A New Pathway for Sympathetic Cardioprotection in Heart Failure

Simpson, Paul C.

doi:10.1161/circresaha.115.307246

Cited by 5 publications

(6 citation statements)

References 35 publications

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“…27,66 Thus, maintenance or increase of β2 and β3 levels in heart failure is likely due to nonmyocyte proliferation, not regulation different from the down-regulated β1 in myocytes. Furthermore, paracrine signaling by nonmyocytes, not direct effects on myocytes, would also seem to explain any myocyte contractile and protective effects of the β2 and β3 (review in 4 ). In this regard, some studies using β2-KO models indicate that β2 activation can be toxic, not protective as generally thought.…”

Section: Discussionmentioning

confidence: 99%

“…The role of the α1B might be cardiac growth, 3 and the β2, β3, and α1A are each implicated in cardioprotection. 4 Current AR radioligand binding data in heart suggest β-AR dominance, comprising 90% β-ARs, present in an 8:2 ratio of β1: β2, and 10% α1-ARs, present in a 6:4 ratio of α1A:α1B. 5 However, very few data exist on binding in isolated cardiac myocytes.…”

Section: Introductionmentioning

confidence: 99%

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Adrenergic Receptors in Individual Ventricular Myocytes

Myagmar

Flynn

Cowley

et al. 2017

Circulation Research

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106

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Rationale It is unknown if every ventricular myocyte expresses all 5 of the cardiac adrenergic receptors (ARs), beta-1, beta-2, beta-3, alpha-1A, and alpha-1B. The beta-1 and beta-2 are thought to be the dominant myocyte ARs. Objective Quantify the 5 cardiac ARs in individual ventricular myocytes. Methods and Results We studied ventricular myocytes from wild type mice, mice with alpha-1A and alpha-1B knockin reporters, and beta-1 and beta-2 knockout mice. Using individual isolated cells, we measured knockin reporters, mRNAs, signaling (phosphorylation of ERK and phospholamban), and contraction. We found that the beta-1 and alpha-1B were present in all myocytes. The alpha-1A was present in 60%, with high levels in 20%. The beta-2 and beta-3 were detected in only about 5% of myocytes, mostly in different cells. In intact heart, 30% of total beta-ARs were beta-2 and 20% were beta-3, both mainly in nonmyocytes. Conclusion The dominant ventricular myocyte ARs present in all cells are the beta-1 and alpha-1B. The beta-2 and beta-3 are mostly absent in myocytes but are abundant in nonmyocytes. The alpha-1A is in just over half of cells, but only 20% have high levels. Four distinct myocyte AR phenotypes are defined: 30% of cells with beta-1 and alpha-1B only; 60% that also have the alpha-1A; and 5% each that also have the beta-2 or beta-3. The results raise cautions in experimental design, such as receptor overexpression in myocytes that do not express the AR normally. The data suggest new paradigms in cardiac adrenergic signaling mechanisms.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Adrenergic Receptors in Individual Ventricular Myocytes

Myagmar

Flynn

Cowley

et al. 2017

Circulation Research

Self Cite

106

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“…As discussed earlier, GLI-based restrictive-pattern does not have an obstructive phenotype and increases the risk of CV death. 10,17,20 As to mechanisms underlying the CV benefit of salmeterol in COPD, we hypothesize improved myocardial performance and/or pulmonary vascular resistance, 31,32 potentially due to improved work of breathing. 33 As a basis for comparison, the current study has undertaken a supplemental analysis of nominal differences in baseline characteristics across three spirometric groups.…”

Section: Discussionmentioning

confidence: 99%

Re-evaluation of combination therapy in chronic obstructive pulmonary disease (COPD)

