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At least 433 records · Page 24Linked to original sources

PubMed2025

Bi-allelic loss-of-function variants in POC5 cause a syndromic retinal, endocrine, and neuromuscular ciliopathy.

PURPOSE: A homozygous loss-of-function (LoF) variant in POC5 was previously described in an individual with retinitis pigmentosa. We identified POC5 variants in 12 probands with a syndromic phenotype. We aim to define the phenotype spectrum and molecular mechanism associated with biallelic POC5 LoF variants. METHODS: We studied a cohort of 12 families with bi-allelic LoF POC5 variants and performed detailed phenotype analysis. POC5 localization studies were performed in 3 proband-derived fibroblast cell lines. RESULTS: Detailed phenotyping of probands with POC5 variants expands the phenotype spectrum beyond ocular manifestations. This syndrome causes not only rod-cone dystrophy but also diabetes mellitus with severe insulin resistance and partial lipodystrophy, kidney disease, and muscle cramps. The POC5 protein plays an essential role during cell cycle and cilium formation. Interestingly, POC5 localization studies in 3 proband-derived fibroblast cell lines show aberrant localization suggesting a ciliary defect. The phenotypes of the 12 families in this study fit well within the ciliopathy phenotype spectrum, except for lipodystrophy, which is not common in ciliopathies. CONCLUSION: We describe a multiorgan syndrome caused by bi-allelic LoF variants in POC5. This underscores the pleiotropic effects of POC5 variants and highlights the significance of adipose tissue and metabolic dysfunction in ciliopathies.

Humans↗

PubMed2026

Scorpion venom peptides: Novel therapeutic approaches for inflammatory and hepatic disorders.

Chronic hepatic disorders, such as metabolic dysfunction associated steatohepatitis (MASH), alcohol associated liver disease (ALD), and viral hepatitis (Hepatitis B virus [HBV]/Hepatitis C virus [HCV]), are primarily driven by persistent immune-mediated inflammation and hepatic stellate cell activation leading to fibrosis, yet conventional therapies lack tissue and molecular specificity. Scorpion venom peptides, refined through evolutionary selection, provide highly potent, target specific scaffolds capable of modulating intrahepatic inflammatory networks. Recent in vivo preclinical studies indicate that voltage gated potassium (Kv1.3) channel blocking peptides, such as BmKK2, significantly reduce macrophage activation and inhibit downstream cytokine production, effectively ameliorating diet-induced steatohepatitis and tissue scarring in murine models. Engineered hepatotropic candidates, such as Smp76 and Mucroporin-M1, demonstrate dual therapeutic functions: they neutralize extracellular Hepatitis C particles and suppress key host transcription factors necessary for Hepatitis B replication. This review systematically examines scorpion venom peptides organized by disease category, covering their historical development, structural classification into disulfide-bridged and non-disulfide-bridged families, ion channel specificity, hepatic anti-inflammatory and antiviral mechanisms, and translational challenges including nano-formulation delivery strategies and computational drug design. These target-specific peptides are ultimately positioned as promising molecular leads that may bridge targeted immunomodulation with the resolution of chronic, progressive liver injury.

Anti-inflammatory effects↗

PubMed2005

Changes in the tibial growth plates of chickens with thiram-induced dyschondroplasia.

Tibial dyschondroplasia (TD) is a metabolic cartilage disease of young poultry in which endochondral bone formation is disrupted leading to the retention of a non-calcified, avascular plug of cartilage in the tibial growth plate. Chicks aged 7 days were fed either a control diet or one containing thiram 100 ppm for 48 h to induce TD. Cell multiplication in the growth plate was determined thereafter with bromodeoxyuridine (BrdU) labelling, and metabolic changes by measuring alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP), and glutathione (GSH) activities. The effect on chondrocyte maturation was examined by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of gene expression. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) and DNA fragmentation were used to determine the effects of thiram on cell survival. The results showed that thiram-induced TD was not due to the multiplication of cells in the post-proliferative zones. Thiram did not affect ALP activity, which would have indicated a loss of calcification potential, but it reduced both TRAP and the glutathione concentrations, suggesting that the growth plate metabolism and remodelling functions were adversely affected. Thiram appeared to have no effect on the expression of type X collagen, transglutaminase, RUNX2, or matrix metalloproteinase-2 (MMP) genes suggesting that it did not alter the maturation potential of chondrocytes. On the contrary, the expressions of MMP-13 and vascular endothelial growth factor (VEGF) genes were "up-regulated," suggesting that thiram has pro-angiogenic activity. However, TUNEL assay showed that thiram induced endothelial cell apoptosis in the capillary vessels of the growth plates, as early as 10 days of age, when TD was not visually evident. The vascular death increased on subsequent days accompanied by massive death of chondrocytes in the transition zone of the growth plate. The induction of apoptosis in the growth plate was also demonstrated by DNA fragmentation. It was concluded that thiram induced TD not through an increase in the multiplication of chondrocytes in the transition zone and not by altering the expression of genes causing the arrest of chondrocytes in a prehypertrophic state, but by creating a metabolic dysfunction which led to the destruction of blood capillaries in the transition zone chondrocytes.

