Effects of long-term monotherapy with enalapril, metoprolol, and digoxin on the progression of left ventricular dysfunction and dilation in dogs with reduced ejection fraction.

Sabbah, Hani N.; Shimoyama, Hisashi; Kono, Tatsuji; Gupta, Ramesh C.; Sharov, Victor G.; Scicli, G; Levine, T. Barry; Goldstein, Sidney

doi:10.1161/01.cir.89.6.2852

Cited by 181 publications

(103 citation statements)

References 38 publications

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“…Consistent with earlier studies from our laboratory (18,20,24), results of the present study indicate that, in the absence of any therapeutic intervention, progressive deterioration of LV systolic function and chamber remodeling occur in dogs with moderate HF, secondary to loss of viable myocardium. The present study demonstrates that long-term monotherapy with high-dose but low-dose selective MMP inhibitor PG-530742 prevents progressive LV dysfunction and LV chamber remodeling in dogs with moderate HF.…”

Section: Discussionsupporting

confidence: 92%

Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure

Morita¹,

Khanal²,

Rastogi³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure. Am J Physiol Heart Circ Physiol 290: H2522-H2527, 2006. First published January 20, 2006 doi:10.1152/ajpheart.00932.2005 contribute to the progression of left ventricular (LV) dysfunction and remodeling associated with heart failure (HF). The present study examined the long-term effects of a selective MMP inhibitor PG-530742 (PG) on the progression of LV dysfunction and remodeling in dogs with HF. Chronic HF [LV ejection fraction (LVEF), Յ36%] was produced by multiple sequential intracoronary microembolizations in 24 dogs. Two weeks after the last embolization, dogs were randomized to 3 mo of therapy with either high-dose (HD) PG (3.5 mg/kg, n ϭ 8), low-dose (LD) PG (0.2 mg/kg, n ϭ 8), or to a matched placebo (PL, n ϭ 8). PG has been shown to produce complete inhibition of MMP-2, -3, -9, and -13, while sparing MMPs-1 and -7. Hemodynamic and echocardiographic measurements were made before and 3 mo after initiating therapy. In PL and LD dogs, LVEF decreased significantly, and LV end-systolic volume (ESV) and LV end-diastolic volume (EDV) increased significantly during the 3-mo follow-up period. Whereas in HD dogs ejection fraction increased from 36 Ϯ 1 to 40 Ϯ 1% (P ϭ 0.003), EDV and ESV decreased (59 Ϯ 4 vs. 57 Ϯ 4 ml, P ϭ 0.02; and 38 Ϯ 2 vs. 34 Ϯ 2 ml, P ϭ 0.00001, respectively). When compared with controls, HD-treated dogs showed 30% reduction in replacement fibrosis, 29% reduction in interstitial fibrosis, and 28% reduction in myocyte cross-sectional area. mRNA expression of selective MMPs was also reduced in LV tissue in HD-but not LD-treated dogs. In conclusion, in dogs with moderate HF, long-term monotherapy with HD selective MMP inhibitor PG prevents LV remodeling and the progression of global LV dysfunction.hemodynamics; PG-530742; left ventricular ejection fraction THE BALANCE BETWEEN extracellular matrix synthesis and degradation has been considered to play a key role in maintaining left ventricular (LV) geometry and function. The extracellular matrix provides structural support for myocyte alignment and blood vessels (26,27). It also coordinates the conversion of myocyte contraction into myocardial force. Furthermore, it can affect myocardial stiffness and diastolic function (26,27).Matrix metalloproteinases (MMPs) are enzymes responsible for proteolytic degradation of specific extracellular matrix components. MMPs are synthesized as inactive zymogens and secreted into the extracellular space. MMPs have been shown to be involved in a variety of pathological and healing processes, such as tumor growth and metastasis, rheumatoid arthritis, and periodontal disease. In the cardiovascular field, it is now becoming clear that extracellular matrix degradation is involved in the pathogenesis of atherosclerosis, restenosis, dilated cardiomyopathy, and myocardial infarction.Expression and activity of MMPs are elevated in both patients and experimental animal mo...

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Section: Discussionsupporting

confidence: 92%

Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure

Morita¹,

Khanal²,

Rastogi³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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“…31 Thus, new therapies must be developed to overcome the poor prognosis of MI. Several alternative strategies based on drug treatments, 32 injections of stem cells or proteins, 4,5 surgical interventions 33 and epicardial restraint devices 34 have been used to regenerate the infarcted heart. The effects of liraglutide have been shown to be beneficial for the treatment of MI.…”

Section: Discussionmentioning

confidence: 99%

Spatiotemporal delivery of nanoformulated liraglutide for cardiac regeneration after myocardial infarction

