RARE DISEASE
Fatty acid oxidation and ketogenesis disorder with dilated cardiomyopathy
Fatty acid oxidation and ketogenesis disorder with dilated cardiomyopathy
Fatty acid oxidation and ketogenesis disorder with dilated cardiomyopathy
Drug discovery
0
drugs
With orphan designations
Overview
Fatty acid oxidation and ketogenesis disorders impair mitochondrial energy production from long-chain fatty acids, leading to systemic energy deficits and toxic metabolite accumulation. In disorders like VLCAD, LCHAD, and TFPD deficiencies, cardiac muscle energy deprivation manifests as dilated cardiomyopathy, particularly in neonatal and infantile presentations. These crises are triggered by fasting or metabolic stress, causing hypoketotic hypoglycemia, rhabdomyolysis, and acute cardiac decompensation [1][2][14].
Burden
Categories: rare cardiac diseases, rare genetic diseases, rare transplant-related disorders
Research Papers
5 drug discovery papers about Fatty acid oxidation and ketogenesis disorder with dilated cardiomyopathy, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
5 drug discovery papers about Fatty acid oxidation and ketogenesis disorder with dilated cardiomyopathy, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2023-12-06 | The changes of cardiac energy metabolism with sodium-glucose transporter 2 inhibitor therapy
To investigate the specific effects of s odium-glucose transporter 2 inhibitor (SGLT2i) on cardiac energy metabolism.A systematic literature search was conducted in eight databases. The retrieved studies were screened according to the inclusion and exclusion criteria, and relevant information was extracted according to the purpose of the study. Two researchers independently screened the studies, extracted information, and assessed article quality.The results of the 34 included studies (including 10 clinical and 24 animal studies) showed that SGLT2i inhibited cardiac glucose uptake and glycolysis, but promoted fatty acid (FA) metabolism in most disease states. SGLT2i upregulated ketone metabolism, improved the structure and functions of myocardial mitochondria, alleviated oxidative stress of cardiomyocytes in all literatures. SGLT2i increased cardiac glucose oxidation in diabetes mellitus (DM) and cardiac FA metabolism in heart failure (HF). However, the regulatory effects of SGLT2i on cardiac FA metabolism in DM and cardiac glucose oxidation in HF varied with disease types, stages, and intervention duration of SGLT2i.SGLT2i improved the efficiency of cardiac energy production by regulating FA, glucose and ketone metabolism, improving mitochondria structure and functions, and decreasing oxidative stress of cardiomyocytes under pathological conditions. Thus, SGLT2i is deemed to exert a benign regulatory effect on cardiac metabolic disorders in various diseases.https://www.crd.york.ac.uk/, PROSPERO (CRD42023484295).
2023-07-05 | Metabolic Approaches for the Treatment of Dilated Cardiomyopathy
In dilated cardiomyopathy (DCM), where the heart muscle becomes stretched and thin, heart failure (HF) occurs, and the cardiomyocytes suffer from an energetic inefficiency caused by an abnormal cardiac metabolism. Although underappreciated as a potential therapeutic target, the optimal metabolic milieu of a failing heart is still largely unknown and subject to debate. Because glucose naturally has a lower P/O ratio (the ATP yield per oxygen atom), the previous studies using this strategy to increase glucose oxidation have produced some intriguing findings. In reality, the vast majority of small-scale pilot trials using trimetazidine, ranolazine, perhexiline, and etomoxir have demonstrated enhanced left ventricular (LV) function and, in some circumstances, myocardial energetics in chronic ischemic and non-ischemic HF with a reduced ejection fraction (EF). However, for unidentified reasons, none of these drugs has ever been tested in a clinical trial of sufficient size. Other pilot studies came to the conclusion that because the heart in severe dilated cardiomyopathy appears to be metabolically flexible and not limited by oxygen, the current rationale for increasing glucose oxidation as a therapeutic target is contradicted and increasing fatty acid oxidation is supported. As a result, treating metabolic dysfunction in HF may benefit from raising ketone body levels. Interestingly, treatment with sodium-glucose cotransporter-2 inhibitors (SGLT2i) improves cardiac function and outcomes in HF patients with or without type 2 diabetes mellitus (T2DM) through a variety of pleiotropic effects, such as elevated ketone body levels. The improvement in overall cardiac function seen in patients receiving SGLT2i could be explained by this increase, which appears to be a reflection of an adaptive process that optimizes cardiac energy metabolism. This review aims to identify the best metabolic therapeutic approach for DCM patients, to examine the drugs that directly affect cardiac metabolism, and to outline all the potential ancillary metabolic effects of the guideline-directed medical therapy. In addition, a special focus is placed on SGLT2i, which were first studied and prescribed to diabetic patients before being successfully incorporated into the pharmacological arsenal for HF patients.