Acid Phosphatase↗

PubMed2005

Effects of different antipsychotics and the antidepressant mirtazapine on glucose transporter mRNA levels in human blood cells.

A relationship between cell metabolism and the expression of glucose transporters (GLUT) has been reported. On the other side, treatment with some antipsychotics has been associated with an increased incidence of hyperglycemia and new-onset type 2 diabetes. We here examined the effects of different concentrations of the conventional antipsychotic haloperidol (400 and 800 microg/ml), of the atypical antipsychotics clozapine (100 and 200 microg/ml) and olanzapine (100 and 200 microg/ml) as well as of the antidepressant mirtazapine (10(-7) mol) on the mRNA levels of GLUT1-5 in the human leukemic blood cell line U937 after incubation for 48 h. After experimental treatment, significant increases were detected by ANOVA and appropriate post-hoc tests for mirtazapine in GLUT4 mRNA levels as well as for haloperidol 400 and 800 microg/ml, olanzapine 200 microg/ml, and mirtazapine in GLUT5 mRNA levels. ANOVAs revealed no statistically significant changes in GLUT1-3 and beta-actin mRNA levels. These findings suggest that direct effects of psychotropic drugs on cellular GLUT4 and GLUT5 may be involved in the metabolic dysfunctions occurring during psychopharmacological treatment.

Actins↗

PubMed2003

Cerebellar metabolite alterations detected in vivo by proton MR spectroscopy.

The aim of our work was to evaluate the feasibility of in vivo single-voxel quantitative proton MR spectroscopy in order to identify possible alterations in the main metabolite concentrations due to some metabolic dysfunctions in the cerebellum of patients suffering from a particular form of migraine called "with aura." Measurements of metabolite levels in the cerebellum disclosed reduced choline values (normalized both to N-acetyl-aspartate and creatine) in the patient group with respect to the age-matched control group. Our interest in this pathology is motivated by the fact that there are no available specific biochemical markers for migraine characterization, and the current diagnostic only takes advantage of the medical history and the clinical examination.

Adult↗

PubMed2006

Modified expression of Bcl-2 and SOD1 proteins in lymphocytes from sporadic ALS patients.

Markers of oxidative stress have been found in spinal cord, cortex, cerebrospinal fluid, and plasma of SALS patients. Mitochondrial and calcium metabolism dysfunction were also found in peripheral lymphocytes from SALS patients. In this study, we demonstrate that lymphocytes from SALS patients are more prone to undergo alteration of cell membrane integrity both in basal conditions and following oxidative stress induced by H2O2 treatment. The expression of the antioxidant proteins, Bcl-2, SOD1 and catalase in basal conditions, was significantly lower in lymphocytes from SALS patients than in lymphocytes from age and sex matched controls. Exposure to H2O2 induced a time-dependent decrease of Bcl-2 and SOD1 in control lymphocytes. Conversely, the levels of these proteins remained unchanged in SALS lymphocytes even after 18 h stress. Catalase expression was not significantly modified by oxidative stress. Our results demonstrate that two factors involved in the genesis and/or progression of the familial form of the disease with SOD1 mutation are altered also in the sporadic form of ALS and suggest that the oxidative stress protection pathway is deregulated in lymphocytes from ALS patients.

Amyotrophic Lateral Sclerosis↗

PubMed2026

Specialized pro-resolving mediators in obesity and overweight conditions: A systematic review of human and animal evidence on comparative differences and associations.

