Topic: Heart Failure

Abstract

Empagliflozin Improves Cardiovascular and Renal Outcomes in Heart Failure Irrespective of Systolic Blood Pressure.

Böhm M, Anker SD, Butler J, Filippatos G, ... Packer M, EMPEROR-Reduced Trial Committees and Investigators
Background
Empagliflozin reduces the risk of cardiovascular death or heart failure (HF) hospitalization in patients with reduced ejection fraction. Its interplay with systolic blood pressure (SBP) is not known.
Objectives
The goal of this study was to evaluate the interplay of SBP and the effects of empagliflozin in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction).
Methods
Study patients (N = 3,730) were randomly assigned to groups according to SBP at baseline (<110 mm Hg, n = 928; 110-130 mm Hg, n = 1,755; >130 mm Hg, n = 1,047). This study explored the influence of SBP on the effects of empagliflozin on cardiovascular death or HF hospitalization (primary outcome), as well as on total HF hospitalizations, rate of decline in estimated glomerular filtration rate, renal outcomes, and empagliflozin\'s effects and significance on SBP.
Results
Over a median of 16 months considering only patients receiving placebo, baseline SBP and the risk of cardiovascular death or hospitalization for HF (P trend = 0.0015) were inversely related. Corrected for placebo, a slight early increase was observed in SBP at <110 mm Hg, no change at 110-130 mm Hg, and a slight reduction at >130 mm Hg. These between-group differences were of borderline significance (P for interaction trend = 0.05-0.10) after 4 and 12 weeks but were not significant later. SBP at baseline did not influence the effect of empagliflozin to reduce the risk of HF events or renal endpoints. When treated with empagliflozin, patients with SBP <110 mm Hg did not have an increased rate of symptomatic hypotension.
Conclusions
Empagliflozin was effective and safe, with no meaningful interaction between SBP and the effects of empagliflozin in the EMPEROR-Reduced trial. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 27 Sep 2021; 78:1337-1348
Böhm M, Anker SD, Butler J, Filippatos G, ... Packer M, EMPEROR-Reduced Trial Committees and Investigators
J Am Coll Cardiol: 27 Sep 2021; 78:1337-1348 | PMID: 34556320
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Abstract

Myeloid-Derived Growth Factor Protects Against Pressure Overload-Induced Heart Failure by Preserving Sarco/Endoplasmic Reticulum Ca-ATPase Expression in Cardiomyocytes.

Korf-Klingebiel M, Reboll MR, Polten F, Weber N, ... Wang Y, Wollert KC
Background
Inflammation contributes to the pathogenesis of heart failure, but there is limited understanding of inflammation\'s potential benefits. Inflammatory cells secrete MYDGF (myeloid-derived growth factor) to promote tissue repair after acute myocardial infarction. We hypothesized that MYDGF has a role in cardiac adaptation to persistent pressure overload.
Methods
We defined the cellular sources and function of MYDGF in wild-type (WT), Mydgf-deficient (Mydgf-/-), and Mydgf bone marrow-chimeric or bone marrow-conditional transgenic mice with pressure overload-induced heart failure after transverse aortic constriction surgery. We measured MYDGF plasma concentrations by targeted liquid chromatography-mass spectrometry. We identified MYDGF signaling targets by phosphoproteomics and substrate-based kinase activity inference. We recorded Ca2+ transients and sarcomere contractions in isolated cardiomyocytes. Additionally, we explored the therapeutic potential of recombinant MYDGF.
Results
MYDGF protein abundance increased in the left ventricular myocardium and in blood plasma of pressure-overloaded mice. Patients with severe aortic stenosis also had elevated MYDGF plasma concentrations, which declined after transcatheter aortic valve implantation. Monocytes and macrophages emerged as the main MYDGF sources in the pressure-overloaded murine heart. While Mydgf-/- mice had no apparent phenotype at baseline, they developed more severe left ventricular hypertrophy and contractile dysfunction during pressure overload than WT mice. Conversely, conditional transgenic overexpression of MYDGF in bone marrow-derived inflammatory cells attenuated pressure overload-induced hypertrophy and dysfunction. Mechanistically, MYDGF inhibited G protein-coupled receptor agonist-induced hypertrophy and augmented SERCA2a (sarco/endoplasmic reticulum Ca2+-ATPase 2a) expression in cultured neonatal rat ventricular cardiomyocytes by enhancing PIM1 (Pim-1 proto-oncogene, serine/threonine kinase) expression and activity. Along this line, cardiomyocytes from pressure-overloaded Mydgf-/- mice displayed reduced PIM1 and SERCA2a expression, greater hypertrophy, and impaired Ca2+ cycling and sarcomere function compared with cardiomyocytes from pressure-overloaded WT mice. Transplanting Mydgf-/- mice with WT bone marrow cells augmented cardiac PIM1 and SERCA2a levels and ameliorated pressure overload-induced hypertrophy and dysfunction. Pressure-overloaded Mydgf-/- mice were similarly rescued by adenoviral Serca2a gene transfer. Treating pressure-overloaded WT mice subcutaneously with recombinant MYDGF enhanced SERCA2a expression, attenuated left ventricular hypertrophy and dysfunction, and improved survival.
Conclusions
These findings establish a MYDGF-based adaptive crosstalk between inflammatory cells and cardiomyocytes that protects against pressure overload-induced heart failure.



Circulation: 11 Oct 2021; 144:1227-1240
Korf-Klingebiel M, Reboll MR, Polten F, Weber N, ... Wang Y, Wollert KC
Circulation: 11 Oct 2021; 144:1227-1240 | PMID: 34372689
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Abstract

Effect of Empagliflozin on Worsening Heart Failure Events in Patients With Heart Failure and Preserved Ejection Fraction: EMPEROR-Preserved Trial.

Packer M, Butler J, Zannad F, Filippatos G, ... Schnee JM, Anker SD
Background
Empagliflozin reduces the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure with preserved ejection fraction, but additional data are needed about its effect on inpatient and outpatient heart failure events.
Methods
We randomly assigned 5988 patients with class II through IV heart failure with an ejection fraction of >40% to double-blind treatment with placebo or empagliflozin (10 mg once daily), in addition to usual therapy, for a median of 26 months. We prospectively collected information on inpatient and outpatient events reflecting worsening heart failure and prespecified their analysis in individual and composite end points.
Results
Empagliflozin reduced the combined risk of cardiovascular death, hospitalization for heart failure, or an emergency or urgent heart failure visit requiring intravenous treatment (432 versus 546 patients [empagliflozin versus placebo, respectively]; hazard ratio, 0.77 [95% CI, 0.67-0.87]; P<0.0001). This benefit reached statistical significance at 18 days after randomization. Empagliflozin reduced the total number of heart failure hospitalizations that required intensive care (hazard ratio, 0.71 [95% CI, 0.52-0.96]; P=0.028) and the total number of all hospitalizations that required a vasopressor or positive inotropic drug (hazard ratio, 0.73 [95% CI, 0.55-0.97]; P=0.033). Compared with patients in the placebo group, fewer patients in the empagliflozin group reported outpatient intensification of diuretics (482 versus 610; hazard ratio, 0.76 [95% CI, 0.67-0.86]; P<0.0001), and patients assigned to empagliflozin were 20% to 50% more likely to have a better New York Heart Association functional class, with significant effects at 12 weeks that were maintained for at least 2 years. The benefit on total heart failure hospitalizations was similar in patients with an ejection fraction of >40% to <50% and 50% to <60%, but was attenuated at higher ejection fractions.
Conclusions
In patients with heart failure with preserved ejection fraction, empagliflozin produced a meaningful, early, and sustained reduction in the risk and severity of a broad range of inpatient and outpatient worsening heart failure events. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057977.



Circulation: 18 Oct 2021; 144:1284-1294
Packer M, Butler J, Zannad F, Filippatos G, ... Schnee JM, Anker SD
Circulation: 18 Oct 2021; 144:1284-1294 | PMID: 34459213
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Abstract

Guidance for Timely and Appropriate Referral of Patients With Advanced Heart Failure: A Scientific Statement From the American Heart Association.

Morris AA, Khazanie P, Drazner MH, Albert NM, ... American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; and Council on Hypertension
Among the estimated 6.2 million Americans living with heart failure (HF), ≈5%/y may progress to advanced, or stage D, disease. Advanced HF has a high morbidity and mortality, such that early recognition of this condition is important to optimize care. Delayed referral or lack of referral in patients who are likely to derive benefit from an advanced HF evaluation can have important adverse consequences for patients and their families. A 2-step process can be used by practitioners when considering referral of a patient with advanced HF for consideration of advanced therapies, focused on recognizing the clinical clues associated with stage D HF and assessing potential benefits of referral to an advanced HF center. Although patients are often referred to an advanced HF center to undergo evaluation for advanced therapies such as heart transplantation or implantation of a left ventricular assist device, there are other reasons to refer, including access to the infrastructure and multidisciplinary team of the advanced HF center that offers a broad range of expertise. The intent of this statement is to provide a framework for practitioners and health systems to help identify and refer patients with HF who are most likely to derive benefit from referral to an advanced HF center.



Circulation: 11 Oct 2021; 144:e238-e250
Morris AA, Khazanie P, Drazner MH, Albert NM, ... American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; and Council on Hypertension
Circulation: 11 Oct 2021; 144:e238-e250 | PMID: 34503343
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Abstract

Dietary carbohydrates restriction inhibits the development of cardiac hypertrophy and heart failure.

Nakamura M, Odanovic N, Nakada Y, Dohi S, ... Abdellatif M, Sadoshima J
Aims
A diet with modified components, such as a ketogenic low-carbohydrate (LC) diet, potentially extends longevity and healthspan. However, how an LC diet impacts on cardiac pathology during haemodynamic stress remains elusive. This study evaluated the effects of an LC diet high in either fat (Fat-LC) or protein (Pro-LC) in a mouse model of chronic hypertensive cardiac remodelling.
Methods and results
Wild-type mice were subjected to transverse aortic constriction, followed by feeding with the Fat-LC, the Pro-LC, or a high-carbohydrate control diet. After 4 weeks, echocardiographic, haemodynamic, histological, and biochemical analyses were performed. LC diet consumption after pressure overload inhibited the development of pathological hypertrophy and systolic dysfunction compared to the control diet. An anti-hypertrophic serine/threonine kinase, GSK-3β, was re-activated by both LC diets; however, the Fat-LC, but not the Pro-LC, diet exerted cardioprotection in GSK-3β cardiac-specific knockout mice. β-hydroxybutyrate, a major ketone body in mammals, was increased in the hearts of mice fed the Fat-LC, but not the Pro-LC, diet. In cardiomyocytes, ketone body supplementation inhibited phenylephrine-induced hypertrophy, in part by suppressing mTOR signalling.
Conclusion
Strict carbohydrate restriction suppresses pathological cardiac growth and heart failure after pressure overload through distinct anti-hypertrophic mechanisms elicited by supplemented macronutrients.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Cardiovasc Res: 27 Sep 2021; 117:2365-2376
Nakamura M, Odanovic N, Nakada Y, Dohi S, ... Abdellatif M, Sadoshima J
Cardiovasc Res: 27 Sep 2021; 117:2365-2376 | PMID: 33070172
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Abstract

Sex differences in heart failure hospitalisation risk following acute myocardial infarction.

Yandrapalli S, Malik A, Pemmasani G, Aronow W, ... Frishman W, Panza J
Objective
We evaluated the sex differences in 6-month heart failure (HF) hospitalisation risk in acute myocardial infarction (AMI) survivors.
Methods
For this retrospective cohort analysis, adult survivors of an AMI between January and June 2014 were identified from the US Nationwide Readmissions Database. The primary outcome was a HF hospitalisation within 6 months. Secondary outcomes were fatal HF hospitalisation and the composite of index in-hospital HF or 6-month HF hospitalisation.
Results
Of 237 549 AMI survivors, females (37.9%) were older (70±14 years vs 65±13 years; p<0.001), had a higher prevalence of cardiac comorbidities and a lower revascularisation rate compared with males. The primary outcome occurred in 12 934 patients (5.4%), at a 49% higher rate in females (6.8% vs 4.6% in males, p<0.001), which was attenuated to a 19% higher risk after multivariable adjustment. Findings were consistent across subgroups of age, AMI type and major risk factors. In the propensity-matched time-to-event analysis, female sex was associated with a 13% higher risk for 6-month HF readmission (6.4% vs 5.8% in males; HR 1.13, 95% CI 1.05 to 1.21, p<0.001), and the increased risk was evident early on after the AMI. Fatal HF rate was similar between groups (4.7% vs 4.6%, p=0.936), but females had a higher rate of the composite HF outcome (36.2% vs 27.5%, p<0.001).
Conclusion
In a large all-comers AMI survivors\' cohort, females had a higher HF hospitalisation risk that persisted after adjustment for baseline risk differences. This was consistent across several clinically relevant subgroups and was evident early on after the AMI.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 29 Sep 2021; 107:1657-1663
Yandrapalli S, Malik A, Pemmasani G, Aronow W, ... Frishman W, Panza J
Heart: 29 Sep 2021; 107:1657-1663 | PMID: 33431424
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Abstract

Temporal relationship between systemic endothelial dysfunction and alterations in erythrocyte function in a murine model of chronic heart failure.

Mohaissen T, Proniewski B, Targosz-Korecka M, Bar A, ... Marzec KM, Chlopicki S
Aims
Endothelial dysfunction (ED) and red blood cell distribution width (RDW) are both prognostic factors in heart failure (HF), but the relationship between them is not clear. In this study, we used a unique mouse model of chronic HF driven by cardiomyocyte-specific overexpression of activated Gαq protein (Tgαq*44 mice) to characterise the relationship between the development of peripheral ED and the occurrence of structural nanomechanical and biochemical changes in red blood cells (RBCs).
Methods and results
Systemic ED was detected in vivo in 8-month-old Tgαq*44 mice, as evidenced by impaired acetylcholine-induced vasodilation in the aorta and increased endothelial permeability in the brachiocephalic artery. ED in the aorta was associated with impaired nitric oxide (NO) production in the aorta and diminished systemic NO bioavailability. ED in the aorta was also characterised by increased superoxide and eicosanoid production. In 4- to 6-month-old Tgαq*44 mice, RBC size and membrane composition displayed alterations that did not result in significant changes in their nanomechanical and functional properties. However, 8-month-old Tgαq*44 mice presented greatly accentuated structural and size changes and increased RBC stiffness. In 12-month-old Tgαq*44 mice, the erythropathy was featured by severely altered RBC shape and elasticity, increased RDW, impaired RBC deformability, and increased oxidative stress (GSH/GSSH ratio). Moreover, RBCs taken from 12-month-old Tgαq*44 mice, but not from 12-month-old FVB mice, co-incubated with aortic rings from FVB mice, induced impaired endothelium-dependent vasodilation and this effect was partially reversed by an arginase inhibitor (ABH, 2(S)-amino-6-boronohexanoic acid).
Conclusion
In the Tgαq*44 murine model of HF, systemic endothelial dysfunction accelerates erythropathy and, conversely, erythropathy may contribute to endothelial dysfunction. These results suggest that erythropathy may be regarded as a marker and a mediator of systemic endothelial dysfunction in HF. In particular, targeting RBC arginase may represent a novel treatment strategy for systemic endothelial dysfunction in HF. RBC arginase and possibly other RBC-mediated mechanisms may represent novel therapeutic targets for systemic endothelial dysfunction in HF.
Translational perspective
Endothelial dysfunction (ED) and red blood cell distribution width (RDW) both have prognostic value for heart failure (HF), but it is not known whether these pathologies are related. We comprehensively characterized endothelial and RBC functional status in a unique murine model of chronic heart failure with a prolonged time course of HF progression. Our results suggest that ED accelerates erythropathy and, conversely, erythropathy may contribute to ED. Accordingly, erythropathy in HF reflects ED and involves various changes (in functional, structural, nanomechanical, and biochemical levels) that could have diagnostic and therapeutic significance for HF.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 06 Oct 2021; epub ahead of print
Mohaissen T, Proniewski B, Targosz-Korecka M, Bar A, ... Marzec KM, Chlopicki S
Cardiovasc Res: 06 Oct 2021; epub ahead of print | PMID: 34617995
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Abstract

Sacubitril/valsartan in the treatment of systemic right ventricular failure.

Zandstra TE, Nederend M, Jongbloed MRM, Kiès P, ... Schalij MJ, Egorova AD
Objective
Pharmacological options for patients with a failing systemic right ventricle (RV) in the context of transposition of the great arteries (TGA) after atrial switch or congenitally corrected TGA (ccTGA) are not well defined. This study aims to investigate the feasibility and effects of sacubitril/valsartan treatment in a single-centre cohort of patients.
Methods
Data on all consecutive adult patients (n=20, mean age 46 years, 50% women) with a failing systemic RV in a biventricular circulation treated with sacubitril/valsartan in our centre are reported. Patients with a systemic RV ejection fraction of ≤35% who were symptomatic despite treatment with β-blocker and ACE-inhibitor/angiotensin II receptor-blockers were started on sacubitril/valsartan. This cohort underwent structural follow-up including echocardiography, exercise testing, laboratory investigations and quality of life (QOL) assessment.
Results
Six-month follow-up data were available in 18 out of 20 patients, including 12 (67%) patients with TGA after atrial switch and 6 (33%) patients with ccTGA. N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) decreased significantly (950-358 ng/L, p<0.001). Echocardiographic systemic RV fractional area change and global longitudinal strain showed small improvements (19%-22%, p<0.001 and -11% to -13%, p=0.014, respectively). The 6 min walking distance improved significantly from an average of 564 to 600 m (p=0.011). The QOL domains of cognitive function, sleep and vitality improved (p=0.015, p=0.007 and p=0.037, respectively).
Conclusions
We describe the first patient cohort with systemic RV failure treated with sacubitril/valsartan. Treatment appears feasible with improvements in NT-pro-BNP and echocardiographic function. Our positive results show the potential of sacubitril/valsartan for this patient population.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

Heart: 30 Oct 2021; 107:1725-1730
Zandstra TE, Nederend M, Jongbloed MRM, Kiès P, ... Schalij MJ, Egorova AD
Heart: 30 Oct 2021; 107:1725-1730 | PMID: 33452121
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Abstract

Myofilament Phosphorylation in Stem Cell Treated Diastolic Heart Failure.

Soetkamp D, Gallet R, Parker SJ, Holewinski R, ... Marban E, Van Eyk JE
Rationale: Phosphorylation of sarcomeric proteins has been implicated in heart failure with preserved ejection fraction (HFpEF); such changes may contribute to diastolic dysfunction by altering contractility, cardiac stiffness, Ca2+-sensitivity and mechanosensing. Treatment with cardiosphere-derived cells (CDCs) restores normal diastolic function, attenuates fibrosis and inflammation, and improves survival in a rat HFpEF model.Objective: Phosphorylation changes that underlie HFpEF and those reversed by CDC therapy, with a focus on the sarcomeric subproteome were analyzed.
Methods and results:
Dahl salt-sensitive rats fed a high-salt diet, with echocardiographically-verified diastolic dysfunction, were randomly assigned to either intracoronary CDCs or placebo. Dahl salt-sensitive rats receiving low salt diet served as controls. Protein, and phosphorylated Ser, Thr and Tyr residues from left ventricular tissue, were quantified by mass spectrometry. HFpEF hearts exhibited extensive hyperphosphorylation with 98% of the 529 significantly changed phospho-sites increased compared to control. Of those 39% were located within the sarcomeric subproteome, with a large group of proteins located or associated with the Z-disk. CDC treatment partially reverted the hyperphosphorylation, with 85% of the significantly altered 76 residues hypophosphorylated. Bioinformatic upstream analysis of the differentially phosphorylated protein residues revealed PKC as the dominant putative regulatory kinase. PKC isoform analysis indicated increases in PKC α, β and δ concentration, whereas CDC treatment led to a reversion of PKCβ. Use of PKC isoform specific inhibition and overexpression of various PKC isoforms strongly suggests PKCβ is the dominant kinase involved in hyperphosphorylation in HFpEF and is altered with CDC treatment. Conclusions: Increased protein phosphorylation at the Z-disk is associated with diastolic dysfunction, with PKC isoforms driving most quantified phosphorylation changes. Because CDCs reverse the key abnormalities in HFpEF and selectively reverse PKCβ upregulation, PKCβ merits being classified as a potential therapeutic target in HFpEF, a disease notoriously refractory to medical intervention.




Circ Res: 12 Oct 2021; epub ahead of print
Soetkamp D, Gallet R, Parker SJ, Holewinski R, ... Marban E, Van Eyk JE
Circ Res: 12 Oct 2021; epub ahead of print | PMID: 34641704
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Abstract

Trimethylamine oxide: a potential target for heart failure therapy.

Lv S, Wang Y, Zhang W, Shang H
Heart failure (HF) is a clinical syndrome in the late stage of cardiovascular disease and is associated with high prevalence, mortality and rehospitalisation rate. The pathophysiological mechanisms of HF have experienced the initial \'water-sodium retention\' mode to \'abnormal hemodynamics\' mode, and subsequent to \'abnormal activation of neuroendocrine\' mode, which has extensively promoted the reform of HF treatment and updated the treatment concept. Since the Human Microbiome Project commencement, the study on intestinal microecology has swiftly developed, providing a new direction to reveal the occurrence of diseases and the mechanisms behind drug effects. Intestinal microecology comprises the gastrointestinal lumen, epithelial secretion, food entering the intestine, intestinal flora and metabolites. Choline and L-carnitine in the diet are metabolised to trimethylamine (TMA) by the intestinal micro-organisms, with TMA being absorbed into the blood. TMA then enters the liver through the portal vein circulation and is oxidised to trimethylamine oxide (TMAO) by the hepatic flavin-containing mono-oxygenase (FMO) family, especially FMO3. The circulating TMAO levels are associated with adverse outcomes in HF (mortality and readmission), and lower TMAO levels indicate better prognosis. As HF progresses, the concentration of TMAO in patients gradually increases. Whether the circulating TMAO level can be decreased by intervening with the intestinal microflora or relevant enzymes, thereby affecting the prognosis of patients with HF, has become a research hotspot. Therefore, based on the HF intestinal hypothesis, exploring the treatment strategy for HF targeting the TMAO metabolite of the intestinal flora may update the treatment concept in HF and improve its therapeutic effect.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 04 Oct 2021; epub ahead of print
Lv S, Wang Y, Zhang W, Shang H
Heart: 04 Oct 2021; epub ahead of print | PMID: 34611047
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Abstract

Heart failure medication dosage and survival in women and men seen at outpatient clinics.

Bots SH, Onland-Moret NC, Tulevski II, van der Harst P, ... Somsen GA, den Ruijter HM
Objective
Women with heart failure with reduced ejection fraction (HFrEF) may reach optimal treatment effect at half of the guideline-recommended medication dose. This study investigates prescription practice and its relation with survival of patients with HF in daily care.
Methods
Electronic health record data from 13 Dutch outpatient cardiology clinics were extracted for HF receiving at least one guideline-recommended HF medication. Dose changes over consecutive prescriptions were modelled using natural cubic splines. Inverse probability-weighted Cox regression was used to assess the relationship between dose (reference≥50% target dose) and all-cause mortality.
Results
The study population comprised 561 women (29% HFrEF (ejection fraction (EF)<40%), 49% heart failure with preserved ejection fraction (EF≥50%); HFpEF and 615 men (47% and 25%, respectively). During a median follow-up of 3.7 years, 252 patients died (48% women; 167 HFrEF, 84 HFpEF). Nine hundred thirty-four patients (46% women) received ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), 795 (48% women) beta blockers and 178 (42% women) mineralocorticoid receptor antagonists (MRAs). In both sexes, the mean target dose across prescriptions was 50% for ACEI/ARBs and beta blockers, and 100% for MRAs. ACEI/ARB dose of <50% was associated with lower mortality in women but not in men with HFrEF. This was not seen in patients with HFpEF. Beta-blocker dose was not associated with all-cause mortality.
Conclusion
Patients with HF seen in outpatient cardiology clinics receive half of the guideline-recommended medication dose. Lower ACEI/ARB dose was associated with improved survival in women with HFrEF. These results underscore the importance of (re)defining optimal medical therapy for women with HFrEF.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Oct 2021; 107:1748-1755
Bots SH, Onland-Moret NC, Tulevski II, van der Harst P, ... Somsen GA, den Ruijter HM
Heart: 30 Oct 2021; 107:1748-1755 | PMID: 34261736
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Abstract

Pathophysiological pathways in patients with heart failure and atrial fibrillation.

