European Heart Journal

Heart failure (HF) with preserved ejection fraction (HFpEF) is a multifactorial disease accounting for a large and increasing proportion of all clinical HF presentations. As a clinical syndrome, HFpEF is characterized by typical signs and symptoms of HF, a distinct cardiac phenotype and raised natriuretic peptides. Non-cardiac comorbidities frequently co-exist and contribute to the pathophysiology of HFpEF. To date, no therapy has proven to improve outcomes in HFpEF, with drug development hampered, at least partly, by lack of consensus on appropriate standards for pre-clinical HFpEF models. Recently, two clinical algorithms (HFA-PEFF and H2FPEF scores) have been developed to improve and standardize the diagnosis of HFpEF. In this review, we evaluate the translational utility of HFpEF mouse models in the context of these HFpEF scores. We systematically recorded evidence of symptoms and signs of HF or clinical HFpEF features and included several cardiac and extra-cardiac parameters as well as age and sex for each HFpEF mouse model. We found that most of the pre-clinical HFpEF models do not meet the HFpEF clinical criteria, although some multifactorial models resemble human HFpEF to a reasonable extent. We therefore conclude that to optimize the translational value of mouse models to human HFpEF, a novel approach for the development of pre-clinical HFpEF models is needed, taking into account the complex HFpEF pathophysiology in humans.

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Untangling the pathophysiologic link between coronary microvascular dysfunction and heart failure with preserved ejection fraction

Aish Sinha, Haseeb Rahman, Andrew Webb, Ajay M Shah, Divaka Perera

doi : 10.1093/eurheartj/ehab653

European Heart Journal, Volume 42, Issue 43, 14 November 2021, Pages 4431–4441

Coronary microvascular disease (CMD), characterized by impaired coronary flow reserve (CFR), is a common finding in patients with stable angina. Impaired CFR, in the absence of obstructive coronary artery disease, is also present in up to 75% of patients with heart failure with preserved ejection fraction (HFpEF). Heart failure with preserved ejection fraction is a heterogeneous syndrome comprising distinct endotypes and it has been hypothesized that CMD lies at the centre of the pathogenesis of one such entity: the CMD–HFpEF endotype. This article provides a contemporary review of the pathophysiology underlying CMD, with a focus on the mechanistic link between CMD and HFpEF. We discuss the central role played by subendocardial ischaemia and impaired lusitropy in the development of CMD–HFpEF, as well as the clinical and research implications of the CMD–HFpEF mechanistic link. Future prospective follow-up studies detailing outcomes in patients with CMD and HFpEF are much needed to enhance our understanding of the pathological processes driving these conditions, which may lead to the development of physiology-stratified therapy to improve the quality of life and prognosis in these patients.

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Regional and ethnic influences on the response to empagliflozin in patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial

Carolyn S P Lam, João Pedro Ferreira, Egon Pfarr, David Sim, Hiroyuki Tsutsui, Stefan D Anker, Javed Butler, Gerasimos Filippatos, Stuart J Pocock, Naveed Sattar, Subodh Verma, Martina Brueckmann, Janet Schnee, Daniel Cotton, Faiez Zannad, Milton Packer

doi : 10.1093/eurheartj/ehab360

European Heart Journal, Volume 42, Issue 43, 14 November 2021, Pages 4442–4451

The aim of this article is to explore the influence of region and race/ethnicity on the effects of empagliflozin in the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced) trial.

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A fourth pillar for all in the treatment of heart failure

Eldrin F Lewis

doi : 10.1093/eurheartj/ehab612

European Heart Journal, Volume 42, Issue 43, 14 November 2021, Pages 4452–4454

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Novel biomarker-driven prognostic models to predict morbidity and mortality in chronic heart failure: the EMPEROR-Reduced trial

Stuart J Pocock, João Pedro Ferreira, John Gregson, Stefan D Anker, Javed Butler, Gerasimos Filippatos, Nicholas D Gollop, Tomoko Iwata, Martina Brueckmann, James L Januzzi, Jr, Adriaan A Voors, Faiez Zannad, Milton Packer

doi : 10.1093/eurheartj/ehab579

European Heart Journal, Volume 42, Issue 43, 14 November 2021, Pages 4455–4464

The aim of this study was to generate a biomarker-driven prognostic tool for patients with chronic HFrEF. Circulating levels of N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) each have a marked positive relationship with adverse outcomes in heart failure with reduced ejection fraction (HFrEF). A risk model incorporating biomarkers and clinical variables has not been validated in contemporary heart failure (HF) trials.

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Biomarker-driven prognostic model for risk prediction in heart failure: ready for Prime time?

Desiree Wussler, Christian Mueller

doi : 10.1093/eurheartj/ehab645

European Heart Journal, Volume 42, Issue 43, 14 November 2021, Pages 4465–4467

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Compensatory post-diuretic renal sodium reabsorption is not a dominant mechanism of diuretic resistance in acute heart failure

Zachary L Cox, Veena S Rao, Juan B Ivey-Miranda, Julieta Moreno-Villagomez, Devin Mahoney, Piotr Ponikowski, Jan Biegus, Jeffrey M Turner, Christopher Maulion, Lavanya Bellumkonda, Jennifer L Asher, Helen Parise, Perry F Wilson, David H Ellison, Christopher S Wilcox, Jeffrey M Testani

doi : 10.1093/eurheartj/ehab620

European Heart Journal, Volume 42, Issue 43, 14 November 2021, Pages 4468–4477

In healthy volunteers, the kidney deploys compensatory post-diuretic sodium reabsorption (CPDSR) following loop diuretic-induced natriuresis, minimizing sodium excretion and producing a neutral sodium balance. CPDSR is extrapolated to non-euvolemic populations as a diuretic resistance mechanism; however, its importance in acute decompensated heart failure (ADHF) is unknown.

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Renal sodium avidity, the prevailing renal target in heart failure

Pieter Martens, W H Wilson Tang, Wilfried Mullens

doi : 10.1093/eurheartj/ehab650

European Heart Journal, Volume 42, Issue 43, 14 November 2021, Pages 4478–4481

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Glucosylceramide synthase deficiency in the heart compromises ?1-adrenergic receptor trafficking

Linda Andersson, Mathieu Cinato, Ismena Mardani, Azra Miljanovic, Muhammad Arif, Ara Koh, Malin Lindbom, Marion Laudette, Entela Bollano, Elmir Omerovic, Martina Klevstig, Marcus Henricsson, Per Fogelstrand, Karl Swärd, Matias Ekstrand, Max Levin, Johannes Wikström, Stephen Doran, Tuulia Hyötyläinen, Lisanna Sinisalu, Matej Oreši?, Åsa Tivesten, Martin Adiels, Martin O Bergo, Richard Proia, Adil Mardinoglu, Anders Jeppsson, Jan Borén, Malin C Levin

doi : 10.1093/eurheartj/ehab412

European Heart Journal, Volume 42, Issue 43, 14 November 2021, Pages 4481–4492

Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function.

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