Diastolic dysfunction and altered energetics in the alphaMHC403/+ mouse model of familial hypertrophic cardiomyopathy
Open accessAbstract
An arginine to glutamine missense mutation at position 403 of the beta-cardiac myosin heavy chain causes familial hypertrophic cardiomyopathy. Here we study mice which have this same missense mutation (alphaMHC403/+) using an isolated, isovolumic heart preparation where cardiac performance is measured simultaneously with cardiac energetics using 31P nuclear magnetic resonance spectroscopy. We observed three major alterations in the physiology and bioenergetics of the alphaMHC403/+ mouse hearts. First, while there was no evidence of systolic dysfunction, diastolic function was impaired during inotropic stimulation. Diastolic dysfunction was manifest as both a decreased rate of left ventricular relaxation and an increase in end-diastolic pressure. Second, under baseline conditions alphaMHC403/+ hearts had lower phosphocreatine and increased inorganic phosphate contents resulting in a decrease in the calculated value for the free energy released from ATP hydrolysis. Third, hearts from alphaMHC403/+ hearts that were studied unpaced responded to increased perfusate calcium by decreasing heart rate approximately twice as much as wild types. We conclude that hearts from alphaMHC403/+ mice demonstrate work load-dependent diastolic dysfunction resembling the human form of familial hypertrophic cardiomyopathy. Changes in high-energy phosphate content suggest that an energy-requiring process may contribute to the observed diastolic dysfunction.
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The energetic changes in human Arg403Gln hypertrophic cardiomyopathy are similar to those previously observed in mice carrying the same mutation.
“In conclusion, myocardial PCr and CK ATP delivery are significantly reduced in patients with HC due to Arg403Gln mutation, akin to prior results from mice”
From iRhythm ZIO: The Diagnostic Yield of a 14-day Continuous Ambulatory ECG Monitor (Turakhia et al., diagnostic yield of extended ambulatory ECG monitoring) (2013) · cites this paper as [3]
The baseline-perfusion results (page not provided) show 22% lower PCr in hearts from mice carrying the Arg403Gln mutation, supporting the comparison for PCr. The paper does not report reduced CK-mediated ATP delivery in those mice; it reports unchanged total CK activity and isoenzyme distribution. The patient findings are the citing authors’ own results, not findings attributed to this mouse study. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe reduction in myocardial PCr with preserved ATP and calculated ADP suggests an increased cost of contraction, as previously reported in the mouse model.
“First, there is a reduction in myocardial [PCr] with preserved [ATP] and calculated [ADP] which would suggest an increased cost of contraction as previously reported in the mouse model carrying this mutation2,3.”
From iRhythm ZIO: The Diagnostic Yield of a 14-day Continuous Ambulatory ECG Monitor (Turakhia et al., diagnostic yield of extended ambulatory ECG monitoring) (2013) · cites this paper as [3]
The contractile-performance results report lower PCr and unchanged ATP in mutant mouse hearts, and the Cardiac energetics section proposes an increased cost of contraction. But calculated ADP was 39% higher than in wild-type hearts, not preserved. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn a murine model, the Arg403Gln mutation manifests an increased energetic cost of contraction.
“Because the murine Arg403Gln model manifests an increased energetic cost of contraction2,3”
From iRhythm ZIO: The Diagnostic Yield of a 14-day Continuous Ambulatory ECG Monitor (Turakhia et al., diagnostic yield of extended ambulatory ECG monitoring) (2013) · cites this paper as [3]
The Cardiac energetics section predicts that shortening against a load will cost more in mutant than wild-type hearts. The Conclusions say the cost of developing pressure *may* be higher, while the measured findings establish altered energetics rather than directly demonstrating an increased cost of contraction. The claim presents that proposed increase as an established manifestation. (LLM, conf=0.87)
Experimental — accuracy not yet measuredBecause hypertrophy is absent in the mouse model, the energetic changes in that model are primary consequences of the myosin mutation rather than secondary to hypertrophy.
“Because hypertrophy is not present in the mouse model, these are not secondary consequences of hypertrophy but must instead be primary consequences of the myosin mutation3.”
