title: From ARB to ARNI in Cardiovascular Control.
abstract: Coexistence of hypertension, diabetes mellitus and chronic kidney disease synergistically aggravates the risk of cardiovascular and renal morbidity and mortality. These high-risk, multi-morbid patient populations benefit less from currently available anti-hypertensive treatment. Simultaneous angiotensin II type 1 receptor blockade and neprilysin inhibition ('ARNI') with valsartan/sacubitril (LCZ696) might potentiate the beneficial effects of renin-angiotensin-aldosterone inhibition by reinforcing its endogenous counterbalance, the natriuretic peptide system. This review discusses effects obtained with this approach in animals and humans. In animal models of hypertension, either alone or in combination with myocardial infarction or diabetes, ARNI consistently reduced heart weight and cardiac fibrosis in a blood pressure-independent manner. Additionally, LCZ696 treatment reduced proteinuria, focal segmental glomerulosclerosis and retinopathy, thus simultaneously demonstrating favourable effects on microvascular complications. These results were confirmed in patient populations. Besides blood pressure reductions in hypertensive patients and greatly improved (cardiovascular) mortality in heart failure patients, ventricular wall stress and albuminuria were reduced particularly in diabetic patients. The exact underlying mechanism remains unknown, but may involve improved renal haemodynamics and reduced glomerulosclerosis, e.g. related to a rise in natriuretic peptide levels. However, the assays of these peptides are hampered by methodological artefacts. Moreover, since sacubitrilat is largely renally cleared, drug accumulation may occur in patients with impaired renal function and thus hypotension is a potential side effect in patients with chronic kidney disease. Further caution is warranted since neprilysin also degrades endothelin-1 and amyloid beta in animal models. Accumulation of the latter may increase the risk of Alzheimer's disease.
authors.affiliation: Division of Pharmacology and Vascular Medicine Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.|Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Estrellita
authors.initials: E
authors.lastname: Uijl
authors.affiliation: Division of Pharmacology and Vascular Medicine Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.|Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Lodi C W
authors.initials: LC
authors.lastname: Roksnoer
authors.affiliation: Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Ewout J
authors.initials: EJ
authors.lastname: Hoorn
authors.affiliation: Division of Pharmacology and Vascular Medicine Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. a.danser@erasmusmc.nl.
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use*; D000818:Animals; D006333:Heart Failure; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D012307:Risk Factors
chemical_list: D057911:Angiotensin Receptor Antagonists
keywords: Angiotensin; Chronic kidney disease; Diabetes; Natriuretic peptide; Neprilysin