Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An 11-month-old girl presented acute episodes of hypoglycaemia and hepatic encephalopathy reminiscent of Reye syndrome and 3-hydroxydicarboxylic aciduria. The patient showed peculiar clinical manifestations of severe sensory-motor neuropathy, pigmentary retinopathy, and cardiomyopathy. She died of cardiac failure. Pathological studies of peripheral nerve showed signs of axonal neuropathy and demyelination. Enzymatic studies in cultured fibroblasts showed a deficiency of mitochondrial long-chain 3-hydroxyacyl-CoA-dehydrogenase. Peripheral nerve involvement and retinal pigmentary degeneration have as yet not been described in patients with proven defects of mitochondrial beta-oxidation.
 ...
PMID:Peripheral sensory-motor polyneuropathy, pigmentary retinopathy, and fatal cardiomyopathy in long-chain 3-hydroxy-acyl-CoA dehydrogenase deficiency. 153 53

Aortic aneurysm and stenosis are the most severe post-interventional complications after angioplasty of CoA and require regular follow-up. Twenty children (4 2/12-13 11/12 years old) underwent MRI within 3 months to 5 7/12 years after dilatation. All children were in a good state of health and showed no signs of heart failure. Three patients suffered from arterial hypertension; seven children showed hypertension on exertion. In six children, a resting gradient (minimal 20 mm Hg, maximal 40 mm Hg) between the upper and lower extremities could be measured. Four children showed pathological changes of the ascending aorta, three had a moderate ectasia, one had severe dilatation of more than 5 cm in diameter. In three cases, a circumscript aneurysm of the descending aorta was found. In many cases, there were mild changes in the aortic wall in the region of dilatation. In 12 children, there was a moderate spindly dilatation distal to the aortic isthmus, which, however, could be seen in the pre-dilatation angiography. After dilatation of CoA, several patients continue to have hypertension and pathological changes of the thoracic aorta. With regard to adequate therapy, regular controls are necessary. Besides routine examinations, MRI is an effective non invasive imaging method for the initial investigation and short-time follow-up evaluation of CoA.
 ...
PMID:[Clinical and magnetic resonance imaging follow-ups of children after dilatation of aortic isthmus stenosis (CoA)]. 227 69

Recent studies in patients with long-term heart failure have suggested that intrinsic abnormalities in skeletal muscle can contribute to the development of early lactic acidosis and fatigue during exercise. The present study provides an analysis of substrate and enzyme content, fiber typing, and capillarization in skeletal muscle biopsy samples obtained at rest from the vastus lateralis in 11 patients with long-term heart failure (left ventricular ejection fraction, 21 +/- 8%) and nine normal subjects. Patients demonstrated a reduced peak exercise oxygen consumption (13.0 +/- 3.3 ml/kg/min) when compared with normals (30.2 +/- 8.6 ml/kg/min, p less than 0.001) and had an accelerated rise in blood lactate levels during exercise. In mixed fiber skeletal muscle, total phosphorylase and glycolytic enzyme activities were not different in the two groups, whereas mitochondrial enzymes involved in terminal oxidation were decreased in patients as compared with normal subjects as indicated by reductions in succinate dehydrogenase (51 +/- 15 vs. 81 +/- 17 microM/g protein/min, p less than 0.001) and citrate synthetase (26 +/- 7 vs. 43 +/- 20 microM/g protein/min, p less than 0.05). 3-Hydroxyacyl-CoA-dehydrogenase, an important enzyme mediating beta-oxidation of fatty acids, was also reduced in patients as compared with normals (18 +/- 7 vs. 27 +/- 10 microM/g protein/min, p less than 0.05). There was no difference in high-energy phosphagens or lactate concentration of mixed muscle in the two groups, whereas glycogen content was decreased in patients (262 +/- 29 vs. 298 +/- 35 microM glucosyl units/kg dry wt, p = 0.01). Patients demonstrated a reduced percentage of slow twitch type I fibers (36 +/- 7% vs. 52 +/- 22%, p less than 0.05) and had a higher percentage of type IIb fast twitch fibers (24 +/- 9% vs. 11 +/- 12%, p = 0.02), which were smaller than the type IIb fibers seen in normal subjects (p less than 0.05). In patients, the number of capillaries per fiber was decreased for type I and type IIa fibers (both, p less than 0.03), but the ratio of capillaries to cross-sectional fiber area was not different for the two groups. These data demonstrate major alterations in skeletal muscle histology and biochemistry in patients with long-term heart failure, including fiber atrophy, a decrease in percentage of composition of type I fibers, and an increase in type IIb fibers accompanied by a decrease in oxidative enzyme capacity.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Skeletal muscle biochemistry and histology in ambulatory patients with long-term heart failure. 229 59

