Abstract
PurposeCurrent evidence indicates that the common AMPD1 gene variant is associated with improved survival in patients with advanced heart failure. Whilst adenosine has been recognized to mediate the cardioprotective effect of C34T AMPD1, the precise pathophysiologic mechanism involved remains undefined to date. To address this issue, we used cardio-pulmonary exercise testing data (CPX) from subjects with myoadenylate deaminase (MAD) defects.MethodsFrom 2009 to 2013, all the patients referred in our laboratory to perform a metabolic exercise testing, i.e. a CPX with measurements of muscle metabolites in plasma during and after exercise testing, were prospectively enrolled. Subjects that also underwent an open muscle biopsy for diagnosis purpose were finally included. The metabolic-chronotropic response was assessed by calculating the slope of the linear relationship between the percent heart rate reserve and the percent metabolic reserve throughout exercise. MAD activity was measured using the Fishbein’s technique in muscle biopsy sample. The common AMPD1 mutation was genotyped and the AMPD1 gene was sequenced to screen rare variants from blood DNA.ResultsSixty-seven patients were included in the study; 5 had complete MAD deficiency, 11 had partial MAD deficiency, and 51 had normal MAD activity. Compared with normal MAD activity subjects, MAD deficient subjects appeared to have a lower-than-expected metabolic-chronotopic response during exercise. The metabolic-chronotropic relationship is more closely correlated with MAD activity in skeletal muscle (Rs = 0.57, p = 5.93E-7, Spearman correlation) than the presence of the common AMPD1 gene variant (Rs = 0.34, p = 0.005). Age-predicted O2 pulse ratio is significantly increased in MAD deficient subjects, indicating a greater efficiency of the cardiovascular system to deliver O2 (p < 0.01, Scheffé’s post hoc test).ConclusionThe metabolic-chronotropic response is decreased in skeletal muscle MAD deficiency, suggesting a biological mechanism by which AMPD1 gene exerts cardiac effect.
Highlights
The clinical course and long-term outcome of patients with chronic heart failure (CHF) vary widely among individuals
Sixty-seven patients were included in the study; 5 had complete myoadenylate deaminase (MAD) deficiency, 11 had partial MAD deficiency, and 51 had normal MAD activity
The metabolic-chronotropic response is decreased in skeletal muscle MAD deficiency, suggesting a biological mechanism by which AMPD1 gene exerts cardiac effect
Summary
The clinical course and long-term outcome of patients with chronic heart failure (CHF) vary widely among individuals. In 1999, using Kaplan-Meier survival-time plot analysis, Loh et al first reported in end-stage cardiomyopathy a significantly greater probability of survival associated with carriage of the AMPD1 gene common mutation [2]. AMPD1 codes for the skeletal muscle isoform of myoadenylate deaminase (MAD). A common mutation in the AMPD1 gene second exon (so-called C34T) in the homozygous state led to a truncated, catalytically inactive enzyme [3]. MAD deficiency is the most common enzymatic defect of skeletal muscle [3,4,5,6,7]. There is ample evidence indicating that adenosine contributes significantly to the cardiovascular effects of C34T AMPD1 [8,9,10]
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