may partly be HR independent (16, 17) and some of which are still emerging.

Proteomic and Mechanistic Analysis of Spironolactone in Patients at Risk for HF

ObjectivesThis study sought to further understand the mechanisms underlying effect of spironolactone and assessed its impact on multiple plasma protein biomarkers and their respective underlying biologic pathways. BackgroundIn addition to their beneficial effects in established heart failure (HF), mineralocorticoid receptor antagonists may act upstream on mechanisms, preventing incident HF. In people at risk for developing HF, the HOMAGE (Heart OMics in AGEing) trial showed that spironolactone treatment could provide antifibrotic and antiremodeling effects, potentially slowing the progression to HF. MethodsBaseline, 1-month, and 9-month (or last visit) plasma samples of HOMAGE participants were measured for protein biomarkers (n = 276) by using Olink Proseek-Multiplex cardiovascular and inflammation panels (Olink, Uppsala, Sweden). The effect of spironolactone on biomarkers was assessed by analysis of covariance and explored by knowledge-based network analysis. ResultsA total of 527 participants were enrolled; 265 were randomized to spironolactone (25 to 50 mg/day) and 262 to standard care (“control”). The median (interquartile range) age was 73 years (69 to 79 years), and 26% were female. Spironolactone reduced biomarkers of collagen metabolism (e.g., COL1A1, MMP-2); brain natriuretic peptide; and biomarkers related to metabolic processes (e.g., PAPPA), inflammation, and thrombosis (e.g., IL17A, VEGF, and urokinase). Spironolactone increased biomarkers that reflect the blockade of the mineralocorticoid receptor (e.g., renin) and increased the levels of adipokines involved in the anti-inflammatory response (e.g., RARRES2) and biomarkers of hemostasis maintenance (e.g., tPA, UPAR), myelosuppressive activity (e.g., CCL16), insulin suppression (e.g., RETN), and inflammatory regulation (e.g., IL-12B). ConclusionsProteomic analyses suggest that spironolactone exerts pleiotropic effects including reduction in fibrosis, inflammation, thrombosis, congestion, and vascular function improvement, all of which may mediate cardiovascular protective effects, potentially slowing progression toward heart failure. (HOMAGE [Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure]; NCT02556450)

Transcatheter Aortic Valve Implantation During the COVID-19 Pandemic

Transcatheter aortic valve implantation (TAVI) outcomes during the coronavirus disease 2019 (COVID-19) pandemic have not been fully evaluated and some structural programs in the world have been suspended during this period. We sought to evaluate and compare clinical outcomes in patients undergoing TAVI in pandemic versus nonpandemic era. In a single center, we compared 198 TAVI patients performed during 2019 to 59 patients performed during the COVID-19 pandemic period (March 1st to June 30th, 2020). Primary outcome was procedural success according to VARC criteria and 30-day mortality rates. VARC-defined procedural success was high in both groups (93.3% vs 96.6%; p = 0.53). There were no differences in any vascular complications (26% vs 19%; p = 0.3), permanent pacemaker implantation (11.8% vs 15.3%; p = 0.63), and length of hospital stay (5.2 vs 4.2 days; p = 0.29). Thirty-day mortality was similar (3% vs 3.4%; p = 1.0). We had no documented COVID-19 disease in our patients during follow up. In conclusion, TAVI procedures can be performed effectively and safely during the COVID-9 pandemic, using a minimalist approach, early discharge, and by maintaining proper use of personal protective equipment.

Mechanistic Insight Into The Effect Of Spironolactone For Preventing Heart Failure: Proteomics And Knowledge-based Network Analysis From The Homage Trial

