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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In addition to regulating vascular tone, there is increasing evidence for the involvement of NO in the modulation of oxygen consumption. Our in-vitro studies indicated that exogenous and endogenous NO reduces the consumption of oxygen in isolated canine skeletal and cardiac muscle, which is probably related to its direct effect on mitochondria, i.e. cytochrome oxidase. In resting, conscious dogs, the blockade of NO synthesis results in an increase in total oxygen consumption. During exercise, there is a significant increase in the release of NO from the coronary circulation in conscious dogs, and there are greater increases in total oxygen consumption, and oxygen consumption in skeletal muscle and in the heart when NO synthesis is blocked. Our results suggest that NO plays a role in matching blood flow to tissue metabolism at rest and during exercise. The modulation of the consumption of O2 by endogenous NO in skeletal or cardiac muscle is blunted after the development of heart failure or diabetes. After heart failure, the heart switches from fatty acid to glucose metabolism, suggesting that NO also plays a role in the regulation of metabolism in the heart.
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PMID:Nitric oxide and oxygen utilization: exercise, heart failure and diabetes. 1042 71

Endothelium-derived NO is considered to be primarily an important determinant of vascular tone and platelet activity; however, the modulation of myocardial metabolism by NO may be one of its most important roles. This modulation may be critical for the regulation of tissue metabolism. Several physiological processes act in concert to make endothelial NO synthase-derived NO potentially important in the regulation of mitochondrial respiration in cardiac tissue, including (1) the nature of the capillary network in the myocardium, (2) the diffusion distance for NO, (3) the low toxicity of NO at physiological (nanomolar) concentrations, (4) the fact that low PO(2) in tissue facilitates the action of NO on cytochrome oxidase, and (5) the formation of oxygen free radicals. A decrease in NO production is involved in the pathophysiological modifications that occur in heart failure and diabetes, disease states associated with altered cardiac metabolism that contributes to the evolution of the disease process. In contrast, several drugs (eg, angiotensin-converting enzyme inhibitors, amlodipine, and statins) can restore or maintain endogenous production of NO by endothelial cells, and this mechanism may explain part of their therapeutic efficiency. Thus, the purpose of this review is to critically evaluate the role of NO in the control of mitochondrial respiration, with special emphasis on its effect on cardiac metabolism.
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PMID:Role of endothelium-derived nitric oxide in the regulation of cardiac oxygen metabolism: implications in health and disease. 1111 Jul 67

Introduction of the constitutively active calcineurin gene into neonatal rat cardiomyocytes by adenovirus resulted in decreased mitochondrial membrane potential (P < 0.05). Infection of H9c2 cells with calcineurin adenovirus resulted in increased superoxide production (P < 0.001). Transgenic mice with cardiac-specific expression of a constitutively active calcineurin cDNA (CalTG mice) exhibit a two- to threefold increase in heart size that progresses to heart failure. We prepared mitochondria enriched for the subsarcolemmal population from the hearts of CalTG mice and transgene negative littermates (control). Intact, well-coupled mitochondria prepared from one to two mouse hearts at a time yielded sufficient material for functional studies. Mitochondrial oxygen consumption was measured with a Clark-type oxygen electrode with substrates for mitochondrial complex II (succinate) and complex IV [tetramethylpentadecane (TMPD)/ascorbate]. CalTG mice exhibited a maximal rate of electron transfer in heart mitochondria that was reduced by approximately 50% (P < 0.002) without a loss of respiratory control. Mitochondrial respiration was unaffected in tropomodulin-overexpressing transgenic mice, another model of cardiomyopathy. Western blotting for mitochondrial electron transfer subunits from mitochondria of CalTG mice revealed a 20-30% reduction in subunit 3 of complex I (ND3) and subunits I and IV of cytochrome oxidase (CO-I, CO-IV) when normalized to total mitochondrial protein or to the adenine nucleotide transporter (ANT) and compared with littermate controls (P < 0.002). Impaired mitochondrial electron transport was associated with high levels of superoxide production in the CalTG mice. Taken together, these data indicate that calcineurin signaling affects mitochondrial energetics and superoxide production. The excessive production of superoxide may contribute to the development of cardiac failure.
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PMID:Calcineurin transgenic mice have mitochondrial dysfunction and elevated superoxide production. 1239 29

