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

The pathogenesis of preeclampsia stems from aberrant changes at the placental interface. The trophoblastic endovascular invasion of tonic spiral arteries that converts them to passive conduits falters. Uteroplacental insufficiency and fetoplacental hypoxemia result. Secondary maternal oxidative stress and an excessive inflammatory response to pregnancy generate the clinical syndrome of preeclampsia. Current treatment focuses on preventing seizures, controlling hypertension, preserving renal function and delivering the baby. We propose that the pathophysiological changes induced by preeclampsia in the placenta parallel those caused by persistent hypoxemia in the lungs at high altitude or with chronic obstructive pulmonary disease. Unrelenting pulmonary hypoxic vasoconstriction induces pulmonary hypertension and cor pulmonale. Inhalation of nitric oxide and phosphodiesterase-5 inhibitors opposes pulmonary hypoxic vasoconstriction, alleviates pulmonary hypertension and improves systemic oxygenation. Notably nitric oxide donor therapy also counters hypoxemic fetoplacental vasoconstriction, a biological response analogous to pulmonary hypoxic vasoconstriction. Fetal oxygenation and nutrition improve. Placental upstream resistance to umbilical arterial blood flow decreases. Fetal right ventricular impedance falls. Heart failure (cor placentale) is avoided. Emergency preterm delivery can be postponed. Other than low dose aspirin and antioxidants vitamins C and E no available therapy specifically targets the underlying disease profile. We hypothesize that, like nitric oxide donation, pharmacological inhibition of placental phosphodiesterase-5 will also protect the fetus but for a longer time. Biological availability of guanosine 3'5'-cyclic monophosphate is boosted due to slowed hydrolysis. Adenosine 3'5'-cyclic monphosphate levels increase in parallel. Cyclic nucleotide accumulation dilates intact tonic spiral arteries and counters hypoxemic fetoplacental vasoconstriction. Intervillous and intravillous perfusion pick up. Maternal to fetal placental circulatory matching improves. Enhanced placental oxygen uptake alleviates hypoxemic fetal stress. Appropriate fetal nutrition resumes. Cor placentale and severe intrauterine growth restriction are averted. Increased maternal cyclic nucleotide concentrations promote systemic vasodilatation so that blood pressures fall. Preemption of oxidative stress initiated by "consumptive" oxidation of nitric oxide stabilizes the vascular endothelium and corrects coagulopathy. Anti-inflammatory and immunosuppressant adenosine 3'5'-cyclic monphosphate offsets the extreme gestational inflammatory response. Cellular injury and multi-organ damage are prevented. One tablet a day of the new long acting phosphodiesterase-5 inhibitor, tadalafil (half life of 17.5 h) theoretically should allow a preterm pregnancy affected by preeclampsia to continue safely. Selective monitoring of vital organ functions guards against life-threatening maternal complications. Regular biophysical profiling warns the obstetrician of impending fetal compromise. Fetal growth and vital organ maturation can continue. As a result workloads imposed upon neonatal intensivists will lighten. Parental anxiety and concern will be allayed. The cost of treating preeclamptic mothers and their extremely low birth weight infants will decrease. Money saved by midwifery services in poorer states can be used to pay for better prenatal care. Severe preeclampsia/eclampsia will be less common. Maternal and perinatal morbidity and mortality will be reduced. Because the human immunodeficiency virus often infects individuals at a workforce eligible age, the global acquired immunodeficiency syndrome pandemic has already brought many nations to the brink of economic ruin. Potentially productive lives saved for the future will help restore them fiscally.
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PMID:Hypothesis: selective phosphodiesterase-5 inhibition improves outcome in preeclampsia. 1550 76

Dysfunction of the vascular endothelium is a hallmark of most conditions that are associated with atherosclerosis and is therefore held to be an early feature in atherogenesis. However, the mechanisms by which endothelial dysfunction occurs in smoking, dyslipidaemia, hyperhomocysteinaemia, diabetes mellitus, arterial hypertension, cerebrovascular diseases, coronary artery disease and heart failure are complex and heterogeneous. Recent data indicate that endothelial dysfunction is often associated with erectile dysfunction, which can precede and predict cardiovascular disease in men. This paper will provide a concise overview of the mechanisms causing endothelial dysfunction in the different cardiovascular risk factors and disease conditions, and of the impact of the intervention measures and treatments.
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PMID:Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension. 1566 7

