Positive Inotropic Therapy Research Articles

The Impact of Positive Inotropic Therapy on Hemodynamics and Organ Function in Acute Heart Failure: A Differentiated View.

Little is known about the impact of treatment with inotropic drugs on the interaction of hemodynamics, biomarkers, and end-organ function in patients with acute decompensated heart failure (HF) of different origins and heart rhythms. Fifty patients with different causes of acute decompensated HF (dilated cardiomyopathy DCM, ischemic cardiomyopathy ICM, atrial fibrillation AF, sinus rhythm/pacemaker lead rhythm SR/PM) were treated with dobutamine or levosimendan. Non-invasive hemodynamics, biomarkers, and parameters of renal organ function were evaluated at hospital admission and after myocardial recompensation (day 5 to 7). Twenty-seven patients with ICM and twenty-three patients with DCM were included. Thirty-nine patients were treated with dobutamine and eleven with levosimendan. Sixteen were accompanied by persistent AF and thirty-four presented either with SR or PM. In the overall cohort, body weight and biomarkers (NT-proBNP/ST2) significantly decreased. GFR significantly increased during therapy with either dobutamine or levosimendan. However, hemodynamic parameters seem to be only improved in patients with DCM, in the levosimendan sub-group, and in patients with SR/PM. Patients with acute decompensated HF benefit from positive inotropic therapy during short-term follow-ups. In particular, patients with DCM, those after levosimendan therapy and those with SR/PM, seem to benefit most from inotropic therapy.

Acute fulminant liver failure, COVID -19 and 2-day intensive care unit follow-up period: A Case Report

We aimed to share our case who developed liver failure due to covid-19, which is more severe than we have ever encountered. A 67-year-old male patient was brought to our hospital by ambulance with complaints of weakness and eating and drinking disorder. In the first examination, the patient was conscious, oriented and cooperative. The liver and kidney function tests and whole blood parameters of the patient at the first admission were within normal limits. The patient was admitted to the intensive care unit because of comorbidities and oxygen support may be required. It was found that the patient’s liver function tests were found to be elevated in the examinations on the first intensive care unit day. Transplantation and Plasmapheresis could not be performed due to the patient's general condition. In the follow-up, orotracheal intubation was performed for the patient whose general condition deteriorated, blood pressure decreasing and positive inotropic therapy was initiated on the second ICU day. The patient whose general condition deteriorated could not be saved despite all interventions. Although our knowledge about SARS-CoV-2 is not sufficient yet, we think that it should be kept in mind that it may also cause fulminant liver failure.

PDE1 Inhibition Modulates Cav1.2 Channel to Stimulate Cardiomyocyte Contraction.

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The occurrence of cardiac abnormalities in canine steroid-responsive meningitis arteritis.

To document the prevalence of cardiac abnormalities in dogs with steroid-responsive meningitis arteritis and to assess resolution of these abnormalities following corticosteroid therapy. Steroid-responsive meningitis arteritis was diagnosed based on signalment, physical examination findings, complete blood count, biochemistry and CSF analysis. Echocardiography, C-reactive protein and cardiac troponin I were measured in all cases before and 10 to 14 days after commencing corticosteroid therapy. Fibrinogen was also measured in a proportion of dogs. Fourteen dogs were prospectively enrolled. Increased cardiac troponin I was identified in five of 14 dogs and echocardiographic abnormalities were detected in 12 of 14 dogs, including spontaneous echo contrast (12 of 14), mild pericardial effusion (five of 14) and mildly decreased fractional shortening (five of 14). All dogs had increased C-reactive protein and fibrinogen was increased in 11 of 12. Corticosteroid treatment was associated with clinical improvement and normalisation of C-reactive protein in all dogs. The cardiac troponin I levels normalised in four of five and fibrinogen had normalised in all five dogs which were retested. Spontaneous echo contrast improved or completely resolved in 12 of 12 and pericardial effusion resolved in five of five dogs. Fractional shortening normalised in two of five dogs. Cardiac changes are common in dogs with steroid-responsive meningitis arteritis and most resolve with therapy. Further investigation into the cause and significance of these changes is necessary in determining whether antithrombotic therapy or positive inotropic therapy is indicated.