Although the specific roles of nitric oxide (NO) in the heart in general and on cardiac mitochondria in particular remain controversial, it is now clear that both endogenous and exogenous sources of NO exert important modulatory effects on mitochondrial function. There is also growing evidence that NO can be produced within the mitochondria themselves. NO can influence respiratory activity, both through direct effects on the respiratory chain or indirectly via modulation of mitochondrial calcium accumulation. At pathological concentrations, NO can cause irreversible alterations in respiratory function and can also interact with reactive oxygen species (ROS) to form reactive nitrogen species, which may further impair mitochondrial respiration and can even lead to opening of the mitochondrial permeability transition pore and cell death. Diabetes, aging, myocardial ischemia, and heart failure have all been associated with altered ROS generation, which can alter the delicate regulatory balance of effects of NO in the mitochondria. As NO competes with oxygen at cytochrome oxidase, it can be argued that experiments exploring the roles of NO on mitochondrial respiration should be performed at physiological (i.e. relatively low) oxygen tensions. Improvements in techniques, and a gradual appreciation of the many potential pitfalls in studying mitochondrial NO, are leading to a recognition of the role of NO in the regulation of mitochondrial function in the heart in health and disease.
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PMID:Effects of NO on mitochondrial function in cardiomyocytes: Pathophysiological relevance. 1651 74

Heart failure is associated with alterations in cardiac and skeletal muscle energy metabolism resulting in a generalized myopathy. We investigated the molecular and cellular effects of angiotensin-converting enzyme inhibition (ACEi) on skeletal muscle metabolism in infarcted animals. Myocardial infarction (MI) was obtained by left descending coronary artery ligation. Sham, MI, and MI-treated rats (perindopril, 2 mg.kg(-1).day(-1) given 7 days after MI) were studied 1 and 4 mo after surgery. Oxygen consumption of white gastrocnemius (Gas) muscle was studied in saponin-permeabilized fibers, using the main substrates of mitochondrial respiration. mRNA expression of nuclear factors (PGC-1alpha, NRF-2alpha, and mtTFA), involved in the transcription of mitochondrial proteins, and of MCIP1, a marker of calcineurin activation, were also determined. Echocardiographic left ventricular fractional shortening was reduced in both MI and perindopril group after 1 and 4 mo, whereas systemic blood pressure was reduced by 16% only in the MI group after 4 mo. The capacity of Gas to oxidize glutamate-malate, glycerol-triphosphate, or pyruvate (-30%, P < 0.01; -32%, P < 0.05; -33%, P < 0.01, respectively), was greatly decreased. Furthermore, PGC-1alpha (-54%), NRF-2alpha (-45%), and MCIP1 (-84%) gene expression were significantly downregulated. ACEi improved survival, left ventricular function, and blood pressure. Perindopril protected also totally the Gas mitochondrial function and preserved the mRNAs concentration of the mitochondrial transcriptional factors. Moreover, PGC-1alpha correlated with Gas oxidative capacity (r = 0.48), mitochondrial cytochrome-c oxidase (r = 0.65), citrate synthase (r = 0.45) activities, and MCIP1 expression (r = 0.44). Thus ACEi totally prevented MI-induced alterations of skeletal muscle mitochondrial function and protein expression, halting the development of this metabolic myopathy.
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PMID:ACE inhibition prevents myocardial infarction-induced skeletal muscle mitochondrial dysfunction. 1661 54

