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 (MHC) gene. Although this is associated with abnormal energy metabolism and progression to heart failure in an animal model, in vivo cardiac energetic shave not been characterized in patients with this mutation. Noninvasive phosphorus saturation transfer magnetic resonance spectroscopy was used to measure the adenosine triphosphate (ATP)supplied by the creatine kinase (CK) reaction and phosphocreatine (PCr), the heart’s primary energy reserve, in 9 of 10 patients from a single kindred with HC caused by Arg403GIn mutation, and 17 age-matched healthy controls. Systolic and diastolic function was assessed by echocardiography in all 10 HC patients. HC patients had impairment of diastolic function as well as mild systolic dysfunction, when assessed using global systolic longitudinal strain. Myocardial [PCr] was significantly decreased by 24% in patients (7.1±2.3μmol/g) compared to controls (9.4±1.2μmol/g; p=0.003). The pseudo-first-order CK rate-constant was 26% lower (0.28±0.15 vs. 0.38±0.07s−1, p=0.035) and the forward CK flux was 44% lower (2.0±1.4 vs3.6±0.9 μmol/g/s, p=0.001) than controls. The contractile abnormalities did not correlate with metabolic indices. 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 with the same mutation. Lack of a relation between energetic and contractile abnormalities suggests the former are due to the sarcomeric mutation and not a late consequence of mechanical dysfunction.

Decreased ATP production and myocardial contractile reserve in metabolic heart disease

“…Taken together with the findings in the ZDF rat, our data suggest that a decrease in CK activity is not a major driver of cardiac energetic deficiency in the cardiomyopathy of MHD, but rather, support the thesis proposed by Bashir et al [34] that the increase in the CK rate constant is a compensatory response that helps to maintain a normal flux through CK in the face of a decrease in [PCr] [34]. Interestingly, in other models of HFpEF such as pressure overload [48] and hypertrophic cardiomyopathy [47] CK flux is decreased, suggesting that the energetic profile in “HFpEF” may be heterogeneous and related to the underlying etiology.…”

“…While decreased CK activity has been observed in systolic heart failure [31,32] and hypertrophic cardiomyopathy [47], relatively little is known about CK function in MHD. Of note, our findings are consistent with those of Bashir et al [34], who likewise found that the forward CK reaction rate constant was higher and CK flux was preserved in hearts from diabetic Zucker Diabetic Fatty (ZDF) rats.…”

A Good Heart Is Hard to Find

“…We previously demonstrated that myocardial phosphocreatine was significantly decreased by 24% in HCM patients with a β-myosin heavy chain mutation compared with controls; pseudo-first-order creatine kinase rate constant was 26% lower and the forward creatine kinase flux 44% lower in HCM. 3 However, in this study, myocardial strain did not correlate with the metabolic indexes. Investigations of cardiac energetics have generally used magnetic resonance spectroscopy.…”

Creatine kinase rate constant in the human heart measured with 3D‐localization at 7 tesla

“…The FAST method has been deployed in a number of studies (Table ) in patients with heart disease ; values have been shown to be a more sensitive indicator of heart failure than the PCr/ATP ratio . Furthermore, CK flux values have been shown to be even more sensitive than values . The BOAST method will open up the possibility of measurements of regional myocardial values, making the technique more relevant to regional myocardial disease.…”