Large Variations in Phenylalanine Concentrations Associate Adverse Cardiac Remodelling in Adult Patients With Phenylketonuria—A Long‐Term CMR Study
Authors: Tanacli Radu , Doeblin Patrick , Faragli Alessandro , Hassel Jan‐Hendrik , Stehning Christian , Plöckinger Ursula , Ziagaki Athanasia , Kelle Sebastian 
Published: January 2025

ABSTRACTBackgroundDespite a phenylalanine (Phe) restrictive diet, most adult patients with ‘classical’ phenylketonuria (PKU) maintain life‐long Phe concentrations above the normal range and receive tyrosine (Tyr) and protein‐enriched diets to maintain acceptable concentrations and ensure normal development. While these interventions are highly successful in preventing adverse neuropsychiatric complications, their long‐ term consequences are incompletely explored. We observed early cardiomyopathic characteristics and associated hemodynamic changes in adult PKU patients and present here the results of a longitudinal evaluation of cardiac phenotype.MethodsFifteen adult patients with PKU (age: 39.8 ± 8.1 years, 9 males and 6 females) underwent a comprehensive follow‐up cardiac magnetic resonance (CMR) imaging assessment after a mean follow‐up interval of 8.3 ± 0.3 years from the initial baseline visit. The CMR protocol included left (LV) and right (RV) ventricular and left atrial (LA) volumetric assessment, LV parametric mapping (precontrast and postcontrast T1 and T2 maps, extracellular volume [ECV]), multilayer LV myocardial strain, systolic and diastolic hemodynamic forces and RV and LA strain and aortic distensibility evaluation. Plasma concentrations of Phe, tyrosine (Tyr) and other biochemical markers of disease were retrospectively collected. For comparison, a group of 20 matched control subjects undergoing an identical CMR protocol was included.ResultsOn average, the LV end‐diastolic volume (EDV) (158 ± 29 vs. 143 ± 29 mL, p = 0.013) and end‐systolic volume (ESV) (68 ± 18 vs. 62 ± 18 mL, p = 0.011) were lower at follow‐up. In contrast, LV mass (LVM) (72 ± 25 vs. 82 ± 29 g, p < 0.001) and the ratio LVM/EDV (0.46 ± 0.12 vs. 0.58 ± 0.23 g/mL, p = 0.005) were increased, and T1 times were longer (940 ± 42 vs. 1010 ± 35 ms, p < 0.001). LV EF (57 ± 6 vs. 57 ± 7%, p = 0.90), longitudinal (GLS) and circumferential (GCS) systolic strain remained unchanged, but early diastolic hemodynamic (HD) forces were more markedly negative (−19.4 ± 7.0 vs. −26.5 ± 12.2%, p = 0.012), while LA strain 43.8 ± 11.3 vs. 37.3 ± 9.6%, p = 0.031) and aortic distensibility (6.38 ± 1.75 vs. 5.21 ± 1.17 10−3 mmHg−1, p = 0.008) decreased at follow‐up. Compared with controls, PKU patients maintain reduced systolic function with lower LV EF and impaired GCS and have more markedly negative early diastolic HD pressures. A higher decrease in Phe concentration (ΔPhe) was associated with longer T1 times, ΔT1 (β = −0.78, p < 0.001), increased ECV, ΔECV (β = −0.61, p = 0.016) and a decrease in systolic function, ΔEF (β = 0.61, p = 0.017). In contrast, variations in Tyr concentrations did not affect the cardiac phenotype.ConclusionsAt long‐term follow‐up, a marked drop in Phe plasma concentration was associated with detrimental cardiac remodelling consisting of decreased LV systolic function and increased diffuse fibrosis, in PKU patients. These new data prompt further investigation into the effects of large Phe variability over time and underline the usefulness of periodic cardiovascular assessment in adults with PKU.