Plasma Carnitine Concentrations Research Articles

Carnitine Replacement in End‐Stage Renal Disease and Hemodialysis

In patients with chronic renal failure, not yet undergoing hemodialysis (HD), plasma acylcarnitines accumulate in part due to a decreased renal clearance of esterified carnitine moieties. In these patients, a high acylcarnitine/free-carnitine ratio is usually found in plasma. Patients undergoing maintenance HD, usually present with plasma carnitine insufficiency, due to accumulation of metabolic intermediates combined with impaired carnitine biosynthesis, reduced protein intake and increased removal via HD. Plasma carnitine concentrations rapidly decrease to 40% of baseline level during the dialysis session, with a slow restoration of the carnitine concentration during the interdialytic period, mainly from organs of storage (skeletal muscle). Dietary intake also plays an important role in carnitine homeostasis of HD patients since the prevalence of malnutrition ranges from 18% to 75% of these cases. This could differentially affect various body compartments, with clinical consequences such as impaired muscle function, decreased wound healing, altered ventilatory response, and abnormal immune function. Repeated hemodialytic treatments are associated with decreased carnitine stores in skeletal muscle. The administration of intravenous L-carnitine (LC) postdialysis replenishes the free carnitine removed from the blood and contributes to replenishment of muscle carnitine content. LC supplementation in selected uremic patients may yield clinical benefits by ameliorating several conditions, such as erythropoietin-resistant anemia, decreased cardiac performance, intradialytic hypotension, muscle symptoms, as well as impaired exercise and functional capacities. Furthermore, LC may positively influence the nutritional status of HD patients by promoting a positive protein balance, and by reducing insulin resistance and chronic inflammation, possibly through an effect on leptin resistance.

Carnitine: a nutritional, biosynthetic, and functional perspective

Carnitine status in humans is reported to vary according to body composition, gender, and diet. Plasma carnitine concentration positively correlates with the dietary intake of carnitine. The content of carnitine in foodstuff is based on old and inadequate methodology. Nevertheless, dietary carnitine is important. The molecular biology of the enzymes of carnitine biosynthesis has recently been accomplished. Carnitine biosynthesis requires pathways in different tissues and is an efficient system. Overall biosynthesis is determined by the availability of trimethyllysine from tissue proteins. Carnitine deficiency resulting from a defect in biosynthesis has yet to be reported. The role of carnitine in long-chain fatty acid oxidation is well defined. Recent evidence supports a role for the voltage-dependent anion channel in the transport of acyl-CoAs through the mitochondrial outer membrane. The mitochondrial outer membrane carnitine palmitoyltransferase-I in liver can be phosphorylated and when phosphorylated the sensitivity to malonyl-CoA is greatly decreased. This may explain the change in sensitivity of liver carnitine palmitoyltransferase-I observed during fasting and diabetes. Recently reported data clarify the role of carnitine and the carnitine transport system in the interplay between peroxisomes and mitochondrial fatty acid oxidation. Lastly, the buffering of the acyl-CoA/CoA coupled by carnitine reflects intracellular metabolism. This mass action effect underlies the use of carnitine as a therapeutic agent. In summary, these new observations help to further our understanding of the molecular aspects of carnitine in medicine.

L‐Carnitine and exercise tolerance in medium‐chain acyl‐coenzyme A dehydrogenase (MCAD) deficiency: A pilot study

Skeletal muscle function may be impaired in patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, but the value of L-carnitine in their long-term management is not clear. This study was designed as a pilot to examine the effects of L-carnitine on exercise tolerance in patients with MCAD deficiency. Four clinically asymoptomatic MCAD-deficient patients, aged 8 to 20 years, were studied. Incremental ramp exercise tests were carried out before and after 4 weeks' treatment with oral L-carnitine (100 mg/kg per day). During exercise without L-carnitine supplementation, plasma carnitine concentrations fell, associated with an increased excretion of urinary acylcarnitines, notably acetylcarnitine, hexanoylcarnitine and octanoylcarnitine. L-carnitine treatment prevented this fall in plasma carnitine and resulted in greater increases in excretion of acylcarnitines. All four patients showed biologically significant improvement in peak oxygen uptake (peak VO2, 18-32% improvement), VO2 at a heart rate of 170 beats/min (15-23% improvement), VO2 at anaerobic threshold (27-42% improvement), and/or oxygen pulse (10-32% improvement). Exercise tolerance in MCAD-deficient patients may be improved by short-term L-carnitine supplementation. This may be the direct result of improved intramitochondrial homeostasis induced by L-carnitine in removing accumulating acyl moieties.