Santema BT, Arita VA, Sama IE, Kloosterman M, ... Rienstra M, Voors AA
Aims
Atrial fibrillation (AF) and heart failure (HF) are two growing epidemics that frequently co-exist. We aimed to gain insights into underlying pathophysiological pathways in HF patients with AF by comparing circulating biomarkers using pathway overrepresentation analyses.
Methods and results
From a panel of 92 biomarkers from different pathophysiological domains available in 1,620 patients with HF, we first tested which biomarkers were dysregulated in patients with HF and AF (n = 648) compared with patients in sinus rhythm (n = 972). Secondly, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in patients who had HF and AF. Findings were validated in an independent HF cohort (n = 1,219, 38% with AF). Patient with AF and HF were older, less often women, and less often had a history of coronary artery disease compared with those in sinus rhythm. In the index cohort, 24 biomarkers were upregulated in patients with AF and HF. In the validation cohort, 8 biomarkers were upregulated, which all overlapped with the 24 biomarkers found in the index cohort. The strongest up-regulated biomarkers in patients with AF were spondin-1 (fold change 1.18, p = 1.33x10-12), insulin-like growth factor-binding protein-1 (fold change 1.32, p = 1.08x10-8), and insulin-like growth factor-binding protein-7 (fold change 1.33, p = 1.35x10-18). Pathway overrepresentation analyses revealed that the presence of AF was associated with activation amyloid-beta metabolic processes, amyloid-beta formation, and amyloid precursor protein catabolic processes with a remarkable consistency observed in the validation cohort.
Conclusion
In two independent cohorts of patients with HF, the presence of AF was associated with activation of three pathways related to amyloid-beta. These hypothesis-generating results warrant confirmation in future studies.
Translational perspective
Using an unbiased approach, we identified and validated dysregulation of three amyloid-beta related pathways in patients who had heart failure (HF) with concomitant atrial fibrillation (AF). Amyloid-beta depositions are a hallmark of Alzheimer\'s disease, but might also play a role in pathophysiological processes outside the central nervous system. Biopsy studies are needed to confirm the pathophysiological role of amyloid-beta in patients with AF and HF. Diagnostic and therapeutic implications should be investigated in the light of potential pathophysiological overlap between the three aging-related epidemics: Alzheimer\'s disease, AF and HF.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 22 Oct 2021; epub ahead of print
Santema BT, Arita VA, Sama IE, Kloosterman M, ... Rienstra M, Voors AA
Cardiovasc Res: 22 Oct 2021; epub ahead of print | PMID: 34687289
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Abstract

Contrasting trends in heart failure incidence in younger and older New Zealanders, 2006-2018.

Chan DZL, Kerr A, Grey C, Selak V, ... Poppe K, Doughty RN
Objective
Studies indicate that age-standardised heart failure (HF) incidence has been decreasing internationally; however, contrasting trends in different age groups have been reported, with rates increasing in younger people and decreasing in the elderly. We aimed to describe age-specific trends in HF incidence in New Zealand (NZ).
Methods
In this nationwide data linkage study, we used routinely collected hospitalisation data to identify incident HF hospitalisations in NZ residents aged ≥20 years between 2006 and 2018. Age-specific and age-standardised incidence rates were calculated for each calendar year. Joinpoint regression was used to compare incidence trends.
Results
116 113 incident HF hospitalisations were identified over the 13-year study period. Between 2006 and 2013, age-standardised incidence decreased from 403 to 323 per 100 000 (annual percentage change (APC) -2.6%, 95% CI -3.6 to -1.6%). This reduction then plateaued between 2013 and 2018 (APC 0.8%, 95% CI -0.8 to 2.5%). Between 2006 and 2018, rates in individuals aged 20-49 years old increased by 1.5% per year (95% CI 0.3 to 2.7%) and decreased in those aged ≥80 years old by 1.2% per year (95% CI -1.7 to -0.7%). Rates in individuals aged 50-79 years old initially declined from 2006 to 2013, and then remained stable or increased from 2013 to 2018. The proportion of HF hospitalisations associated with ischaemic heart disease decreased from 35.1% in 2006 to 28.0% in 2018.
Conclusion
HF remains an important problem in NZ. The decline in overall incidence has plateaued since 2013 due to increasing rates of HF in younger age groups despite an ongoing decline in the elderly.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 21 Oct 2021; epub ahead of print
Chan DZL, Kerr A, Grey C, Selak V, ... Poppe K, Doughty RN
Heart: 21 Oct 2021; epub ahead of print | PMID: 34686566
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Abstract

Interpreting Device Diagnostics for Lead Failure.

Swerdlow CD, Ploux S, Poole JE, Nair SG, Himes A, Ellenbogen KA
Implantable cardioverter-defibrillators (ICDs) incorporate automated, lead-monitoring alerts (alerts) and other diagnostics to detect defibrillation lead failure (LF) and minimize its adverse clinical consequences. Partial conductor fractures cause oversensing, but pacing or high-voltage alerts for high impedance detect only complete conductor fracture. In both pacing and high-voltage insulation breaches, low-impedance alerts require complete breach with metal-to-metal contact. Oversensing alerts for pace-sense LF also require complete breach, but not metal-to metal contact. Electrograms (EGMs) from leads with confirmed fractures have characteristics findings. In insulation breach however, oversensed EGMs reflect characteristics of the source signal. Oversensing alerts that operate on the sensing channel analyze R-R intervals for two patterns typical of LF but uncommon in other conditions, a rapidly-increasing count of \"non-physiologic,\" short intervals and rapid \"nonsustained tachycardias.\" These alerts are sensitive but nonspecific. Alerts that compare sensing and shock channels define oversensing as sensed events that do not correlate temporally with EGMs on the shock channel. Their performance depends on implementation. Specific advantages and limitations are reviewed. Most ICD measure impedance using subthreshold pulses. Patterns in impedance trends provide diagnostic information, whether or not an alert is triggered. Gradual increases in impedance do not indicate structural LF, but they may cause failed defibrillation if shock impedance is high enough. Since impedance-threshold alerts are insensitive, normal impedance trends never exclude LF; but an abrupt increase that triggers an alert almost always indicates a header-connection issue or LF. Methods for discriminating connection issues from LF are reviewed.

Copyright © 2021. Published by Elsevier Inc.

Heart Rhythm: 27 Sep 2021; epub ahead of print
Swerdlow CD, Ploux S, Poole JE, Nair SG, Himes A, Ellenbogen KA
Heart Rhythm: 27 Sep 2021; epub ahead of print | PMID: 34597770
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Abstract

Rationale and design of the comparison of outcomes and access to care for heart failure (COACH) trial: A stepped wedge cluster randomized trial.

Lee DS, Straus SE, Austin PC, Mohamed S, ... Mak S, Ross HJ
Background
Heart failure (HF) is an ambulatory care sensitive condition and a leading reason for emergency department (ED) visits and hospitalizations. Improved decision-making and care may enhance safety and efficiency for patients presenting to the ED with acute HF.
Objectives
We will evaluate an intervention comprised of 2 complementary components: (1) the Emergency Heart Failure Mortality Risk Grade simultaneous 7- and 30-day (EHMRG30-ST) risk scores, which will inform admission-discharge decisions, and (2) a rapid outpatient follow-up (RAPID-HF) clinic for low-to-intermediate risk patients on cardiovascular readmissions or death.
Study design
Stepped wedge cluster randomized trial with cross-sectional measurement at 10 acute care hospitals in Ontario, Canada. Patients presenting during control and intervention periods are eligible if they have a primary ED diagnosis of HF. In the intervention periods, access to the EHMRG30-ST web calculator will become available to hospitals\' internet protocol (IP) addresses, and referral to the RAPID-HF clinic will be facilitated by a study nurse navigator. Patients with a high risk EHMRG30-ST score will be admitted to hospital. The RAPID-HF clinic will accept referrals for patients: (1) with low risk 7- and 30-day EHMRG30-ST scores who are discharged directly from the ED, or (2) intermediate risk patients with hospital length of stay < 72 hours. The RAPID-HF clinic, staffed by a nurse-clinician and cardiologist, will provide care during the 30-day transition after hospital separation.
Conclusion
This trial will determine whether novel risk stratification coupled with rapid ambulatory care achieves better outcomes than conventional decision-making and care for patients with HF.

Copyright © 2021. Published by Elsevier Inc.

Am Heart J: 29 Sep 2021; 240:1-10
Lee DS, Straus SE, Austin PC, Mohamed S, ... Mak S, Ross HJ
Am Heart J: 29 Sep 2021; 240:1-10 | PMID: 33984316
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Abstract

Clinical and Echocardiographic Characteristics of Patients Hospitalized With Acute Versus Chronic Heart Failure With Preserved Ejection Fraction (From the ARIC Study).

Chunawala ZS, Fudim M, Arora S, Qamar A, ... Pandey A, Caughey MC
An expanding number of therapies are now indicated for comorbidity management in heart failure with preserved ejection fraction (HFpEF). Whether comorbidity burdens differ for patients with HFpEF who are hospitalized for acute decompensated heart failure (ADHF) versus those with chronic stable heart failure (CSHF) who are hospitalized for other causes is uncertain. Since 2005, the Atherosclerosis Risk in Communities (ARIC) study has conducted adjudicated community surveillance of hospitalized heart failure. Hospitalized ADHF and CSHF were sampled identically, using prespecified discharge codes and demographic strata, but were differentiated by signs or symptoms of acute or worsening heart failure upon physician review of the medical record. HFpEF was defined by an ejection fraction ≥50%. All events were weighted by the inverse of the sampling probability for statistical analyses. From 2005 to 2014, 13,706 weighted (2,936 unweighted) hospitalizations (mean age 77 years, 64% women, 29% Black) were sampled among patients with HFpEF and adjudicated ADHF (86%) or CSHF (14%). Comorbidity prevalence was high both for ADHF and CSHF hospitalizations, irrespective of gender. Women hospitalized with ADHF versus CSHF had greater prevalence of hypertension (89% vs 84%) diabetes mellitus (48% vs 39%) and renal disease (85% vs 74%). Echocardiographic features such as left ventricular hypertrophy and valvular abnormalities were more common with ADHF than CSHF, for both genders. However, the 28-day and 1-year mortality risk were comparable for ADHF and CSHF. In conclusion, hospitalized patients with HFpEF have a high comorbidity burden and risk of death, irrespective of the cause of hospitalization.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 31 Oct 2021; 158:59-65
Chunawala ZS, Fudim M, Arora S, Qamar A, ... Pandey A, Caughey MC
Am J Cardiol: 31 Oct 2021; 158:59-65 | PMID: 34474908
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Abstract

Preservation of Cardiac Reserve and Cardiorespiratory Fitness in Patients With Acute De Novo Versus Acute on Chronic Heart Failure With Reduced Ejection Fraction.

Del Buono MG, Mihalick V, Damonte JI, Billingsley H, ... Abbate A, Canada JM
There is limited understanding on the potential differences in the pathophysiology between de novo heart failure with reduced ejection fraction (HFrEF) and acute on chronic HFrEF. The aim of this study was to assess differences in cardiorespiratory fitness (CRF) parameters between de novo heart failure and acute on chronic HFrEF using cardiopulmonary exercise testing (CPX). We retrospectively analyzed CPX data measured within 2 weeks of discharge following acute hospitalization for HFrEF. Data are reported as median and interquartile range or frequency and percentage (%). We included 102 patients: 32 (31%) women, 81 (79%) black, 57 (51 to 64) years of age, BMI of 34 (29 to 39) Kg/m2. Of these, 26 (25%) had de novo HFrEF and 76 (75%) had acute on chronic HFrEF. When compared with acute on chronic, patients with de novo HFrEF had a significantly higher peak oxygen consumption (VO2) (16.5 [12.2 to 19.4] vs 12.8 [10.1 to 15.3] ml·kg-1·min-1, p <0.001), %-predicted peak VO2 (58% [51 to 75] vs 49% [42 to 59]) p = 0.012), peak heart rate (134 [117 to 147] vs 117 [104 to 136] beats/min, p = 0.004), peak oxygen pulse (12.2 [10.5 to 15.5] vs 9.9 [8.0 to 13.1] ml/beat, p = 0.022) and circulatory power (2,823 [1,973 to 3,299] vs 1,902 [1,372 to 2,512] mm Hg·ml·kg-1·min-1, p = 0.002). No significant difference in resting left ventricular ejection fraction was found between groups. In conclusion, patients with de novo HFrEF have better CRF parameters than those with acute on chronic HFrEF. These differences are not explained by resting left ventricular systolic function but may be related to greater preservation in cardiac reserve during exercise in de novo HFrEF patients.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 31 Oct 2021; 158:74-80
Del Buono MG, Mihalick V, Damonte JI, Billingsley H, ... Abbate A, Canada JM
Am J Cardiol: 31 Oct 2021; 158:74-80 | PMID: 34465455
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Abstract

Prognosticators of All-Cause Mortality in Patients With Heart Failure With Preserved Ejection Fraction.

Lopuszynski JB, Downing AJ, Finley CM, Zahid M
Heart failure with preserved ejection fraction (HFpEF) represents ∼50% of all cases of congestive heart failure (CHF) with prevalence expected to increase with aging of the population. We performed an observational study of all patients admitted to 3 hospitals in the ExcelaHealth care system, Greensburg, PA, with a primary diagnosis of HFpEF heart failure exacerbation between January 2014 and January 2017. Demographic data, laboratory results, and echocardiograms performed closest to index hospitalization were collected. A total of 487 patients were admitted with a primary diagnosis of CHF exacerbation and HFpEF, with a mean age of 80.5 years (±10.9), 62% women and predominantly Caucasian (98.8%). Over a median follow-up of 21.7 months, 246 patients died with an all-cause mortality rate of 51.3%. Receiver operator curves were generated for multiple continuous variables to identify optimal cut-off values Kaplan-Meir survival curves were then generated. Clinical factors were tested by univariate Cox regression modeling, with significant factors entered into a step-wise multivariate model. Our modeling identified age>80 years, serum albumin level<3.2 g/dl, N-terminal pro-brain natriuretic peptide (NT-proBNP) >5,000 pg/mL and medial E/e\'≥20 as significant, independent predictors of all-cause mortality (p-value <0.0001). Surprisingly, lack of a diagnosis of hypertension was associated with significantly increased mortality risk. In a community-based sample of HFpEF patients, we identified multiple factors that were strong, independent predictors of all-cause mortality that can be easily applied in a clinical setting.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 31 Oct 2021; 158:66-73
Lopuszynski JB, Downing AJ, Finley CM, Zahid M
Am J Cardiol: 31 Oct 2021; 158:66-73 | PMID: 34465456
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Abstract

Impact of oral soluble guanylate cyclase stimulators in heart failure: A systematic review and Meta-analysis of randomized controlled trials.

Moghaddam N, Malhi N, Toma M
Background
Soluble guanylate cyclase (sGC) stimulators are a novel class of medications with emerging role in heart failure (HF). The aim of this study is to evaluate the efficacy and safety of oral sGC stimulators in patients with HF with reduced and preserved ejection fraction (HFrEF and HFpEF) by pooling data from all available randomized control trials (RCT).
Methods
A comprehensive search of electronic databases from 2000-2020 was performed. Seven RCTs, three HFrEF and four HFpEF studies, were identified. The follow-up duration ranged from 1 month to a median of 10.8 months. A random-effects meta-analysis was conducted to summarize the studies.
Results
The study population included 7190 patients: 5707 HFrEF and 1483 HFpEF patients. In HFrEF, oral sGC stimulators reduced the composite incidence of HF hospitalization and cardiovascular death (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.78-0.97; I2 = 0%), primarily driven by lower HF hospitalization (HR 0.88, 95% CI 0.78-0.99; I2 = 0%). There was no significant reduction in all-cause death in HFrEF (HR 0.95, 95% CI 0.83-1.09; I2 = 0%). In HFpEF, there were no improvements in Kansas City Cardiomyopathy Questionnaire clinical summary scores (mean difference 0.81, 95% CI -2.16-3.77; I2 = 72%) or 6-minute walk distance (mean difference 3.34 meters, 95% CI -7.86-14.54; I2 = 28%). There was no difference in all-cause mortality in HFpEF (HR 1.94, 95% CI 0.92-4.09; I2 = 0%). Overall, oral sGC stimulators had low medication-related serious adverse events.
Conclusion
Oral sGC stimulators are well tolerated in HF and reduce the incidence of HF hospitalization but not cardiovascular death among patients with HFrEF. However, there are no apparent benefits in HFpEF.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am Heart J: 30 Oct 2021; 241:74-82
Moghaddam N, Malhi N, Toma M
Am Heart J: 30 Oct 2021; 241:74-82 | PMID: 34283990
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Abstract

Days alive out of hospital in heart failure: Insights from the PARADIGM-HF and CHARM trials.

Chen Y, Lawrence J, Stockbridge N
Background
An endpoint that has received some attention in recent cardiovascular trials is \'days alive and out of hospital\' (DAOH). Percent DAOH is a natural extension of DAOH that adjusts for differences in length of follow-up. This endpoint measure incorporates mortality and morbidity together in a way that has the potential to give more insight regarding treatment effects compared to conventional time-to-event endpoints. Other advantages of this measure include the relative ease of collection and interpretation. However, research on how to analyze this measure is still limited.
Methods
We propose using the one-inflated beta model to analyze percent DAOH. This model is appropriate for highly left-skewed data with a large proportion of boundary values. Data from the Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ACEI [Angiotensin-Converting-Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF) and Candesartan in Heart Failure Assessment of Reduction in Mortality and morbidity (CHARM) trials are used to illustrate this method.
Results
Statistically significant differences in percent DAOH were observed for PARADIGM-HF and CHARM in favor of treatment. In PARADIGM-HF, treatment with sacubitril plus valsartan increased DAOH on average by 11 days (95% CI: 1.4-20.9 days) and increased percent DAOH by 1.64% at a fixed follow-up length of 1,000 days (95% CI: 0.61%- 2.67%). For the CHARM overall program, the candesartan group has 1.79% more DAOH (95% CI: 0.91%- 2.68%).
Conclusion
DAOH, and especially percent DAOH, can enhance our understanding of treatment effects in future cardiovascular trials, and the one-inflated beta model is an appropriate choice for its analysis.

Published by Elsevier Inc.

Am Heart J: 30 Oct 2021; 241:108-119
Chen Y, Lawrence J, Stockbridge N
Am Heart J: 30 Oct 2021; 241:108-119 | PMID: 33984319
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Abstract

The effect of left atrial appendage closure on heart failure biomarkers: A PRAGUE-17 trial subanalysis.

Herman D, Osmancik P, Neuzil P, Hala P, ... Reddy VY, PRAGUE-17 Trial Investigators
Introduction
The randomized PRAGUE-17 trial demonstrated noninferiority of left atrial appendage closure (LAAC) to non-vitamin K anticoagulants (NOACs) for the prevention of major cardiovascular or cerebrovascular events. However, the left atrial appendage is an important source of natriuretic peptides and plays a role in left atrial reservoir function. Changes of heart failure (HF) biomarkers after LAAC compared to NOAC has not been studied. The aim of the study was to compare the changes in concentrations of HF biomarkers between LAAC and NOAC patients.
Methods
Of 402 patients randomized in the PRAGUE-17 trial, biomarkers were analyzed in 144 patients (73 in the NOAC and 71 in the LAAC group). Both groups had similar baseline characteristics. Serum concentration of NT-proBNP, NT-proANP, Galectin-3, and GDF-15 were measured at baseline (before the procedure in the LAAC group), at the 6-month (and at 24-month for NT-proBNP) follow-up timepoint.
Results
There were no significant differences in baseline, 6 month, and delta (δ = baseline - 6 month) concentrations of NT-proANP between the groups (NOAC: baseline 2.6 [0.5; 4.9], 6-month 3.1 [1.8; 4.8], p = .068; LAAC: baseline 3.3 [1.1; 4.6], 6-month 2.6 [0.9; 5.3], p = .51; p value for δ in concentrations between groups = 0.42). Similarly, there were no significant differences in baseline, 6, 24 months, and delta concentrations of NT-proBNP between the groups (NOAC: baseline 461.0 [113.5; 1342.0], 6 month 440.0 [120.5; 1291.5], 24 month 798 [274; 2236], p = .39; LAAC: baseline 421.0 [100.0; 1320.0], 6 month 601.0 [145.0; 1230.0], 24 month 855 [410; 1367], p = .28; p value for δ in concentrations between groups = 0.73 at 6 months, and 0.58 at 24 months). Finally, no significant differences were present in baseline, 6 month, and δ concentrations of Galectin-3 and GDF-15 between the two groups.
Conclusion
LAAC did not significantly influence the levels of HF biomarkers 6 months after the procedure.

© 2021 Wiley Periodicals LLC.

J Cardiovasc Electrophysiol: 29 Sep 2021; 32:2645-2654
Herman D, Osmancik P, Neuzil P, Hala P, ... Reddy VY, PRAGUE-17 Trial Investigators
J Cardiovasc Electrophysiol: 29 Sep 2021; 32:2645-2654 | PMID: 34402135
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Abstract

The cost of non-response to cardiac resynchronization therapy: characterizing heart failure events following cardiac resynchronization therapy.

Varma N, Auricchio A, Connolly AT, Boehmer J, ... Nabutovsky Y, Gold M
Aims
The aim of this study is to quantify healthcare resource utilization among non-responders to cardiac resynchronization therapy (CRT-NR) by heart failure (HF) events and influence of comorbidities.
Methods and results
The ADVANCE CRT registry (2013-2015) prospectively identified responders/CRT-NRs 6 months post-implant using the clinical composite score. Heart failure event rates and associated cost, both overall and separated for inpatient hospitalizations, office visits, emergency room visits, and observational stays, were quantified. Costs of events were imputed from payments for similar real-world encounters in subjects with CRT-D/P devices in the MarketScan™ commercial and Medicare Supplemental insurance claims databases. Effects of patient demographics and comorbidities on event rates and cost were evaluated. Of 879 US patients (age 69 ± 11 years, 29% female, ischaemic disease 52%), 310 (35%) were CRT-NR. Among CRT-NRs vs. responders, more patients developed HF (41% vs. 11%, P < 0.001), HF event rate was higher (67.0 ± 21.7 vs. 11.4 ± 3.7/100 pt-year, P < 0.001), and HF readmission within 30 days was more common [hazard ratio 7.06, 95% confidence interval (2.1-43.7)]. Inpatient hospitalization was the most common and most expensive event type in CRT-NR. Comorbid HF was increased by diabetes, hypertension, and pulmonary disorders. Over 2 years, compared to CRT responders, each CRT-NR resulted in excess cost of $6388 ($3859-$10 483) to Medicare (P = 0.015) or $10 197 ($6161-$17 394) to private insurances (P = 0.014).
Conclusion
Healthcare expenditures associated with contemporary CRT non-response management are among the highest for any HF patient group. This illustrates an unmet need for interventions to improve HF outcomes and reduce costs among some CRT recipients.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected]

Europace: 08 Oct 2021; 23:1586-1595
Varma N, Auricchio A, Connolly AT, Boehmer J, ... Nabutovsky Y, Gold M
Europace: 08 Oct 2021; 23:1586-1595 | PMID: 34198334
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Abstract

Protein Aggregation Is an Early Manifestation of Phospholamban p.(Arg14del)-Related Cardiomyopathy: Development of PLN-R14del-Related Cardiomyopathy.