Obesity and overweight are characterized by persistent low-grade inflammation. Specialized pro-resolving mediators (SPMs), polyunsaturated fatty acid-derived metabolites, actively promote inflammatory resolution, and their dysregulation has been linked to unresolved inflammation and metabolic disturbances in obesity. This systematic review synthesized human and animal evidence on adiposity-related differences and associations in SPMs and SPM precursors. The protocol was prospectively registered in PROSPERO (CRD420251067464). PubMed/MEDLINE, Scopus, Web of Science, and Embase were searched up to 22 May 2026. Eligible studies included human and animal research comparing SPMs and/or SPM precursors between overweight/obese and normal-weight/lean groups or assessing their associations with adiposity indices. Due to heterogeneity across matrices and analytical platforms, findings were synthesized narratively. Twenty-seven unique studies were included, providing 28 experimental datasets (14 animal and 14 human). The most consistent alterations were observed in adipose tissue and circulation, where overweight/obesity was frequently associated with lower concentrations of SPMs and/or SPM precursors. In humans, circulating Resolvin E1 showed reproducible reductions and was inversely associated with adiposity measures in several cohorts. In contrast, selected metabolites, including SPM Lipoxin A4 and the SPM precursors 15-HETE and 18-HEPE, exhibited mixed directionality across studies. Evidence for hepatic and central nervous system compartments was limited and heterogeneous. Overall, available evidence suggests that excess adiposity is associated with altered SPM and precursor profiles, most consistently in adipose tissue and circulation, whereas hepatic and central nervous system findings remain inconsistent. Future studies using standardized quantification and tissue-specific designs are needed to clarify whether targeting pro-resolving pathways has translational potential in obesity-related metabolic dysfunction.

Animals↗

PubMed2006

Insulin resistance and cardiovascular risk: New insights from molecular and cellular biology.

Insulin resistance has been described in several diseases that increase cardiovascular risk and mortality, such as diabetes, obesity, hypertension, metabolic syndrome, and heart failure. Abnormalities of insulin signaling account for insulin resistance. Insulin mediates its action on target organs through phosphorylation of a transmembrane-spanning tyrosine kinase receptor, the insulin receptor (IR). Several mechanisms have been described as responsible for the inhibition of insulin-stimulated tyrosine phosphorylation of IR and the IR substrate (IRS) proteins, including proteasome-mediated degradation, phosphatase-mediated dephosphorylation, and kinase-mediated serine/threonine phosphorylation. In particular, phosphorylation of IRS-1 on serine Ser612 causes dissociation of the p85 subunit of phosphatidylinositol 3-kinase, inhibiting further signaling. On the other hand, phosphorylation of IRS-1 on Ser307 results in its dissociation from the IR and triggers proteasome-dependent degradation. Dysregulation of sympathetic nervous and renin-angiotensin systems resulting in enhanced stimulation of both adrenergic and angiotensin II receptors is a typical feature of several cardiovascular diseases and, at the same time, is involved in the pathogenesis of insulin resistance. The characterization of molecular mechanisms involved in the pathogenesis of insulin resistance may help to design efficacious pharmacologic molecules to treat endothelial and metabolic dysfunction associated with insulin resistance states to reduce the cardiovascular risk and to ameliorate the prognosis of patients with cardiovascular diseases.

Animals↗

PubMed1979

Calcific stenosis of the porcine heterograft.

We have encountered two cases of late calcification of the porcine heterograft. A patient in chronic renal failure died of sepsis and endocarditis fifteen months after replacement of the mitral and tricuspid valves. At postmortem examination, both heterograft valves exhibited severe calcification and thrombosis. A second patient with rheumatic heart disease and sickle cell disease underwent mitral valve replacement for severe regurgitation. Thirty months later, cardiac catheterization revealed prosthetic valve stenosis. The valve was replaced successfully, and the excised heterograft exhibited severe calcification with restriction of leaflet motion. Although calcification of the porcine heterograft is known to occur in patients with infection or disorders of calcium metabolism, dysfunction of the heterograft is rare in our experience.

Adolescent↗

PubMed1997

PET brain mapping study of auditory verbal supraspan memory versus visual fixation in schizophrenia.