Effect of L-carnitine administration on the seminal characteristics of oligoasthenospermic stallions

The effect of orally administered l-carnitine on the quality of semen obtained from stallions with different semen qualities was investigated. Four stallions with proven fertility (high motility group, HM) and with normal seminal characteristics (>50% progressive motility and >80×106 spermatozoa/ml), and four questionable breeders (low motility group, LM) with <50% of sperm progressive motility and <80×106 spermatozoa/ml, received p.o. 20g of l-carnitine for 60 days. Blood and semen samples were collected before treatment (T0) and after 30 (T1) and 60 days (T2). Semen evaluation were performed on five consecutive daily ejaculates (n=120 ejaculates) and conventional semen analysis was carried out on each ejaculate, both at collection and after refrigeration for 24, 48, and 72h. Furthermore l-carnitine, acetylcarnitine, pyruvate, and lactate concentrations, and carnitine acetyltransferase activity (CAT) were determined both in raw semen and seminal plasma. There were an increase in progressive motile spermatozoa only in the LM group (26.8±12.9, 39.1±15.5, and 48.8±8.6 for T0, T1, and T2, respectively). Free seminal plasma carnitine concentration was higher in the LM group compared to the HM one. Both pyruvate and lactate were higher in the LM group. Raw semen and seminal plasma carnitine and acetylcarnitine levels correlate positively with both sperm concentration and progressive motility; moreover, acetylcarnitine content was positively correlated with total motile morphologically normal spermatozoa. In conclusion, oral administration of l-carnitine to stallions with questionable seminal characteristics may improve spermatozoa kinetics and morphological characteristics; whereas, it seem to be ineffective in normospermic animals.

Reference ranges for muscle carnitine concentration in children.

We investigated muscle and plasma carnitine concentrations in children to establish reference intervals for use following biopsy of skeletal muscle. The study comprised 50 children from newborns up to 14 years of age, all undergoing elective surgery. They were divided into six age groups, the youngest 0-2 days and the oldest 11-14 years. The samples were taken at the beginning of surgery. Gestational age was a major determinant of the total muscle carnitine concentration in newborns (Spearman's r(s) = 0.692, P < 0.01). This concentration was low during the first year, but subsequently did not differ between age groups. In neonates the median value (range) for total carnitine concentration in skeletal muscle was 5.9 (2.2-15.9) micro mol/g dry weight and the free to total carnitine ratio was 62 (31-81)%. In children 1-12 months old the corresponding figures were 6.0 (3.5-7.9) micro mol/g dry weight and 51 (28-71)% and in those 1-14 years they were 12.1 (6.6-17.4) micro mol/g dry weight and 76 (42-92)%. This study shows that muscle carnitine concentrations in newborns are dependent on gestational age. The data suggest that there is an accretion of carnitine in skeletal muscle during the first year of life. Reference intervals are given.

Effect of L-carnitine supplementation on cardiac carnitine palmitoyltransferase activities and plasma carnitine concentrations in adriamycin-treated rats.

Adriamycin (ADR) inhibits the carnitine palmitoyl transferase (CPT) system and consequently the transport of long-chain fatty acids across mitochondrial membranes. l-Carnitine (CARN) plays a major role in fatty acid oxidation by translocating activated long-chain fatty acids into the matrix of mitochondria. CARN has been shown to be of benefit in certain cardiac conditions including cardiomyopathy and myocardial infarction. This study was devised to investigate the effect of CARN on altered CPT I and CPT II activity in the cardiomyopathy associated with ADR therapy. We also assessed the effect of CARN on the plasma free, total, and acylcarnitine concentrations. Four groups, each consisting of four male Sprague-Dawley rats, were studied: group 1(n = 4) was not given either ADR or CARN; group 2 (n = 4) was given ADR (15 and 20 mg/kg, respectively, cumulative dose) by i.p. injections for 1 and 2 wk; group 3 (n = 4) was given the same dose of ADR with CARN (200 mg/kg); and group 4 (n = 4) was given CARN (200 mg/kg). The activities of CPT I and CPT II in heart were significantly decreased in the ADR-treated rats (p < 0.05) in a dose-dependent manner. The reduced activities of CPT I and CPT II, inhibited by ADR, were not normalized by supplementation with CARN (p < 0.05). In rats supplemented with CARN alone, the activities of CPT I and CPT II were elevated approximately 50% above those of the control rats (p < 0.05). ADR treatment resulted in elevation of plasma free and total CARN concentrations (p < 0.05). Supplementation with CARN did not effect the increased plasma CARN concentrations resulting from ADR treatment (p < 0.05). This study supports the concept that ADR toxicity results from the inhibition of both CPT I and CPT II activities and that one of the causes of ADR-induced cardiomyopathy is a result of globally impaired fatty acid oxidation.

