This study demonstrated carnitine may be associated with an increase in LVEF in pediatric patients with left ventricular systolic dysfunction. Carnitine was also associated with improvement in markers of myocardial stress in N-terminal-pro-brain-natriuretic peptide, markers of aerobic metabolism in serum lactate, and markers of kidney function in creatinine over a 6-month study period. As LVEF was the primary focus of this study, these values were adjusted for other concomitant interventions and a significant increase remained. Adjusted LVEF increased from 45.7% immediately prior to carnitine initiation to 58.0%, representing an absolute increase of 12.3% in LVEF over 6-months.
Previous studies have demonstrated similar increases in LVEF. Pooled analyses by Loomba et al demonstrated that in 144 pediatric patients across six studies LVEF significantly increased by 3.68%. These same pooled analyses also demonstrated a significant increase in left ventricular shortening fraction .
The original studies included in the aforementioned pooled analyses included three with cardiomyopathy patients. Of these, only two, that by Wang et al as well as that by Kotby et al quantified ventricular function by ejection fraction, both noting improvements in ejection fraction and shortening fraction associated with carnitine. Both studies also demonstrated improvement in clinical symptoms associated with carnitine [6, 7]. Thus, this current study is among a small number of studies focusing on delineating the effect of carnitine supplementation on LVEF in children with left ventricular systolic dysfunction.
Cardiomyocytes rely on β-oxidation, the aerobic breakdown of fat within the mitochondria, to produce energy . Levocarnitine, or L-carnitine, is a cofactor  involved in the transport of fatty acids across the inner mitochondrial membrane. L-carnitine plays an integral role in ATP production and assists in removing acylcarnitine derivatives from the mitochondria . Defects in the carnitine shuttle can impair mitochondrial energy production. The myocardium cannot synthesize carnitine and thus relies on the liver and kidney as well as dietary sources to provide the necessary carnitine to transport fatty acids across the mitochondrial membrane. Neonates and infants in particular have decreased biosynthetic capacity and are at risk of developing carnitine deficiency, particularly when they are not receiving enteral nutrition [10, 11].
In the process of β-oxidation, the fatty acid is activated into fatty acyl-CoA by coenzyme A. The fatty acyl-CoA cannot cross the inner mitochondrial membrane without carnitine which acts as a cofactor. Carnitine acyltransferase I enables the formation of an acylcarnitine molecule which can be transported across the inner mitochondrial membrane by Carnitine acyltranslocase. In the mitochondrial matrix, carnitine acyltransferase II transfers the fatty acylcarnitine molecule back to CoA forming fatty acyl-CoA. The fatty acyl-CoA can then undergo β-oxidation .
Through the aforementioned process, carnitine modulates the transfer of fatty acids into the mitochondrial matrix. Once this transfer is complete, Carnitine can be relocated to the cytosol by carnitine acyltranslocase. Carnitine acyltransferase II may complex carnitine with acyl-CoA in the mitochondrial matrix to form an ester. The ester may be removed from the mitochondria by translocase providing a pathway to remove acyl derivatives .
Carnitine is an especially attractive option for intervention in this patient population as it has few adverse effects. Most adverse effects are gastrointestinal symptoms such as reflux and diarrhea . Those with known seizure disorders may have increased frequency of seizures potentially related to carnitine and thus carnitine must be used with caution in this patient population .
In addition to its limited adverse event profile, carnitine is also fairly inexpensive. Using local data, carnitine is approximately $0.40 per 200 mg. Using the mean weight and mean daily dose from the current study results in approximately 1,000 mg/day of carnitine being prescribed. At the local price for carnitine that translates into a $2.00 daily cost of carnitine in the current study population. To put this in perspective, afterload reduction with enalapril in our population at 0.1mg/kg twice daily would result in about 3mg daily at a local of $4.30 per mg. This results in a total daily cost of $12.90 for enalapril in this population. Using the adjust means for LVEF, there was an absolute increase in ejection fraction of 4.2 over the 6-month study period. This would result in a $360 cost of carnitine in this period for the 4.2 increase noted in ejection fraction. Previous studies have demonstrated indirect association of LVEF and self-reported quality of life scores [15–17]. Thus, a 4.2 increase in ejection fraction associated with carnitine and its associated cost may also lead to meaningful increase in quality of life. This further highlights the potential cost effectiveness of carnitine in the setting of pediatric left ventricular systolic dysfunction.
This study is not without limitations. The most apparent limitation of this study is the lack of a control group in this retrospective study. This was not a controlled study with a non-carnitine arm. While the paired statistical analyses in this study utilize the patient’s baseline levels as controls there remains the possibility that the ejection fraction would have improved with time without carnitine. While the effects of other medications can be estimated and adjusted for in these analyses as not all patients received them at any single point, this cannot be done for carnitine as inclusion into the study was based on receiving carnitine. Thus, time and carnitine are essentially combined as a variable in the paired regression analyses without the real ability to discern what degree of the change was from either component in the paired analyses. A regression analysis was conducted in an unpaired fashion to help determine the independent association of time and ejection fraction and this demonstrated no significant association between time and ejection fraction. Another recently published pediatric study has also shown improvement in echocardiographic parameters with carnitine supplementation, perhaps further supporting the potential impact of carnitine on cardiac function .
Despite the limitations, these data are additive to the literature as they are able to quantify the effect of carnitine and the other medications over the same time-period even though the effect of time itself cannot be quantified. Additionally, the current study demonstrates safety of carnitine in pediatric patients with left ventricular dysfunction.