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

Shah, Sanjiv J.; Blair, John E.; Filippatos, Gerasimos; Macarie, Cezar; Rużyłło, Witold; Korewicki, J; Bubenek-Turconi, Serban I.; Ceracchi, Maurizio; Bianchetti, Maria; Carminati, Paolo; Kremastinos, Dimitrios Th.; Grzybowski, Jacek; Valentini, Giovanni; Sabbah, Hani N.; Gheorghiade, Mihai

doi:10.1016/j.ahj.2009.03.007

Cited by 128 publications

(102 citation statements)

References 32 publications

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“…Istaroxime represents a new class of Na + /K + -ATPase inhibitors and stimulates SERCA, thereby exhibiting inotropic and lusitropic effects [131,132]. In animal models, this new drug exerts inotropic activity comparable with that of digitalis but produces less arrhythmia [133].…”

Section: Novel Therapies For the Septic Heartmentioning

confidence: 99%

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

Rudiger¹,

Singer

2013

CVP

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Septic shock is characterized by circulatory compromise, microcirculatory alterations and mitochondrial damage, which all reduce cellular energy production. In order to reduce the risk of major cell death and a diminished likelihood of recovery, adaptive changes appear to be activated. As a result, cells and organs may survive in a non-functioning hibernation-like condition. Sepsis-induced cardiac dysfunction may represent an example of such functional shutdown. Sepsis-induced myocardial dysfunction is common, corresponds to the severity of sepsis, and is reversible in survivors. Its mechanisms include the attenuation of the adrenergic response at the cardiomyocyte level, alterations of intracellular calcium trafficking and blunted calcium sensitivity of contractile proteins. All these changes are mediated by cytokines. Treatment includes preload optimization with sufficient fluids. However, excessive volume loading is harmful. The first line vasopressor recommended at present is norepinephrine, while vasopressin can be started as a salvage therapy for those not responding to catecholamines. During early sepsis, cardiac output can be increased by dobutamine. While early administration of catecholamines might be necessary to restore adequate organ perfusion, prolonged administration might be harmful. Novel therapies for sepsis-induced cardiac dysfunction are discussed in this article. Cardiac inotropy can be increased by levosimendan, istaroxime or omecamtiv mecarbil without greatly increasing cellular oxygen demands. Heart rate reduction with ivabradine reduces myocardial oxygen expenditure and ameliorates diastolic filling. Beta-blockers additionally reduce local and systemic inflammation. Advances may also come from metabolic interventions such as pyruvate, succinate or high dose insulin substitutions. All these potentially advantageous concepts require rigorous testing before implementation in routine clinical practice. While early administration of catecholamines might be necessary to restore adequate organ perfusion and pressure, prolonged administration might be harmful.Novel therapies for sepsis-induced cardiac dysfunction are discussed in this article. Cardiac inotropy can be increased by levosimendan, istaroxime or omecamtiv mecarbil without greatly increasing cellular oxygen demands. Heart rate reduction with ivabradine will reduce myocardial oxygen expenditure and ameliorate diastolic filling. Beta-blockers additionally reduce local and systemic inflammation. Advances may also come from metabolic interventions such as pyruvate, succinate or high dose insulin substitutions. However, all these potentially advantageous concepts require rigorous testing before implementation in routine clinical practice.-3 -Alain Rudiger & Mervyn Singer: The heart in sepsis

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Section: Novel Therapies For the Septic Heartmentioning

confidence: 99%

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

Rudiger¹,

Singer

2013

CVP

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“…Of these, pharmacological phosphodiesterase inhibition to increase cAMP availability and hence SERCA activity has been translated from the laboratory setting to clinical trial stages, only to be withdrawn because of an increased incidence of sudden death. 18 In a similar vein, pharmacological stimulation of SERCA with the Na/K ATPase antagonist istaroxime [19][20][21] has also been pursued in heart failure. However, once again, after initial promise in experimental studies and early clinical trials, substantive clinical trials were suspended.…”