Neonatal blood carnitine concentrations: normative data by electrospray tandem mass spectometry.

Despite a number of published reports, there is limited information about carnitine metabolism in the newborn. To establish normative data, we analyzed whole-blood carnitine concentrations in 24,644 newborns at age 1.85 +/- 0.95 d and umbilical cord whole blood and plasma carnitine concentrations in 50 full-term newborns. Total carnitine (TC), free carnitine (FC), and acylcarnitine (AC) were measured by electrospray tandem mass spectrometry. AC/FC ratios were derived from these measurements. The entire cohort was stratified according to TC values into a middle TC group representing 90% of the population and lower and upper TC groups representing 5% of the population, respectively. Normative data were derived from the middle TC group of full-term infants (N = 19,595). TC was 72.42 +/- 20.75 microM, FC was 44.94 +/- 14.99 microM, AC was 27.48 +/- 8.05 microM, and AC/FC ratio was 0.64 +/- 0.19 (+/-SD). These values differed significantly from umbilical cord whole blood TC values of 31.27 +/- 10.54 microM determined in 50 samples. No meaningful correlation was found between TC and gestational age or birth weight in any group. In controlled analyses, prematurity was not associated with TC levels, whereas low birth weight (<2500 g) and male sex were significantly associated with higher TC levels. The association of low birth weight with higher TC values may be related to decreased tissue carnitine uptake. The sex effect may be related to hormonal influences on carnitine metabolism. Our study provides normative data of carnitine values measured by the highly precise method of electrospray tandem mass spectrometry in a large cohort of newborns and provides the basis for future studies of carnitine metabolism in health and disease states during the neonatal period.

Carnitina libre y total en sangre de cordón umbilical

Se han encontrado concentraciones anormales de carnitina en niños asociadas con deficiencias primaria y secundaria de carnitina, con disminución de las concentraciones en sangre y tejidos, así como niveles elevados en algunos errores innatos del metabolismo. El presente estudio tiene como objetivo la obtención de valores de referencia para carnitina libre y total en sangre de cordón umbilical, como herramienta en el diagnóstico temprano de errores innatos del metabolismo. Se analizaron mediante espectrometría de masas en tándem (MS/MS) 130 muestras de sangre de cordón umbilical de nacimientos con embarazos a término y peso normal al nacer (78 niños y 52 niñas) de una población colombiana. No se encontró diferencia estadísticamente significativa dependiente del sexo del recién nacido. Reportamos valores de referencia para carnitina libre y total en sangre de cordón umbilical de 18,5 ± 3,4 µmol/L y 20,9 ± 4,2 µmol/L respectivamente.

Pivalate-generating prodrugs and carnitine homeostasis in man.

Prodrugs that liberate pivalate (trimethylacetic acid) after hydrolysis have been developed to improve the bioavailability of therapeutic candidates. Catabolism of pivalate released by activation of a prodrug is limited in mammalian tissues. Pivalate can be activated to a coenzyme A thioester in cells. In humans, formation and urinary excretion of pivaloylcarnitine generated from pivaloyl-CoA is the major route of pivalate elimination. Because the total body carnitine pool is limited and can only slowly be replenished through normal diet or biosynthesis, treatment with large doses of pivalate prodrugs may deplete tissue carnitine content. Animal models and long-term treatment of patients with pivalate prodrugs have resulted in toxicity consistent with carnitine depletion. However, low plasma carnitine concentrations after pivalate prodrug exposure may not reflect tissue carnitine content and, thus, cannot be used as a surrogate for potential toxicity. The extent of tissue carnitine depletion will be dependent on the dose of pivalate, because carnitine losses may approximate the pivalate exposure on a stoichiometric basis. These concepts, combined with estimates of carnitine dietary intake and biosynthetic rates, can be used to estimate the impact of pivalate exposure on carnitine homeostasis. Thus, even in populations with altered carnitine homeostasis due to underlying conditions, the use of pivalate prodrugs for short periods of time is unlikely to result in clinically significant carnitine depletion. In contrast, long-term treatment with substantial doses of pivalate prodrugs may require administration of carnitine supplementation to avoid carnitine depletion.

