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Excessive neuro-hormonal activation associated with cardiac injury or overload induces extensive 7TMR signaling perturbations, and the modulation of 7TMR signaling in several different animal models of cardiac overload has been consistently shown to ameliorate cardiac remodeling and function Thus, many efforts have been made to identify the crucial pathways involved in pathological cardiac remodeling and reliable circulating markers of molecular abnormalities occurring in the heart.

The conceptual basis for these investigations is that cardiovascular diseases, and particularly HF, are systemic disorders in which a complex interplay between different organs occurs. HF is a multi-organ disorder originating in the heart and affecting many other extra-cardiac sites, including the immune system 11 , Inflammation plays a key role in the progressive deterioration of cardiac function by inducing ventricular dilatation, contractile dysfunction, fibrosis, and both apoptotic and necrotic cardiomyocyte death 13 , It has been clearly recognized that autonomic nervous system perturbations, a hallmark of HF, determine the activation of the immune system.

Autonomic nervous system deregulation is also characterized by increased production and secretion of angiotensinogen, which, through its conversion into angiotensin-II ANG-II and the subsequent induction of aldosterone production, promotes oxidative stress, inflammatory state, and cytokine expression both in the myocardium and circulating leukocytes As a consequence, it has been proposed that abnormalities of 7TMR signaling in particular, adrenergic signaling in peripheral leukocytes might mirror those occurring in the heart, and particularly the molecular modifications of patients with pathological remodeling or overt HF 13 , Figure 1.

Immune activation leads to the recruitment of different populations of white blood cells, participating to various phases of cardiac remodeling. It is becoming increasingly clear that specific cell populations might exert specific roles in these processes. In particular, it has been suggested that neutrophils might play a significant role in the early response to myocardial ischemia, since innate immune signals rapidly recall these cells to clear the infarct area from dead cells and matrix debris, and to activate fibroblasts and matrix metalloproteinases During post-ischemic cardiac remodeling, dendritic cells are also mobilized from spleen in the systemic circulation and might exert a critical function, albeit still poorly studied, in modulating immune system activation Several lines of evidence have shown that T lymphocytes exert an important role in cardiovascular remodeling and heart failure 23 , T-helper lymphocytes responses can be classified into T-lymphocyte helper type 1 Th1 and type 2 Th2 according to the predominant cytokines involved.

Interestingly, some of the classic drugs used for the treatment of cardiovascular diseases and HF appear to equilibrate this imbalance in favor of Th2 responses 26 , Interestingly, this phenomenon seems reversible, since normalization of sodium salt dietary intake partially restored the impairment in cyclic-AMP production after isoproterenol administration to cultured lymphocytes from hypertensive subjects This beta-blocker induced shift toward TH2 polarization has been associated with increased cAMP levels within peripheral T-helper lymphocytes from patients with HF According to this view, T-helper cells might really represent a new potential target for pharmacological modulatory strategies in patients with HF.

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These insights might offer novel additional tools in the future management of HF patients. GRK2 levels and activation have been shown to directly correlate to the amount of sympathetic outflow and inversely correlate to sensitivity and responsiveness to adrenergic signals, both in hypertension and HF 36 , Recently, a correlation between increased GRK2 levels and vascular dysfunction has been also demonstrated in lymphocytes In this study, hypertensive patients were characterized by impaired vasodilatation after isoprenaline injection when compared with normotensive subjects, with a partial restore after the injection of the non-specific GRKs inhibitor heparin Interestingly, the administration of the beta-adrenergic blocker metoprolol has been shown to reduce GRK2 expression in peripheral blood lymphocytes from advanced elderly patients with HF 40 , Indeed, in these patients, a restoration of myocardial beta-adrenergic receptor signaling, assessed by membrane beta-adrenergic receptor density, adenylyl cyclase activity, and GRK2 expression and activity, has been observed after implantation of the assist device Hata and coworkers have also shown that cardiac reduction of GRK2 activation after left ventricular assist device is mirrored by peripheral lymphocytes More recently, Akter and coworkers have correlated the decreased levels of activation of GRK2 in peripheral lymphocytes of patients subjected to left ventricular assist device with an increased total beta-adrenergic receptor density on plasma membrane, and an augmented basal and isoproterenol-induced cyclic-AMP production in the myocardium In a recently published manuscript, Rengo and coworkers have observed a significant reduction in lymphocyte GRK2 protein levels in HF patients after physical exercise, obtained by a 3-month program of training Not surprisingly, HF patients who did not show reduced lymphocyte GRK2 protein levels after training had a worst outcome We have recently analyzed the correlation between cardiac pressure overload and the activation of mitogen-activated protein kinases MAPKs , extracellular-signal regulated kinase ERK , c-Jun terminal kinase JNK , and p38 in myocardial tissues or peripheral blood leukocytes from mice undergoing transverse aortic constriction Cardiac activation of ERK, JNK, and p38 was significantly increased by pressure overload, and correlated with a consistent and coherent activation of the same MAPKs in leukocytes from the same animals Furthermore, ERK phosphorylation was increased in leukocytes isolated from hypertensive patients with uncontrolled values of arterial blood pressure compared to normotensive volunteers, while leukocytes isolated from patients with controlled blood pressure displayed reduced MAPK activation.

These results suggest that MAPKs might be sensors of cardiac pressure overload, and suggest that leukocytes might represent important cellular targets mirroring cardiac signaling Notably, similar modifications are poorly described in other classes of white blood cells.

Despite several numbers of studies, a great deal of characterization is still required to fully understand the mechanisms involved in HF. Obviously, a huge limitation for basic research in HF is related to the difficulty in collecting human myocardial specimens for in vivo analysis. Thus, the phenomenon of mirroring in peripheral lymphocytes might represent an exciting and useful tool to non-invasively assess and monitor signal abnormalities in HF, with a feasible relevance for diagnosis, prognostic assessment, and therapy. At the same time, this concept should not be extremely forced to the assumption that every signal modifications in the heart might always be reproduced in peripheral lymphocytes.

