Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a sensitive functional marker in heart disease, including left ventricular hypertrophy (LVH) secondary to valvular aortic stenosis (AS). We evaluated the association between NT-proBNP changes, oxidative stress, energy status and severity of LVH in patients with AS. Ten patients undergoing aortic valve replacement for AS were studied. Plasma NT-proBNP concentrations were performed by electroluminescence immunoassay 15min after the induction of anesthesia (t0), before aortic cross-clamping (t1), before clamp removal (t2), 15min after myocardial reperfusion (t3), and 24h after surgery (t4). Heart biopsies were obtained and high energy phosphates (ATP, ADP, AMP) were analyzed by capillary electrophoresis (CE). In plasma samples from the coronary sinus, nitrate plus nitrite (NOx) concentrations were also analyzed by CE. Echocardiographic measurements were acquired and correlations between biochemical markers and severity of AS were assessed. NT-proBNP peaked significantly at t4 (p<0.001). A linear correlation between NT-proBNP values measured at t0 and t4 was found (R(2)=0.89; p<0.001). A negative correlation between NT-proBNP production and phosphorylation potential (ATP/ADP ratio) was observed (R(2)=0.62; p<0.01). NOx values positively correlated with NT-proBNP levels (p<0.01). NT-proBNP inversely correlated with aortic valvular area (r=81, p<0.01), positively correlated with mean (r=0.82, p<0.01) and maximum left ventricle-to-aortic gradients (r=0.80, p<0.01), and with left ventricular mass (r=0.69, p<0.01). NT-proBNP is a useful marker of LVH and severity of AS. It may complement echocardiographic evaluation of patients with AS in identifying the optimum time for surgery.
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PMID:NT-proBNP changes, oxidative stress, and energy status of hypertrophic myocardium following ischemia/reperfusion injury. 1735 Feb 21

Utilizing aortopulmonary vascular graft placement in the fetal lamb, we have developed a model (shunt) of pulmonary hypertension that mimics congenital heart disease with increased pulmonary blood flow. Our previous studies have identified a progressive development of endothelial dysfunction in shunt lambs that is dependent, at least in part, on decreased nitric oxide (NO) signaling. The purpose of this study was to evaluate the possible role of a disruption in carnitine metabolism in shunt lambs and to determine the effect on NO signaling. Our data indicate that at 2 wk of age, shunt lambs have significantly reduced expression (P < 0.05) of the key enzymes in carnitine metabolism: carnitine palmitoyltransferases 1 and 2 as well as carnitine acetyltransferase (CrAT). In addition, we found that CrAT activity was inhibited due to increased nitration. Furthermore, free carnitine levels were significantly decreased whereas acylcarnitine levels were significantly higher in shunt lambs (P < 0.05). We also found that alterations in carnitine metabolism resulted in mitochondrial dysfunction, since shunt lambs had significantly decreased pyruvate, increased lactate, and a reduced pyruvate/lactate ratio. In pulmonary arterial endothelial cells cultured from juvenile lambs, we found that mild uncoupling of the mitochondria led to a decrease in cellular ATP levels and a reduction in both endothelial NO synthase-heat shock protein 90 (eNOS-HSP90) interactions and NO signaling. Similarly, in shunt lambs we found a loss of eNOS-HSP90 interactions that correlated with a progressive decrease in NO signaling. Our data suggest that mitochondrial dysfunction may play a role in the development of endothelial dysfunction and pulmonary hypertension and increased pulmonary blood flow.
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PMID:Altered carnitine homeostasis is associated with decreased mitochondrial function and altered nitric oxide signaling in lambs with pulmonary hypertension. 1802 21

Transport ATPases can be lumped into four distinct types, P, F, V, and ABC, with the first three designated 20 years ago (Pedersen, P.L. and Carafoli, E., Trends Biochem. Sci. 12, 146-150, 1987) and the ABC type included more recently. The mini-reviews (>20) that comprise this volume of the Journal of Bioenergetics and Biomembranes describe work presented at the 2007 FASEB Conference (6th) on Transport ATPases (Kathleen Sweadner, Chair; Rajini Rao, Co-Chair). Since these conferences began in 1997, the "transport ATPase field" has seen tremendous progress. Advances include a much better understanding of the structure, mechanism, and regulation of each of the four major ATPase types as well as their physiological and medical relevance. In fact, the transport ATPase field has entered a new era in which work on these enzymes is likely to contribute to new therapies for multiple diseases that affect both people and animals. Among these are cancer and heart disease, mitochondrial diseases, osteoporosis, macromolecular degeneration, immune deficiency, cystic fibrosis, diabetes, ulcers, nephro-toxicity, hearing loss, skin disorders, lupus, and malaria. In addition, as several members of the transport ATPase family include those involved in drug resistance their study may help alleviate this recurring problem in drug development. Finally, the transport ATPase field is also paving the way for nanotechnology focused on nano-motors with work on the F-type ATPases (F(0)F(1)) leading the way. These ATPases driven in reverse by a proton gradient have the capacity to interconvert electrochemical energy into mechanical energy and finally into chemical energy conserved in the terminal bond of ATP. In mammalian mitochondria these events occur on a larger complex or "nano-machine" called the "ATP synthasome" that consists of the ATP synthase in complex formation with carriers for P(i) and ADP/ATP.
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PMID:Transport ATPases into the year 2008: a brief overview related to types, structures, functions and roles in health and disease. 1817 9

