Pathological Responses Associated with HF
HF is a progressive syndrome with multiple pathological processes that affect the heart and cause stress on the body.1
Neurohormonal systems activate, providing some benefit by compensating for cardiac dysfunction; however, this can ultimately lead to progressive damage and worsening HF.1‑4
circulatory 
cardiovascular 
renal SNS AND RAAS
Vasoconstriction5 ↑ Contractility2 ↑ Hypertrophy5 ↑ Blood pressure1,6 ↑ Fibrosis5 ↑ Fluid volume5,6 ↑ Heart rate2 ↑ NP SYSTEM
Blood pressure7 ↓ Hypertrophy7 ↓ Vasoconstriction5 ↓ Fibrosis7 ↓ Remodeling7,8 ↓ NO-sGC-CGMP SYSTEM
Cardiomyocyte stiffness9 ↑ Myocardial dysfunction and damage9 ↑ Further RAAS stimulation8,9 ↑ Fibrosis8 ↑ Where care stands today
Several drug classes target compensatory responses to HF.1 Confounding factors, such as the inability to tolerate therapy and concerns about side effects or overlapping drug side effects, limit the ability to achieve guideline-directed medication goals.10‑13
circulatory cardiovascular renal BETA BLOCKERS/HR MODULATORS (SNS)
INHIBIT OVERACTIVE SNS, AND ALSO AFFECT:2
Blood pressure1 ↓ Remodeling1 ↓ Fluid retention1 ↑ Heart rate1,14 ↓ SGLT2is (SNS)
REDUCE SNS ACTIVITY, AND ALSO AFFECT:15
Blood pressure16 ↓ Plasma volume17 ↓ Fluid retention18 ↓ ACEis, ARBs, ARNis, MRAs (RAAS)
INHIBIT RAAS, AND ALSO AFFECT:2,5,7,19
Blood pressure1,7,19 ↓ Serum potassium1,19,20 ↑ Fluid retention6,7,21 ↓ NEPis, ARNis (NP SYSTEM)
AUGMENT NP SYSTEM ACTIVATION, AND ALSO AFFECT7
Blood pressure7 ↓ Fibrosis7 ↓ Remodeling7 ↓ sGC STIMULATORS (sGC SENSITIVITY)
ENHANCE SGC SENSITIVITY TO ENDOGENOUS NO IN AN NO-INDEPENDENT MANNER, MAY ALSO AFFECT:8,9
Anemia8 ↑ 
The ACC Expert Consensus acknowledges
Comorbidities such as abnormal renal function and/or hyperkalemia are common barriers to initiation and titration of GDMT22
ACC, American College of Cardiology; ACEi, angiotensin‑converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ARNi, angiotensin receptor‑neprilysin inhibitor; CGMP, cyclic guanosine monophosphate; GDMT, guideline‑directed medical therapy; HF, heart failure; HR, heart rate; MRA, mineralocorticoid receptor antagonist; NEPi, neprilysin inhibitor; NO, nitric oxide; NP, natriuretic peptide; RAAS, renin‑angiotensin‑aldosterone system; sGC, soluble guanylate cyclase; SGLT2i, sodium‑glucose cotransporter‑2 inhibitor; SNS, sympathetic nervous system.
References:
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