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The Direct Inotropic and Chronotropic Effects of Trimethylamine-N-Oxide on Cardiac Muscle
Başlık:
The Direct Inotropic and Chronotropic Effects of Trimethylamine-N-Oxide on Cardiac Muscle
Yazar:
Oakley, Carlee, author. (orcid)0000-0001-8691-7714
ISBN:
9780438037694
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (34 pages)
Genel Not:
Source: Masters Abstracts International, Volume: 57-06M(E).
Advisors: Won Choi Committee members: Jason Stubbs; Michael Wacker.
Özet:
Background: Cardiovascular disease is endemic among patients with chronic kidney disease (CKD). Growing evidence suggests the gut microbiome plays an obligatory role in cardiovascular pathogenesis. Trimethylamine-N-oxide (TMAO) is a downstream byproduct of intestinal microbe metabolism of phosphatidylcholine and L-carnitine that may directly promote atherosclerosis formation. Since clearance of this uremic metabolite is dependent on urinary excretion, plasma levels of TMAO increase with decrements in kidney function. Association studies have linked plasma levels of TMAO to adverse cardiovascular outcomes in patients with renal dysfunction; however, the direct effect on the heart itself remains largely unexplored.
Objective: The objective of this study was to determine if TMAO alone could acutely alter ex vivo cardiac contractile function on a beat-to-beat basis.
Methods: CD1 adult mouse hearts were extracted, attached to a force transducer, oxygenated, and paced within an organ bath. Changes in contractility were measured after infusing TMAO or vehicle into the organ bath. As a follow-up approach, mouse hearts were reverse perfused through the aorta via a modified Langendorff apparatus to facilitate TMAO delivery into the myocardium. Subsequently, to determine if our findings translated to the human heart, we performed contractility experiments using human atrial appendage biopsy tissue, which was retrieved during cardiopulmonary bypass procedures prior to cannula placement. To investigate whether TMAO alters contractile rate, in a separate series of experiments, the atria and sinoatrial node of isolated mouse hearts were kept intact to allow for spontaneous beating without artificial pacing. Changes in contraction rate (in beats per minute) were measured after treatment with TMAO or vehicle. Additionally, calcium imaging was performed on spontaneously beating embryonic (E18) rat cardiomyocytes. Changes in intracellular Ca2+ oscillations were measured, following treatment with 300 muM TMAO or vehicle, using the fluorescent Ca 2+ indicator Fluo-4 AM.
Results: Acute exposure to TMAO in the organ bath increased average contraction amplitude 17% and 41% at 300 muM and 3,000 muM, respectively (P < 0.05, n = 6-7 animals). Langendorff reverse perfusion of mouse hearts ex vivo with 300 muM TMAO generated an even greater response than non-perfusion peripheral exposure and increased isometric force 34% compared to vehicle (P < 0.05, n = 2-3). Consistent with what we observed in the animal model, incubation of human atrial muscle tissue with TMAO at 3,000 muM increased isometric tension 29% compared to vehicle (P < 0.05, n = 4-5). Average beating frequency of mouse hearts ex vivo increased 27% and 46% compared to vehicle following treatment with TMAO at 300 muM and 3,000 muM, respectively (P < 0.05, n = 3). Similarly, 300 muM TMAO increased average calcium oscillation frequency within embryonic rat cardiomyocytes by 42% compared to vehicle ( P < 0.05, n = 3-4).
Conclusions: TMAO, at pathological concentrations, directly increases the force and rate of cardiac contractility. Initially, these inotropic and chronotropic actions may help maintain cardiac output during CKD; however, chronic increases in isometric tension and beating frequency are known to promote cardiac remodeling, left ventricular hypertrophy, and heart failure. Further in vivo studies are needed to determine how chronic exposure to TMAO may contribute to cardiac pathology in CKD and to examine if TMAO represents a therapeutic target for reducing cardiovascular mortality in patients with CKD. Our findings lay the groundwork for future translational research on the intricate relationship between the microbiome, kidneys, and heart.
Notlar:
School code: 0099
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(693295.1) | 693295-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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