Exercise is associated with increased ATP need and an enhanced aerobic and/or anaerobic metabolism, which results in an increased formation of reactive oxygen species (ROS). Regular exercise seems to decrease the incidence of a wide range of ROS-associated diseases, including heart disease, type II diabetes, rheumatic arthritis, Alzheimer and Parkinson diseases, and certain cancers. The preventive effect of regular exercise, at least in part, is due to oxidative stress-induced adaptation. The oxidative challenge-related adaptive process of exercise is probably not just dependent upon the generated level of ROS but primarily on the increase in antioxidant and housekeeping enzyme activities, which involves the oxidative damage repair enzymes. Therefore, the effects of exercise resemble the characteristics of hormesis. In addition, it seems that the oxidative challenge-related effects of exercise are systemic. Skeletal muscle, liver, and brain have very different metabolic rates and functions during exercise, but the adaptive response is very similar: increased antioxidant/damage repair enzyme activity, lower oxidative damage, and increased resistance to oxidative stress, due to the changes in redox homeostasis. Hence, it is highly possible that the well-known beneficial effects of exercise are due to the capability of exercise to produce increased levels of ROS. Or in other words, it seems that the vulnerability of the body to oxidative stress and diseases is significantly enhanced in a sedentary compared to a physically active lifestyle.
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PMID:Systemic adaptation to oxidative challenge induced by regular exercise. 1819 51

Five types of oral antihyperglycemic drugs are currently approved for the treatment of diabetes: biguanides, sulfonylureas, meglitinides, glitazones and alpha-glucosidase inhibitors. We briefly review the cardiovascular effects of the most commonly used antidiabetic drugs in these groups in an attempt to improve knowledge and awareness regarding their influences and potential risks when treating patients with coronary artery disease (CAD). Regarding biguanides, gastrointestinal disturbances such as diarrhea are frequent, and the intestinal absorption of group B vitamins and folate is impaired during chronic therapy. This deficiency may lead to increased plasma homocysteine levels which, in turn, accelerate the progression of vascular disease due to adverse effects on platelets, clotting factors, and endothelium. The existence of a graded association between homocysteine levels and overall mortality in patients with CAD is well established. In addition, metformin may lead to lethal lactic acidosis, especially in patients with clinical conditions that predispose to this complication, such as heart failure or recent myocardial infarction. Sulfonylureas avoid ischemic preconditioning. During myocardial ischemia, they may prevent opening of the ATP-dependent potassium channels, impeding the necessary hyperpolarization that protects the cell by blocking calcium influx. Meglitinides may exert similar effects due to their analogous mechanism of action. During treatment with glitazones, edema has been reported in 5% of patients, and these drugs are contraindicated in diabetics with NYHA class III or IV cardiac status. The long-term effects of alpha-glucosidase inhibitors on morbidity and mortality rates and on diabetic micro- and macrovascular complications is still unknown. Combined sulfonylurea/metformin therapy reveals additive effects on mortality. Four points should be mentioned: (1) the five oral antidiabetic drug groups present proven or potential cardiac hazards; (2) these hazards are not mere 'side effects' but are deeply rooted in the drugs' mechanisms of action; (3) current data indicate that combined glibenclamide/metformin therapy seems to present a special risk and should be avoided in the long-term management of type 2 diabetics with proven CAD, and (4) Non-Insulin Antidiabetic Therapy in Diabetic Cardiac Patients 155 customized antihyperglycemic pharmacological approaches should be investigated for the optimal treatment of diabetic patients with heart disease. New possibilities are represented by incretin mimetic compounds, dipeptidyl peptidase (DPP)-4 inhibitors, inhaled insulin and eventually oral insulin.
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PMID:Non-insulin antidiabetic therapy in cardiac patients: current problems and future prospects. 1823 Sep 61