Chronic, rapid ventricular pacing produces congestive heart failure in dogs. The objectives of this study were to determine whether or not (i) in vitro myocardial biochemical alterations reported for heart failure by volume or pressure overload also occurred with heart failure due to rate overload, and (ii) these biochemical alterations were related to relevant in vivo cardiac physiologic alterations. We compared 27 dogs that were paced to advanced heart failure with 21 sham-operated dogs. Dogs with heart failure had 55% lower left ventricular ejection fraction (22.5 +/- 7.6 vs. 50.5 +/- 5.1%) and cardiac index (81 +/- 22 vs. 178 +/- 48 mL.min-1.kg-1), 287% higher pulmonary capillary wedge pressure (27.5 +/- 6.8 vs. 7.1 +/- 3.4 mmHg; 1 mmHg = 133.3 Pa), and 64% greater left ventricular diastolic area (18.4 +/- 3.7 vs. 11.2 +/- 1.3 cm2) (all p less than 0.05). Dogs with heart failure also had (i) 69% lower norepinephrine (232 +/- 139 vs. 747 +/- 220 ng/g protein), (ii) 25-50% lower activities of myofibrillar Ca ATPase (0.188 +/- 0.026 vs. 0.253 +/- 0.051 U/mg myofibrils), sarcoplasmic reticulum Ca-transport ATPase (0.155 +/- 0.074 vs. 0.288 +/- 0.043 U/mg membrane), and the glycolytic enzyme phosphofructokinase (33.4 +/- 10.0 and 47.7 +/- 15.8 U/g), (iii) 32% higher activity of the beta-oxidation enzyme hydroxyacyl-CoA dehydrogenase (11.43 +/- 1.48 vs. 8.67 +/- 1.70 U/g), and (iv) 60% higher activity of Krebs cycle oxoglutarate dehydrogenase (2.89 +/- 0.77 vs. 1.81 +/- 0.95 U/g) (all p less than 0.05). No differences between groups were observed for isozyme patterns and ATPase activity of myosin.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Rapid ventricular pacing of dogs to heart failure: biochemical and physiological studies. 232 42

Two sibs with the acute neonatal form of glutaric aciduria type II (deficient in vivo activity of multiple acyl-CoA dehydrogenases) are described. In the second case diagnosis was made prenatally on the basis of reduced oxidation of palmitate by cultured amniotic fluid cells. With prompt intervention in the neonatal period and a carefully controlled diet later, this second progressed well up to 4 months of age but died suddenly of cardiac failure, probably attributable to accumulation of fat. Neither patient showed any congenital morphological abnormality. Cultured fibroblasts from the second case showed a marked defect in the oxidation of a range of substrates requiring acyl-CoA dehydrogenases for their catabolism, but residual activity for some substrates was quite high. Large quantities of sarcosine were excreted in urine, again suggesting that the mutation leaves some residual dehydrogenation activity. Butyryl-, octanoyl- and palmitoyl-CoA dehydrogenases were present in essentially normal quantities in postmortem liver.
 ...
PMID:Glutaric aciduria type II: biochemical investigation and treatment of a child diagnosed prenatally. 620 79

