Does vericiguat (soluble guanylate cyclase stimulator) increase cardiac contractility?

Vericiguat Does Not Increase Cardiac Contractility

Vericiguat does not increase cardiac contractility but instead works through a different mechanism involving soluble guanylate cyclase (sGC) stimulation, which leads to vasodilation rather than direct effects on myocardial contractility.

Mechanism of Action

• Vericiguat is a soluble guanylate cyclase (sGC) stimulator that works by enhancing the nitric oxide (NO) signaling pathway 1
• It directly stimulates sGC, both independently of and synergistically with nitric oxide, which augments levels of intracellular cyclic guanosine monophosphate (cGMP) 1
• This increased cGMP leads to smooth muscle relaxation and vasodilation rather than increased cardiac contractility 1, 2
• Heart failure is associated with impaired synthesis of NO and decreased activity of sGC, which may contribute to myocardial and vascular dysfunction; vericiguat addresses this pathway deficiency 1

Hemodynamic Effects

• Vericiguat's primary hemodynamic effect is a modest reduction in systolic blood pressure (approximately 1-2 mmHg greater than placebo) 1
• In the VICTORIA trial, patients with an initial systolic blood pressure ≥110 mmHg experienced a more pronounced initial decline in SBP with vericiguat compared to placebo over the first 16 weeks before returning to baseline levels 3
• Unlike inotropic agents (such as dobutamine, milrinone, or levosimendan), vericiguat does not directly enhance myocardial contractility 3

Comparison with True Inotropic Agents

• Inotropes like dobutamine work by stimulating β1-receptors to increase myocardial contractility, which increases cardiac output at the cost of increased cardiac work and oxygen consumption 3
• Phosphodiesterase inhibitors (e.g., milrinone, enoximone) increase myocardial contractility by inhibiting the breakdown of cAMP, leading to increased cardiac output and stroke volume 3
• Levosimendan increases contractility through calcium sensitization of cardiac myofibrils 3
• In contrast, vericiguat works through the NO-sGC-cGMP pathway without directly affecting cardiac contractility 2

Clinical Evidence

• The FDA label for vericiguat explicitly states that it works "by directly stimulating sGC, independently of and synergistically with NO, vericiguat augments levels of intracellular cGMP, leading to smooth muscle relaxation and vasodilation" 1
• Unlike agents that increase contractility, vericiguat's clinical benefits in the VICTORIA trial (10% relative reduction in the primary composite outcome of death from cardiovascular causes or first hospitalization for heart failure) were achieved without increasing myocardial oxygen demand 4
• The VICTORIA trial showed that vericiguat was well-tolerated with a low incidence of symptomatic hypotension and syncope compared to placebo, consistent with its vasodilatory rather than inotropic mechanism 4, 5

Clinical Implications

• Vericiguat is indicated for patients with heart failure with reduced ejection fraction (LVEF <45%) who have had recent heart failure worsening 6
• Unlike inotropic agents that increase myocardial oxygen consumption, vericiguat's mechanism does not pose the same risks of increased myocardial demand 2
• When selecting agents for heart failure management, it's important to recognize that vericiguat works through vasodilation rather than increased contractility, making it suitable for long-term oral therapy rather than acute management of decompensated heart failure requiring inotropic support 3, 6

Potential Pitfalls and Caveats

• Vericiguat should not be confused with inotropic agents when treating acute decompensated heart failure requiring increased cardiac contractility 3
• Vericiguat is contraindicated in patients with systolic blood pressure <100 mmHg, severe renal impairment (eGFR <15 mL/min/1.73m²), or concomitant use with long-acting nitrates 6
• Combined use of vericiguat and phosphodiesterase type-5 inhibitors has not been studied in patients with HFrEF and is not recommended due to the potential increased risk for symptomatic hypotension 7