Bridge to recovery with the use of left ventricular assist device and clenbuterol

Hon, Jimmy Kim Fatt; Yacoub, Magdi H.

doi:10.1016/s0003-4975(03)00460-0

Cited by 86 publications

(64 citation statements)

References 54 publications

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“…Ten of 15 patients treated with clenbuterol in this study had significant cardiac improvement, allowing for assist device explantation for recovery (Hon and Yacoub, 2003). This series represents a rate of myocardial recovery that is more than double that of any previously reported study.…”

mentioning

confidence: 49%

β₂-Adrenergic Stimulation Attenuates Left Ventricular Remodeling, Decreases Apoptosis, and Improves Calcium Homeostasis in a Rodent Model of Ischemic Cardiomyopathy

Xydas

Kherani²,

Chang³

et al. 2006

J Pharmacol Exp Ther

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The benefit of the ␤ 2 -adrenergic agonist, clenbuterol, in left ventricular assist device patients with dilated cardiomyopathy has been reported, but its effect on ischemic heart failure (HF) is unknown. We investigated whether clenbuterol improves left ventricular remodeling, myocardial apoptosis and has synergy with a ␤ 1 antagonist, metoprolol, in a model of ischemic HF. Rats were randomized to: 1) HF only; 2) HF ϩ clenbuterol; 3) HF ϩ metoprolol; 4) HF ϩ clenbuterol ϩ metoprolol; and 5) rats with sham surgery. HF was induced by left anterior descending artery (LAD) artery ligation and confirmed by decreased left ventricular fractional shortening, decreased maximum left ventricular dP/dt (dP/dt max ), and elevated left ventricular end-diastolic pressure (LVEDP) compared with sham rats (p Ͻ 0.01). After 9 weeks of oral therapy, echocardiographic, hemodynamic, and ex vivo end-diastolic pressure-volume relationship (EDPVR) measurements were obtained. Immunohistochemistry was performed for myocardial apoptosis and DNA damage markers. Levels of calcium-handling proteins were assessed by Western blot analysis. Clenbuterol-treated HF rats had increased weight gain and heart weights versus HF rats (p Ͻ 0.05). EDPVR curves revealed a leftward shift in clenbuterol rats versus metoprolol and HF rats (p Ͻ 0.05). The metoprololtreated group had a lower LVEDP and higher dP/dt max versus the HF group (p Ͻ 0.05). Clenbuterol and metoprolol groups had decreased myocardial apoptosis and DNA damage markers and increased DNA repair markers versus HF rats (all p Ͻ 0.01). Protein levels of the ryanodine receptor and sarcoplasmic reticulum calcium-ATPase were improved in clenbuterol-, metoprolol-, and clenbuterolϩmetoprolol-treated groups versus HF rats. However, as a combination therapy, there were no synergistic effects of clenbuterolϩmetoprolol treatment. We conclude that clenbuterol ameliorates EDPVR, apoptosis, and calcium homeostasis but does not have synergy with metoprolol in our model of ischemic HF.Clenbuterol is a ␤ 2 -adrenergic receptor agonist first used in the mid-1970s to treat asthma and is approved for this indication in Europe (Salorinne et al., 1975). The drug bears structural similarity to albuterol but has enhanced oral absorption and ␤ 2 -selectivity. Clenbuterol also increases muscle bulk (Choo et al., 1992;Maltin et al., 1993;Carter and Lynch, 1994) because of an anabolic effect that may be mediated via long-term ␤ 2 -activation (MacLennan and Edwards, 1989;Choo et al., 1992). Because of this anabolic action, oral clenbuterol has been abused by athletes to enhance size and strength (Beckett, 1992;Perry, 1993). Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

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mentioning

confidence: 49%

β₂-Adrenergic Stimulation Attenuates Left Ventricular Remodeling, Decreases Apoptosis, and Improves Calcium Homeostasis in a Rodent Model of Ischemic Cardiomyopathy

Xydas

Kherani²,

Chang³

et al. 2006

J Pharmacol Exp Ther

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“…Although coupling of ␤-AR subtypes to specific signaling pathways can be species specific and vary from mouse to rat to humans (Port and Bristow, 2001), the effectiveness of therapies that are now clinically accepted for humans has been demonstrated in animal experimental models. Moreover, successful use of ␤2-AR agonist clenbuterol in conjunction with left ventricular assist device to help to attenuate myocardial atrophy before heart transplantation (Hon and Yacoub, 2003) suggests that the translation of current finding to clinical practice seems rational.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Efficacy of a Combination of a β1-Adrenoreceptor (AR) Blocker and β2-AR Agonist in a Rat Model of Postmyocardial Infarction Dilated Heart Failure Exceeds That of a β1-AR Blocker plus Angiotensin-Converting Enzyme Inhibitor

