Uric acid in heart failure: a biomarker or therapeutic target?

There is a need for a cost-effective prognostic biomarker in heart failure (HF). Substantial evidence suggests that uric acid (UA) is an independent marker for adverse prognosis in acute and chronic HF of varying severity. Whether UA is a merely a marker of poor prognosis or is an active participant in disease pathogenesis is currently unknown. In the setting of HF, at least two different processes can be responsible for increased UA: increased production, which may result from oxidative stress, and decreased excretion due to renal insufficiency, which can be a consequence of cardio-renal syndrome, renal congestion, or comorbidities. While pioneer studies have raised the possibility of preventing HF through the use of UA lowering agents, namely xanthine oxidase inhibitors and uricosurics, the literature is still conflicting on whether the reduction in UA will result in a measurable clinical benefit. In this review, we examine the evidence relating UA to HF prognosis, the mechanisms that contribute to increased UA levels in HF, and future novel treatments aimed at reducing UA levels.     

The role of nitric oxide in arthritic joints: a therapeutic target?

Nitric oxide (NO) is produced by many cell types in the joint, and its expression is delicately regulated. Depending on its concentration and cellular origin, NO appears to have both pro- and anti-inflammatory potential in the joint. Constitutively expressed nitric oxide synthase (NOS) produces small amounts of NO, which is essential for normal physiological homeostasis. However, inflammatory stimuli such as endotoxins, cytokines, and growth factors promote inducible NOS (iNOS) expression, initially as an anti-inflammatory response, and catalyse a high output of NO. Excessive NO can amplify inflammatory pathways and contribute to the development and maintenance of arthritis. Consequently, proper regulation of NO synthesis can lead to a novel therapeutic approach for inflammatory joint diseases. Further careful study will be necessary to develop new drugs to regulate the NO pathway and to determine the dosage, timing of administration, and duration of treatment in order to avoid both undesirable immunostimulatory effects and immunosuppressive effects. Received: February 18, 2000     

New therapeutic options in heart failure. What's on the horizon? An overview

Heart failure is a complex clinical syndrome responsible for high morbidity and mortality in the world. Despite advances in the management of heart failure, the prognosis of these patients remains poor and there is a critical need for new treatment strategies improving the clinical outcomes. New approaches in heart failure therapies target cellular mechanisms, as well as mechanical and structural aspects of heart failure that are not addressed by recent therapies. These include abnormalities in molecular mechanisms, electrical conduction and ventricular remodeling. This review presents the pathophysiological basis, mechanisms of action and available clinical efficacy and safety data of drugs and mechanical therapies that are currently under development.     

Cardiac mitochondrial nitric oxide: a regulator of heart rate?

Alterations in autonomic control and myocardial nitric-oxide (NO) production are likely linked to the development and progression of heart dysfunction. By focusing on heart rate, the complexity of the actions of NO at distinct levels throughout the autonomic nervous system and its relationship with other regulators can be demonstrated. Given the multiple and opposing actions of NO on cardiac control, it is difficult to interpret a response after a global intervention in the NO system. The diversity of intracellular pathways activated by NO, and their differing sensitivities to different levels of NO, might account for some aspects of reported specific but opposite effects. We discuss factors that might contribute to this diversity of actions. A proper elucidation of the effects of NO on metabolic pathways and on energy generation could lead to novel therapeutic strategies aimed at the early treatment of heart dysfunction.     

Is depressed myocyte contractility centrally involved in heart failure?

This review examines the evidence for and against the hypothesis that abnormalities in cardiac contractility initiate the heart failure syndrome and drive its progression. There is substantial evidence that the contractility of failing human hearts is depressed and that abnormalities of basal Ca2+ regulation and adrenergic regulation of Ca2+ signaling are responsible. The cellular and molecular defects that cause depressed myocyte contractility are not well established but seem to culminate in abnormal sarcoplasmic reticulum uptake, storage, and release. There are also strong links between Ca2+ regulation, Ca2+ signaling pathways, hypertrophy, and heart failure that need to be more clearly delineated. There is not substantial direct evidence for a causative role for depressed contractility in the initiation and progression of human heart failure, and some studies show that heart failure can occur without depressed myocyte contractility. Stronger support for a causal role for depressed contractility in the initiation of heart failure comes from animal studies where maintaining or improving contractility can prevent heart failure. Recent clinical studies in humans also support the idea that beneficial heart failure treatments, such as beta-adrenergic antagonists, involve improved contractility. Current or previously used heart failure treatments that increase contractility, primarily by increasing cAMP, have generally increased mortality. Novel heart failure therapies that increase or maintain contractility or adrenergic signaling by selectively modulating specific molecules have produced promising results in animal experiments. How to reliably implement these potentially beneficial inotropic therapies in humans without introducing negative side effects is the major unanswered question in this field.     

Could interferon-gamma be a therapeutic target for treating heart failure?

