Arrhythmogenic Effects of β
            2
            -Adrenergic Stimulation in the Failing Heart Are Attributable to Enhanced Sarcoplasmic Reticulum Ca Load

Abnormalities in calcium handling have been implicated as a significant source of electrical instability in heart failure (HF). While these abnormalities have been investigated extensively in isolated myocytes, how they manifest at the tissue level and trigger arrhythmias is not clear. We hypothesize that in HF, triggered activity (TA) is due to spontaneous calcium release from the sarcoplasmic reticulum that occurs in an aggregate of myocardial cells (an SRC) and that peak SCR amplitude is what determines whether TA will occur. Calcium and voltage optical mapping was performed in ventricular wedge preparations from canines with and without tachycardia-induced HF. In HF, steady-state calcium transients have reduced amplitude [135 vs. 170 ratiometric units (RU), P < 0.05] and increased duration (252 vs. 229 s, P < 0.05) compared with those of normal. Under control conditions and during β-adrenergic stimulation, TA was more frequent in HF (53% and 93%, respectively) compared with normal (0% and 55%, respectively, P < 0.025). The mechanism of arrhythmias was SCRs, leading to delayed afterdepolarization-mediated triggered beats. Interestingly, the rate of SCR rise was greater for events that triggered a beat (0.41 RU/ms) compared with those that did not (0.18 RU/ms, P < 0.001). In contrast, there was no difference in SCR amplitude between the two groups. In conclusion, TA in HF tissue is associated with abnormal calcium regulation and mediated by the spontaneous release of calcium from the sarcoplasmic reticulum in aggregates of myocardial cells (i.e., an SCR), but importantly, it is the rate of SCR rise rather than amplitude that was associated with TA.

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Relation between contractile function and regulatory cardiac proteins in hypertrophied hearts

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1996.270.6.h2021 ◽

1996 ◽

Vol 270 (6) ◽

pp. H2021-H2028 ◽

Cited By ~ 9

Author(s):

B. Stein ◽

S. Bartel ◽

U. Kirchhefer ◽

S. Kokott ◽

E. G. Krause ◽

...

Keyword(s):

Sarcoplasmic Reticulum ◽

Troponin I ◽

Contractile Function ◽

Papillary Muscles ◽

Camp Accumulation ◽

Adrenergic Stimulation ◽

Beta Adrenergic ◽

C Protein ◽

Camp Formation ◽

Phosphate Incorporation

The aim of this study was to examine the mechanism(s) underlying the reduced isoproterenol-induced positive inotropic and lusitropic effects in hypertrophied hearts. Chronic beta-adrenergic stimulation (2.4 mg isoproterenol.kg-1. day-1 for 4 days) induced cardiac hypertrophy by 33 +/- 2% in rats. A parallel downregulation of phospholamban (PLB) and sarcoplasmic reticulum Ca2(+)-ATPase (SERCA2) protein expression by 49 and 40%, respectively, was observed, whereas troponin I (TNI) and C protein remained unchanged. In papillary muscles from chronically beta-adrenergically stimulated rats, the isoproterenol-induced positive inotropic and lusitropic effects, as well as adenosine 3',5'-cyclic monophosphate (cAMP) accumulation, were attenuated compared with those in control animals. Acute exposure to isoproterenol induced phosphate incorporation into PLB, TNI, and C protein of 48 +/- 4.6, 55 +/- 5.0, and 27 +/- 4.9 pmol/mg homogenate protein, respectively, in control animals. In the hypertrophied hearts, phosphate incorporation into PLB was reduced by 76%, whereas phosphate incorporation into TNI or C protein remained unchanged. In conclusion, chronic beta-adrenergic stimulation reduced the isoproterenol-stimulated positive inotropic and lusitropic effects in papillary muscles, which were accompanied by 1) diminished cAMP formation, 2) attenuation of cAMP-mediated PLB phosphorylation, and 3) downregulation of PLB and SERCA2 protein.