Eijgenraam TR, Boogerd CJ, Stege NM, Oliveira Nunes Teixeira V, ... Silljé HHW, de Boer RA
Background
The p.(Arg14del) pathogenic variant (R14del) of the PLN (phospholamban) gene is a prevalent cause of cardiomyopathy with heart failure. The exact underlying pathophysiology is unknown, and a suitable therapy is unavailable. We aim to identify molecular perturbations underlying this cardiomyopathy in a clinically relevant PLN-R14del mouse model.
Methods
We investigated the progression of cardiomyopathy in PLN-R14∆/∆ mice using echocardiography, ECG, and histological tissue analysis. RNA sequencing and mass spectrometry were performed on cardiac tissues at 3 (before the onset of disease), 5 (mild cardiomyopathy), and 8 (end stage) weeks of age. Data were compared with cardiac expression levels of mice that underwent myocardial ischemia-reperfusion or myocardial infarction surgery, in an effort to identify alterations that are specific to PLN-R14del-related cardiomyopathy.
Results
At 3 weeks of age, PLN-R14∆/∆ mice had normal cardiac function, but from the age of 4 weeks, we observed increased myocardial fibrosis and impaired global longitudinal strain. From 5 weeks onward, ventricular dilatation, decreased contractility, and diminished ECG voltages were observed. PLN protein aggregation was present before onset of functional deficits. Transcriptomics and proteomics revealed differential regulation of processes involved in remodeling, inflammation, and metabolic dysfunction, in part, similar to ischemic heart disease. Altered protein homeostasis pathways were identified exclusively in PLN-R14∆/∆ mice, even before disease onset, in concert with aggregate formation.
Conclusions
We mapped the development of PLN-R14del-related cardiomyopathy and identified alterations in proteostasis and PLN protein aggregation among the first manifestations of this disease, which could possibly be a novel target for therapy.



Circ Heart Fail: 29 Sep 2021:CIRCHEARTFAILURE121008532; epub ahead of print
Eijgenraam TR, Boogerd CJ, Stege NM, Oliveira Nunes Teixeira V, ... Silljé HHW, de Boer RA
Circ Heart Fail: 29 Sep 2021:CIRCHEARTFAILURE121008532; epub ahead of print | PMID: 34587756
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Abstract

Practice Patterns and Patient Outcomes After Widespread Adoption of Remote Heart Failure Care.

Yuan N, Botting PG, Elad Y, Miller SJ, ... Ebinger JE, Kittleson MM
Background
An unprecedented shift to remote heart failure outpatient care occurred during the coronavirus disease 2019 (COVID-19) pandemic. Given challenges inherent to remote care, we studied whether remote visits (video or telephone) were associated with different patient usage, clinician practice patterns, and outcomes.
Methods
We included all ambulatory cardiology visits for heart failure at a multisite health system from April 1, 2019, to December 31, 2019 (pre-COVID) or April 1, 2020, to December 31, 2020 (COVID era), resulting in 10 591 pre-COVID in-person, 7775 COVID-era in-person, 1009 COVID-era video, and 2322 COVID-era telephone visits. We used multivariable logistic and Cox proportional hazards regressions with propensity weighting and patient clustering to study ordering practices and outcomes.
Results
Compared with in-person visits, video visits were used more often by younger (mean 64.7 years [SD 14.5] versus 74.2 [14.1]), male (68.3% versus 61.4%), and privately insured (45.9% versus 28.9%) individuals (P<0.05 for all). Remote visits were more frequently used by non-White patients (35.8% video, 37.0% telephone versus 33.2% in-person). During remote visits, clinicians were less likely to order diagnostic testing (odds ratio, 0.20 [0.18-0.22] video versus in-person, 0.18 [0.17-0.19] telephone versus in-person) or prescribe β-blockers (0.82 [0.68-0.99], 0.35 [0.26-0.47]), mineralocorticoid receptor antagonists (0.69 [0.50-0.96], 0.48 [0.35-0.66]), or loop diuretics (0.67 [0.53-0.85], 0.45 [0.37-0.55]). During telephone visits, clinicians were less likely to prescribe ACE (angiotensin-converting enzyme) inhibitor/ARB (angiotensin receptor blockers)/ARNIs (angiotensin receptor-neprilysin inhibitors; 0.54 [0.40-0.72]). Telephone visits but not video visits were associated with higher rates of 90-day mortality (1.82 [1.14-2.90]) and nonsignificant trends towards higher rates of 90-day heart failure emergency department visits (1.34 [0.97-1.86]) and hospitalizations (1.36 [0.98-1.89]).
Conclusions
Remote visits for heart failure care were associated with reduced diagnostic testing and guideline-directed medical therapy prescription. Telephone but not video visits were associated with increased 90-day mortality.



Circ Heart Fail: 29 Sep 2021:CIRCHEARTFAILURE121008573; epub ahead of print
Yuan N, Botting PG, Elad Y, Miller SJ, ... Ebinger JE, Kittleson MM
Circ Heart Fail: 29 Sep 2021:CIRCHEARTFAILURE121008573; epub ahead of print | PMID: 34587763
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Impact:
Abstract

Multiparametric Implantable Cardioverter-Defibrillator Algorithm for Heart Failure Risk Stratification and Management: An Analysis in Clinical Practice.

Calò L, Bianchi V, Ferraioli D, Santini L, ... D\'Onofrio A, Full list of participant centers and investigators
Background
The HeartLogic algorithm combines multiple implantable cardioverter-defibrillator sensors to identify patients at risk of heart failure (HF) events. We sought to evaluate the risk stratification ability of this algorithm in clinical practice. We also analyzed the alert management strategies adopted in the study group and their association with the occurrence of HF events.
Methods
The HeartLogic feature was activated in 366 implantable cardioverter-defibrillator and cardiac resynchronization therapy implantable cardioverter-defibrillator patients at 22 centers. The median follow-up was 11 months [25th-75th percentile: 6-16]. The HeartLogic algorithm calculates a daily HF index and identifies periods IN alert state on the basis of a configurable threshold.
Results
The HeartLogic index crossed the threshold value 273 times (0.76 alerts/patient-year) in 150 patients. The time IN alert state was 11% of the total observation period. Patients experienced 36 HF hospitalizations, and 8 patients died of HF during the observation period. Thirty-five events were associated with the IN alert state (0.92 events/patient-year versus 0.03 events/patient-year in the OUT of alert state). The hazard ratio in the IN/OUT of alert state comparison was (hazard ratio, 24.53 [95% CI, 8.55-70.38], P<0.001), after adjustment for baseline clinical confounders. Alerts followed by clinical actions were associated with less HF events (hazard ratio, 0.37 [95% CI, 0.14-0.99], P=0.047). No differences in event rates were observed between in-office and remote alert management.
Conclusions
This multiparametric algorithm identifies patients during periods of significantly increased risk of HF events. The rate of HF events seemed lower when clinical actions were undertaken in response to alerts. Extra in-office visits did not seem to be required to effectively manage HeartLogic alerts. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02275637.



Circ Heart Fail: 29 Sep 2021; 14:e008134
Calò L, Bianchi V, Ferraioli D, Santini L, ... D'Onofrio A, Full list of participant centers and investigators
Circ Heart Fail: 29 Sep 2021; 14:e008134 | PMID: 34190592
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Abstract

COVID-19 vaccination in patients with heart failure: a position paper of the Heart Failure Association of the European Society of Cardiology.

Rosano G, Jankowska EA, Ray R, Metra M, ... Volterrani M, Coats AJS
Patients with heart failure (HF) who contract SARS-CoV-2 infection are at a higher risk of cardiovascular and non-cardiovascular morbidity and mortality. Regardless of therapeutic attempts in COVID-19, vaccination remains the most promising global approach at present for controlling this disease. There are several concerns and misconceptions regarding the clinical indications, optimal mode of delivery, safety and efficacy of COVID-19 vaccines for patients with HF. This document provides guidance to all healthcare professionals regarding the implementation of a COVID-19 vaccination scheme in patients with HF. COVID-19 vaccination is indicated in all patients with HF, including those who are immunocompromised (e.g. after heart transplantation receiving immunosuppressive therapy) and with frailty syndrome. It is preferable to vaccinate against COVID-19 patients with HF in an optimal clinical state, which would include clinical stability, adequate hydration and nutrition, optimized treatment of HF and other comorbidities (including iron deficiency), but corrective measures should not be allowed to delay vaccination. Patients with HF who have been vaccinated against COVID-19 need to continue precautionary measures, including the use of facemasks, hand hygiene and social distancing. Knowledge on strategies preventing SARS-CoV-2 infection (including the COVID-19 vaccination) should be included in the comprehensive educational programmes delivered to patients with HF. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 05 Oct 2021; epub ahead of print
Rosano G, Jankowska EA, Ray R, Metra M, ... Volterrani M, Coats AJS
Eur J Heart Fail: 05 Oct 2021; epub ahead of print | PMID: 34612556
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Impact:
Abstract

Clinical Heart Failure Among Patients With and Without Severe Mental Illness and the Association With Long-Term Outcomes.

Polcwiartek C, Loewenstein D, Friedman DJ, Johansson KG, ... Jackson KP, Atwater BD
Background
Patients with severe mental illness (SMI) including schizophrenia, bipolar disorder, and severe depression have earlier onset of cardiovascular risk factors, predisposing to worse future heart failure (HF) compared with the general population. We investigated associations between the presence/absence of SMI and long-term HF outcomes.
Methods
We identified patients with HF with and without SMI in the Duke University Health System from 2002 to 2017. Using multivariable Cox regression, we examined the primary outcome of all-cause mortality. Secondary outcomes included rates of implantable cardioverter defibrillator use, cardiac resynchronization therapy, left ventricular assist device implantation, and heart transplantation.
Results
We included 20 906 patients with HF (SMI, n=898; non-SMI, n=20 008). Patients with SMI presented clinically 7 years earlier than those without SMI. We observed an interaction between SMI and sex on all-cause mortality (P=0.002). Excess mortality was observed among men with SMI compared with men without SMI (hazard ratio, 1.36 [95% CI, 1.17-1.59]). No association was observed among women with and without SMI (hazard ratio, 0.97 [95% CI, 0.84-1.12]). Rates of implantable cardioverter defibrillator use, cardiac resynchronization therapy, left ventricular assist device implantation, and heart transplantation were similar between patients with and without SMI (6.1% versus 7.9%, P=0.095). Patients with SMI receiving these procedures for HF experienced poorer prognosis than those without SMI (hazard ratio, 2.12 [95% CI, 1.08-4.15]).
Conclusions
SMI was associated with adverse HF outcome among men and not women. Despite equal access to procedures for HF between patients with and without SMI, those with SMI experienced excess postprocedural mortality. Our data highlight concurrent sex- and mental health-related disparities in HF prognosis, suggesting that patients with SMI, especially men, merit closer follow-up.



Circ Heart Fail: 29 Sep 2021:CIRCHEARTFAILURE121008364; epub ahead of print
Polcwiartek C, Loewenstein D, Friedman DJ, Johansson KG, ... Jackson KP, Atwater BD
Circ Heart Fail: 29 Sep 2021:CIRCHEARTFAILURE121008364; epub ahead of print | PMID: 34587762
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Impact:
Abstract

Acute-phase initiation of cardiac rehabilitation and clinical outcomes in hospitalized patients for acute heart failure.

Kaneko H, Itoh H, Kamiya K, Morita K, ... Yasunaga H, Komuro I
Background
Extensive data support the clinical benefit of cardiac rehabilitation (CR) for patients with chronic heart failure (HF). However, whether CR could be beneficial for patients hospitalized for acute heart failure remains unclear.
Methods
We retrospectively analyzed data from the Diagnosis Procedure Combination database, a nationwide inpatient database. We included patients hospitalized for HF, who were aged ≥20 years and with New York Heart Association class ≥II, between January 2010 and March 2018. We excluded patients with length of hospital stay ≤2 days, those undergoing major procedures under general anesthesia, those requiring advanced mechanical supports within 2 days after admission, and those with disturbance of consciousness. Propensity score matching and instrumental variable analyses were conducted to compare clinical outcomes between the patients with and without acute-phase initiation of CR defined as initiation of CR within two days after hospital admission.
Results
Among 430,216 eligible patients, 63,470 patients (14.8%) received the acute-phase initiation of CR. Propensity score matching created 63,470 pairs and found that the acute-phase initiation of CR was associated with lower in-hospital mortality (odds ratio [OR] 0.76, 95% confidence interval [CI] 0.73-0.80), shorter hospital stay and lower incidence of 30-day readmission due to HF. The instrumental variable analysis also showed patients with acute-phase initiation of CR was associated with lower in-hospital mortality than those without (OR, 0.73; 95% CI, 0.68-0.79).
Conclusion
Our analysis suggested a potential benefit of acute-phase initiation of CR for short-term clinical outcomes in hospitalized patients with acute HF.

Copyright © 2021 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Sep 2021; 340:36-41
Kaneko H, Itoh H, Kamiya K, Morita K, ... Yasunaga H, Komuro I
Int J Cardiol: 30 Sep 2021; 340:36-41 | PMID: 34454966
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Abstract

Sodium-glucose co-transporter-2 inhibitors eligibility in patients with heart failure with reduced ejection fraction.

Monzo L, Ferrari I, Cicogna F, Tota C, Calò L
Background
The sodium-glucose co-transporter-2 (SGLT2) inhibitors dapagliflozin and empagliflozin have been demonstrated to reduce adverse cardiovascular outcomes in patients with heart failure with reduced ejection fraction (HFrEF). Limited data are available characterizing the generalizability of SGLT2 inhibitors treatment in the clinical practice. The aim of the study was to evaluate the proportion of outpatients with HFrEF that would be eligible for SGLT2 inhibitors in a contemporary real-world population.
Methods
We retrospectively evaluated patients with chronic stable HFrEF followed-up at the HF outpatient clinic of our institution. Patients\' eligibility was assessed according to the entry criteria of DAPA-HF (dapagliflozin) and EMPEROR-Reduced (empagliflozin) trials and to US Food and Drug Administration (FDA) label criteria (only dapagliflozin).
Results
A total of 441 HFrEF patients was enrolled. According to the major inclusion and exclusion criteria from DAPA-HF and EMPEROR-Reduced trials, 198 (45%) patients would be candidates for initiation of both dapagliflozin and empagliflozin, 61 (14%) would be eligible only to dapagliflozin and 23 (5%) only to empagliflozin, without significant differences between diabetic and non-diabetic patients (p = 0.23). Among patients not suitable for gliflozins treatment (159 patients; 36%), the major determinant of ineligibility was the failure to achieve the predefined NT-proBNP inclusion threshold. Excluding NTproBNP as per FDA label criteria, dapagliflozin eligibility increased to 86%.
Conclusions
In our real-world analysis a large proportion of HFrEF patients would be candidates for initiation of SGLT2 inhibitors, supporting its broad generalizability in clinical practice. This would be expected to reduce morbidity and mortality in eligible patients.

Copyright © 2021 Elsevier B.V. All rights reserved.

Int J Cardiol: 14 Oct 2021; 341:56-59
Monzo L, Ferrari I, Cicogna F, Tota C, Calò L
Int J Cardiol: 14 Oct 2021; 341:56-59 | PMID: 34454968
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Abstract

Association of hospital performance measures with readmissions for patients with heart failure: A report from JROAD-DPC study.

Nakao K, Yasuda S, Noguchi T, Sumita Y, ... Gale CP, Ogawa H
Background
Measuring quality of care is central to quality improvement. Improving outcomes for heart failure (HF) may relate to hospital care delivery. However, there is limited nationwide data on the relationship between hospital-level HF performance measures and clinical outcomes.
Methods
From the Japanese Registry of All cardiac and vascular Diseases (JROAD-DPC) database, 83,567 HF patients hospitalised in 731 certificated hospitals in 2014 by the Japanese Circulation Society were analysed. Five performance measures were prescription rate of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, beta-blocker, and mineralocorticoid receptor antagonist and measurement rate of echocardiography and B-type natriuretic peptide during hospitalisation. Relationships between these measures and 1-year readmission due to HF were analysed. Composite performance score (CPS) obtained from the five performance measures and outcomes were also analysed. We also investigated the relationships between CPS and hospital structural factors.
Results
From the cohort (mean age; 78.2 years, woman 48.4%), HF readmission rate at 1 year was 19.6% (n = 16,368). Readmission rate decreased with higher quartiles of prescription rate in each medication and diagnostic performance rates. The highest CPS group was associated with a 15% risk reduction in HF readmission compared with the lowest CPS group (hazard ratio, 0.85, 95% confidence interval [0.80-0.89], p < 0.001) after covariate adjustment. Several structural factors such as number of cardiology specialists, hospital case volume for HF, and presence of cardiac surgery division were associated with high CPS.
Conclusion
Higher hospital performance measures for HF were inversely associated with HF readmissions.

Copyright © 2021 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Sep 2021; 340:48-54
Nakao K, Yasuda S, Noguchi T, Sumita Y, ... Gale CP, Ogawa H
Int J Cardiol: 30 Sep 2021; 340:48-54 | PMID: 34419528
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Abstract

Performance of the HFPEF and the HFA-PEFF scores for the diagnosis of heart failure with preserved ejection fraction in Japanese patients: A report from the Japanese multicenter registry.

Tada A, Nagai T, Omote K, Iwano H, ... Saito Y, Anzai T
Background
Diagnosing heart failure with preserved ejection fraction (HFpEF) is challenging. Although the H2FPEF score and HFA-PEFF algorithm have been proposed for diagnosing HFpEF, previous validation studies were conducted in stable chronic heart failure (HF). Moreover, information on their applicability in the Asian population is limited. We sought to investigate these scores\' diagnostic performance for HFpEF in Japanese patients recently hospitalized due to acute decompensated HF.
Methods
We examined patients with HFpEF recently hospitalized with acute decompensated HF from a nationwide HFpEF-specific multicenter registry (HFpEF group) and control patients who underwent echocardiography to investigate the cause of dyspnea in our hospital (Non-HFpEF group).
Results
The studied population included 372 patients (194 HFpEF group and 178 Non-HFpEF group; HFpEF prevalence, 52%). A high H2FPEF score (6-9 points) could diagnose HFpEF with a high specificity of 97% and a positive predictive value (PPV) of 94%, and a low H2FPEF score (0-1 point) could rule out HFpEF with a high sensitivity of 97% and a negative predictive value (NPV) of 93%. HFpEF could be diagnosed with a high HFA-PEFF score (5-6 points) (specificity, 84%; PPV, 82%) or ruled out with a low HFA-PEFF score (0-1 point) (sensitivity, 99%; NPV, 89%). The H2FPEF score was significantly superior to the HFA-PEFF score in diagnostic accuracy (area under the curve: 0.89 vs. 0.82, respectively, p = 0.004).
Conclusions
The H2FPEF and the HFA-PEFF scores had acceptable diagnostic accuracy in diagnosing HFpEF in Japanese patients.

Copyright © 2021 Elsevier B.V. All rights reserved.

Int J Cardiol: 31 Oct 2021; 342:43-48
Tada A, Nagai T, Omote K, Iwano H, ... Saito Y, Anzai T
Int J Cardiol: 31 Oct 2021; 342:43-48 | PMID: 34364907
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Abstract

Estimation of Stressed Blood Volume in Patients With Cardiogenic Shock From Acute Myocardial Infarction and Decompensated Heart Failure.

Whitehead EH, Thayer KL, Sunagawa K, Hernandez-Montfort J, ... Kapur NK, Burkhoff D
Background
Sympathetically mediated redistribution of blood from the unstressed venous reservoir to the hemodynamically active stressed compartment is thought to contribute to congestion in cardiogenic shock (CS). We used a novel computational method to estimate stressed blood volume (SBV) in CS and assess its relationship with clinical outcomes.
Methods and results
Hemodynamic parameters including estimated SBV (eSBV) were compared among patients from the Cardiogenic Shock Working Group registry with a complete set of hemodynamic data. eSBV was compared across shock etiologies (acute myocardial infarction and CS (AMI-CS) vs heart failure with CS (HF-CS), Society for Cardiovascular Angiography and Interventions stage, and between survivors and nonsurvivors. Among 528 patients with patients analyzed, the mean eSBV was 2423 mL/70 kg and increased with increasing Society for Cardiovascular Angiography and Interventions stage (B, 2029 mL/70 kg; C, 2305 mL/70 kg; D, 2496 mL/70 kg; E, 2707 mL/70 kg; P < .001). The eSBV was significantly greater among patients with HF-CS who died compared with survivors (2733 vs 2357 mL/70 kg; P < .001), whereas no significant difference was observed between outcome groups in AMI-CS (2501 mL/70 kg vs 2384 mL/70 kg; P = .19).
Conclusions
eSBV is a novel integrated index of congestion which correlates with shock severity. eSBV was higher in patients with HF-CS who died; no difference was observed in patients with AMI-CS, suggesting that congestion may play a more significant role in the deterioration of patients with HF-CS.

Copyright © 2021 Elsevier Inc. All rights reserved.

J Card Fail: 29 Sep 2021; 27:1141-1145
Whitehead EH, Thayer KL, Sunagawa K, Hernandez-Montfort J, ... Kapur NK, Burkhoff D
J Card Fail: 29 Sep 2021; 27:1141-1145 | PMID: 33862252
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Abstract

Diabetes Mellitus in Advanced Heart Failure.

Dunlay SM, Killian JM, McCoy RG, Redfield MM
Background
Diabetes mellitus is associated with increased mortality in patients with less severe (stage C) HF. The prevalence of diabetes and its complications in advanced (stage D) HF and their contributions to mortality risk, are unknown.
Methods and results
We conducted a retrospective population-based cohort study of all adult residents of Olmsted County, Minnesota with advanced HF between 2007-2017. Patients with diabetes were identified using HEDIS criteria. Diabetes complications were captured using the Diabetes Complications Severity Index (DCSI). Of 936 patients with advanced HF, 338 (36.1%) had diabetes. Overall, median (IQR) survival after development of advanced HF was 13.1 (3.9-33.1) months; mortality did not vary by diabetes status (aHR 1.06, 95% CI 0.90-1.25, p=0.45) or by HbA1c in those with diabetes (aHR 1.01 per 1% increase, 95% CI 0.93-1.10, p=0.82). However, patients with diabetes and 4 (aHR 1.24, 95% CI 0.92-1.67) or 5-7 (aHR 1.49, 95% CI 1.09-2.03) diabetes complications were at increased mortality risk compared to those with ≤3 complications.
Conclusions
More than one-third of patients with advanced HF have diabetes. In advanced HF, overall prognosis is poor, but we found no evidence that diabetes is associated with a significantly higher mortality risk.

Copyright © 2021. Published by Elsevier Inc.

J Card Fail: 10 Oct 2021; epub ahead of print
Dunlay SM, Killian JM, McCoy RG, Redfield MM
J Card Fail: 10 Oct 2021; epub ahead of print | PMID: 34648970
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Abstract

Polypharmacy in Palliative Care for Advanced Heart Failure: The PAL-HF Experience.

Granger BB, Tulsky JA, Kaufman BG, Clare RM, ... Rogers JG, Mentz RJ
Background
Palliative care (PC) in advanced heart failure (HF) aims to improve symptoms and quality of life (QOL), in part through medication management. The impact of PC on polypharmacy (>5 medications) remains unknown.
Methods and results
We explored patterns of polypharmacy in the Palliative Care in HF (PAL-HF) randomized controlled trial of standard care versus interdisciplinary PC in advanced HF (N=150). We describe differences in medication counts between arms at 2, 6, 12, and 24 weeks for HF (12 classes) and PC (6 classes) medications. General linear mixed models were used to evaluate associations between treatment arm and polypharmacy over time. The median age of the patients was 72 (62-80) years, and 47% were female while 41% were Black. Overall, 48% had ischemic etiology, and 55% had an ejection fraction </= 40%. Polypharmacy was present at baseline in 100% of patients. HF and PC medication counts increased in both arms, with no significant differences in counts by drug class at any time-point between arms.
Conclusion
In a trial of patients with advanced HF considered eligible for PC, polypharmacy was universal at baseline and increased during follow-up with no effect of the palliative intervention on medication counts relative to standard care.