Fragoso

Gill

Ness

2019

Respiratory Medicine

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BACKGROUND: Clinical trials of COPD pharmacotherapy typically involve aging populations with moderate-to-severe COPD, but the latter is often diagnosed by spirometric criteria that are not age-appropriate across the continuum of lung function. We have therefore re-evaluated the clinical effect of combination therapy (salmeterol plus fluticasone) in moderate-to-severe COPD, using more age-appropriate spirometric criteria from the Global Lung Function Initiative (GLI) and trial data from Towards a Revolution in COPD Health (TORCH). METHODS: Of the 6112 TORCH participants, 5688 (93.1%) had GLI-based moderate-to-severe COPD (mean age 64.8 years). The primary outcome was all-cause mortality and the primary comparison was combination therapy vs. placebo. Secondary outcomes included COPD and cardiovascular (CV) mortality and pneumonia. A modified intention-to-treat analysis evaluated differences in time-to-event over a three-year period, using Cox proportional hazards models with statistical significance at p <0.010 (acknowledging repeated significance testing). RESULTS: Relative to placebo, combination therapy yielded a statistically non-significant reduction in all-cause mortality-adjusted hazard ratio [adjHR] 0.78 (95% confidence interval [CI]: 0.64, 0.95), p=0.012. Relative to placebo, combination therapy also yielded statistically nonsignificant reductions in COPD and CV mortality-adjHR 0.75 (95% CI: 0.55, 1.02), p=0.068 and adjHR 0.76 (95% CI: 0.53, 1.09), p=0.135, respectively. In contrast, combination therapy yielded a statistically significant increased risk of pneumonia, relative to placebo-adjHR 1.80 (95% CI: 1.46, 2.21), p<0.001.

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“…In the healthy heart, coronary blood flow is linked to the production of metabolites, which modulate smooth muscle tone in a redox-dependent manner. Some ion channels such as ATP-sensitive potassium (KATP) channels, voltage-gated potassium (Kv) channels, voltage-gated sodium (Nav) channels, and the L-Type ryanodine Ca 2+ channel, among others, play a critical role in coupling myocardial blood flow to cardiac metabolism [18,134,135]. In fact, genetic polymorphisms or the absence of these channels disassociates metabolism from flow, resulting in tissue hypoxia, myocardial ischemia and cardiac pump dysfunction [134,135].…”

Section: Strategies To Decrease Factors Inducing Heart Damagementioning

confidence: 99%

“…Some ion channels such as ATP-sensitive potassium (KATP) channels, voltage-gated potassium (Kv) channels, voltage-gated sodium (Nav) channels, and the L-Type ryanodine Ca 2+ channel, among others, play a critical role in coupling myocardial blood flow to cardiac metabolism [18,134,135]. In fact, genetic polymorphisms or the absence of these channels disassociates metabolism from flow, resulting in tissue hypoxia, myocardial ischemia and cardiac pump dysfunction [134,135]. Thus, it would be interesting to determine whether genetic polymorphisms encoding for ion channels may be related to a major susceptibility to alcohol-induced myocardial ischemia and cardiac pump dysfunction [135,136].…”

Section: Strategies To Decrease Factors Inducing Heart Damagementioning

confidence: 99%

New Treatment Strategies for Alcohol-Induced Heart Damage

Fernández‐Solà

Porta

2016

IJMS

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High-dose alcohol misuse induces multiple noxious cardiac effects, including myocyte hypertrophy and necrosis, interstitial fibrosis, decreased ventricular contraction and ventricle enlargement. These effects produce diastolic and systolic ventricular dysfunction leading to congestive heart failure, arrhythmias and an increased death rate. There are multiple, dose-dependent, synchronic and synergistic mechanisms of alcohol-induced cardiac damage. Ethanol alters membrane permeability and composition, interferes with receptors and intracellular transients, induces oxidative, metabolic and energy damage, decreases protein synthesis, excitation-contraction coupling and increases cell apoptosis. In addition, ethanol decreases myocyte protective and repair mechanisms and their regeneration. Although there are diverse different strategies to directly target alcohol-induced heart damage, they are partially effective, and can only be used as support medication in a multidisciplinary approach. Alcohol abstinence is the preferred goal, but control drinking is useful in alcohol-addicted subjects not able to abstain. Correction of nutrition, ionic and vitamin deficiencies and control of alcohol-related systemic organ damage are compulsory. Recently, several growth factors (myostatin, IGF-1, leptin, ghrelin, miRNA, and ROCK inhibitors) and new cardiomyokines such as FGF21 have been described to regulate cardiac plasticity and decrease cardiac damage, improving cardiac repair mechanisms, and they are promising agents in this field. New potential therapeutic targets aim to control oxidative damage, myocyte hypertrophy, interstitial fibrosis and persistent apoptosis In addition, stem-cell therapy may improve myocyte regeneration. However, these strategies are not yet approved for clinical use.

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A New Pathway for Sympathetic Cardioprotection in Heart Failure

Cited by 5 publications

References 35 publications

Adrenergic Receptors in Individual Ventricular Myocytes

Adrenergic Receptors in Individual Ventricular Myocytes

Re-evaluation of combination therapy in chronic obstructive pulmonary disease (COPD)

New Treatment Strategies for Alcohol-Induced Heart Damage

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