Dilated cardiomyopathy in dystrophic epidermolysis bullosa: a lethal complication of epidermolysis bullosa

EDITOR: We read with interest the review article by Iohom and Lyons concerning their experience of patients with epidermolysis bullosa presenting for anaesthesia [1]. We would like to highlight respectfully an omission that, although infrequent, is a serious complication of dystrophic epidermolysis bullosa, and which has significant anaesthetic implications. In 1996, Melville and colleagues reported two cases of fatal dilated cardiomyopathy occurring in recessive dystrophic epidermolysis bullosa; both patients were malnourished and had severe growth problems [2]. It was suggested that the most likely cause for the cardiomyopathy was a micronutrient deficiency, most probably of selenium, since the serum selenium concentration was reduced in one of the two cases and in 14 of 25 other children with dystrophic epidermolysis bullosa. In 2000, Sidwell and colleagues [3], in a review, presented data from the same institution that had accumulated over the preceding 7 yr where patients with dystrophic epidermolysis bullosa were routinely screened by echocardiography for the development of dilated cardiomyopathy. They found that six of the 61 patients with dystrophic epidermolysis bullosa attending hospital developed dilated cardiomyopathy (four of whom had not been previously reported), and three of these subsequently died. In the children who died, there was a rapid deterioration in cardiac function resulting in death within a few months of the diagnosis of dilated cardiomyopathy being made. The cardiac status of two of the other patients had remained stable since this diagnosis, while the remaining patient showed a gradual decline in cardiac function but had not yet required specific therapy. In this report, they also measured the plasma concentrations of both total and free carnitine, and of selenium in the patients who had dilated cardiomyopathy and compared them to those who did not. Those patients who subsequently developed dilated cardiomyopathy had an initial carnitine concentration significantly lower than those who remained normal (P = 0.006). The plasma selenium concentrations were non-significantly lower in those with dilated cardiomyopathy. As a result of these findings, these authors advocate routinely screening patients with dystrophic epidermolysis bullosa for evidence of development of dilated cardiomyopathy. They also highlight the need to maintain adequate plasma carnitine concentrations and consider the need for early gastrostomy. We suggest that this serious and potentially fatal complication should be borne in mind by those asked to provide anaesthesia for these challenging patients, and that any patient with cardiovascular symptoms or signs should undergo echocardiographic investigation before anaesthesia. P. M. D. Cunnington St Helier Hospital, Carshalton; London, UK R. Addison Medway Maritime Hospital, Gillingham; Kent, UK

Assessment of plasma carnitine concentrations in relation to ceroid lipofuscinosis in Tibetan Terriers.

To determine whether the late onset form of inherited ceroid lipofuscinosis (CL) in Tibetan Terriers is accompanied by low plasma carnitine concentrations prior to the appearance of clinical signs. 129 healthy Tibetan Terriers, 12 Tibetan Terriers with CL, and 95 healthy purebred dogs of other breeds. After withholding food, blood samples were collected from all dogs into tubes containing EDTA. Blood samples were analyzed for plasma-free carnitine and acyl-carnitines concentrations. Neither the mean plasma total carnitine concentration nor the mean fraction of carnitine in the free form differed significantly between Tibetan Terriers with CL and healthy Tibetan Terriers. Among Tibetan Terriers and the general dog population, plasma carnitine concentration increased with age. Castrated males had an overall increase in plasma carnitine concentrations and variability, compared with sexually intact males. By comparison, plasma carnitine concentrations were not significantly different between spayed and sexually intact females. The mean plasma carnitine concentration in the Tibetan Terriers was approximately 22% higher than in the general population of healthy dogs of other breeds. Contrary to what is seen in early onset CL in English Setters and in humans with some forms of CL, plasma carnitine concentrations are not decreased in the late-onset disorder in Tibetan Terriers. Our large-scale study establishes reference range values for plasma carnitine concentrations in dogs as functions of age and sex that will be useful in evaluating potential carnitine deficiencies in other disorders in dogs.

