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      Drug Design, Development and Therapy (submit here)

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      Current and future G protein-coupled receptor signaling targets for heart failure therapy


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          Although there have been significant advances in the therapy of heart failure in recent decades, such as the introduction of β-blockers and antagonists of the renin–angiotensin–aldosterone system, this devastating disease still carries tremendous morbidity and mortality in the western world. G protein-coupled receptors, such as β-adrenergic and angiotensin II receptors, located in the membranes of all three major cardiac cell types, ie, myocytes, fibroblasts, and endothelial cells, play crucial roles in regulation of cardiac function in health and disease. Their importance is reflected by the fact that, collectively, they represent the direct targets of over one-third of the currently approved cardiovascular drugs used in clinical practice. Over the past few decades, advances in elucidation of the signaling pathways they elicit, specifically in the heart, have led to identification of an increasing number of new molecular targets for heart failure therapy. Here, we review these possible targets for heart failure therapy that have emerged from studies of cardiac G protein-coupled receptor signaling in health and disease, with a particular focus on the main cardiac G protein-coupled receptor types, ie, the β-adrenergic and the angiotensin II type 1 receptors. We also highlight key issues that need to be addressed to improve the chances of success of novel therapies directed against these targets.

          Most cited references99

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          Trends in heart failure incidence and survival in a community-based population.

          The epidemic of heart failure has yet to be fully investigated, and data on incidence, survival, and sex-specific temporal trends in community-based populations are limited. To test the hypothesis that the incidence of heart failure has declined and survival after heart failure diagnosis has improved over time but that secular trends have diverged by sex. Population-based cohort study using the resources of the Rochester Epidemiology Project conducted in Olmsted County, Minnesota. Patients were 4537 Olmsted County residents (57% women; mean [SD] age, 74 [14] years) with a diagnosis of heart failure between 1979 and 2000. Framingham criteria and clinical criteria were used to validate the diagnosis Incidence of heart failure and survival after heart failure diagnosis. The incidence of heart failure was higher among men (378/100 000 persons; 95% confidence interval [CI], 361-395 for men; 289/100 000 persons; 95% CI, 277-300 for women) and did not change over time among men or women. After a mean follow-up of 4.2 years (range, 0-23.8 years), 3347 deaths occurred, including 1930 among women and 1417 among men. Survival after heart failure diagnosis was worse among men than women (relative risk, 1.33; 95% CI, 1.24-1.43) but overall improved over time (5-year age-adjusted survival, 43% in 1979-1984 vs 52% in 1996-2000, P<.001). However, men and younger persons experienced larger survival gains, contrasting with less or no improvement for women and elderly persons. In this community-based cohort, the incidence of heart failure has not declined during 2 decades, but survival after onset of heart failure has increased overall, with less improvement among women and elderly persons.
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            Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure.

            Hemodynamics, plasma norepinephrine, and plasma renin activity were measured at supine rest in 106 patients (83 men and 23 women) with moderate to severe congestive heart failure. During follow-up lasting 1 to 62 months, 60 patients died (57 per cent); 47 per cent of the deaths were sudden, and 45 per cent were related to progressive heart failure. Statistically unrelated to the risk of mortality were cause of disease (60 patients had coronary disease, and 46 had cardiomyopathy), age (mean, 54.8 years), cardiac index (mean, 2.11 liters per minute per square meter of body-surface area), pulmonary wedge pressure (mean, 24.5 mm Hg), and mean arterial pressure (mean, 83.2 mm Hg). A multivariate analysis of the five significant univariate prognosticators--heart rate (mean, 84.4 beats per minute), plasma renin activity (mean, 15.4 ng per milliliter per hour), plasma norepinephrine (mean, 700 pg per milliliter), serum sodium (mean, 135.7 mmol per liter), and stroke-work index (mean, 21.0 g-meters per square meter)--found only plasma norepinephrine to be independently (P = 0.002) related to the subsequent risk of mortality. Norepinephrine was also higher in patients who died from progressive heart failure than in those who died suddenly. These data suggest that a single resting venous blood sample showing the plasma norepinephrine concentration provides a better guide to prognosis than other commonly measured indexes of cardiac performance.
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              Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology.


                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                11 October 2013
                : 7
                : 1209-1222
                Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL, USA
                Author notes
                Correspondence: Anastasios Lymperopoulos, Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, 3200 S University Drive, HPD (Terry) Building/Room 1338, Fort Lauderdale, FL 33328, USA, Tel +1 954 262 1338, Fax +1 954 262 2278, Email al806@ 123456nova.edu
                © 2013 Siryk-Bathgate et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.


                Pharmacology & Pharmaceutical medicine
                heart failure,g protein-coupled receptor,signaling,cardiac,therapeutic target


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