β-Arrestin2 Improves Post-Myocardial Infarction Heart Failure via Sarco(endo)plasmic Reticulum Ca2+-ATPase-Dependent Positive Inotropy in Cardiomyocytes.

Heart failure is the leading cause of death in the Western world, and new and innovative treatments are needed. The GPCR (G protein-coupled receptor) adapter proteins βarr (β-arrestin)-1 and βarr-2 are functionally distinct in the heart. βarr1 is cardiotoxic, decreasing contractility by opposing β1AR (adrenergic receptor) signaling and promoting apoptosis/inflammation post-myocardial infarction (MI). Conversely, βarr2 inhibits apoptosis/inflammation post-MI but its effects on cardiac function are not well understood. Herein, we sought to investigate whether βarr2 actually increases cardiac contractility. Via proteomic investigations in transgenic mouse hearts and in H9c2 rat cardiomyocytes, we have uncovered that βarr2 directly interacts with SERCA2a (sarco[endo]plasmic reticulum Ca2+-ATPase) in vivo and in vitro in a β1AR-dependent manner. This interaction causes acute SERCA2a SUMO (small ubiquitin-like modifier)-ylation, increasing SERCA2a activity and thus, cardiac contractility. βarr1 lacks this effect. Moreover, βarr2 does not desensitize β1AR cAMP-dependent procontractile signaling in cardiomyocytes, again contrary to βarr1. In vivo, post-MI heart failure mice overexpressing cardiac βarr2 have markedly improved cardiac function, apoptosis, inflammation, and adverse remodeling markers, as well as increased SERCA2a SUMOylation, levels, and activity, compared with control animals. Notably, βarr2 is capable of ameliorating cardiac function and remodeling post-MI despite not increasing cardiac βAR number or cAMP levels in vivo. In conclusion, enhancement of cardiac βarr2 levels/signaling via cardiac-specific gene transfer augments cardiac function safely, that is, while attenuating post-MI remodeling. Thus, cardiac βarr2 gene transfer might be a novel, safe positive inotropic therapy for both acute and chronic post-MI heart failure.

P05.12: The prognostic value of highly sensitive cardiac troponin I in pregnancies with pre‐eclampsia: bicentric prospective study

The objective of this study was to compare the highly sensitive cardiac troponin I (hsTnI) levels between normal pregnant women and those with pre-eclampsia. A total of 60 patients were included in the study. Patients with infection, pregestational gestational diabetes history, premature membrane rupture, oligo/polyhydramnios, organic heart valve disease, hypertension, chronic renal insufficiency and those requiring positive inotropic therapy were not included in the study. The patients were assigned into two groups as the pre-eclamptic pregnant group (study group PEG, n=40) and normotensive pregnant group (control group CG, n=20). Plasma samples (ARCHITECT STAT High Sensitive Troponin-I Assay) were obtained at the time of delivery (H0), H4 and H24. The level of HsTnI at H0 was significantly higher in patients with pre-eclampsia (5.2 [interquartile range IQR: 1.4 – 15.65] vs 0.2 [0 – 1.85] in normal pregnant women; p=0.001]. We found also a statistically significant difference between the two groups at H4 (hsTnI: 9.3 [IQR: 1.4 -29] in PEG vs. 1 [0.7 – 2.5]; p=0.005) and H24 (hsTn: 3.4 [IQR: 1.4 - 8] in PEG vs. 0.6 [0.18 – 2.95]; p=0.020). Pre-eclampsia was associated with a rise in high sensitive troponin I levels in our study. Patients with pre-eclampsia and elevated troponin levels should have further cardiac investigations.

