Cardiovascular Research

Cardiovascular Research 2003 57(4):871-872; doi:10.1016/S0008-6363(02)00849-0
© 2003 by European Society of Cardiology

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Copyright © 2003, European Society of Cardiology

Sodium and the heart: a hidden key factor in cardiac regulation

Burkert Pieske^a,*, Steven R Houser^b, Gerd Hasenfuss^a and Donald M Bers^c

^aDepartment of Cardiology and Pneumology, University of Göttingen, Göttingen, Germany
^bMolecular and Cellular Cardiology Laboratories, Temple University School of Medicine, Philadelphia, PA 19140, USA
^cDepartment of Physiology, Loyola University Chicago, Maywood, IL 60153, USA

pieske{at}med.uni-goettingen.de

^* Corresponding author. Tel.: +49-551-3989-25; fax: +49-551-3919-127.

Myocyte Na⁺ homeostasis is crucially involved in a number of vital cell functions, such as excitability, excitation–contraction coupling, energy metabolism, pH regulation, as well as cardiac development and growth. However, consideration of Na⁺ regulation is often relegated to a secondary position in the discussion of cardiac (patho-)physiology, where the focus is typically on contractile proteins, Ca²⁺ regulation and pH regulation which appear more directly related to contractile function. However, myocyte Na⁺ homeostasis is as complex as Ca²⁺ or pH homeostasis and [Na⁺]_i very directly influences intracellular [Ca²⁺] and pH via powerful cardiac Na/Ca exchange, Na/H exchange and Na-bicarbonate cotransport systems. Na⁺ flux my even be central in mediating effects of mechanical loading of the heart on excitation–contraction coupling. Moreover, [Na⁺]_i homeostasis is regulated by a delicate balance of Na⁺ channels and transporters in the surface and mitochondrial membrane that maintain a large [Na⁺] gradient across the sarcolemmal membrane.

Given this fundamental but often overlooked contribution of Na⁺ homeostasis to regulation of cardiac function, we, the guest editors, organized an international symposium focused on ‘Sodium and the Heart’, held at Schloss Waldeck, Germany, in May 2002. This meeting was stimulating and many aspects of myocyte Na⁺ regulation and transport were addressed in depth.

There was extensive discussion of how Na⁺ handling is altered in a number of cardiac pathologies (e.g., hypertrophy, heart failure, ischemia/reperfusion injury and digitalis toxicity). Special emphasis was put on function of Na⁺ channels, Na/Ca exchange, Na/H exchange, and Na/K-ATPase in cardiac health and disease. It was also postulated that Na⁺ may even alter gene expression by direct effects on gene responsive elements or indirectly via changes in pH_i or [Ca²⁺]_i.

There was general agreement on some central issues (e.g., that [Na⁺]_i is elevated in hypertrophy, heart failure, during ischemia/reperfusion and the slow force response to mechanical stretch). However, there remains substantial controversy concerning both the molecular mechanisms by which these [Na⁺]_i changes occur and the precise downstream consequences. This produced lively debate at the symposium and also stimulated the notion of this novel spotlight issue on Sodium and the Heart in Cardiovascular Research (an idea supported by the journal editors). Many of the participants of the Waldeck symposium contributed to this issue, which contains nine state-of-the-art reviews (including some that pair up co-authors with different perspectives) and 13 original contributions submitted at large.