2006-05-17 | Parenteral and enteral metabolism of anaplerotic triheptanoin in normal rats
A new chronic treatment for inherited disorders of long-chain fatty acid oxidation involves administering up to one-third of dietary calories as triheptanoin, a medium-odd-chain triglyceride (Roe CR, Sweetman L, Roe DS, David F, and Brunengraber H. J Clin Invest 110: 259–269, 2002). Heptanoate and C 5 -ketone bodies derived from its partial oxidation in liver are precursors of anaplerotic propionyl-CoA in peripheral tissues. It was hypothesized that increasing anaplerosis in peripheral tissues would boost energy production. In the present study, we tested the potential of a triheptanoin emulsion as an intravenous nutrient. Normal rats were infused with triheptanoin intravenously or intraduodenally at up to 40% of caloric requirement. The blood concentration ratio (heptanoate/C 5 -ketone bodies) was high with intravenous and low with intraduodenal triheptanoin infusion. During intravenous infusion of triheptanoin, lipolysis was stimulated but appeared compensated by fatty acid reesterification. During intraduodenal infusion of triheptanoin, lipolysis was not stimulated. Our data support the hypothesis that intravenous triheptanoin could be used to treat decompensated patients with long-chain fatty acid oxidation disorders.
1983-05-01 | Hypoglycemia, Hepatic Dysfunction, Muscle Weakness, Cardiomyopathy, Free Carnitine Deficiency and Long-Chain Acylcarnitine Excess Responsive to Medium Chain Triglyceride Diet
Summary: Fraternal twins who had fasting hypoglycemia, hypoketonemia, muscle weakness, and hepatic dysfunction are reported. The hepatic dysfunction occurred only during periods of caloric deprivation. The surviving patient developed a cardiomyopathy. In this sibling, muscle weakness and cardiomyopathy were markedly improved by a diet high in medium chain triglycerides. There was a marked deficiency of muscle total carnitine and a mild deficiency of hepatic total carnitine. Unlike patients with systemic carnitine deficiency, serum and muscle long-chain acylcarnitine were elevated and renal reabsorption of carnitine was normal. It was postulated that the defect in long-chain fatty acid oxidation in this disorder is caused by an abnormality in the mitochondrial acylcarnitine transport. Detailed studies of the cause of the hypoglycemia revealed that insulin, growth hormone, cortisol, and glucagon secretion were appropriate and that it is unlikely that there was a major deficiency of a glycolytic or gluconeogenic enzyme. Glucose production and alanine conversion to glucose were in the low normal range when compared to normal children in the postabsorptive state. The hypoglycemia in our patients was probably due to a modest increase in glucose consumption, secondary to the decreased oxidation of fatty acids and ketones, alternate fuels which spare glucose utilization, plus a modest decrease in hepatic glucose production secondary to decreased available hepatic energy substrates.
1982-11-01 | Carnitine deficiency presenting as familial cardiomyopathy: A treatable defect in carnitine transport
We studied a boy who presented at age 3 1/2 years with cardiomegaly, a distinctive electrocardiogram, and a history of a brother dying with cardiomyopathy. From age 3 1/2 to 5 years, cardiac disease progressed, resulting in intractable congestive heart failure. Skeletal muscle weakness developed and a muscle biopsy showed lipid myopathy. Muscle and plasma carnitine were reduced to 2 and 10% of the normal mean values, respectively. Therapy with l-carnitine (174 mg/kg/day) was begun at age 5 1/2 years and continued to the present (age 6 1/2 years). The cardiac disease has resolved and the muscle strength has returned to normal. Plasma carnitine concentrations have risen to the low-normal range, while urinary carnitine excretion has increased to values which are 30 times normal. The renal clearance of carnitine exceeds normal at all plasma concentrations and plasma carnitine values do not change acutely after an oral carnitine load. These results suggest that there is a distinct form of carnitine deficiency which presents as cardiomyopathy and may be successfully treated with l-carnitine. A defect in renal and possibly gastrointestinal transport of carnitine is a likely cause of this patient's disorder. We studied a boy who presented at age 3 1/2 years with cardiomegaly, a distinctive electrocardiogram, and a history of a brother dying with cardiomyopathy. From age 3 1/2 to 5 years, cardiac disease progressed, resulting in intractable congestive heart failure. Skeletal muscle weakness developed and a muscle biopsy showed lipid myopathy. Muscle and plasma carnitine were reduced to 2 and 10% of the normal mean values, respectively. Therapy with l-carnitine (174 mg/kg/day) was begun at age 5 1/2 years and continued to the present (age 6 1/2 years). The cardiac disease has resolved and the muscle strength has returned to normal. Plasma carnitine concentrations have risen to the low-normal range, while urinary carnitine excretion has increased to values which are 30 times normal. The renal clearance of carnitine exceeds normal at all plasma concentrations and plasma carnitine values do not change acutely after an oral carnitine load. These results suggest that there is a distinct form of carnitine deficiency which presents as cardiomyopathy and may be successfully treated with l-carnitine. A defect in renal and possibly gastrointestinal transport of carnitine is a likely cause of this patient's disorder.
