Low-level inotropic stimulation with type III phosphodiesterase inhibitors in patients with advanced symptomatic chronic heart failure receiving β-blocking agents

Shakar, Simon F.; Bristow, Michael R.

doi:10.1007/s11886-001-0027-8

Cited by 16 publications

(8 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Trials of oral preparations, not included in the current analysis, have shown an adverse effect on survival [30,31]. Consistent, peripheral, vasodilator effects, lusitropic effects [32–34] and persistent effects despite beta‐blockade [35], may give PDE inhibitors an important advantage over beta‐agonists.…”

Section: Introductionmentioning

confidence: 99%

The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure—a meta‐regression analysis

Thackray

Easthaugh

Freemantle

et al. 2002

European J of Heart Fail

277

153

View full text Add to dashboard Cite

Aims: To review systematically the use of intravenous (IV) inotropic agents acting through the adrenergic signalling pathway, compared with placebo or an active agent, in patients with heart failure. Methods: Studies investigating the use of intravenous inotropes in patients with heart failure published between 1966 and 2000 were identified using MEDLINE, the Cochrane register and Embase databases. Reference lists from relevant papers and reviews were hand searched for further papers. In total, 21 trials, that included 632 patients receiving IV inotropic drugs, placebo or non-treatment control, were identified. Drugs of the following classes were included, the b-agonists; dobutamine, high-dose ()2.5 mgykgymin) dopamine, dopexamine and the phosphodiesterase (PDE) inhibitors; amrinone, milrinone, enoximone and toborinone. Sixteen trials (474 patients) contributed data from acute invasive haemodynamic studies of symptomatically severe heart failure. Five trials (158 patients) were based on intermittent inotropic therapy in an outpatient context. Results: With few exceptions, trials of intravenous inotropic agents were small and often failed to report clinically important outcomes. Compared to placebo, intravenous inotropic agents acting through the adrenergic system tended to increase mortality (odds ratio 1.50 (95% CIs0.51 to 3.92) but this did not reach significance and insufficient data were available to determine whether symptoms improved. There appeared to be little difference in the effect of beta-agonists compared to PDE inhibitors on patient outcomes but this could be attributed to the paucity of data. Conclusions: Intravenous inotropic agents acting through the adrenergic pathway are often used in patients with worsening heart failure to achieve arbitrary haemodynamic targets. Our analyses show that there is very little evidence that such treatment improves symptoms or patient outcomes and may not be safe. This highlights the need for further well designed randomised clinical trials.

show abstract

Section: Introductionmentioning

confidence: 99%

The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure—a meta‐regression analysis

Thackray

Easthaugh

Freemantle

et al. 2002

European J of Heart Fail

277

153

View full text Add to dashboard Cite

show abstract

“…In chronic heart failure patients starting treatment with "-AR blocker, a concomitant PDE inhibitor administration prevents transient reduction in ventricular systolic function due to withdrawal of inotropic support provided by resting adrenergic tone [19][20][21][22]. In end-stage heart failure, a combination therapy with PDE inhibitor and "-AR blocker could be used as a bridge to cardiac transplantation [23][24][25].…”

mentioning

confidence: 99%

Myocardial Phosphodiesterases and Regulation of Cardiac Contractility in Health and Cardiac Disease

Osadchii

2007

Cardiovasc Drugs Ther

View full text Add to dashboard Cite

Phosphodiesterase (PDE) inhibitors are potent cardiotonic agents used for parenteral inotropic support in heart failure. Contractile effects of these agents are mediated through cAMP-protein kinase A-induced stimulation of I (Ca2+) which ultimately results in increased Ca(2+)-induced sarcoplasmic reticulum Ca(2+) release. A number of additional effects such as increases in sarcoplasmic reticulum Ca(2+) stores, stimulation of reverse mode Na(+)-Ca(2+) exchange, direct or cAMP-mediated effects on sarcoplasmic reticulum ryanodine receptor, stimulation of the voltage-sensitive sarcoplasmic reticulum Ca(2+) release mechanism, as well as A(1) adenosine receptor blockade could contribute to positive inotropic responses to PDE inhibitors. Moreover, some PDE inhibitors exhibit Ca(2+) sensitizer properties as they could increase the affinity of troponin C Ca(2+)-binding sites as well as reduce Ca(2+) threshold for thin myofilament sliding and facilitate cross-bridge cycling. Inotropic responses to PDE inhibitors are significantly reduced in cardiac disease, an effect largely attributed to downregulation of cAMP-mediated signalling due to sustained sympathetic activation. Four PDE isoenzymes (PDE1, PDE2, PDE3 and PDE4) are present in myocardial tissue of various mammalian species, of which PDE3 and PDE4 are particularly involved in regulation of cardiac myocyte contraction. PDE cAMP-hydrolysing activity is preserved in compensated cardiac hypertrophy but significantly reduced in animal models of heart failure. However, clinical studies have not revealed any changes in distribution profile as well as kinetic and regulatory properties of myocardial PDEs in failing human hearts. A reduction of PDE inhibitors-induced contractile responses in heart failure has therefore been ascribed to reduced cAMP synthesis due to uncoupling of adenylyl cyclase from beta-adrenoreceptor. In cardiac myocytes, PDEs are targeted to distinct subcellular compartments by scaffolding proteins such as myomegalin, mAKAP and beta-arrestins. Over subcellular microdomains, cAMP hydrolysis by PDE3 and PDE4 allows to control the activity of local pools of protein kinase A and therefore the extent of protein kinase A-mediated phosphorylation of cellular proteins.

show abstract

“…34,35 Inotropic agents that act through inhibition of phospholamban are desirable and best tolerated. 36,37 Based on our clinical experience, we cannot determine whether increasing BB dose in DHF patients receiving chronic BB therapy will have similar hemodynamic improvement. A post-hoc analysis of the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study reported worse mortality in patients whose BB were withdrawn upon randomization to milrinone (28.6% vs. 7.7%, p-value not reported).…”

Section: Discussionmentioning

confidence: 99%

Combination Therapy With Beta Blocker and Inotrope in Decompensated Heart Failure: A Clinical Observation

Jaiswal¹,

Nguyen²,

Carry³

et al. 2017

Heart Res Open J

View full text Add to dashboard Cite

show abstract

Low-level inotropic stimulation with type III phosphodiesterase inhibitors in patients with advanced symptomatic chronic heart failure receiving β-blocking agents

Cited by 16 publications

References 68 publications

The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure—a meta‐regression analysis

The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure—a meta‐regression analysis

Myocardial Phosphodiesterases and Regulation of Cardiac Contractility in Health and Cardiac Disease

Combination Therapy With Beta Blocker and Inotrope in Decompensated Heart Failure: A Clinical Observation

Contact Info

Product

Resources

About