Dissociation between cardiomyocyte function and remodeling with β-adrenergic receptor blockade in isolated canine mitral regurgitation

The low-pressure volume overload of isolated mitral regurgitation (MR) is associated with increased adrenergic drive, left ventricular (LV) dilatation, and loss of interstitial collagen. We tested the hypothesis that β1-adrenergic receptor blockade (β1-RB) would attenuate LV remodeling after 4 mo of MR in the dog. β1-RB did not attenuate collagen loss or the increase in LV mass in MR dogs. Using MRI and three-dimensional (3-D) analysis, there was a 70% increase in the LV end-diastolic (LVED) volume-to-LV mass ratio, a 23% decrease in LVED midwall circumferential curvature, and a >50% increase in LVED 3-D radius/wall thickness in MR dogs that was not attenuated by β1-RB. However, β1-RB caused a significant increase in LVED length from the base to apex compared with untreated MR dogs. This was associated with an increase in isolated cardiomyocyte length (171 ± 5 μm, P < 0.05) compared with normal (156 ± 3 μm) and MR (165 ± 4 μm) dogs. Isolated cardiomyocyte fractional shortening was significantly depressed in MR dogs compared with normal dogs (3.73 ± 0.31 vs. 5.02 ± 0.26%, P < 0.05) and normalized with β1-RB (4.73 ± 0.48%). In addition, stimulation with the β-adrenergic receptor agonist isoproterenol (25 nM) increased cardiomyocyte fractional shortening by 215% ( P < 0.05) in β1-RB dogs compared with normal (56%) and MR (50%) dogs. In summary, β1-RB improved LV cardiomyocyte function and β-adrenergic receptor responsiveness despite further cell elongation. The failure to attenuate LV remodeling associated with MR could be due to a failure to improve ultrastructural changes in extracellular matrix organization.

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Mechanisms of cardiac hypertrophy in canine volume overload

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1998.275.1.h65 ◽

1998 ◽

Vol 275 (1) ◽

pp. H65-H74 ◽

Cited By ~ 5

Author(s):

Takeshi Matsuo ◽

Blase A. Carabello ◽

Yoshitatsu Nagatomo ◽

Masaaki Koide ◽

Masayoshi Hamawaki ◽

...

Keyword(s):

Protein Synthesis ◽

Mitral Regurgitation ◽

Protein Degradation ◽

Volume Overload ◽

Left Ventricular ◽

Translational Efficiency ◽

Protein Accumulation ◽

Severe Mitral Regurgitation ◽

Fractional Rate ◽

Lv Mass

This study tested whether the modest hypertrophy that develops in dogs in response to mitral regurgitation is due to a relatively small change in the rate of protein synthesis or, alternatively, is due to a decreased rate of protein degradation. After 3 mo of severe experimental mitral regurgitation, the left ventricular (LV) mass-to-body weight ratio increased by 23% compared with baseline values. This increase in LV mass occurred with a small, but not statistically significant, increase in the fractional rate of myosin heavy chain (MHC) synthesis (Ks), as measured using continuous infusion with [3H]leucine in dogs at 2 wk, 4 wk, and 3 mo after creation of severe mitral regurgitation. Translational efficiency was unaffected by mitral regurgitation as measured by the distribution of MHC mRNA in polysome gradients. Furthermore, there was no detectable increase in translational capacity as measured by either total RNA content or the rate of ribosome formation. These data indicate that translational mechanisms that accelerate the rate of cardiac protein synthesis are not responsive to the stimulus of mitral regurgitation. Most of the growth after mitral regurgitation was accounted for by a decrease in the fractional rate of protein degradation, calculated by subtracting fractional rates of protein accumulation at each time point from the corresponding Ks values. We conclude that 1) volume overload produced by severe mitral regurgitation does not trigger substantial increases in the rate of protein synthesis and 2) the modest increase in LV mass results primarily from a decrease in the rate of protein degradation.