Specifically, Bers et al. [1] give an introductory overview on Na⁺ handling in myocytes, including quantitative estimations of Na⁺ influx via Na⁺ channels and transporters under normal and pathological conditions. They also consider the potential functional implications of local Na⁺ gradients within the cells. Pogwidz et al. [2] follow with an in-depth discussion of altered Na⁺ handling in animal models of hypertrophy and failure (which in most cases demonstrate elevated Na⁺ levels), resulting in functional (slowed relaxation, slowed recovery from acidosis) as well as proarrhythmogenic consequences. Next, Pieske and Houser [3] discuss the evidence of elevated Na⁺ levels in the failing human heart, as well as potential underlying mechanisms and functional consequences (e.g., increased systolic, but impaired diastolic function). Tan et al. [4] review in depth how aberrant Na⁺ channel function due to genetic defects may cause life-threatening arrhythmias. Schillinger et al. [5] follow with an overview on the delicate role of the Na⁺/Ca²⁺ exchanger for Ca and Na⁺ homeostasis, and how this balance may be affected by altered function (or expression) of the exchanger. Avkiran and Haworth [6] summarise recently unravelled regulatory pathways for activation and inhibition of the Na/H exchanger (e.g., via G-protein coupled receptors, ERKs, rS6K, and PKC) and their potential as novel therapeutic targets. This is followed Cingolani et al. [7] who review stretch-dependent signal pathways for activation of the Na/H-exchanger, and by Allen and Xiao [8] who discuss the role of the Na/H exchanger during ischemia and reperfusion (and conclude that the Na/H exchanger is largely inhibited during ischemia). In the last of this series of reviews, Schwinger et al. [9] address the potential role of altered Na/K-ATPase expression and function in the failing human heart.

There are also original contributions that cluster around Na⁺ channel regulation, function, and genetic defects [10–13], subsarcolemmal [Na⁺] gradients [14], elevated [Na⁺]_i and reverse-mode Na/Ca exchange [15,16], functional effects of Na/Ca exchanger overexpression [17], as well as the role of the Na/H exchanger in increased [Na⁺]_i during stretch [18] and in animal models of hypertrophy [19] and failure [20]. Finally, novel findings address how altered Na/K-ATPase function is involved in ischemia [21] and hypertrophy [22], thereby contributing to elevated [Na⁺]_i levels.

Even where conceptual overlap occurs, different authors bring different data to bear and diverse interpretational perspectives to the understanding of these topics. We sincerely hope that this Spotlight Issue on ‘Sodium and the Heart’ will be both informative on the issues and also stimulating in terms of integrating Na⁺ regulation more comprehensively into our understanding of cardiomyocyte function.

	References

Top References

 

