Articles On Inflammation & Heart Failure

The emerging role of the gut in chronic heart failure. [Review] [90 refs] Sandek A. Rauchhaus M. Anker SD. von Haehling S. Current Opinion in Clinical Nutrition & Metabolic Care. 11(5):632-9, 2008 PURPOSE OF REVIEW: Chronic heart failure is a multisystem disease with increased sympathetic tone, an anabolic/catabolic dysbalance, and chronic inflammation. Recent studies suggest an altered morphology, permeability, and absorption of the digestive tract in chronic heart failure. Due to nonocclusive mesenterial ischaemia and disturbed intestinal microcirculation, bacterial endotoxin is thought to enter the bloodstream through the hypoperfused, oedematous gut wall, thereby triggering an inflammatory response. Circulating cytokines act as cardiosuppressors. Their plasma levels predict increased mortality in chronic heart failure. RECENT FINDINGS: The present article focuses on specific alterations of the gastric, small intestinal, and large intestinal region in chronic heart failure. It describes the leaky intestinal barrier with an augmented bacterial biofilm that may contribute to chronic inflammation and malnutrition. Furthermore, we review methods for bowel perfusion measurement and potential therapeutic approaches. SUMMARY: It remains unclear whether increased adherent bacteria in patients with chronic heart failure are a primary or secondary event and whether they contribute to systemic inflammation. Both lack of mucosal integrity with consecutive local and systemic inflammation and dysfunction of transport proteins may worsen the clinical symptoms of chronic heart failure. Therefore, future studies need to address the pathophysiology of the intestinal barrier whose reactivity seems to be crucial for heart function. 

Anemia and chronic heart failure implications and treatment options. [Review] [104 refs] Anand IS. Journal of the American College of Cardiology. 52(7):501-11, 2008  Anemia is a common comorbidity in patients with heart failure and is associated with worse long-term outcomes. Although the cause of anemia in heart failure is unclear, the weight of evidence suggests that renal dysfunction, along with neurohormonal and proinflammatory cytokine activation in heart failure, favors the development of anemia of chronic disease, with defective iron utilization, inappropriate erythropoietin production, and depressed bone marrow function. Similarly, the mechanisms by which anemia worsens heart failure outcomes are unknown but may be related to increased myocardial workload. If anemia is a mediator and not just a marker of poor outcomes, correcting anemia could become an important and novel therapeutic target to improve long-term outcomes in such patients. Indeed, several small-sized studies have shown the beneficial effects of empirically treating anemia in heart failure patients with recombinant erythropoietin and intravenous iron. However, the ideal threshold at which therapy should be initiated and the extent of correction considered safe and desirable in the individual patient with heart failure need to be known. These issues become more important because of increasing safety concerns that recombinant erythropoietin therapy for treating anemia may be associated with adverse cardiovascular outcomes in patients with chronic kidney disease and may worsen cancer in patients receiving chemotherapy to treat various types of cancer. Therefore, further prospectively designed studies are required to address some of these questions. Fortunately, 2 large mortality morbidity trials, TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) in patients with chronic kidney disease and RED-HF (Reduction of Events with Darbepoetin alfa in Heart Failure) in heart failure patients, are in progress and are likely to provide definitive answers. 

New cardiovascular biomarkers: clinical implications in patients with valvular heart disease. [Review] [83 refs] Moura LM. Rocha-Goncalves F. Zamorano JL. Barros I. Bettencourt P. Rajamannan N. Expert Review of Cardiovascular Therapy. 6(7):945-54, 2008  Valvular heart disease (VHD) is characterized by an ongoing, inflammatory cellular response which results in a left ventricular hemodynamic stress change in response to valvulopathy. The current inflammatory hypothesis suggests that as the heart valve disease progresses the inflammatory cytokine response is activated causing continuation of deleterious effects on the heart and vasculature. This can lead to progression of heart failure and left ventricular dysfunction. Over the last 10 years, a number of biologically active molecules, termed biomarkers, have been discovered in VHD. These can be used to detect the progression and pathogenesis of heart failure and to assess the severity of inflammation (e.g., C-reactive protein). Brain natriuretic peptide (BNP) can diagnose underlying cardiac systolic and diastolic dysfunction. In high-risk patients BNP is also considered to be a useful tool for assisting in the diagnosis and monitoring the progression of VHD. Patients with symptomatic VHD benefit from aortic valve surgery; however, management in the absence of symptoms remains challenging. While the lack of symptoms can delay aortic valve replacement, unselected premature aortic valve replacement may be associated with unbalanced risks of cardiac surgery. This review summarizes the current and emerging clinical and potential research application of specific biomarkers of VHD. 