Copyright © 2021. Published by Elsevier Inc.

J Card Fail: 06 Oct 2021; epub ahead of print
Granger BB, Tulsky JA, Kaufman BG, Clare RM, ... Rogers JG, Mentz RJ
J Card Fail: 06 Oct 2021; epub ahead of print | PMID: 34628013
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Abstract

The association between socioeconomic status, sex, race/ethnicity and in-hospital mortality among patients hospitalized for heart failure.

Averbuch T, Mohamed MO, Islam S, DeFilippis EM, ... Mamas MA, Van Spall H
Background
The association between socioeconomic status (SES), sex, race/ethnicity and outcomes during hospitalization for heart failure (HF) has not previously been investigated.
Methods
We analyzed HF hospitalizations in the United States National Inpatient Sample between 2015-2017. Using a hierarchical, multivariable Poisson regression model to adjust for hospital- and patient-level factors, we assessed the association between SES, sex, and race/ethnicity and all-cause in-hospital mortality. We estimated the direct costs (USD) across SES groups.
Results
Among 4,287,478 HF hospitalizations, 40.8% were in high SES, 48.7% in female, and 70.0% in White patients. Relative to these comparators, low SES (homelessness or lowest quartile of median neighborhood income) (Relative risk [RR] 1.02, 95% CI 1.00-1.05) and male sex (RR 1.09, 95% CI 1.07-1.11) were associated with increased risk, whilst Black (RR 0.79, 95% CI 0.76-0.81) and Hispanic (RR 0.90, 95% CI 0.86-0.93) race/ethnicity were associated with reduced risk of in-hospital death. There were significant interactions between race/ethnicity and both, SES (p<0.01) and sex (p=0.04) such that racial/ethnic differences in outcome were more pronounced in low SES groups and in male patients. The median direct cost of admission was lower in low vs high SES groups ($9324.60 vs $10940.40), female patients vs male patients ($9866.60 vs $10217.10), and Black vs White patients ($9077.20 vs $10019.80). The median costs increased with SES in all demographic groups.
Conclusions
SES, race/ethnicity, and sex were independently associated with in-hospital mortality during HF hospitalization, highlighting possible care disparities. Racial/ethnic differences in outcome were more pronounced in low SES groups and in male patients.

Copyright © 2021. Published by Elsevier Inc.

J Card Fail: 06 Oct 2021; epub ahead of print
Averbuch T, Mohamed MO, Islam S, DeFilippis EM, ... Mamas MA, Van Spall H
J Card Fail: 06 Oct 2021; epub ahead of print | PMID: 34628014
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Abstract

Multiple Cardiac Biomarker Testing Among Patients with Acute Dyspnea from the ICON-RELOADED Study.

Abboud A, Kui N, Gaggin HK, Ibrahim NE, ... Walters EL, Januzzi JL
Background
Among patients with acute dyspnea, concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT) and insulin-like growth factor binding protein-7 (IGFBP7) predict cardiovascular outcomes and death. Understanding the optimal means to interpret these elevated biomarkers in patients presenting with acute dyspnea remains unknown.
Methods and results
Concentrations of NT-proBNP, hs-cTnT, and IGFBP7 were analyzed in 1,448 patients presenting with acute dyspnea from the prospective, multicenter ICON-RELOADED (International Collaborative of NT-proBNP-Re-evaluation of Acute Diagnostic Cut-Offs in the Emergency Department) Study. Eight biogroups were derived based upon patterns in biomarker elevation at presentation and compared for differences in baseline characteristics. Of 441 patients with elevations in all three biomarkers, 218 (49.4%) were diagnosed with acute heart failure (HF). The frequency of acute HF diagnosis in this biogroup was higher than those with elevations in two biomarkers (18.8%, 44 out of 234), one biomarker (3.8%, 10 out of 260), or no elevated biomarkers (0.4%, 2 out of 513). The absolute number of elevated biomarkers on admission was prognostic of the composite endpoint of mortality and HF rehospitalization. In adjusted models, patients with one, two, and three elevated biomarkers had 3.74 (95% CI, 1.26-11.1; P=0.017), 12.3 (95% CI, 4.60-32.9; P <0.001), and 12.6 (95% CI, 4.54-35.0; P <0.001) fold increased risk of 180-day mortality or HF rehospitalization.
Conclusions
A multimarker panel of NT-proBNP, hsTnT, and IGBFP7 provides unique clinical, diagnostic and prognostic information in patients presenting with acute dyspnea. Differences in the number of elevated biomarkers at presentation may allow for more efficient clinical risk stratification of short-term mortality and HF rehospitalization.

Copyright © 2021. Published by Elsevier Inc.

J Card Fail: 07 Oct 2021; epub ahead of print
Abboud A, Kui N, Gaggin HK, Ibrahim NE, ... Walters EL, Januzzi JL
J Card Fail: 07 Oct 2021; epub ahead of print | PMID: 34634446
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Abstract

Hospitalization for heart failure in the USA, UK, Taiwan and Japan: an international comparison of administrative health records on 417,385 individual patients.

Sundaram V, Nagai T, Chiang CE, Reddy YN, ... Sahadevan J, Quint JK
Background
Registries show international variations in the characteristics and outcome of patients with heart failure (HF) but national samples are rarely large, and case-selection may be biased due to enrolment in academic centres. National administrative datasets provide large samples with a low risk of bias. In this study, we compared the characteristics, healthcare resource utilization (HRU) and outcomes of patients with primary HF hospitalizations (HFH) using electronic health records (EHR) from four high-income countries (USA, UK, Taiwan, Japan) on three continents.
Methods and results
We used EHR to identify unplanned HFH between 2012-2014. We identified 231,512, 10,991, 36,900 and 133,982 patients with a primary HFH from USA, UK, Taiwan and Japan, respectively. HFH per 100,000 population was highest in USA and lowest in Taiwan. Patients in Taiwan and Japan were older but fewer were obese or had chronic kidney disease. LOHS was shortest in USA (median 4 days) and longer in UK, Taiwan and Japan (medians 7, 9 and 17 days, respectively). HRU during hospitalization was highest in Japan and lowest in UK. Crude and direct standardized in-hospital mortality was lowest in USA (direct standardized rates: 1.8 [95%CI:1.7-1.9]%)and progressively higher in Taiwan (direct standardized rates: 3.9 [95%CI:3.8-4.1]%), UK (direct standardized rates: 6.4 [95%CI:6.1-6.7]%) and Japan (direct standardized rates: 6.7 [95%CI:6.6-6.8]%). 30-day all-cause (25.8%) and HF (7.2%) readmissions were highest in USA and lowest in Japan (11.9% and 5.1% respectively).
Conclusion
Marked international variations in patient characteristics, HRU and clinical outcome exist; understanding them might inform health care policy and international trial design.

Copyright © 2021. Published by Elsevier Inc.

J Card Fail: 07 Oct 2021; epub ahead of print
Sundaram V, Nagai T, Chiang CE, Reddy YN, ... Sahadevan J, Quint JK
J Card Fail: 07 Oct 2021; epub ahead of print | PMID: 34634448
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Abstract

Full Time Cardiac Intensive Care Unit Staffing by Heart Failure Specialists and Association with Mortality.

Sims DB, Kim Y, Kalininskiy A, Yanamandala M, ... Shah A, Jorde UP
Background
Cardiac intensive care units (CICUs) serve medically complex patients with multi-organ dysfunction. Whether a CICU staffed full time by heart failure (HF) specialists is associated with decreased mortality is unclear.
Methods and results
Retrospective review of consecutive CICU admissions from January 1, 2012 to Dec 31, 2016 was performed. In January 2014, the CICU changed from an open unit staffed by any cardiologist to a closed unit managed by HF specialists. Patients\' baseline characteristics were determined, and a multivariate regression analysis was performed to ascertain CICU mortality. Baseline severity of illness was higher in the closed/HF specialist CICU model (p<0.001). Death occurred in 101 of 1,185 CICU admissions (8.5%) in the open unit model and in 139 of 2,163 admissions (6.4%) in the closed/HF specialist model (absolute risk reduction 2.1%, 95% confidence interval [CI] 0.1-4.0%, p =0.01). The transition from an open to a closed/HF specialist model was associated with a lower overall CICU mortality (odds ratio [OR] 0.63; 95% CI 0.43-0.93). Prespecified interaction of a mechanical circulatory support (MCS) device and unit model showed that treatment with MCS was associated with lower CICU mortality in the closed/HF specialist model (OR 0.6; 95% CI 0.18-0.78, p for interaction <0.01).
Conclusion
Transition to a closed unit model staffed with a dedicated HF specialist is associated with lower CICU mortality.

Copyright © 2021. Published by Elsevier Inc.

J Card Fail: 07 Oct 2021; epub ahead of print
Sims DB, Kim Y, Kalininskiy A, Yanamandala M, ... Shah A, Jorde UP
J Card Fail: 07 Oct 2021; epub ahead of print | PMID: 34634449
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Abstract

Right Ventricular Dysfunction Is Common and Identifies Patients at Risk of Dying in Cardiogenic Shock.

Jain P, Thayer KL, Abraham J, Everett KD, ... Burkhoff D, Kapur NK
Background
Understanding the prognostic impact of right ventricular dysfunction (RVD) in cardiogenic shock (CS) is a key step toward rational diagnostic and treatment algorithms and improved outcomes. Using a large multicenter registry, we assessed (1) the association between hemodynamic markers of RVD and in-hospital mortality, (2) the predictive value of invasive hemodynamic assessment incorporating RV evaluation, and (3) the impact of RVD severity on survival in CS.
Methods and results
Inpatients with CS owing to acute myocardial infarction (AMI) or heart failure (HF) between 2016 and 2019 were included. RV parameters (right atrial pressure, right atrial/pulmonary capillary wedge pressure [RA/PCWP], pulmonary artery pulsatility index [PAPI], and right ventricular stroke work index [RVSWI]) were assessed between survivors and nonsurvivors, and between etiology and SCAI stage subcohorts. Multivariable logistic regression analysis determined hemodynamic predictors of in-hospital mortality; the resulting models were compared with SCAI staging alone. Nonsurvivors had a significantly higher right atrial pressure and RA/PCWP and lower PAPI and RVSWI than survivors, consistent with more severe RVD. Compared with AMI, patients with HF had a significantly lower RA/PCWP (0.58 vs 0.66, P = .001) and a higher PAPI (2.71 vs 1.78, P < .001) and RVSWI (5.70 g-m/m2 vs 4.66 g-m/m2, P < .001), reflecting relatively preserved RV function. Paradoxically, multiple RVD parameters (PAPI, RVSWI) were associated with mortality in the HF but not the AMI cohort. RVD was more severe with advanced SCAI stage, although its prognostic value was progressively diluted in stages D and E. Multivariable modelling incorporating the RA/PCWP improved the predictive value of SCAI staging (area under the curve [AUC] 0.78 vs 0.73, P < .001), largely driven by patients with HF (AUC 0.82 vs 0.71, P < .001).
Conclusions
RVD is associated with poor outcomes in CS, with key differences across etiology and shock severity. Further studies are needed to assess the usefulness of RVD assessment in guiding therapy.

Copyright © 2021. Published by Elsevier Inc.

J Card Fail: 29 Sep 2021; 27:1061-1072
Jain P, Thayer KL, Abraham J, Everett KD, ... Burkhoff D, Kapur NK
J Card Fail: 29 Sep 2021; 27:1061-1072 | PMID: 34625126
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Abstract

De Novo vs Acute-on-Chronic Presentations of Heart Failure-Related Cardiogenic Shock: Insights from the Critical Care Cardiology Trials Network Registry.

Bhatt AS, Berg DD, Bohula EA, Alviar CL, ... Van Diepen S, Morrow DA
Background
Heart failure-related cardiogenic shock (HF-CS) accounts for an increasing proportion of cases of CS in contemporary cardiac intensive care units. Whether the chronicity of HF identifies distinct clinical profiles of HF-CS is unknown.
Methods and results
We evaluated admissions to cardiac intensive care units for HF-CS in 28 centers using data from the Critical Care Cardiology Trials Network registry (2017-2020). HF-CS was defined as CS due to ventricular failure in the absence of acute myocardial infarction and was classified as de novo vs acute-on-chronic based on the absence or presence of a prior diagnosis of HF, respectively. Clinical features, resource use, and outcomes were compared among groups. Of 1405 admissions with HF-CS, 370 had de novo HF-CS (26.3%), and 1035 had acute-on-chronic HF-CS (73.7%). Patients with de novo HF-CS had a lower prevalence of hypertension, diabetes, coronary artery disease, atrial fibrillation, and chronic kidney disease (all P < 0.01). Median Sequential Organ Failure Assessment (SOFA) scores were higher in those with de novo HF-CS (8; 25th-75th: 5-11) vs acute-on-chronic HF-CS (6; 25th-75th: 4-9, P < 0.01), as was the proportion of Society of Cardiovascular Angiography and Intervention (SCAI) shock stage E (46.1% vs 26.1%, P < 0.01). After adjustment for clinical covariates and preceding cardiac arrest, the risk of in-hospital mortality was higher in patients with de novo HF-CS than in those with acute-on-chronic HF-CS (adjusted hazard ratio 1.36, 95% confidence interval 1.05-1.75, P = 0.02).
Conclusions
Despite having fewer comorbidities, patients with de novo HF-CS had more severe shock presentations and worse in-hospital outcomes. Whether HF disease chronicity is associated with time-dependent compensatory adaptations, unique pathobiological features and responses to treatment in patients presenting with HF-CS warrants further investigation.

Copyright © 2021 Elsevier Inc. All rights reserved.

J Card Fail: 29 Sep 2021; 27:1073-1081
Bhatt AS, Berg DD, Bohula EA, Alviar CL, ... Van Diepen S, Morrow DA
J Card Fail: 29 Sep 2021; 27:1073-1081 | PMID: 34625127
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Abstract

Lactate Clearance Is Associated With Improved Survival in Cardiogenic Shock: A Systematic Review and Meta-Analysis of Prognostic Factor Studies.

Marbach JA, Stone S, Schwartz B, Pahuja M, ... Rabinowitz JB, Kapur NK
Objective
Elevated blood lactate levels are strongly associated with mortality in patients with cardiogenic shock. Recent evidence suggests that the degree and rate at which blood lactate levels decrease after the initiation of treatment may be equally important in patient prognosis. We performed a systematic review and meta-analysis to evaluate the usefulness of lactate clearance as a prognostic factor in cardiogenic shock.
Methods and results
We performed searches of Ovid MEDLINE, Elsevier EMBASE, EBM Reviews-Cochrane Central Register of Controlled Trials, and Web of Science to identify studies comparing lactate clearance between survivors and nonsurvivors at one or more timepoints. Both prospective and retrospective studies were eligible for inclusion. Two study investigators independently screened, extracted data, and assessed the quality of all included studies. Twelve studies were included in the meta-analysis. The median lactate clearance at 6-8 hours was 21.9% (interquartile range [IQR] 14.6%-42.1%) in survivors and 0.6% (IQR -3.7% to 14.6%) in nonsurvivors. At 24 hours, the median lactate clearance was 60.7% (IQR 58.1%-76.3%) and 40.3% (IQR 30.2%-55.8%) in survivors and nonsurvivors, respectively. Accordingly, the pooled mean difference in lactate clearance between survivors and nonsurvivors at 6-8 hours was 17.3% (95% CI 11.6%-23.1%, P < .001) at 6-8 hours and 27.9% (95% CI 14.1%-41.7%, P < .001) at 24 hours.
Conclusions
Survivors had significantly greater lactate clearance at 6-8 hours and at 24 hours compared with nonsurvivors, suggesting that lactate clearance is an important prognostic marker in cardiogenic shock.

Copyright © 2021 Elsevier Inc. All rights reserved.

J Card Fail: 29 Sep 2021; 27:1082-1089
Marbach JA, Stone S, Schwartz B, Pahuja M, ... Rabinowitz JB, Kapur NK
J Card Fail: 29 Sep 2021; 27:1082-1089 | PMID: 34625128
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Impact:
Abstract

Risk Prediction in Cardiogenic Shock: Current State of Knowledge, Challenges and Opportunities.

Kalra S, Ranard LS, Memon S, Rao P, ... Fried JA, Burkhoff D
Cardiogenic shock (CS) is a condition associated with high mortality rates in which prognostication is uncertain for a variety of reasons, including its myriad causes, its rapidly evolving clinical course and the plethora of established and emerging therapies for the condition. A number of validated risk scores are available for CS prognostication; however, many of these are tedious to use, are designed for application in a variety of populations and fail to incorporate contemporary hemodynamic parameters and contemporary mechanical circulatory support interventions that can affect outcomes. It is important to separate patients with CS who may recover with conservative pharmacological therapies from those in who may require advanced therapies to survive; it is equally important to identify quickly those who will succumb despite any therapy. An ideal risk-prediction model would balance incorporation of key hemodynamic parameters while still allowing dynamic use in multiple scenarios, from aiding with early decision making to device weaning. Herein, we discuss currently available CS risk scores, perform a detailed analysis of the variables in each of these scores that are most predictive of CS outcomes and explore a framework for the development of novel risk scores that consider emerging therapies and paradigms for this challenging clinical entity.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Card Fail: 29 Sep 2021; 27:1099-1110
Kalra S, Ranard LS, Memon S, Rao P, ... Fried JA, Burkhoff D
J Card Fail: 29 Sep 2021; 27:1099-1110 | PMID: 34625129
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Impact:
Abstract

Quality of Heart Failure Care in the Intensive Care Unit.

Metkus TS, Lindsley J, Fair L, Riley S, ... Hsu S, Gilotra NA
Patients with heart failure (HF) who are seen in an intensive care unit (ICU) manifest the highest-risk, most complex and most resource-intensive disease states. These patients account for a large relative proportion of days spent in an ICU. The paradigms by which critical care is provided to patients with HF are being reconsidered, including consideration of various multidisciplinary ICU staffing models and the development of acute-response teams. Traditional HF quality initiatives have centered on the peri- and postdischarge period in attempts to improve adherence to guideline-directed therapies and reduce readmissions. There is a compelling rationale for expanding high-quality efforts in treating patients with HF who are receiving critical care so we can improve outcomes, reduce preventable harm, improve teamwork and resource use, and achieve high health-system performance. Our goal is to answer the following question: For a patient with HF in the ICU, what is required for the provision of high-quality care? Herein, we first review the epidemiology of HF syndromes in the ICU and identify relevant critical care and quality stakeholders in HF. We next discuss the tenets of high-quality care for patients with HF in the ICU that will optimize critical care outcomes, such as ICU staffing models and evidence-based management of cardiac and noncardiac disease. We discuss strategies to mitigate preventable harm, improve ICU culture and conduct outcomes review, and we conclude with our summative vision of high-quality of ICU care for patients with HF; our vision includes clinical excellence, teamwork and ICU culture.

Copyright © 2021 Elsevier Inc. All rights reserved.

J Card Fail: 29 Sep 2021; 27:1111-1125
Metkus TS, Lindsley J, Fair L, Riley S, ... Hsu S, Gilotra NA
J Card Fail: 29 Sep 2021; 27:1111-1125 | PMID: 34625130
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Abstract

Heart Failure-Related Cardiogenic Shock: Pathophysiology, Evaluation and Management Considerations: Review of Heart Failure-Related Cardiogenic Shock.

Abraham J, Blumer V, Burkhoff D, Pahuja M, ... Hernandez-Montfort JA, Kapur NK
Despite increasing prevalence in critical care units, cardiogenic shock related to HF (HF-CS) is incompletely understood and distinct from acute myocardial infarction related CS. This review highlights the pathophysiology, evaluation, and contemporary management of HF-CS.

Copyright © 2021 Elsevier Inc. All rights reserved.

J Card Fail: 29 Sep 2021; 27:1126-1140
Abraham J, Blumer V, Burkhoff D, Pahuja M, ... Hernandez-Montfort JA, Kapur NK
J Card Fail: 29 Sep 2021; 27:1126-1140 | PMID: 34625131
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Abstract

Aortic Pulsatility Index: A Novel Hemodynamic Variable for Evaluation of Decompensated Heart Failure.

Belkin MN, Kalantari S, Kanelidis AJ, Miller T, ... Kim G, Grinstein J
Background
Right heart catheterization for invasive hemodynamics has shown only modest correlation with clinical outcomes. We designed a novel hemodynamic variable that incorporates ventricular output and filling pressure. We anticipated that the aortic pulsatility index (API) would correlate with clinical outcomes in patients with heart failure.
Methods and results
We retrospectively analyzed consecutive patients undergoing right heart catheterization with milrinone drug study at our institution (February 2013 to November 2019). The API was calculated as (systolic blood pressure - diastolic blood pressure)/pulmonary capillary wedge pressure. The primary outcome was freedom from advanced therapies, defined as the need for inotropes, temporary mechanical circulatory support, a left ventricular assist device, or orthotopic heart transplantation, or death at 30 days. A total of 224 patient encounters, age 57 years (48-66 years; 34% women; 31% ischemic cardiomyopathy) were included. In univariable analysis, lower baseline API was significantly associated with progression to advanced therapies or death at 30-days (odds ratio 0.43, 95% confidence interval 0.30-0.61; P < .001) compared with those on continued medical management. Receiver operator characteristic analysis specified an optimal cutpoint of 1.45 for API. A Kaplan-Meier analysis indicated an association of API with the primary outcome (79% for API ≥ 1.45 vs 48% for API < 1.45). In multivariable analysis, higher API was strongly associated with freedom from advanced therapies or death (odds ratio 0.38, 95% confidence interval 0.22-0.65, P ≤ .001), even when adjusted for baseline characteristics and routine right heart catheterization measurements.
Conclusions
The API is a novel invasive hemodynamic measurement that is associated independently with freedom from advanced therapies or death at 30-day follow-up.

Copyright © 2021 Elsevier Inc. All rights reserved.

J Card Fail: 29 Sep 2021; 27:1045-1052
Belkin MN, Kalantari S, Kanelidis AJ, Miller T, ... Kim G, Grinstein J
J Card Fail: 29 Sep 2021; 27:1045-1052 | PMID: 34048919
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Abstract

Captopril Versus Hydralazine-Isosorbide Dinitrate Vasodilator Protocols in Patients With Acute Decompensated Heart Failure Transitioning From Sodium Nitroprusside.

Amar M, Lam SW, Faulkenberg K, Perez A, Tang WHW, Williams JB
Background
The role of oral vasodilators in the management of acute decompensated heart failure (ADHF) is not clearly defined. We evaluated the use of captopril vs hydralazine-isosorbide dinitrate (H-ISDN) in the transition from sodium nitroprusside (SNP) in patients with ADHF.
Methods and results
A retrospective chart review was performed of 369 consecutive adult patients in the intensive care unit with ADHF and reduced ejection fraction, who received either a captopril or an H-ISDN protocol to transition from SNP. Captopril patients were matched 1:2 to H-ISDN patients, based on serum creatinine and race (Black vs non-Black). Baseline demographics, serum chemistry and use of angiotensin converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) were similar in both groups. Time to SNP discontinuation (46.9 vs 40.4 hours, P = 0.11) and length of hospital stay (9.86 vs 7.99 days, P = 0.064) were similar in both groups. Length of hospital stay in the intensive care unit was statistically shorter in the H-ISDN group (4.11 vs 3.96 days, P = 0.038). Fewer H-ISDN protocol patients were discharged on ACEis/ARBs (82.9 % vs 69.9%, P = 0.003) despite similar kidney function at time of discharge (serum creatinine 1.1 vs 1.2, P = 0.113). No difference was observed in rates of readmission (40.7% vs 50%, P = 0.09) or mortality (16.3% vs 17.5 %, P = 0.77) at 1 year postdischarge.
Conclusion
Similar inpatient and 1-year outcomes were observed between patients using H-ISDN vs ACEi when transitioning from SNP, even though fewer H-ISDN protocol patients were discharged taking ACEis/ARBs despite similar kidney function.