A large body of evidence indicates that sporadic Alzheimer's disease (AD) is a vascular disorder with neurodegenerative consequences and needs to be treated and managed as such. Epidemiologic studies of vascular risk factors, together with preclinical detection tools for AD are proof of concept that cerebral hypoperfusion is one of the earliest pathological signs in the development of cognitive failure. Vascular risk factors involving heart disease and stroke in the elderly individual who already possesses a dwindling cerebrovascular reserve due to advancing age contribute to further decline in cerebral blood flow (CBF) resulting in unrelenting brain hypoperfusion. Brain hypoperfusion, in turn, can reach a critically attained threshold of cerebral hypoperfusion (CATCH) giving rise to a neuronal energy crisis via reduced ATP synthesis. The ensuing metabolic energy crisis initially carves up ischemic-sensitive neurons in the hippocampus and posterior parietal cortex setting up cognitive meltdown and progressive neurodegenerative and atrophic changes in the brain. Neuronal energy compromise accelerates oxidative stress, excess production of reactive oxygen species, aberrant protein synthesis, ionic membrane pump dysfunction, signal transduction impairment, neurotransmitter failure, abnormal processing of amyloid precursor protein resulting in beta-amyloid deposition and axonal microtubule disruption from tau hyperphosphorylation. The high energy metabolic changes leading to oxidative stress and cellular hypometabolism precede clinical expression of AD. Regional CBF measurements using neuroimaging techniques can predict AD preclinically at the mild cognitive impairment stage or even before any clinical manifestation of dementia is expressed. Clinical diagnostic assessment of elderly persons who could develop or already present with memory complaints can prevent, reverse or slow down AD development. Although pathologic aging is the subject of thousands of studies, the question of why the elderly (and not younger people) succumb to AD has not been adequately addressed. The explanation(s) as to why vascular risk factors, for example, can trigger AD or vascular dementia usually in the elderly and not the young should provide vital clues in the search for a strategically effective dementia treatment. This review offers inductive hypothetical darts relative to that critical question.
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PMID:Pathophysiology of neuronal energy crisis in Alzheimer's disease. 1832 69

The disturbance of myocardial energy metabolism has been discussed as contributing to the progression of heart failure. Little however is known about the cardiac mitochondrial/cytosolic energy transfer in murine and human inflammatory heart disease. We examined the myocardial creatine kinase (CK) system, which connects mitochondrial ATP-producing and cytosolic ATP-consuming processes and is thus of central importance to the cellular energy homeostasis. The time course of expression and enzymatic activity of mitochondrial (mtCK) and cytosolic CK (cytCK) was investigated in Coxsackievirus B3 (CVB3)-infected SWR mice, which are susceptible to the development of chronic myocarditis. In addition, cytCK activity and isoform expression were analyzed in biopsies from patients with chronic inflammatory heart disease (n = 22). Cardiac CVB3 titer in CVB3-infected mice reached its maximum at 4 days post-infection (pi) and became undetectable at 28 days pi; cardiac inflammation cumulated 14 days pi but persisted through the 28-day survey. MtCK enzymatic activity was reduced by 40% without a concurrent decrease in mtCK protein during early and acute MC. Impaired mtCK activity was correlated with virus replication and increased level of interleukine 1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and elevated catalase expression, a marker for intracellular oxidative stress. A reduction in cytCK activity of 48% was observed at day 14 pi and persisted to day 28 pi. This restriction was caused by a decrease in cytCK subunit expression but also by direct inhibition of specific cytCK activity. CytCK activity and expression were also reduced in myocardial biopsies from enterovirus genome-negative patients with inflammatory heart disease. The decrease in cytCK activity correlated with the number of infiltrating macrophages. Thus, viral infection and myocardial inflammation significantly influence the myocardial CK system via restriction of specific CK activity and down-regulation of cytCK protein. These changes may contribute to the progression of chronic inflammatory heart disease and malfunction of the heart.
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PMID:Impact of myocardial inflammation on cytosolic and mitochondrial creatine kinase activity and expression. 1919 Sep 56