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Mast Cell Stabilization added to Beta‐Adrenergic Receptor Blockade has beneficial effects on Left Ventricular Function, Remodeling and Isolated Cardiomyocyte function in Canine Mitral Regurgitation

The FASEB Journal ◽

10.1096/fasebj.22.1_supplement.970.17 ◽

2008 ◽

Vol 22 (S1) ◽

Author(s):

Betty M Pat ◽

Cheryl Killingsworth ◽

Thomas Denney ◽

Pam Powell ◽

Michael Tillson ◽

...

Keyword(s):

Mast Cell ◽

Mitral Regurgitation ◽

Left Ventricular Function ◽

Ventricular Function ◽

Adrenergic Receptor ◽

Left Ventricular ◽

Receptor Blockade ◽

Beneficial Effects ◽

Mast Cell Stabilization ◽

Cell Stabilization

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Neurally mediated cardiac effects of forskolin in conscious dogs

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1996.271.4.h1473 ◽

1996 ◽

Vol 271 (4) ◽

pp. H1473-H1482 ◽

Cited By ~ 2

Author(s):

M. Iwase ◽

Y. Ishikawa ◽

Y. T. Shen ◽

R. P. Shannon ◽

N. Sato ◽

...

Keyword(s):

Heart Rate ◽

Adenylyl Cyclase ◽

Adrenergic Receptor ◽

Left Ventricular ◽

Conscious Dogs ◽

Receptor Blockade ◽

Beta Adrenergic Receptor ◽

Beta Adrenergic ◽

Ganglionic Blockade ◽

Adrenergic Receptor Blockade

Because major cardiovascular disease states are characterized by defects in adenylyl cyclase regulation, it becomes important to understand the mechanisms by which adenylyl cyclase activators affect inotropy and chronotropy in intact conscious animals. Accordingly, we examined the inotropic and chronotropic responses to forskolin in 11 normal conscious, chronically instrumented dogs and 3 dogs with ventricular denervation (VD). Left ventricular first derivative of pressure (LV dP/dt) increased by 96 +/- 7%, P < 0.05, in response to forskolin (50 nmol.kg-1.min-1) in normal dogs and by significantly less, 52 +/- 14%, in VD dogs. Circulating norepinephrine (NE) levels increased similarly in both groups (from 226 +/- 18 to 389 +/- 33 pg/ml in normal dogs, from 177 +/- 23 to 329 +/- 71 pg/ml in VD dogs). In the presence of ganglionic blockade, the increase in LV dP/dt in response to forskolin was reduced (+62 +/- 4%) in normal dogs but was unchanged in VD dogs (+52 +/- 12%). Ganglionic blockade abolished the increase in circulating NE levels in both groups. Increases in heart rate in the presence of ganglionic blockade (+54 +/- 6 beats/min) were less than in the presence of atropine alone (+92 +/- 10 beats/min). Notably, the LV dP/dt and heart rate responses to forskolin were further attenuated by beta-adrenergic receptor blockade in the presence and absence of ganglionic blockade. Morphine also attenuated the increases in both LV dP/dt and plasma NE in response to forskolin. Increases in LV dP/dt in response to NKH-477 (30 micrograms/kg), a water-soluble forskolin derivative, were similar before and after ganglionic blockade (+63 +/- 8 and +51 +/- 10%, respectively). However, in vitro experiments in LV sarcolemmal membrane preparations demonstrated that stimulation of adenylyl cyclase by forskolin and NKH-477 was not affected by beta-adrenergic receptor blockade. These results indicate that in conscious dogs, inotropic and chronotropic effects of forskolin are not only due to direct activation of adenylyl cyclase, but the effects also are mediated by neural mechanisms and potentiated by the prevailing level of sympathetic tone.

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Direct Effects of chronic beta-adrenergic receptor blockade on left ventricular and myocyte function in a model of tachycardia-induced congestive heart failure

Journal of Cardiac Failure ◽

10.1016/s1071-9164(96)80018-2 ◽

1996 ◽

Vol 2 (4) ◽

pp. 311-318 ◽

Cited By ~ 1

Author(s):

Francis G. Spinale ◽

Wendy S. Johnson ◽

Yinghua Wang ◽

Zhongling Wang ◽

Rupak Mukherjee ◽

...

