FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4383107002> ?p ?o ?g. }

• W4383107002 endingPage "2089" @default.
• W4383107002 startingPage "2087" @default.
• W4383107002 abstract "The β1-adrenoceptor remains central to pharmacologic inotropic support. Novel targets for inotropic support are currently under development, and have the potential to overcome current issues with inotropes targeting the β1-adrenoceptor. Herein, inotropes under development are discussed, including those acting via sarcoendoplasmic reticulum Ca2+ -ATPase (SERCA2a) modulation, calcium release-activated calcium channel protein 1 (ORAI1), direct myosin activation, and the apelin receptor, and reference made to the specific clinical scenario in which they may find their use. Acute heart failure is a common reason for admission to an intensive care unit to allow the administration of inotropes to augment cardiac output pharmacologically. Many current inotropes function by the augmentation of β-adrenoceptor signaling, either as direct agonists or by antagonizing the phosphodiesterases, which antagonize cyclic adenosine monophosphate-based signaling downstream of β-adrenoceptors. Both these mechanisms increase cyclic adenosine monophosphate, causing not only positive inotropy but also contributing to myocardial ischemia and arrhythmogenesis, and these effects may contribute to the observation that catecholamine-based inotropes are, in fact, associated with increased mortality.1Mebazaa A Parissis J Porcher R et al.Short-term survival by treatment among patients hospitalized with acute heart failure: The global ALARM-HF registry using propensity scoring methods.Intensive Care Med. 2011; 37: 290-301Crossref PubMed Scopus (181) Google Scholar Several previous reviews have highlighted potential novel directions for adrenergic pharmacology to reduce these effects.2Garland H. Subcellular compartmentalization of cyclic adenosine monophosphate in heart failure and inotropic pharmacology.J Cardiothorac Vasc Anesth. 2023; 37: 480-482Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar,3Garland H Vuylsteke A. Biased agonism: The future (and present) of inotropic support.J Cardiothorac Vasc Anesth. 2020; 34: 3449-3451Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Several novel noncatecholamine targets for inotropic support are emerging. The mechanisms of cardiac excitation-contraction coupling are now well-understood, and in-depth discussion is not required but can be found in several detailed reviews. Briefly, when a cardiac myocyte is depolarized, it causes calcium entry into the dyadic space. Calcium binding to type-2 ryanodine receptors causes further calcium release in a process termed calcium-induced calcium release.4Bers DM. Cardiac excitation-contraction coupling.Nature. 2002; 415: 198-205Crossref PubMed Scopus (3458) Google Scholar Calcium binds to troponin, unmasking the myosin binding site on actin. Myosin then hydrolyses adenosine triphosphate to walk along actin leading to sarcomeric shortening. Calcium then dissociates from troponin when cytosolic calcium falls because of extrusion from the cell by the sodium-calcium exchanger or sequestration into the sarcoplasmic reticulum by sarcoendoplasmic reticulum calcium ATPase 2 (SERCA2). Sarcoendoplasmic reticulum Ca2+ -ATPase is a calcium pump that causes cardiac relaxation by the sequestration of calcium into the sarcoplasmic reticulum. The activity of SERCA2a is important in determining the size of the sarcoplasmic calcium store, which, in turn, determines contractile force. At rest, SERCA2a is inhibited by phospholamban, but when phosphorylated by protein kinase A downstream of β-adrenoceptors, this inhibition is released, leading to greater calcium stores and contractile force.5Hoydal MA Kirkeby-Garstad I Karevold A et al.Human cardiomyocyte calcium handling and transverse tubules in mid-stage of post-myocardial-infarction heart failure.ESC Heart Fail. 2018; 5: 332-342Crossref PubMed Scopus (29) Google Scholar Istaroxime is a novel SERCA2a activator and has similar activity to cardiac glycosides, such as digoxin, at the sodium-calcium antiporter,6Forzano I Mone P Mottola G et al.Efficacy of the new inotropic agent istaroxime in acute heart failure.J Clin Med. 2022; 11: 7503Crossref PubMed Scopus (1) Google Scholar with inotropic and lusitropic actions. In randomized controlled trials in acute heart failure, istaroxime has been shown to decrease pulmonary capillary wedge pressure, increase systolic blood pressure and increase cardiac index,7Gheorghiade M Blair JE Filippatos GS et al.Hemodynamic, echocardiographic, and neurohormonal effects of istaroxime, a novel intravenous inotropic and lusitropic agent: A randomized controlled trial in patients hospitalized with heart failure.J Am Coll Cardiol. 