The mammalian heart is normally well oxygenated and anaerobic glycolysis is extremely rare except for the production of extra ATP during extreme exercise like a marathon race. Anaerobic glycolysis plays a role when there is a serious impairment in coronary blood flow such as during heart attack and open heart surgery. The control of glycolysis in ischemic myocardial tissue appears to be extremely complex. During aerobic glycolysis, phosphofructokinase is the most important regulatory enzyme that controls the energy requirements of the cell. Under anaerobic conditions, however, glyceraldehyde-3-phosphate dehydrogenase becomes the key enzyme because it responds promptly to any changes in the essential supply of co-factors for oxidation. The conversion of pyruvate to acetyl CoA (aerobic metabolism) involves a series of chain reactions primarily catalyzed by pyruvate dehydrogenase complex which is situated at the cross roads between both aerobic and anaerobic glycolysis. It is important to remember that substrate utilization is carefully controlled by substrate availability. During aerobic metabolism, control mechanisms using fatty acids, lactate and glucose as energy substrates regulate the rate of ATP production according to energy demand. This precise mechanism is upset during ischemia and post-ischemic reperfusion for reasons discussed in this review. The demand for ATP can no longer be met by its supply because of severely reduced anaerobic glycolysis and significantly inhibited beta-oxidation of fatty acids. The impairment of bioenergetics is discussed in the context of several diseases such as cardiomyopathy, heart failure, diabetes, arrhythmias, cardiac surgery, heart-lung transplantation, and also in aging and oxidative stress. The regulation of energy metabolism in preconditioned heart is also discussed. Finally, methods used to preserve energy in ischemic myocardium are summarized and quantitation of the high-energy phosphates is discussed. This review challenges scientists to discover drugs which will stimulate energy supply during myocardial ischemia.
 ...
PMID:Bioenergetics, ischemic contracture and reperfusion injury. 880 94

Canine rapid ventricular pacing produces a low output cardiomyopathic state which is similar to dilated cardiomyopathy. In this study dogs were paced at 245 beats per minute (bpm) for 3-4 weeks until signs of heart failure were apparent. Unpaced dogs were used as controls. A previous study identified myocardial protein changes in the pH region 4-7 following ventricular pacing by using two-dimensional electrophoresis (2-DE) (Heinke et al., Electrophoresis 1998 19, 2021-2030). Many of these proteins were associated with mitochondria, energy metabolism within the cardiomyocyte, the cytoskeleton and calcium cycling. The present study aimed to examine the proteins migrating in the more basic region of the 2-DE pattern using immobilised pH gradient 3-10 strips to separate myocardial proteins. The expression of 31 proteins was altered in the paced myocardium: 21 were decreased and 10 increased. Following the identification of 23 of these spots by either amino acid compositional analysis or peptide mass fingerprinting or a combination of both, we confirm that many of the proteins whose expression is altered following ventricular pacing are associated with the mitochondria and energy production within the cardiomyocyte, including creatine kinase M, triosephosphate isomerase, phosphoglycerate mutase, cytochrome c oxidase, cytochrome b5, hydroxymethyl glutaryl CoA synthase, myoglobin, and 3,2-trans-enoyl-CoA transferase. Additionally, the cytoskeletal protein actin was increased in the paced hearts. These results strongly support the notion that energy production is impaired and mitochondrial dysfunction is involved in the development of heart failure in the paced dog.
 ...
PMID:Changes in myocardial protein expression in pacing-induced canine heart failure. 1045 Nov 20