Changes in regional cerebral blood flow (rCBF), associated with performance of an auditory verbal supraspan memory task, were studied in eight remitted DSM-III-R schizophrenic patients and eight pair-wise matched normal controls. Four positron emission tomography (PET) scans, using the [15O]-H2O technique, were acquired: two while subjects fixated a cross hair and two while performing a verbal free-recall supraspan memory task. Task performance showed typical patterns of recency and primacy effects in both groups; however, patients performed more poorly than controls on the primary (working) memory aspect of the task. Regions showing rCBF changes overlapped in both groups and were similar to those seen in previous studies of normals; however, patients had smaller increases in rCBF than controls in frontal and superior temporal cortical regions bilaterally. Our results suggest that remitted patients with schizophrenia demonstrate impairments of capacity-limited information processing, which may be related to metabolic dysfunction within a distributed network of brain structures, including the prefrontal and temporal cortical regions; however, dysfunction limited to the frontal cortex cannot be ruled out by the results of this experiment.

Adult↗

PubMed2001

Behavioral, electrophysiological, and histopathological consequences of mild fluid-percussion injury in the rat.

Metabolic dysfunction in the relay nuclei of the rat vibrissa circuit follows traumatic brain injury (TBI). This study examined the effects of mild (1.4-1.5 atm) parasagittal fluid-percussion injury on the electrophysiology of this circuit. TBI caused significant reductions in slope and increases in latency of vibrissa-evoked field potentials 3 days after injury. Assessment of open-field swimming revealed an increase in thigmotaxis 2 days after injury. TBI caused mild selective cortical damage and limited axonal swelling at the injury site. Thus mild injury disrupts somatosensory electrophysiology and exploratory behavior.

Afferent Pathways↗

PubMed1998

Reduced pulmonary metabolism of endothelin-1 in canine tachycardia-induced heart failure.

OBJECTIVES: Plasma endothelin-1 (ET-1) increases in congestive heart failure (CHF). The pulmonary vascular bed could contribute to this increase through a reduced clearance. We evaluated the effect of tachycardia-induced CHF on pulmonary ET-1 kinetics. To discern between changes due to variations in pulmonary hemodynamics from true alterations of endothelial cell functions, we quantified ET-1 kinetics in isolated rat lungs under variable pressure and flow-rate conditions. METHODS AND RESULTS: Indicator-dilution studies were performed in anesthetized dogs (n = 14) before and 3 weeks after rapid ventricular pacing and in isolated lungs from healthy rats (n = 4). In isolated lungs, graded increases in perfusion rate from 5-25 ml/min caused gradual reductions in ET-1 extraction from 60 +/- 1.5% to 17 +/- 4.9% (mean +/- S.D.). The capacity to clear ET-1 from the circulation, as computed from the permeability-surface area product (PS), however did not vary over this range of flows. CHF increased plasma ET-1 (11.2 +/- 11.4 vs. 5.2 +/- 1.6 fmol/ml, p < 0.01), did not affect pulmonary ET-1 extraction (29.4 +/- 12.5% vs. 29.9 +/- 12.9%), but decreased the PS (8.3 +/- 5.4 cm3/s vs. 14.4 +/- 9.9 cm3/s, p = 0.038). Contrary to the invariability of the PS in normal isolated rat lungs, CHF was associated with a positive relationship between the PS and pulmonary plasma flow (r = 0.65, p < 0.01). ET-1 binding studies in lung tissues showed no significant variations in ETA and ETB receptors densities but revealed a threefold decrease in binding affinity (p < 0.01) that may explain the reduced clearance. CONCLUSION: CHF causes a reduction of pulmonary ET-1 clearance that likely contributes to the increased circulating ET-1 levels and reflects pulmonary metabolic dysfunction associated with this condition.

Analysis of Variance↗

PubMed2003

Salivary cortisol on ROCHE Elecsys immunoassay system: pilot biological variation studies.

OBJECTIVES: Salivary analysis is a noninvasive alternative that may be more acceptable to patients, especially children. As such, it has the potential for incorporation into comprehensive, dynamic investigations of metabolic dysfunctions - a significant advancement over a single time point serum analysis. In this study, we wanted to determine if the serum cortisol assay on our routine immunoassay analyzer could reliably measure salivary cortisol concentrations. Because of potential fluctuations in salivary concentrations, we included a biologic variation study as a main facet of our preliminary method evaluation. DESIGN AND METHODS: Twenty-eight healthy individuals (12 males, 16 females) volunteered to provide 5 nonconsecutive first morning saliva samples over a two-week period. Samples were stored frozen at home until the completion of the study. Following thawing and centrifugation, cortisol was measured in batch mode for each set of participant samples on the ROCHE Elecsys. Biologic variation was determined following removal of outliers. A method comparison was performed with the DPC Coat-A-Count Cortisol assay following the recommended modifications for salivary analysis, and with the Salimetrics HS-Cortisol two-site monoclonal assay optimized for salivary cortisol. RESULTS: Mean salivary cortisol concentration was 20.4 nmol/L. Analytical variation (CV(A) = 3.8%), within-subject variation (CV(I) = 6.3%), between-subject variation (CV(G) = 20.5%), index of individuality (II = 0.36) and reference change value (RCV = 20.4%) were determined. A negative 40% proportional bias was observed on the Elecsys compared to the two methods that have already been optimized for salivary analysis. CONCLUSIONS: This study demonstrated that salivary cortisol can be reliably measured on a routine automated immunoassay analyzer such as the ROCHE Elecsys. This particular assay needs to be optimized at the low end of the standard curve for routine use with salivary samples. Based on the relatively small intra-individual variation and low index of individuality, reference change values are preferable to the use of population reference intervals for this assay.