Background Further to their beneficial effects in established heart failure (HF), mineralocorticoid receptor antagonists may act upstream on mechanisms preventing incident HF. In people at risk for developing HF, the “Heart OMics in Aging” (HOMAGE) trial showed that spironolactone treatment could provide antifibrotic and anti-remodelling effects, potentially slowing the progression to HF. Aims To further understand the mechanisms underlying spironolactone effect, we assessed its impact on multiple plasma protein biomarkers and respective underlying biological pathways. Methods Baseline, 1-month and 9-months (or last visit), plasma samples of HOMAGE participants were measured for protein biomarkers (n=276) using Olink®Proseek-Multiplex cardiovascular and inflammation panels. Spironolactone effect on biomarkers was assessed by analysis of covariance (ANCOVA) and explored by knowledge-based network analysis. Results 527 participants were enrolled, 265 were randomized to spironolactone (25-50 mg/day) and 262 to standard care (“control”). The median (percentile25-75) age was 73 (69-79) years and 26% were female. Spironolactone reduced biomarkers of collagen metabolism (e.g., COL1A1, MMP2), BNP, biomarkers related to metabolic processes (e.g., PAPPA), inflammation and thrombosis (e.g., IL17A, VEGF and urokinase). Spironolactone increased biomarkers that reflect the blockade of the mineralocorticoid receptor (e.g., renin), increased the levels of adipokines involved in anti-inflammatory response (e.g., RARRES2), biomarkers of haemostasis maintenance (e.g., tPA, UPAR), myelosuppressive activity (e.g., CCL16), insulin suppression (e.g., RETN), and inflammatory regulation (e.g., IL12B). Conclusion Proteomic analyses suggest that spironolactone exerts pleiotropic effects including reduction in fibrosis, inflammation, thrombosis, congestion and vascular function improvement, all of which may mediate cardiovascular protective effects potentially slowing progression toward heart failure.

Design of a prospective patient-level pooled analysis of two parallel trials of empagliflozin in patients with established heart failure.

AimThe EMPEROR‐Reduced trial demonstrated that empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with a reduced ejection fraction, and the EMPEROR‐Preserved trial is currently evaluating the effect of the drug on the same endpoint in patients with an ejection fraction >40%. However, neither the trial was designed to have adequate statistical power to evaluate the effects of empagliflozin and dapagliflozin on major adverse renal outcomes or on mortality. Herein we describe the design of a prospective individual patient‐level pooled analysis of two large‐scale trials with empagliflozin (EMPEROR‐Reduced and EMPEROR‐Preserved) in patients with heart failure across the spectrum of ejection fraction.MethodsThe trials were carried out in parallel using the same administrative structure and committees, randomization procedure, schedule of study visits and adjudication criteria and similar groups of investigators and case report forms. The two component trials specified the same primary and key secondary endpoints and used an identical hierarchical testing procedure, which included a pooled analysis of the two trials as a key component of the hierarchy. Consequently, the pooled analysis has been prospectively assigned a false positive error rate, which is conditional on one or both trials first achieving success on their primary and one or both key secondary endpoints. The pooled analysis has its own statistical plan with its own endpoints, and this plan was finalized before either trial had begun recruitment of patients into either study. The primary endpoint of the pooled analysis is a composite of serious adverse renal outcomes, defined by chronic dialysis, renal transplantation and a profound or sustained decrease in glomerular filtration rate. All‐cause and cardiovascular mortality are specified as secondary endpoints.ConclusionThe planned pooled analysis has an unusually high degree of statistical rigour that will allow it to address important questions that cannot be fully addressed by the individual trials.

Abstract 15762: Intensive Weight Management Improves Functional Capacity in Heart Failure With Preserved Ejection Fraction

Background: Obesity is associated with incident heart failure (HF), particularly HF with preserved ejection fraction (HFpEF). Weight loss is difficult to achieve in patients with limited physical capacity and the benefits remain uncertain in established HF. Methods: Patients with EF &gt; 50% and at least 1 objective criteria for HFpEF (BNP 200 pg/ml, elevated resting or exercise wedge pressure (15 or 25 mmHg) or pulmonary edema on CXR) and BMI 30 kg/m2 were enrolled in a 15-week weight management program that entailed weekly counseling, weight checks, and meal replacement (twice daily weeks 1-8, once daily weeks 9-12). Primary endpoints were change from baseline to 15-weeks for weight, Minnesota Living With HF (MLWHF) score and 6 minute walk (6MW). Paired t-test was used to test for differences from baseline to the 15 week clinical endpoint, and one-way ANOVA was used to evaluate if these differences persisted at 26 week follow up. Results: 65 patients signed consent, 41 completed the 15-week program and 37 had 26-week follow up. Mean age was 67±9 years, BMI 41±6 kg/m 2 , 65% were female, and 43% black. Mean weight decreased by 8.1±6.6 kg at the 15-week endpoint (p&lt;0.001) and persisted at 26-week follow up (p&lt;0.001). 74% of patients lost more than 5% of their baseline body weight at week 15. Blacks lost a mean of 6±6% body weight compared to 9±4% in Caucasians (p&lt;0.05). At 15 weeks, mean 6MW distance increased from 221±111 m to 286±99 m (p&lt;0.001) and then fell to 275±144 m at 26 weeks (p=0.043). MLWHF score improved from 60±24 to 38±27 (p&lt;0.001) and 38±26 (p&lt;0.001) at 15 and 26 weeks, respectively. BNP did not change (109 to 114 pg/ml). E/e’ decreased significantly from 13.9±6.8 to 11.9±5.6 at 26 weeks follow up (p&lt;0.01). BNP levels decreased by 39±103 pg/ml in blacks vs. an increase of 17±53 mg/dl in Caucasians (p&lt;0.05) at 15-week follow up. Conclusions: Clinically relevant weight loss is possible in patients with established HFpEF and when it occurs, this is associated with significant improvements in quality of life and exercise capacity. There may be racial differences in the biochemical response to weight management in this population.