Copyright © 2021 Elsevier Inc. All rights reserved.

J Card Fail: 29 Sep 2021; 27:1053-1060
Amar M, Lam SW, Faulkenberg K, Perez A, Tang WHW, Williams JB
J Card Fail: 29 Sep 2021; 27:1053-1060 | PMID: 34051349
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Abstract

Right Heart Dysfunction and Readmission Risk Across Left Ventricular Ejection Fraction Status in Patients With Acute Heart Failure.

Santas E, Miñana G, Palau P, Espriella R, ... Bayes-Genís A, Núñez J
Background
Right heart dysfunction (RHD) parameters are increasingly important in heart failure (HF). This study aimed to evaluate the association of advanced RHD with the risk of recurrent admissions across the spectrum of left ventricular ejection fraction (LVEF).
Methods and results
We included 3383 consecutive patients discharged for acute HF. Of them, in 1435 patients (42.4%), the pulmonary artery systolic pressure could not be measured accurately, leaving a final sample size of 1948 patients. Advanced RHD was defined as the combination of a ratio of tricuspid annular plane systolic excursion/pulmonary artery systolic pressure of less than 0.36 and significant tricuspid regurgitation (n = 196, 10.2%). Negative binomial regression analyses were used to evaluate the risk of recurrent admissions. At a median follow-up of 2.2 years (interquartile range 0.63-4.71), 3782 readmissions were registered in 1296 patients (66.5%). Patients with advanced RHD showed higher readmission rates, but only if the LVEF was 40% or greater (P < .001). In multivariable analyses, this differential association persisted for cardiovascular and HF recurrent admissions (P value for interaction = .015 and P = .016; respectively). Advanced RHD was independently associated with the risk of recurrent cardiovascular and HF admissions if HF with an LVEF of 40% or greater (incidence rate ratio 1.64, 95% confidence interval 1.18-2.26, P = .003; and incidence rate ratio 1.73; 95% confidence interval 1.25-2.41, P = .001;respectively). In contrast, it was not associated with readmission risks if the LVEF was less than 40%.
Conclusions
After an admission for acute HF, advanced RHD was strongly associated with a higher risk of recurrent cardiovascular and HF admissions, but only in patients with an LVEF of 40% or greater.

Copyright © 2021 Elsevier Inc. All rights reserved.

J Card Fail: 29 Sep 2021; 27:1090-1098
Santas E, Miñana G, Palau P, Espriella R, ... Bayes-Genís A, Núñez J
J Card Fail: 29 Sep 2021; 27:1090-1098 | PMID: 34273477
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Abstract

Real-world experience of feasibility and efficacy of electrical muscle stimulation in elderly patients with acute heart failure: A randomized controlled study.

Arenja N, Mueller C, Tomilovskaya E, Koryak Y, Poltavskaya M, Saner H
Background
Reduced aerobic capacity and deconditioning contributes to morbidity and mortality in elderly acute heart failure (AHF) patients. Electrical muscle stimulation (EMS) has shown to be a suitable alternative to exercise in AHF. However, feasibility and efficacy are unknown in a real-world setting.
Methods
This is a prospective, open label blinded, randomized, controlled study, investigating feasibility and efficacy of high-intensity versus low-intensity EMS versus controls in elderly AHF patients. Patients and investigators were blinded to the intervention. EMS was offered to >60 years old AHF patients, initiated during hospitalization and continued at home. Outcome measures included changes in 6-min walk distance (6-MWTD), functional capacity and quality-of-life at 3 and 6 weeks.
Results
Among 97 consecutive AHF patients (78.1 ± 9.4 years, 42.3% females), 60 (61.9%) were eligible for EMS. Of these, 27 provided written informed consent and were randomly assigned to high-intensity (n = 10), low-intensity EMS (n = 9) and controls (n = 8). 13/27 completed the intervention. Main reason for dropouts was intolerance of the overall intervention burden. MACE occurred in 5 and were not associated with the study. EMS groups showed significant improvement of 6-MWTD (controls vs low-intensity p = 0.018) and of independence in daily living (for both p < 0.05).
Conclusions
Changes in 6-MWDT suggest efficacy of EMS. Whereas all tolerated EMS well, the burden of study intervention was too high and resulted in a consent rate of <50% and high dropouts, which limit the interpretability of our data. Less demanding EMS protocols are required to evaluate the full potential of EMS in elderly AHF patients.

Copyright © 2021 Elsevier Ireland Ltd. All rights reserved.

Int J Cardiol: 06 Oct 2021; epub ahead of print
Arenja N, Mueller C, Tomilovskaya E, Koryak Y, Poltavskaya M, Saner H
Int J Cardiol: 06 Oct 2021; epub ahead of print | PMID: 34627967
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Abstract

Early and short-term intensive management after discharge for patients hospitalized with acute heart failure, a randomized study (ECAD-HF).

Logeart D, Berthelot E, Bihry N, Eschalier R, ... Vicaut E, Isnard R
Aims
Hospitalization for acute heart failure (HF) is followed by a vulnerable time with increased risk of readmission or death, thus requiring particular attention after discharge. In this study we examined the impact of intensive, early follow-up among patients at high readmission risk at discharge after treatment for acute HF.
Methods and results
Hospitalized acute HF patients were included with at least one of the following: previous acute HF < 6 months, systolic blood pressure ≤ 110 mmHg, creatininemia ≥180 μmol/L, or BNP ≥350 pg/mL or NTproBNP ≥2200 pg/mL. Patients were randomized to either optimized care and education with serial consultations with HF specialist and dietician during the first 2-3 weeks, or to standard post-discharge care according to guidelines. Primary end-point was all-cause death or first unplanned hospitalization during 6-month follow-up. Among 482 randomized patients (median age 77 and median left ventricular ejection fraction 35%), 224 were hospitalized or died. In the intensive group, loop diuretics (46%), betablockers (49%), ACE-inhibitors or angiotensin receptors blockers (39%) and mineralocorticoid receptor antagonists (47%) were titrated. No difference was observed between the two groups for primary end-point (HR 0.97; 95CI 0.74-1.26), nor for mortality at 6 or 12 months or unplanned HF rehospitalization. Additionally, no difference between the two groups according to age, previous HF and left ventricular ejection fraction was found.
Conclusion
In high-risk HF, we found intensive follow-up early post-discharge did not improve outcomes. This vulnerable post-discharge time requires further studies to clarify useful transitional care services. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 08 Oct 2021; epub ahead of print
Logeart D, Berthelot E, Bihry N, Eschalier R, ... Vicaut E, Isnard R
Eur J Heart Fail: 08 Oct 2021; epub ahead of print | PMID: 34628697
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Abstract

Feasibility and efficacy of transcatheter interatrial shunt devices for chronic heart failure: A systematic review and meta-analysis.

Lauder L, Pereira TV, Degenhardt MC, Ewen S, ... da Costa BR, Mahfoud F
Aims
To assess the feasibility and efficacy of interatrial shunt devices (IASD) for the treatment of chronic heart failure (CHF).
Methods
MEDLINE and the Cochrane Central Register of Controlled Trials from inception until April 2021 were searched for prospective studies investigating dedicated transcatheter IASD for the treatment of CHF. Standardised mean differences were calculated for the within-group changes before and after implantation of the IASD. The predefined primary outcome was change in six-minute walking distance (6MWD) from baseline to 12 months. Other outcomes were change in NYHA class, health-related quality of life (HRQoL), echocardiographic and hemodynamic data, device performance and safety. Subgroup analyses were crude univariable meta-regression analyses.
Results
Six studies (five single-arm open-label studies, one sham-controlled trial) were included. In these, 226 patients underwent IASD implantation using four different devices. From baseline to 12 months, 6MWD increased by 28.1 m (95% CI: 10.9 to 45.3) with no evidence for a difference between devices (p for interaction = 0.66) and patients with left-ventricular ejection fraction (LVEF) >40% or ≤ 40% (p for interaction = 0.21). At 12 months, HRQoL improved by 17.7 points (95% CI: 10.8 to 24.6) and pulmonary capillary wedge pressure (PCWP) decreased by 2.0 mmHg (95% CI: -3.6 to -0.4), respectively. There were no changes in LVEF or NT-proBNP during follow-up. Shunt patency ranged from 50% for the first-generation v-Wave to 100% for the Corvia IASD II and the second-generation v-Wave system. The summary risk of serious adverse device-related effects was 8% (95% CI: 1 to 20) at 12 months.
Conclusion
IASD implantation in CHF is feasible and associates with improved submaximal exercise capacity (measured by 6MWD) and HRQoL, and reductions in PCWP. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 09 Oct 2021; epub ahead of print
Lauder L, Pereira TV, Degenhardt MC, Ewen S, ... da Costa BR, Mahfoud F
Eur J Heart Fail: 09 Oct 2021; epub ahead of print | PMID: 34628706
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Abstract

Plasma Biomarkers Associated with Adverse Outcomes in Patients with Calcific Aortic Stenosis.

Vidula MK, Orlenko A, Zhao L, Salvador L, ... Gordon D, Chirinos JA
Aims
Enhanced risk stratification of patients with aortic stenosis (AS) is necessary to identify patients at high risk for adverse outcomes, and may allow for better management of patient subgroups at high risk of myocardial damage. The objective of this study was to identify plasma biomarkers and multimarker profiles associated with adverse outcomes in AS.
Methods and results
We studied 708 patients with calcific AS and measured 49 biomarkers using a Luminex platform. We studied the correlation between biomarkers and the risk of 1) death and 2) death or heart failure hospitalization (DHFA). We also utilized machine-learning (ML) methods (a tree-based pipeline optimizer platform) to develop multimarker models associated with the risk of death and DHFA. In this cohort with median follow-up of 2.8 years, multiple biomarkers were significantly predictive of death in analyses adjusted for clinical confounders, including TNF-α (hazard ratio (HR) 1.28, p < 0.0001), TNFRI (TNFRSF1A; HR 1.38, p < 0.0001), fibroblast growth factor (FGF)-23 (HR 1.22, p < 0.0001), NT-proBNP (HR 1.58, p < 0.0001), MMP-7 (HR 1.24, p = 0.0002), syndecan-1 (HR 1.27, p = 0.0002), ST2 (IL1RL1; HR 1.22, p = 0.0002), IL-8 (CXCL8; HR 1.22, p = 0.0005), pentraxin (PTX)-3 (HR 1.17, p = 0.001), NGAL (LCN2; HR 1.18, p < 0.0001), osteoprotegerin (OPG) (TNFRSF11B; HR 1.26, p = 0.0002), and endostatin (COL18A1; HR 1.28, p = 0.0012). Several biomarkers were also significantly predictive of DHFA in adjusted analyses including FGF-23 (HR 1.36, p < 0.0001), TNF-α (HR 1.26, p < 0.0001), TNFRI (HR 1.34, p < 0.0001), angiopoietin-2 (HR 1.26, p < 0.0001), syndecan-1 (HR 1.23, p = 0.0006), ST2 (HR 1.27, p < 0.0001), IL-8 (HR 1.18, p = 0.0009), PTX-3 (HR 1.18, p = 0.0002), OPG (HR 1.20, p = 0.0013), and NT-proBNP (HR 1.63, p < 0.0001). ML-multimarker models were strongly associated with adverse outcomes (mean 1-year probability of death of 0%, 2%, and 60%; mean 1-year probability of DHFA of 0%, 4%, 97%; p < 0.0001). In these models, IL-6 (a biomarker of inflammation) and FGF-23 (a biomarker of calcification) emerged as the biomarkers of highest importance.
Conclusion
Plasma biomarkers are strongly associated with the risk of adverse outcomes in patients with AS. Biomarkers of inflammation and calcification were most strongly related to prognosis. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 09 Oct 2021; epub ahead of print
Vidula MK, Orlenko A, Zhao L, Salvador L, ... Gordon D, Chirinos JA
Eur J Heart Fail: 09 Oct 2021; epub ahead of print | PMID: 34632675
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Abstract

The prevalence and clinical associations of ultrasound measures of congestion in patients at risk of developing heart failure.

Cuthbert JJ, Pellicori P, Flockton R, Kallvikbacka-Bennett A, ... Cleland JGF, Clark AL
Aims
Congestion is a cardinal feature of untreated heart failure (HF) and might be detected by ultrasound (US) before overt clinical signs appear.
Methods and results
We investigated the prevalence and clinical associations of subclinical congestion in 238 patients with at least one clinical risk factor for HF (diabetes, ischaemic heart disease, or hypertension) using three US variables: (i) inferior vena cava (IVC) diameter; (ii) jugular vein distensibility (JVD) ratio (the ratio of the jugular vein diameter during the Valsalva manoeuvre to that at rest); (iii) the number of B-lines from a 28-point lung US. US congestion was defined as IVC diameter > 2.0 cm, JVD ratio < 4.0 or B-lines count > 14. The prevalence of subclinical congestion (defined as at least one positive US marker of congestion) was 30% (13% by IVC diameter, 9% by JVD ratio and 13% by B-line quantification). Compared to patients with no congestion on US, those with at least one marker had larger left atria and higher plasma concentrations of natriuretic peptides. Patients with raised plasma N-terminal pro-B-type natriuretic peptide/B-type natriuretic peptide had a lower JVD ratio (7.69 vs. 8.80; P = 0.05) and more often had at least one lung B-line (74% vs. 63%; P = 0.05). However, plasma natriuretic peptide concentrations were more closely related to left atrial volume than other US measures of congestion.
Conclusions
Subclinical evidence of congestion by US is common in patients with clinical risk factors for HF. Whether these measurements provide additional value for predicting the development of HF and its prevention deserves consideration.

© 2021 European Society of Cardiology.

Eur J Heart Fail: 09 Oct 2021; epub ahead of print
Cuthbert JJ, Pellicori P, Flockton R, Kallvikbacka-Bennett A, ... Cleland JGF, Clark AL
Eur J Heart Fail: 09 Oct 2021; epub ahead of print | PMID: 34632680
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Abstract

Effects of an outpatient intervention comprising nurse-led non-invasive assessments, telemedicine support and remote cardiologists\' decisions in patients with heart failure (AMULET Study): a randomised controlled trial.

Krzesiński P, Jankowska EA, Siebert J, Galas A, ... Ponikowski P, Gielerak G
Aim
Prevention of heart failure (HF) hospitalisations and deaths constitutes a major therapeutic aim in patients with HF. The role of telemedicine in this context remains equivocal. We investigated whether an outpatient telecare based on nurse-led non-invasive assessments supporting remote therapeutic decisions (AMULET telecare) could improve clinical outcomes in patients after an episode of acute HF during the12-month follow-up.
Methods and results
In this prospective randomised controlled trial, patients with HF and left ventricular ejection fraction (LVEF) ≤49%, after an episode of acute HF within recent 6 months, were randomly assigned to receive either an outpatient telecare based on nurse-led non-invasive assessments (n = 300) (AMULET model) or standard care (n = 305). The primary outcome, being a composite of unplanned HF hospitalisation or cardiovascular death, occurred in 51 (17.1%) patients in the telecare group and 73 (23.9%) patients in the standard care group up to 12 months after randomization (HR: 0.69, 95% CI: 0.48-0.99, p = 0.044). The implementation of AMULET telecare, as compared to the standard care, reduced the risk of first unplanned HF hospitalisation (HR: 0.62; 95% CI: 0.42-0.91, p = 0.015) as well as the risk of total unplanned HF hospitalisations (HR: 0.64, 95% CI: 0.41-0.99, p = 0.044).There was no difference in cardiovascular mortality between the study groups (HR: 1.03, 95% CI: 0.54-1.67, p = 0.930).
Conclusion
AMULET telecare as compared to standard care significantly reduced the risk of HF hospitalisation or cardiovascular death during the 12-month follow-up among patients with HF and LVEF≤49% after an episode of acute HF (ClinicalTrials.gov: NCT03476590).

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 05 Oct 2021; epub ahead of print
Krzesiński P, Jankowska EA, Siebert J, Galas A, ... Ponikowski P, Gielerak G
Eur J Heart Fail: 05 Oct 2021; epub ahead of print | PMID: 34617373
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Abstract

A randomized clinical trial on the short-term effects of 12-week sacubitril/valsartan vs. enalapril on peak oxygen consumption in patients with heart failure with reduced ejection fraction: results from the ACTIVITY-HF study.

Halle M, Schöbel C, Winzer EB, Bernhardt P, ... Sieder C, Lecker LSM
Aims
ACTIVITY-HF was a randomized, double-blind, active-controlled study, which assessed the short-term effect of sacubitril/valsartan compared with the active comparator enalapril on improving maximal exercise capacity in patients with heart failure with reduced ejection fraction (HFrEF).
Methods and results
A total of 201 ambulatory patients with HFrEF (left ventricular ejection fraction ≤ 40%, New York Heart Association class III) across 34 centres in Germany were randomized (1:1) to receive sacubitril/valsartan 97/103 mg bid (n = 103) or enalapril 10 mg bid (n = 98). The primary endpoint of the study was the change from baseline in peak oxygen consumption (VO2 ; adjusted to body weight) after 12 weeks, and the key secondary endpoint was change from baseline in peak VO2 after 6 weeks. The study population was predominantly male (81.1%) with a mean age of 66.9 years and a body mass index of 29.4 kg/m2 . Change in peak VO2 from baseline to Week 12 was similar between sacubitril/valsartan and enalapril groups [least squares mean difference: 0.32 mL/min/kg; 95% confidence interval (CI) -0.21, 0.85; P = 0.2327]. Similarly, no significant differences were observed between the two treatment groups in minute ventilation to carbon dioxide production slope, exercise capacity at first ventilatory threshold or Borg scale at either Week 6 or Week 12. Change in heart rate at first ventilatory threshold was lower in the sacubitril/valsartan group compared with the enalapril group at Week 12 (mean -3.75 bpm; 95% CI -7.03, -0.48; P = 0.0248). The safety of sacubitril/valsartan was comparable to enalapril.
Conclusion
In patients with HFrEF, short-term treatment with sacubitril/valsartan for 12 weeks did not result in significant benefits on peak VO2 when compared with enalapril.

© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Eur J Heart Fail: 29 Sep 2021; epub ahead of print
Halle M, Schöbel C, Winzer EB, Bernhardt P, ... Sieder C, Lecker LSM
Eur J Heart Fail: 29 Sep 2021; epub ahead of print | PMID: 34591356
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Abstract

Changing age-specific trends in incidence, comorbidities and mortality of hospitalised heart failure in Western Australia between 2001 and 2016.

Weber C, Hung J, Hickling S, Li I, Murray K, Briffa T
Background
Incident heart failure (HF) hospitalisation rates in most high-income countries are stable or declining. However, HF incidence may be increasing in younger people linked to changing risk factor profiles in the general population. We examined age and sex-specific patterns of incidence, comorbidities and mortality of hospitalised HF in Western Australia (WA) between 2001 and 2016.
Methods and results
All WA residents aged 25-94 years, with an incident (first-ever) principal HF discharge diagnosis between 2001 and 2016 were included (n = 22,476). Poisson regression derived annual age and sex-standardised rates of incident HF and 1-year mortality overall, and by age groups (25-54, 55-74, 75-94), across the study period. Overall, the age and sex-standardised rates of incident HF increased marginally by 0.6% per year (95% confidence interval (CI), 0.3, 0.8) whereas incidence increased by 3.1% per year (95% CI, 2.2, 4.0) in the 25-54 year age-group (trend p < 0.0001). There was a high prevalence (≥15%) of obesity, diabetes mellitus, cardiomyopathy, hypertension, ischemic heart disease, atrial fibrillation, and chronic kidney disease in younger HF patients. Overall standardised 1-year mortality declined by -1.0% per year (95%CI, -0.4, -1.6), driven largely by the mortality decline in the 55-74 year age group.
Conclusion
Incident HF hospitalisation rates have been rising in WA since 2006, notably in individuals under 55 years. The underlying reasons require further investigation, particularly the population-attributable risk related to increasing obesity and diabetes mellitus in the general population. Rising HF incidence along with declining mortality rates portends to an increasing HF burden in the community.

Copyright © 2021 Elsevier B.V. All rights reserved.

Int J Cardiol: 14 Nov 2021; 343:56-62
Weber C, Hung J, Hickling S, Li I, Murray K, Briffa T
Int J Cardiol: 14 Nov 2021; 343:56-62 | PMID: 34520794
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Impact:
Abstract

Non-cardiology vs. cardiology care of patients with heart failure and reduced ejection fraction is associated with lower use of guideline-based care and higher mortality: Observations from The Swedish Heart Failure Registry.

Kapelios CJ, Canepa M, Benson L, Hage C, ... Savarese G, Lund LH
Background
Patients with heart failure (HF) are often cared for by non-cardiologists. The implications are unknown.
Methods
In a nationwide HF cohort with reduced ejection fraction (HFrEF), we compared demographics, clinical characteristics, guideline-based therapy use and outcomes in non-cardiology vs. cardiology in-patient and out-patient care.
Results
Between 2000 and 2016, 36,076 patients with HFrEF were enrolled in the Swedish HF registry (19,337 [54%] in-patients overall), with 44% of in-patients and 45% of out-patients managed in non-cardiology settings. Predictors of treatment in non-cardiology were age > 75 years (adjusted odds ratio for non-cardiology 1.20; 95% confidence interval 1.14-1.27), lower education level (0.71; 0.66-0.76 for university vs. compulsory), valve disease (1.24; 1.18-1.31) and systolic blood pressure (SBP) >120 mmHg (1.05; 1.00-1.10). Non-cardiology care was significantly associated with lower use of beta-blockers (0.80; 0.74-0.86) and devices (intracardiac defibrillator [ICD] and/or cardiac resynchronization therapy [CRT]: 0.63; 0.56-0.71), and less frequent specialist follow-up (0.61; 0.57-0.65). Over 1-year follow-up the risk of all-cause mortality (adjusted hazard ratio 1.09; 1.03-1.15) was higher but the risk of first HF (re-) hospitalization was lower (0.93; 0.89-0.97) in non-cardiology vs. cardiology care.
Conclusions
In HFrEF, non-cardiology care was independently associated with older ageand lower education. After covariate adjustment, non-cardiology care was associated with lower use of beta-blockers and devices, higher mortality, and lower risk of HF hospitalization. Access to cardiology care may not be equitable and this may have implications for use of guideline-based care and outcomes.

Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.

Int J Cardiol: 14 Nov 2021; 343:63-72
Kapelios CJ, Canepa M, Benson L, Hage C, ... Savarese G, Lund LH
Int J Cardiol: 14 Nov 2021; 343:63-72 | PMID: 34517016
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Impact:
Abstract

Effects of the exercise training on skeletal muscle oxygen consumption in heart failure patients with reduced ejection fraction.

