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      Impact of KChIP2 on Cardiac Electrophysiology and the Progression of Heart Failure

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          Abstract

          Electrophysiological remodeling of cardiac potassium ion channels is important in the progression of heart failure. A reduction of the transient outward potassium current ( I to) in mammalian heart failure is consistent with a reduced expression of potassium channel interacting protein 2 (KChIP2, a K V4 subunit). Approaches have been made to investigate the role of KChIP2 in shaping cardiac I to, including the use of transgenic KChIP2 deficient mice and viral overexpression of KChIP2. The interplay between I to and myocardial calcium handling is pivotal in the development of heart failure, and is further strengthened by the dual role of KChIP2 as a functional subunit on both K V4 and Ca V1.2. Moreover, the potential arrhythmogenic consequence of reduced I to may contribute to the high relative incidence of sudden death in the early phases of human heart failure. With this review, we offer an overview of the insights into the physiological and pathological roles of KChIP2 and we discuss the limitations of translating the molecular basis of electrophysiological remodeling from animal models of heart failure to the clinical setting.

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          Most cited references81

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          ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM).

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            Lifetime risk for developing congestive heart failure: the Framingham Heart Study.

            Congestive heart failure (CHF) is an increasing public health problem. Among Framingham Heart Study subjects who were free of CHF at baseline, we determined the lifetime risk for developing overt CHF at selected index ages. We followed 3757 men and 4472 women from 1971 to 1996 for 124 262 person-years; 583 subjects developed CHF and 2002 died without prior CHF. At age 40 years, the lifetime risk for CHF was 21.0% (95% CI 18.7% to 23.2%) for men and 20.3% (95% CI 18.2% to 22.5%) for women. Remaining lifetime risk did not change with advancing index age because of rapidly increasing CHF incidence rates. At age 80 years, the lifetime risk was 20.2% (95% CI 16.1% to 24.2%) for men and 19.3% (95% CI 16.5% to 22.2%) for women. Lifetime risk for CHF doubled for subjects with blood pressure >/=160/100 versus <140/90 mm Hg. In a secondary analysis, we only considered those who developed CHF without an antecedent myocardial infarction; at age 40 years, the lifetime risk for CHF was 11.4% (95% CI 9.6% to 13.2%) for men and 15.4% (95% CI 13.5% to 17.3%) for women. When established clinical criteria are used to define overt CHF, the lifetime risk for CHF is 1 in 5 for both men and women. For CHF occurring in the absence of myocardial infarction, the lifetime risk is 1 in 9 for men and 1 in 6 for women, which highlights the risk of CHF that is largely attributable to hypertension. These results should assist in predicting the population burden of CHF and placing greater emphasis on prevention of CHF through hypertension control and prevention of myocardial infarction.
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              More 'malignant' than cancer? Five-year survival following a first admission for heart failure.

              The prognostic impact of heart failure relative to that of 'high-profile' disease states such as cancer, within the whole population, is unknown. All patients with a first admission to any Scottish hospital in 1991 for heart failure, myocardial infarction or the four most common types of cancer specific to men and women were identified. Five-year survival rates and associated loss of expected life-years were then compared. In 1991, 16224 men had an initial hospitalisation for heart failure (n=3241), myocardial infarction (n=6932) or cancer of the lung, large bowel, prostate or bladder (n=6051). Similarly, 14842 women were admitted for heart failure (n=3606), myocardial infarction (n=4916), or cancer of the breast, lung, large bowel or ovary (n=6320). With the exception of lung cancer, heart failure was associated with the poorest 5-year survival rate (approximately 25% for both sexes). On an adjusted basis, heart failure was associated with worse long-term survival than bowel cancer in men (adjusted odds ratio, 0.89; 95% CI, 0.82-0.97; P<0.01) and breast cancer in women (odds ratio, 0.59; 95% CI, 0.55-0.64; P<0.001). The overall population rate of expected life-years lost due to heart failure in men was 6.7 years/1000 and for women 5.1 years/1000. With the notable exception of lung cancer, heart failure is as 'malignant' as many common types of cancer and is associated with a comparable number of expected life-years lost.
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                Author and article information

                Journal
                Front Physiol
                Front Physiol
                Front. Physio.
                Frontiers in Physiology
                Frontiers Research Foundation
                1664-042X
                03 April 2012
                04 May 2012
                2012
                : 3
                : 118
                Affiliations
                [1] 1simpleDanish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen Copenhagen, Denmark
                Author notes

                Edited by: Carol Ann Remme, University of Amsterdam, Netherlands

                Reviewed by: Dirk Snyders, University of Antwerp, Belgium; Arun Sridhar, GlaxoSmithKline, UK

                *Correspondence: Morten B. Thomsen, Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3b, Building 12.5.36, DK-2200 Copenhagen, Denmark. e-mail: mbthom@ 123456sund.ku.dk

                This article was submitted to Frontiers in Cardiac Electrophysiology, a specialty of Frontiers in Physiology.

                Article
                10.3389/fphys.2012.00118
                3343377
                22586403
                d36eb25b-44f1-4724-a18c-bd9cc60fd4ec
                Copyright © 2012 Grubb, Calloe and Thomsen.

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

                History
                : 27 February 2012
                : 11 April 2012
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 92, Pages: 9, Words: 8763
                Categories
                Physiology
                Review Article

                Anatomy & Physiology
                action potential,knockout mice,ion channels,sudden death,potassium,repolarization,heart failure,ventricular arrhythmia

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