Is there a role for positive inotropic agents in congestive heart failure: Focus on mortality

Amidon, Thomas M.; Parmley, William W.

doi:10.1002/clc.4960171203

Cited by 12 publications

(7 citation statements)

References 51 publications

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“…Unfortunately, most inotropic therapies that have been tested in patients over the past few decades have either had no effect on survival16 or have increased death rates 17,18. Therapies19 that have clinical benefit in HF, inhibitors of excess renin–angiotensin and β -adrenergic signaling, reduce rather than enhance myocyte contractility,19,20 suggesting that myocyte contractile abnormalities in HF might be the consequence of the excessive contractility demands rather than the cause of HF per se.…”

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confidence: 99%

Increasing Cardiac Contractility After Myocardial Infarction Exacerbates Cardiac Injury and Pump Dysfunction

Zhang

Chen

Gao

et al. 2010

Circulation Research

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Rationale: Myocardial infarction (MI) leads to heart failure (HF) and premature death. The respective roles of myocyte death and depressed myocyte contractility in the induction of HF after MI have not been clearly defined and are the focus of this study. Objectives:We developed a mouse model in which we could prevent depressed myocyte contractility after MI and used it to test the idea that preventing depression of myocyte Ca 2؉ -handling defects could avert post-MI cardiac pump dysfunction. Key Words: myocardial infarction Ⅲ cardiac contractility Ⅲ heart failure Ⅲ Ca 2ϩ handling V ascular disease can lead to interruption of blood flow to the heart (myocardial infarction [MI]). The resulting loss of contractile mass causes an acute reduction in cardiac pump function. Cardiac output and blood pressure are initially maintained by activation of sympathetic reflex responses that increase myocyte contractility in regions of the heart where blood flow is maintained. Soon after MI, the ventricles begin to remodel (dilate), which further increases the work demands (systolic wall stress) on the surviving myocardium. Methods andMyocyte contractility is increased after MI through activation of adrenergic signaling pathways that increase Ca 2ϩ influx and sarcoplasmic reticulum (SR) uptake, storage, and release. The increased myocyte Ca 2ϩ transients that enhance contractile function after MI are also thought to induce myocyte hypertrophy, 1-3 increasing contractile mass and partially normalizing the increased systolic wall stress. However, persistent pathological stress in the remodeled, post-MI heart is associated with abnormal myocyte contractile properties 4,5 and increases in the rate of myocyte death. 6 -8 These two changes develop with congestive heart failure (CHF) and increase during its progression. 6,9 The respective contributions of myocyte contractile abnormalities (weak myocytes) and myocyte death (not enough myocytes) in the induction and progression of HF after MI is still not clearly defined. We studied this issue by preventing depression of myocyte contractile function in genetically modified mice subjected to MI.Persistent pathological stress (MI and hypertension) induces abnormalities in myocyte Ca 2ϩ handling 5,10 and sympathetic signaling cascades. 11 SR Ca 2ϩ uptake rates are slowed; Ca 2ϩ transient and action potential durations are prolonged 5,12 ; and inotropic responses to sympathetic agonists are blunted. 13 These changes are centrally involved in Original

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confidence: 99%

Increasing Cardiac Contractility After Myocardial Infarction Exacerbates Cardiac Injury and Pump Dysfunction

Zhang

Chen

Gao

et al. 2010

Circulation Research

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“…Furthermore, these agents potentiate the cardiotoxic and arrhythmogenic effects associated with elevated intracellular calcium (20). Their hemodynamic and symptomatic benefits are short-lived, and the detrimental effects on mortality in the long-term restrict the use of these agents (21). Levosimendan, on the other hand, stabilizes the cross-bridges, which form between actin and myosin by binding to cardiac troponin C. This stabilization provides a more efficient contraction by prolonging the time both proteins interact together during systole.…”

Section: Discussionmentioning

confidence: 99%

Value of IGF-I levels in the evaluation of response to treatment with levosimendan in patients with severe heart failure