Analysis of Variance↗

PubMed2003

Impaired voltage-gated K+ channel expression in brain during experimental cancer cachexia.

Cancer-induced cachexia affects most advanced cancer patients. It is characterized by anorexia, profound metabolic dysfunctions, and severe neurological disorders. Here we show that voltage-gated potassium channel (Kv) expression is impaired in the brain of tumor-bearing animals. Expression of both delayed rectifier (Kv1.1, Kv1.2, Kv1.3, Kv1.5, Kv1.6, Kv2.1, Kv3.1, Kv4.2) and A-type potassium channels (Kv1.4, Kv3.3, Kv3.4) was greatly down-regulated in brain from animals bearing a Yoshida AH-130 ascites hepatoma. The possible compensatory mechanisms (Kv1.4/Kv4.2), expression of redundant genes (Kv3.1/Kv3.3) and heteromultimeric channel formation (Kv2.1/Kv9.3) were also affected. The high circulating levels of TNFalpha and the reduced expression of the anti-apoptotic protein Bcl-XL found in the brain of tumor-bearing animals indicate that this response could be mediated by an increase in brain cell death due to apoptosis. The results suggest that brain function is impaired during cancer cachexia, and may account for the cancer-induced anorectic response and other neurological alterations.

Animals↗

PubMed1986

Alterations of hepatic mitochondrial function in a model of peritonitis in immature rats.

Severe intra-abdominal infection results in significant metabolic dysfunction, multiple systems failure, and mortality. Although the course of peritonitis is particularly rapid and severe in neonates and small children, its physiologic consequences have been poorly studied in these age groups. In order to assess hepatic mitochondrial integrity in a model of fulminant peritonitis in immature animals, the following study was undertaken. Thirty-three immature Sprague-Dawley rats (21 to 28 days of age) and 32 mature rats (weight greater than 250 g) were anesthetized and laparotomies performed. The animals received either cecal ligation and gross perforation (CLP) or cecal manipulation alone (sham). Animals were killed at 2 and 4 hours and livers removed. Mitochondria were isolated by differential centrifugation. Mitochondrial respirations were studied polarographically with glutamate and succinate as substrates in the presence (state 3) and absence (state 4) of adenosine diphosphate (ADP). The Respiratory Control Index (RCI) is the ratio of state 3 to state 4 respiration and is a sensitive indicator of mitochondrial coupling. Results revealed that in mature animals, peritonitis produced a significant increase in RCI with glutamate as substrate (5.2 +/- 0.2) by 4 hours duration as compared with sham operated rats (4.3 +/- 0.1, P less than 0.01). Succinate as substrate revealed no significant alteration in mitochondrial coupling in mature rat hepatic mitochondria in animals subjected to peritonitis. By contrast, peritonitis in immature animals produced a significantly decreased RCI (3.6 +/- 0.2) with glutamate as substrate as compared with sham operated animals (4.8 +/- 0.2, P less than 0.01) by two hours duration.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

PubMed2001

Brain SPECT with 123I-IMP for the early diagnosis of Creutzfeldt-Jakob disease.

