Two to three percent of all people suffer from heart failure, at 70 - to 80-year-olds there are 10 - 20 percent. Despite modern therapies with beta-blockers, ACE inhibitors and diuretics the prognosis is very unfavorable. Overall, half of the patients die within 4 years. Of those who are hospitalized for heart failure, 40% will die in a year or be re-hospitalized [1]. The mortality rate for heart failure is similar to that of cancer diseases [2].

 

Heart failure is a complex syndrome in which a patient has typical symptoms (difficult breathing (dyspnoea), fatigue, weakness) and signs (tachycardia with heart rate greater than 100 per minute, edema) that are caused by a malfunction of the heart. Main causes of heart failure are coronary heart diseases (ischemic heart disease, angina pectoris), further high blood pressure (hypertension) and diseases of the heart muscle (cardiomyopathy).

 

According to a generally accepted hypothesis coronary heart diseases are caused by atherosclerosis ("hardening of the arteries"). Deposits in the artery walls lead to a stiffening of the artery walls, as well as to an increasing reduction of the artery cross-section up to complete blockage. The result is an impairment of the blood circulation and thus a reduced oxygen supply to the heart muscle. This results in a mismatch between oxygen demand and oxygen supply, which is known as ischemia or coronary insufficiency. With increasing progression of the disease increases the probability for the occurrence of cardiac arrhythmias and acute, life-threatening complications such as heart attack and sudden cardiac death.

 

Drug therapy of heart failure with beta-blockers and ACE inhibitors has no effect on atherosclerosis and blood flow to the heart muscle. To resolve this apparent contradiction between suspected cause of heart failure and the practiced medication today often not only impaired circulation is postulated as a cause. Heart failure is rather viewed as a multisystemic disorder that is characterized by dysfunctions of the heart, skeletal muscles and renal function. These dysfunctions induce a complex pattern of compensatory neurohumoral changes - including stimulation of the sympathetic nervous system [3]. This definition is less hemodynamically oriented and thus facilitates the understanding for example of the effectiveness of beta-blockers for a reduced contractible heart.

 

Doubt on atherosclerosis as a cause of heart failure

 

The hypothesis that coronary heart disease is caused by atherosclerosis derives from epidemiological surveys conducted by Keys and White in the 1950s. They postulated a relationship between fat diet and the incidence of cardiovascular disease. In particular, a high-cholesterol diet (meat, egg, milk, butter and other dairy products) would lead to increased cholesterol levels. The increased cholesterol levels lead to atherosclerosis and thus via impaired circulation to heart failure and heart attack.

 

To date, no biochemical mechanism has been identified which links cholesterol and elevated cholesterol level with the formation of atherosclerosis and heart disease. Nevertheless, the hypothesis that cholesterol-rich diet and high blood cholesterol levels play a causal role in the development of heart failure and heart attacks has become a central dogma of medicine. A positive effect of lipid-lowering agents (statins) in heart failure has not yet been demonstrated [4,5]. The effect of statins on the reduction of heart attacks is still controversial. Nevertheless, more than 25 million people worldwide regularly take cholesterol-lowering drugs. Cholesterol-lowering drugs today are the biggest segment of the pharmaceutical market.

 

Extensive clinical studies and experimental research indicate that there is no demonstrable correlation between impaired circulation caused by atherosclerosis and heart failure [6 and references cited therein, 6b]. Many patients with angina pectoris and signs of ischemia have no detectable coronary atherosclerosis and vice versa. Many patients with severe coronary atherosclerosis neither suffer from chest pain nor can one provide evidence of myocardial ischemia. Extreme cases are reported where total occlusion of all three major coronary arteries still allowed sufficient blood flow and normal heart function. An extensive network of anastomoses and collaterals ensures adequate blood flow to the heart [7].

 

Also, invasive methods of coronary revascularization (stents) and bypass are afflicted with high rates of relapse and only have minor effects on the survival rate of patients with heart failure [6, 6b]. The presence or absence of coronary atherosclerosis is only of limited importance to the diagnosis and treatment of heart failure.

