Creatine kinase adenosine triphosphate and phosphocreatine energy supply in a single kindred of patients with hypertrophic cardiomyopathy

M. Roselle Abraham, Paul A Bottomley, Veronica Lea Dimaano, Aurelio Pinheiro, Angela Steinberg, Thomas A Traill, Theodore P. Abraham, Robert George Weiss

Research output: Contribution to journalArticle

Abstract

A lethal and extensively characterized familial form of hypertrophic cardiomyopathy (HC) is due to a point mutation (Arg403Gln) in the cardiac β-myosin heavy chain gene. Although this is associated with abnormal energy metabolism and progression to heart failure in an animal model, in vivo cardiac energetics have not been characterized in patients with this mutation. Noninvasive phosphorus saturation transfer magnetic resonance spectroscopy was used to measure the adenosine triphosphate supplied by the creatine kinase (CK) reaction and phosphocreatine, the heart's primary energy reserve, in 9 of 10 patients from a single kindred with HC caused by the Arg403GIn mutation and 17 age-matched healthy controls. Systolic and diastolic function was assessed by echocardiography in all 10 patients with HC. The patients with HC had impairment of diastolic function and mild systolic dysfunction, when assessed using global systolic longitudinal strain. Myocardial phosphocreatine was significantly decreased by 24% in patients (7.1 ± 2.3 μmol/g) compared with the controls (9.4 ± 1.2 mmol/g; p = 0.003). The pseudo-first-order CK rate-constant was 26% lower (0.28 ± 0.15 vs 0.38 ± 0.07 s -1, p = 0.035) and the forward CK flux was 44% lower (2.0 ± 1.4 vs 3.6 ± 0.9 mmol/g/s, p = 0.001) than in the controls. The contractile abnormalities did not correlate with the metabolic indexes. In conclusion, myocardial phosphocreatine and CK-ATP delivery are significantly reduced in patients with HC caused by the Arg403Gln mutation, akin to previous results from mice with the same mutation. A lack of a relation between energetic and contractile abnormalities suggests the former result from the sarcomeric mutation and not a late consequence of mechanical dysfunction.

Original languageEnglish (US)
Pages (from-to)861-866
Number of pages6
JournalThe American Journal of Cardiology
Volume112
Issue number6
DOIs
StatePublished - Sep 15 2013

Fingerprint

Phosphocreatine
Hypertrophic Cardiomyopathy
Creatine Kinase
Adenosine Triphosphate
Mutation
Familial Hypertrophic Cardiomyopathy
Cardiac Myosins
MB Form Creatine Kinase
Myosin Heavy Chains
Point Mutation
Phosphorus
Energy Metabolism
Echocardiography
Magnetic Resonance Spectroscopy
Animal Models
Heart Failure
Genes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Creatine kinase adenosine triphosphate and phosphocreatine energy supply in a single kindred of patients with hypertrophic cardiomyopathy. / Abraham, M. Roselle; Bottomley, Paul A; Dimaano, Veronica Lea; Pinheiro, Aurelio; Steinberg, Angela; Traill, Thomas A; Abraham, Theodore P.; Weiss, Robert George.

In: The American Journal of Cardiology, Vol. 112, No. 6, 15.09.2013, p. 861-866.

Research output: Contribution to journalArticle

@article{fabb756331fb4bb2a05f785903282aef,
title = "Creatine kinase adenosine triphosphate and phosphocreatine energy supply in a single kindred of patients with hypertrophic cardiomyopathy",
abstract = "A lethal and extensively characterized familial form of hypertrophic cardiomyopathy (HC) is due to a point mutation (Arg403Gln) in the cardiac β-myosin heavy chain gene. Although this is associated with abnormal energy metabolism and progression to heart failure in an animal model, in vivo cardiac energetics have not been characterized in patients with this mutation. Noninvasive phosphorus saturation transfer magnetic resonance spectroscopy was used to measure the adenosine triphosphate supplied by the creatine kinase (CK) reaction and phosphocreatine, the heart's primary energy reserve, in 9 of 10 patients from a single kindred with HC caused by the Arg403GIn mutation and 17 age-matched healthy controls. Systolic and diastolic function was assessed by echocardiography in all 10 patients with HC. The patients with HC had impairment of diastolic function and mild systolic dysfunction, when assessed using global systolic longitudinal strain. Myocardial phosphocreatine was significantly decreased by 24{\%} in patients (7.1 ± 2.3 μmol/g) compared with the controls (9.4 ± 1.2 mmol/g; p = 0.003). The pseudo-first-order CK rate-constant was 26{\%} lower (0.28 ± 0.15 vs 0.38 ± 0.07 s -1, p = 0.035) and the forward CK flux was 44{\%} lower (2.0 ± 1.4 vs 3.6 ± 0.9 mmol/g/s, p = 0.001) than in the controls. The contractile abnormalities did not correlate with the metabolic indexes. In conclusion, myocardial phosphocreatine and CK-ATP delivery are significantly reduced in patients with HC caused by the Arg403Gln mutation, akin to previous results from mice with the same mutation. A lack of a relation between energetic and contractile abnormalities suggests the former result from the sarcomeric mutation and not a late consequence of mechanical dysfunction.",
author = "Abraham, {M. Roselle} and Bottomley, {Paul A} and Dimaano, {Veronica Lea} and Aurelio Pinheiro and Angela Steinberg and Traill, {Thomas A} and Abraham, {Theodore P.} and Weiss, {Robert George}",
year = "2013",
month = "9",
day = "15",
doi = "10.1016/j.amjcard.2013.05.017",
language = "English (US)",
volume = "112",
pages = "861--866",
journal = "American Journal of Cardiology",
issn = "0002-9149",
publisher = "Elsevier Inc.",
number = "6",