Abstract 16640: Neutrophil Expansion is Essential for Adverse Left Ventricular Remodeling and Dysfunction in Chronic Ischemic Heart Failure

Chronic inflammation contributes significantly to disease progression in heart failure (HF), and is characterized by expansion of activated macrophages, dendritic cells, and T cells in the failing heart. Neutrophils play a well-known role as the initial drivers of inflammatory response to myocardial infarction (MI), thereby providing the platform for the subsequent recruitment of macrophages and T cells. However, whether and how neutrophils contribute to inflammation and adverse LV remodeling in chronic HF are unknown. We tested the hypothesis that activated neutrophils are required for tissue remodeling and disease progression in HF. Male C57Bl/6 mice were studied 4 and 8 weeks after left coronary artery ligation during established ischemic HF (sham-operated controls). As assessed by flow cytometry, CD11b + Ly6G + neutrophils were expanded in the peripheral blood (4 w post-MI), and in the bone marrow, spleen, and heart at 8 w post-MI. Immunostaining revealed that in the failing heart, neutrophils were primarily localized to the MI border zone, but also augmented in remote zone myocardium. CXCL1 and CXCL5 chemokine expression was increased in the failing heart, consistent with chemotactic signals for myocardial neutrophil recruitment. Isolated naïve neutrophils also exhibited increased chemotaxis in response to plasma from HF mice (versus plasma from naïve mice), as assessed by time-lapse video microscopy. Moreover, blood neutrophils isolated from HF mice exhibited significantly increased neutrophil extracellular trap (NET) production as compared to control neutrophils, whereas plasma NETs (histone-DNA complexes) were increased in HF mice. Finally, the in vivo role of neutrophils in chronic HF (8 w post-MI) was determined via depletion studies using genetic (Ly6G-diptheria toxin receptor mice) and antibody (1A8) based approaches. In both models, 2 and 4 w of neutrophil depletion, respectively, significantly improved LV systolic function and reduced end systolic volume. 1A8 treated HF mice also exhibited reduced remote zone fibrosis. We conclude: neutrophil expansion and activation are important components of the chronic inflammatory response in HF, and play an obligatory role in the progression of LV remodeling in ischemic cardiomyopathy.

Abstract 13921: Targeting Receptor-Interacting Protein 140 to Modulate Energy Metabolism in the Failing Heart