Chronic pain in the elderly is frequently a result of arthritic disorders, particularly osteoarthritis. The cyclo-oxygenase (COX)-2 inhibitors are as effective as standard NSAIDs for the relief of pain and for improving function in elderly patients with osteoarthritis and rheumatoid arthritis. COX-2 inhibitors increase the risk of serious gastroduodenal adverse reactions but there is evidence that they carry a lower risk for these adverse effects than standard NSAIDs, except when there is concurrent aspirin use. Since gastroduodenal disorders are the most frequently reported serious adverse effects of NSAIDs and these disorders occur more frequently in the elderly, COX-2 inhibitors offer an alternative to standard NSAIDs in this age group. However, they are not appropriate for many patients with cardiovascular and renal disease. The adverse reaction profile of the COX-2 inhibitors has confirmed the role of the COX-2 enzyme in renal function, salt and water homeostasis and the vascular endothelium. Thus, like standard NSAIDs, COX-2 inhibitors can cause renal failure, hypertension and exacerbation of cardiac failure. Of note is that these disorders are dose related. Thus, there are good reasons to avoid high doses of COX-2 inhibitors in the elderly. Clinical trials indicate that daily doses of rofecoxib 12.5 mg, celecoxib 100-200 mg, valdecoxib 10mg and etoricoxib 60 mg are the minimum effective doses of these agents. Data from the New Zealand Intensive Medicines Monitoring Programme indicate that celecoxib 200 mg/day and rofecoxib 25 mg/day are/were the most commonly prescribed doses and that 6% of patients had taken rofecoxib 50 mg/day for longer than recommended. Recent research indicates that COX-2 inhibitors have a thrombotic potential, especially in high doses and when use is prolonged, and this further limits the extent to which they can be used in the elderly. Important interactions with COX-2 inhibitors in the elderly include those with warfarin, which can result in loss of control of anticoagulation, and those with ACE inhibitors, angiotensin II type 1 receptor antagonists and diuretics, which can result in loss of control of blood pressure and cardiac failure and, in hypovolaemic conditions, renal failure. The clinical significance of an interaction between celecoxib and aspirin to reduce the antiplatelet effect of the latter drug is unknown. Preliminary information from spontaneous reporting systems indicates that there may be differences in the risk of cardiac failure and hypertension between standard NSAIDs and COX-2 inhibitors and between rofecoxib and celecoxib. More formal studies using equivalent doses are needed to test this observation. Use of COX-2 inhibitors may be considered in the elderly to reduce the risk of gastroduodenal complications associated with standard NSAIDs but only when consideration has first been given to use of less toxic medicines as alternatives or supplements, the appropriate dose of the COX-2 inhibitor or standard NSAID, the presence and possible impact of co-morbidities, and the implications of taking COX-2 inhibitors with any concomitant medications. Equally important is regular monitoring of the patient taking a COX-2 inhibitor for efficacy and adverse effects, and ensuring that the patient has a continuing need to keep taking the drug. Close attention also needs to be paid to intercurrent illnesses and new prescriptions that may reduce the safety of the COX-2 inhibitor. A standard NSAID plus a proton pump inhibitor may be equally effective as a COX-2 inhibitor in reducing the risk of gastroduodenal toxicity and if used the same prescribing advice applies. Current knowledge concerning the thrombotic potential of COX-2 inhibitors suggests that this combination, if tolerated, may be preferable to a COX-2 inhibitor, particularly where prolonged use is required. This knowledge also indicates that for patients with or at high risk of ischaemic heart disease or stroke, COX-2 inhibitors are contraindicated.
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PMID:Cyclo-oxygenase-2 inhibitors: when should they be used in the elderly? 1581 52

Evidence suggests that vascular endothelium plays key role in the regulation of vascular tone, in the process of inflammation and in the thrombotic mechanisms. Recent studies indicate that it is an important component of the pathophysiological mechanisms of heart failure. Heart failure may induce endothelial dysfunction by different mechanisms, such as reduced synthesis and release of nitric oxide (NO), increased degradation of NO or by increased production of endothelin-1. In addition, endothelial dysfunction has been associated with the progression of heart failure. Alterations in neurotransmitters, hormones and also in physiological stimuli are present in heart failure and affect the vascular endothelium. Treatments with beneficial effects on endothelial dysfunction may also improve prognosis in patients with heart failure.
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PMID:Inflammation and endothelial dysfunction as therapeutic targets in patients with heart failure. 1583 76