Inotropes and vasopressors

Inotropic agents are used to increase myo-cardial contraction while vasopressors are used to increase vascular tone. They are often used for treatment of patients whose tissue perfusion is insufficient to meet metabolic requirements. Therefore, these agents are usually administered in inten-sive care units where continuous and inva-sive monitoring of cardiac function can be applied.Inotropic agents can be divided into those that increase cAMP levels and those that do not. Adrenergic receptor agonists and phosphodiesterase inhibitors (PDEi) in-crease cAMP levels and are currently the mainstay of positive inotropic therapy. Le-vosimendan acts as calcium sensitizer and increases myocardial contraction force without increasing intracellular calcium levels. In addition to existing inotropic agents, new promising inotropes are be-ing developed. These include sarcoplasmic reticulum calcium pump (istaroxime), cardiac myosin activators (omecamtivme-carbil), gene therapy, nitroxyl donors and ryanodine receptor stabilizers.Current treatments of heart failure are aimed at prolonging survival and not just alleviating symptoms. This review pro-vides a short description of the physiology of myocardial contraction and adrenergic receptors. We also provide a short descrip-tion of commonly used inotropic agents and vasopressor drugs as well as a short re-view of agents that are expected are in use in the future.Inotropes are agents used to increase myo-cardial contractility, while vasopressors are administered to increase vascular tone (1). Their use ismostly confined to critically ill patients whose hemodynamic impairment is such that tissue perfusion is insufficient to meet metabolic requirements (2). Pa-tients in need of inotropic or vasopressor support are often presented with septic or cardiogenic shock and severe heart failure, and are victims of major trauma or un-dergoing major surgery.These drugs are therefore administered usually to patients treated in intensive care settings where continuous monitoring of cardiac rhythm, arterial oxygenation, urine output and other invasive hemodynamic monitoring can be applied.Inotropic and vasopressor drugs should be administered through a central venous catheter via infusion pumps that can deliver precise flow rates. These agents are mostly short acting with rapid onset and offset of action. Therefore, they can be used without an initial bolus and can be titrated frequently. Abrupt dis-continuation should be avoided because of possible hypotension.

Inodilators in the Management of Low Cardiac Output Syndrome After Pediatric Cardiac Surgery.

Postoperative low cardiac output syndrome has been shown to have both a central and a peripheral vascular involvement. Therefore, inodilators which provide with a combination of positive inotropic and vasodilating therapy, conceptually should be an ideal form of treatment. However, contradictory data on these drugs exist. Phosphodiesterase inhibitors (e.g., milrinone) and more recently calcium sensitizers (e.g., levosimendan) have been most commonly used groups in the clinical setting. This review will summarize the pharmacology of inodilators with a special foccus on current clinical evidence. This article addresses the sixth of eight topics comprising the special issue entitled "Pharmacologic strategies with afterload reduction in low cardiac output syndrome after pediatric cardiac surgery".

92 - Nitroxyl as a Positive Inotropic Therapy in Heart Failure: cMyBP-C as a Target?

Root development in higher plants is achieved by a precise intercellular communication which determines cell fate in the primary embryonic meristem where the gasotransmitters H2S, NO and CO participate dynamically. Furthermore, the rhizosphere interaction of these molecules with microbial and soil metabolism also affects root development. NO regulates root growth and architecture in association with several other biomolecules like auxin indole-3-acetic acid (IAA), ethylene, jasmonic acid (JA), strigolactones, alkamides and melatonin. The CO-mediated signal transduction pathway in roots is closely linked to the NO-mediated signal cascades. Interestingly, H2S acts also as an upstream component in IAA and NO-mediated crosstalk during root development. Heme oxygenase (HO) 1 generates CO and functions as a downstream component in H2S-mediated adventitious rooting and H2S–CO crosstalk. Likewise, reactive oxygen species (ROS), H2S and NO crosstalk are important components in the regulation of root architecture. Deciphering these interactions will be a potential biotechnological tool which could provide benefits in crop management in soils, especially under adverse environmental conditions. This review aims to provide a comprehensive update of the complex networks of these gasotransmitters during the development of roots.

Toward safe inotropic therapy.

The use of currently available positive inotropic agents is associated with an unfavorable clinical outcome. The disappointment with positive inotropic therapy is to some extent foreseeable as currently available inotropic agents may precipitate ventricular arrhythmias due to a diastolic rise in intracellular [Ca], trigger/worsen myocardial ischemia due to an increased oxygen demand, and foster fuel deprivation from an energy starved heart. Safe use of presently available inotropic agents and development of novel inotropic agents must ensure that they are not associated with a diastolic rise in intracellular [Ca], an increase in myocardial oxygen consumption, and energy expenditure. Agents that improve left ventricular systolic performance through prolongation of left ventricular ejection time and not through increased myocardial contractility, that is, myosin activators, may be associated with a favorable outcome as they do not affect diastolic intracellular [Ca], myocardial oxygen demand, and presumably fuel expenditure.

