Cardiac fibroblast paracrine factors alter impulse conduction and ion channel expression of neonatal rat cardiomyocytes

Pedrotty, Dawn M.; Klinger, Rebecca Y.; Kirkton, Robert D.; Bursac, Nenad

doi:10.1093/cvr/cvp164

Cited by 128 publications

(126 citation statements)

References 35 publications

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“…In cell-cultures, a significant paracrine effect was found on CV, resulting in reduced CV. 22 However, our data showed an increase in CV L in the presence of many fibroblasts, thus it is unlikely that the paracrine influences on CV have a major role in these patients.…”

contrasting

confidence: 51%

Atrial Fibrosis and Conduction Slowing in the Left Atrial Appendage of Patients Undergoing Thoracoscopic Surgical Pulmonary Vein Isolation for Atrial Fibrillation

Gründeman

Berger

Smit

et al. 2015

Circ: Arrhythmia and Electrophysiology

103

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Background— Atrial fibrosis is an important component of the arrhythmogenic substrate in patients with atrial fibrillation (AF). We studied the effect of interstitial fibrosis on conduction velocity (CV) in the left atrial appendage of patients with AF. Methods and Results— Thirty-five left atrial appendages were obtained during AF surgery. Preparations were superfused and stimulated at 100 beats per minute. Activation was recorded with optical mapping. Longitudinal CV (CV L ), transverse CV (CV T ), and activation times (>2 mm distance) were measured. Interstitial collagen was quantified and graded qualitatively. The presence of fibroblasts and myofibroblasts was assessed immunohistochemically. Mean CV L was 0.55±0.22 m/s, mean CV T was 0.25±0.15 m/s, and the mean activation time was 9.31±5.45 ms. The amount of fibrosis was unrelated to CV or patient characteristics. CV L was higher in left atrial appendages with thick compared with thin interstitial collagen strands (0.77±0.22 versus 0.48±0.19 m/s; P =0.012), which were more frequently present in persistent patients with AF. CV T was not significantly different ( P =0.47), but activation time was 14.93±4.12 versus 7.95±4.12 ms in patients with thick versus thin interstitial collagen strands, respectively ( P =0.004). Fibroblasts were abundantly present and were associated with the presence of thick interstitial collagen strands ( P =0.008). Myofibroblasts were not detected in the left atrial appendage. Conclusions— In patients with AF, thick interstitial collagen strands are associated with higher CV L and increased activation time. Our observations demonstrate that the severity and structure of local interstitial fibrosis is associated with atrial conduction abnormalities, presenting an arrhythmogenic substrate for atrial re-entry.

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contrasting

confidence: 51%

Atrial Fibrosis and Conduction Slowing in the Left Atrial Appendage of Patients Undergoing Thoracoscopic Surgical Pulmonary Vein Isolation for Atrial Fibrillation

Gründeman

Berger

Smit

et al. 2015

Circ: Arrhythmia and Electrophysiology

103

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“…In addition to direct electric interactions, fibroblasts can affect cardiomyocyte bioelectricity by secreting biologically active substances that cause paracrine effects. 193 Whether fibroblastcardiomyocyte interactions promote arrhythmogenesis depends on the number of fibroblasts, their size, and (for electric interactions) the extent of electric coupling between the 2 cell types. 194,195 Thus, although fibroblasts can directly induce cardiomyocyte arrhythmic activity in cocultured in vitro systems, whether this happens in vivo is still unclear.…”