Very long chain fatty acid dehydrogenase (VLCAD) deficiency is a rare but treatable cause of cardiomyopathy, fatty liver, skeletal myopathy, pericardial effusions, ventricular arrhythmias, and sudden death. Unrecognized, VLCAD deficiency may be rapidly progressive and fatal, secondary to its cardiac involvement. Because early diagnosis improves outcome, we present a neonate with VLCAD deficiency in whom retrospective analysis of the newborn screening card revealed that a correct diagnosis could have been made by newborn screening using tandem mass spectrometry. Our patient demonstrated a classic neonatal course with transient hypoglycemia at birth, interpreted as culture-negative sepsis, followed by a quiescent period notable only for hypotonia and poor feeding. At 3 months, he presented with cardiorespiratory failure and pericardial effusions, requiring pericardiocentesis, tracheostomy, and prolonged mechanical ventilation. Plasma free-fatty acid and acylcarnitine profiles demonstrated small but significant elevations of C14:2, C14:1, C16, and C18:1 acylcarnitine species, findings consistent with a biochemical diagnosis of VLCAD deficiency. Enteral feeds were changed to Portagen formula with marked improvement in cardiac symptoms over several weeks. To confirm the biochemical diagnosis, molecular analysis was performed by analysis of genomic DNA on a blood sample of the patient. Sequencing analysis and delineation of VLCAD mutations were performed using polymerase chain reaction and genomic sequencing. The patient was heterozygous for 2 different disease-causing mutations at the VLCAD locus. The maternal mutation was a deletion of bp 842-3 in exon 8, causing a shift in the reading frame. The paternal mutation was G+1A in the consensus donor splice site after exon 1; this splice-site mutation would likely result in decreased mRNA. The likely consequence of these mutations is essentially a null phenotype. To determine whether this case could have been picked up by tandem mass spectrometry analysis at birth when the patient was asymptomatic, acylcarnitine analysis was performed on the patient's original newborn card (after obtaining parental consent, the original specimen was provided courtesy of Dr Kenneth Pass, Director, New York State Newborn Screening Program). The blood sample had been obtained at 1 week of age and stored at room temperature for 6 months and at 70 degrees C thereafter for 18 months. Electrospray tandem mass spectrometry used a LC-MS/MS API 2000 operated in ion evaporation mode with the TurboIonSpray ionization probe source. The acylcarnitine profile obtained from the patient's original newborn card was analyzed 2 years after it was obtained. In comparison with a normal control, there was a significant accumulation of long chain acylcarnitine species, with a prominent peak of tetradecenoylcarnitine (C14:1), the most characteristic metabolic marker of VLCAD deficiency. This profile would have likely been even more significant if it had been analyzed at the time of collection, yet 2 years later is sufficient to provide strong biochemical evidence of the underlying disorder. Discussion. VLCAD was first discovered in 1992, and clinical experience with VLCAD deficiency has been accumulating rapidly. Indeed, the patients originally diagnosed with long chain acyl-CoA deficiency suffer instead from VLCAD deficiency. The phenotype of VLCAD deficiency is heterogeneous, ranging from catastrophic metabolic and cardiac failure in infancy to mild hypoketotic, hypoglycemia, and exertional rhabdomyolysis in adults. This case demonstrates that VLCAD deficiency could have been detected from the patient's own neonatal heel-stick sample. Most likely, a presymptomatic diagnosis would have avoided at least part of a lengthy and intensive prediagnosis hospitalization that had an estimated cost of $400 000. Although VLCAD is relatively rare, timely and correct diagnosis leads to dramatic recovery, so that detection by newborn screening could prevent the onset of arrhythmias, heart failure, metabolic insufficiency, and death. Fatty acid oxidation defects, including VLCAD deficiency, may account for as many as 5% of sudden infant death patients. Recent instrumentation advances have made automated tandem mass spectrometry of routine neonatal heel-stick samples technically feasible. Pilot studies have demonstrated an incidence of fatty acid oxidation defects, including short chain, medium chain, and very long chain acyl-CoA dehydrogenase deficiencies, of approximately 1/12 000. As a result, cost-benefit ratios for this approach should be systematically examined.
 ...
PMID:Diagnosis of very long chain acyl-dehydrogenase deficiency from an infant's newborn screening card. 1143 98