Single Center Experience with Outpatient Continuous Infusion of Positive Inotropic Therapy

Single Center Experience with Outpatient Continuous Infusion of Positive Inotropic Therapy

Physalin promotes positive cardiac inotropism by a PKARYR2‐ dependent pathway

Long‐term positive cardiac inotropic therapy that increases both life quality and expectancy is still lacking. A phytosteroid isolated from Physalis angulata (Solonacea), and denominated F9, was probed in guinea‐pig cardiac tissues in vitro. Concentration‐response curves (0.2 to 200 μM) were performed in both spontaneous beating right atria and eletrically driven left atria. The effects of F9 in the atria were evaluated either in the absence or presence of propranolol (1 μM), verapamil (0.1 μM), staurosporine (0.1μM ) and H89 (10μM). Saponin‐skinned fibers were studied in order to further study its mechanism of action. F9 increased left atria tension to 377.57±24.73 % without any remarkable arrhythmogenic, chronotropic or tonotropic effect. This positive inotropic effect was not affected by pretreating tissues with propranolol, staurosporine or verapamil. Nevertheless, this effect was blunted by 91.8% by H89 (n=5) a PKA inhibitor. F9 (10μM) evoked a contraction of trabecular skinned fiber that attained 53% of the maximal contraction achieved with 0.25 μM Ca2+. This compound did neither affect calcium loading nor shifted the concentration‐response curve to pCa (7.0– 4.8). The increase in tension promoted by F9 in skinned fibers was not blocked by xestopongin C (3μM) or herbymicin A (1μM) but was blunted by either ruthenium red (30μM) or genistein (100μM). F9 does neither affect NKA enzymatic activity nor cAMP levels. The positive cardiac inotropic effect of F9 seems to be dependent of activation of PKA and RYR2 phosphorylation. This hypothesis is being currently tested.

GRK2 Inhibition in Heart Failure: Something Old, Something New

Despite significant advances in pharmacological and clinical treatment, heart failure (HF) remains the number one killer disease in the western world. HF is a chronic and progressive clinical syndrome mainly characterized by reduction in left ventricular ejection fraction and adverse remodeling of the myocardium. One of its hallmark molecular abnormalities is elevation of cardiac G protein-coupled receptor (GPCR) kinase (GRK)-2, originally termed beta-adrenergic receptor kinase-1 (βARK1), a member of the GRK family of serine/threonine protein kinases which phosphorylate and desensitize GPCRs. Up-regulated GRK2 in the heart underlies the diminished contractile responsiveness of the heart to positive inotropes, as it abrogates the pro-contractile signaling of various important cardiac receptors: mainly β-adrenergic receptors (βARs), but also angiotensin II type 1 receptors (AT(1)Rs), etc. Thus, cardiac-specific GRK2 inhibition via various transgenic approaches is postulated to combat chronic HF symptoms by increasing cardiac function, and even be salutary in some cases by increasing survival. This has been extensively documented over the past 15 years through a vast series of preclinical studies on animals of all sizes and shapes, from small mice up to large rabbits and pigs closely resembling human physiology, and genetically manipulated to have cardiac GRK2 inhibited or deleted, transiently or permanently. However, over the past several years, it has become increasingly clear that GRK2, like other members of the GRK family, exerts additional effects that can aggravate HF, in addition to merely blunt cardiac contractility by opposing cardiac βAR G protein-mediated signaling. One of these newly discovered cardiotoxic effects of GRK2, uncovered by our laboratory, is promotion by adrenal GRK2 of sympathetic hyperactivity of the failing heart, a significant morbidity factor in HF, targeted therapeutically nowadays by the use of beta-blockers in HF pharmacotherapy. Thus, new avenues for therapeutic exploitation of GRK2 inhibition in HF treatment might be possible in the near future. The present review gives first a brief account of what has already been documented about the benefits of cardiac GRK2 genetic manipulation in HF as a positive inotropic therapy for the disease, and then goes on to discuss in detail the intriguing new possibility that has emerged of lowering GRK2 activity in the adrenal gland, which could constitute a novel sympatholytic therapy for HF that helps relieve the devastatingly cardiotoxic sympathetic overload of the failing heart.