Biomarkers: past, present, and future. [Review] [40 refs]  Mueller C. Muller B. Perruchoud AP. Swiss Medical Weekly. 138(15-16):225-9, 2008  In recent decades biomarkers have become accepted tools in clinical practice [1]. Although there is no widely accepted definition of what constitutes a biomarker, for the context of this review we consider a biomarker to be a protein or other macromolecule that is associated with a biological process or regulatory mechanism. Hence measurement of this biomarker in blood, for example, might provide quantitative information that could be clinically helpful regarding this biological process or regulatory mechanism. In this paper we review recent advances with the use of biomarkers in three major clinical areas: diagnosis of myocardial infarction, diagnosis and management of heart failure, and diagnosis and management of inflammatory conditions in general and systemic infections in particular. Although these may look like unrelated medical challenges, recent clinical research in these areas by our groups and others has opened up opportunities and challenges that seem fundamental for biomarkers in general. 

Cytokines and acute heart failure. [Review] [54 refs] Chen D. Assad-Kottner C. Orrego C. Torre-Amione G. Critical Care Medicine. 36(1 Suppl):S9-16, 2008 In patients with chronic heart failure, ongoing myocardial injury partially results from activation of the inflammatory system, with production and release of proinflammatory cytokines, activation of the complement system, production of autoantibodies, overexpression of major histocompatibility complex molecules, and expression of adhesion molecules that may perpetuate the inflammatory state. Acute decompensated heart failure modifies the course of chronic heart failure and worsens outcomes via a combination of potential mechanisms, including neurohormonal activation, apoptosis, and the inflammatory cascade. Proinflammatory cytokines, including tumor necrosis factor-alpha and interleukin-6, play a pathogenetic role in chronic heart failure, and anti-inflammatory immune therapy is currently under investigation. In acute decompensation of chronic heart failure, the change in the inflammatory cytokine activation cascade is less clear. Larger investigational studies are needed to assess the exact roles of circulating and intracardiac cytokines in this particular patient population. 

Heart failure and cachexia: insights offered from molecular biology. [Review] [83 refs] Conraads VM. Hoymans VY. Vrints CJ. Frontiers in Bioscience. 13:325-35, 2008. Chronic heart failure (CHF) is an enormous medical and communal burden. The syndrome is common, carries a grim prognosis and severely impacts quality of life. Those patients who develop cardiac cachexia combat both important disability and a poor outlook. Muscle wasting is a critical component of cachexia. The pathophysiological determinants are numerous and some of them are common to other chronic severe illnesses. There is increasing awareness, however, that heart failure related myopathy is a distinct entity, characterized by specific functional, structural and morphologic changes and the involvement of several neurohormonal pathways, catabolic processes, a pro-inflammatory environment and increased oxidative stress. Although clear-cut evidence based solutions for the problem are not readily available, the modulating effects of regular exercise in CHF patients suggest that physical training should at least be incorporated in the essentially multi-disciplinary approach. 

Immune-inflammatory activation in heart failure. [Review] [46 refs] Candia AM. Villacorta H Jr. Mesquita ET. Arquivos Brasileiros de Cardiologia. 89(3):183-90, 201-8, 2007 Despite being relatively recent, a growing and significant accumulation of experimental and clinical evidence has been observed that points to a gradual state of immune-inflammatory activation in patients with heart failure (HF). High levels of several cytokines are found in the circulation and cardiac muscle of individuals with HF, and invariably correlate with the severity of the disease. These cytokines act on endothelial dysfunction, oxidative stress, induction of anemia, myocyte apoptosis, and on the progressive loss of skeletal muscle mass which is conventionally called the inflammatory paradigm of HF. Not only the myocardium, but also several tissues seem to synthesize these cytokines and perpetuate this continuous inflammatory state at a low degree, including leukocytes, monocytes, skeletal muscle cells and endothelial cells in response to hemodynamic and infectious stimuli, to hypoxia, to oxidative stress, to neurohumoral activation, and others. Thus, a network of molecules that interact with each other is formed, and connections with other axes that effectively contribute to the clinical deterioration of the patients are also established which fits into the pathophysiological model of multisystemic involvement that has been increasingly attributed to HF. Although the determination of these biomarkers in peripheral blood provides solid evidence of prognostic power, the results of therapeutic trials that modulated the immune-inflammatory loop in the clinical phase have been, so far, hardly encouraging. Therefore, we believe that a better understanding of the inflammatory activation and its multifaceted relation with the axes of decompensation of the disease is key for new therapeutic perspectives with a relevant impact to be established in the near future. 

Sepsis-induced myocardial dysfunction. [Review] [61 refs] Sharma AC. Shock. 28(3):265-9, 2007 Despite the fact that septic patients exhibit altered cardiac function, it is not considered a major pathology during sepsis. Thus, the molecular mechanisms underlying sepsis-induced myocardial dysfunction have not been studied extensively. In a polymicrobial septic rat model, +dP/dt and -dP/dt on day 1 were not altered but found depressed later, i.e., at 3 and 7 days postsepsis. Diastolic dysfunction characterized by an elevation of the time constant of left ventricular relaxation, tau, was evident at 1, 3, and 7 days postsepsis. Recent data from our laboratory demonstrated that sepsis-induced cardiodynamic alterations correlated with upregulation of TNF receptor-associated death domain, Bax, Smac (both mitochondrial and cytosolic fractions), total nuclear factor kappaB expression, p38-mitogen-activated protein kinase and c-Jun N-terminal kinase phosphorylation, and cytochrome c levels in the rat heart at 3 and 7 days postsepsis. Data from various laboratories emphasized that molecular myocardial alteration, which occurs during early and late stages of sepsis, needs to be elucidated thoroughly. A poor understanding of myocardial signaling during early sepsis could be one of the main reasons for limited success of pharmacotherapeutic options for sepsis. We anticipate that an increased understanding of pathophysiological mechanisms leading to sepsis-induced myocardial dysfunction would generate new enthusiasm among various research groups in this area of research. 