2008; 51: 2276-2285Crossref PubMed Scopus (125) Google Scholar as well as showing improvements in echocardiographic parameters and subjective dyspnea without an increase in cardiac adverse events.8Carubelli V Zhang Y Metra M et al.Treatment with 24 hour istaroxime infusion in patients hospitalised for acute heart failure: A randomised, placebo-controlled trial.Eur J Heart Fail. 2020; 22: 1684-1693Crossref PubMed Scopus (33) Google Scholar Istaroxime has demonstrable lusitropic as well as inotropic actions. During istaroxime infusion, there is an increase in systolic blood pressure with decreased diastolic stiffness.9Shah SJ Blair JE Filippatos GS et al.Effects of istaroxime on diastolic stiffness in acute heart failure syndromes: Results from the hemodynamic, echocardiographic, and neurohormonal effects of istaroxime, a novel intravenous inotropic and Lusitropic agent: A randomized controlled trial in patients hospitalized with heart failure (HORIZON-HF) trial.Am Heart J. 2009; 157: 1035-1041Crossref PubMed Scopus (109) Google Scholar This has led to the suggestion that istaroxime may prove particularly useful in patients with heart failure with preserved ejection fraction, although some studies also have demonstrated promising results in heart failure with reduced ejection fraction.8Carubelli V Zhang Y Metra M et al.Treatment with 24 hour istaroxime infusion in patients hospitalised for acute heart failure: A randomised, placebo-controlled trial.Eur J Heart Fail. 2020; 22: 1684-1693Crossref PubMed Scopus (33) Google Scholar Unfortunately, other studies have failed to replicate this finding but found that the effect of istaroxime is inversely correlated with body mass index.10Sarma S MacNamara JP Hieda M et al.SERCA2a Agonist effects on cardiac performance during exercise in heart failure with preserved ejection fraction.JACC Heart Fail. 2023; 11: 760-771Crossref PubMed Scopus (3) Google Scholar Istaroxime is a steroid-like molecule, and further studies are required to determine optimal dosing in obesity. Istaroxime is given by intravenous infusion8Carubelli V Zhang Y Metra M et al.Treatment with 24 hour istaroxime infusion in patients hospitalised for acute heart failure: A randomised, placebo-controlled trial.Eur J Heart Fail. 2020; 22: 1684-1693Crossref PubMed Scopus (33) Google Scholar and, therefore, is well-suited for use in anesthesia and intensive care. Omecamtiv mecarbil is a promising new drug with an intriguing mechanism. It binds to an allosteric site on myosin that stabilizes the lever arm in a primed position, thus providing more heads available to bind actin and leading to increased power during contraction.11Planelles-Herrero VJ Hartman JJ Robert-Paganin J et al.Mechanistic and structural basis for activation of cardiac myosin force production by omecamtiv mecarbil.Nat Commun. 2017; 8: 190Crossref PubMed Scopus (118) Google Scholar This is exciting because it does not change calcium transients or oxygen consumption,11Planelles-Herrero VJ Hartman JJ Robert-Paganin J et al.Mechanistic and structural basis for activation of cardiac myosin force production by omecamtiv mecarbil.Nat Commun. 2017; 8: 190Crossref PubMed Scopus (118) Google Scholar which can aggravate arrhythmias and ischemia, respectively. In contrast to catecholamine-based inotropes that increase myocardial oxygen demand and increase the rate of force generation, direct myosin activators increase the systolic ejection time but do not affect the myocardial oxygen demand.12Shen YT Malik FI Zhao X et al.Improvement of cardiac function by a cardiac Myosin activator in conscious dogs with systolic heart failure.Circ Heart Fail. 2010; : 3522-3527Google Scholar Clinical trials of the direct myosin activator omecamtiv mecarbil in chronic heart failure with reduced ejection fraction have shown a lower incidence of a composite of a heart failure event or death from cardiovascular causes than in those who received a placebo.13Teerlink JR Diaz R Felker GM et al.Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure.N Engl J Med. 2021; 384: 105-116Crossref PubMed Scopus (319) Google Scholar In studies in rats, omecamtiv mecarbil improved neurologic outcomes after cardiac arrest when given, after a return of spontaneous circulation.14Wu SN Tsai MS Huang CH et al.Omecamtiv mecarbil treatment improves post-resuscitation cardiac function and neurological outcome in a rat model.PLoS One. 2022; 17e0264165Google Scholar Trials have studied both oral13Teerlink JR Diaz R Felker GM et al.Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure.N Engl J Med. 2021; 384: 105-116Crossref PubMed Scopus (319) Google Scholar and intravenous12Shen YT Malik FI Zhao X et al.Improvement of cardiac function by a cardiac Myosin activator in conscious dogs with systolic heart failure.Circ Heart Fail. 2010; : 3522-3527Google Scholar administration of omecamtiv mecarbil. More recently, a second direct myosin activator, danicamtiv, has entered clinical trials. Danicamtiv shows a dose-dependent increase in left ventricular systolic volume and systolic ejection time.15Voors AA Tamby JF Cleland JG et al.Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: Experimental data and clinical results from a phase 2a trial.Eur J Heart Fail. 2020; 22: 1649-1658Crossref PubMed Scopus (36) Google Scholar Compared with omecamtiv mecarbil, danicamtiv shows greater augmentation of systolic function with less of an adverse effect on diastolic function, with a wider therapeutic window and enhancement of the Frank-Starling mechanism.16Shen S Sewanan LR Jacoby DL et al.Danicamtiv enhances systolic function and frank-starling behavior at minimal diastolic cost in engineered human myocardium.J Am Heart Assoc. 2021; 10e020860Crossref Scopus (10) Google Scholar These reports have focused on the oral administration of danicamtiv.15Voors AA Tamby JF Cleland JG et al.Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: Experimental data and clinical results from a phase 2a trial.Eur J Heart Fail. 2020; 22: 1649-1658Crossref PubMed Scopus (36) Google Scholar Clinical trials have focused on the use of myosin activators in heart failure with reduced ejection fraction. Thus far, trials have been focused on chronic heart failure, and further investigations are required to determine if similar results can be replicated in acute or acute chronic heart failure. Direct myosin activators increase diastolic stiffness, so their use may be limited to isolated systolic dysfunction. The apelin receptor (also known as APJ) was orphaned until 1998 when its first endogenous ligand, apelin, was identified,17Tatemoto K Hosoya M Habata Y et al.Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor.Biochem Biophys Res Commun. 1998; 251: 471-476Crossref PubMed Scopus (1384) Google Scholar which was followed later by a second endogenous ligand, known as ELABELA (ELA, Apela, Toddler).18Chng SC Ho L Tian J et al.ELABELA: A hormone essential for heart development signals via the apelin receptor.Dev Cell. 2013; 27: 672-680Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar The apelin receptor is expressed widely throughout the circulatory system and has been implicated recurrently in cardiovascular diseases. Apelin analogs have been shown to increase coronary blood flow, increase cardiac index and reduce systemic vascular resistance,19Japp AG Cruden NL Barnes G et al.Acute cardiovascular effects of apelin in humans: Potential role in patients with chronic heart failure.Circulation. 2010; 121: 1818-1827Crossref PubMed Scopus (261) Google Scholar and this action as an inodilator may be beneficial in cardiogenic shock. These effects are augmented in agonists biased toward signaling via heterotrimeric G-protein,20Brame AL Maguire JJ Yang P et al.Design, characterization, and first-in-human study of the vascular actions of a novel biased apelin receptor agonist.Hypertension. 