From iRhythm ZIO: The Diagnostic Yield of a 14-day Continuous Ambulatory ECG Monitor (Turakhia et al., diagnostic yield of extended ambulatory ECG monitoring) (2013) · cites this paper as [3]
The Conclusions state that the energetic abnormalities are likely to be primary effects of the myosin mutation and unlikely to be secondary consequences of hypertrophy; they also note that these mice lack gross cardiac hypertrophy. The citing sentence overstates that qualified conclusion by saying the changes “must” be primary consequences. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn an animal model, the Arg403Gln mutation is associated with abnormal energy metabolism and progression to heart failure.
“Although this is associated with abnormal energy metabolism and progression to heart failure in an animal model”
From iRhythm ZIO: The Diagnostic Yield of a 14-day Continuous Ambulatory ECG Monitor (Turakhia et al., diagnostic yield of extended ambulatory ECG monitoring) (2013) · cites this paper as [3]
The Discussion and Cardiac energetics sections report altered energy metabolism in Arg403Gln mutant mouse hearts. They do not report progression to heart failure in the mice; the energetics section only compares their metabolic pattern with one observed in human heart failure. The Introduction also says heterozygous mutant mice appear to have a normal life span. Page numbers were not provided in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Hypertrophic cardiomyopathy is a genetic disorder caused by mutations typically in sarcomeric proteins, some of which increase the cost of force production and ATP turnover.
“In contrast to pressure-overload left ventricular hypertrophy, HC is a genetic disorder caused by mutations typically in sarcomeric proteins, some of which increase the cost of force production resulting in increased ATP turnover3,22.”
From iRhythm ZIO: The Diagnostic Yield of a 14-day Continuous Ambulatory ECG Monitor (Turakhia et al., diagnostic yield of extended ambulatory ECG monitoring) (2013) · cites this paper as [3]
The Introduction (page unavailable) links familial hypertrophic cardiomyopathy to mutations in the myosin heavy-chain gene. The Conclusions (page unavailable) say the cost of developing pressure may be higher in mutant mouse hearts, but caution against extrapolating to patients. The paper does not establish increased ATP turnover or that all hypertrophic cardiomyopathy is genetic; the Introduction says approximately half of cases are inherited. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn heterozygous mice with the Arg403Gln mutation, myocardial PCr is decreased and inorganic phosphate is increased while ATP is unchanged under conditions associated with diastolic dysfunction.
“In heterozygous mice bearing the Arg403Gln mutation there is a decrease in myocardial [PCr] and increase in inorganic phosphate [Pi] with unchanged [ATP] under conditions associated with diastolic dysfunction3.”
Hypertrophy is not present in the mouse model of Arg403Gln hypertrophic cardiomyopathy.
“Because hypertrophy is not present in the mouse model”
The cardiac metabolic results in this study agree with invasive measurements of metabolites in the Arg403Gln mouse model.
“Moreover, our cardiac metabolic results agree with invasive measurements of metabolites in the Arg403Gln mouse model.”
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- Authors
- Spindler, M., Saupe, K. W., Christe, M. E., Sweeney, H. L., Seidman, C. E., Seidman, J. G., & Ingwall, J. S.
- Affiliations
- Brigham and Women's Hospital (US)
- University of Pennsylvania (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Ingwall, J S
- Venue
- Journal of Clinical Investigation
- Published
- 1998-04-15
- Volume
- 101
- Issue
- 8
- Pages
- 1775-1783
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC508760
- OpenAlex
- W1968754807
- Cited by
- 268
- References
- 18
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 3 · 2023: 8 · 2022: 6 · 2021: 4 · 2020: 6 · 2019: 9 · 2018: 17 · 2017: 8 · 2016: 9 · 2015: 10 · 2014: 13 · 2013: 4 · 2012: 6
- FWCI
- 9.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (1f32hl009259-01, 5r01hl052350-09)
- National Heart, Lung, and Blood Institute (HL52350, HL-09259)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- familial hypertrophic cardiomyopathy, diastolic dysfunction, missense mutations, cardiac energetics, high-energy phosphates, phosphocreatine, inorganic phosphate, ATP hydrolysis free energy, left ventricular relaxation, end-diastolic pressure, 31P NMR
- MeSH terms
- Adenosine Triphosphate, Animals, Blood Pressure, Calcium, Cardiomyopathy, Hypertrophic, Diastole, Disease Models, Animal, Dose-Response Relationship, Drug, Energy Metabolism, Female, Heart Rate, Humans, Male, Mice, Mutant Strains, Myocardial Contraction, Magnetic Resonance Spectroscopy, Perfusion, Systole, Point Mutation, Myosin Heavy Chains, Mice, In Vitro Techniques
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