Influence of L-Carnitine on Performance and Ruminal and Blood Metabolites of Grazing Calves and Finishing Lambs

<h2>ABSTRACT</h2> Three experiments were conducted to study the influence of level and type of L-carnitine (<b>LC</b>) on performance and rumiasl and plasma metabolites of weanling calves and finishing lambs. Weanling calves (84) grazing dormant dallisgrass-bermudagrass forage were fed a 20% CP supplement to provide 0, 0.5, 1, or 2 g of ruminally unprotected (<b>RUP</b>) LC per calf daily in Exp. 1. There was a linear increase (P=0.01) and cubic response (P=0.03) to RUP LC in growth rate and quadratic changes (P=0.01) in plasma ammonia N (<b>PAN</b>) and plasma urea N (<b>PUN</b>). In Exp. 2, 32 lambs were individually fed 14% CP diets containing 0, 50, 100, or 200ppm RUP LC or ruminally protected (<b>RP</b>) LC in a 2 × 4 arrangement of treatments. Lambs gained BW faster (P=0.03) and more efficiently (P=0.07) as the LC level increased to 100ppm and then declined at 200ppm (quadratic response). Longissimus area decreased (P=0.03), and fat cover tended (P=0.15) to decline, at 50 and 100ppm LC and increased at 200ppm (linear and quadratic response). Ruminal ammonia N levels were reduced at 50ppm LC but increased at greater LC levels (linear, quadratic, and cubic response, P=0.02). Plasma carnitine concentrations increased (P=0.01) as the dietary level of LC increased. Protected LC was more effective than RUP LC in increasing growth rate (P=0.06) and reducing PAN (P=0.1). In Exp. 3, 16 wether and 16 ewe lambs were individually fed corn-based or soybean hull-based diets with 0 or 100ppm RP LC in a 2 × 2 arrangement of treatments. Lambs fed RP LC gained BW faster and more efficiently (P=0.04) than lambs that were not fed LC. Lambs fed corn-based and soybean hull-based diets responded similarly to RP LC; however, performance was greater (P=0.03) for lambs fed the corn-based diet. Gender of lambs did not influence the response to diet or RP LC. Supplementing the diet with 100ppm RP LC reduced (P=0.01) ruminal pH and ammonia N. Plasma carnitine concentrations were increased (P=0.01), and PAN was decreased (P=0.04) by feeding 100ppm RP LC. Ruminnaly unprotected and RP LC were effective in improving growth rate in ruminants; the latter appeared to be more effective in finishing lambs. L-carnitine reduced ruminal ammonia N and plasma glucose and, in some cases, PAN and PUN.

Dietary l-Carnitine Supplementation in Obese Cats Alters Carnitine Metabolism and Decreases Ketosis during Fasting and Induced Hepatic Lipidosis

This study was designed to determine whether dietary carnitine supplement could protect cats from ketosis and improve carnitine and lipid metabolism in experimental feline hepatic lipidosis (FHL). Lean spayed queens received a diet containing 40 (CL group, n = 7) or 1000 (CH group, n = 4) mg/kg of L-carnitine during obesity development. Plasma fatty acid, beta-hydroxybutyrate and carnitine, and liver and muscle carnitine concentrations were measured during experimental induction of FHL and after treatment. In control cats (CL group), fasting and FHL increased the plasma concentrations of fatty acids two- to threefold (P < 0.0001) and beta-hydroxybutyrate > 10-fold (from a basal 0.22 +/- 0.03 to 1.70 +/- 0.73 after 3 wk fasting and 3.13 +/- 0.49 mmol/L during FHL). In carnitine-supplemented cats, these variables increased significantly (P < 0.0001) only during FHL (beta-hydroxybutyrate, 1.42 +/- 0.17 mmol/L). L-Carnitine supplementation significantly increased plasma, muscle and liver carnitine concentrations. Liver carnitine concentration increased dramatically from the obese state to FHL in nonsupplemented cats, but not in supplemented cats, which suggests de novo synthesis of carnitine from endogenous amino acids in control cats and reversible storage in supplemented cats. These results demonstrate the protective effect of a dietary L-carnitine supplement against fasting ketosis during obesity induction. Increasing the L-carnitine level of diets in cats with low energy requirements, such as after neutering, and a high risk of obesity could therefore be recommended.