Mitochondrial Ca(2+) plays important roles in the regulation of energy metabolism and cellular Ca(2+) homeostasis. In this study, we characterized mitochondrial Ca(2+) accumulation in Syrian hamster hearts with hereditary cardiomyopathy (strain BIO 14.6). Exposure of isolated mitochondria from 70 nM to 30 microM Ca(2+) ([Ca(2+)](o)) caused a concentration-dependent increase in intramitochondrial Ca(2+) concentrations ([Ca(2+)](m)). The [Ca(2+)](m) was significantly lower in cardiomyopathic (CMP) hamsters than in healthy hamsters when [Ca(2+)](o) was higher than 1 microM and a decrease of about 52% was detected at [Ca(2+)](o) of 30 microM (916 +/- 67 nM vs 1,932 +/- 132 nM in control). A possible mechanism responsible for the decreased mitochondrial Ca(2+) uptake in CMP hamsters is the depolarization of mitochondrial membrane potential (Delta psi (m)). Using a tetraphenylphosphonium (TPP(+)) electrode, the measured Delta psi (m) in failing heart mitochondria was -136 +/- 1.5 mV compared with -159 +/- 1.3 mV in controls. Analyses of mitochondrial respiratory chain demonstrated a significant impairment of complex I and complex IV activities in failing heart mitochondria. In summary, a less negative Delta psi (m) resulting from defects in the respiratory chain may lead to attenuated mitochondrial Ca(2+) accumulation, which in turn may contribute to the depressed energy production and myocardial contractility in this model of heart failure. In addition to other known impairments of ion transport in sarcoplasmic reticulum and plasma membrane, results from this paper on mitochondrial dysfunctions expand our understanding of the molecular mechanisms leading to heart failure.
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PMID:Mechanisms of reduced mitochondrial Ca2+ accumulation in failing hamster heart. 1738 8

The mitochondrial phospholipid cardiolipin is required for optimal mitochondrial respiration. In this study, cardiolipin molecular species and cytochrome oxidase (COx) activity were studied in interfibrillar (IF) and subsarcolemmal (SSL) cardiac mitochondria from Spontaneously Hypertensive Heart Failure (SHHF) and Sprague-Dawley (SD) rats throughout their natural life span. Fisher Brown Norway (FBN) and young aortic-constricted SHHF rats were also studied to investigate cardiolipin alterations in aging versus pathology. Additionally, cardiolipin was analyzed in human hearts explanted from patients with dilated cardiomyopathy. A loss of tetralinoleoyl cardiolipin (L(4)CL), the predominant species in the healthy mammalian heart, occurred during the natural or accelerated development of heart failure in SHHF rats and humans. L(4)CL decreases correlated with reduced COx activity (no decrease in protein levels) in SHHF cardiac mitochondria, but with no change in citrate synthase (a matrix enzyme) activity. The fraction of cardiac cardiolipin containing L(4)CL became much lower with age in SHHF than in SD or FBN mitochondria. In summary, a progressive loss of cardiac L(4)CL, possibly attributable to decreased remodeling, occurs in response to chronic cardiac overload, but not aging alone, in both IF and SSL mitochondria. This may contribute to mitochondrial respiratory dysfunction during the pathogenesis of heart failure.
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PMID:Loss of cardiac tetralinoleoyl cardiolipin in human and experimental heart failure. 1742 48

Although linked with cardiac dysfunction, the association of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) and pulmonary artery hypertension (PAH) has not been previously described. PAH and right ventricular heart failure were identified by echocardiography in a 3-year-old boy with a history of hypotonia, microcephaly and developmental delay. He initially presented with a 10-day history of dyspnoea, dependent oedema and reduced oral intake. Lactic acidosis was noted on serial arterial blood sampling and cerebrospinal fluid. Muscle biopsy demonstrated cytochrome-c oxidase-positive 'ragged-red' fibres consistent with MELAS; subsequent analyses revealed the m.3243A>G point mutation most commonly associated with MELAS. The mutation was heteroplasmic, representing 92% of the total mtDNA from a lung sample. Nitric oxide and epoprostenol were administered without significant clinical or echocardiographic improvement of his PAH. A 'mitochondrial cocktail' including biotin, riboflavin, carnitine and coenzyme Q10 also was provided. Five months after presentation, he developed seizures; MRI imaging of his brain demonstrated multiple focal lesions. His clinical status worsened with increasing cardiopulmonary failure. He died two months later. Although therapy for both MELAS and PAH remains limited, recent investigations suggest a beneficial role for l-arginine in both conditions, implying a possible common pathophysiology. Mitochondrial diseases such as MELAS should be considered in cases of idiopathic PAH, particularly when associated with multisystem involvement including short stature, hearing loss, renal dysfunction, retinopathy, diabetes mellitus, migraines, seizures, ophthalmoplegia, fatigability and weakness.
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PMID:Pulmonary artery hypertension in a child with MELAS due to a point mutation of the mitochondrial tRNA((Leu)) gene (m.3243A>G). 1818 Oct 29

