Neurohumoral stimulation is a key finding in syndromes such as chronic heart failure (CHF), type-2 diabetes mellitus (T2DM), and chronic renal insufficiency. There, the activation of cardiovascular hormonal systems such as the renin-angiotensin II-aldosterone system (RAAS) translates into progression of the underlying disease and/or development of cardiovascular comorbidity including an increased risk for major adverse cardiac events.
In CHF, epidemiologic data support the notion that plasma levels of norepinephrine (1) as well as brain-natriuretic peptide (BNP) (2) are reliable markers for patient outcome. Landmark studies have shown that CHF patients benefit from angiotensin-converting-enzyme (ACE) inhibitors, betaadrenergic blockade, and mineralocorticoid- receptor blockade. Concerning ACE inhibition, the inherent bradykininergic effects appear to be important in the CHF condition, rendering ACE inhibitors superior to angiotensin receptor blockers (3). Regarding the rationale for betaadrenergic blockade in CHF, the “Cardiac Insufficiency Bisoprolol Study II” (CIBIS II), amongst other studies, has shown a 34% mortality reduction in patients staged NYHA class III and IV when bisoprolol was added to standard of care therapy (4;5). Even after the introduction of betaadrenergic blockade and ACE inhibition in CHF, an additional improvement in the prognosis of CHF patients has been achieved by mineralocorticoid-receptor blockade as demonstratd by the “Randomized Aldactone Evaluation Study” (RALES) (6) and “Eplerenone Post Acute Myocardial Infarction Efficacy and Survival Study” (EPHESUS) (7, 8).
Beyond CHF, outcome-related research has tested the blockade of neurohumoral pathways in coronary artery disease (CAD) as well: the “Heart Outcomes Prevention Evaluation Study” (HOPE) has proven a 26% reduction in cardiovascular deaths in patients with coronary artery disease without signs of CHF when treated with an ACE inhibitor (8). Therefore, a direct role for RAAS activation with regard to pathogenesis and/or disease progression of CAD has been suggested. Both in animal research and in outcome-related research involving patients, indirect evidence suggests angiotensin 2 to promote aortic aneurysm formation (9). A connection between angiotensin 2 and makrophage infiltration of the arterial vessel wall has been established (10).
As far as chronic renal insufficiency is concerned, treatment of underlying diseases such as type 2 diabetes mellitus (T2DM) is warranted to favorably affect renal function. However, going along with a decrease of renal function, the prevalence of cardiovascular comorbidity and incidence of major adverse cardiac events rises in a linear fashion (11). The underlying causes and the role for cardiovascular-hormone activation such as the RAAS has to be further investigated. Recent data suggest that vitamin D receptor activation reduces blood pressure, for instance, by suppressing the expression of angiotensinogen, angiotensin II type 1 receptor, renin activity and renin receptor (13). Other animal models have shown that active vitamin D3 promotes arterial stiffening and the pathogenesis of systolic hypertension (14). Of note in this context, macrophages (for instance, in the atherosclerotic or “inflammatory” plaque) can convert/activate vitamin D3 to calcitriol.
Last, an emerging body of data points at specific states of neurohumoral stimulation in T2DM and its precursor states such as obesity (15). As type-2 diabetes is tightly connected with obesity, obesity-related mechanisms of insulin resistance and neurohumoral stimulation become subject of research interest. Besides non-pharmacologic interventions such as increased physical activity and a low-caloric diet, medical interventions influencing appetite and metabolic rate are investigated. The fact that patients with male-type obesity are more prone to developing T2DM than patients with female-type obesity has influenced the definition of metabolic syndrome by the “Third Report of the National Cholesterol Education Program’s Adult Treatment Panel” (ATP III). There, waist circumference is used instead of body-mass index (16). The established diagnosis of metabolic syndrome based on the ATP III criteria serves to predict the risk for type-2 diabetes (24 fold increased) and for atherosclerosis (3-4 fold increased) (17). According to a study among 359,387 participants from nine countries in the European Prospective Investigation into Cancer and Nutrition (EPIC), using Cox regression analysis, the optimal waist circumference for women was between 75 and 80 cm, and for men, between 90 and 95 cm. Each increase by 5 cm increased the mortality risk by 17 percent for men, and by 13 percent for women (18). Neurohumoral mechanisms may offer additional insights into evolution towards T2DM. Among hypertensives treated either with losartan or atenolol in the LIFE study, the losartan-treated branch had a greater benefit in terms of T2DM prevention when compared to the atenolol-treated group while blood-pressure control was equal (19). That is, specific neurohumoral mechanisms such as the RAAS may be intimately involved in diabetes evolution.
Research issues remain to be solved regarding specific signal cascades involved in states of neurohumoral stimulation such as CHF, chronic renal insufficiency, or T2DM. A better understanding of neurohumoral compensatory responses to prior dysregulations may help explain a number of puzzles, thereby identifying therapeutic targets or effective preventive measures.
Overall, in this chapter, pertinent cardiovascular hormone actions are being highlighted with regard to hemodynamic actions as documented by alterations of systemic vascular resistance and cardiac output as well as non-hemodynamic effects such as inflammation and oxidative stress.