Metabolic effects in neonates receiving intravenous medium‐chain triglycerides

The effects of two lipid emulsions, one with 50% each of medium‐chain and long‐chain triglycerides, and a long‐chain triglycerides lipid emulsion as a control, were evaluated for lipid and carnitine metabolism and respiratory quotient when given to neonates after major surgery during a short period of total parenteral nutrition. Each group included 10 neonates, and all tolerated the total parenteral nutrition well. The relative contents of linoleic acid and α‐linolenic acid increased in all lipid esters in plasma and adipose tissue in both groups, indicating that the content of these fatty acids is sufficient even in the medium‐chain triglycerides emulsion. The serum concentration of ketones was within normal limits. Free fatty acids in plasma did not increase in either group. The total plasma carnitine concentration decreased in both groups but the distribution of free carnitine and acylcarnitine did not change. The total muscle carnitine did not change significantly but the ratio of acylcarnitine to free carnitine tended to increase in muscle in the treatment group, probably an effect of the medium‐chain triglyceride supplementation. Conclusions: The two groups displayed the same fatty acid pattern in plasma and adipose tissue and the same respiratory quotient during the treatment period. Regarding carnitine status, essentially the same changes were seen in the two groups. However, discrete changes were seen in muscle tissue in the treatment group.

Plasma and liver carnitine status of children with chronic liver disease and cirrhosis.

Carnitine is an essential cofactor in the transfer of long-chain fatty acids across the inner mitochondrial membrane for oxidation. As its synthesis is performed in the liver, alterations in carnitine metabolism is expected in liver diseases, especially in cirrhosis. In this study, we investigated plasma and liver carnitine concentrations of 68 children with chronic liver disease, 36 of whom had cirrhosis as well. Carnitine level was determined by enzymatic method. Plasma and liver carnitine concentrations were not correlated. Mean plasma carnitine level of cirrhotic children was significantly lower than that of the control group (P<0. 0001). While there was no difference between liver carnitine concentrations of children with chronic liver disease and cirrhosis (P>0.05), mean plasma level of cirrhotics were lower (P<0.05). Plasma carnitine was correlated with albumin, triglyceride and gamma glutamyl transpeptidase (GGT) in patients with chronic liver disease (P<0.05). Liver carnitine was correlated with GGT in cirrhotic patients (P<0.005). Children with malnutrition had higher plasma and liver carnitine levels (P<0.05). The highest plasma and liver carnitine levels were detected in children with biliary atresia and criptogenic cirrhosis, respectively. Both the lowest plasma and liver carnitine levels were detected in Wilson's disease. Children with cirrhosis have low plasma carnitine concentrations. This finding is prominent in children with Wilson's disease. As carnitine is an essential factor in lipid metabolism, the carnitine supplementation for patients with cirrhosis in childhood, especially with Wilson's disease, seems to be mandatory.

Metabolic and structural abnormalities in dogs with early left ventricular dysfunction induced by incessant tachycardia.

To assess morphologic and metabolic abnormalities in dogs with early left ventricular dysfunction (ELVD) induced by rapid right ventricular pacing (RRVP). 7 Beagles. Plasma carnitine concentrations were measured before and after development of ELVD induced by RRVP. At the same times, transvenous endomyocardial biopsy was performed, and specimens were submitted for determination of myocardial carnitine concentrations and histologic, morphometric, and ultrastructural examination. In 4 dogs in which baseline plasma total carnitine concentration was normal, RRVP induced a decrease in myocardial total and free carnitine concentrations and an increase in myocardial esterified carnitine concentration. In 3 dogs in which baseline plasma total carnitine concentration was low, plasma and myocardial carnitine concentrations were unchanged after pacing. Structural changes associated with pacing included perinuclear vacuolization in 3 dogs. Morphometric analyses indicated there was a decrease in myofiber cross-sectional diameter and area following pacing. Electron microscopy revealed changes in myofibrils and mitochondria following pacing. Results indicated that moderate to severe alterations in myocyte cytoarchitecture are present in dogs with ELVD induced by RRVP and that in dogs with normal plasma carnitine concentrations, myocardial carnitine deficiency may be a biochemical marker of ELVD. Results also indicated that transvenous endomyocardial biopsy can be used to evaluate biochemical and structural myocardial changes in dogs with cardiac disease.

