A 66-year-old man comes to the office for a follow-up appointment. The patient has a history of heart failure with reduced ejection fraction and has had persistent dyspnea despite taking the maximal dosage of his heart failure medications. He has had no lightheadedness or chest pain. Blood pressure is 133/72 mm Hg and pulse is 76/min. Physical examination shows normal lung sounds and no lower extremity edema. His medical treatment is modified with the addition of a combination pill that inhibits neprilysin and blocks angiotensin II receptors. Which of the following is the most likely effect of this medication?

Question

A 66-year-old man comes to the office for a follow-up appointment.  The patient has a history of heart failure with reduced ejection fraction and has had persistent dyspnea despite taking the maximal dosage of his heart failure medications.  He has had no lightheadedness or chest pain.  Blood pressure is 133/72 mm Hg and pulse is 76/min.  Physical examination shows normal lung sounds and no lower extremity edema.  His medical treatment is modified with the addition of a combination pill that inhibits neprilysin and blocks angiotensin II receptors.  Which of the following is the most likely effect of this medication?

Quizplus · Accepted Answer

11ec160b_3c90_3dfa_9249_11c24949ab86_MD0001_00 Most pharmacologic therapies for heart failure with reduced ejection fraction (eg, beta blockers, ACE inhibitors, angiotensin II receptor blockers, aldosterone antagonists) are targeted toward the inhibition of detrimental neurohormonal pathways involving the sympathetic nervous system and renin-angiotensin-aldosterone system (RAAS). However, an additional strategy involves augmenting beneficial counter-regulatory mechanisms, such as those involving natriuretic peptides. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are released from the myocardium in response to high atrial and ventricular filling pressures (myocardial stretch). These peptides induce vasodilation and diuresis (excretion of salt and water) by antagonizing the actions of RAAS and also protect against the deleterious myocardial remodeling and fibrosis that occur in heart failure. Neprilysin is a metalloprotease that cleaves and inactivates both ANP and BNP. Therefore, medications that inhibit neprilysin (eg, sacubitril) lead to increased levels of ANP and BNP and promote beneficial effects in heart failure. However, because neprilysin is also responsible for inactivating angiotensin II, inhibition of neprilysin further stimulates deleterious vasoconstriction and fluid retention via increased angiotensin II levels. Therefore, in treating heart failure, neprilysin inhibitors are combined with an angiotensin II-receptor blocker (eg, sacubitril-valsartan) to mitigate these negative effects. (Choice A) Increased levels of ANP and BNP stimulate the excretion of both salt and water. Decreased reabsorption of free water (water without solute) can be achieved with medications that block vasopressin-2 receptors (eg, tolvaptan) on the renal collecting tubule. (Choices B and D) The vasodilatory effects of ANP and BNP increase (rather than decrease) venous compliance and decrease (rather than increase) peripheral arterial resistance, leading to a reduction in both cardiac preload and afterload and a consequent reduction in cardiac work. These effects would be counteracted by angiotensin II-induced vasoconstriction, but angiotensin II activity is blocked by combining the neprilysin inhibitor with an angiotensin II-receptor blocker. (Choice C) Neprilysin inhibition combined with angiotensin II receptor blockade improves cardiac output in heart failure via a reduction in the cardiac work required to attain a certain stroke volume; however, cardiac contractility is not significantly affected. Educational objective: Neprilysin is responsible for the breakdown of the natriuretic peptides and angiotensin II; therefore, inhibition of neprilysin increases the activity of these peptides. For treatment of heart failure, neprilysin inhibition is combined with angiotensin II receptor blockade to optimize the positive effects of the natriuretic peptides (eg, vasodilation, diuresis) while blocking the negative effects of angiotensin II (eg, vasoconstriction, fluid retention).

A 66-Year-Old Man Comes to the Office for a Follow-Up