Cardiac Magnetic Resonance Reveals Incipient Cardiomyopathy Traits in Adult Patients with Phenylketonuria

Background: Phenylketonuria (PKU) is the most common inborn error of amino-acid metabolism, which, when untreated results to severe neuropsychological complications. . New born screenings programs and immediate beginning of phenylalanine-restricted diet, greatly ameliorate the prognosis. However, previous studies have shown that PKU patients have elevated levels of oxidative stress and collateral metabolic abnormalities such as dyslipidemia, predisposing to cardiovascular disease. The purpose of this study was to characterize the cardiac phenotype of adult subjects with PKU using advanced cardiac imaging. Methods: Thirty-nine adult patients with PKU (age 30.5±8.7 year old, median 10 year phenylalanine concentration (Phe) 924±330 µmol/L) and thirty-nine age- and gender- matched healthy controls were investigated. Participants underwent a comprehensive cardiac magnetic resonance imaging (CMR) and echocardiography examination to determine systolic and diastolic left (LV) and right (RV) ventricular function, LV mass, ventricular fibrosis, left atrial function and aortic distensibility. CMR parametric mapping was used to characterize structural tissue modification. All available quarterly plasma levels of Phe and tyrosine (Tyr) levels were averaged for 10 years prior to the CMR scan to evaluate therapeutic efficacy and compliance. Results: PKU patients had thinner LV walls (Septal end-diastolic (ED) thickness 7.0±17 vs 8.8±1.7 mm, p 1200µmol/L (909±48 ms). Both mean Phe (p=0.013) and Tyr (p=0.035) concentration levels were independently predictive for lower T1 values in a regression model. Conclusion: Taken together our findings indicate an early stage LV dysfunction in patients with PKU which associates lower T1 native levels probably reflecting an infiltration with lipids of the myocardium. These results suggest the importance of regular cardiac follow-up in clinical monitoring of the adult subjects with PKU. Funding Statement: Sebastian Kelle is supported by a grant from Philips Healthcare and received funding from the DZHK (German Centre for Cardiovascular Research) and by the BMBF (German Ministry of Education and Research). Declaration of Interests: None of the other authors reports a relationship with industry and other relevant entities – financial or otherwise – that might pose a conflict of interest in connection with the submitted article. The following authors report financial activities outside the submitted work: Radu Tanacli reports no conflict of interest. Burkert Pieske reports having received consultancy and lecture honoraria from Bayer Daiichi Sankyo, MSD, Novartis, Sanofi-Aventis, Stealth Peptides and Vifor Pharma; and editor honoraria from the Journal of the American College of Cardiology. Radu Tanacli and the other co-authors report no conflict of interest. Ethics Approval Statement: The study was approved by the Ethics Committee of the Charite University of Medicine in Berlin, complied with the Declaration of Helsinki and was registered at the German Register for Clinical Studies (DRK1120).