Guimarães GV, Ribeiro F, Castro RE, Roque JM, ... Ferreira SA, Bocchi EA
Aims
Skeletal muscle dysfunction is a systemic consequence of heart failure (HF) that correlates with functional capacity. However, the impairment within the skeletal muscle is not well established. We investigated the effect of exercise training on peripheral muscular performance and oxygenation in HF patients.
Methods and results
HF patients with ejection fraction ≤40% were randomized 2:1 to exercise training or control for 12 weeks. Muscle tissue oxygen was measured noninvasively by near-infrared spectroscopy (NIRS) during rest and a symptom-limited cardiopulmonary exercise test (CPET) before and after intervention. Measurements included skeletal muscle oxygenated hemoglobin concentration, deoxygenated hemoglobin concentration, total hemoglobin concentration, VO2 peak, VE/VCO2 slope, and heart rate. Muscle sympathetic nerve activity by microneurography, and muscle blood flow by plethysmography were also assessed at rest pre and post 12 weeks. Twenty-four participants (47.5 ± 7.4 years, 58% men, 75% no ischemic) were allocated to exercise training (ET, n = 16) or control (CG, n = 8). At baseline, no differences between groups were found. Exercise improved VO2 peak, slope VE/VCO2, and heart rate. After the intervention, significant improvements at rest were seen in the ET group in muscle sympathetic nerve activity and muscle blood flow. Concomitantly, a significant decreased in Oxy-Hb (from 29.4 ± 20.4 to 15.7 ± 9.0 μmol, p = 0.01), Deoxi-Hb (from 16.3 ± 8.2 to 12.2 ± 6.0 μmol, p = 0.003) and HbT (from 45.7 ± 27.6 to 27.7 ± 13.4 μmol, p = 0.008) was detected at peak exercise after training. No changes were observed in the control group.
Conclusion
Exercise training improves skeletal muscle function and functional capacity in HF patients with reduced ejection fraction. This improvement was associated with increased oxygenation of the peripheral muscles, increased muscle blood flow, and decreased sympathetic nerve activity.

Copyright © 2021 Elsevier B.V. All rights reserved.

Int J Cardiol: 14 Nov 2021; 343:73-79
Guimarães GV, Ribeiro F, Castro RE, Roque JM, ... Ferreira SA, Bocchi EA
Int J Cardiol: 14 Nov 2021; 343:73-79 | PMID: 34506822
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Impact:
Abstract

Effects of SGLT-2 inhibitors on health-related quality of life and exercise capacity in heart failure patients with reduced ejection fraction: A systematic review and meta-analysis.

He Z, Yang L, Nie Y, Wang Y, ... Yao Y, Zhang Z
Objective
Improving health-related quality of life (HRQoL) and exercise capacity is an important goal of treatment in heart failure (HF). However, evidence for the effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on the improvement of HRQoL and exercise capacity seems to be conflicted. We performed a systematic review and meta-analysis to evaluate the effects of SGLT-2 inhibitors on HRQL and exercise capacity in patients with heart failure and reduced ejection fraction (HFrEF).
Methods
All studies (up to March 20, 2021) evaluating the effects of SGLT-2 inhibitors on HRQoL and exercise capacity in patients with HFrEF were initially searched from four electronic search engines: PubMed, Web of Science, Cochrane Library, and SinoMed. All statistical analyses were performed with RevMan 5.4.
Results
We included 9 articles describing 7 trials with 9428 patients. SGLT-2 inhibitors group exhibited significant improvement in HRQoL assessed by Kansas City Cardiomyopathy Questionnaires (KCCQ) (MD: 2.13, 95% CI: 1.11 to 3.14, p < 0.001) and the rate of KCCQ-overall summary score improvement≥5 points (RR 1.15, 95%CI 1.08 to 1.21, P < 0.001) compared with placebo. No significant difference was observed in exercise capacity assessed by 6-min walk test distance between SGLT-2 inhibitors and placebo (MD 24.45, 95%CI -22.82 to 71.72, P = 0.31).
Conclusions
Our meta-analysis demonstrates that SGLT-2 inhibitors significantly improve HRQoL, and supports the concept that SGLT-2 inhibitors do not significantly improve exercise capacity in patients with HFrEF. Studies with larger sample sizes and longer follow-up duration are needed to determine whether the treatment with SGLT-2 inhibitors may improve exercise ability.
Prospero
CRD42021248346.

Copyright © 2021. Published by Elsevier B.V.

Int J Cardiol: 11 Oct 2021; epub ahead of print
He Z, Yang L, Nie Y, Wang Y, ... Yao Y, Zhang Z
Int J Cardiol: 11 Oct 2021; epub ahead of print | PMID: 34653575
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Impact:
Abstract

Associations between prognostic awareness, acceptance of illness and psychological and spiritual well-being among patients with heart failure.

Ozdemir S, Lee JJ, Malhotra C, Teo I, ... Sim KLD, Finkelstein E
Background
This study aimed to (1) investigate the association of prognostic awareness with psychological (distress and emotional well-being) and spiritual well-being among patients with heart failure, and (2) assess the main and moderating effects of illness acceptance on the relationship between prognostic awareness and psychological (distress level and emotional well-being) and spiritual well-being.
Methods and results
This study used baseline data of a Singapore cohort of patients with heart failure (n=245) who had New York Heart Association class 3 or 4 symptoms. Patients reported their awareness of prognosis and extent of illness acceptance. Multivariable linear regressions were used to investigate the associations. Prognostic awareness was not significantly associated with psychological and spiritual well-being. Illness acceptance was associated with lower levels of distress [β (SE) = -0.9 (0.2); p<0.001], higher emotional well-being [β (SE) = 2.2 (0.4); p<0.001], and higher spiritual well-being [β (SE) = 5.4 (0.7); p<0.001]. Illness acceptance did not moderate the associations of prognostic awareness with psychological and spiritual well-being.
Conclusions
This study suggests that illness acceptance could be a key factor in improving patient well-being. Illness acceptance should be regularly assessed and interventions to enhance illness acceptance should be considered for those with poor acceptance.

Copyright © 2021 Elsevier Ltd. All rights reserved.

J Card Fail: 12 Oct 2021; epub ahead of print
Ozdemir S, Lee JJ, Malhotra C, Teo I, ... Sim KLD, Finkelstein E
J Card Fail: 12 Oct 2021; epub ahead of print | PMID: 34655774
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Impact:
Abstract

Exception Status Listing - A Critical Pathway to Heart Transplantation For Adults with Congenital Heart Diseases.

Rali AS, Ranka S, Mazurek JA, Brinkley MD, ... Schlendorf K, Menachem JN
Adults with congenital heart diseases may not be candidates for conventional therapies for ventricular systolic dysfunction including MCS which moves potential heart transplantation recipients to a higher priority listing status. This results in longer wait list times and mortality. Exception status listing allows for one pathway for this complex and anatomically heterogenous group of patients to be listed for heart transplantation at appropriately high listing status. Our study queried the United Network for Organ Sharing (UNOS) registry to evaluate trends in utilization of exception status listing amongst adults with congenital heart diseases awaiting heart transplantation. While uptrend in utilization of exception status listing precedes the new allocation system, it been greatest since change in allocation system. It continues to remain a vital pathway in allowing adults with CHD, whose waitlist mortality is often not adequately characterized using the waitlist status criteria, timely access to heart transplantation.

Copyright © 2021. Published by Elsevier Inc.

J Card Fail: 16 Oct 2021; epub ahead of print
Rali AS, Ranka S, Mazurek JA, Brinkley MD, ... Schlendorf K, Menachem JN
J Card Fail: 16 Oct 2021; epub ahead of print | PMID: 34670174
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Impact:
Abstract

Changing Demographics, Temporal Trends in Waitlist, and Posttransplant Outcomes After Heart Transplantation in the United States: Analysis of the UNOS Database 1991-2019.

Akintoye E, Alvarez P, Shin D, Egbe A, ... Sellke F, Briasoulis A
Background
We sought to investigate temporal trends in patient characteristics, waitlist, and posttransplant outcomes after heart transplantation in the United States.
Methods
Using data from the United Network of Organ Sharing, we identified adults listed for heart transplantation between 1991 and 2019. Patients were divided into 4 eras based on the 3 time points in which changes were made to the patient selection/allocation policy (Era 1=January 1991-January 1999; Era 2=January 1999-July 2006; Era 3=July 2006-October 2018; and Era 4=October 2018-March 2020), and patient characteristics, waitlist, and posttransplant outcomes were evaluated for each era.
Results
Between 1991 and 2019, 95 179 patients were added to the heart transplantation waitlist. Compared with Era 1, patients listed in Era 4 were older (mean age: 50 versus 52 years) and with higher risk comorbidities (eg, 10% versus 28.8% diabetes, 23.3% versus 35.6% obese). Over the study period, 22 738 patients died or were permanently delisted for deterioration on the waitlist while 61 687 were transplanted. Compared with the preceding era, there was significant decrease in death or deterioration in the last 2 eras (sub-hazard ratio, 0.67 [95% CI, 0.65-0.70] for Era 3 versus Era 2 and sub-hazard ratio, 0.65 [95% CI, 0.58-0.73] for Era 4 versus 3). Across the years, 27.1% to 40.5% of those on the waitlist were transplanted. Among those transplanted, there was increase in the rates of in-hospital stroke (2.8% in Era 1 to 3.7% in Era 4), renal failure requiring dialysis (7.2%-17.1%), and length-of-stay (14-17days), P<0.001. However, this did not negatively impact short-term survival when compared with the preceding era (1-year graft survival from Era 1 to Era 4=84.1%, 86.4%, 90.4%, and 89.7%, respectively).
Conclusions
There have been significant changes in the characteristics of patients listed for heart transplantation. Although transplant volume has increased, the wide supply-demand gap persisted. The last two changes in the allocation policy achieved their primary objective of reducing waitlist mortality.



Circ Heart Fail: 24 Oct 2021:CIRCHEARTFAILURE121008764; epub ahead of print
Akintoye E, Alvarez P, Shin D, Egbe A, ... Sellke F, Briasoulis A
Circ Heart Fail: 24 Oct 2021:CIRCHEARTFAILURE121008764; epub ahead of print | PMID: 34689572
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Impact:
Abstract

Death of a child and the risk of heart failure: a population-based cohort study from Denmark and Sweden.

Wei D, Li J, Janszky I, Chen H, ... Ljung R, László KD
Aims
We aimed to investigate whether the death of a child, one of the most severe stressors, is associated with the risk of heart failure (HF).
Methods and results
We conducted a population-based cohort study involving parents of live-born children recorded in the Danish and Swedish Medical Birth Registers during 1973-2016 and 1973-2014, respectively (n=6,717,349). We retrieved information on child death, HF diagnosis and sociodemographic characteristics of the parents from several nationwide registries. We performed Poisson regression models to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI) for HF in relation to bereavement. A total of 129,829 (1.9%) parents lost at least one child during the follow-up. Bereaved parents had a 35% higher risk of HF than the non-bereaved [IRR (95% CI): 1.35 (1.29-1.41), P<0.001]. The increased HF risk was observed not only when the child died due to cardiovascular or other natural causes, but also when the loss was due to unnatural causes. The association tended to be U-shaped when we categorized the exposed parents by the number of remaining live children at loss or by the age of the deceased child.
Conclusion
We found that the death of a child was associated with an increased risk of HF. The finding that not only cardiovascular and other natural deaths, but also unnatural deaths were associated with HF suggests that stress-related mechanisms may contribute to the development of HF. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 23 Oct 2021; epub ahead of print
Wei D, Li J, Janszky I, Chen H, ... Ljung R, László KD
Eur J Heart Fail: 23 Oct 2021; epub ahead of print | PMID: 34693593
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Impact:
Abstract

Rationale and Design of the Dapagliflozin after Transcatheter Aortic Valve Implantation (DapaTAVI) randomized trial.

Amat-Santos IJ, Sánchez-Luna JP, Abu-Assi E, Melendo Viu M, ... Raposeiras-Roubín S, Dapagliflozin after Transcatheter Aortic Valve Implantation (DapaTAVI) investigators
Aims
Despite aortic stenosis (AS) relief, patients undergoing transcatheter aortic valve implantation (TAVI) are at increased risk of developing heart failure (HF) within first months of intervention. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors have been shown to reduce the risk of HF hospitalization in individuals with diabetes mellitus (DM), reduced left ventricular ejection fraction (LVEF) and chronic kidney disease (CKD). However, the effect of SGLT-2 inhibitors on outcomes after TAVI is unknown. The Dapagliflozin after Transcatheter Aortic Valve Implantation (DapaTAVI) trial is designed to assess the clinical benefit and safety of the SGLT-2 inhibitor dapagliflozin in patients undergoing TAVI.
Methods
DapaTAVI is an independent pragmatic, controlled, prospective, randomized, open-label blinded end-point, multi-center trial conducted in Spain, evaluating the effect of dapagliflozin 10 mg/day on the risk of death and worsening HF in patients with severe AS undergoing a TAVI. Candidate patients should have prior history of HF admission plus ≥1 of the following criteria: 1) DM, 2) LVEF ≤40%, or 3) estimated glomerular filtrate rate between 25 and 75 mL/min/1.73 m2. A total of 1020 patients will be randomized (1:1) to dapagliflozin versus no dapagliflozin. Key secondary outcomes include: (i) Incidence rate of individual components of the primary outcome; (ii) Cardiovascular mortality; (iii) The composite of HF hospitalization or CV death; (iv) Total number of recurrent HF hospitalizations.
Conclusion
DapaTAVI will determine the efficacy and safety of dapagliflozin in a broad spectrum of frail patients after AS relief by TAVI. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 23 Oct 2021; epub ahead of print
Amat-Santos IJ, Sánchez-Luna JP, Abu-Assi E, Melendo Viu M, ... Raposeiras-Roubín S, Dapagliflozin after Transcatheter Aortic Valve Implantation (DapaTAVI) investigators
Eur J Heart Fail: 23 Oct 2021; epub ahead of print | PMID: 34693613
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Impact:
Abstract

Diuretic Changes, Health Care Resource Utilization, and Clinical Outcomes for Heart Failure With Reduced Ejection Fraction: From the Change the Management of Patients With Heart Failure Registry.

Khan MS, Greene SJ, Hellkamp AS, DeVore AD, ... Fonarow GC, Butler J
Background
Diuretics are a mainstay therapy for the symptomatic treatment of heart failure. However, in contemporary US outpatient practice, the degree to which diuretic dosing changes over time and the associations with clinical outcomes and health care resource utilization are unknown.
Methods
Among 3426 US outpatients with chronic heart failure with reduced ejection fraction in the Change the Management of Patients with Heart Failure registry with complete medication data and who were prescribed a loop diuretic, diuretic dose increase was defined as: (1) change to a total daily dose higher than their previous total daily dose, (2) addition of metolazone to the regimen, (3) change from furosemide to either bumetanide or torsemide, and the change persists for at least 7 days. Adjusted hazard ratios or rate ratios along with 95% CIs were reported for clinical outcomes among patients with an increase in oral diuretic dose versus no increase in diuretic dose.
Results
Overall, 796 (23%) had a diuretic dose increase (18 episodes per 100 patient-years). The proportion of patients with dyspnea at rest (38% versus 26%), dyspnea at exertion (79% versus 67%), orthopnea (32% versus 21%), edema (60% versus 43%), and weight gain (40% versus 23%) were significantly (all P <0.001) higher in the diuretic increase group. Baseline angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (hazard ratio, 0.75 [95% CI, 0.65-0.87]) use were associated with lower likelihood of diuretic increase over time. Patients with a diuretic dose increase had a significantly higher number of heart failure hospitalizations (rate ratio, 2.53 [95% CI, 2.10-3.05]), emergency department visits (rate ratio, 1.84 [95% CI, 1.56-2.17]), and home health visits (rate ratio, 1.88 [95% CI, 1.39-2.54]), but not all-cause mortality (hazard ratio, 1.10 [95% CI, 0.89-1.36]). Similarly, greater furosemide dose equivalent increases were associated with greater resource utilization but not with mortality, compared with smaller increases.
Conclusions
In this contemporary US registry, 1 in 4 patients with heart failure with reduced ejection fraction had outpatient escalation of diuretic therapy over longitudinal follow-up, and these patients were more likely to have sign/symptoms of congestion. Outpatient diuretic dose escalation of any magnitude was associated with heart failure hospitalizations and resource utilization, but not all-cause mortality.



Circ Heart Fail: 21 Oct 2021:CIRCHEARTFAILURE121008351; epub ahead of print
Khan MS, Greene SJ, Hellkamp AS, DeVore AD, ... Fonarow GC, Butler J
Circ Heart Fail: 21 Oct 2021:CIRCHEARTFAILURE121008351; epub ahead of print | PMID: 34674536
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Impact:
Abstract

Association of Hyper-Polypharmacy With Clinical Outcomes in Heart Failure With Preserved Ejection Fraction.

Minamisawa M, Claggett B, Suzuki K, Hegde SM, ... Solomon SD, Vardeny O
Background
Polypharmacy is associated with a poor prognosis in the elderly, however, information on the association of polypharmacy with cardiovascular outcomes in heart failure with preserved ejection fraction is sparse. This study sought to investigate the relationship between polypharmacy and adverse cardiovascular events in patients with heart failure with preserved ejection fraction.
Methods
Baseline total number of medications was determined in 1758 patients with heart failure with preserved ejection fraction enrolled in the Americas regions of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist), by 3 categories: nonpolypharmacy (<5 medications), polypharmacy (5-9), and hyper-polypharmacy (≥10). We examined the relationship of polypharmacy status with the primary outcome (cardiovascular death, HF hospitalization, or aborted cardiac arrest), hospitalizations for any reason, and serious adverse events.
Results
The proportion of patients taking 5 or more medications was 92.5% (inclusive of polypharmacy [38.7%] and hyper-polypharmacy [53.8%]). Over a 2.9-year median follow-up, compared with patients with polypharmacy, hyper-polypharmacy was associated with an increased risk for the primary outcome, hospitalization for any reason and any serious adverse events in the univariable analysis, but not significantly associated with mortality. After multivariable adjustment for demographic and comorbidities, hyper-polypharmacy remained significantly associated with an increased risk for hospitalization for any reason (hazard ratio, 1.22 [95% CI, 1.05-1.41]; P=0.009) and any serious adverse events (hazard ratio, 1.23 [95% CI, 1.07-1.42]; P=0.005), whereas the primary outcome was no longer statistically significant.
Conclusions
Hyper-polypharmacy was common and associated with an elevated risk of hospitalization for any reason and any serious adverse events in patients with heart failure with preserved ejection fraction. There were no significant associations between polypharmacy status and mortality.



Circ Heart Fail: 21 Oct 2021:CIRCHEARTFAILURE120008293; epub ahead of print
Minamisawa M, Claggett B, Suzuki K, Hegde SM, ... Solomon SD, Vardeny O
Circ Heart Fail: 21 Oct 2021:CIRCHEARTFAILURE120008293; epub ahead of print | PMID: 34674539
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Impact:
Abstract

Pathophysiology of Takotsubo Syndrome - a joint scientific statement from the Heart Failure Association Takotsubo Syndrome Study Group and Myocardial Function Working Group of the European Society of Cardiology - Part 2: vascular pathophysiology, gender and sex hormones, genetics, chronic cardiovascular problems and clinical implications.

Omerovic E, Citro R, Bossone E, Redfors B, ... Heymans S, Lyon AR
While the first part of the scientific statement on the pathophysiology of Takotsubo syndrome was focused the catecholamines and sympathetic nervous system, in the second part we focus on the vascular pathophysiology including coronary and systemic vascular responses, the role of the central and peripheral nervous systems during the acute phase and abnormalities in the subacute phase, the gender differences and integrated effects of sex hormones, genetics of Takotsubo syndrome including insights from microRNA studies and inducible pluripotent stem cell models of Takotsubo syndrome. We then discuss the chronic abnormalities of cardiovascular physiology in survivors, the limitations of current clinical and preclinical studies, the implications of the knowledge of pathophysiology for clinical management and future perspectives and directions of research. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 15 Oct 2021; epub ahead of print
Omerovic E, Citro R, Bossone E, Redfors B, ... Heymans S, Lyon AR
Eur J Heart Fail: 15 Oct 2021; epub ahead of print | PMID: 34655287
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Impact:
Abstract

Myocardial Perfusion in Hypoplastic Left Heart Syndrome: Risk Factors for the Right Ventricular Microcirculation.

Rickers C, Wegner P, Silberbach M, Madriago E, ... Jerosch-Herold M, Kramer HH
Background
The status of the systemic right ventricular coronary microcirculation in hypoplastic left heart syndrome (HLHS) is largely unknown. It is presumed that the systemic right ventricle\'s coronary microcirculation exhibits unique pathophysiological characteristics of HLHS in Fontan circulation. The present study sought to quantify myocardial blood flow by cardiac magnetic resonance imaging and evaluate the determinants of microvascular coronary dysfunction and myocardial ischemia in HLHS.
Methods
One hundred nineteen HLHS patients (median age, 4.80 years) and 34 healthy volunteers (median age, 5.50 years) underwent follow-up cardiac magnetic resonance imaging ≈1.8 years after total cavopulmonary connection. Right ventricle volumes and function, myocardial perfusion, diffuse fibrosis, and late gadolinium enhancement were assessed in 4 anatomic HLHS subtypes. Myocardial blood flow (MBF) was quantified at rest and during adenosine-induced hyperemia. Coronary conductance was estimated from MBF at rest and catheter-based measurements of mean aortic pressure (n=99).
Results
Hyperemic MBF in the systemic ventricle was lower in HLHS compared with controls (1.89±0.57 versus 2.70±0.84 mL/g per min; P<0.001), while MBF at rest normalized by the rate-pressure product, was similar (1.25±0.36 versus 1.19±0.33; P=0.446). Independent risk factors for a reduced hyperemic MBF were an HLHS subtype with mitral stenosis and aortic atresia (P=0.017), late gadolinium enhancement (P=0.042), right ventricular diastolic dysfunction (P=0.005), and increasing age at total cavopulmonary connection (P=0.022). The coronary conductance correlated negatively with systemic blood oxygen saturation (r, -0.29; P=0.02). The frequency of late gadolinium enhancement increased with age at total cavopulmonary connection (P=0.014).
Conclusions
The coronary microcirculation of the systemic ventricle in young HLHS patients shows significant differences compared with controls. These hypothesis-generating findings on HLHS-specific risk factors for microvascular dysfunction suggest a potential benefit from early relief of frank cyanosis by total cavopulmonary connection.



Circ Cardiovasc Imaging: 05 Oct 2021:CIRCIMAGING121012468; epub ahead of print
Rickers C, Wegner P, Silberbach M, Madriago E, ... Jerosch-Herold M, Kramer HH
Circ Cardiovasc Imaging: 05 Oct 2021:CIRCIMAGING121012468; epub ahead of print | PMID: 34610753
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Impact:
Abstract

Interleukin-1 blockade with Anakinra and heart failure following ST-segment elevation myocardial infarction: results from a pooled analysis of the VCUART clinical trials.

Abbate A, Wohlford GF, Del Buono MG, Chiabrando JG, ... Lipinski MJ, Van Tassell BW
Aims
ST segment elevation myocardial infarction (STEMI) is associated with an intense acute inflammatory response and an increased risk of death and heart failure (HF). In this study we sought to evaluate the effect of anakinra, a recombinant interleukin-1 receptor antagonist, on the incidence of HF.
Methods and results
We performed a pooled analysis of three early phase randomized clinical trials. The endpoints included the composite of all-cause death and new-onset HF, and the composite of all-cause death and hospitalization for HF at 1 year follow-up. Safety events, including injection site reaction and serious infections, were also recorded. We analyzed 139 patients with STEMI from three separate trials: VCUART (N = 10), VCUART2 (N = 30), and VCUART3 (N = 99). Of these, 84 (60%) patients were randomized to anakinra and 55 (40%) to placebo. Treatment with anakinra significantly reduced the incidence of all-cause death or new-onset HF (7 [8.2%] vs 16 [29.1%], log-rank P = 0.002) and of all-cause death or HF hospitalization (0 [0] vs 5 [9.1%], log-rank P = 0.007). Patients treated with anakinra had significantly higher injection site reactions (19 [22.6%] vs 3 [5.5%], P = 0.016) without a significant difference in the incidence of serious infections (11 [13.1%] vs 7 [12.7%], P = 0.435). Treatment with anakinra significantly reduced the area under the curve for high-sensitivity C-Reactive-Protein between baseline and 14 days (75.48 [41.7-147.47] vs 222.82 [222.82 [117.22-399.28] mg•day/L, P < 0.001).
Conclusions
IL-1 blockade with anakinra for 14 days in patients with STEMI reduces the incidence of new onset HF or hospitalization for HF at 1 year following STEMI.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Pharmacother: 06 Oct 2021; epub ahead of print
Abbate A, Wohlford GF, Del Buono MG, Chiabrando JG, ... Lipinski MJ, Van Tassell BW
Eur Heart J Cardiovasc Pharmacother: 06 Oct 2021; epub ahead of print | PMID: 34617567
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Impact:
Abstract

Diabetes status-related differences in risk factors and mediators of heart failure in the general population: results from the MORGAM/BiomarCaRE consortium.

