Endogenous Cardiotonic Hormones: A New Argument for the  Myogenic Theory of Myocardial Infarction

 The first to postulate the existence of an endogenous digitalis in mammals was Ringer in 1885. Alberto Szent-Györgyi advocated a similar idea in 1953 (1).

Cardiotonic steroids of the cardenolide (digoxin and ouabain) and bufadienolide (Proscilaridine-A and Marinobufagenin) types have been isolated from human tissues and body fluids (2, 3, 4, 5).

Elevated concentrations of endogenous ouabain have been found under different conditions like sodium imbalance, chronic renal failure and congestive heart failure. Taking in view the significant relations of plasma ouabain concentration with cardiac index and mean arterial pressure it was assumed that endogenous ouabain may be an important homeostatic factor in humans (6, 7, 8).

The endogenous ouabain changes rapidly in human and dogs upon physical exercise and is in control of epinephrine and angiotensin II. Hence, the steroid acts as a rapidly acting hormone (9).

A clinical study published in 2003 attempted to determine the incidence of critically  ill patients displaying endogenous digitalis-like immunoreactive substances (DLIS) and to examine the relationship of these hormones to routine laboratory variables, the underlying disease, myocardial function, hemodynamic status, severity of illness, systematic inflammation, and mortality rate. The blood of 401 pacients, not treated with cardiac glycosides, were analysed for DLIS (digitoxin and digoxin) and endogenous ouabain. It was concluded that different types of endogenous glycosides including endogenous ouabain are elevated in a significant proportion of critically ill patients. The occurrence of these susbstances is associated with increased morbidity and hospital mortality rates, possible due to systemic inflammatory processes. The study also found that DLIS but not endogenous ouabain concentrations are related to left ventricular function (10).

A study published in 1991 demonstrated there was a 2.5 fold increase in plasma digoxin-like immunoreactivity in patients with myocardial infarction as compared with five healthy controls and nine patients with unstable angina (11).

In a study published in 1992, it was examined endogenous digitalis-like factor concentrations in the serum and urine in 65 patients with acute myocardial infarction. Radioimmunoassay was used for the examination and patients data were analyzed in relation to sex, risk factors and acute myocardial infarction complications. The concentrations of digitalis-like factor found in the serum of men and women with acute myocardial infarction were much higher compared with values of healthy men and women. According the authors these findings are in agreement with data published by others and suggest a role of digitalis-like factor in the pathogenesis of myocardial infarction (12,13).

A study published in 1994 showed an increase of plasma EDLF (concentration of endogenous digoxin-like factor) during the 1st day after acute myocardial infarction, and that higher plasma EDLF may be associated with the development of ventricular arrhythmias (14).

A study published in 1990 measured the ability of plasma to inhibit a human renal NA (+) - K + ATPase before and immediately after percutaneous transluminal coronary angioplasty (PTCA) in 6 patients suffering angina pectoris and severe coronary stenosis. Related to the increase of concentration of the digitalis-like factor in plasma the authors placed the hypothesis that the reduction in cardiac output during PTCA by raising cardiac pressures may stimulate the production of a factor of compensatory inotropic significance (15).

In a study from 1988 the perioperative digoxin concentrations were measured in 20 unselected adult patients undergoing coronary surgery. None of the patients were receiving treatment with digoxin. A digoxin-like immunoreactive substance was found in 16 patients postoperatively (16).

A study published in 1998 have described the purification of the marinobufagenin bufadienolide from the urine of patients with myocardial infarction and with increased concentration in the blood plasma. The authors placed that these data suggest a role for this substance in the pathogenesis of myocardial ischemia (5).

Another study published in 2002 measured the plasma levels of marinobufagenin in 23 consecutive hypertensive male patients with CHF (congestive heart failure) showing progressive increases in a graded manner with the severity of CHF (17) .

We also have the cardiotonic apelin, a peptide endogenous hormone discovered in 1998, found in high concentration in the cardiac tissue (18).

Study published in 2002 show that apelin is one of the most potent endogenous positive inotropic substances yet identified and that it regulates cardiac contractility (19)

A study published in 2003 reported for the first time circulating human apelin levels and demonstrating increases in the plasma level of apelin in patients with left ventricular dysfunction with it emerging as an important novel mediator of cardiovascular control (20).