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Abstract 65: β-Adrenergic Signaling Promotes Survival and Proliferation of Mouse Cardiac Progenitor Cells Prior to Lineage Commitment

Circulation Research ◽

10.1161/res.111.suppl_1.a65 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Mohsin Khan ◽

Sadia Mohsin ◽

Daniele Avitabile ◽

Jonathan Nguyen ◽

Natalie Gude ◽

...

Keyword(s):

Recovery Of Function ◽

Cardiac Contractility ◽

Stem Cell Marker ◽

Adrenergic Blockade ◽

Adrenergic Stimulation ◽

Myocardial Repair ◽

Akt Phosphorylation ◽

Failing Heart

Rationale: Short term β-adrenergic stimulation promotes contractility in response to stress, but is ultimately detrimental in the failing heart due to accrual of cardiomyocyte death. Endogenous myocardial repair may partially offset cardiomyocyte losses, but consequences of long term β-adrenergic drive upon myocardial repair and regeneration are unknown. Objective: Modest recovery of cardiac contractility following long term β-adrenergic blockade in the clinical setting may depend, in part, upon restoration of endogenous repair therefore we sought to determine the relationship between β-adrenergic activity and regulation of cardiac progenitor cell (CPC) function and influence upon myocardial repair. Methods and results: Mouse and human CPCs express only β2 adrenergic receptor (β2-AR) in conjunction with stem cell marker c-kit. Activation of β2-AR signaling promotes proliferation associated with increased Akt phosphorylation, up-regulation of eNOS and cyclin D1, and decreased levels of GRK2. Conversely, silencing of β2-AR expression or treatment with β2-antagonist ICI 118, 551 impairs proliferation and survival. β1-AR expression in CPC is induced by differentiation stimuli, sensitizing CPC to isoproterenol-induced cell death that is abrogated by the β1-AR specific antagonist metoprolol. Efficacy of β1-AR blockade by metoprolol to increase CPC survival and proliferation was confirmed in vivo by adoptive transfer of CPC into failing mouse myocardium, concomitant with increased ejection fraction, fractional shortening and hemodynamic performance. Conclusions: β-adrenergic stimulation promotes expansion and survival of CPCs through β2-AR, but acquisition of β1-AR upon commitment to the myocyte lineage results in loss of early myocyte precursors and ineffective myocardial repair. Thus, β1-AR-specific blockade is likely to provide for enhanced CPC participation in recovery of function in the failing heart.

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SK Channel Block and Adrenergic Stimulation Counteract Acetylcholine-Induced Arrhythmogenic Effects in Human Atria

2020 42nd Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC) ◽

10.1109/embc44109.2020.9175886 ◽

2020 ◽

Author(s):

Chiara Celotto ◽

Carlos Sanchez ◽

Konstantinos A. Mountris ◽

Pablo Laguna ◽

Esther Pueyo

Keyword(s):

Channel Block ◽

Adrenergic Stimulation ◽

Sk Channel ◽

Arrhythmogenic Effects

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Arrhythmogenic effects of catecholamines are decreased in heart failure induced by rapid pacing in dogs

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1993.265.5.h1654 ◽

1993 ◽

Vol 265 (5) ◽

pp. H1654-H1662 ◽

Cited By ~ 2

Author(s):

H. G. Li ◽

D. L. Jones ◽

R. Yee ◽

G. J. Klein

Keyword(s):