Vuori MA, Reinikainen J, Söderberg S, Bergdahl E, ... Kuulasmaa K, Niiranen TJ
Background
The risk of heart failure among diabetic individuals is high, even under tight glycemic control. The correlates and mediators of heart failure risk in individuals with diabetes need more elucidation in large population-based cohorts with long follow-up times and a wide panel of biologically relevant biomarkers.
Methods
In a population-based sample of 3834 diabetic and 90,177 non-diabetic individuals, proportional hazards models and mediation analysis were used to assess the relation of conventional heart failure risk factors and biomarkers with incident heart failure.
Results
Over a median follow-up of 13.8 years, a total of 652 (17.0%) and 5524 (6.1%) cases of incident heart failure were observed in participants with and without diabetes, respectively. 51.4% were women and the mean age at baseline was 48.7 (standard deviation [SD] 12.5) years. The multivariable-adjusted hazard ratio (HR) for heart failure among diabetic individuals was 2.70 (95% confidence interval, 2.49-2.93) compared to non-diabetic participants. In the multivariable-adjusted Cox models, conventional cardiovascular disease risk factors, such as smoking (diabetes: HR 2.07 [1.59-2.69]; non-diabetes: HR 1.85 [1.68-2.02]), BMI (diabetes: HR 1.30 [1.18-1.42]; non-diabetes: HR 1.40 [1.35-1.47]), baseline myocardial infarction (diabetes: HR 2.06 [1.55-2.75]; non-diabetes: HR 2.86 [2.50-3.28]), and baseline atrial fibrillation (diabetes: HR 1.51 [0.82-2.80]; non-diabetes: HR 2.97 [2.21-4.00]) had the strongest associations with incident heart failure. In addition, biomarkers for cardiac strain (represented by nT-proBNP, diabetes: HR 1.26 [1.19-1.34]; non-diabetes: HR 1.43 [1.39-1.47]), myocardial injury (hs-TnI, diabetes: HR 1.10 [1.04-1.16]; non-diabetes: HR 1.13 [1.10-1.16]), and inflammation (hs-CRP, diabetes: HR 1.13 [1.03-1.24]; non-diabetes: HR 1.29 [1.25-1.34]) were also associated with incident heart failure. In general, all these associations were equally strong in non-diabetic and diabetic individuals. However, the strongest mediators of heart failure in diabetes were the direct effect of diabetes status itself (relative effect share 43.1% [33.9-52.3] and indirect effects (effect share 56.9% [47.7-66.1]) mediated by obesity (BMI, 13.2% [10.3-16.2]), cardiac strain/volume overload (nT-proBNP, 8.4% [-0.7-17.4]), and hyperglycemia (glucose, 12.0% [4.2-19.9]).
Conclusions
The findings suggest that the main mediators of heart failure in diabetes are obesity, hyperglycemia, and cardiac strain/volume overload. Conventional cardiovascular risk factors are strongly related to incident heart failure, but these associations are not stronger in diabetic than in non-diabetic individuals. Active measurement of relevant biomarkers could potentially be used to improve prevention and prediction of heart failure in high-risk diabetic patients.

© 2021. The Author(s).

Cardiovasc Diabetol: 27 Sep 2021; 20:195
Vuori MA, Reinikainen J, Söderberg S, Bergdahl E, ... Kuulasmaa K, Niiranen TJ
Cardiovasc Diabetol: 27 Sep 2021; 20:195 | PMID: 34583686
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Impact:
Abstract

The association of hepatic steatosis and fibrosis with heart failure and mortality.

Park J, Kim G, Kim H, Lee J, ... Hur KY, Kim JH
Background
Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic disease and independently affects the development of cardiovascular (CV) disease. We investigated whether hepatic steatosis and/or fibrosis are associated with the development of incident heart failure (iHF), hospitalized HF (hHF), mortality, and CV death in both the general population and HF patients.
Methods
We analyzed 778,739 individuals without HF and 7445 patients with pre-existing HF aged 40 to 80 years who underwent a national health check-up from January 2009 to December 2012. The presence of hepatic steatosis and advanced hepatic fibrosis was determined using cutoff values for fatty liver index (FLI) and BARD score. We evaluated the association of FLI or BARD score with the development of iHF, hHF, mortality and CV death using multivariable-adjusted Cox regression models.
Results
A total of 28,524 (3.7%) individuals in the general population and 1422 (19.1%) pre-existing HF patients developed iHF and hHF respectively. In the multivariable-adjusted model, participants with an FLI ≥ 60 were at increased risk for iHF (hazard ratio [HR], 95% confidence interval [CI], 1.30, 1.24-1.36), hHF (HR 1.54, 95% CI 1.44-1.66), all-cause mortality (HR 1.62, 95% CI 1.54-1.70), and CV mortality (HR 1.41 95% CI 1.22-1.63) in the general population and hHF (HR 1.26, 95% CI 1.21-1.54) and all-cause mortality (HR 1.54 95% CI 1.24-1.92) in the HF patient group compared with an FLI < 20. Among participants with NAFLD, advanced liver fibrosis was associated with increased risk for iHF, hHF, and all-cause mortality in the general population and all-cause mortality and CV mortality in the HF patient group (all p < 0.05).
Conclusion
Hepatic steatosis and/or advanced fibrosis as assessed by FLI and BARD score was significantly associated with the risk of HF and mortality.

© 2021. The Author(s).

Cardiovasc Diabetol: 27 Sep 2021; 20:197
Park J, Kim G, Kim H, Lee J, ... Hur KY, Kim JH
Cardiovasc Diabetol: 27 Sep 2021; 20:197 | PMID: 34583706
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Impact:
Abstract

Serum biomarkers of acute rejection: Towards precision medicine in heart transplant.

Ortiz-Bautista C, Fernández-Avilés F, Delgado Jiménez JF
Despite the important changes in the management of heart transplantation in the recent decades, the use of endomyocardial biopsy is still necessary for the follow-up of these patients. However, this technique has several limitations, the most important being the substantial interobserver variability. In the last years multiple attempts have been made to find non-invasive assays for cardiac allograft surveillance, such as imaging modalities and serum biomarkers. This state-of-the-art review focuses on describing the different serum biomarkers that have been proposed for non-invasive diagnosis of acute rejection and that are paving the way towards precision medicine in the field of heart transplantation.

Copyright © 2021. Published by Elsevier Inc.

J Heart Lung Transplant: 29 Sep 2021; 40:1090-1097
Ortiz-Bautista C, Fernández-Avilés F, Delgado Jiménez JF
J Heart Lung Transplant: 29 Sep 2021; 40:1090-1097 | PMID: 34330605
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Impact:
Abstract

Development and validation of specific post-transplant risk scores according to the circulatory support status at transplant: A UNOS cohort analysis.

Coutance G, Bonnet G, Kransdorf EP, Loupy A, ... Kobashigawa JA, Patel JK
Background
The clinical use of post-transplant risk scores is limited by their poor statistical performance. We hypothesized that developing specific prognostic models for each type of circulatory support at transplant may improve risk stratification.
Methods
We analyzed the UNOS database including contemporary, first, non-combined heart transplantations (2013-2018). The endpoint was death or retransplantation during the first year post-transplant. Three different circulatory support statuses at transplant were considered: no support, durable mechanical support and temporary support (inotropes, temporary mechanical support). We generated 1,000 bootstrap samples that we randomly split into derivation and test sets. In each sample, we derived an overall model and 3 specific models (1 for each type of circulatory support) using Cox regressions, and compared, in the test set, their statistical performance for each type of circulatory support.
Results
A total of 13,729 patients were included; 1,220 patients (8.9%) met the composite endpoint. Circulatory support status at transplant was associated with important differences in baseline characteristics and distinct prognosis (p = 0.01), interacted significantly with important predictive variables included in the overall model, and had a major impact on post-transplant predictive models (type of variables included and their corresponding hazard ratios). However, specific models suffered from poor discriminative performance and significantly improved risk stratification (discrimination, reclassification indices, calibration) compared to overall models in a very limited proportion of bootstrap samples (<15%). These results were consistent across several sensitivity analyzes.
Conclusion
Circulatory support status at transplant reflected different disease states that influenced predictive models. However, developing specific models for each circulatory support status did not significantly improve risk stratification.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1235-1246
Coutance G, Bonnet G, Kransdorf EP, Loupy A, ... Kobashigawa JA, Patel JK
J Heart Lung Transplant: 29 Sep 2021; 40:1235-1246 | PMID: 34274182
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Impact:
Abstract

IRF4 ablation in B cells abrogates allogeneic B cell responses and prevents chronic transplant rejection.

Wang G, Zou D, Wang Y, Gonzalez NM, ... Chen W, Gaber AO
Backgound
B cells contribute to chronic transplant rejection by producing donor-specific antibodies and promoting T cell response, but how these processes are regulated at the transcriptional level remains unclear. Herein, we investigate the role of transcription factor interferon regulatory factor 4 (IRF4) in controlling B cell response during chronic transplant rejection.
Methods
We generated the Irf4gfp reporter mice to determine IRF4 expression in B cell lineage. We then used mice with B cell-specific IRF4 deletion to define the role of IRF4 in B cell response after NP-KLH immunization or allogeneic heart transplantation. In particular, graft survival and histology, as well as B and T cell responses, were evaluated after transplantation.
Results
IRF4 is dynamically expressed at different stages of B cell development and is absent in germinal center (GC) B cells. However, IRF4 ablation in the B cell lineage primarily eliminates GC B cells in both naïve and NP-KLH immunized mice. In the transplantation setting, IRF4 functions intrinsically in B cells and governs allogeneic B cell responses at multiple levels, including GC B cell generation, plasma cell differentiation, donor-specific antibody production, and support of T cell response. B cell-specific IRF4 deletion combined with transient CTLA4-Ig treatment abrogates acute and chronic cardiac allograft rejection in naïve recipient mice but not in donor skin-sensitized recipients.
Conclusions
B cells require IRF4 to mediate chronic transplant rejection. IRF4 ablation in B cells abrogates allogeneic B cell responses and may also inhibit the ability of B cells to prime allogenic T cells. Targeting IRF4 in B cells represents a potential therapeutic strategy for eliminating chronic transplant rejection.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1122-1132
Wang G, Zou D, Wang Y, Gonzalez NM, ... Chen W, Gaber AO
J Heart Lung Transplant: 29 Sep 2021; 40:1122-1132 | PMID: 34253454
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Impact:
Abstract

Implantable cardioverter defibrillators in left ventricular assist device patients: Α systematic review and meta-analysis.

Rorris FP, Antonopoulos CN, Kyriakopoulos CP, Drakos SG, Charitos C
Implantable cardioverter-defibrillators (ICDs) remain the standard of care in advanced heart failure with reduced ejection fraction patients for the prevention of sudden cardiac death. However, current guidelines remain conflicting with respect to the use of ICDs in patients supported with a continuous flow left ventricular assist device (CF-LVAD). The current review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies comparing the use of ICD in patients with CF-LVADs were included. The 2 primary outcomes studied were all-cause mortality, and a successful bridge to heart transplantation. We calculated pooled odds ratios (ORs) with 95% confidence intervals (CIs). We also compared baseline characteristics between US and European studies, for CF-LVAD patients with an ICD. Among all studies, the use of an ICD was not associated with all-cause mortality in patients with CF-LVADs (OR: 0.85, 95% CIs: 0.64-1.12, p = 0.24). The presence of an ICD was associated with a trend towards increased likelihood of successful bridge to heart transplantation (OR: 1.12, 95% CI: 1.0-1.3, p = 0.06). A subgroup analysis of studies published by European centers revealed a significant decrease in pooled mortality (OR: 0.58, 95% CI: 0.4-0.83, p = 0.003) with the use of ICD, contrary to an increase in pooled mortality among studies published by US centers (OR: 1.2, 95% CI 1.02-1.33, p = 0.025). Moreover, we identified significant differences in baseline characteristics such as bridge to transplantation rate, Interagency Registry for Mechanically Assisted Circulatory Support profiles, and use of an intra-aortic balloon pump or extracorporeal membrane oxygenation preoperatively, between the US and European populations. While this meta-analysis did not show an overall survival benefit with the use of an ICD in CF-LVAD patients, it revealed significant differences in the derived benefit, in distinct patient populations. This might reflect differences in baseline patient characteristics and warrants further investigation.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1098-1106
Rorris FP, Antonopoulos CN, Kyriakopoulos CP, Drakos SG, Charitos C
J Heart Lung Transplant: 29 Sep 2021; 40:1098-1106 | PMID: 34176727
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Impact:
Abstract

Improved heart transplant survival for children with congenital heart disease and heterotaxy syndrome in the current era: An analysis from the pediatric heart transplant society.

Khan A, Pahl E, Koehl DA, Cantor RS, ... Azeka E, Everitt MD
Background
Challenges exist with heterotaxy due to the complexity of heart disease, abnormal venous connections, and infection risks. This study aims to understand heart transplant outcomes for children with heterotaxy.
Methods
All children with congenital heart disease listed for transplant from 1993 to 2018 were included. Those with and without heterotaxy were compared. Waitlist outcomes and survival post-listing and transplant were analyzed. Post-transplant risk factors were identified using multiphase parametric hazard modeling.
Results
There were 4814 children listed, of whom 196 (4%) had heterotaxy. Heterotaxy candidates were older (5.8 ± 5.7 vs 4.2 ± 5.5 years, p < 0.01), listed at a lower urgency status (29.8% vs 18.4%, p < 0.01), more commonly single ventricle physiology (71.3% vs 59.2%, p < 0.01), and less often supported by mechanical ventilation (22% vs 29.1%, p < 0.05) or extracorporeal membrane oxygenation (3.6% vs 7.5%, p < 0.05). There were no differences in waitlist outcomes of transplant, death, or removal. Overall, post-transplant survival was worse for children with heterotaxy: one-year survival 77.2% vs 85.1%, with and without heterotaxy, respectively. Heterotaxy was an independent predictor for early mortality in the earliest era (1993-2004), HR 2.09, CI 1.16-3.75, p = 0.014. When stratified by era, survival improved with time. Heterotaxy patients had a lower freedom from infection and from severe rejection, but no difference in vasculopathy or malignancy.
Conclusions
Mortality risk associated with heterotaxy is mitigated in the recent transplant era. Early referral may improve waitlist outcomes for heterotaxy patients who otherwise have a lower status at listing. Lower freedom from both infection and severe rejection after transplant in heterotaxy highlights the challenges of balancing immune suppression.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1153-1163
Khan A, Pahl E, Koehl DA, Cantor RS, ... Azeka E, Everitt MD
J Heart Lung Transplant: 29 Sep 2021; 40:1153-1163 | PMID: 34366230
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Impact:
Abstract

Lung protective ventilation based on donor size is associated with a lower risk of severe primary graft dysfunction after lung transplantation.

Tague LK, Bedair B, Witt C, Byers DE, ... Gelman A, Hachem RR
Background
Mechanical ventilation immediately after lung transplantation may impact the development of primary graft dysfunction (PGD), particularly in cases of donor-recipient size mismatch as ventilation is typically based on recipient rather than donor size.
Methods
We conducted a retrospective cohort study of adult bilateral lung transplant recipients at our center between January 2010 and January 2017. We defined donor-based lung protective ventilation (dLPV) as 6 to 8 ml/kg of donor ideal body weight and plateau pressure <30 cm H2O. We calculated the donor-recipient predicted total lung capacity (pTLC) ratio and used logistic regression to examine relationships between pTLC ratio, dLPV and PGD grade 3 at 48 to 72 hours. We used Cox proportional hazards modelling to examine the relationship between pTLC ratio, dLPV and 1-year survival.
Results
The cohort included 373 recipients; 24 (6.4%) developed PGD grade 3 at 48 to 72 hours, and 213 (57.3%) received dLPV. Mean pTLC ratio was 1.04 ± 0.18. dLPV was associated with significantly lower risks of PGD grade 3 (OR = 0.44; 95% CI: 0.29-0.68, p < 0.001) and 1-year mortality (HR = 0.49; 95% CI: 0.29-0.8, p = 0.018). There was a significant association between pTLC ratio and the risk of PGD grade 3, but this was attenuated by the use of dLPV.
Conclusions
dLPV is associated with decreased risk of PGD grade 3 at 48 to 72 hours and decreased 1-year mortality. Additionally, dLPV attenuates the association between pTLC and both PGD grade 3 and 1-year mortality. Donor-based ventilation strategies may help to mitigate the risk of PGD and other adverse outcomes associated with size mismatch after lung transplantation.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1212-1222
Tague LK, Bedair B, Witt C, Byers DE, ... Gelman A, Hachem RR
J Heart Lung Transplant: 29 Sep 2021; 40:1212-1222 | PMID: 34353713
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Impact:
Abstract

Effect of riociguat on right ventricular function in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

Benza RL, Ghofrani HA, Grünig E, Hoeper MM, ... Meier C, Ghio S
Background
In the Phase III PATENT-1 (NCT00810693) and CHEST-1 (NCT00855465) studies, riociguat demonstrated efficacy vs placebo in patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Clinical effects were maintained at 2 years in the long-term extension studies PATENT-2 (NCT00863681) and CHEST-2 (NCT00910429).
Methods
This post hoc analysis of hemodynamic data from PATENT-1 and CHEST-1 assessed whether riociguat improved right ventricular (RV) function parameters including stroke volume index (SVI), stroke volume, RV work index, and cardiac efficiency. REVEAL Risk Score (RRS) was calculated for patients stratified by SVI and right atrial pressure (RAP) at baseline and follow-up. The association between RV function parameters and SVI and RAP stratification with long-term outcomes was assessed.
Results
In PATENT-1 (n = 341) and CHEST-1 (n = 238), riociguat improved RV function parameters vs placebo (p < 0.05). At follow-up, there were significant differences in RRS between patients with favorable and unfavorable SVI and RAP, irrespective of treatment arm (p < 0.0001). Multiple RV function parameters at baseline and follow-up were associated with survival and clinical worsening-free survival (CWFS) in PATENT-2 (n = 396; p < 0.05) and CHEST-2 (n = 237). In PATENT-2, favorable SVI and RAP at follow-up only was associated with survival and CWFS (p < 0.05), while in CHEST-2, favorable SVI and RAP at baseline and follow-up were associated with survival and CWFS (p < 0.05).
Conclusion
This post hoc analysis of PATENT and CHEST suggests that riociguat improves RV function in patients with PAH and CTEPH.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1172-1180
Benza RL, Ghofrani HA, Grünig E, Hoeper MM, ... Meier C, Ghio S
J Heart Lung Transplant: 29 Sep 2021; 40:1172-1180 | PMID: 34353714
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Impact:
Abstract

The modified US heart allocation system improves transplant rates and decreases status upgrade utilization for patients with hypertrophic cardiomyopathy.

Fowler CC, Helmers MR, Smood B, Iyengar A, ... Kelly J, Atluri P
Background
On October 18, 2018, the US heart allocation policy was restructured to improve transplant waitlist outcomes. Previously, hypertrophic cardiomyopathy (HCM) patients experienced significant waitlist mortality and functional decline, often requiring status exemptions to be transplanted. This study aims to examine changes in waitlist mortality and transplant rates of HCM patients in the new system.
Methods
Retrospective analysis was performed of the United Network for Organ Sharing Transplant Database for all isolated adult single-organ first-time heart transplant patients with HCM listed between October 17, 2013 and September 4, 2020. Patients were divided by listing date into eras based on allocation system. Era 1 spanned October 17, 2013 to October 17th, 2018 and Era 2 spanned October 18th, 2018 to September 4, 2020.
Results
During the study period, 436 and 212 HCM patients were listed in Eras 1 and 2, respectively. Across eras, no differences in gender, ethnicity, BMI or functional status were noted (p>0.05). LVAD utilization remained low (Era 1: 3.7% vs Era 2: 3.3%, p = 0.297). Status upgrades decreased from 49.1% to 31.6% across eras (p = 0.001). There was no statistically significant difference in waitlist mortality across eras (p = 0.332). Transplant rates were improved in Era 2 (p = 0.005). Waitlist time among transplanted patients decreased in Era 2 from 97.1 to 63.9 days (p<0.001). There was no difference in one-year survival post-transplant (p = 0.602).
Conclusions
The new allocation system has significantly increased transplant rates, shortened waitlist times, and decreased status upgrade utilization for HCM patients. Moreover, waitlist mortality remained unchanged in the new system.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1181-1190
Fowler CC, Helmers MR, Smood B, Iyengar A, ... Kelly J, Atluri P
J Heart Lung Transplant: 29 Sep 2021; 40:1181-1190 | PMID: 34332861
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Impact:
Abstract

Plasma kallikrein predicts primary graft dysfunction after heart transplant.

Giangreco NP, Lebreton G, Restaino S, Jane Farr M, ... Tatonetti NP, Fine BM
Background
Primary graft dysfunction (PGD) is the leading cause of early mortality after heart transplant. Pre-transplant predictors of PGD remain elusive and its etiology remains unclear.
Methods
Microvesicles were isolated from 88 pre-transplant serum samples and underwent proteomic evaluation using TMT mass spectrometry. Monte Carlo cross validation (MCCV) was used to predict the occurrence of severe PGD after transplant using recipient pre-transplant clinical characteristics and serum microvesicle proteomic data. Putative biological functions and pathways were assessed using gene set enrichment analysis (GSEA) within the MCCV prediction methodology.
Results
Using our MCCV prediction methodology, decreased levels of plasma kallikrein (KLKB1), a critical regulator of the kinin-kallikrein system, was the most predictive factor identified for PGD (AUROC 0.6444 [0.6293, 0.6655]; odds 0.1959 [0.0592, 0.3663]. Furthermore, a predictive panel combining KLKB1 with inotrope therapy achieved peak performance (AUROC 0.7181 [0.7020, 0.7372]) across and within (AUROCs of 0.66-0.78) each cohort. A classifier utilizing KLKB1 and inotrope therapy outperforms existing composite scores by more than 50 percent. The diagnostic utility of the classifier was validated on 65 consecutive transplant patients, resulting in an AUROC of 0.71 and a negative predictive value of 0.92-0.96. Differential expression analysis revealed a enrichment in inflammatory and immune pathways prior to PGD.
Conclusions
Pre-transplant level of KLKB1 is a robust predictor of post-transplant PGD. The combination with pre-transplant inotrope therapy enhances the prediction of PGD compared to pre-transplant KLKB1 levels alone and the resulting classifier equation validates within a prospective validation cohort. Inflammation and immune pathway enrichment characterize the pre-transplant proteomic signature predictive of PGD.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1199-1211
Giangreco NP, Lebreton G, Restaino S, Jane Farr M, ... Tatonetti NP, Fine BM
J Heart Lung Transplant: 29 Sep 2021; 40:1199-1211 | PMID: 34330603
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Impact:
Abstract

Outcomes of pre- heart transplantation desensitization in a series of highly sensitized patients bridged with left ventricular assist devices.