The nuclear receptors, peroxisome proliferator-activated receptors (PPARs), estrogen-related receptors (ERRs), and their co-regulator PPARγ coactivator-1α (PGC-1α), control postnatal cardiac mitochondrial biogenesis and energy metabolism. During the development of heart failure (HF), the activity of PGC-1/PPAR/ERR is reduced resulting in diminished capacity for fatty acid oxidation (FAO) and ATP production potentially contributing to an “energy-starved” state that contributes to progression of HF. Receptor-Interacting protein 140 (RIP140) serves as a co-repressor of PGC-1/PPAR/ERR in skeletal muscle and adipose tissue. We hypothesized that RIP140 represses cardiac energy metabolism in the normal and failing heart. Accordingly, we targeted Nrip1 (encoding RIP140) using a muscle creatinine kinase (MCK)-driven Cre recombinase to generate striated muscle-specific RIP140 knockout (msRIP140 KO) mice. msRIP140 KO mice appeared normal at baseline with no difference in survival or cardiac systolic function compared to littermate controls. RNA-sequence analysis demonstrated that the expression of genes involved in a wide array of mitochondrial energy metabolic pathways including FAO, tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and branched-chain amino acid (BCAA) degradation pathways were upregulated in msRIP140 KO ventricles, and in msRIP140 KO skeletal muscle. msRIP140 KO mice exhibited significantly less cardiac hypertrophy and diastolic dysfunction in response to chronic pressure overload. Next, cardiac-specific (cs) RIP140 KO mice were generated and subjected to transverse aortic constriction/apical myocardial infarction surgery (TAC/MI), an established HF model. csRIP140 KO mice exhibited less cardiac remodeling and systolic dysfunction compared to littermate controls, along with less downregulation of metabolic genes and induction of cardiac stress ( Nppa and Nppb ) and fibrosis response markers ( Tgfb2 and Col3a1 ). We conclude that RIP140 serves as a global co-repressor of cardiac energy metabolic genes in the adult heart and that modulation of RIP140 activity could prove to be a novel therapeutic approach for HF.

Abstract 196: Development and Validation of Machine Learning-based Race-specific Models to Predict 10-year Risk of Heart Failure: A Multi-cohort Analysis

Introduction: Heart failure (HF) risk and the underlying biological risk factors vary by race. Machine learning (ML) may improve race-specific HF risk prediction but this has not been fully evaluated. Methods: The study included participants from 4 cohorts (ARIC, DHS, JHS, and MESA) aged &gt; 40 years, free of baseline HF, and with adjudicated HF event follow-up. Black adults from JHS and white adults from ARIC were used to derive race-specific ML models to predict 10-year HF risk. The ML models were externally validated in subgroups of black and white adults from ARIC (excluding JHS participants) and pooled MESA/DHS cohorts and compared to prior established HF risk scores developed in ARIC and MESA. Harrell’s C-index and Greenwood-Nam-D’Agostino chi-square were used to assess discrimination and calibration, respectively. Results: In the derivation cohorts, 288 of 4141 (7.0%) black and 391 of 8242 (4.7%) white adults developed HF over 10 years. The ML models had excellent discrimination in both black and white participants (C-indices = 0.88 and 0.89). In the external validation cohorts for black participants from ARIC (excluding JHS, N = 1072) and MESA/DHS pooled cohorts (N = 2821), 131 (12.2%) and 115 (4.1%) developed HF. The ML model had adequate calibration and demonstrated superior discrimination compared to established HF risk models (Fig A). A consistent pattern was also observed in the external validation cohorts of white participants from the MESA/DHS pooled cohorts (N=3236; 100 [3.1%] HF events) (Fig A). The most important predictors of HF in both races were NP levels. Cardiac biomarkers and glycemic parameters were most important among blacks while LV hypertrophy and prevalent CVD and traditional CV risk factors were the strongest predictors among whites (Fig B). Conclusions: Race-specific and ML-based HF risk models that integrate clinical, laboratory, and biomarker data demonstrated superior performance when compared to traditional risk prediction models.

Cardio-Protective Effects of Sodium-Glucose Co-Transporter 2 Inhibitors: Focus on Heart Failure.

Type 2 diabetes mellitus (DM) is associated with a considerable risk of cardiovascular and renal diseases, including heart failure. Sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated unprecedented cardiorenal protective effects in large-scale clinical trials of patients with or without diabetes and either established cardiovascular disease (CV) or multiple CV risk factors. Herein we aim to focus on the role of SGLT2 inhibitors regarding the improvement in heart failure outcomes and the proposed mechanisms of action by which these drugs confer their beneficial effect. PubMed, Embase, and Google Scholar databases were searched to identify eligible articles that are comprehensively summarized and discussed in this study. The most commonly discussed mechanisms of action are diuresis and natriuresis, reduction in preload, afterload, and ventricular mass, as well as stimulation of erythropoietin production and improved myocardial energetics. SGLT2 inhibitors improve outcomes in patients with established heart failure (HF) and reduce the risk of death and HF admissions in patients with established chronic HF with reduced ejection fraction (HFrEF), either with or without diabetes. Potential key mechanisms that may explain the notable cardioprotective benefits of SGLT2 inhibitors have been outlined. These agents have recently received class Ia recommendation in specific groups of people with DM to lower the risk of hospitalization for HF and risk of death, while these benefits may also extend to people without diabetes. It remains to be seen whether they will also emerge as treatment approaches in the acute phase of CV episodes.