Heart Failure ◽

Ventricular Arrhythmias ◽

Control Group ◽

Purkinje Fibers ◽

Failure Group ◽

Failing Heart ◽

Minimal Dose ◽

Arrhythmogenic Effect ◽

Rapid Pacing ◽

Arrhythmogenic Effects

Increased circulating catecholamines are considered to be arrhythmogenic in heart failure. It is unclear whether increased circulating catecholamines contribute directly to ventricular arrhythmias or are only markers of the severity of heart failure. The present study determined the sensitivity of the failing heart to the arrhythmogenic effect of exogenous norepinephrine in a rapid pacing-induced model of heart failure in dogs (240 beats for 4 wk, n = 14). A similarly operated, non-paced group served as controls (n = 9). Cardiac sensitivity to the arrhythmogenic effect of catecholamines was determined by measuring the minimal dose of exogenous norepinephrine that induced ventricular tachycardia (arrhythmogenic threshold dose, ATD). ATD significantly increased after development of heart failure in heart-failure group (1.62 +/- 0.32 microgram/kg at baseline vs. 16.65 +/- 3.48 micrograms/kg at restudy, P < 0.01), whereas no significant change was noted in the control group (1.08 +/- 0.36 microgram/kg at baseline vs. 2.53 +/- 0.36 micrograms/kg at restudy, P > 0.10). Action potential duration was unchanged by superfusion with 10(-7) M isoproterenol in both ventricular muscles (230.2 +/- 6.1 vs. 229.7 +/- 5.3 ms, P = NS) and Purkinje fibers (273.2 +/- 6.5 vs. 283.8 +/- 4.2 ms, P = NS) from the failing hearts, although isoproterenol induced a shortening in the control group (204.8 +/- 0.9 vs. 181.3 +/- 1.6 ms in ventricular muscles, P < 0.01; 313.8 +/- 6.5 vs. 279.5 +/- 5.7 ms in Purkinje fibers, P < 0.01). We conclude that the failing heart has a decreased sensitivity to the arrhythmogenic effect of catecholamines.

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The calcium stored in the sarcoplasmic reticulum acts as a safety mechanism in rainbow trout heart

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00127.2014 ◽

2014 ◽

Vol 307 (12) ◽

pp. R1493-R1501 ◽

Cited By ~ 12

Author(s):

Caroline Cros ◽

Laurent Sallé ◽

Daniel E. Warren ◽

Holly A. Shiels ◽

Fabien Brette

Keyword(s):

Rainbow Trout ◽

Sarcoplasmic Reticulum ◽

Ventricular Myocytes ◽

Adrenergic Stimulation ◽

Relative Contribution ◽

Safety Mechanism ◽

Rapid Changes ◽

Intracellular Ca ◽

As Stress

Cardiomyocyte contraction depends on rapid changes in intracellular Ca2+. In mammals, Ca2+ influx as L-type Ca2+ current ( ICa) triggers the release of Ca2+ from sarcoplasmic reticulum (SR) and Ca2+-induced Ca2+ release (CICR) is critical for excitation-contraction coupling. In fish, the relative contribution of external and internal Ca2+ is unclear. Here, we characterized the role of ICa to trigger SR Ca2+ release in rainbow trout ventricular myocytes using ICa regulation by Ca2+ as an index of CICR. ICa was recorded with a slow (EGTA) or fast (BAPTA) Ca2+ chelator in control and isoproterenol conditions. In the absence of β-adrenergic stimulation, the rate of ICa inactivation was not significantly different in EGTA and BAPTA (27.1 ± 1.8 vs. 30.3 ± 2.4 ms), whereas with isoproterenol (1 μM), inactivation was significantly faster with EGTA (11.6 ± 1.7 vs. 27.3 ± 1.6 ms). When barium was the charge carrier, inactivation was significantly slower in both conditions (61.9 ± 6.1 vs. 68.0 ± 8.7 ms, control, isoproterenol). Quantification revealed that without isoproterenol, only 39% of ICa inactivation was due to Ca2+, while with isoproterenol, inactivation was Ca2+-dependent (∼65%) and highly reliant on SR Ca2+ (∼46%). Thus, SR Ca2+ is not released in basal conditions, and ICa is the main trigger of contraction, whereas during a stress response, SR Ca2+ is an important source of cytosolic Ca2+. This was not attributed to differences in SR Ca2+ load because caffeine-induced transients were not different in both conditions. Therefore, Ca2+ stored in SR of trout cardiomyocytes may act as a safety mechanism, allowing greater contraction when higher contractility is required, such as stress or exercise.

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