We performed brain CT and single-photon emission computed tomography (SPECT) using N-isopropyl-p-[123I] iodoamphetamine (123I-IMP) as a tracer in the early stage of seven patients with Creutzfeldt-Jakob disease (CJD). In four of the patients, we determined absolute values of regional cerebral blood flow (rCBF) in the frontal, temporal, parietal and occipital lobes, thalamus and cerebellum using an autoradiographic method with a single blood sample. Brain CT demonstrated no abnormal findings other than a mild age-related atrophy in all patients except for one patient with a low-density area in the left cerebellar hemisphere due to an old hemorrhage, whereas SPECT revealed a decreased uptake of the tracer in various parts of the cerebral cortex of all patients, sometimes in an asymmetrical pattern. Absolute values of rCBF showed a significant decrease in all examined regions of the patients as against healthy controls (P<0.0001). In three patients, SPECT demonstrated a decreased uptake throughout the cerebral cortex on visual inspection, whereas absolute values of rCBF revealed an obvious decrease of the uptake also in the thalamus and cerebellum. These results suggest that SPECT with quantification of rCBF using 123I-IMP might be a sensitive and useful technique not only for detecting a focal metabolic dysfunction but also for diagnosis in the early stage of CJD.

Aged↗

PubMed1998

Cerebral blood flow and oxygen metabolism before and after a stroke-like episode in patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS).

Cerebral blood flow and oxygen metabolism were examined in two patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) using positron emission tomography (PET). Regional cerebral blood flow (rCBF), regional cerebral oxygen metabolic rate (rCMRO2) and regional oxygen extraction fraction (rOEF) were determined with the steady-state technique using oxygen-15-labeled tracers (15O2, C15O2 and C15O). Case 1, a 45-year-old woman, presented with abrupt onset of fluent aphasia. T2-weighted magnetic resonance imaging (MRI) showed a high signal intensity lesion in the left temporoparietal region. The first PET study on day 16 showed increased rCBF and decreased rCMRO2 in the temporal region. In the second PET study, on day 35, rCBF in the temporal region had decreased. Case 2 was a 19-year-old male; the second son of Case 1. He complained of transient blurring of vision, and then generalized tonic-clonic convulsion occurred. A PET study six days before this stroke-like episode demonstrated increased rCBF in both frontal lobes and putamen, where MRI showed lesions after the episode. Focal hyperemia of the lesion antedated and lasted for at least sixteen days after the stroke-like episode in these MELAS patients. These stroke-like episodes appear to be the result of metabolic dysfunction in neural tissue, although the role of an ischemic vascular event cannot be ruled out.

Adult↗

PubMed1998

Improvement of myocardial mitochondrial function after hemodynamic support with left ventricular assist devices in patients with heart failure.

OBJECTIVES: Mitochondrial abnormalities have been described in cardiac tissue of patients with heart failure. These changes may result from chronic hypoxia. Our goal was to determine whether mitochondrial functional capacity can be improved in patients with heart failure by means of long-term left ventricular assist device therapy, which improves myocardial oxygen supply by decreasing myocardial work. METHODS: Mitochondria were isolated from myocardial tissue obtained from 13 patients with heart failure without a left ventricular assist device (HF group) and seven patients with heart failure treated with a left ventricular assist device (LVAD-HF group). Mitochondrial respiratory rates (State 2, State 3, and State 4) were measured by means of polarographic techniques with reduced nicotinamide adenine dinucleotide-dependent (pyruvate/malate, alpha-ketoglutarate, glutamate) and -independent (succinate) substrates. The respiratory control index of Chance (State 3/State 4) and Lardy (State 3/State 2) and phosphorus to oxygen ratios were determined. RESULTS: The respiratory control index of Chance was higher in LVAD-HF than in HF when using NADH-dependent substrates pyruvate/malate and alpha-ketoglutarate (pyruvate/malate HF: 4.9 +/- 1.0; LVAD-HF: 6.5 +/- 1.5; alpha-ketoglutarate HF: 8.5 +/- 2.4; LVAD-HF: 11.8 +/- 2.9; both p = 0.04). Similarly, the respiratory control index of Lardy was greater in the LVAD-HF than the HF group when alpha-ketoglutarate and glutamate were used as substrates (alpha-ketoglutarate HF: 7.8 +/- 1.7; LVAD-HF: 9.9 +/- 1.5; glutamate HF: 7.6 +/- 2.2; LVAD-HF: 10.7 +/- 2.1; both p = 0.04). The phosphorus to oxygen ratio was comparable for both groups using all substrates. No change in mitochondrial respiration was observed after left ventricular assist device therapy with the NADH-independent substrate, succinate. CONCLUSION: Cardiomyocyte mitochondrial function is improved by long-term therapy with a left ventricular assist device. This improvement suggests that cardiomyocyte metabolic dysfunction in heart failure may be reversed with left ventricular assist device support.

Adult↗