Case Report: Exercise in a Patient with Acute Decompensated Heart Failure Receiving Positive Inotropic Therapy

The projected increase in persons with advanced heart failure and associated costs warrant the examination of exercise in patients receiving inotropic therapy. Literature supports the use of exercise and inotropic therapy in the treatment of patients with advanced heart failure. The purposes of this paper are to illustrate the use of exercise prescription and outcomes assessment with a 6-minute walk test in a patient with acute decompensated heart failure receiving tailored therapy with dobutamine and to discuss potential relationships resulting in observed improvements. A 67-year old man was admitted to an acute care hospital with acute decompensated heart failure for tailored medical therapy including dobutamine. The patient received 14 days of tailored medical therapy, of which 12 days included exercise training by a physical therapist. Functional outcomes showed a clinically significant improvement in distance walked and improvement in the cardiorespiratory response. The improvement in estimated peak oxygen consumption was 7% greater than that predicted to be from tailored medical therapy. Exercise was safely provided to a patient hospitalized with advanced heart failure on continuous inotropic therapy. The 6-minute walk test was effectively used to prescribe exercise and examine patient outcomes.

Evaluation for a Ventricular Assist Device

Case presentation: A 57-year-old woman with ischemic and valvular heart disease presents with progressive heart failure while awaiting cardiac transplantation. Several years ago, after a large anterior myocardial infarction, she underwent 4-vessel CABG. Her subsequent course was complicated by atrial fibrillation and then recurrent heart failure. She also developed progressive aortic stenosis and mitral and tricuspid regurgitation and underwent aortic valve replacement with a 17-mm St. Jude valve, as well as mitral and tricuspid valvuloplasty. Two years later, she developed worsening symptoms of heart failure. She continued to fail despite escalating medical therapy and was listed for cardiac transplantation 6 months before this hospitalization. She is now admitted with severe heart failure and has been stabilized on intravenous positive inotropic therapy. She is 5 feet 2 inches tall, weighs 104 pounds, and has a body surface area of 1.4 m2. What are the best options to manage her as she awaits transplantation: Continued parenteral inotropic support, a ventricular assist device (VAD), or both as a bridge to transplantation? Heart failure is the final pathway of a progressive disease that can originate from a variety of cardiovascular processes. Improved acute medical care and prevention of sudden cardiac death have led to an increased prevalence of advanced heart failure. The prognosis of heart failure is dismal, with 50% of patients dead within 4 years, a percentage that matches that of many common malignancies.1 Of those hospitalized with an acute exacerbation, the mortality rate within 1 year has been reported to be between 30% and 50%.2,3 Numerous factors in clinical studies consistently have been identified to be associated with poor prognosis: Advanced age, decreased blood pressure, reduced ejection fraction, chronic kidney disease, diabetes mellitus, anemia, hyponatremia, and persistently high levels of natriuretic peptides. Yet, no single clinical variable or …

2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults

published online Mar 26, 2009; J. Am. Coll. Cardiol. Lynne Warner Stevenson, and Clyde W. Yancy Ganiats, Marvin A. Konstam, Donna M. Mancini, Peter S. Rahko, Marc A. Silver, Abraham, Donald E. Casey, Arthur M. Feldman, Gary S. Francis, Theodore G. Silver, Lynne Warner Stevenson, Clyde W. Yancy, Mariell Jessup, William T. Konstam, Donna M. Mancini, Keith Michl, John A. Oates, Peter S. Rahko, Marc A. M. Feldman, Gary S. Francis, Theodore G. Ganiats, Mariell Jessup, Marvin A. Transplantation, Sharon Ann Hunt, William T. Abraham, Marshall H. Chin, Arthur Force on Practice Guidelines, International Society for Heart and Lung American College of Cardiology Foundation/American Heart Association Task Diagnosis and Management of Heart Failure in Adults 2009 Focused Update Incorporated Into the ACC/AHA 2005 Guidelines for the This information is current as of March 27, 2009 http://content.onlinejacc.org/cgi/content/full/j.jacc.2008.11.013v1 located on the World Wide Web at: The online version of this article, along with updated information and services, is

