Molecular mechanisms in evolutionary cardiology failure

Swynghedauw, Bernard; Delcayre, Claude; Samuel, Jane‐Lise; Mebazaa, Alexandre; Cohen‐Solal, Alain

doi:10.1111/j.1749-6632.2009.05084.x

Cited by 24 publications

(16 citation statements)

References 42 publications

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“…The failing cardiac phenotype is characterized by a shift toward a more "fetal" expression profile, encompassing increases in expression of fetal structural and contractile protein isoforms, and preferential use of glucose and lactate as energy sources over fatty acids (21). This expression profile is similar to that observed in RNCM.…”

Section: Discussionsupporting

confidence: 55%

AMPK and substrate availability regulate creatine transport in cultured cardiomyocytes

Darrabie

Arciniegas

Mishra

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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Darrabie MD, Arciniegas AJ, Mishra R, Bowles DE, Jacobs DO, Santacruz L. AMPK and substrate availability regulate creatine transport in cultured cardiomyocytes. Am J Physiol Endocrinol Metab 300: E870 -E876, 2011. First published March 1, 2011; doi:10.1152/ajpendo.00554.2010.-Profound alterations in myocellular creatine and phosphocreatine levels are observed during human heart failure. To maintain its intracellular creatine stores, cardiomyocytes depend upon a cell membrane creatine transporter whose regulation is not clearly understood. Creatine transport capacity in the intact heart is modulated by substrate availability, and it is reduced in the failing myocardium, likely adding to the energy imbalance that characterizes heart failure. AMPK, a key regulator of cellular energy homeostasis, acts by switching off energy-consuming pathways in favor of processes that generate energy. Our objective was to determine the effects of substrate availability and AMPK activation on creatine transport in cardiomyocytes. We studied creatine transport in rat neonatal cardiomyocytes and HL-1 cardiac cells expressing the human creatine transporter cultured in the presence of varying creatine concentrations and the AMPK activator 5-aminoimidazole-4-carboxamide-1-␤-D-ribonucleoside (AICAR). Transport was enhanced in cardiomyocytes following incubation in creatine-depleted medium or AICAR. The changes in transport were due to alterations in Vmax that correlated with changes in total and cell surface creatine transporter protein content. Our results suggest a positive role for AMPK in creatine transport modulation for cardiomyocytes in culture. myocardial creatine content; cardiac energy metabolism; adenosine 5=-monophosphate-activated protein kinase; cardiac failure CREATINE (Cr) and its phosphorylated form phosphocreatine (PCr), together with creatine kinases (CK), comprise a system that helps maintain ATP stores in cardiac and skeletal myocytes (23). During cardiac hypertrophy and heart failure, the myocardium exhibits marked changes in energy metabolism, including changes in substrate utilization, as well as in the content of high-energy metabolites. The PCr/ATP ratio decreases (9,19

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Section: Discussionsupporting

confidence: 55%

AMPK and substrate availability regulate creatine transport in cultured cardiomyocytes

Darrabie

Arciniegas

Mishra

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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“…Thermodynamic data have suggested that this reduction is due to a decreased recruitment of myosin crossbridges. Whereas the diminution of V max is a beneficial event at the cardiomyocyte level, allowing the cardiac fiber to contract at a normal energy cost, at the LV level the diminution of V max is the first step that will finally lead to dysfunction/failure [12].…”

Section: Response Of the Cardiomyocyte To Pressure Overloadmentioning

confidence: 99%

Hypertensive left ventricular hypertrophy risk: beyond adaptive cardiomyocytic hypertrophy

Fröhlich

González²,

Díez

2011

Journal of Hypertension

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The heart is a remarkably adaptive organ, capable of increasing its minute output and overcoming short-term or prolonged pressure overload. The structural response, in addition to the foregoing functional demands, is that of myocardial hypertrophy. Then, why should an adaptive response increase cardiovascular risk in hypertensive patients with left ventricular hypertrophy (LVH)? Evidence shows that the functional performance of hypertrophied cardiomyocytes is impaired, and that additional alterations develop in cardiomyocytes themselves, the extracellular matrix and the intramyocardial vasculature, leading to myocardial remodelling and providing the basis for the adverse prognosis associated with pathological LVH in hypertensive patients (i.e., hypertensive heart disease, HHD). As molecular information accumulates, the pathophysiological understanding and the clinical approach to HHD are changing. The time has come to develop novel diagnostic and therapeutic strategies aimed at improving the prognosis of HHD on the basis of reversing or even preventing the aforementioned changes in the ventricular myocardium.

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“…An integral nodal point during the development of heart failure is cardiac hypertrophy. 5,6 Cardiac hypertrophy is heritable 7 and is a recognized risk factor for heart failure. 8,9 In this study, we hypothesized that interindividual variability in the genetic risk factors for the hypertrophy trait may also influence the risk for developing heart failure or its prognosis over time.…”

Section: Introductionmentioning

confidence: 99%

Hypertrophy‐Associated Polymorphisms Ascertained in a Founder Cohort Applied to Heart Failure Risk and Mortality

Parsa

Chang

Kelly

et al. 2011

Clinical Translational Sci

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A three-stage approach was undertaken using genome-wide, case-control, and case-only association studies to identify genetic variants associated with heart failure mortality. In an Amish founder population (n = 851), cardiac hypertrophy, a trait integral to the adaptive response to failure, was found to be heritable (h2 = 0.28, p = 0.0002) and GWAS revealed 21 candidate hypertrophy SNPs. In a case (n = 1,610)-control (n = 463) study in unrelated Caucasians, one of the SNPs associated with hypertrophy (rs2207418, p = 8 × 10−6), was associated with heart failure, RR = 1.85(1.25–2.73, p = 0.0019). In heart failure cases rs2207418 was associated with increased mortality, HR = 1.51(1.20–1.97, p = 0.0004). There was consistency between studies, with the GG allele being associated with increased ventricular mass (~13 g/m2) in the Amish, heart failure risk, and heart failure mortality. This SNP is in a gene desert of chromosome 20p12. Five genes are within 2.0 mbp of rs2207418 but with low LD between their SNPs and rs2207418. A region near this SNP is highly conserved in multiple vertebrates (lod score = 1,208). This conservation and the internal consistency across studies suggests that this region has biologic importance in heart failure, potentially acting as an enhancer or repressor element. rs2207418 may be useful for predicting a more progressive form of heart failure that may require aggressive therapy.

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Molecular mechanisms in evolutionary cardiology failure

Cited by 24 publications

References 42 publications

AMPK and substrate availability regulate creatine transport in cultured cardiomyocytes

AMPK and substrate availability regulate creatine transport in cultured cardiomyocytes

Hypertensive left ventricular hypertrophy risk: beyond adaptive cardiomyocytic hypertrophy

Hypertrophy‐Associated Polymorphisms Ascertained in a Founder Cohort Applied to Heart Failure Risk and Mortality

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