Plasma Carnitine Levels of Pregnant Adolescents in Labor

Study Objective: To determine the concentration of plasma carnitine (total, free, and acylcarnitine) during the delivery of uncomplicated pregnancies of adolescent women. To investigate the relationship between maternal and neonatal levels of carnitine and to compare these carnitine levels between pregnant and nonpregnant adolescents. Design: Samples of maternal and umbilical blood were taken at the time of delivery and examined for the determination of the carnitine—total, free, and acylcarnitine—concentration by the use of an enzymatic-radioisotope method. Twenty-two cases of uncomplicated adolescent pregnancies with a normal labor and without perinatal complications were examined. The plasma level of carnitine was also examined in 17 healthy nonpregnant adolescent women, which constituted the control group. Results: The concentrations of plasma carnitine in adolescent pregnancies at the time of delivery were calculated at 19.6 ± 2.15 μMol/L (total), 12.62 ± 1.31 μMol/L (free), and 6.98 ± 1.55 μMol/L (acylcarnitine). The corresponding mean values in umbilical plasma were 30.31 ± 2.06 μMol/L, 22.39 ± 1.64 μMol/L, and 7.92 ± .96 μMol/L. There is a statistically significant difference between the mean values in maternal and umbilical plasma ( P < .0001 for total and free carnitine and P < .012 for acylcarnitine). The correlations between adolescent pregnant women and their infants as regards total, free, and acylcarnitine were 0.137, 0.018, and 0.33, respectively. Neither of these parameters was statistically significant. The corresponding mean values of carnitine in nonpregnant adolescent women were statistically significantly higher than in adolescent pregnant women (total carnitine: 41.61 ± 3.09 μMol/L, free: 31.39 ± 2.81 μMol/L, acylcarnitine: 10.22 ± 1.88 μMol/L, P < .0001). Conclusions: The concentration of plasma carnitine at the end of adolescent pregnancy is low compared to the levels of umbilical carnitine at birth and that found in nonpregnant adolescent women. It may not have an obvious impact on the utilization of fatty acids in an uncomplicated full-term pregnancy; however, it suggests the potential risk for neonatal fatty-acid oxidation in a preterm or complicated pregnancy.

Intravenous l-carnitine increases plasma carnitine, reducesfatigue, and may preserve exercise capacity in hemodialysis patients

Exercise capacity in patients with end-stage renal disease (ESRD) remains impaired despite correction ofanemia. Carnitine insufficiency may contribute to impaired exercise and functional capacities in patients with ESRD. Two randomized placebo-controlled trials were conducted to test whether intravenous l-carnitine improves exercise capacity (assessed by maximal rate of oxygen consumption [VO2max]) and quality of life (measured by the Kidney Disease Questionnaire [KDQ]) in patients with ESRD. In study A, patients were administered l.-carnitine, 20 mg/kg (n = 28), or placebo (n = 28) intravenously at the conclusion of each thrice-weekly dialysis session for 24 weeks. In study B, a dose-ranging study, patients were administered intravenous l-carnitine, 10 mg/kg (n = 32), 20 mg/kg (n = 30), or 40 mg/kg (n = 32), or placebo (n = 33) as in study A. The prospective primary statistical analysis evaluated changes in VO2max in each study and specified that changes in the KDQ were assessed only in the combined populations. l-Carnitine supplementation increased plasma carnitine concentrations, but did not affect VO2max in either study. Because change in VO2max showed significant heterogeneity, a secondary analysis using a mixture of linear models approach on the combined study populations was performed. l-Carnitine therapy (combined all doses) was associated with a statistically significant smaller deterioration in VO2max (-0.88 ± 0.26 versus −0.05 ± 0.19 mL/kg/min, placebo versus l-carnitine, respectively; P = 0.009). l-Carnitine significantly improved the fatigue domain of the KDQ after 12 (P = 0.01) and 24 weeks (P = 0.03) of treatment compared with placebo using the primary analysis but did not significantly affect the total score (P = 0.10) or other domains of the instrument (P > 0.11). Carnitine was well tolerated, and no drug-related adverse effects were identified. Intravenous l-carnitine treatment increased plasma carnitine concentrations, improved patient-assessed fatigue, and may prevent the decline in peak exercise capacity in hemodialysis patients. VO2max in the primary analysis and other assessed end points were unaffected by carnitine therapy.