2009 Focused Update: ACCF/AHA Guidelines for the Diagnosis and Management of Heart Failure in Adults

2009;53;1343-1382; originally published online Mar 26, 2009; J. Am. Coll. Cardiol. Rahko, Marc A. Silver, Lynne Warner Stevenson, and Clyde W. Yancy Francis, Theodore G. Ganiats, Marvin A. Konstam, Donna M. Mancini, Peter S. Mariell Jessup, William T. Abraham, Donald E. Casey, Arthur M. Feldman, Gary S. Heart and Lung Transplantation Developed in Collaboration With the International Society for Guidelines Cardiology Foundation/American Heart Association Task Force on Practice Management of Heart Failure in Adults: A Report of the American College of 2009 Focused Update: ACCF/AHA Guidelines for the Diagnosis and This information is current as of August 30, 2010 http://content.onlinejacc.org/cgi/content/full/53/15/1343 located on the World Wide Web at: The online version of this article, along with updated information and services, is

Lentiviral Vector–mediated SERCA2 Gene Transfer Protects Against Heart Failure and Left Ventricular Remodeling After Myocardial Infarction in Rats

Reduced expression of the SERCA2 gene impairs the calcium-handling and contractile functions of the heart. We developed an SERCA2 gene transfer system using lentiviral vectors, and examined the long-term effect of SERCA2 gene transfer in the rat ischemic heart failure model. A lentiviral vector containing the SERCA2 gene was infused into a rat heart by hypothermic intracoronary delivery 2 weeks after myocardial infarction (MI). The transduction efficiency was approximately 40%. Six months after transduction, echocardiogram and pressure-volume measurements revealed that the SERCA2 gene transfer had significantly protected against left ventricular (LV) dilation, and had improved systolic and diastolic function, resulting in reduction in mortality rates. The brain natriuretic peptide mRNA level showed a significantly decrease and the phosphorylation level of serine residue of phospholamban (PLN) showed an increase in the Lenti-SERCA2-transduced heart. Further, DNA microarray analysis disclosed that SERCA2 gene transfer had increased cardioprotective gene expression and lowered the expression of genes that are known to exacerbate heart failure. The SERCA2 gene was successfully integrated into the host heart, induced favorable molecular remodeling, prevented LV geometrical remodeling, and improved the survival rate. These results suggest that a strategy to compensate for reduced SERCA2 gene expression by lentiviral vectors serves as a positive inotropic, lucitropic, and cardioprotective therapy for post-MI heart failure.

Update on inotropic therapy in the management of acute heart failure

The use of classic inotropic agents activating the beta-receptor-cyclic adenosine monophosphate (cAMP) pathway (ie, dobutamine or milrinone) should be restricted to a "rescue" therapy in patients with acute heart failure and signs of peripheral hypoperfusion (hypotension, renal dysfunction) that is refractory to volume replacement, diuretics, and vasodilators. This approach is largely supported by observations from clinical trials suggesting that both short-term treatment of acute heart failure without an essential requirement of inotropic support as well as long-term inotropic therapy in patients with severe chronic heart failure with classical inotropic agents can increase arrhythmia and mortality. Vice versa, beta-receptor blockade, whenever tolerated, improves survival in patients with severe stable heart failure, further supporting the concept that beta-receptor stimulation has adverse long-term effects. Positive inotropic therapy stimulating the beta-receptor-cAMP pathway should, therefore, be used with caution, given the potential harmful effects. Levosimendan, a novel calcium sensitizer, has recently attracted substantial clinical interest and may be superior to classical inotropes with respect to improving cardiac mechanical efficiency and avoiding adverse effects such as increasing myocardial oxygen uptake or cardiomyocyte death. Earlier clinical studies have suggested a beneficial effect on survival compared with dobutamine or placebo in patients with acute heart failure (LIDO , RUSSLAN , and CASINO trials). However, more recent data from two large clinical trials (SURVIVE and REVIVE trials) did not confirm these beneficial effects on mortality. Therefore, additional data are required with respect to the optimum dosing of levosimendan and patient selection to reach a definitive conclusion about the role of levosimendan in the management of patients with acute heart failure.

The use of positive inotropes in end-of-life heart failure care

End-stage heart failure is associated with mortality equivalent to cancer, yet there is little information about palliative therapy for this disease. Chronic outpatient support with inotropes provides symptomatic relief and life extension for those select patients demonstrating dependence on positive inotropic therapy. The purpose of this review is to provide information about process and implementation of chronic outpatient support with inotropes in patients with end-stage heart failure.