Recent large clinical trials have shown that angiotensin II type I receptor blockers (ARBs) reduce cardiovascular morbidity and mortality in patients with heart failure, acute myocardial infarction, and hypertension. However, the mechanism underlying antiatherogenic effects of ARBs remains unclear. The vascular endothelium is involved in the release of various vasodilators, including nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor as well as vasoconstrictors. NO plays an important role in the regulation of vascular tone, the inhibition of platelet aggregation, and the suppression of smooth muscle cell proliferation. Several investigators have reported impairment in endothelium-dependent vasodilation in the forearm, coronary, and renal vasculature in cardiovascular diseases, including hypertensive patients. Cardiovascular diseases are associated with alteration in endothelial function. Endothelial dysfunction is the initial step in the pathogenesis of atherosclerosis. Anti-renin-angiotensin system agents, angiotensin-converting enzyme (ACE) inhibitors improve endothelial function in patients with hypertension, diabetes mellitus, and coronary artery disease. It is well known that ACE inhibitors augment endothelium-dependent vasodilation through an increase in NO bioavailability, by an increase in NO production and a decrease in NO inactivation. ARBs are also thought to prevent cardiovascular complications through an augmentation of endothelial function. In this review, we focus on recent findings and putative mechanisms of the beneficial effects of ARBs on endothelial function.
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PMID:Angiotensin II type I receptor blocker and endothelial function in humans: role of nitric oxide and oxidative stress. 1585

Cardiovascular disease is the single leading cause of death and morbidity for Canadians. A universal feature of cardiovascular disease is dysfunction of the vascular endothelium, thus disrupting control of vasodilation, tissue perfusion, hemostasis, and thrombosis. Nitric oxide bioavailability, crucial for maintaining vascular endothelial health and function, depends on the processes controlling synthesis and destruction of nitric oxide as well as on the sensitivity of target tissue to nitric oxide. Evidence supports a major contribution by oxidative stress-induced destruction of nitric oxide to the endothelial dysfunction that accompanies a number of cardiovascular disease states including hypertension, diabetes, chronic heart failure, and atherosclerosis. Regular physical activity (exercise training) reduces cardiovascular disease risk. Numerous studies support the hypothesis that exercise training improves vascular endothelial function, especially when it has been impaired by preexisting risk factors. Evidence is emerging to support a role for improved nitric oxide bioavailability with training as a result of enhanced synthesis and reduced oxidative stress-mediated destruction. Molecular targets sensitive to the exercise training effect include the endothelial nitric oxide synthase and the antioxidant enzyme superoxide dismutase. However, many fundamental details of the cellular and molecular mechanisms linking exercise to altered molecular and functional endothelial phenotypes have yet to be discovered. The working hypothesis is that some of the cellular mechanisms contributing to endothelial dysfunction in cardiovascular disease can be targeted and reversed by signals associated with regular increases in physical activity. The capacity for exercise training to regulate vascular endothelial function, nitric oxide bioavailability, and oxidative stress is an example of how lifestyle can complement medicine and pharmacology in the prevention and management of cardiovascular disease.
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PMID:Vascular nitric oxide and oxidative stress: determinants of endothelial adaptations to cardiovascular disease and to physical activity. 1625 83

The endothelin (ET) system consists of 3 ET isopeptides, several isoforms of activating peptidases, and 2 G-protein-coupled receptors, ETA and ETB, that are linked to multiple signaling pathways. In the cardiovascular system, the components of the ET family are expressed in several tissues, notably the vascular endothelium, smooth muscle cells, and cardiomyocytes. There is general agreement that ETs play important physiological roles in the regulation of normal cardiovascular function, and excessive generation of ET isopeptides has been linked to major cardiovascular pathologies, including hypertension and heart failure. However, several recent clinical trials with ET receptor antagonists were disappointing. In the present review, the authors take the stance that ETs are mainly and foremost essential regulators of cardiovascular function, hence that antagonizing normal ET actions, even in patients, will potentially do more harm than good. To support this notion, we describe the predominant roles of ETs in blood vessels, which are (indirect) vasodilatation and ET clearance from plasma and interstitial spaces, against the background of the subcellular mechanisms mediating these effects. Furthermore, important roles of ETs in regulating and adapting heart functions to different needs are addressed, including recent progress in understanding the effects of ETs on diastolic function, adaptations to changes in preload, and the interactions between endocardial-derived ET-1 and myocardial pump function. Finally, the potential dangers (and gains) resulting from the suppression of excessive generation or activity of ETs occurring in some cardiovascular pathological states, such as hypertension, myocardial ischemia, and heart failure, are discussed.
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PMID:Cardiovascular endothelins: essential regulators of cardiovascular homeostasis. 1645 92