 

Hyperactivity of the sympathetic nervous system causes heart failure

 

Already in the 1930s, several researchers (Gollwitz-Meier, Gremels, and others) had proven that in the explanation of ischemic conditions of the heart muscle (mismatch between oxygen demand and oxygen supply) not only the arterial oxygen supply to the myocardium is to be considered, but also the oxygen consumption of the heart, which is controlled by the autonomic nervous system. In the 1950s and 1960s Schimert [8], Selye [9] (creator of the stress concept) Raab [10, 11, 12, 20] and many other researchers have then proven that it is beyond doubt, that an excessive activity of the sympathetic nervous system leads to an extreme increase the oxygen consumption of the heart and thus causes oxygen deficiency that leads to necrosis (death of heart cells). Schimert, Selye and Raab have further demonstrated that not only physical "stress" but also emotional arousal ("emotional stress") causes increased release of stress hormones (epinephrine, norepinephrine, cortisol) and thus leads to increased oxygen demand of the heart. Recent studies show that a high percentage of angina pectoris and heart attacks are triggered by emotional stress [13,14].

 

If blood flow is restricted through impaired coronary compensatory dilatability or by vascular rigidity and narrowing, oxygen-consuming excessive cardiac sympathetic activity will produce damage of the myocardium. Therefore, atherosclerosis is merely an important risk factor, but not a causal trigger of heart failure and myocardial infarction. The intensity of adrenergic stimulation determines the progression of heart failure - not the extent of atherosclerosis, which can be additionally compensated by collateral blood flow. The eruption of vulnerable plaques is a non-predictable random event that is not causally related to normal progression of angina pectoris and heart failure, which may end in myocardial infarction. This well explains the non-existence of thrombi and occlusions in many instances of myocardial infarction [7].

 

Current research shows that in heart failure regardless of its pathogenesis a disorder of myocardial metabolism exists. Human left ventricular systolic dysfunction is associated with markedly diminished mitochondrial oxidative phosphorylation capacity [21]. Cardiac energetic impairment is a feature of systolic heart failure irrespective of the underlying etiology, and the magnitude of this impairment is predictive of subsequent mortality [22]. An excessive sympathetic stimulation as well as a vagal weakness damage myocardial metabolism, which can lead to heart failure and myocardial infarction [15]. It is therefore beyond doubt that a dysregulation of the autonomic nervous system causes heart disease.

 

Serum concentrations of norepinephrine are closely correlated with the severity and poor prognosis in heart failure [16]. Guideline compliant medical therapy of heart failure with beta-blockers and ACE inhibitors aims to mitigate the effects sympathetic overstimulation by blockade of beta-receptors and blockade of the renin-angiotensin-aldosterone system (RAAS) excited by the sympathetic nervous system. However, an increased activity of these systems is still not regarded as a cause of heart failure, but by maintaining the atherosclerosis dogma it is classified as response of the organism to impaired circulation caused by heart failure [3,17,23].

 

Activity and metabolism of the heart are controlled by the autonomic nervous system. Its antagonistic components - the sympathetic nerve and vagus nerve - interact in specific ways. Stimulation or inhibition of one always causes a partial stimulation / inhibition of the counterpart. This unique interaction is referred to as "accentuated antagonism". Modulating the autonomic nervous system, which is acting on the two components, therefore, is more effective than a mere blockade of receptors of one component. Hence, stimulation of the vagus nerve, as occurs also during physical exercise, has shifted into the focus of research. Pharmacological modulation of parasympathetic activity in the treatment of heart failure is considered a promising new approach [18]. Vagal stimulation by implanted electrodes in patients with heart failure has been proven to be feasible and safe. Preliminary data suggest that this intervention provides subjective and objective improvements [19].

 

Ouabain modulates the autonomic nervous system

 

The cardiac glycoside ouabain modulates the autonomic nervous system. Vagomimetic and sympatholytic effects characterize its therapeutic effects. Ouabain inhibits not only the adrenergic overstimulation but also supplies the heart vagomimetically by pronounced insulin-like anabolic effects with life-saving energy. 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.

 

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