Işık

Çetın²,

Çiçekçioğlu³

et al. 2011

Anadolu Kardiyol Derg

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ÖZETAmaç: Akut dekompanse kalp yetersizliğinde (KY) levosimendan tedavisi pozitif inotropik, "antistunning" ve kardiyoprotektif etkilidir. Kalp yetersizliği tedavisine yönelik yürütülen çalışmalar arasında büyüme hormonuna dayalı olanlar ilgi çekicidir. Levosimendan tedavisinden fayda görmede bazal insülin benzeri büyüme faktörü 1 (IGF-I)'in değerini araştırmak üzere çalışmayı planladık. Yöntemler: Bu prospektif kohort çalışmaya standart KY tedavisi altında NYHA sınıflamasına göre fonksiyonel kapasitesi 3-4 ve sol ventrikül (SV) ejeksiyon fraksiyonu <%35 olan 30 hasta alındı. Hastaların tedavi öncesi ve sonrası (levosimendan infüzyonu bitiminden 72 saat sonra) semptomları, ekokardiyografik parametreleri değerlendirildi ve kan örnekleri alındı. İstatistiksel analizde Mann-Whitney U, Pearson Chi-square ve Wilcoxon işaret sıralama testleri kullanıldı. Korelasyon Spearman korelasyon analizi ile değerlendirildi. Bulgular: Hastaların ortalama yaşı 62.6±10.1 yıl idi (minimum 40 maksimum 82). Hastaların %83.3'ü erkek ve %16.7'si kadın idi. Ortalama bazal IGF-I düzeyi 106.9±47.0 µg/L idi (minimum 39, maksimum 258). Hastaların tedavi sonrasında NYHA sınıfı, B-tip natriüretik peptit (BNP) düzeyleri, SV ejeksiyon fraksiyonu ve SV sistol sonu hacim değerlerinde tedavi öncesine göre istatistiksel olarak anlamlı düzelme saptandı (3.5±0.5 ve ABSTRACT Objective: Levosimendan treatment has inotropic, anti-stunning, and cardioprotective effects in the setting of acute decompensated heart failure (HF). Among studies conducted on the treatment of heart failure, those based on the growth hormone axis are of particular interest. The aim of this study was to determine the value of baseline insulin-like growth factor 1 (IGF-I) measurements in predicting response to levosimendan treatment. Methods: The study population included patients on standard heart failure treatment who presented with functional capacity NYHA class 3-4 and left ventricular (LV) ejection fraction less than 35% were enrolled in this prospective, cohort study. Pre-and post-treatment symptoms of patients (72 hours after the completion of levosimendan infusion) and echocardiographic parameters were evaluated and blood samples were collected. Mann-Whitney U, Pearson Chi-square and Wilcoxon Sign Rank tests were used for statistical analysis. Correlations were determined using Spearman correlation analysis. Results: Thirty patients were enrolled in this study, 83.3% of whom were male and 16.7% were female, with a mean age of 62.6 ±10.1 years. Mean baseline IGF-I level was 106.9±47.0 µg/L. Statistically significant improvements were observed in NYHA class, mean brain natriuretic peptide (BNP) levels, LV ejection fraction and LV end-systolic volume values following treatment with levosimendan (respective pre-treatment and post-treatment values: 3.5±0.5 vs. 2.5±0.7, p<0.001; 1209.8±398.6 pg/ml vs. 704.1±344.6 pg/ml, p<0.001, and 25.7±6.6% vs. 29.0±6.8%, p=0.021, and 164.1±45.7 ml vs. 152.8±50.6 ml, p=0.012). Fourteen patients (46.7%) had low IGF-I levels, taking into consider...

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“…The positive inotropic effect of many drugs that are effective in animal studies is substantially impaired in human heart failure (1,5,29). For instance, the positive inotropic effect of P-adrenoceptor agonists is markedly reduced in human end-stage heart failure (6).…”

Section: Introductionmentioning

confidence: 99%

“…The first clinically relevant compounds to exert such Ca2+-sensitizing effects were sulmazole and pimobendan (1,21), which also possess a very potent phosphodiesterase inhibitory effect (3,8, for review see ref. 17,25).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological Profile of CGP 48506, A New Positive Inotropic Agent

Neumann

Zimmermann

1997

Cardiovascular Drug Reviews

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Key Words: Benzodiazocine-Calcium-sensitizing agents-Phosphodiesterase inhibitionPositive inotropy.The purpose of this review is to summarize the studies on the mechanism(s) of action of a new cardiotonic agent, CGP 48506. Cardiotonic drugs are expected to alleviate symptoms of heart failure and reduce mortality of patients suffering from this disease. To put the positive inotropic mechanism(s) of action of CGP 48506 into perspective, some important and well investigated positive inotropic mechanisms are described. The methods used to distinguish the inotropic mechanism(s) of action of CGP 48506 from those of other drugs are briefly discussed. The concept of Ca2+ sensitization by drugs is delineated. Potential advantages and disadvantages of Ca2+ sensitizers for the treatment of heart failure are mentioned. Evidence is presented that CGP 48506 acts primarily as a Ca2+ sensitizer. Data on the effect of CGP 48506 in animal as well as human cardiac preparations indicate that CGP 48506 is a novel and effective positive inotropic agent.

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Is there a role for positive inotropic agents in congestive heart failure: Focus on mortality

Cited by 12 publications

References 51 publications

Increasing Cardiac Contractility After Myocardial Infarction Exacerbates Cardiac Injury and Pump Dysfunction

Increasing Cardiac Contractility After Myocardial Infarction Exacerbates Cardiac Injury and Pump Dysfunction

Value of IGF-I levels in the evaluation of response to treatment with levosimendan in patients with severe heart failure

Pharmacological Profile of CGP 48506, A New Positive Inotropic Agent

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