2015; 65: 834-840Crossref PubMed Scopus (116) Google Scholar which is consistent with an earlier discussion of the likely role of biased agonism in inotropic pharmacology.3Garland H Vuylsteke A. Biased agonism: The future (and present) of inotropic support.J Cardiothorac Vasc Anesth. 2020; 34: 3449-3451Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar This G-protein-biased agonist has been given by intravenous infusion during human trials.20Brame AL Maguire JJ Yang P et al.Design, characterization, and first-in-human study of the vascular actions of a novel biased apelin receptor agonist.Hypertension. 2015; 65: 834-840Crossref PubMed Scopus (116) Google Scholar Drugs targeting the apelin receptor have been proposed for use in acute myocardial infarction and cardiopulmonary bypass due to their ability to protect from ischemia-reperfusion and to prevent adverse cardiac remodeling.21Popov SV Maslov LN Mukhomedzyanov AV et al.Apelin is a prototype of novel drugs for the treatment of acute myocardial infarction and adverse myocardial remodeling.Pharmaceutics. 2023; 15: 1029Crossref PubMed Scopus (1) Google Scholar These properties, combined with that of an inodilator, make drugs acting on the apelin receptor attractive prospects for treating acute myocardial infarction complicated by cardiogenic shock. When the sarcoplasmic reticulum is depleted of calcium, store-operated calcium entry occurs to restore sarcoplasmic calcium concentration. The underlying mechanism is believed to be that stromal interaction molecule 1 senses intrasarcoplasmic calcium depletion and activates ORAI1, which is a calcium channel allowing calcium influx.22Zhang SL Yu Y Roos J et al.STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane.Nature. 2005; 437: 902-905Crossref PubMed Scopus (1157) Google Scholar Studies of ORAI1-deficient mice showed a rapid development of dilated cardiomyopathy in response to pressure overload.23Horton JS Buckley CL Alvarez EM et al.The calcium release-activated calcium channel Orai1 represents a crucial component in hypertrophic compensation and the development of dilated cardiomyopathy.Channels (Austin). 2014; 8: 35-48Crossref PubMed Scopus (25) Google Scholar Calcium release-activated calcium channel protein 1 inhibitors have been shown to protect systolic function in response to pressure overload.24Bartoli F Bailey MA Rode B et al.Orai1 channel inhibition preserves left ventricular systolic function and normal Ca(2+) handling after pressure overload.Circulation. 2020; 141: 199-216Crossref PubMed Scopus (34) Google Scholar Calcium release-activated calcium channel protein 1 inhibitors have been suggested as a novel treatment for pulmonary hypertension due to their ability to normalize the phenotype of pulmonary artery smooth muscle cells.25Masson B Le Ribeuz H Sabourin J et al.Orai1 inhibitors as potential treatments for pulmonary arterial hypertension.Circ Res. 2022; 131: e102-e119Crossref PubMed Scopus (5) Google Scholar Inotropes acting on ORAI1 and/or stromal interaction molecule 1 are in the early stage of development, and human studies are awaited; early murine data might suggest ORAI1 inhibitors could be particularly useful in the pressure-overloaded, failing ventricle. Murine studies have used administration via a subcutaneous osmotic minipump,24Bartoli F Bailey MA Rode B et al.Orai1 channel inhibition preserves left ventricular systolic function and normal Ca(2+) handling after pressure overload.Circulation. 2020; 141: 199-216Crossref PubMed Scopus (34) Google Scholar and further work is necessary to explore routes of administration in humans. Several targets for novel inotropes are being explored, and potentially can improve the management of acute cardiac failure. SERCA2a modulators and direct myosin activators are already in the latter stages of development, whereas drugs targeting the apelin receptor and ORAI1 are in the early stages of development but showing promise in preclinical trials. Current knowledge of the specific pharmacologic characteristics of each of these potential novel inotropes is explored, and the clinical scenario in which they may be most useful is inferred. SERCA2a modulators show significant promise for heart failure with preserved ejection fraction, whereas direct myosin activators show particular promise for heart failure with reduced ejection fraction." @default.
