Combined Oral Positive Inotropic and Beta-Blocker Therapy for Treatment of Refractory Class IV Heart Failure

Shakar, Simon F.; Abraham, William T.; Gilbert, Edward M.; Robertson, Alastair D.; Lowes, Brian D.; Zisman, Lawrence S.; Ferguson, Debra A.; Bristow, Michael R.

doi:10.1016/s0735-1097(98)00077-1

Cited by 126 publications

(74 citation statements)

References 31 publications

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“…Phosphodiesterase inhibitors can maintain systolic function when used in combination with a ␤-adrenoceptor blocker in patients with advanced heart failure (35). Despite the well-documented therapeutic benefits of these agents, there is, nevertheless, substantial evidence that heart failure results in an attenuated phosphodiesterase inhibitorinduced contractile response (6).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of histone deacetylase on ventricular remodeling in infarcted rats

Lee

Lin

Chang

2007

American Journal of Physiology-Heart and Circulatory Physiology

142

110

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Lee T-M, Lin M-S, Chang N-C. Inhibition of histone deacetylase on ventricular remodeling in infarcted rats. Am J Physiol Heart Circ Physiol 293: H968-H977, 2007. First published March 30, 2007; doi:10.1152/ajpheart.00891.2006.-Histone deacetylase (HDAC) determines the acetylation status of histones and, thereby, controls the regulation of gene expression. HDAC inhibitors have been shown to inhibit cardiomyocyte growth in vitro and in vivo. We assessed whether HDAC inhibitors exert a beneficial effect on the remodeling heart in infarcted rats. At 24 h after ligation of the left anterior descending artery, male Wistar rats were randomized to vehicle, HDAC inhibitors [valproic acid (VPA) and tributyrin], an agonist of HDAC (theophylline), VPA ϩ theophylline, or tributyrin ϩ theophylline for 4 wk. Significant ventricular hypertrophy was detected as increased myocyte size at the border zone isolated by enzymatic dissociation after infarction. Cardiomyocyte hypertrophy and collagen formation at the remote region and border zone were significantly attenuated by VPA and tributyrin with a similar potency compared with that induced by the vehicle. Left ventricular shortening fraction was significantly higher in the VPA-and tributyrin-treated groups than in the vehicle-treated group. Increased synthesis of atrial natriuretic peptide mRNA after infarction was confirmed by RT-PCR, consistent with the results of immunohistochemistry and Western blot for acetyl histone H4. The beneficial effects of VPA and tributyrin were abolished by theophylline, implicating HDAC as the relevant target. Inhibition of HDAC by VPA or tributyrin can attenuate ventricular remodeling after infarction. This might provide a worthwhile therapeutic target.hypertrophy; infarction HISTONE ACETYLATION PLAYS a critical role in cardiac development and disease. Acetylation of histone residues results in unwinding of the DNA, which allows transcription factors and RNA polymerase II to bind more readily to DNA and, thereby, increase gene transcription (40). Histone deacetylase (HDAC) inhibitors have been shown to cause cell cycle arrest. Class I and II HDACs are involved in the control of cardiac hypertrophy (4,16,40). Class I HDACs can be recruited by homeodomain-only protein or other hypertrophic stimuli, resulting in inhibition of serum response factor and the antihypertrophic gene program (16). Class II HDACs can act as signal-responsive repressors of cardiac hypertrophy by inhibiting expression of the gene that is dependent on myocyte enhancer factor 2C (4, 40). Consistent with this repressive role, mutant mice lacking the class II HDAC9 are hypersensitive to hypertrophic signals (26, 40). Paradoxically, HDAC inhibitors such as valproic acid (VPA) (33) and tributyrin induce growth arrest, differentiation, and/or apoptosis of cardiomyocytes in vitro (3). These inhibitory effects are believed to be caused, in part, by accumulation of acetylated proteins, such as nucleosomal histones, which appear to play a major role in regulation of transcription of ge...

