The metabolic syndrome and erectile dysfunction: multiple vascular risk factors and hypogonadism.
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Comorbidity↗
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Effects of metabolic modifiers such as carnitines, coenzyme Q10, and PUFAs against different forms of neurotoxic insults: metabolic inhibitors, MPTP, and methamphetamine.
A number of strategies using the nutritional approach are emerging for the protection of the brain from damage caused by metabolic toxins, age, or disease. Neural dysfunction and metabolic imbalances underlie many diseases, and the inclusion of metabolic modifiers may provide an alternative and early intervention approach that may prevent further damage. Various models have been developed to study the impact of metabolism on brain function. These have also proven useful in expanding our understanding of neurodegeneration processes. For example, the metabolic compromise induced by inhibitors such as 3-nitropropionic acid (3-NPA), rotenone, and 1-methyl-4-phenylpyridinium (MPP+) can cause neurodegeneration in animal models and these models are thought to simulate the processes that may lead to diseases such as Huntington's and Parkinson's diseases. These inhibitors of metabolism are thought to selectively kill neurons by inhibiting various mitochondrial enzymes. However, the eventual cell death is attributed to oxidative stress damage of selectively vulnerable cells, especially highly differentiated neurons. Various studies indicate that the neurotoxicity resulting from these types of metabolic compromise is related to mitochondrial dysfunction and may be ameliorated by metabolic modifiers such as L-carnitine (L-C), creatine, and coenzyme Q10, as well as by antioxidants such as lipoic acid, vitamin E, and resveratrol. Mitochondrial function and cellular metabolism are also affected by the dietary intake of essential polyunsaturated fatty acids (PUFAs), which may regulate membrane composition and influence cellular processes, especially the inflammatory pathways. Cellular metabolic function may also be ameliorated by caloric restriction diets. L-C is a naturally occurring quaternary ammonium compound that is a vital cofactor for the mitochondrial entry and oxidation of fatty acids. Any factors affecting L-C levels may also affect ATP levels. This endogenous compound, L-C, together with its acetyl ester, acetyl-L-carnitine (ALC), also participates in the control of the mitochondrial acyl-CoA/CoA ratio, peroxisomal oxidation of fatty acids, and production of ketone bodies. A deficiency of carnitine is known to have major deleterious effects on the CNS. We have examined L-C and its acetylated derivative, ALC, as potential neuroprotective compounds using various known metabolic inhibitors, as well as against drugs of abuse such as methamphetamine.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Effects of indomethacin on PMA-induced pulmonary endothelial enzyme dysfunction in vivo.
We investigated the effects of phorbol myristate acetate (PMA) on metabolic pulmonary endothelial ectoenzyme dysfunction. Anesthetized rabbits were placed on total heart bypass, and the single-pass transpulmonary metabolism of [3H]benzoyl-Phe-Ala-Pro (BPAP) by endothelial-bound angiotensin-converting enzyme (ACE) and [14C]adenosine 5'-monophosphate (AMP) by 5'-nucleotidase (NCT) was calculated before and after PMA (10 micrograms/kg iv), a dose that does not produce histologically evident endothelial damage. Under conditions of partial microvascular recruitment (blood flow = 400 ml/min through the entire lung), PMA, but not the vehicle, significantly reduced substrate utilization of both BPAP and adenosine 5'-monophosphate (AMP) and increased the apparent Michaelis constant (Km) values of ACE for BPAP, indicative of metabolic dysfunction. These changes were completely prevented by pretreatment with indomethacin. Under conditions of near full microvascular recruitment (blood flow = 640 ml/min through the left lung only), PMA similarly reduced substrate utilization and increased the apparent Km of ACE for BPAP. In this case, however, indomethacin failed to prevent the observed PMA-induced metabolic dysfunction. We conclude that PMA alters endothelial ectoenzyme substrate metabolism independently from changes in pulmonary blood flow; indomethacin appears to antagonize the effects of PMA under conditions of partial microvascular recruitment only, perhaps by diverting flow to previously unperfused, unexposed to PMA, and hence metabolically healthy vessels.
5'-Nucleotidase↗
Metabolic disorders characterized by angiokeratomas and neurologic dysfunction.