Role of inflammation in the progression of heart failure. [Review] [52 refs] Yndestad A. Damas JK. Oie E. Ueland T. Gullestad L. Aukrust P. Current Cardiology Reports. 9(3):236-41, 2007 Chronic heart failure (HF) is a disorder characterized in part by immune activation and inflammation. Thus, patients with HF have elevated levels of a number of inflammatory cytokines, both in the circulation and in the failing heart itself. Several mechanisms for this immune activation, which are not mutually exclusive, have been suggested, including neurohormonal activation, hemodynamic overload, and activation of the innate immune system secondary to cardiac stress. Importantly, experimental studies have shown that inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1b, and monocyte chemoattractant peptide-1 may contribute to the development and progression of HF by promoting myocardial hypertrophy, activating matrix metalloproteinases, provoking contractile dysfunction, and inducing apoptosis. However, inflammatory cytokines may also have adaptive and cardioprotective effects. This important aspect of cytokine biology must be kept in mind when designing new immunomodulatory treatment modalities in HF. 

Activation of immune and inflammatory systems in chronic heart failure: novel therapeutic approaches.[see comment]. [Review] [64 refs] Gong KZ. Song G. Spiers JP. Kelso EJ. Zhang ZG. International Journal of Clinical Practice. 61(4):611-21, 2007 Despite extensive research and novel treatments, chronic heart failure (CHF) remains a cause of high morbidity and mortality. Mounting evidence suggested that immune activation and inflammation play critical roles in the pathogenesis of CHF. In this review, we examine the current evidence regarding this contemporary pathophysiological mechanism, and evaluate the effects of conventional and novel cardiovascular drugs, such as calcium sensitisers and statins, on the immune and inflammatory mediator's network. Although therapies, which specifically antagonise tumour necrosis factor-alpha have not demonstrated considerable benefit in patients with CHF, there is an increasing evidence to suggest greater value from non-specific anti-inflammatory approaches, including: pentoxifylline, intravenous immunoglobulin, immune modulation therapy, growth hormones, physical training and nutrition regulation. Several innovative therapeutic targets, such as peroxisome proliferator-activated receptor gamma activators, Rho-kinase, p38 mitogen-activated protein kinase, nuclear transcription factor NF-kappaB, recovering or augmenting parasympathetic tone, cardiac resynchronisation therapy, macrophage inhibitors and chemokine receptor antagonists, are briefly discussed in this review. While we have recently demonstrated the potential merits of combining low-dose methotrexate with conventional therapy, through extensively modulating the activated immune and inflammatory mediator's network, there is a need for further rigorous research of this complex network, especially involving current promising therapies which modulate this system. Such evidence has the potential to revolutionise changes for the management of this disorder. Based on the 'heterogeneity' of immune activation and inflammation among different CHF populations, an 'optimised combination treatment' may offer exciting benefits for individual therapy in the future. 

Viewpoint: the prothrombotic state in heart failure: a maladaptive inflammatory response?. [Review] [64 refs] Chong AY. Lip GY. European Journal of Heart Failure. 9(2):124-8, 2007 Patients with heart failure (HF) are at an increased risk of stroke, sudden death and venous thromboembolism, which are all linked to thrombus formation (thrombogenesis). The present 'viewpoint' article will discuss how the prothrombotic state in HF may be perpetuated by a chronic inflammatory state that is maladaptive. Indeed, there is considerable evidence that thrombogenesis and endothelial (dys)function can be intimately linked to inflammation in HF. 

Complement-related molecular events in sepsis leading to heart failure. [Review] [82 refs] Hoesel LM. Niederbichler AD. Ward PA. Molecular Immunology. 44(1-3):95-102, 2007 Despite intensive ongoing research efforts, the mortality of patients with sepsis remains unacceptably high. A significant number of clinical trials have failed to produce sufficient therapeutic strategies despite showing promising results in animal models. So far, many studies have focused on deterioration of the humoral and cellular components of the immune system, the main cause of death in septic patients being multi-organ failure. However, not much is known about the effects of the complement system on parenchymal cells of organs such as the heart. Recently, septic cardiomyopathy has been recognized as one of the major complications during sepsis, often determining the clinical outcome. In this review, we describe molecular events which are thought to be related to cardiac dysfunction during sepsis. A special emphasis will be placed on the complement system, which generates powerful anaphylatoxins (such as C5a) and which has recently been associated with septic cardiomyopathy. Together with the impact on cardiac function of various cytokines we will provide a synopsis of the current knowledge regarding the pathophysiology underlying cardiac failure during sepsis with a special emphasis on C5a and C5aR.