Although results from these studies are very promising and exciting, further investigations will be needed in the future to better understand the true biological meaning of mirroring and to define specific cell populations and new candidate signaling pathways. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Liu L, Eisen HJ. Epidemiology of heart failure and scope of the problem. Cardiol Clin 32 1 :1—8,vii. Molecular and cellular mechanisms involved in cardiac remodeling after acute myocardial infarction.

J Mol Cell Cardiol 50 3 — Cardiac remodeling — concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an international forum on cardiac remodeling. J Am Coll Cardiol 35 3 — Progressive left ventricular dysfunction and remodeling after myocardial infarction. Potential mechanisms and early predictors. Until the results of WATCH are available, low-dose aspirin remains the antiplatelet agent of choice in patients with CHF and atherosclerotic disease and should usually be coprescribed with an ACE inhibitor.

Introduction

Previous experience with orally administered inotropic agents was unfavorable. The precise mechanism underlying this increased hazard is unknown but may reflect a proarrhythmic effect of agents of this type.


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Similarly, levosimendan, a calcium-sensitizing agent, has shown promise in acute heart failure, and further trials are planned. There has been much recent interest in the finding that a high proportion of patients with CHF are anemic and that correction of this anemia with iron supplementation and erythropoietin may improve symptoms and morbidity. Selective A 1 adenosine receptor blockade may induce diuresis and natriuresis in CHF without reducing glomerular filtration rate.

They may also take multiple treatments for concomitant problems. This polypharmacy is a cause of concern, not least from the adherence point of view.

There is growing interest in the notion of targeting therapy either on the basis of biological mechanisms or genetic makeup. This subject has been the focus of much recent interest and the source of considerable controversy, with suggestions that African Americans may respond less well to ACE inhibitor therapy and better to hydralazine and isosorbide dinitrate combination therapy. In addition to knowing which therapies to give to patients, we also need to understand better how to decide how much treatment patients require.

It has recently been suggested that plasma natriuretic peptide concentrations might provide a simple biochemical means of tailoring therapy. The recent availability of simple, rapid assays for natriuretic peptides and near-patient testing kits make such an approach a realistic one in ordinary clinical practice. Further exploration of this therapeutic strategy is undoubtedly needed. A consistent finding across many countries is that evidence-based therapy for CHF and other conditions is frequently underused. For these and other reasons, better approaches to the organized and systematic care of patients with CHF have been sought.

What is the optimal timing, intensity, and duration of such interventions? Do these interventions have long-term benefits?

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Are they cost-effective? What are the exact mechanisms of their beneficial effects? Are programs of this type associated with improved survival? Many, if not the majority, of patients with CHF have underlying coronary artery disease, and as alluded to above, existing, successful therapies may exert some of their beneficial effects by preventing new acute coronary events see Part I.

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Molecular Approaches to Heart Failure Therapy | SpringerLink

There is also much interest in specifically addressing recurrent ischemia and hibernation as therapeutic targets in CHF. Pharmacological and interventional strategies are under investigation. A surprisingly high proportion of patients with CHF and coronary artery disease have substantial areas of hibernating myocardium.

Chronic Management of Heart Failure: A Guideline Approach (Myung Park, MD)

The safety and efficacy of myocardial revascularization, especially surgical revascularization, is uncertain in CHF. The short-term benefits of exercise training on functional capacity, symptoms, neurohumoral activity, muscle performance, and baroreceptor function are well recognized. To date, however, a definitive randomized trial studying the effect of exercise prescription on morbidity and mortality is awaited. This electromechanical dyssynchrony may lead to suboptimal atrioventricular coupling, uncoordinated ventricular contraction, and presystolic mitral regurgitation.

Post hoc analysis of both trials suggested that the greatest benefit was obtained in patients with the lowest LVEF. The primary end point is all-cause mortality. There is renewed interest in mechanical support for, or replacement of, the failing heart as a stand-alone therapy, rather than as a bridge to transplantation. A detailed review of this topic is beyond the scope of this review. Multiple recent reports suggest that there is an exciting potential for gene therapy and cell therapy both in preventing and in treating CHF.

New Therapeutic Options in Congestive Heart Failure

They do, however, offer the possibility of revolutionizing therapy for CHF, for example, by allowing fibrotic scar tissue to be replaced by new myocytes. This algorithm also maps the focus of many of the investigational approaches summarized in the preceding text.


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  • This treatment algorithm represents a summary of the main options available, and the reader is referred to more extensive guidelines published elsewhere. Lifestyle measures, such as smoking cessation, moderation of alcohol consumption, restriction of salt intake, healthy eating, and regular exercise, are also of benefit. Combination therapy with a loop and a thiazide diuretic or metolazone may be particularly effective in resistant cases. Patient self-adjustment of diuretic therapy should be taught and encouraged.

    Some also advocate revascularization of symptomless ischemia when a substantial area of hibernating myocardium can be demonstrated. Standard secondary preventive measures should be used in patients with coronary artery disease smoking cessation, antiplatelet therapy, cholesterol lowering therapy, etc. There will undoubtedly be more trials in this previously neglected minority of patients with CHF. Many other important questions cannot be discussed here in detail. We still do not understand some of the most basic aspects of drug development and trial design.

    Selecting a dose, or range of doses, to test remains a relatively arbitrary process and may have resulted in problems with a number of the therapies discussed above. Targeting therapy has been mentioned earlier, but will the sponsors of large trials, the pharmaceutical industry, encourage this?