Cost-effectiveness of dapagliflozin in chronic heart failure: an analysis from the Australian healthcare perspective

Abstract Background The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial demonstrated that dapagliflozin reduced heart failure hospitalisations and mortality in patients with established heart failure, regardless of diabetic status. Purpose To assess the cost-effectiveness of dapagliflozin in addition to standard care versus standard care alone in patients with chronic heart failure, from the perspective of the Australian public healthcare system. Methods A Markov model populated with 1000 hypothetical individuals was constructed based on the DAPA-HF trial to assess the clinical outcomes and costs of patients with established heart failure and reduced ejection fraction over a lifetime time horizon. The model consisted of three health states: “Alive and event-free”, “Alive after non-fatal hospitalisation for heart failure” or “Dead”. Costs and utilities were estimated from published sources. Outcomes of interest were the incremental cost-effectiveness ratios (ICERs) in terms of cost per quality-adjusted life year (QALY) gained and cost per year of life saved (YoLS). All outcomes were discounted at a rate of 5% annually. Results Over a lifetime analysis, addition of dapagliflozin to standard care in patients with chronic heart failure prevented 88 acute heart failure hospitalisations (including readmission), and saved 416 (discounted) years of life and 288 (discounted) QALYs, at an additional cost of A$3,692,440 or €2,263,204 (discounted). This resulted in ICERs of A$8,875 (€5,439) per YoLS and A$12,482 (€7,650) per QALY gained, well below the Australian arbitrary willingness-to-pay threshold of A$50,000 (€30,645). Conclusion From the Australian public healthcare perspective, dapagliflozin is cost-effective when used as an adjunct therapy to standard care compared to standard care alone for the treatment of chronic heart failure with reduced ejection fraction. Funding Acknowledgement Type of funding source: None

Progressive left ventricular post-infarction remodelling: impact on outcome

Abstract Background While the presence left ventricular (LV) remodelling after ST-segment elevation myocardial infarction (STEMI) is known to worsen prognosis, the impact of progressive vs. stable LV remodelling on outcome has not been established. Purpose To investigate the impact of progressive LV remodelling on outcome in STEMI patients who were treated with primary percutaneous coronary intervention (PCI) and optimal pharmacotherapy. Methods Baseline, 3-, 6- and 12-month echocardiograms were analysed. Early LV remodelling (ER) was defined as a ≥20% increase in LV end-diastolic volume (EDV) during the first 3 months post-STEMI, and mid-term remodelling (MTR) as ≥20% LVEDV change by 6 months. Progressive LV remodelling was defined according to spline curve analyses: ≥0% LVEDV increase by 6 months (i.e. further increase after 3 months) for ER, and ≥20% by 12 months (i.e. an additional increase after 6 months) for MTR. The impact of progressive LV remodelling on outcome was evaluated with a Log rank test. Results 589 STEMI patients (mean age 61±12 years, 78% male) who demonstrated LV remodelling in the first 6 months post-infarct, were analysed: 408 (69%) ER and 181 (31%) MTR. Progressive LV remodelling occurred in 146 (36%) ER and in 12 (7%) MTR. After a median follow-up of 90 (IQR 64–117) months, 39 (10%) ER were hospitalised for heart failure. 25 (14%) MTR remodellers died after a median follow-up of 86 (IQR 66–112) months. Progressive LV remodelling in ER led to a higher rate of heart failure hospitalisation (P=0.017 vs. non-progressive ER, Fig. 1A) but no mortality difference (P=0.10 vs. non-progressive ER). In contrast, MTR with progressive LV remodelling experienced worse survival (P=0.01 vs. non-progressive MTR, Fig. 1B) but no increase in heart failure hospitalisation (P=0.65 vs. non-progressive MTR). Conclusions Progressive LV remodelling causes an increased risk of heart failure in ER post-infarct, vs. higher mortality in MTR. These two patterns of progressive, post-infarct LV remodelling possibly represent different underlying pathophysiological mechanisms: i.e. evolution of true post-infarct remodelling in ER, vs. natural history of established heart failure in MTR. Figure 1 Funding Acknowledgement Type of funding source: None

Recurrent Admissions for Acute Decompensated Heart Failure Among Patients With and Without Peripheral Artery Disease: The ARIC Study.