Another recent study show that apelin levels were increased in 4.7-fold in chronic heart failure due to coronary heart disease and 3.3-fold due to idiopathic dilated cardiomyopathy, whereas atrial apelin levels were unchange. The authors of the study tell their results suggest that apelin and APJ receptor may contribute to the pathophysiology of human congestive heart failure (21).

The studies about endogenous cardiotonic hormones are just starting. However, it is possible to predict, with a high degree of certainty, the studies will confirm the exogenous cardiotonics as anti-infarction drugs, complementing, providentialy, an insufficient production of the endogenous cardiotonic hormones by the human body, in order to support the cardiac metabolism and protect the heart from the infarction as defended by the Myogenic Theory of Myocardial Infarction (23).

"Cardiotonic drugs represent to heart disease the same as insulin for diabetes.. "

Bibliography

1. Wilhelm Schoner - Endogenous cardiac glycosides, a new class of steroid hormones, Eur J Biochem. 268, 2440-2448, 2002.

2. Shaik I et al. Isolation of a urinary digitalis-factor indistinguishable from digoxin. Biochem Biophys Res Comm, 1990; 173:1093-1101

3. Hamlyn JM et al - Identification and characterization of a ouabain-like compound from human plasma. Proc Natl Acad Sci U S A, 1991;88:6259-6263

4. Schneider R, Wray V, et al - Bovine adrenals contain, in addition to ouabain, a second inhibitor of the sodium pump. J.Biol. Chem 273,784-792, 1998.

5. Alexei Y Bagrov, Olga V Fedorova, et al - Characterization of a urinary bufodienolide Na+, K+ - ATPase inhibitor after acute myocardial infarction. Hypertension, 31:1097-1103, 1998

6. Blaustein MP - Physiological effects of endogenous ouabain: control of intracellular Ca(2+) stores and cell responsiveness. Am J.  Physiol. 264 (Cell Physiol 33), C1367 - C1387; 1993.

7. Hamlyn JM et al - Observations on the nature, biosynthesis, secretion and significance of endogenous ouabain. Clin Exp Hypertens. 20, 523-533; 1998. 

8. Gottlieb SS et al - Elevated concentrations of endogenous ouabain in patients with congestive heart failure. Circulation 86, 420-425; 1992.

9. Schoner W et al - Ouabain as a mammalian hormone, Ann N Y Acad Sci. 2003 Apr;986:678-84

10. Berendes et al - Endogenous glycosides in critically ill patients, Crit Care Med. May; 31 (5): 1331-7, 2003.

11. Bagrov AYa et al - Endogenous plasma Na,K-ATPase inhibitory activity and digoxin like immunoreactivity after acute myocardial infarction, Cardiovasc Res, May; 25 (5):371-7, 1991.

12. Kohn R et al - Endogenous digitalis-like factor in patients with acute myocardial infarction, Cor Vasa, 34 (3):227-37, 1992.  

13. Kohn R et al - Personnal experience with determination of endogenous, digoxin-like substances in patients with myocardial infarct and other cardiopathies, Bratisl Lek Listy. 1995 Feb; 96(2):82-7.

14. Bagrov AY et al - Endogenous digoxin-like-factor in acute myocardial infarction, J Intern Med, Jan;235 (1):63-7, 1994.

15. Delva P et al - Increase in plasma digitalis-like activity during percutaneous transluminal coronary angioplasty in patients with coronary stenosis, Life Sci, 47(5):385-9, 1990.

16. Nashef SA et al - Endogenous digoxin-like immunoreactive substance in patients undergoing coronary surgery. Preliminary report, Eur J Cardiothorac Surg, 2(5):380-1, 1988.

17. Fridman AI et al - Marinobufagenin, an endogenous ligand of alpha-1 sodium pump, is a marker of congestive heart failure severity. J Hypertension. 2002 Jun;20(6):1189-94

18. K Tatemoto et al. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor, Biochem. Biophys. Res Commun, 1998;251:771-746.

19. István Szokodi et al. Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility, Circulation Research, 2002;91:434

20. Mary M. Chen et al. Novel role for the potent endogenous inotropic apelin in human cardiac dysfunction, Circulation, 2003;108:1432

21. Foldes G et al. Circulating and cardiac levels of apelin, the novel ligand of the orphan receptor APJ, in patients with heart failure, Biochem Biophys. Res Commun, 2003 Aug 29;308 (3):480-5.

22. The Myogenic Theory of Myocardial Infarction

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