Ahmet¹,

Morrell²,

Lakatta³

et al. 2009

J Pharmacol Exp Ther

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We had proposed previously a novel combination of ␤2-adrenoreceptor (AR) agonist and ␤1-AR blocker that in the rat model of postmyocardial infarction (MI) dilated cardiomyopathy exceeds the therapeutic effectiveness of either monotherapy. In the present study, we compared that treatment with a combination of ␤1-AR blocker and angiotensin-converting enzyme inhibitor (ACEi), a current standard chronic heart failure (CHF) therapy. Two weeks after coronary artery ligation, rats were divided into groups of similar average MI size, measured by echocardiography, and the following 12-month treatments were initiated: fenoterol (250 g/kg/day), a ␤2-AR agonist, plus metoprolol (100 mg/kg/day), a ␤1-AR blocker (␤1-␤2ϩ); metoprolol plus enalapril (20 mg/kg/day), an ACEi (␤1-ACEi); and a combination of all three drugs (␤1-␤2ϩACEi). These treatment groups were compared with each other and with nontreated (nT) and sham groups. The 12-month mortality was significantly reduced in all treatment groups (44% in ␤1-␤2ϩ, 56% in ␤1-␤2ϩACEi, 59% in ␤1-ACEi versus 81% in nT). Bimonthly echocardiography revealed significant attenuation of the left ventricular (LV) chamber remodeling, LV functional deterioration, and MI expansion in all three treatment groups, but effects were significantly more pronounced when treatment included a ␤2-AR agonist. The results indicated that a combination of ␤1-AR blocker and ␤2-AR agonist is equipotent to a combination of ␤1-AR blocker and ACEi in the treatment of CHF in rats, with the respect to mortality, and exceeds the latter with respect to cardiac remodeling and MI expansion. Thus, this novel therapeutic regimen for CHF warrants detailed clinical investigation.

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“…There is now compelling evidence that prolonged unloading of the left ventricle with the use of an LVAD is associated with structural reverse remodeling (Mancini et al, 1998;Drakos et al, 2007) that can be accompanied by significant functional improvement (Dandel et al, 2005). Therefore, a new, although relatively rare indication for mechanical support is emerging, namely bridge to recovery (Hon & Yacoub, 2003). However, before the use of ventricular assist devices as a "bridge to myocardial improvement" or complete recovery becomes feasible, reliable methods to detect complete recovery need to be developed.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Cardiac Function after VAD Implantation

Terrovitis¹,

Tseliou²,

Drakos³

et al. 2011

New Aspects of Ventricular Assist Devices

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Bridge to recovery with the use of left ventricular assist device and clenbuterol

Cited by 86 publications

References 54 publications

β₂-Adrenergic Stimulation Attenuates Left Ventricular Remodeling, Decreases Apoptosis, and Improves Calcium Homeostasis in a Rodent Model of Ischemic Cardiomyopathy

β₂-Adrenergic Stimulation Attenuates Left Ventricular Remodeling, Decreases Apoptosis, and Improves Calcium Homeostasis in a Rodent Model of Ischemic Cardiomyopathy

Therapeutic Efficacy of a Combination of a β1-Adrenoreceptor (AR) Blocker and β2-AR Agonist in a Rat Model of Postmyocardial Infarction Dilated Heart Failure Exceeds That of a β1-AR Blocker plus Angiotensin-Converting Enzyme Inhibitor

Evaluation of Cardiac Function after VAD Implantation

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Bridge to recovery with the use of left ventricular assist device and clenbuterol

Cited by 86 publications

References 54 publications

β2-Adrenergic Stimulation Attenuates Left Ventricular Remodeling, Decreases Apoptosis, and Improves Calcium Homeostasis in a Rodent Model of Ischemic Cardiomyopathy

β2-Adrenergic Stimulation Attenuates Left Ventricular Remodeling, Decreases Apoptosis, and Improves Calcium Homeostasis in a Rodent Model of Ischemic Cardiomyopathy

Therapeutic Efficacy of a Combination of a β1-Adrenoreceptor (AR) Blocker and β2-AR Agonist in a Rat Model of Postmyocardial Infarction Dilated Heart Failure Exceeds That of a β1-AR Blocker plus Angiotensin-Converting Enzyme Inhibitor

Evaluation of Cardiac Function after VAD Implantation

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β₂-Adrenergic Stimulation Attenuates Left Ventricular Remodeling, Decreases Apoptosis, and Improves Calcium Homeostasis in a Rodent Model of Ischemic Cardiomyopathy

β₂-Adrenergic Stimulation Attenuates Left Ventricular Remodeling, Decreases Apoptosis, and Improves Calcium Homeostasis in a Rodent Model of Ischemic Cardiomyopathy