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

Abstract

Background Phenylketonuria is the most common inborn error of amino acid metabolism, where oxidative stress and collateral metabolic abnormalities are likely to cause cardiac structural and functional modifications. We aim herein to characterize the cardiac phenotype of adult subjects with phenylketonuria using advanced cardiac imaging. Methods and Results Thirty-nine adult patients with phenylketonuria (age, 30.5±8.7 years; 10-year mean phenylalanine concentration, 924±330 µmol/L) and 39 age- and sex-matched healthy controls were investigated. Participants underwent a comprehensive cardiac magnetic resonance and echocardiography examination. Ten-year mean plasma levels of phenylalanine and tyrosine were used to quantify disease activity and adherence to treatment. Patients with phenylketonuria had thinner left ventricular walls (septal end-diastolic thickness, 7.0±17 versus 8.8±1.7 mm [P<0.001]; lateral thickness, 6.1±1.4 versus 6.8±1.2 mm [P=0.004]), more dilated left ventricular cavity (end-diastolic volume, 87±14 versus 80±14 mL/m² [P=0.0178]; end-systolic volume, 36±9 versus 29±8 mL/m² [P<0.001]), lower ejection fraction (59±6% versus 64±6% [P<0.001]), reduced systolic deformation (global circumferential strain, -29.9±4.2 % versus -32.2±5.0 % [P=0.027]), and lower left ventricular mass (38.2±7.9 versus 47.8±11.0 g/m² [P<0.001]). T1 native values were decreased (936±53 versus 996±26 ms [P<0.001]), with particular low values in patients with phenylalanine >1200 µmol/L (909±48 ms). Both mean phenylalanine (P=0.013) and tyrosine (P=0.035) levels were independently correlated with T1; and in a multiple regression model, higher phenylalanine levels and higher left ventricular mass associate with lower T1. Conclusions Cardiac phenotype of adult patients with phenylketonuria reveals some traits of an early-stage cardiomyopathy. Regular cardiology follow-up, tighter therapeutic control, and prophylaxis of cardiovascular risk factors, in particular dyslipidemia, are recommended.

Keywords: T1 native; cardiac magnetic resonance; cardiomyopathy; dyslipidemia; phenylketonuria.

Figure 1. Cardiac structural and functional remodeling in adult patients with phenylketonuria (PKU) and age‐ and sex‐matched controls.

Left ventricular end‐diastolic volume (LVEDV) (A), left ventricular end‐systolic volume (LVESV) (B), cardiac index (C), left ventricular (LV) ejection fraction (D), global longitudinal strain (GLS) (E), global circumferential strain (GCS) (F), LV mass (G), T1 native (H), and extracellular volume (ECV) (I) (number mean and SD referenced in literature [Dabir et al, J Cardiovasc Magn Reson. 2014;16:69] for similar scanner and magnetic field strength). A P<0.05 was considered statistically significant. *P<0.05, **P<0.01, and ***P<0.001.

Figure 2. Univariate and bivariate regression to determine the relation between 10‐year average levels of phenylalanine (Phe) and tyrosine (Tyr) and T1 native values.

A, Linear regression between Phe plasma levels and T1. B, Linear regression between Tyr plasma levels and T1 (continuous line represents the regression best fit equation line, and the dotted lines represent the 95% confidence limits). C, Regression parameters and B coefficients. A P<0.05 was considered statistically significant; Phe and Tyr plasma levels predict independently T1 values, indicating that therapeutic intervention not only to reduce Phe levels but also to augment the Tyr levels may be beneficial to correct cardiac changes. § indicates statistical significance.

Figure 3. In a multivariate regression model, the independent predictors of T1 native are the averaged levels of plasma phenylalanine (Phe) (B coefficient standardized, −0.34) and respectively left ventricular mass (B coefficient standardized, −0.43), both negatively correlated with T1 native times.

We suggest that the pathologic substrate that may be responsible for lower T1 times is more present in the myocardium tissue of patients with worse control of the disease. § indicates statistical significance.

Figure 4. Lipid profile in 3 subgroups of adult patients with phenylketonuria, divided according to the 10‐year mean phenylalanine (Phe) level (from left to right in each graph: group 1, Phe ≤900 µmol/L; group 2, 900 µmol/L1200 µmol/L).

Total cholesterol (Chol) (A), triglycerides (B), high‐density lipoprotein (HDL) cholesterol (C), low‐density lipoprotein (LDL) cholesterol (D), and LDL/HDL cholesterol ratio (E). Significant differences were recorded between the level of triglycerides and LDL/HDL cholesterol ratio, with a more pronounced dyslipidemic profile observed in patients with poor control of the disease (ie, higher mean Phe values).

Figure 5. Representative steady‐state free precession (SSFP) cine (first row), late gadolinium enhancement (middle row), and T1 native maps (lower row) of 3 subjects with phenylketonuria from 3 groups, divided according to mean 10‐year value of plasma phenylalanine (Phe) concentrations: group 1, Phe ≤900 µmol/L; group 2, 900 µmol/L1200 µmol/L, displayed as follows: group 1 subject (left column), group 2 subject (middle column), and group 3 subject (right column).

In the absence of any focal lesion, there is a diffuse process that shortens T1 native times in patients in whom the therapeutic control of Phe is suboptimal.