Qi¹,

Lü

Li³

et al. 2017

IJN

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The local, intramyocardial injection of proteins into the infarcted heart is an attractive option to initiate cardiac regeneration after myocardial infarction (MI). Liraglutide, which was developed as a treatment for type 2 diabetes, has been implicated as one of the most promising protein candidates in cardiac regeneration. A significant challenge to the therapeutic use of this protein is its short half-life in vivo. In this study, we evaluated the therapeutic effects and long-term retention of liraglutide loaded in poly(lactic- co -glycolic acid)–poly(ethylene glycol) (PLGA–PEG) nanoparticles (NP-liraglutide) on experimental MI. PLGA–PEG nanoparticles (NPs) have been shown to efficiently load liraglutide and release bioactive liraglutide in a sustained manner. For in vitro test, the released liraglutide retained bioactivity, as measured by its ability to activate liraglutide signaling pathways. Next, we compared the effects of an intramyocardial injection of saline, empty NPs, free liraglutide and NP-liraglutide in a rat model of MI. NPs were detected in the myocardium for up to 4 weeks. More importantly, an intramyocardial injection of NP-liraglutide was sufficient to improve cardiac function ( P <0.05), attenuate the infarct size ( P <0.05), preserve wall thickness ( P <0.05), promote angiogenesis ( P <0.05) and prevent cardiomyocyte apoptosis ( P <0.05) at 4 weeks after injection without affecting glucose levels. The local, controlled, intramyocardial delivery of NP-liraglutide represents an effective and promising strategy for the treatment of MI.

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“…Digitalis traditionally has been used to manage supraventricular tachyarrhythmias14 and dilated cardiomyopathy in dogs,14, 15, 16 but evidence for clinical efficacy is sparse. A positive effect on left ventricular systolic function was identified in digoxin‐treated dogs with experimentally decreased left ventricular ejection fraction,17 and in a small retrospective study of dogs with idiopathic DCM receiving digoxin, decreased heart rate was identified with less pronounced benefit on left ventricular fractional shortening 18. Pimobendan, a calcium‐sensitizing drug with both inotropic and vasodilatory properties, is commonly used to manage CHF in dogs with MMVD and DCM 19, 20.…”

mentioning

confidence: 99%

Long‐term Outcome of Irish Wolfhound Dogs with Preclinical Cardiomyopathy, Atrial Fibrillation, or Both Treated with Pimobendan, Benazepril Hydrochloride, or Methyldigoxin Monotherapy

Vollmar¹,

Fox

2016

Veterinary Internal Medicne

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BackgroundDilated cardiomyopathy (DCM) is a common cause of morbidity and mortality in the Irish Wolfhound (IW). However, the benefit of medical treatment in IW dogs with preclinical DCM, atrial fibrillation (AF), or both has not been demonstrated.ObjectivesCompare the time to develop congestive heart failure (CHF) or sudden death in IW dogs with preclinical DCM, AF, or both receiving monotherapy with pimobendan, methyldigoxin, or benazepril hydrochloride.AnimalsSeventy‐five client‐owned IW dogs.MethodsIrish Wolfhound dogs were prospectively randomized to receive pimobendan (Vetmedin®)1, benazepril HCl (Fortekor®)2, or methyldigoxin (Lanitop®)3 monotherapy in a 1:1:1 ratio in a blinded clinical trial. The prospectively defined composite primary endpoint was onset of CHF or sudden death. To assure stringent evaluation of treatment effect, data from dogs complying with the study protocol were analyzed.ResultsSixty‐six IW fulfilling the study protocol included 39 males, 27 females; median (interquartile range) age, 4.0 years (3.0–5.0 years) and weight, 70.0 kg (63.0–75.0 kg). Primary endpoint was reached in 5 of 23 (21.7%) IW receiving pimobendan, 11 of 22 (50.0%) receiving benazepril HCl, and 9 of 21 (42.9%) receiving methyldigoxin. Median time to primary endpoint was significantly longer for pimobendan (1,991 days; 65.4 months) compared to methyldigoxin (1,263 days; 41.5 months; P = .031) or benazepril HCl‐(997 days; 32.8 months; P = .008) treated dogs.Conclusions and Clinical ImportanceIn IW dogs with preclinical DCM, AF or both, pimobendan monotherapy significantly prolonged time to onset of CHF or sudden death than did monotherapy with benazepril HCl or methyldigoxin.

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Effects of long-term monotherapy with enalapril, metoprolol, and digoxin on the progression of left ventricular dysfunction and dilation in dogs with reduced ejection fraction.

Abstract: In dogs with reduced LVEF, long-term therapy with enalapril or metoprolol prevents the progression of LV systolic dysfunction and LV chamber dilation. Therapy with digoxin maintains LV systolic function but does not prevent progressive LV enlargement.

Cited by 181 publications

References 38 publications

Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure

Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure

Spatiotemporal delivery of nanoformulated liraglutide for cardiac regeneration after myocardial infarction

Long‐term Outcome of Irish Wolfhound Dogs with Preclinical Cardiomyopathy, Atrial Fibrillation, or Both Treated with Pimobendan, Benazepril Hydrochloride, or Methyldigoxin Monotherapy

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