Abstract:
:Background - Variants within the alpha-tropomyosin gene (TPM1) cause dominantly inherited cardiomyopathies, including dilated (DCM), hypertrophic (HCM) and restrictive (RCM) cardiomyopathy. Here we investigated whether TPM1 variants observed in DCM and HCM patients affect cardiomyocyte physiology differently. Methods - We identified a large family with DCM carrying a recently identified TPM1 gene variant (T201M) and a child with RCM with compound heterozygote TPM1 variants (E62Q and M281T) whose family members carrying single variants show diastolic dysfunction and HCM. The effects of TPM1 variants (T201M, E62Q or M281T) and of a plasmid containing both the E62Q and M281T variants on single-cell Ca2+ transients (CaT) in HL-1 cardiomyocytes were studied. To define toxic threshold levels, we performed dose-dependent transfection of TPM1 variants. In addition, cardiomyocyte structure was studied in human cardiac biopsies with TPM1 variants. Results - Overexpression of TPM1 variants led to time-dependent progressive deterioration of CaT, with the smallest effect seen for E62Q and larger and similar effects seen for the T201M and M281T variants. Overexpression of E62Q/M281T did not exacerbate the effects seen with overexpression of a single TPM1 variant. T201M (DCM) replaced endogenous tropomyosin dose-dependently, while M281T (HCM) did not. Human cardiac biopsies with TPM1 variants revealed loss of sarcomeric structures. Conclusion - All TPM1 variants result in reduced cardiomyocyte CaT amplitudes and loss of sarcomeric structures. These effects may underlie pathophysiology of different cardiomyopathy phenotypes.
journal_name
Int J Cardioljournal_title
International journal of cardiologyauthors
Dorsch LM,Kuster DWD,Jongbloed JDH,Boven LG,van Spaendonck-Zwarts KY,Suurmeijer AJH,Vink A,du Marchie Sarvaas GJ,van den Berg MP,van der Velden J,Brundel BJJM,van der Zwaag PAdoi
10.1016/j.ijcard.2020.08.101subject
Has Abstractpub_date
2021-01-15 00:00:00pages
251-258eissn
0167-5273issn
1874-1754pii
S0167-5273(20)33728-1journal_volume
323pub_type
杂志文章abstract:BACKGROUND:Intuitively higher exercise program volume may be the primary stimulus for physical adaptation. We sought to establish if aerobic exercise training program characteristics produced different effect sizes for change in cardiorespiratory fitness in heart failure patients. METHODS:We conducted a MEDLINE search...
journal_title:International journal of cardiology
pub_type: 杂志文章,meta分析
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journal_title:International journal of cardiology
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journal_title:International journal of cardiology
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journal_title:International journal of cardiology
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journal_title:International journal of cardiology
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