Scientific basics and clinical experience

Heart failure is one of the most common internal medical diseases. There is no causal treatment. Main causes of heart failure are coronary heart diseases (ischemic heart disease, angina pectoris), high blood pressure (hypertension) and diseases of the heart muscle (cardiomyopathy). Despite modern therapies with beta-blockers, ACE inhibitors and diuretics the prognosis is very unfavorable. Overall, half of the patients die within four years. Of those who are hospitalized for heart failure, All available therapies are limited to symptom relief. Consequently, there is high interest by clinicians and pharmaceutical companies to substances, which offer effective treatment.

 

In heart failure, a state of autonomic dysregulation exists involving an increase in sympathetic tone and a decrease in parasympathetic tone. Risk factors for cardiovascular diseases such as obesity, hypertension and smoking are all characterized by increased sympathetic activation. Even with depression, anxiety, social isolation and chronic stress, increased sympathetic tone is observed. The degree of sympathetic activation is an important and independent determinant in the prognosis of myocardial and cerebral diseases. Elevated plasma catecholamine levels closely correlate with increased mortality.

 

Beta-adrenergic blockade (beta-blockers) is used in combination with inhibition of the renin-angiotensin-aldosterone system (ACE inhibitors, AT1 inhibitors, aldosterone antagonists, renin inhibitors) to reduce the hyper-adrenergic drive. However, inhibition of the sympathetic nervous system affects only one half of the autonomic imbalance. The activation of the reduced vagal tone is just as promising therapeutic approach. In clinical trials vagal stimulation through implanted electrodes in patients with heart failure results in subjective and objective improvements. Pharmacological modulation of parasympathetic activity in heart failure has become an attractive therapeutic approach.

 

Cardiac glycosides inhibit not only the sodium-potassium ATPase. They also modulate the autonomic nervous system. A tabulation of the therapeutic and toxic effects of cardiac glycosides is strikingly similar to a tabulation of the combined effects of acetylcholine and adrenaline. In the lipophilic digitalis glycosides (digoxin, digitoxin) sympathomimetic effects dominate; the hydrophilic Strophanthus glycoside (k-strophanthin, ouabain) show pronounced vagomimetic effects.

 

Digitalis glycosides have a pronounced positive inotropic effect. In addition, there is evidence of a weak modulation of the autonomic nervous system, which is reflected in vagomimetic and sympatholytic effects.

Unlike digitalis derivatives, the positive inotropic effect of ouabain is only very weakly pronounced. In Strophanthus derivatives the modulation of the autonomic nervous system dominates. Vagomimetic and sympatholytic effects characterize their therapeutic effects. However, unlike ACE inhibitors and β-blockers ouabain inhibits not only the adrenergic overstimulation but also supplies the heart via distinct insulin-like anabolic effects with life-saving energy.Ouabain modulates the cardiac metabolism. It stimulates glycogen synthesis, and increases the lactate utilization by the heart muscle. It reduces catecholamine serum concentrations, promotes the secretion of insulin, induces the release of acetylcholine from synaptosomes, and potentiates the stimulation of glucose metabolism by insulin and acetylcholine.

 

In high (toxic) concentrations ouabain inhibits the sodium pump similar to digitalis. At therapeutic concentrations, it induces intracellular signaling cascades, which are responsible for the stimulation of myocardial metabolism. Ouabain just like the currently intensively researched phenomenon of ischemic preconditioning activates endogenous protective mechanisms (RISK signaling cascade) against insufficient oxygen supply to the heart muscle. With this unique profile of mechanism of action ouabain qualifies as tailor made drug for the treatment of heart failure.

 

The experimentally well-documented mechanisms of action of ouabain* translate into favorable therapeutic effects, which are significantly different from the ones of digitalis derivatives. Indications for the use of digitalis are heart failure with tachycardia, atrial fibrillation and ventricular fibrillation. However, Strophanthus glycosides are indicated for the treatment of angina pectoris, ischemic heart disease (coronary artery disease) and heart failure as a result of infectious disease, obesity and stress. Digitalis derivatives have no significant effect on blood pressure. Ouabain "normalizes" blood pressure: high blood pressure is lowered, low blood pressure increases. In cardiac patients with insomnia as a result of dyspnoea digitalis shows no effect, while ouabain provides rapid relief.

 

The dominating vagomimetic and sympatholytic effects of ouabain also explain its stress-resolving effect frequently observed in clinical practice. In patients treated with ouabain often a general freshness and increased activity willingness with improved mood is observed, which can not be explained with the improvement of heart function. This clinical experience will allow to develop ouabain not only for the treatment of heart failure but also to target specifically the treatment of stress conditions (burnout).

 

Clinical experiences with ouabain in the treatment of heart failure are documented in numerous reports in the German scientific literature. Since in the Anglo-Saxon countries almost exclusively Digitalis derivatives have been used in medical therapy, there are only few English-language reports on the therapeutic use of ouabain. Hence, the many years of successful use of ouabain for the treatment of heart failure today are hardly known in science (for details see: history). The scientific interest focuses mainly on ouabain as an agent for inhibiting the sodium pump in studies to elucidate the physiological functions of the sodium pump. The finding that ouabain may be an endogenous substance and current findings that ouabain is very effective in several cancer models as well as the finding that ouabain in rats in-vivo protects kidney development from adverse effects of malnutrition refocuses the interest in ouabain on its untapped therapeutic potential.

 

* Described in detail in these reviews:

Ouabain - the insulin of the heart, Fürstenwerth H. 

Int J Clin Pract. 2010 Nov;64(12):1591-4, download

 

On the Differences Between Ouabain and Digitalis Glycosides, Fuerstenwerth H.

Am J Ther. 2014 Jan-Feb;21(1):35-42

 doi: http://dx.doi.org/10.1097/MJT.0b013e318217a609

 download

 

Ouabain - The Key to Cardioprotection? Fuerstenwerth H.

Am J Ther. 2014 September/October;21(5):395-402.

 doi: http://dx.doi.org/10.1097/MJT.0b013e31824d622c

 download

 

Rethinking heart failure , Fürstenwerth H.

Cardiol Res. 2012;3(6):243-257,  download

http://www.cardiologyres.org/index.php/Cardiologyres/article/view/228/230

 

On Correlation and Causality, Fürstenwerth H.
Critical Care Medicine 41 (7), e140-e141. download

 

 

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