BackgroundPeripheral artery disease (PAD) is both a common comorbidity and a contributing factor to heart failure. Whether PAD is associated with hospitalization for recurrent decompensation among patients with established heart failure is uncertain.Methods and ResultsSince 2005, the ARIC (Atherosclerosis Risk in Communities) study has conducted active surveillance of hospitalized acute decompensated heart failure (ADHF), with events verified by physician review. From 2005 to 2016, 1481 patients were hospitalized with ADHF and discharged alive (mean age, 78 years; 69% White). Of these, 207 (14%) had diagnosis of PAD. Those with PAD were more often men (55% versus 44%) and smokers (17% versus 8%), with a greater prevalence of coronary artery disease (72% versus 52%). Patients with PAD had an increased risk of at least 1 ADHF readmission, both within 30 days (11% versus 7%) and 1 year (39% versus 28%) of discharge from the index hospitalization. After adjustments, PAD was associated with twice the hazard of ADHF readmission within 30 days (HR, 2.02; 95% CI, 1.14–3.60) and a 60% higher hazard of ADHF readmission within 1 year (HR, 1.60; 95% CI, 1.25–2.05). The 1‐year hazard of ADHF readmission associated with PAD was stronger with heart failure with reduced ejection fraction (HR, 2.01; 95% CI, 1.29–3.13) than preserved ejection fraction (HR, 1.04; 95% CI, 0.69–1.56); P for interaction=0.05.ConclusionsPatients with ADHF and concomitant PAD have a higher likelihood of ADHF readmission. Strategies to prevent ADHF readmissions in this high‐risk group are warranted.

Endothelial dysfunction and the risk of heart failure in a community-based study: the Multi-Ethnic Study of Atherosclerosis.

AimsWe aimed to investigate the association between endothelial dysfunction, assessed by brachial flow‐mediated dilation (FMD), and the incidence of heart failure (HF) in the community‐based Multi‐Ethnic Study of Atherosclerosis.Methods and resultsBrachial artery FMD was measured in a nested case‐cohort sample including 3496 of 6814 Multi‐Ethnic Study of Atherosclerosis participants without prevalent cardiovascular disease (mean age 61 years, 50% women). Multivariable probability‐weighted Cox proportional hazards analysis was used to examine the association between FMD and incident HF. We also investigated the association between FMD and HF with reduced vs. preserved ejection fraction [HFrEF (left ventricular ejection fraction <45%) vs. HFpEF (left ventricular ejection fraction ≥45%)]. During follow‐up (median 12 years), 149 participants developed incident HF (incidence rate 3.7 events per 1000 person years). There were 56 HFrEF and 69 HFpEF events (incidence rates 1.4 and 1.7 events per 1000 person years, respectively). In multivariable models adjusted for established HF risk factors (age, sex, race/ethnicity, body mass index, systolic blood pressure, antihypertensive treatment, heart rate, diabetes mellitus, history of myocardial infarction, current smoker, and former smoker status), individuals in the highest quartile of FMD (reflecting better endothelial function) had a lower HF risk compared with individuals in the lowest quartile [hazard ratio 0.53, 95% confidence interval (CI) 0.31–0.95]. Lower risk according to higher FMD was particularly evident for HFrEF, but not for HFpEF (hazard ratio per standard deviation increase 0.79, 95% CI 0.64–0.97 vs. 0.99, 95% CI 0.78–1.26, respectively). Results remained similar after adjustment for baseline natriuretic peptide levels. The addition of FMD to established HF risk factors generally rendered no or only modest improvement in C‐statistics [C‐statistics for model with established HF risk factors: 0.774, and with the addition of FMD: 0.776 (delta C 0.002, 95% confidence interval −0.002 to 0.006)].ConclusionsEndothelial dysfunction was independently associated with HF in this community cohort, suggesting a pathophysiological contribution of endothelial function to the development of HF, in particular HFrEF. However, the value of FMD measurements for HF risk prediction seems limited.