Section: Nature and Role Of Structural Remodelingmentioning

confidence: 99%

The Clinical Profile and Pathophysiology of Atrial Fibrillation

Andrade

Khairy

Dobrev

et al. 2014

Circulation Research

897

289

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Atrial fibrillation (AF) is the most common arrhythmia (estimated lifetime risk, 22%–26%). The aim of this article is to review the clinical epidemiological features of AF and to relate them to underlying mechanisms. Long-established risk factors for AF include aging, male sex, hypertension, valve disease, left ventricular dysfunction, obesity, and alcohol consumption. Emerging risk factors include prehypertension, increased pulse pressure, obstructive sleep apnea, high-level physical training, diastolic dysfunction, predisposing gene variants, hypertrophic cardiomyopathy, and congenital heart disease. Potential risk factors are coronary artery disease, kidney disease, systemic inflammation, pericardial fat, and tobacco use. AF has substantial population health consequences, including impaired quality of life, increased hospitalization rates, stroke occurrence, and increased medical costs. The pathophysiology of AF centers around 4 general types of disturbances that promote ectopic firing and reentrant mechanisms, and include the following: (1) ion channel dysfunction, (2) Ca 2+ -handling abnormalities, (3) structural remodeling, and (4) autonomic neural dysregulation. Aging, hypertension, valve disease, heart failure, myocardial infarction, obesity, smoking, diabetes mellitus, thyroid dysfunction, and endurance exercise training all cause structural remodeling. Heart failure and prior atrial infarction also cause Ca 2+ -handling abnormalities that lead to focal ectopic firing via delayed afterdepolarizations/triggered activity. Neural dysregulation is central to atrial arrhythmogenesis associated with endurance exercise training and occlusive coronary artery disease. Monogenic causes of AF typically promote the arrhythmia via ion channel dysfunction, but the mechanisms of the more common polygenic risk factors are still poorly understood and under intense investigation. Better recognition of the clinical epidemiology of AF, as well as an improved appreciation of the underlying mechanisms, is needed to develop improved methods for AF prevention and management.

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“…Briefly, excised ventricles were minced and incubated overnight in a 0.07% solution of trypsin (Sigma-Aldrich) at 4°C, followed by four-step dissociation in 0.1% collagenase II (Worthington Biochemical, Lakewood, NJ) at 37°C (Pedrotty et al, 2009). Dissociated cells were resuspended in culture medium (DMEM-F12 medium [Invitrogen] supplemented with 10% calf serum [Colorado Serum Company, Denver, CO] and 10% horse serum [HyClone/Thermo Fisher Scientific, Logan, UT]) and preplated in two 1-hr steps to remove faster adhering nonmyocytes (Pedrotty et al, 2009). …”

Section: Rat Neonatal Cardiomyocyte Isolationmentioning

confidence: 99%

X-Linked Inhibitor of Apoptosis Protein-Mediated Attenuation of Apoptosis, Using a Novel Cardiac-Enhanced Adeno-Associated Viral Vector

et al. 2012

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Successful amelioration of cardiac dysfunction and heart failure through gene therapy approaches will require a transgene effective at attenuating myocardial injury, and subsequent remodeling, using an efficient and safe delivery vehicle. Our laboratory has established a well-curated, high-quality repository of human myocardial tissues that we use as a discovery engine to identify putative therapeutic transgene targets, as well as to better understand the molecular basis of human heart failure. By using this rare resource we were able to examine ageand sex-matched left ventricular samples from (1) end-stage failing human hearts and (2) nonfailing human hearts and were able to identify the X-linked inhibitor of apoptosis protein (XIAP) as a novel target for treating cardiac dysfunction. We demonstrate that XIAP is diminished in failing human hearts, indicating that this potent inhibitor of apoptosis may be central in protecting the human heart from cellular injury culminating in heart failure. Efforts to ameliorate heart failure through delivery of XIAP compelled the design of a novel adenoassociated viral (AAV) vector, termed SASTG, that achieves highly efficient transduction in mouse heart and in cultured neonatal rat cardiomyocytes. Increased XIAP expression achieved with the SASTG vector inhibits caspase-3/7 activity in neonatal cardiomyocytes after induction of apoptosis through three common cardiac stresses: protein kinase C-c inhibition, hypoxia, or b-adrenergic receptor agonist. These studies demonstrate the potential benefit of XIAP to correct heart failure after highly efficient delivery to the heart with the rationally designed SASTG AAV vector.

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Cardiac fibroblast paracrine factors alter impulse conduction and ion channel expression of neonatal rat cardiomyocytes

Abstract: Paracrine factors from neonatal CFs alone produced significant electrophysiological changes in neonatal rat cardiomyocytes resembling those found in several cardiac pathologies.

Cited by 128 publications

References 35 publications

Atrial Fibrosis and Conduction Slowing in the Left Atrial Appendage of Patients Undergoing Thoracoscopic Surgical Pulmonary Vein Isolation for Atrial Fibrillation

Atrial Fibrosis and Conduction Slowing in the Left Atrial Appendage of Patients Undergoing Thoracoscopic Surgical Pulmonary Vein Isolation for Atrial Fibrillation

The Clinical Profile and Pathophysiology of Atrial Fibrillation

X-Linked Inhibitor of Apoptosis Protein-Mediated Attenuation of Apoptosis, Using a Novel Cardiac-Enhanced Adeno-Associated Viral Vector

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