Pharmacological stimulation of the parasympathetic system – a promising means of cardioprotection in heart failure

Chronic heart failure (HF) has attracted the utmost attention of cardiologists for more than half a century. Insight into the pathophysiology of this tricky condition has undergone principal changes during the last decades that determined adjustments to the therapeutic approaches [ 1 ]. During the 1950s, fluid retention was considered the dominant alteration in HF. As a result of blood flow reduction to- and impaired venous return from the kidneys, both leading to renal dysfunction with fluid excess, a cardiorenal model of HF was established and diuretics and digoxin became the principal treatment modalities. Twenty years later, blood redistribution in terms of vasoconstriction of the arterial and venous system to favour blood supply to the vital tissues was presumed to participate in a circulatory imbalance, leading to the establishment of the cardiocirculatory model of HF. Vasodilators were considered a rational strategy to attenuate the increased preload and afterload of the heart and to improve peripheral perfusion. In the 1990s, clinical studies revealed that increased plasma levels of stress hormones, such as noradrenaline or renin, in HF patients were associated with accelerated mortality. These surprising findings resulted in the concept of a neurohumoral model of HF. It was based on the idea that increased catecholamine, angiotensin II (Ang II) or aldosterone production, although hemodynamically beneficial during acute heart damage, are potentially deleterious in chronic HF as a result of the stress hormones‘ proliferative, vasoconstrictive and energy-consuming actions, which outperform their hemodynamic benefit. The unfavourable impact of the stress humoral players from a long-term perspective resulted in the introduction of angiotensin/aldosterone and catecholamines antagonists in HF treatment [ 1 ]. Later, this view was expanded to include the potential benefits of counterregulatory humoral molecules with antiproliferative and vasodilative effects, such as natriuretic peptides, and the sodium-glucose cotransporter 2 (SGLT2) inhibitors with a yet unknown mechanism of cardioprotection in HF [ 2 ].