The cytokine interferon-gamma (IFN-γ) is the only known member of the type II family of interferons, and as such, binds to its own distinct receptor. It is important in host defense against infection, as well as adaptive immune responses. While a wide array of cytokines are known to be involved in adverse remodeling of the heart and the progression to heart failure, the role of IFN-γ is unclear. Recent evidence from clinical studies, animal models of myocarditis and hypertension, as well as isolated cell studies, provide conflicting data as to whether IFN-γ is pathological or protective in the heart. Thus, it is important to highlight these discrepant findings so that areas of future investigation can be identified to more clearly determine the precise role of IFN-γ in the heart. Accordingly, this review will (1) discuss the source of IFN-γ in the diseased heart; (2) summarize the data from animal studies; (3) discuss the effects of IFN-γ on isolated cardiac fibroblasts and cardiomyocytes; (4) identify signaling mechanisms that may be invoked by IFN-γ in the heart; and (5) present the clinical evidence supporting a role for IFN-γ in heart failure.     

Innate immune receptors in heart failure: Side effect or potential therapeutic target?

Heart failure(HF) is a leading cause of mortality and morbidity in western countries and occasions major expenses for public health systems. Although optimal medical treatment is widely available according to current guidelines, the prognosis of patients with HF is still poor. Despite the etiology of the disease, increased systemic or cardiac activation of the innate immune system is well documented in several types of HF. In some cases there is evidence of an association between innate immune activation and clinical outcome of patients with this disease. However, the few large trials conducted with the use of anti-inflammatory medication in HF have not revealed its benefits. Thus, greater understanding of the relationship between alteration in the immune system and development and progression of HF is urgently necessary: prior to designing therapeutic interventions that target pathological inflammatory processes in preventing harmful cardiac effects of immune modulatory therapy. In this regard, relatively recently discovered receptors of the innate immune system, i.e., namely toll-like receptors(TLRs) and nodlike receptors(NLRs)-are the focus of intense cardiovascular research. These receptors are main up-stream regulators of cytokine activation. This review will focus on current knowledge of the role of TLRs and NLRs, as well as on downstream cytokine activation, and will discuss potential therapeutic implications.     

Protein kinase Cα as a heart failure therapeutic target

Heart failure afflicts ~ 5 million people and causes ~ 300,000 deaths a year in the United States alone. Heart failure is defined as a deficiency in the ability of the heart to pump sufficient blood in response to systemic demands, which results in fatigue, dyspnea, and/or edema. Identifying new therapeutic targets is a major focus of current research in the field. We and others have identified critical roles for protein kinase C (PKC) family members in programming aspects of heart failure pathogenesis. More specifically, mechanistic data have emerged over the past 6-7 years that directly implicate PKCα, a conventional PKC family member, as a nodal regulator of heart failure propensity. Indeed, deletion of the PKCα gene in mice, or its inhibition in rodents with drugs or a dominant negative mutant and/or inhibitory peptide, has shown dramatic protective effects that antagonize the development of heart failure. This review will weigh all the evidence implicating PKCα as a novel therapeutic target to consider for the treatment of heart failure. This article is part of a special issue entitled “Key Signaling Molecules in Hypertrophy and Heart Failure.”     

Tumor necrosis factor–α–induced hypertension in pregnant rats results in decreased renal neuronal nitric oxide synthase expression

BackgroundPreeclampsia is associated with increases in plasma levels of tumor necrosis factor–α (TNF-α), a cytokine known to contribute to endothelial dysfunction. We recently reported that a twofold elevation in plasma TNF-α produces significant reductions in renal function and hypertension in pregnant rats. The purpose of this study was to determine the role of the nitric oxide (NO) system in TNF-α–induced hypertension in pregnant rats.MethodsTumor necrosis factor–α (50 ng/day) was chronically infused starting at day 14 of gestation. Mean arterial pressure, 24-h urinary nitrite/nitrate excretion, and renal nitric oxide synthase (NOS) protein expression by Western blot analysis was measured at day 19 of gestation.ResultsA twofold increase in plasma TNF-α levels in pregnant rats resulted in a significant increase in arterial pressure (97 ± 3.6 v 116 ± 2.1 mm Hg, pregnant versus TNF-α pregnant, respectively, P < .05), but no significant change in urinary nitrite/nitrate excretion (22.0 ± 1.9 v 20.8 ± 2.5 μmol/24 h, pregnant versus TNF-α pregnant, respectively), a measure of whole body NO production. As abnormalities in renal production of NO would not be reflected in the measure of whole body NO production, changes in renal NOS protein levels were determined. The protein expression of both neuronal (nNOS) and inducible (iNOS) nitric oxide synthase were significantly decreased in the medulla of TNF-α pregnant rats (nNOS: 10.6 ± 0.7 v 8.2 ± 0.8 densitometric units, P < .05; and iNOS: 19.2 ± 0.9 v 15.4 ± 0.8 densitometric units, P < .05, pregnant versus TNF-α pregnant, respectively).Conclusion:The hypertension associated with a chronic twofold increase in TNF-α in pregnant rats is associated with significant decreases in renal nNOS and iNOS protein production.     

Xanthine oxidase inhibition for chronic heart failure: is allopurinol the next therapeutic advance in heart failure?

A substantial body of evidence has accumulated to suggest a role for the xanthine oxidase metabolic pathway in the pathophysiology of chronic heart failure and other cardiovascular diseases.