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thesis.pdf (2.83 MB)
ETD Abstract Container
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Contractile Dysfunction in Heart Failure and Familial Hypertrophic Cardiomyopathy
Author Info
Cheng, Yi-Hsin
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=case1378894204
Abstract Details
Year and Degree
, Doctor of Philosophy, Case Western Reserve University, Physiology and Biophysics.
Abstract
Elevations in plasma and myocardial lipids can exacerbate the progression of heart failure (HF). However, our previous studies reported that high saturated fat (SAT) feeding improves
in vivo
myocardial contractile function after infarction. Since alterations in cardiomyocyte Ca
2+
kinetics and myofilament proteins also contribute to contractile dysfunction in HF, in the first study we hypothesize that SAT improves contractile function by ameliorating these alterations in HF. Rats underwent coronary artery ligation or sham surgery (SH) and were fed normal chow (SHNC and HFNC) or SAT (SHSAT and HFSAT) for 8 weeks. SAT reduced
in vivo
myocyte hypertrophy and improved
in vivo
(LV d
P
/d
t
max/min
) and
in vitro
contractility (-d
L
/d
t
) in HF. MHC isoform switched from fast MHCα to slow MHCβ in HFNC but reversed in HFSAT. Alterations in Ca
2+
transients, L-type Ca
2+
currents and expression of Ca
2+
handling proteins could not account for changes in
in vivo
contractile properties. Together, the cardioprotective effects associated with SAT in HF occur at the level of cardiomyocyte, specifically involving changes in myofilament function, but not Ca
2+
handling properties. Mutations in cardiac myosin binding protein C (MyBP-C) cause familial hypertrophic cardiomyopathy (FHC). Most MyBP-C mutations reduce MyBP-C expression, however, the consequences of MyBP-C deficiency are unclear. In the second study, we employed MyBP-C null (MyBP-C
-/-
) and heterozygous null (MyBP-C
+/-
) mice. Complete MyBP-C deficiency altered
in vivo
and
in vitro
contractile function, Ca
2+
handling, electrical activity, and chamber remodeling of MyBP-C
-/-
hearts. Partial MyBP-C deficiency and concomitant down-regulated MyBP-C phosphorylation in MyBP-C
+/-
hearts altered cross-bridge function which contributed to
in vitro
and
in vivo
contractile dysfunction and ECG abnormalities in the absence of adaptations in Ca
2+
handling or LV chamber remodeling. Contractile dysfunction in MyBP-C
+/-
myofilaments and intact hearts were normalized by β-agonists, suggesting that their basal contractile dysfunction is partly mediated by impaired MyBP-C phosphorylation. Collectively, our data show that reduced MyBP-C expression and phosphorylation in the sarcomere results in myofilament dysfunction, contributing to contractile dysfunction that precedes adaptations in Ca
2+
handling and chamber remodeling. Perturbations in mechanical and electrical activity in these mice could also increase their susceptibility to arrhythmia.
Committee
Julian Stelzer (Advisor)
Subject Headings
Physiology
Recommended Citations
Refworks
EndNote
RIS
Mendeley
Citations
Cheng, Y.-H. (n.d.).
Contractile Dysfunction in Heart Failure and Familial Hypertrophic Cardiomyopathy
[Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1378894204
APA Style (7th edition)
Cheng, Yi-Hsin.
Contractile Dysfunction in Heart Failure and Familial Hypertrophic Cardiomyopathy .
Case Western Reserve University, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=case1378894204.
MLA Style (8th edition)
Cheng, Yi-Hsin. "Contractile Dysfunction in Heart Failure and Familial Hypertrophic Cardiomyopathy ." Doctoral dissertation, Case Western Reserve University. Accessed MAY 21, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=case1378894204
Chicago Manual of Style (17th edition)
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Document number:
case1378894204
Download Count:
987
Copyright Info
© , some rights reserved.
Contractile Dysfunction in Heart Failure and Familial Hypertrophic Cardiomyopathy by Yi-Hsin Cheng is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.