Exercise training improves functional capacity and quality of life in patients with heart failure. However, the long-term effects of exercise on mortality associated with hypertensive heart disease have not been well defined. In the present study, we investigated the effect of low-intensity exercise training on disease progression and survival in female spontaneously hypertensive heart failure rats. Animals with severe hypertension (16 months old) were treadmill trained (14.5 m/min, 45 min/d, 3 d/wk) until they developed terminal heart failure or were euthanized because of age-related complications. Exercise delayed mortality resulting from heart failure (P<0.001) and all causes (P<0.05) and transiently attenuated the systolic hypertension and contractile dysfunction observed in the sedentary animals but had no effect on cardiac morphology or contractile function in end-stage heart failure. Training had no effect on terminal myocardial protein expression of antioxidant enzymes, calcium handling proteins, or myosin heavy chain isoforms but was associated with higher cytochrome oxidase activity in cardiac mitochondria (P<0.05) and a greater mitochondrial content of cardiolipin, a phospholipid that is essential for optimal mitochondrial energy metabolism. In conclusion, low-intensity exercise training significantly delays the onset of heart failure and improves survival in female hypertensive heart failure rats without eliciting sustained improvements in blood pressure, cardiac function, or expression of several myocardial proteins associated with the cardiovascular benefits of exercise. The effects of exercise on cytochrome oxidase and cardiolipin provide novel evidence that training may improve prognosis in hypertensive heart disease by preserving mitochondrial energy metabolism.
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PMID:Low-intensity exercise training delays heart failure and improves survival in female hypertensive heart failure rats. 1825 16

Propofol (2, 6-diisopropylphenol) is a potent intravenous hypnotic agent that is widely used in adults and children for sedation and the induction and maintenance of anaesthesia. Propofol has gained popularity for its rapid onset and rapid recovery even after prolonged use, and for the neuroprotection conferred. However, a review of the literature reveals multiple instances in which prolonged propofol administration (>48 hours) at high doses (>4 mg/kg/h) may cause a rare, but frequently fatal complication known as propofol infusion syndrome (PRIS). PRIS is characterized by metabolic acidosis, rhabdomyolysis of both skeletal and cardiac muscle, arrhythmias (bradycardia, atrial fibrillation, ventricular and supraventricular tachycardia, bundle branch block and asystole), myocardial failure, renal failure, hepatomegaly and death. PRIS has been described as an 'all or none' syndrome with sudden onset and probable death. The literature does not provide evidence of degrees of symptoms, nor of mildness or severity of signs in the clinical course of the syndrome. Recently, a fatal case of PRIS at a low infusion rate (1.9-2.6 mg/kg/h) has been reported. Common laboratory and instrumental findings in PRIS are myoglobinuria, downsloping ST-segment elevation, an increase in plasma creatine kinase, troponin I, potassium, creatinine, azotaemia, malonylcarnitine and C5-acylcarnitine, whereas in the mitochondrial respiratory electron transport chain, the activity of complex IV and cytochrome oxidase ratio is reduced. Propofol should be used with caution for sedation in critically ill children and adults, as well as for long-term anesthesia in otherwise healthy patients, and doses exceeding 4-5 mg/kg/h for long periods (>48 h) should be avoided. If PRIS is suspected, propofol must be stopped immediately and cardiocirculatory stabilization and correction of metabolic acidosis initiated. So, PRIS must be kept in mind as a rare, but highly lethal, complication of propofol use, not necessarily confined to its prolonged use. Furthermore, the safe dosage of propofol may need re-evaluation, and new studies are needed.
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PMID:Propofol infusion syndrome: an overview of a perplexing disease. 2002 84


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