small molecules
2023-12-06 | The changes of cardiac energy metabolism with sodium-glucose transporter 2 inhibitor therapy
To investigate the specific effects of s odium-glucose transporter 2 inhibitor (SGLT2i) on cardiac energy metabolism.A systematic literature search was conducted in eight databases. The retrieved studies were screened according to the inclusion and exclusion criteria, and relevant information was extracted according to the purpose of the study. Two researchers independently screened the studies, extracted information, and assessed article quality.The results of the 34 included studies (including 10 clinical and 24 animal studies) showed that SGLT2i inhibited cardiac glucose uptake and glycolysis, but promoted fatty acid (FA) metabolism in most disease states. SGLT2i upregulated ketone metabolism, improved the structure and functions of myocardial mitochondria, alleviated oxidative stress of cardiomyocytes in all literatures. SGLT2i increased cardiac glucose oxidation in diabetes mellitus (DM) and cardiac FA metabolism in heart failure (HF). However, the regulatory effects of SGLT2i on cardiac FA metabolism in DM and cardiac glucose oxidation in HF varied with disease types, stages, and intervention duration of SGLT2i.SGLT2i improved the efficiency of cardiac energy production by regulating FA, glucose and ketone metabolism, improving mitochondria structure and functions, and decreasing oxidative stress of cardiomyocytes under pathological conditions. Thus, SGLT2i is deemed to exert a benign regulatory effect on cardiac metabolic disorders in various diseases.https://www.crd.york.ac.uk/, PROSPERO (CRD42023484295).
2023-07-05 | Metabolic Approaches for the Treatment of Dilated Cardiomyopathy
In dilated cardiomyopathy (DCM), where the heart muscle becomes stretched and thin, heart failure (HF) occurs, and the cardiomyocytes suffer from an energetic inefficiency caused by an abnormal cardiac metabolism. Although underappreciated as a potential therapeutic target, the optimal metabolic milieu of a failing heart is still largely unknown and subject to debate. Because glucose naturally has a lower P/O ratio (the ATP yield per oxygen atom), the previous studies using this strategy to increase glucose oxidation have produced some intriguing findings. In reality, the vast majority of small-scale pilot trials using trimetazidine, ranolazine, perhexiline, and etomoxir have demonstrated enhanced left ventricular (LV) function and, in some circumstances, myocardial energetics in chronic ischemic and non-ischemic HF with a reduced ejection fraction (EF). However, for unidentified reasons, none of these drugs has ever been tested in a clinical trial of sufficient size. Other pilot studies came to the conclusion that because the heart in severe dilated cardiomyopathy appears to be metabolically flexible and not limited by oxygen, the current rationale for increasing glucose oxidation as a therapeutic target is contradicted and increasing fatty acid oxidation is supported. As a result, treating metabolic dysfunction in HF may benefit from raising ketone body levels. Interestingly, treatment with sodium-glucose cotransporter-2 inhibitors (SGLT2i) improves cardiac function and outcomes in HF patients with or without type 2 diabetes mellitus (T2DM) through a variety of pleiotropic effects, such as elevated ketone body levels. The improvement in overall cardiac function seen in patients receiving SGLT2i could be explained by this increase, which appears to be a reflection of an adaptive process that optimizes cardiac energy metabolism. This review aims to identify the best metabolic therapeutic approach for DCM patients, to examine the drugs that directly affect cardiac metabolism, and to outline all the potential ancillary metabolic effects of the guideline-directed medical therapy. In addition, a special focus is placed on SGLT2i, which were first studied and prescribed to diabetic patients before being successfully incorporated into the pharmacological arsenal for HF patients.