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Adrenergic Receptor ◽

Left Ventricular ◽

Receptor Blockade ◽

Direct Effects ◽

Beta Adrenergic Receptor ◽

Beta Adrenergic ◽

Myocyte Function ◽

Adrenergic Receptor Blockade

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β 1 -Adrenergic Receptor Blockade Attenuates Angiotensin II–Mediated Catecholamine Release Into the Cardiac Interstitium in Mitral Regurgitation

Circulation ◽

10.1161/01.cir.0000079226.48637.5a ◽

2003 ◽

Vol 108 (2) ◽

pp. 225-230 ◽

Cited By ~ 41

Author(s):

José Tallaj ◽

Chih-Chang Wei ◽

Gerald H. Hankes ◽

Merrilee Holland ◽

Patricia Rynders ◽

...

Keyword(s):

Angiotensin Ii ◽

Mitral Regurgitation ◽

Adrenergic Receptor ◽

Catecholamine Release ◽

Receptor Blockade ◽

Adrenergic Receptor Blockade

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Disproportionate Mitral Regurgitation Determines Survival in Acute Heart Failure

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.742224 ◽

2021 ◽

Vol 8 ◽

Author(s):

Max Berrill ◽

Ian Beeton ◽

David Fluck ◽

Isaac John ◽

Otar Lazariashvili ◽

...

Keyword(s):

Heart Failure ◽

Mitral Regurgitation ◽

Acute Heart Failure ◽

Volume Overload ◽

Left Ventricular ◽

Left Ventricular Volumes ◽

Clinical Trial Registration ◽

Proximal Isovelocity Surface Area ◽

End Diastolic Volume ◽

Lv Remodeling

Objectives: To assess the prevalence and impact of mitral regurgitation (MR) on survival in patients presenting to hospital in acute heart failure (AHF) using traditional echocardiographic assessment alongside more novel indices of proportionality.Background: It remains unclear if the severity of MR plays a significant role in determining outcomes in AHF. There is also uncertainty as to the clinical relevance of indexing MR to left ventricular volumes. This concept of disproportionality has not been assessed in AHF.Methods: A total of 418 consecutive patients presenting in AHF over 12 months were recruited and followed up for 2 years. MR was quantitatively assessed within 24 h of recruitment. Standard proximal isovelocity surface area (PISA) and a novel proportionality index of effective regurgitant orifice/left ventricular end-diastolic volume (ERO/LVEDV) >0.14 mm2/ml were used to identify severe and disproportionate MR.Results: Every patient had MR. About 331/418 (78.9%) patients were quantifiable by PISA. About 165/418 (39.5%) patients displayed significant MR. A larger cohort displayed disproportionate MR defined by either a proportionality index using ERO/LVEDV > 0.14 mm2/ml or regurgitant volumes/LVEDV > 0.2 [217/331 (65.6%) and 222/345 (64.3%), respectively]. The LVEDV was enlarged in significant MR−129.5 ± 58.95 vs. 100.0 ± 49.91 ml in mild, [p < 0.0001], but remained within the normal range. Significant MR was associated with a greater mortality at 2 years {44.2 vs. 34.8% in mild MR [hazard ratio (HR) 1.39; 95% CI: 1.01–1.92, p = 0.04]}, which persisted with adjustment for comorbid conditions (HR; 1.43; 95% CI: 1.04–1.97, p = 0.03). Disproportionate MR defined by ERO/LVEDV >0.14 mm2/ml was also associated with worse outcome [42.4 vs. 28.3% (HR 1.62; 95% CI 1.12–2.34, p = 0.01)].Conclusions: MR was a universal feature in AHF and determines outcome in significant cases. Furthermore, disproportionate MR, defined either by effective regurgitant orifice (ERO) or volumetrically, is associated with a worse prognosis despite the absence of adverse left ventricular (LV) remodeling. These findings outline the importance of adjusting acute volume overload to LV volumes and call for a review of the current standards of MR assessment.Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT02728739, identifier NCT02728739.

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