Section: Restoration Of Serca As a Therapeutic Strategymentioning

confidence: 99%

Sarcoplasmic Reticulum Ca-ATPase and Heart Failure 20 Years Later

Eisner

Caldwell

Trafford

2013

Circulation Research

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T his article reflects on the impact of a classic paper identifying the effects of loss of sarcoplasmic reticulum Ca-ATPase activity in heart failure. The Classic ArticleUnderstanding the effects of heart failure on contraction and Ca signaling in the heart has long been a priority. By the late 1980s, many studies on animal models had shown that heart failure resulted in a slowing of the decay of the systolic Ca transient 1 because of a decrease in the expression of the sarcoplasmic reticulum (SR) Ca-ATPase (SERCA).2 Work using human tissue found similar changes.3,4 In 1994, Hasenfuss et al 5 published a now classic article in Circulation Research entitled "Relation between myocardial function and expression of sarcoplasmic reticulum Ca-ATPase in failing and non-failing human myocardium." Previous work had shown that SERCA expression and activity were decreased in heart failure. Other work had shown that the increase of force seen on increasing the frequency of stimulation (the positive forcefrequency curve) disappeared in heart failure. Hasenfuss et al 5 showed that the degree of change in the force-frequency relationship correlated with the loss of SERCA. Hearts with low levels of SERCA developed maximum force at lower frequencies than those with higher levels. In addition, and suggested as causative of the reduced force-frequency responses, the failing hearts had reduced SERCA-mediated Ca uptake.The work in this article has influenced 2 areas of research: changes of SR function in heart failure and restoration of SERCA as a therapeutic strategy. We consider these in turn. SR Function in Heart FailureTwenty years later, the role of changes of SERCA expression in heart failure is well-established. The majority of studies of heart failure in either humans or experimental animals show that SERCA activity is decreased in heart failure. This decrease of SERCA has 2 immediate effects on Ca signaling. First, it slows the rate of decay of the systolic Ca transient, thereby impairing relaxation. Second, as a consequence of decreasing SR Ca content, it will decrease the amplitude of the systolic Ca transient and thus contraction. However, subsequent work has shown that changes of SERCA are part of a group of changes of Ca signaling that occur in heart failure. As highlighted in Figure, 2 other factors will also decrease the SR Ca content. First, there is an increase of NCX expression or activity. [6][7][8] This adaptation has the benefit of making up for the reduced SERCA, thereby preserving relaxation. In a subsequent article, Hasenfuss et al 9 showed that patients with increased NCX had better diastolic function than did those with lower NCX. However, although increased NCX improves diastolic function, it will decrease SR Ca content and thereby depress systolic function further. Second, many studies have now shown that the open probability of the RyR is increased in heart failure. [10][11][12] This may occur as a result of phosphorylation, 10 hyponitrosylation, 13 or oxidation. 14 This increased opening will lead to a...

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“…According to pressure -volume analysis and tissue Doppler imaging, istaroxime increased contractility and decreased diastolic stiffness compared with placebo. 53 Myocardial Fibrosis and Matrix Remodeling Following myocardial injury, LV remodeling manifests a phenotype characterized by thinning of the myocardium at the site of injury, compensatory hypertrophy of viable myocardium and dilatation of the ventricular chamber. Reparative deposition of extracellular matrix (ECM) in the injured region occurs in an attempt to maintain the structural integrity of the heart.…”

Section: Myocardial Targetsmentioning

confidence: 99%

The Future of Pharmacological Therapy for Heart Failure

Sata

Krum

2010

Circ J

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Current pharmacological therapy for heart failure (HF) is based on improved understanding of the pathophysiological mechanisms of HF progression. In particular, inhibition of key activated neurohormonal systems (eg, the renin-angiotensin-aldosterone system) and the sympathetic nervous system has been the cornerstone of drug therapy for this condition. However, despite these major advances, many HF patients still only marginally respond to these therapies. Novel therapeutic approaches have been tested. Several recent phase III studies have failed, however, despite intriguing pathophysiological concepts and promising pilot data. In other studies, significant benefits have been observed in certain subgroups only, suggesting the need for a more tailored approach to individual risk and comorbidity. This review will focus on recent and potential future pharmacological HF therapies and where drug treatment may be in the next few years. In discussing future pharmacological therapy for HF, 3 key strategies will be considered: (1) optimization of conventional therapies, (2) a focus on new drug development within areas not yet adequately represented by major clinical data and (3) new drugs affecting novel therapeutic targets. (Circ J 2010; 74: 809 - 817)

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Cited by 128 publications

References 32 publications

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

Sarcoplasmic Reticulum Ca-ATPase and Heart Failure 20 Years Later

The Future of Pharmacological Therapy for Heart Failure

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