Semicarbazide-sensitive amine oxidase (SSAO) resides on the vascular endothelium and smooth muscle cell surface and is capable of deaminating short chain aliphatic amines and producing toxic aldehydes and hydrogen peroxide. The enzyme, also known as a vascular adhesion protein-1, is involved in the inflammation process. This intriguing protein with dual functions is increased in the serum of diabetic and heart failure patients. In the present study we assessed the involvement of SSAO in a lipopolysaccharide-induced pulmonary inflammation model using transgenic mice that overexpress human vascular adhesion protein-1. Overexpression of SSAO activity increased the formation of protein-formaldehyde deposits in tissues. Lysine residues of proteins were the primary targets for cross-linkage with formaldehyde derived from deamination of methylamine. Lipo-polysaccharide-induced increases in inflammatory cells in the bronchoalveolar lavage (BAL) fluid were significantly higher in the transgenic than in the nontransgenic mice. BAL cell counts were also higher in the untreated transgenic than in nontransgenic mice. Blocking SSAO activity with a selective inhibitor significantly reduced the number of neutrophils as well as levels of macrophage inflammatory protein-1alpha, granulocyte colony-stimulating factor, tumor necrosis factor-alpha, and interleukin-6 in the BAL fluid. Inhalation of methylamine also increased BAL neutrophil counts. Together, these results suggest a role for SSAO-mediated deamination in pulmonary inflammation.
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PMID:Involvement of semicarbazide-sensitive amine oxidase-mediated deamination in lipopolysaccharide-induced pulmonary inflammation. 1650 87

Understanding metabolism of nitric oxide (NO), signal molecule releasing from endothelial cells and influencing vascular tone, belongs to the most remarkable knowledge of last ten years. NO increases vascular tone, inhibits adhesion of monocytes and leukocytes to the vascular endothelium and reduces atherogenic process. Low NO level is one of pathogenic factors starting cardiovascular diseases. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of enzyme NO synthase, enzyme catalyzing NO production from arginine. This article gives a brief overview of contemporary state of the relation between ADMA and cardiovascular diseases. Increased ADMA levels are associated with reduced NO synthesis as assessed by impaired endothelium-dependent vasodilatation. In several prospective studies, ADMA evolved as a marker of cardiovascular risk. In the first chapters is described state of the art of biosynthesis, degradation and excretion of ADMA in connection with endothelial dysfunction, coronary artery disease, chronic heart failure, cardiovascular risk in haemodialysis patients, diabetes mellitus, hypertension, lipid metabolism disorders and intensive care unit treatment. Next chapters shortly summarize methods of ADMA detection and their applications. In conclusion clinical relevance of measurement of ADMA levels as a marker of endothelial dysfunction is discussed. Future research tasks of ADMA lead to prospective studies with different types of patients and also healthy population. Moreover ADMA is becoming a goal for pharmacotherapeutic intervention to improve endothelium-dependent vascular function in subjects with high ADMA levels.
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PMID:[Asymmetric dimethylarginine--a novel cardiovascular risk factor]. 1672 56

C-type natriuretic peptide (CNP) is a peptide produced by the vascular endothelium with vasodilative properties. It shares structural and physiological properties with the atrial and brain natriuretic peptides (ANP and BNP), whose central role in the pathophysiology of heart failure (CHF) is firmly established. The role of CNP, first isolated from porcine brain, has not been yet completely determined. The transcription of the gene, that in man is located on chromosome 2, is regulated by factors such as tumor necrosis factor and interleukin-1. Two mature forms of the peptide exist: CNP-53, that predominates in tissues and CNP-22, found mainly in plasma. As recently found, CNP is produced directly in the myocardium and an increase in plasma levels of this peptide and of its precursor was observed in CHF. The aim of this review was to examine the current literature relating to cardiovascular functions of CNP and in particular to its role in CHF. In fact, CNP may represent an important new local autocrine and endocrine mediator in CHF although further evaluations are required to define its full pathophysiological role in this disease.
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PMID:C-type natriuretic peptide and heart failure. 1690 35


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