Classical non-insulin antihyperglycemic drugs currently approved for the treatment of type 2 diabetes mellitus (T2DM) comprise five groups: biguanides, sulfonylureas, meglitinides, glitazones and alpha-glucosidase inhibitors. Novel compounds are represented by the incretin mimetic drugs like glucagon like peptide-1 (GLP-1), the dipeptidyl peptidase 4 (DPP-4) inhibitors, dual peroxisome proliferator-activated receptors (PPAR) agonists (glitazars) and amylin mimetic drugs. We review the cardiovascular effects of these drugs in an attempt to improve knowledge regarding their potential risks when treating T2DM in cardiac patients. Metformin may lead to lethal lactic acidosis, especially in patients with clinical conditions that predispose to this complication, such as recent myocardial infarction, heart or renal failure. Sulfonylureas exert their effect by closing the ATP-dependent potassium channels. This prevents the opening of these channels during myocardial ischemia, impeding the necessary hyperpolarization that protects the cell. The combined sulfonylurea/metformin therapy reveals additive effects on mortality in patients with coronary artery disease (CAD). Meglitinides effects are similar to those of sulfonylureas, due to their almost analogous mechanism of action. Glitazones lower leptin levels, leading to weight gain and are unsafe in NYHA class III or IV. The long-term effects of alpha-glucosidase inhibitors on morbidity and mortality rates is yet unknown. The incretin GLP-1 is associated with reductions in body weight and appears to present positive inotropic effects. DPP-4 inhibitors influences on the cardiovascular system seem to be neutral and patients do not gain weight. The future of glitazars is presently uncertain following concerns about their safety. The amylin mimetic drug paramlintide, while a satisfactory adjuvant medication in insulin-dependent diabetes, is unlikely to play a major role in the management of T2DM. Summarizing the present information it can be stated that 1. Four out the five classical oral antidiabetic drug groups present proven or potential cardiac hazards; 2. These hazards are not mere 'side effects', but biochemical phenomena which are deeply rooted in the drugs' mechanism of action; 3. Current data indicate that the combined glibenclamide/metformin therapy seems to present special risk and should be avoided in the long-term management of T2DM with proven CAD; 4. Glitazones should be avoided in patients with overt heart failure; 5, The novel incretin mimetic drugs and DPP-4 inhibitors--while usually inadequate as monotherapy--appear to be satisfactory adjuvant drugs due to the lack of known undesirable cardiovascular effects; 6. Customized antihyperglycemic pharmacological approaches should be implemented for the achievement of optimal treatment of T2DM patients with heart disease. In this context, it should be carefully taken into consideration whether the leading clinical status is CAD or heart failure.
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PMID:A cardiologic approach to non-insulin antidiabetic pharmacotherapy in patients with heart disease. 1961 27

Investigation of phosphorus ((31)P) magnetic resonance spectroscopy under stress conditions provides a non-invasive tool to examine alterations in cardiac high-energy phosphate metabolism that may not be evident at rest. Our aim was to establish cardiac (31)P MR spectroscopy during leg exercise at 3T. The increased field strength should provide a higher signal to noise ratio than at lower field strengths. Furthermore, relatively high temporal resolution at a sufficiently fine spatial resolution should be feasible. (31)P MR spectra were obtained with a 3D acquisition weighted chemical shift imaging sequence in 20 healthy volunteers at rest, during dynamic physiological leg exercise and after recovery at 3T. Haemodynamic measurements were made throughout and the rate pressure product calculated. With exercise, the mean heart rate increased by 73%, achieving a mean increase in rate pressure product of 115%. The corrected PCr/ATP ratio for subjects at rest was 2.02 +/- 0.43, exercise 2.14 +/- 0.67 (P = 0.54 vs. rest) and at recovery 2.03 +/- 0.52 (P = 0.91 vs. rest, P = 0.62 vs. exercise). A cardiac (31)P MR spectroscopy physiological exercise-recovery protocol is feasible at 3T. There was no significant change in high-energy cardiac phosphate metabolite concentrations in healthy volunteers at rest, during physiological leg exercise or during recovery. When applied to patients with heart disease, this protocol should provide insights into physiological and pathological cardiac metabolism.
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PMID:(31)P cardiac magnetic resonance spectroscopy during leg exercise at 3 Tesla. 1969 52

Heterodimeric nucleotide binding domains NBD1/NBD2 distinguish the ATP-binding cassette protein SUR2A, a recognized regulatory subunit of cardiac ATP-sensitive K(+) (K(ATP)) channels. The tandem function of these core domains ensures metabolism-dependent gating of the Kir6.2 channel pore, yet their structural arrangement has not been resolved. Here, purified monodisperse and interference-free recombinant particles were subjected to synchrotron radiation small-angle X-ray scattering (SAXS) in solution. Intensity function analysis of SAXS profiles resolved NBD1 and NBD2 as octamers. Implemented by ab initio simulated annealing, shape determination prioritized an oblong envelope wrapping NBD1 and NBD2 with respective dimensions of 168x80x37A(3) and 175x81x37A(3) based on symmetry constraints, validated by atomic force microscopy. Docking crystal structure homology models against SAXS data reconstructed the NBD ensemble surrounding an inner cleft suitable for Kir6.2 insertion. Human heart disease-associated mutations introduced in silico verified the criticality of the mapped protein-protein interface. The resolved quaternary structure delineates thereby a macromolecular arrangement of K(ATP) channel SUR2A regulatory domains.
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PMID:Quaternary structure of KATP channel SUR2A nucleotide binding domains resolved by synchrotron radiation X-ray scattering. 1991 49


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