A number of metabolic disorders are characterized by generalized angiokeratomas and neurologic dysfunction. Fabry's disease (angiokeratoma corporis diffusum universale) is an X-linked recessive disorder caused by a deficiency of alpha-galactosidase A. Fucosidosis is an autosomal recessive disorder caused by a lack of fucosidase. Sialidosis with deficiencies of neuraminidase and beta-galactosidase is the third important association.
Fabry Disease↗
Coronary blood flow, metabolism, and function in dysfunctional viable myocardium before and early after surgical revascularisation.
OBJECTIVES: To assess the link between perfusion, metabolism, and function in viable myocardium before and early after surgical revascularisation. DESIGN: Myocardial blood flow (MBF, thermodilution technique), metabolism (lactate, glucose, and free fatty acid extraction and fluxes), and function (transoesophageal echocardiography) were assessed in patients with critical stenosis of the left anterior descending coronary artery (LAD) before and 30 minutes after surgical revascularisation. SETTING: Tertiary cardiac centre. PATIENTS: 23 patients (mean (SEM) age 57 (1.7) years with LAD stenosis: 17 had dysfunctional viable myocardium in the LAD territory, as shown by thallium-201 rest redistribution and dobutamine stress echocardiography (group 1), and six had normally contracting myocardium (group 2). RESULTS: LAD MBF was lower in group 1 than in group 2 (58 (7) v 113 (21) ml/min, p < 0.001) before revascularisation and improved postoperatively in group 1 (129 (133) ml/min, p < 0.001) but not in group 2 (105 (20) ml/min, p = 0.26). Group 1 also had functional improvement in the LAD territory at intraoperative echocardiography (mean regional wall motion score from 2.6 (0.85) to 1.5 (0.98), p < 0.01). Oxidative metabolism, with lactate and free fatty acid extraction, was found preoperatively and postoperatively in both groups; however, lactate and free fatty acid uptake increased after revascularisation only in group 1. CONCLUSIONS: MBF is reduced and oxidative metabolism is preserved at rest in dysfunctional but viable myocardium. Surgical revascularisation yields immediate perfusion and functional improvement, and increases the uptake of lactate and free fatty acids.
Angina Pectoris↗
[Sexual dysfunction and disordered carbohydrate metabolism (author's transl)].
Sexual impotence with inability to produce erection is a frequent accompaniment of diabetes. Only exceptionally however is impotence complained of as a symptom. Though in no direct sense a danger to the patient's life, impotence is sometimes a source of major distress and, in a few exceptional cases, may lead to suicide. It is therefore important to distinguish the different mechanisms underlying impotence, and in particular to differentiate psychogenic mechanisms, far more relevant than formerly thought in diabetic patients, from organic mechanisms, in particular neuropathic and vascular, uncommonly, endocrine. Besides cases of unequivocal diabetes, there is an abnormally high proportion of patients suffering from "psychogenic" impotence affecting erection who have impaired glucose tolerance. In such patients the disordered metabolism could reflect at neuroendocrine level the existence of neuro-psychological dysfunction, either a cause or a consequence of the impotence. A second possibility is that the metabolic disorder directly impairs neurological function, resulting in neuropathic impotence. Clearer understanding of the complex mechanisms relating disturbance of carbohydrate metabolism to sexual impotence requires multidisciplinary approaches. Such arrangements are necessary for the planning and conduct of schemes of treatment involving to varying extents the special approaches of psychology, sexology, endocrinology, urology and vascular surgery. The success of such treatment will depend largely upon the quality of the diagnostic and therapeutic approach which requires individualised planning.
Blood Glucose↗
Diabetes mellitus/male infertility.
Diabetes mellitus (DM), associated with very subtle disorders, affects, either directly or indirectly, various functions of the reproductive system. Adequate, regular, and timely therapy may prevent or delay these disorders. The T synthesis disorder is caused by molecular changes at the level of Leydig cells and may lead to other disorders in all target organs and tissues. The close correlation between Leydig and Sertoli cells function, i.e., between spermatogenesis and second sex glands function, results in certain anomalies in diabetic patients' spermiograms. Parallel lesions associated with DM, through CNS (hypothalamus-hypophysis), and endocrine profile are indirectly intensified or induced by these disorders, which reflect dysfunction of homeostatic balance in carbohydrate metabolism. Sexual dysfunction in all its forms (reduced erection, impotence, and other libido dissociations) is an accompanying phenomenon of the diabetic disease. However, manifestations of these disorders are related to the regulation of carbohydrate metabolism and to the duration of disease. The duration of disease is not necessarily correlated with sexual dysfunction. Even carbohydrate metabolism remains within normal range in addition to other lesions, diabetes leads gradually but progressively to premature aging of body cells.
Diabetes Complications↗
The metabolic syndrome and endothelial dysfunction: common highway to type 2 diabetes and CVD.
Due to global lifestyle changes, obesity (the main driver of type 2 diabetes and cardiovascular disease ) is reaching pandemic proportions. The metabolic syndrome, which is regarded as a prediabetic state, is characterized by a concurrence of interrelated cardiovascular risk factors, including abdominal obesity, insulin resistance, hypertension, dyslipidemia, and glucose intolerance. Endothelial dysfunction (ED) is common in the metabolic syndrome and is associated with increased risk for T2D and CVD. This review focuses on the mechanisms linking ED to the metabolic syndrome, T2D, and CVD, and the possible therapies that may improve ED and reduce T2D and CVD risk.
Cardiovascular Diseases↗
Relationship between CYP 2D6 metabolic status and sexual dysfunction in paroxetine treatment.
This article describes the incidence of sexual dysfunction in 30 patients subjected to long-term treatment by paroxetine in dependence on the P 450 CYP 2D6 isoenzyme metabolic status. Measured on the Arizona Sexual Experience Scale (ASEX; McGahuey, Delgado, & Gelenberg, 1999), the incidence of sexual dysfunction in patients converted to CYP 2D6 poor metabolizers was markedly higher compared with patients who had no history of such conversion, a difference that reached the level of statistical significance. Our article discusses the incidence of sexual dysfunction in connection with reduced CYP 2D6 capacity.
Adult↗
Altered pharmacokinetics and metabolism of CPT-11 in liver dysfunction: a need for guidelines.
Metabolic conversion of CPT-11 is a major route of elimination of this new topoisomerase 1 inhibitor. Presently, recommendations for dose adjustments of CPT-11 in patients with liver dysfunction are lacking. We describe the case of a patient with metastatic colon cancer with liver dysfunction treated with CPT-11 at two different dose levels (100 mg/m2 and 30 mg/m2, single dose, administered as a 90-min i.v. infusion). The lactones and carboxylates of CPT-11 and SN-38 were determined by high-performance liquid chromatography. SN-38 glucuronide was determined after deglucuronidation. The procedures allowed intrapatient comparison of pharmacokinetics and metabolism of the drug. Severe side effects were encountered, which could be explained by the reduced clearance of CPT-11 and its metabolites. These included neutropenic fever with culture-proven septicemia, thrombocytopenia, somnolence, diarrhea, and signs and symptoms of transient hepatic failure. Our findings offer important data for the further development of guidelines for dose reduction of CPT-11 in patients with liver dysfunction.
Antineoplastic Agents, Phytogenic↗
Digital pathology and spatial omics in steatohepatitis: Clinical applications and discovery potentials.
Steatohepatitis with diverse etiologies is the most common histological manifestation in patients with liver disease. However, there are currently no specific histopathological features pathognomonic for metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, or metabolic dysfunction-associated steatotic liver disease with increased alcohol intake. Digitizing traditional pathology slides has created an emerging field of digital pathology, allowing for easier access, storage, sharing, and analysis of whole-slide images. Artificial intelligence (AI) algorithms have been developed for whole-slide images to enhance the accuracy and speed of the histological interpretation of steatohepatitis and are currently employed in biomarker development. Spatial biology is a novel field that enables investigators to map gene and protein expression within a specific region of interest on liver histological sections, examine disease heterogeneity within tissues, and understand the relationship between molecular changes and distinct tissue morphology. Here, we review the utility of digital pathology (using linear and nonlinear microscopy) augmented with AI analysis to improve the accuracy of histological interpretation. We will also discuss the spatial omics landscape with special emphasis on the strengths and limitations of established spatial transcriptomics and proteomics technologies and their application in steatohepatitis. We then highlight the power of multimodal integration of digital pathology augmented by machine learning (ML)algorithms with spatial biology. The review concludes with a discussion of the current gaps in knowledge, the limitations and premises of these tools and technologies, and the areas of future research.
Humans↗
Minimal operative mortality in patients undergoing coronary artery bypass with significant left ventricular dysfunction by maximization of metabolic and mechanical support.
Between January 1, 1992, and January 23, 1996, 111 consecutive patients with severe left ventricular dysfunction underwent isolated coronary artery bypass grafting. The ejection fraction in these patients ranged from 10% to 34% (mean 27.9% +/- 5.4%); in 18 patients the value was less than 20%. The high operative mortality rate (7.6% in Society of Thoracic Surgeons database) in this group of patients at high risk was targeted for reduction by provision of, in addition to the usual inotropic support, progressively more intensive metabolic and mechanical support. The metabolic support consisted of triiodothyronine; glucose, insulin, and potassium; aspartate/glutamate in the cardioplegic solution; and warm-cold-warm/antegrade-retrograde-antegrade cardioplegia. Mechanical support included liberal use of the intraaortic balloon pump, use of a new occlusive retrograde cardioplegia catheter, ultrafiltration to remove myocardial depressant factors, and, finally, delayed sternal closure. The operative mortality rate was 1.8% (2/111). Complications included reoperation because of bleeding (3.6%, 4/111), mediastinitis (1.8%, 2/111), and stroke (0.9%, 1/111) and there were no occurrences of new postoperative acute renal failure (0.0%, 0/111). The intensive care unit stay was 2.2 +/- 0.9 days with a length of stay in the hospital of 13.7 +/- 22.1 days. These techniques done before operation, intraoperatively, and postoperatively optimize the milieu of the depressed left ventricle by maximizing perioperative high-energy phosphate bonds; increasing the effectiveness of inotropic agents; unloading the left ventricle by chemical, metabolic, and mechanical support; and removing known myocardial depressant factors, which reduced the operative mortality rate to 1.8% compared with 7.6% as reported in the Society of Thoracic Surgeons' database.
Adult↗
[Metabolic syndrome and erectile dysfunction. Epidemiologic associations and pathogenetic links].
There is abundant evidence for the association between erectile dysfunction (ED) and the traditional atherosclerotic risk factors, such as dyslipidemia, hypertension, glucose intolerance, and obesity, that make up the metabolic syndrome. Recent findings have demonstrated a linear relationship between the number of these risk factors and the prevalence of ED. There is also growing evidence that endothelial dysfunction characterized by decreased bioavailability of nitrogen monoxide (NO) and a proinflammatory, prothrombotic, and proliferative phenotype is the common pathogenetic pathway linking ED to peripheral vascular diseases. Since ED often occurs several years before any clinical manifestation of systemic cardiovascular disease, ED should be seen as a warning of early atherosclerotic disease and an opportunity for doctor and patient to initiate preventive measures.
Atherosclerosis↗
Myocardial dysfunction and depressed fatty acid metabolism in patients with cyanotic congenital heart disease.
BACKGROUND: Myocardial contractile dysfunction has been frequently observed in adolescents or adults with cyanotic congenital heart disease. Impaired energy metabolism may be present in such dysfunctional myocardium. METHODS AND RESULTS: To evaluate the findings of myocardial free fatty acid metabolism, and its relations to ventricular wall motion and myocardial perfusion in cyanotic congenital heart disease, we performed a combined study of iodine 123-labeled 15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) scintigraphy, thallium scintigraphy, and contrast cine-angiography in seven patients with single right or left ventricle. The results showed that wall motion was reduced in 17 of 35 ventricular segments (49%), which were mostly identical in location to decreased BMIPP uptake. The severity of BMIPP uptake deficit correlated positively with the degree of impairment of wall motion. On the other hand, thallium uptake was abnormal only in 5 of 35 segments (14%), and the severity of the perfusion defect did not correlate with the degree of wall motion abnormality. CONCLUSIONS: Contractile dysfunction in cyanotic heart disease was primarily linked to impaired free fatty acid metabolism rather than to myocardial scar as represented by perfusion defect on thallium imaging.
