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Research Article
Brandon Ason
Amgen Research
Corresponding Author
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Heart failure (HF) and cardiac arrhythmias share overlapping pathological mechanisms that act cooperatively to accelerate disease pathogenesis. Cardiac fibrosis is associated with both pathological conditions. Our previous work identified a link between phytosterol accumulation and cardiac injury in a mouse model of phytosterolemia, a rare disorder characterized by elevated circulating phytosterols and increased cardiovascular disease risk. Here, we uncover a previously unknown pathological link between phytosterols and cardiac arrhythmias in the same animal model. Phytosterolemia resulted in inflammatory pathway induction, premature ventricular contractions (PVC) and ventricular tachycardia (VT). Both pharmacological and genetic inhibition of phytosterol absorption prevented the induction of both pathways. Inhibition of phytosterol absorption reduced inflammation and cardiac fibrosis, improved cardiac function, reduced the incidence of arrhythmias and increased survival in a mouse model of phytosterolemia. Collectively, this work identified a pathological mechanism whereby elevated phytosterols result in inflammation and cardiac fibrosis leading to impaired cardiac function, arrhythmias and sudden death. These phytosterolemia-associated comorbidities provide novel insight into the underlying pathophysiological mechanism that predispose these patients to increased risk of sudden cardiac death.
Keywords
Heart failure (HF), pathological conditions, accelerate disease pathogenesis, premature ventricular contractions
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Competing interest reported. All authors were employed by Amgen at the time the work was conducted, and all work was funded by Amgen, Inc.
This is a list of supplementary files associated with this preprint. Click to download.
- Supplement.pdf
ADDITIONAL INFORMATION All authors were employed by Amgen at the time the work was conducted, and all work was funded by Amgen, Inc.
- supplementaltable1.xlsx
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CURRENT STATUS: Under Review
Version 1
Posted 10 May, 2021
No community comments so far
Editorial decision: Major revision
On 01 Jun, 2021
Reviews received
Received 20 May, 2021
Reviewers agreed
On 10 May, 2021
Reviewers invited
Invitations sent on 09 May, 2021
Editor assigned
On 06 May, 2021
Editor invited
On 06 May, 2021
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On 06 May, 2021
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On 28 Apr, 2021
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This preprint is under consideration at Scientific Reports. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research Article
Brandon Ason
Amgen Research
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 10 May, 2021
No community comments so far
Editorial decision: Major revision
On 01 Jun, 2021
Reviews received
Received 20 May, 2021
Reviewers agreed
On 10 May, 2021
Reviewers invited
Invitations sent on 09 May, 2021
Editor assigned
On 06 May, 2021
Editor invited
On 06 May, 2021
Submission checks complete
On 06 May, 2021
First submitted
On 28 Apr, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Heart failure (HF) and cardiac arrhythmias share overlapping pathological mechanisms that act cooperatively to accelerate disease pathogenesis. Cardiac fibrosis is associated with both pathological conditions. Our previous work identified a link between phytosterol accumulation and cardiac injury in a mouse model of phytosterolemia, a rare disorder characterized by elevated circulating phytosterols and increased cardiovascular disease risk. Here, we uncover a previously unknown pathological link between phytosterols and cardiac arrhythmias in the same animal model. Phytosterolemia resulted in inflammatory pathway induction, premature ventricular contractions (PVC) and ventricular tachycardia (VT). Both pharmacological and genetic inhibition of phytosterol absorption prevented the induction of both pathways. Inhibition of phytosterol absorption reduced inflammation and cardiac fibrosis, improved cardiac function, reduced the incidence of arrhythmias and increased survival in a mouse model of phytosterolemia. Collectively, this work identified a pathological mechanism whereby elevated phytosterols result in inflammation and cardiac fibrosis leading to impaired cardiac function, arrhythmias and sudden death. These phytosterolemia-associated comorbidities provide novel insight into the underlying pathophysiological mechanism that predispose these patients to increased risk of sudden cardiac death.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Competing interest reported. All authors were employed by Amgen at the time the work was conducted, and all work was funded by Amgen, Inc.
This is a list of supplementary files associated with this preprint. Click to download.
- Supplement.pdf
ADDITIONAL INFORMATION All authors were employed by Amgen at the time the work was conducted, and all work was funded by Amgen, Inc.
- supplementaltable1.xlsx
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