1. Date of download: 5/29/2016 Copyright © The American College of Cardiology. All rights reserved. From: The Path to an Angiotensin Receptor Antagonist-Neprilysin Inhibitor in the Treatment of Heart Failure J Am Coll Cardiol. 2015;65(10):1029-1041. doi:10.1016/j.jacc.2015.01.033 The Tigerstedt and Bergman Experiments Excerpts from Tigerstedt and Berman’s paper (9), which led to the discovery of renin. Four separate experiments are illustrated. Figure Legend:

2. Date of download: 5/29/2016 Copyright © The American College of Cardiology. All rights reserved. From: The Path to an Angiotensin Receptor Antagonist-Neprilysin Inhibitor in the Treatment of Heart Failure J Am Coll Cardiol. 2015;65(10):1029-1041. doi:10.1016/j.jacc.2015.01.033 Effects of LCZ696 on BP BP reduction in patients with moderate hypertension with AHU 377 (sacubitril), the prodrug for the NEPi LBQ657, and also with various doses of valsartan and LCZ696. Doses of the latter 2 drugs provided comparable degrees of angiotensin receptor blockade. BP = blood pressure; pbo = placebo; vals = valsartan; other abbreviations as in Figure 1. Figure Legend:

3. Date of download: 5/29/2016 Copyright © The American College of Cardiology. All rights reserved. From: The Path to an Angiotensin Receptor Antagonist-Neprilysin Inhibitor in the Treatment of Heart Failure J Am Coll Cardiol. 2015;65(10):1029-1041. doi:10.1016/j.jacc.2015.01.033 Timeline of the Path to the PARADIGM HF Trial Numbers in parentheses refer to text references. ACE = angiotensin-converting enzyme; ACEi = angiotensin-converting enzyme inhibitor; ANP = atrial natriuretic peptide; ARB = angiotensin receptor blocker; ARNi = angiotensin receptor antagonist-neprilysin inhibitor; HF = heart failure; NEP = neprilysin; NEPi = neprilysin inhibitor; PARADIGM-HF = Prospective comparison of ARNi with ACEi to Determine Impact on Global Mortality and morbidity in the Heart Failure. Figure Legend:

4. Date of download: 5/29/2016 Copyright © The American College of Cardiology. All rights reserved. From: The Path to an Angiotensin Receptor Antagonist-Neprilysin Inhibitor in the Treatment of Heart Failure J Am Coll Cardiol. 2015;65(10):1029-1041. doi:10.1016/j.jacc.2015.01.033 Angiotensin-Neprilysin Inhibition in Heart Failure: Central Role of LCZ696 in Cardiovascular Regulation The central role of LCZ696 in the dual inhibition of the RAAS and of NEP. Green lines and arrows denote stimulation or activation. Red lines denote blockade. HFrEF activates both the SNS and the RAAS, which act in concert to increase the release of renin. RAAS acts on angiotensinogen to produce ANG I. ACE catalyzes the formation of ANG II, which acts on the ATIR, whose biological actions include the release of aldosterone from the adrenal cortex. β1 receptor blockers, ACEis, ARBs, and MRCBs block the SNS and RAAS at several levels; ACEi also blocks the degradation of bradykinin. The increasing wall stress in HFrEF activates the NPS with release of ANP and BNP, which in turn activate the NPRA, GC-A, cGMP, and PKG, and result in vasodilation, natriuresis, diuresis, and fibrosis inhibition. ANP also blocks the release of renin. NEP breaks down ANP, whereas NEPi preserves ANP by blocking NEP. LCZ696 has 2 components—an ARB and a NEPi, which block RAAS activation while enhancing the adaptive actions of ANP. ACE = angiotensin-converting enzyme; ACEi = angiotensin-converting enzyme inhibitor; ANG = angiotensin; ANP = atrial natriuretic peptide; ARB = angiotensin receptor blocker; AT1R = angiotensin II type 1 receptor; BNP = brain natriuretic peptide; cGMP = cyclic guanosine monophosphate; GC-A = guanylyl cyclase A; HFrEF = heart failure with reduced ejection fraction; MRCB = mineralocorticoid receptor blocker; NEP = neprilysin; NEPi = neprilysin inhibitor; NPRA = natriuretic peptide receptor A; NPS = natriuretic peptide system; PKG = protein kinase G; RAAS = renin angiotensin aldosterone system; SNS = sympathetic nervous system. Figure Legend:

5. Date of download: 5/29/2016 Copyright © The American College of Cardiology. All rights reserved. From: The Path to an Angiotensin Receptor Antagonist-Neprilysin Inhibitor in the Treatment of Heart Failure J Am Coll Cardiol. 2015;65(10):1029-1041. doi:10.1016/j.jacc.2015.01.033 Effects of LCZ696 in HFpEF Primary results of the PARAMOUNT trial in patients with HFpEF. HFpEF = heart failure with preserved ejection fraction; NT- proBNP = N-terminal fragment of pro–B-type natriuretic peptide; PARAMOUNT = Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion. Figure Legend: