Abstract 2989: Systemic Glutathione Deficiency in LMNA-mutated: Relation With Left Ventricular Dysfunction and Functional Status
Background: Patients carrying lamin A/C gene (LMNA) mutations have frequent cardiac involvement characterized by atrial fibrillation, atrio-ventricular conduction defect, heart failure and sudden death. Glutathione (L-gamma-glutamyl-cysteinyl-glycine) plays a key role in cell defence against oxidative stress and is essential to cell survival. In a murine model of LMNA mutation, deficiency in cardiac and systemic glutathione was associated with increased type-1 Tumor Necrosis Factor soluble receptor (sTNFR1), heart failure severity and its progression.
Aim: To examine the possible relationship between systemic glutathione, systemic sTNFR1 and the clinical status of LMNA-mutated patients.
Methods: Consecutive patients with documented LMNA mutations were included and compared to 15 age-sex matched controls. Detailed cardiac investigations were obtained from all patients; depressed left ventricular (LV) contractility was assessed using standard echocardiography and pulsed tissue-Doppler echocardiography (TDE). Serum glutathione and sTNFR1 were measured in LMNA-mutated patients and controls.
Results: 24 patients were included (11 males, mean age 38.2±19.1 years); 19 patients were of NYHA class I and 5 were of NYHA class II. Sinus rhythm was recorded in all. Overall, 8 patients had depressed LV contractility. Systemic glutathione was significantly depressed in LMNA-mutated patients (1.87±0.36 versus 2.13±0.15mM in controls, p=0.004) whereas there was only a trend for increased systemic sTNFR1 (0.32±0.14 versus 0.25±0.38ng/ml, p=0.088) Using a cut-off value for glutathione of 1.835mM, depressed systemic glutathione was associated with reduced LV contractility (p=0.027), reduced mitral annular velocity by TDE (p=0.014), and NYHA functional class (p=0.014).
Conclusion: Systemic glutathione is depressed and is related to both the functional status and cardiac function in LMNA-mutated patients of NYHA class I and II. Conversely, sTNFR1 seems to be of limited value to discriminate LMNA-mutated patients of NYHA class I and II from healthy controls. The impact of strategies aimed at improving glutathione status of LMNA-mutated patients and value of glutathione as a test to detect LV dysfunction remain to be established.