Cardiac sodium-calcium exchange and efficient excitation-contraction coupling: implications for heart disease

Adv Exp Med Biol. 2013;961:355-64. doi: 10.1007/978-1-4614-4756-6_30.


Cardiovascular disease is a leading cause of death worldwide, with ischemic heart disease alone accounting for >12% of all deaths, more than HIV/AIDS, tuberculosis, lung, and breast cancer combined. Heart disease has been the leading cause of death in the United States for the past 85 years and is a major cause of disability and health-care expenditures. The cardiac conditions most likely to result in death include heart failure and arrhythmias, both a consequence of ischemic coronary disease and myocardial infarction, though chronic hypertension and valvular diseases are also important causes of heart failure. Sodium-calcium exchange (NCX) is the dominant calcium (Ca2+) efflux mechanism in cardiac cells. Using ventricular-specific NCX knockout mice, we have found that NCX is also an essential regulator of cardiac contractility independent of sarcoplasmic reticulum Ca2+ load. During the upstroke of the action potential, sodium (Na+) ions enter the diadic cleft space between the sarcolemma and the sarcoplasmic reticulum. The rise in cleft Na+, in conjunction with depolarization, causes NCX to transiently reverse. Ca2+ entry by this mechanism then "primes" the diadic cleft so that subsequent Ca2+ entry through Ca2+ channels can more efficiently trigger Ca2+ release from the sarcoplasmic reticulum. In NCX knockout mice, this mechanism is inoperative (Na+ current has no effect on the Ca2+ transient), and excitation-contraction coupling relies upon the elevated diadic cleft Ca2+ that arises from the slow extrusion of cytoplasmic Ca2+ by the ATP-dependent sarcolemmal Ca2+ pump. Thus, our data support the conclusion that NCX is an important regulator of cardiac contractility. These findings suggest that manipulation of NCX may be beneficial in the treatment of heart failure.

Publication types

  • Review

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Female
  • Heart Failure / genetics
  • Heart Failure / metabolism*
  • Heart Failure / pathology
  • Heart Failure / therapy
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Myocardial Contraction*
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Sarcoplasmic Reticulum / genetics
  • Sarcoplasmic Reticulum / metabolism
  • Sarcoplasmic Reticulum / pathology
  • Sodium-Calcium Exchanger / genetics
  • Sodium-Calcium Exchanger / metabolism*


  • Muscle Proteins
  • Sodium-Calcium Exchanger
  • Calcium