• W4383107002 created "2023-07-05" @default.
• W4383107002 creator A5012145322 @default.
• W4383107002 date "2023-10-01" @default.
• W4383107002 modified "2023-10-06" @default.
• W4383107002 title "Emerging Pharmacologic Targets for Inotropic Support" @default.
• W4383107002 cites W171959177 @default.
• W4383107002 cites W1989706089 @default.
• W4383107002 cites W1991814810 @default.
• W4383107002 cites W1992427742 @default.
• W4383107002 cites W2001917660 @default.
• W4383107002 cites W2050824263 @default.
• W4383107002 cites W2054665636 @default.
• W4383107002 cites W2060660919 @default.
• W4383107002 cites W2083350649 @default.
• W4383107002 cites W2109058223 @default.
• W4383107002 cites W2741413018 @default.
• W4383107002 cites W2788591268 @default.
• W4383107002 cites W2999877102 @default.
• W4383107002 cites W3001727981 @default.
• W4383107002 cites W3036860026 @default.
• W4383107002 cites W3047663391 @default.
• W4383107002 cites W3098430919 @default.
• W4383107002 cites W3170016849 @default.
• W4383107002 cites W4297261343 @default.
• W4383107002 cites W4310056350 @default.
• W4383107002 cites W4312211891 @default.
• W4383107002 cites W4360618783 @default.
• W4383107002 cites W4366371546 @default.
• W4383107002 doi "https://doi.org/10.1053/j.jvca.2023.06.042" @default.
• W4383107002 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37500367" @default.
• W4383107002 hasPublicationYear "2023" @default.
• W4383107002 type Work @default.
• W4383107002 citedByCount "0" @default.
• W4383107002 crossrefType "journal-article" @default.
• W4383107002 hasAuthorship W4383107002A5012145322 @default.
• W4383107002 hasBestOaLocation W43831070021 @default.
• W4383107002 hasConcept C155710745 @default.
• W4383107002 hasConcept C164705383 @default.
• W4383107002 hasConcept C177713679 @default.
• W4383107002 hasConcept C71924100 @default.
• W4383107002 hasConceptScore W4383107002C155710745 @default.
• W4383107002 hasConceptScore W4383107002C164705383 @default.
• W4383107002 hasConceptScore W4383107002C177713679 @default.
• W4383107002 hasConceptScore W4383107002C71924100 @default.
• W4383107002 hasIssue "10" @default.
• W4383107002 hasLocation W43831070021 @default.
• W4383107002 hasLocation W43831070022 @default.
• W4383107002 hasOpenAccess W4383107002 @default.
• W4383107002 hasPrimaryLocation W43831070021 @default.
• W4383107002 hasRelatedWork W1531601525 @default.
• W4383107002 hasRelatedWork W2748952813 @default.
• W4383107002 hasRelatedWork W2758277628 @default.
• W4383107002 hasRelatedWork W2899084033 @default.
• W4383107002 hasRelatedWork W2935909890 @default.
• W4383107002 hasRelatedWork W2948807893 @default.
• W4383107002 hasRelatedWork W3173606202 @default.
• W4383107002 hasRelatedWork W3183948672 @default.
• W4383107002 hasRelatedWork W2778153218 @default.
• W4383107002 hasRelatedWork W3110381201 @default.
• W4383107002 hasVolume "37" @default.
• W4383107002 isParatext "false" @default.
• W4383107002 isRetracted "false" @default.
• W4383107002 workType "article" @default.