Effect of various levels of supplementation with sodium pivalate on tissue carnitine concentrations and urinary excretion of carnitine in the rat

In previous studies, sodium pivalate has been administered to rats in their drinking water (20 mmoles/L; equivalent to 0.3% of the diet) as a way to lower the concentration of carnitine in tissues and to produce a model of secondary carnitine deficiency. Although this level of supplementation results in a marked decrease in carnitine concentration in a variety of tissues, it does not produce the classical signs of carnitine deficiency (i.e., decreased fatty acid oxidation and ketogenesis). The present study was designed (1) to determine if increasing the level of pivalate supplementation (0.6, 1.0% of the diet) would further reduce the concentrations of total and free carnitine in rat tissues without altering growth or food intake, and (2) to examine the effect of length of feeding (4 vs. 8 weeks) on these variables. Male, Sprague-Dawley rats were randomly assigned to either a control (0.2% sodium bicarbonate) or experimental diet (0.3, 0.6, 1.0% sodium pivalate) for either four or eight weeks. Animals ( n = 6/group) were housed in metabolic cages; food and water were provided ad libitum throughout the study. Supplementation with sodium pivalate did not alter water intake or urine output. Ingestion of a diet containing 1.0% pivalic acid decreased food intake (g/day; P < 0.05), final body weight ( P < 0.007), and growth rate ( P < 0.001) after four weeks. The concentration of total carnitine in plasma, heart, liver, muscle, and kidney was reduced in all experimental groups ( P < 0.001), regardless of level of supplementation or length of feeding. The concentration of free carnitine in heart, muscle, and kidney was also reduced ( P < 0.001) in rats treated with pivalate for either four or eight weeks. The concentration of free carnitine in liver was reduced in animals supplemented with pivalate for eight weeks ( P < 0.05), but no effect was observed in livers from rats treated for four weeks. Excretion of total carnitine and short chain acylcarnitine in urine was increased in pivalate supplemented rats throughout the entire feeding period ( P < 0.001). Free carnitine excretion was increased during Weeks 1 and 2 ( P < 0.01), but began to decline during Week 3 in experimental groups. During Weeks 6 and 8, free carnitine excretion in pivalate supplemented rats was less than that of control animals ( P < 0.01). In summary, no further reduction in tissue carnitine concentration was observed when rats were supplemented with sodium pivalate at levels greater than 0.3% of the diet. Food intake (g/day) and growth were decreased in rats fed a diet containing 1.0% sodium pivalate. These data indicate that maximal lowering of tissue carnitine concentrations is achieved by feeding diets containing 0.3% sodium pivalate or less.

Effects of L-carnitine on nitrogen retention and blood metabolites of growing steers and performance of finishing steers.

Two experiments were conducted to evaluate L-carnitine supplementation to cattle fed grain-based diets. In Exp. 1, seven Angus-cross steers (216 kg) were used in a 7 x 4 incomplete Latin square experiment to evaluate the effects of supplemental L-carnitine on N balance and blood metabolites. Steers were fed a corn-based diet (17.5% CP) at 2.5% of BW. Treatments were 0, 0.25, 0.5, 1.0, 1.5, 2.0, and 3.0 g/d of supplemental carnitine. The 18-d periods included 13 d for adaptation and 5 d for collection of feces and urine. Blood was collected before feeding and 3 and 6 h after feeding on d 18 of each period. Dry matter intakes tended to be highest when 1.5 g/d of carnitine was supplied, but N retention was not affected by carnitine and averaged 29.3 g/d. Plasma carnitine concentrations and urinary excretion increased with increasing carnitine supply, indicating that at least some of the carnitine escaped ruminal degradation and was absorbed by the steers. Plasma concentrations of NEFA demonstrated a treatment x time interaction; they decreased linearly in response to carnitine before feeding but increased linearly in response to carnitine at 6 h after feeding. Serum insulin and plasma glucagon, IGF-I, cholesterol, triglyceride, and amino acids were not affected by carnitine. Plasma concentrations of glucose, glycerol, urea, and beta-hydroxybutyrate all were increased by some of the levels of carnitine supplementation, but results for these measurements did not follow easily described patterns and seemed to be related to differences in DMI. In Exp. 2, 95 crossbred steers (357 kg initial BW) were fed finishing diets (14.5% CP) for 129 d. Diets were based on steam-flaked corn and contained 6% alfalfa and 4% tallow. Feed intakes, gains, and feed efficiencies were not affected by supplementation with 2 g/d L-carnitine. However, steers receiving L-carnitine tended to have fatter carcasses, as indicated by tendencies (P < 0.2) for thicker backfat, higher marbling scores, and higher yield grades. In conclusion, carnitine supplementation did not alter lean deposition in growing steers but it did alter plasma NEFA concentrations of growing steers fed a corn-based diet and also seemed to increase fat deposition in finishing cattle.