1. Bers D.M., Barry W.H., Despa S. Intracellular Na⁺ regulation in cardiac myocytes. Cardiovasc Res (2003) 57:897–912.[Abstract/Free Full Text]
2. Pogwidz S.M., Sipido K.R., Verdonck F., Bers D.M. Intracellular Na in animal models of hypertrophy and heart failure: contractile function and arrhythmogenesis. Cardiovasc Res (2003) 57:887–896.[Free Full Text]
3. Pieske B., Houser S.R. [Na⁺]_i handling in the failing human heart. Cardiovasc Res (2003) 57:874–886.[Abstract/Free Full Text]
4. Tan H.L., Bezzina C.R., Smits J.P., Verkerk A.O., Wilde A.M. Genetic control of sodium channel function. Cardiovasc Res (2003) 57:961–973.[Abstract/Free Full Text]
5. Schillinger W., Fiolet J.W., Schlotthauer K., Hasenfuss G. Relevance of Na⁺/Ca²⁺ exchange in heart failure. Cardiovasc Res (2003) 57:921–933.[Free Full Text]
6. Avkiran M., Haworth R.S. Regulatory effects of G-protein-coupled receptors on cardiac sarcolemmal Na/H exchanger activity: signaling and significance. Cardiovasc Res (2003) 57:942–952.[Abstract/Free Full Text]
7. Cingolani H.E., Pérez N.G., Pieske B., von Lewinski D., Camilón de Hurtado M.C. Stretch-elicited Na⁺/H⁺ exchanger activation: the autocrine/paracrine loop and its mechanical counterpart. Cardiovasc Res (2003) 57:953–960.[Abstract/Free Full Text]
8. Allen D.G., Xiao X.H. Role of the Na⁺/H⁺ exchanger during ischemia and reperfusion. Cardiovasc Res (2003) 57:934–941.[Abstract/Free Full Text]
9. Schwinger R.H.G., Bundgaard H., Müller-Ehmsen J., Kjeldsen K. The Na/K, ATPase in the failing human heart. Cardiovasc Res (2003) 57:913–920.[Abstract/Free Full Text]
10. Boehmer C., Wilhlem V., Palmada M., Wallisch S., Henke G., Brinkmeier H., Cohen P., Pieske B., Lang F. Serum and glucocorticoid inducible kinases in the regulation of the cardiac sodium channel SCN5A. Cardiovasc Res (2003) 57:1079–1084.[Abstract/Free Full Text]
11. Starmer C.F., Grant A.O., Colatsky T.J. What happens when cardiac Na channel function is compromised? 2. Numerical studies of the vulnerable period in tissue altered by drugs. Cardiovasc Res (2003) 57:1062–1071.[Abstract/Free Full Text]
12. Fabritz L., Kirchhof P., Franz M.R., Nuyens D., Rossenbacker T., Ottenhof A., Haverkamp W., Breithardt G., Carmeliet E., Carmeliet P. Effect of pacing and mexiletine on dispersion of repolarisation and arrhythmias in KPQ SCN5A (Long QT syndrome) mice. Cardiovasc Res (2003) 57:1085–1093.[Abstract/Free Full Text]
13. Groenewegen W.A., Bezzina C.R., van Tintelen J.P., Hoorntje T.M., Mannens A., Wilde A.M., Jongsma H.J., Rook M.B. A novel LQT3 mutation implicated the human cardiac sodium channel domain IVS6 in inactivation kinetics. Cardiovasc Res (2003) 57:1072–1078.[Abstract/Free Full Text]
14. Silvermann B.d.Z., Warley A., Miller J.I.A., James A.F., Shattock M.J. Is there a transient rise in sub-sarcolemmal Na and activation of Na/K pump current following activation of I_Na in ventricular myocardium? Cardiovasc Res (2003) 57:1025–1034.[Abstract/Free Full Text]
15. Baartscheer A., Schumacher C.A., Beltermann C.N.W., Coronel R., Fiolet J.W.T. [Na⁺]_i and the driving force for the Na/Ca exchanger in heart failure. Cardiovasc Res (2003) 57:986–995.[Abstract/Free Full Text]
16. Weisser-Thomas J., Piacentino V. 3rd, Gaughan J.P., Margulies K., Houser S.R. Calcium entry via Na/Ca exchange during the action potential directly contributes to contraction of failing human ventricular myocytes. Cardiovasc Res (2003) 57:974–985.[Abstract/Free Full Text]
17. Schillinger W., Ohler A., Emami S., Müller F., Christians C., Janssen P., Teucher N., Pieske B., Seidler T., Hasenfuss G. The functional effect of adenoviral Na/Ca exchanger overexpression in rabbit myocytes depends on the activity of the Na/K-ATPase. Cardiovasc Res (2003) 57:996–1003.[Abstract/Free Full Text]
18. Bak M.I., Ingwall J.S. The contribution of Na/H exchange to Na⁺ overload in the ischemic hypertrophied rat heart. Cardiovasc Res (2003) 57:1004–1014.[Abstract/Free Full Text]
19. Baartscheer A., Schumacher C.A., van Borren M.M.G., Belterman C.N.W., Coronel R., Fiolet J.W.T. Increased Na/H-exchange activity is the cause of increased [Na⁺]_i and underlies disturbed calcium handling in the rabbit pressure and volume overload heart failure model. Cardiovasc Res (2003) 57:1015–1024.[Abstract/Free Full Text]
20. von Lewinski D., Stumme B., Maier L.S., Luers C., Bers D.M., Pieske B. Stretch-dependent slow force response in isolated rabbit myocardium is Na⁺ dependent. Cardiovasc Res (2003) 57:1052–1061.[Abstract/Free Full Text]
21. Fuller W., Parmar V., Eaton P., Bell J.R., Shattock M.J. Cardiac ischemia causes inhibition of the Na/K ATPase by a labile cytosolic compound whose production is linked to oxidant stress. Cardiovasc Res (2003) 57:1044–1051.[Abstract/Free Full Text]
22. Verdonck F., Volders P.G.A., Vos M.A., Sipido K.R. Increased Na⁺ concentration and altered Na/K pump activity in hypertrophied canine ventricular cells. Cardiovasc Res (2003) 57:1035–1043.[Abstract/Free Full Text]

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Copyright © 2009 European Society of Cardiology

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