Saadi TA, Lawrecki T, Narang N, Joshi A, ... Cotts W, Andrade A
Desensitization therapy for heart transplantation (HT) candidates can shorten transplant wait times and broaden the donor pool. Specific evidence-based recommendations on both protocols and indications are lacking. We retrospectively assessed left ventricular assist devices-bridged candidates who received pre-HT desensitization therapy. The therapeutic protocol consisted of intravenous immunoglobulin and rituximab followed by bortezomib and plasmapheresis if an insufficient response was achieved. Desensitization was attempted in 10 patients; only 7 tolerated therapy and underwent transplant. For those patients, median decrease in unacceptable calculated panel reactive antibody was 11%; there was no significant decrease for 3 patients. Post-desensitization adverse events were observed in all patients which included coagulopathy, bone marrow suppression, and infection. Median time to first infection was 16 days. One patient had clinically significant rejection and 3 patients had uptrending donor-specific antibodies. Decisions to proceed with desensitization should be individualized understanding potential risks and benefits.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1107-1111
Saadi TA, Lawrecki T, Narang N, Joshi A, ... Cotts W, Andrade A
J Heart Lung Transplant: 29 Sep 2021; 40:1107-1111 | PMID: 34281777
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Impact:
Abstract

Assessment of Omecamtiv Mecarbil for the Treatment of Patients With Severe Heart Failure: A Post Hoc Analysis of Data From the GALACTIC-HF Randomized Clinical Trial.

Felker GM, Solomon SD, Claggett B, Diaz R, ... Malik FI, Teerlink JR
Importance
Heart failure with reduced ejection fraction is a progressive clinical syndrome, and many patients\' condition worsen over time despite treatment. Patients with more severe disease are often intolerant of available medical therapies.
Objective
To evaluate the efficacy and safety of omecamtiv mecarbil for the treatment of patients with severe heart failure (HF) enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) randomized clinical trial.
Design, setting, and participants
The GALACTIC-HF study was a global double-blind, placebo-controlled phase 3 randomized clinical trial that was conducted at multiple centers between January 2017 and August 2020. A total of 8232 patients with symptomatic HF (defined as New York Heart Association symptom class II-IV) and left ventricular ejection fraction of 35% or less were randomized to receive omecamtiv mecarbil or placebo and followed up for a median of 21.8 months (range, 15.4-28.6 months). The current post hoc analysis evaluated the efficacy and safety of omecamtiv mecarbil therapy among patients classified as having severe HF compared with patients without severe HF. Severe HF was defined as the presence of all of the following criteria: New York Heart Association symptom class III to IV, left ventricular ejection fraction of 30% or less, and hospitalization for HF within the previous 6 months.
Interventions
Participants were randomized at a 1:1 ratio to receive either omecamtiv mecarbil or placebo.
Main outcomes and measures
The primary end point was time to first HF event or cardiovascular (CV) death. Secondary end points included time to CV death and safety and tolerability.
Results
Among 8232 patients enrolled in the GALACTIC-HF clinical trial, 2258 patients (27.4%; mean [SD] age, 64.5 [11.6] years; 1781 men [78.9%]) met the specified criteria for severe HF. Of those, 1106 patients were randomized to the omecamtiv mecarbil group and 1152 to the placebo group. Patients with severe HF who received omecamtiv mecarbil experienced a significant treatment benefit for the primary end point (hazard ratio [HR], 0.80; 95% CI, 0.71-0.90), whereas patients without severe HF had no significant treatment benefit (HR, 0.99; 95% CI, 0.91-1.08; P = .005 for interaction). For CV death, the results were similar (HR for patients with vs without severe HF: 0.88 [95% CI, 0.75-1.03] vs 1.10 [95% CI, 0.97-1.25]; P = .03 for interaction). Omecamtiv mecarbil therapy was well tolerated in patients with severe HF, with no significant changes in blood pressure, kidney function, or potassium level compared with placebo.

Conclusions:
and relevance
In this post hoc analysis of data from the GALACTIC-HF clinical trial, omecamtiv mecarbil therapy may have provided a clinically meaningful reduction in the composite end point of time to first HF event or CV death among patients with severe HF. These data support a potential role of omecamtiv mecarbil therapy among patients for whom current treatment options are limited.
Trial registration
ClinicalTrials.gov Identifier: NCT02929329.



JAMA Cardiol: 12 Oct 2021; epub ahead of print
Felker GM, Solomon SD, Claggett B, Diaz R, ... Malik FI, Teerlink JR
JAMA Cardiol: 12 Oct 2021; epub ahead of print | PMID: 34643642
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Impact:
Abstract

Growth differentiation factor 15 predicts poor prognosis in patients with heart failure and reduced ejection fraction and anemia: results from RED-HF.

Ueland T, Gullestad L, Kou L, Young JB, ... Anand IS, Aukrust P
Aims
We aimed to assess the value of GDF-15, a stress-responsive cytokine, in predicting clinical outcomes in patients with heart failure (HF) with reduced ejection fraction (HFrEF) and anemia METHODS AND
Results:
Serum GDF-15 was assessed in 1582 HFrEF and mild-to-moderate anemia patients who where followed for 28 months in the Reduction of Events by Darbepoetin alfa in Heart Failure (RED-HF) trial, an overall neutral RCT evaluating the effect darbepoetin alfa on clinical outcomes in patients with systolic heart failure and mild-to-moderate anemia. Association between baseline and change in GDF-15 during 6 months follow-up and the primary composite outcome of all-cause death or HF hospitalization were evaluated in multivariable Cox-models adjusted for conventional clinical and biochemical risk factors. The adjusted risk for the primary outcome increased with (i) successive tertiles of baseline GDF-15 (tertile 3 HR 1.56 [1.23-1.98] p < 0.001) as well as with (ii) a 15% increase in GDF-15 levels over 6 months of follow-up (HR 1.68 [1.38-2.06] p < 0.001). Addition of change in GDF-15 to the fully adjusted model improved the C-statistics (p < 0.001). No interaction between treatment and baseline or change in GDF-15 on outcome was observed. GDF-15 was inversely associated with several indices of anemia and correlated positively with ferritin.
Conclusions
In patients with HF and anemia, both higher baseline serum GDF-15 levels and an increase in GDF-15 during follow-up, were associated with worse clinical outcomes. GDF-15 did not identify subgroups of patients who might benefit from correction of anemia but was associated with several indices of anemia and iron status in the HF patients.

© 2021. The Author(s).

Clin Res Cardiol: 04 Oct 2021; epub ahead of print
Ueland T, Gullestad L, Kou L, Young JB, ... Anand IS, Aukrust P
Clin Res Cardiol: 04 Oct 2021; epub ahead of print | PMID: 34611778
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Impact:
Abstract

Circulating and Myocardial Cytokines Predict Cardiac Structural and Functional Improvement in Patients With Heart Failure Undergoing Mechanical Circulatory Support.

Diakos NA, Taleb I, Kyriakopoulos CP, Shah KS, ... Stellos K, Drakos SG

Background:
Recent prospective multicenter data from patients with advanced heart failure demonstrated that left ventricular assist device (LVAD) support combined with standard heart failure medications, induced significant cardiac structural and functional improvement, leading to high rates of LVAD weaning in selected patients. We investigated whether preintervention myocardial and systemic inflammatory burden could help identify the subset of patients with advanced heart failure prone to LVAD-mediated cardiac improvement to guide patient selection, treatment, and monitoring. Methods and Results Ninety-three patients requiring durable LVAD were prospectively enrolled. Myocardial tissue and blood were acquired during LVAD implantation, for measurement of inflammatory markers. Cardiac structural and functional improvement was prospectively assessed via serial echocardiography. Eleven percent of the patients showed significant reverse remodeling following LVAD support (ie, responders). Circulating tumor necrosis factor alpha, interleukin (IL)-4, IL-5, IL-6, IL-7, IL-13, and interferon gamma were lower in responders, compared with nonresponders (P<0.05, all comparisons). The myocardial tissue signal transducer and activator of transcription-3, an inflammatory response regulator, was less activated in responders (P=0.037). Guided by our tissue studies and a multivariable dichotomous regression analysis, we identified that low levels of circulating interferon gamma (odds ratio [OR], 0.06; 95% CI, 0.01-0.35) and tumor necrosis factor alpha (OR, 0.05; 95% CI, 0.00-0.43), independently predict cardiac improvement, creating a 2-cytokine model effectively predicting responders (area under the curve, 0.903; P<0.0001).
Conclusions:
Baseline myocardial and systemic inflammatory burden inversely correlates with cardiac improvement following LVAD support. A circulating 2-cytokine model predicting significant reverse remodeling was identified, warranting further investigation as a practical preintervention tool in identifying patients prone to LVAD-mediated cardiac improvement and device weaning.




J Am Heart Assoc: 30 Sep 2021:e020238; epub ahead of print
Diakos NA, Taleb I, Kyriakopoulos CP, Shah KS, ... Stellos K, Drakos SG
J Am Heart Assoc: 30 Sep 2021:e020238; epub ahead of print | PMID: 34595931
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Impact:
Abstract

Enhanced Heart Failure in Redox-Dead Cys17Ser PKARIα Knock-In Mice.

Islam MMT, Tarnowski D, Zhang M, Trum M, ... Sag CM, Wagner S

Background:
PKARIα (protein kinase A type I-α regulatory subunit) is redox-active independent of its physiologic agonist cAMP. However, it is unknown whether this alternative mechanism of PKARIα activation may be of relevance to cardiac excitation-contraction coupling. Methods and Results We used a redox-dead transgenic mouse model with homozygous knock-in replacement of redox-sensitive cysteine 17 with serine within the regulatory subunits of PKARIα (KI). Reactive oxygen species were acutely evoked by exposure of isolated cardiac myocytes to AngII (angiotensin II, 1 µmol/L). The long-term relevance of oxidized PKARIα was investigated in KI mice and their wild-type (WT) littermates following transverse aortic constriction (TAC). AngII increased reactive oxygen species in both groups but with RIα dimer formation in WT only. AngII induced translocation of PKARI to the cell membrane and resulted in protein kinase A-dependent stimulation of ICa (L-type Ca current) in WT with no effect in KI myocytes. Consequently, Ca transients were reduced in KI myocytes as compared with WT cells following acute AngII exposure. Transverse aortic constriction-related reactive oxygen species formation resulted in RIα oxidation in WT but not in KI mice. Within 6 weeks after TAC, KI mice showed an enhanced deterioration of contractile function and impaired survival compared with WT. In accordance, compared with WT, ventricular myocytes from failing KI mice displayed significantly reduced Ca transient amplitudes and lack of ICa stimulation. Conversely, direct pharmacological stimulation of ICa using Bay K8644 rescued Ca transients in AngII-treated KI myocytes and contractile function in failing KI mice in vivo.
Conclusions:
Oxidative activation of PKARIα with subsequent stimulation of ICa preserves cardiac function in the setting of acute and chronic oxidative stress.




J Am Heart Assoc: 28 Sep 2021:e021985; epub ahead of print
Islam MMT, Tarnowski D, Zhang M, Trum M, ... Sag CM, Wagner S
J Am Heart Assoc: 28 Sep 2021:e021985; epub ahead of print | PMID: 34583520
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Abstract

The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-eighth adult lung transplantation report - 2021; Focus on recipient characteristics.

Chambers DC, Perch M, Zuckermann A, Cherikh WS, ... Stehlik J, International Society for Heart and Lung Transplantation
For over 30 years, the International Society for Heart and Lung Transplantation (ISHLT) International Thoracic Organ Transplant (TTX) Registry has gathered data regarding transplant procedures, donor and recipient characteristics, and outcomes from a global community of transplant centers. Almost 70,000 adult lung transplant procedures have been reported to the Registry since its inception, each one providing an opportunity for a recipient with end-stage lung disease to regain quality of life and longevity. With each year\'s report, we provide more detailed analyses on a particular focus theme important to recipient outcomes. Since 2013, these have been donor and recipient age; retransplantation; early graft failure; indication for transplant; allograft ischemic time; multiorgan transplantation; and donor and recipient size matching.1-7 In response to a changing regulatory environment, the ISHLT TTX Registry is undergoing an update in data acquisition, and the patient cohort examined in this report is therefore derived from the same data source or datasets as that examined in the 2019 annual reports.2,8-10 We refer the reader to the 2019 and prior reports for a detailed description of the baseline characteristics of the cohort, and additional core analyses not directly related to the focus explored in this year\'s report. To complement the 2020 report which focussed on donor characteristics, the goal of this year\'s report was to focus entirely on changes in recipient factors over the past 3 decades and to identify important recipient characteristics and transplant processes that may influence post-transplant outcomes. Due to small numbers, heart-lung transplant recipient characteristics and transplant outcomes have not been included. This 38th annual adult lung transplant report is hence based on data submitted to the ISHLT TTX Registry on 67,493 adult recipients of deceased recipient transplants between January 1, 1992 and June 30, 2018.

Published by Elsevier Inc.

J Heart Lung Transplant: 29 Sep 2021; 40:1060-1072
Chambers DC, Perch M, Zuckermann A, Cherikh WS, ... Stehlik J, International Society for Heart and Lung Transplantation
J Heart Lung Transplant: 29 Sep 2021; 40:1060-1072 | PMID: 34446355
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Abstract

Venous thromboembolism in lung transplant recipients real world experience from a high volume center.

Zheng M, Yousef I, Mamary AJ, Zhao H, ... Rali P, Sehgal S
Background
Venous thromboembolism (VTE) post lung transplantation is common and has been associated with worse post transplant survival. We report a comprehensive single center review of VTE incidence in the first post transplant year, investigate modifiable risk factors and assess impact on short term outcomes.
Methods
Retrospective review of all lung transplant recipients between August 2016 to 2018 at Temple University Hospital. Patients were followed for 1 year post transplant. All patients were screened for deep venous thrombosis (DVT) within the first 2 weeks with a venous duplex study. Pre transplant, intra operative, post operative variables, and peri-operative practice patterns were compared between VTE positive and VTE negative groups. Logistic regression modeling was used to identify risk factors for early VTE (VTE within 30 days after transplant).
Results
A total of 235 patients were included in the study, 58 patients (24.7%) developed a VTE in the first post transplant year. Median time to diagnosis was 17 days. Of the patients with VTE, 76% had an isolated DVT, 13.5 % had an isolated pulmonary embolism (PE), and 10.3% had concomitant DVT and PE. In a multivariate logistic regression model, cardiopulmonary bypass (CPB) (OR 1.93 p = 0.015) and interruption of VTE prophylaxis (OR 4.42 p < 0.0001) were predictive of early VTE.
Conclusion
VTE post lung transplant is common despite the use of prophylactic anticoagulation. CPB use and interruption of DVT prophylaxis are risk factors for early post transplant VTE. Measures to ensure consistent and uninterrupted prophylaxis may help decrease VTE incidence after lung transplantation.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1145-1152
Zheng M, Yousef I, Mamary AJ, Zhao H, ... Rali P, Sehgal S
J Heart Lung Transplant: 29 Sep 2021; 40:1145-1152 | PMID: 34389222
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Abstract

Prognostic Importance of Pulmonary Arterial Capacitance in Acute Decompensated Heart Failure With Preserved Ejection Fraction.

Nakagawa A, Yasumura Y, Yoshida C, Okumura T, ... Sakata Y, Osaka CardioVascular Conference (OCVC)‐Heart Failure investigators

Background:
Although the prognostic importance of pulmonary arterial capacitance (PAC; stroke volume/pulmonary arterial pulse pressure) has been elucidated in heart failure with reduced ejection fraction, whether its significance in patients suffering from heart failure with preserved ejection fraction is not known. We aimed to examine the association of PAC with outcomes in inpatients with heart failure with preserved ejection fraction. Methods and Results We prospectively studied 705 patients (median age, 83 years; 55% women) registered in PURSUIT-HFpEF (Prospective Multicenter Observational Study of Patients With Heart Failure With Preserved Ejection Fraction). We investigated the association of echocardiographic PAC at discharge with the primary end point of all-cause death or heart failure rehospitalization with a mean follow-up of 384 days. We further tested the acceptability of the prognostic significance of PAC in a subgroup of patients (167/705 patients; median age, 81 years; 53% women) in whom PAC was assessed by right heart catheterization. The median echocardiographic PAC was 2.52 mL/mm Hg, with a quartile range of 1.78 to 3.32 mL/mm Hg. Univariable and multivariable Cox regression testing revealed that echocardiographic PAC was associated with the primary end point (unadjusted hazard ratio, 0.82; 95% CI, 0.72-0.92; P=0.001; adjusted hazard ratio, 0.86; 95% CI, 0.74-0.99; P=0.035, respectively). Univariable Cox regression testing revealed that PAC assessed by right heart catheterization (median calculated PAC, 2.82 mL/mm Hg) was also associated with the primary end point (unadjusted HR, 0.70; 95% CI, 0.52-0.91; P=0.005).
Conclusions:
A prospective cohort study revealed that impaired PAC diagnosed with both echocardiography and right heart catheterization was associated with adverse outcomes in inpatients with heart failure with preserved ejection fraction. Registration URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000024414. Unique identifier: UMIN000021831.




J Am Heart Assoc: 05 Oct 2021:e023043; epub ahead of print
Nakagawa A, Yasumura Y, Yoshida C, Okumura T, ... Sakata Y, Osaka CardioVascular Conference (OCVC)‐Heart Failure investigators
J Am Heart Assoc: 05 Oct 2021:e023043; epub ahead of print | PMID: 34612057
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Abstract

Circulating miR-19b-3p as a Novel Prognostic Biomarker for Acute Heart Failure.

Su Y, Sun Y, Tang Y, Li H, ... Ong SB, Xu D

Background:
Circulating microRNAs are emerging biomarkers for heart failure (HF). Our study aimed to assess the prognostic value of microRNA signature that is differentially expressed in patients with acute HF. Methods and Results Our study comprised a screening cohort of 15 patients with AHF and 5 controls, a PCR-discovery cohort of 50 patients with AHF and 26 controls and a validation cohort of 564 patients with AHF from registered study DRAGON-HF (Diagnostic, Risk Stratification and Prognostic Value of Novel Biomarkers in Patients With Heart Failure). Through screening by RNA-sequencing and verification by reverse-transcription quantitative polymerase chain reaction, 9 differentially expressed microRNAs were verified (miR-939-5p, miR-1908-5p, miR-7706, miR-101-3p, miR-144-3p, miR-4732-3p, miR-3615, miR-484 and miR-19b-3p). Among them, miR-19b-3p was identified as the microRNA signature with the highest fold-change of 8.4 and the strongest prognostic potential (area under curve with 95% CI, 0.791, 0.654-0.927). To further validate its prognostic value, in the validation cohort, the baseline level of miR-19b-3p was measured. During a follow-up period of 19.1 (17.7, 20.7) months, primary end point comprising of all-cause mortality or readmission due to HF occurred in 48.9% patients, while patients in the highest quartile of miR-19b-3p level presented the worst survival (Log-rank P<0.001). Multivariate Cox model showed that the level of miR-19b-3p could independently predict the occurrence of primary end point (adjusted hazard ratio,1.39; 95% CI, 1.18-1.64). In addition, miR-19b-3p positively correlated with soluble suppression of tumorigenicity 2 and echocardiographic indexes of left ventricular hypertrophy.
Conclusions:
Circulating miR-19b-3p could be a valuable prognostic biomarker for AHF. In addition, a high level of circulating miR-19b-3p might indicate ventricular hypertrophy in AHF subjects. Registration URL: https://www.clinicaltrials.gov. Unique Identifier: NCT03727828.




J Am Heart Assoc: 05 Oct 2021:e022304; epub ahead of print
Su Y, Sun Y, Tang Y, Li H, ... Ong SB, Xu D
J Am Heart Assoc: 05 Oct 2021:e022304; epub ahead of print | PMID: 34612058
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Abstract

Long-Term Exposure to Air Pollution, Road Traffic Noise, and Heart Failure Incidence: The Danish Nurse Cohort.

Lim YH, Jørgensen JT, So R, Cole-Hunter T, ... Maric M, Andersen ZJ

Background:
We examined the association of long-term exposure to air pollution and road traffic noise with incident heart failure (HF). Methods And Results Using data on female nurses from the Danish Nurse Cohort (aged >44 years), we investigated associations between 3-year mean exposures to air pollution and road traffic noise and incident HF using Cox regression models, adjusting for relevant confounders. Incidence of HF was defined as the first hospital contact (inpatient, outpatient, or emergency) between cohort baseline (1993 or 1999) and December 31, 2014, based on the Danish National Patient Register. Annual mean levels of particulate matter with a diameter <2.5 µm since 1990 and NO2 and road traffic noise since 1970 were estimated at participants\' residences. Of the 22 189 nurses, 484 developed HF. We detected associations with all 3 pollutants, with hazard ratios (HRs) of 1.17 (95% CI, 1.01-1.36), 1.10 (95% CI, 0.99-1.22), and 1.12 (95% CI, 0.99-1.26) per increase of 5.1 µg/m3 in particulate matter with a diameter <2.5 µm, 8.6 µg/m3 in NO2, and 9.3 dB in road traffic noise, respectively. We observed an enhanced risk of HF incidence for those exposed to high levels of the 3 pollutants; however, the effect modification of coexposure was not statistically significant. Former smokers and nurses with hypertension showed the strongest associations with particulate matter with a diameter <2.5 µm (Peffect modification<0.05).
Conclusions:
We found that long-term exposures to air pollution and road traffic noise were independently associated with HF.




J Am Heart Assoc: 05 Oct 2021:e021436; epub ahead of print
Lim YH, Jørgensen JT, So R, Cole-Hunter T, ... Maric M, Andersen ZJ
J Am Heart Assoc: 05 Oct 2021:e021436; epub ahead of print | PMID: 34612059
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Abstract

Sacubitril/Valsartan Initiation Among Veterans Who Are Renin-Angiotensin-Aldosterone System Inhibitor Naïve With Heart Failure and Reduced Ejection Fraction.

Mohanty AF, Levitan EB, King JB, Dodson JA, ... Fang JC, Bress AP

Background:
Sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor, received US Food and Drug Administration approval in 2015 for heart failure with reduced ejection fraction (HFrEF). Our objective was to describe the sacubitril/valsartan initiation rate, associated characteristics, and 6-month follow-up dosing among veterans with HFrEF who are renin-angiotensin-aldosterone system inhibitor (RAASi) naïve. Methods and Results Retrospective cohort study of veterans with HFrEF who are RAASi naïve defined as left ventricular ejection fraction (LVEF) ≤40%; ≥1 in/outpatient heart failure visit, first RAASi (sacubitril/valsartan, angiotensin-converting enzyme inhibitor [ACEI]), or angiotensin-II receptor blocker [ARB]) fill from July 2015 to June 2019. Characteristics associated with sacubitril/valsartan initiation were identified using Poisson regression models. From July 2015 to June 2019, we identified 3458 sacubitril/valsartan and 29 367 ACEI or ARB initiators among veterans with HFrEF who are RAASi naïve. Sacubitril/valsartan initiation increased from 0% to 26.5%. Sacubitril/valsartan (versus ACEI or ARB) initiators were less likely to have histories of stroke, myocardial infarction, or hypertension and more likely to be older and have diabetes mellitus and lower LVEF. At 6-month follow-up, the prevalence of ≥50% target daily dose for sacubitril/valsartan, ACEI, and ARB initiators was 23.5%, 43.2%, and 47.1%, respectively.
Conclusions:
Sacubitril/valsartan initiation for HFrEF in the Veterans Administration increased in the 4 years immediately following Food and Drug Administration approval. Sacubitril/valsartan (versus ACEI or ARB) initiators had fewer baseline cardiovascular comorbidities and the lowest proportion on ≥50% target daily dose at 6-month follow-up. Identifying the reasons for lower follow-up dosing of sacubitril/valsartan could support guideline recommendations and quality improvement strategies for patients with HFrEF.




J Am Heart Assoc: 05 Oct 2021:e020474; epub ahead of print
Mohanty AF, Levitan EB, King JB, Dodson JA, ... Fang JC, Bress AP
J Am Heart Assoc: 05 Oct 2021:e020474; epub ahead of print | PMID: 34612065
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