Adolescent↗
Endocrine dysfunction and parameters of the metabolic syndrome after bone marrow transplantation during childhood and adolescence.
Endocrine dysfunction and parameters of metabolic syndrome were assessed in 91 patients aged 4.3-32.5 years who underwent allogeneic or autologous BMT in childhood. Final short stature, found in five of the 35 patients who attained final height, was associated with the underlying disease (specifically, Fanconi anemia) (P=0.0013), previous cranial irradiation (P=0.0007), type of conditioning irradiation (P<0.05) and allogeneic BMT (P=0.05). Growth hormone deficiency (n=10) was associated with previous cranial irradiation (P<0.005) and conditioning total body irradiation (P<0.001). Twelve patients had primary hypothyroidism, one had hyperthyroidism and one papillary thyroid carcinoma. Hypothyroidism was associated with neck/mediastinal (P<0.005) and conditioning irradiation (P<0.05). Primary gonadal failure was found in 24 of the mature patients (62.5% females). Hypogonadism was associated with the underlying disease (especially hematological malignancies) (P<0.05), pretransplant treatment (P<0.05), irradiation conditioning (P<0.001), older age (P<0.005) and advanced pubertal stage at BMT (P<0.05). Obesity (body mass index >2 s.d.) was found in 4.4% and type II diabetes and impaired glucose tolerance in 3.3% each. Dyslipidemia was found in 27.9% of the 43 patients tested. These findings emphasize the need for long-term follow-up of endocrine and metabolic parameters in young patients after BMT in order to offer proper treatment and improve quality of life.
Adolescent↗
[Evolution of concept and metabolic basis of ischemic dysfunction of the myocardium].
Myocardial contractile function during acute as well as chronic ischemia is reduced due to activation of a number of metabolic energy protecting mechanisms. Their abolition during reperfusion, associated with oxidative stress and incomplete restoration of function may cause cellular apoptosis due to impairment of aerobic ATP resynthesis. Strategy of postischemic reperfusion of the heart should be based on the use of natural protective mechanisms providing preferential restoration of high energy phosphates. The state of mitochondria is decisive for survival or restoration of function of cells.
Humans↗
Pulmonary cellular dysfunction in endotoxin shock: metabolic and transport derangements.
Lung cell metabolic and ion transport alterations in endotoxin shock have been studied to elucidate mechanisms of endotoxin-induced pulmonary dysfunction. Glucose oxidation to lactate as well as to CO2 is significantly increased with a decrease in the lung ATP contents. Active Na+ transport is impaired, indicating an increase in lung intracellular fluid. The altered glucose metabolism and active ion transport could potentially contribute to lung edemagenesis in endotoxicosis.
Adenine Nucleotides↗
Hemodynamic and metabolic basis of impaired exercise tolerance in patients with severe left ventricular dysfunction.
Hemodynamic and metabolic changes were measured at rest and during exercise in 23 patients with chronic heart failure and in 6 control subjects. Exercise was limited by leg fatigue in both groups and capacity was 40% lower in the patients with failure. At rest, comparing patients with control subjects, heart rate and right atrial and pulmonary wedge pressure were higher; cardiac output, stroke volume and work indexes and ejection fraction were lower; mean arterial and right atrial pressure and systemic resistance were similar. During all phases of exercise in patients with heart failure, pulmonary wedge pressure and systemic vascular resistance were higher and pulmonary vascular resistance remained markedly elevated compared with values in control subjects. Cardiac output was lower in the patients with failure, but appeared to have the same physiologic distribution in both groups during exercise. Although arterial-femoral venous oxygen content difference was higher in patients with heart failure, this increase did not compensate for the reduced blood flow. Even though the maximal oxygen consumption was significantly reduced, femoral venous lactate and pH values were higher than values in control subjects, but femoral venous pH was similar in both groups at their respective levels of maximal exercise. Ejection fraction was lower in those with heart failure at rest and did not increase with exercise. Ventilation in relation to oxygen consumption was higher in patients with failure than in control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