2006-05-17 | Parenteral and enteral metabolism of anaplerotic triheptanoin in normal rats
A new chronic treatment for inherited disorders of long-chain fatty acid oxidation involves administering up to one-third of dietary calories as triheptanoin, a medium-odd-chain triglyceride (Roe CR, Sweetman L, Roe DS, David F, and Brunengraber H. J Clin Invest 110: 259–269, 2002). Heptanoate and C 5 -ketone bodies derived from its partial oxidation in liver are precursors of anaplerotic propionyl-CoA in peripheral tissues. It was hypothesized that increasing anaplerosis in peripheral tissues would boost energy production. In the present study, we tested the potential of a triheptanoin emulsion as an intravenous nutrient. Normal rats were infused with triheptanoin intravenously or intraduodenally at up to 40% of caloric requirement. The blood concentration ratio (heptanoate/C 5 -ketone bodies) was high with intravenous and low with intraduodenal triheptanoin infusion. During intravenous infusion of triheptanoin, lipolysis was stimulated but appeared compensated by fatty acid reesterification. During intraduodenal infusion of triheptanoin, lipolysis was not stimulated. Our data support the hypothesis that intravenous triheptanoin could be used to treat decompensated patients with long-chain fatty acid oxidation disorders.
1983-05-01 | Hypoglycemia, Hepatic Dysfunction, Muscle Weakness, Cardiomyopathy, Free Carnitine Deficiency and Long-Chain Acylcarnitine Excess Responsive to Medium Chain Triglyceride Diet
Summary: Fraternal twins who had fasting hypoglycemia, hypoketonemia, muscle weakness, and hepatic dysfunction are reported. The hepatic dysfunction occurred only during periods of caloric deprivation. The surviving patient developed a cardiomyopathy. In this sibling, muscle weakness and cardiomyopathy were markedly improved by a diet high in medium chain triglycerides. There was a marked deficiency of muscle total carnitine and a mild deficiency of hepatic total carnitine. Unlike patients with systemic carnitine deficiency, serum and muscle long-chain acylcarnitine were elevated and renal reabsorption of carnitine was normal. It was postulated that the defect in long-chain fatty acid oxidation in this disorder is caused by an abnormality in the mitochondrial acylcarnitine transport. Detailed studies of the cause of the hypoglycemia revealed that insulin, growth hormone, cortisol, and glucagon secretion were appropriate and that it is unlikely that there was a major deficiency of a glycolytic or gluconeogenic enzyme. Glucose production and alanine conversion to glucose were in the low normal range when compared to normal children in the postabsorptive state. The hypoglycemia in our patients was probably due to a modest increase in glucose consumption, secondary to the decreased oxidation of fatty acids and ketones, alternate fuels which spare glucose utilization, plus a modest decrease in hepatic glucose production secondary to decreased available hepatic energy substrates.
1982-11-01 | Carnitine deficiency presenting as familial cardiomyopathy: A treatable defect in carnitine transport
We studied a boy who presented at age 3 1/2 years with cardiomegaly, a distinctive electrocardiogram, and a history of a brother dying with cardiomyopathy. From age 3 1/2 to 5 years, cardiac disease progressed, resulting in intractable congestive heart failure. Skeletal muscle weakness developed and a muscle biopsy showed lipid myopathy. Muscle and plasma carnitine were reduced to 2 and 10% of the normal mean values, respectively. Therapy with l-carnitine (174 mg/kg/day) was begun at age 5 1/2 years and continued to the present (age 6 1/2 years). The cardiac disease has resolved and the muscle strength has returned to normal. Plasma carnitine concentrations have risen to the low-normal range, while urinary carnitine excretion has increased to values which are 30 times normal. The renal clearance of carnitine exceeds normal at all plasma concentrations and plasma carnitine values do not change acutely after an oral carnitine load. These results suggest that there is a distinct form of carnitine deficiency which presents as cardiomyopathy and may be successfully treated with l-carnitine. A defect in renal and possibly gastrointestinal transport of carnitine is a likely cause of this patient's disorder. We studied a boy who presented at age 3 1/2 years with cardiomegaly, a distinctive electrocardiogram, and a history of a brother dying with cardiomyopathy. From age 3 1/2 to 5 years, cardiac disease progressed, resulting in intractable congestive heart failure. Skeletal muscle weakness developed and a muscle biopsy showed lipid myopathy. Muscle and plasma carnitine were reduced to 2 and 10% of the normal mean values, respectively. Therapy with l-carnitine (174 mg/kg/day) was begun at age 5 1/2 years and continued to the present (age 6 1/2 years). The cardiac disease has resolved and the muscle strength has returned to normal. Plasma carnitine concentrations have risen to the low-normal range, while urinary carnitine excretion has increased to values which are 30 times normal. The renal clearance of carnitine exceeds normal at all plasma concentrations and plasma carnitine values do not change acutely after an oral carnitine load. These results suggest that there is a distinct form of carnitine deficiency which presents as cardiomyopathy and may be successfully treated with l-carnitine. A defect in renal and possibly gastrointestinal transport of carnitine is a likely cause of this patient's disorder.
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