Carnitine is an ammo acid derivative found in high energy demanding tissues (skeletal muscles, myocardium, the liver and the suprarenal glands). It is essential for the intermediary metabolism of fatty acids. Carnitine is indispensable for beta-oxidation of long-chain fatty acids in the mitochondria but also regulates CoA concentration and removal of the produced acyl groups. AcylCoAs act as restraining factor for several enzymes participating in intermediary metabolism. Transformation of AcylCoA into acylcarnitine is an important system for removing the toxic acyl groups. Although primary deficiency is unusual, depletion due to secondary causes, such as a disease or a medication side effect, can occur. Primary carnitine deficiency is caused by a defect in plasma membrane carnitine transporter in muscle and kidneys. Secondary carnitine deficiency is associated with several inborn errors of metabolism and acquired medical or iatrogenic conditions, for example in patients under valproate and zidovuline treatment. In cirrhosis and chronic renal failure, carnitine biosynthesis is impaired or carnitine is lost during hemodialysis. Other chronic conditions like diabetes mellitus, heart failure, Alzheimer disease may cause carnitine deficiency also observed in conditions with increased catabolism as in critical illness. Preterm neonates develop carnitine deficiency due to impaired proximal renal tubule carnitine re-absorption and immature carnitine biosynthesis. Carnitine stabilizes the cellular membrane and raises red blood cell osmotic resistance but has no metabolic influence on lipids in dialysis patients. L-Carnitine has been administered in senile dementia, metabolic nerve diseases, in HIV infection, tuberculosis, myopathies, cardiomyopathies, renal failure anemia and included in baby foods and milk.
 ...
PMID:Carnitine metabolism and deficit--when supplementation is necessary? 1276 64

Several experimental studies have shown that levocarnitine reduces myocardial injury after ischemia and reperfusion by counteracting the toxic effect of high levels of free fatty acids, which occur in ischemia, and by improving carbohydrate metabolism. In addition to increasing the rate of fatty acid transport into mitochondria, levocarnitine reduces the intramitochondrial ratio of acetyl-CoA to free CoA, thus stimulating the activity of pyruvate dehydrogenase and increasing the oxidation of pyruvate. Supplementation of the myocardium with levocarnitine results in an increased tissue carnitine content, a prevention of the loss of high-energy phosphate stores, ischemic injury, and improved heart recovery on reperfusion. Clinically, levocarnitine has been shown to have anti-ischemic properties. In small short-term studies, levocarnitine acts as an antianginal agent that reduces ST segment depression and left ventricular end-diastolic pressure. These short-term studies also show that levocarnitine releases the lactate of coronary artery disease patients subjected to either exercise testing or atrial pacing. These cardioprotective effects have been confirmed during aortocoronary bypass grafting and acute myocardial infarction. In a randomized multicenter trial performed on 472 patients, levocarnitine treatment (9 g/day by intravenous infusion for 5 initial days and 6 g/day orally for the next 12 months), when initiated early after acute myocardial infarction, attenuated left ventricular dilatation and prevented ventricular remodeling. In treated patients, there was a trend towards a reduction in the combined incidence of death and CHF after discharge. Levocarnitine could improve ischemia and reperfusion by (1) preventing the accumulation of long-chain acyl-CoA, which facilitates the production of free radicals by damaged mitochondria; (2) improving repair mechanisms for oxidative-induced damage to membrane phospholipids; (3) inhibiting malignancy arrhythmias because of accumulation within the myocardium of long-chain acyl-CoA; and (4) reducing the ischemia-induced apoptosis and the consequent remodeling of the left ventricle. Propionyl-L-carnitine is a carnitine derivative that has a high affinity for muscular carnitine transferase, and it increases cellular carnitine content, thereby allowing free fatty acid transport into the mitochondria. Moreover, propionyl-L-carnitine stimulates a better efficiency of the Krebs cycle during hypoxia by providing it with a very easily usable substrate, propionate, which is rapidly transformed into succinate without energy consumption (anaplerotic pathway). Alone, propionate cannot be administered to patients in view of its toxicity. The results of phase-2 studies in chronic heart failure patients showed that long-term oral treatment with propionyl-L-carnitine improves maximum exercise duration and maximum oxygen consumption over placebo and indicated a specific propionyl-L-carnitine effect on peripheral muscle metabolism. A multicenter trial on 537 patients showed that propionyl-L-carnitine improves exercise capacity in patients with heart failure, but preserved cardiac function.
 ...
PMID:Therapeutic effects of L-carnitine and propionyl-L-carnitine on cardiovascular diseases: a review. 1559 Oct 5


1 2 3 4 5 Next >>