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Section: Discussionmentioning

confidence: 99%

Inhibition of histone deacetylase on ventricular remodeling in infarcted rats

Lee

Lin

Chang

2007

American Journal of Physiology-Heart and Circulatory Physiology

142

110

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“…62 Some but not all of these problems might be overcome by the development of heart failure-designed "fourth-generation" ␤-blockers, 57 other effective types of antiadrenergic therapy, or ␤-blockers combined with positive inotropic agents. 117 The importance of the ␤-blocker data set is not that it demonstrates a "cure" for chronic heart failure but rather that it has shown that in some patients, prognosis can be substantially improved by medical therapy. This observation should provide the impetus to develop further types of treatment that improve the biological properties of the failing heart.…”

Section: Who Should Be Treated With a ␤-Blocking Agent?mentioning

confidence: 99%

β-Adrenergic Receptor Blockade in Chronic Heart Failure

2000

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“…However, β-blockers can aggravate the cardiac symptoms of humans with severe heart failure due to a depression of cardiac function [4,7,14,20]. Similarly, β-blockers can lead to a worsening of the cardiac symptoms in dogs with severe heart failure, and administration of β-blockers to such dogs is contraindicated.…”

Section: Discussionmentioning

confidence: 99%

“…Although the present study was performed using healthy dogs, carvedilol attenuated the increase in HR, FS, and left ventricular contractility that was induced by the administration of dobutamine or dopamine, whereas the increase in FS induced by milrinone was unaffected by carvedilol. The administration of milrinone during carvedilol administration for the treatment of severe heart failure in humans may be beneficial for some patients [8,11,20]. For example, in patients with severe heart failure (New York Heart Association grades IIIb and IV), the combined administration of carvedilol and milrinone improved symptoms to grades II or IIIa [14].…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular Effects of a Phosphodiesterase III inhibitor in the Presence of Carvedilol in Dogs

Uechi

Hori

Fujimoto

et al. 2006

The Journal of Veterinary Medical Science

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ABSTRACT. The aim of this study was to determine whether dobutamine, dopamine, or milrinone (a phosphodiesterase [PDE] III inhibitor) would support cardiac function that had been attenuated by administration of the β-blocker, carvedilol (0.2, 0.4, or 0.8 mg/kg). Hemodynamic and cardiac parameters including the heart rate (HR), left-ventricular fractional shortening (FS), and arterial pressure were measured in six healthy dogs without cardiac disease. Carvedilol did not affect FS or arterial pressure, but decreased the HR significantly. The positive inotropic and chronotropic responses to dobutamine and dopamine were attenuated by carvedilol, whereas arterial pressure was unaffected. Milrinone did not affect the HR and decreased arterial pressure, whereas FS was significantly greater both in the control and carvedilol-treated groups. Although milrinone affect the negative chronotropic effects of carvedilol, milrinone increased FS and prevented the decrease in arterial pressure. These results suggest that inhibition of PDE III preserves cardiac contractility and hemodynamic function in the presence of carvedilol.KEY WORDS: β-blocker, cardiac function, heart failure, inotropic agent.J. Vet. Med. Sci. 68(6): 549-553, 2006 Clinical studies on humans have shown that treatment of congestive heart failure with β-blockers can reduce mortality [4,5,10,16] by improving myocardial energy metabolism, reducing arrhythmia, reducing damage to cardiac myocytes, up-regulating β 1 receptor expression, and improving diastolic function [5]. However, cardiac function must be monitored carefully in heart failure patients who are undergoing treatment with β-blockers because such treatment is associated with side effects that include bradycardia, hypotension, and A-V node blocking [2,21].It has been established that sympathomimetic drugs such as dobutamine and dopamine may prevent acute heart failure and circulatory collapse. However, the down-regulation of myocardial β-receptors that occurs during heart failure leads to an attenuation of the chronotropic and inotropic effects of β-receptor agonists such as adrenaline, noradrenaline, dobutamine, and dopamine [3,7,9]. Milrinone, an inhibitor of phosphodiesterase (PDE) III, increases the concentration of intracellular cyclic adenosine monophosphate (cAMP) by retarding the degradation of this molecule [1,22]. The modulation of intracellular cAMP by milrinone produces inotropic and chronotropic effects on the heart and relaxation of vessels in the absence of β-receptor stimulation [1,12,23]. Therefore, milrinone may produce beneficial effects even though myocardial β-receptors are downregulated during heart failure. Presumably, the beneficial effects of milrinone also apply in situations in which β-receptors have been blocked by the administration of a β-The objective of this study was to determine whether dobutamine, dopamine, or milrinone could support cardiac function that had been attenuated by the administration of a β-blocker. To achieve the objective, the hemodynamic and cardia...

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Combined Oral Positive Inotropic and Beta-Blocker Therapy for Treatment of Refractory Class IV Heart Failure

Cited by 126 publications

References 31 publications

Inhibition of histone deacetylase on ventricular remodeling in infarcted rats

Inhibition of histone deacetylase on ventricular remodeling in infarcted rats

β-Adrenergic Receptor Blockade in Chronic Heart Failure

Cardiovascular Effects of a Phosphodiesterase III inhibitor in the Presence of Carvedilol in Dogs

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