}

TY - JOUR

T1 - Creatine kinase adenosine triphosphate and phosphocreatine energy supply in a single kindred of patients with hypertrophic cardiomyopathy

AU - Abraham, M. Roselle

AU - Bottomley, Paul A

AU - Dimaano, Veronica Lea

AU - Pinheiro, Aurelio

AU - Steinberg, Angela

AU - Traill, Thomas A

AU - Abraham, Theodore P.

AU - Weiss, Robert George

PY - 2013/9/15

Y1 - 2013/9/15

N2 - A lethal and extensively characterized familial form of hypertrophic cardiomyopathy (HC) is due to a point mutation (Arg403Gln) in the cardiac β-myosin heavy chain gene. Although this is associated with abnormal energy metabolism and progression to heart failure in an animal model, in vivo cardiac energetics have not been characterized in patients with this mutation. Noninvasive phosphorus saturation transfer magnetic resonance spectroscopy was used to measure the adenosine triphosphate supplied by the creatine kinase (CK) reaction and phosphocreatine, the heart's primary energy reserve, in 9 of 10 patients from a single kindred with HC caused by the Arg403GIn mutation and 17 age-matched healthy controls. Systolic and diastolic function was assessed by echocardiography in all 10 patients with HC. The patients with HC had impairment of diastolic function and mild systolic dysfunction, when assessed using global systolic longitudinal strain. Myocardial phosphocreatine was significantly decreased by 24% in patients (7.1 ± 2.3 μmol/g) compared with the controls (9.4 ± 1.2 mmol/g; p = 0.003). The pseudo-first-order CK rate-constant was 26% lower (0.28 ± 0.15 vs 0.38 ± 0.07 s -1, p = 0.035) and the forward CK flux was 44% lower (2.0 ± 1.4 vs 3.6 ± 0.9 mmol/g/s, p = 0.001) than in the controls. The contractile abnormalities did not correlate with the metabolic indexes. In conclusion, myocardial phosphocreatine and CK-ATP delivery are significantly reduced in patients with HC caused by the Arg403Gln mutation, akin to previous results from mice with the same mutation. A lack of a relation between energetic and contractile abnormalities suggests the former result from the sarcomeric mutation and not a late consequence of mechanical dysfunction.

AB - A lethal and extensively characterized familial form of hypertrophic cardiomyopathy (HC) is due to a point mutation (Arg403Gln) in the cardiac β-myosin heavy chain gene. Although this is associated with abnormal energy metabolism and progression to heart failure in an animal model, in vivo cardiac energetics have not been characterized in patients with this mutation. Noninvasive phosphorus saturation transfer magnetic resonance spectroscopy was used to measure the adenosine triphosphate supplied by the creatine kinase (CK) reaction and phosphocreatine, the heart's primary energy reserve, in 9 of 10 patients from a single kindred with HC caused by the Arg403GIn mutation and 17 age-matched healthy controls. Systolic and diastolic function was assessed by echocardiography in all 10 patients with HC. The patients with HC had impairment of diastolic function and mild systolic dysfunction, when assessed using global systolic longitudinal strain. Myocardial phosphocreatine was significantly decreased by 24% in patients (7.1 ± 2.3 μmol/g) compared with the controls (9.4 ± 1.2 mmol/g; p = 0.003). The pseudo-first-order CK rate-constant was 26% lower (0.28 ± 0.15 vs 0.38 ± 0.07 s -1, p = 0.035) and the forward CK flux was 44% lower (2.0 ± 1.4 vs 3.6 ± 0.9 mmol/g/s, p = 0.001) than in the controls. The contractile abnormalities did not correlate with the metabolic indexes. In conclusion, myocardial phosphocreatine and CK-ATP delivery are significantly reduced in patients with HC caused by the Arg403Gln mutation, akin to previous results from mice with the same mutation. A lack of a relation between energetic and contractile abnormalities suggests the former result from the sarcomeric mutation and not a late consequence of mechanical dysfunction.

UR - http://www.scopus.com/inward/record.url?scp=84886653686&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84886653686&partnerID=8YFLogxK

U2 - 10.1016/j.amjcard.2013.05.017

DO - 10.1016/j.amjcard.2013.05.017

M3 - Article

C2 - 23751935

AN - SCOPUS:84886653686

VL - 112

SP - 861

EP - 866

JO - American Journal of Cardiology

JF - American Journal of Cardiology

SN - 0002-9149

IS - 6

ER -