A First-in-Class Approach to Myocardial Bioenergetic Rescue
The failing heart suffers from a fundamental deficit of ATP production. Multiple randomized controlled trials now demonstrate that exogenous ketones produce reproducible, dose-dependent hemodynamic improvements across the heart failure spectrum—from stable chronic disease to cardiogenic shock. These effects rival the magnitude of inotropic support, without the associated arrhythmogenic risk.
SNV-801 is an oral acetoacetate-releasing prodrug designed to achieve sustained therapeutic ketosis (1.0–3.5 mM). Unlike β-hydroxybutyrate (BHB), acetoacetate enters cardiac oxidation without consuming NAD⁺ and in fact regenerates NAD⁺, restoring the redox balance that the failing heart critically requires. This brief summarizes the human clinical evidence and mechanistic rationale supporting this approach.
Heart failure is increasingly understood as a disease of metabolic inflexibility. The healthy heart is omnivorous, deriving ATP from fatty acids, glucose, lactate, and ketones depending on availability. In the failing heart, this flexibility is lost—substrate utilization becomes constrained, ATP production falls, and contractile function declines accordingly.1
SGLT2 inhibitors, now standard of care across the heart failure spectrum, mildly elevate circulating ketones (0.1–0.3 mM). Mechanistic studies suggest this metabolic shift contributes meaningfully to their cardiovascular benefit, independent of their glucosuric and natriuretic effects.2 This observation raises an important question: what would happen if we delivered therapeutic-level ketones directly?
The clinical evidence now provides a clear answer.
Six randomized, controlled studies have evaluated exogenous ketone administration in patients with heart failure. Across populations ranging from stable outpatients to ICU-admitted cardiogenic shock, the hemodynamic response is consistent: improved cardiac output, improved filling pressures, and reduced biomarkers of myocardial stress.
Patients with chronic HFrEF (EF 32±7%) received 3-hour intravenous 3-hydroxybutyrate infusion versus isocaloric glucose control, on background guideline-directed medical therapy. Peak circulating BHB reached approximately 3.3 mM.
Myocardial external efficiency remained unchanged, indicating that the improved hemodynamics occurred without an increase in oxygen consumption.
ICU patients with cardiogenic shock received a single enteral ketone ester bolus versus maltodextrin placebo, with invasive pulmonary artery catheter monitoring. All patients were on mechanical or pharmacological circulatory support.
This represents acute biventricular improvement in the highest-acuity population studied—patients already receiving maximal conventional support.
Patients with stable HFrEF on optimal guideline-directed therapy received oral ketone ester (4 doses daily × 14 days) versus isocaloric comparator, with invasive hemodynamic assessment at baseline and follow-up.
Patients with HFpEF and comorbid type 2 diabetes received oral ketone ester versus placebo for 14 days, with invasive exercise hemodynamic testing.
The reduction in peak exercise PCWP and the right-shift of the end-diastolic pressure-volume relationship suggest both improved hemodynamics and reduced diastolic stiffness—a particularly meaningful finding in HFpEF.
Single oral dose of (R)-1,3-butanediol (0.5 g/kg) versus placebo, with 6-hour echocardiographic monitoring.
Patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension received 2-hour IV 3-OHB infusion versus saline, with invasive right heart catheterization.
Simultaneous improvement in cardiac output and reduction in pulmonary vascular resistance—a desirable "inodilator" profile—was observed acutely.
SNV-801 engages multiple validated molecular targets relevant to cardiac pathophysiology. The table below summarizes the key mechanisms and their relevance to heart failure.
| Molecular Target | Primary Ligand | Threshold | Cardiac Effect | Biomarker/Endpoint |
|---|---|---|---|---|
| ATP Synthesis | Total Ketones | ≥0.5 mM | Restores myocardial ATP in energy-starved failure | Ejection Fraction, CO |
| NAD⁺ Regeneration | Acetoacetate | Ratio-dependent | Generates NAD⁺; restores mitochondrial redox | Efficiency metrics |
| NLRP3 Inflammasome | BHB | ≥1.0 mM | Inhibits sterile inflammation post-infarct | hs-CRP, IL-1β |
| HDAC Inhibition | BHB | ~1.0–2.0 mM | Reduces cardiac fibrosis and adverse remodeling | Cardiac MRI (fibrosis) |
| SIRT3 Activation | BHB | ≥0.5 mM | Restores mitochondrial protein acetylation balance | Oxidative stress markers |
| HCA2/GPR109A | BHB | EC₅₀ ~0.7 mM | Cardioprotective GPCR signaling (vasodilation) | SVR, Blood Pressure |
| mTOR Inhibition | BHB | ≥1.0 mM | Activates autophagy; reduces infarct size at reperfusion | Infarct size |
SNV-801 is designed to achieve sustained 1.0–3.5 mM ketosis, engaging all listed targets at therapeutic exposures.
The clinical evidence for ketone-based hemodynamic improvement is now substantial. The question is how to translate this into an optimized therapeutic.
Circulating ketones exist as two interconvertible species: β-hydroxybutyrate (BHB) and acetoacetate (AcAc). In the heart, BHB is oxidized to acetoacetate by the mitochondrial enzyme β-hydroxybutyrate dehydrogenase (BDH1). This reaction consumes NAD⁺, converting it to NADH.
In the heart failure state, the NAD⁺/NADH ratio is already depressed—a contributing factor to impaired mitochondrial function. Delivering BHB as the exogenous ketone further draws down the NAD⁺ pool at the very moment of oxidation.
Acetoacetate enters myocardial ketolysis downstream of the NAD⁺-consuming step. When the heart oxidizes AcAc directly, it bypasses BDH1 entirely. More importantly, the oxidation of acetoacetate via succinyl-CoA:3-ketoacid-CoA transferase (SCOT) and subsequent acetyl-CoA production regenerates NAD⁺ during mitochondrial electron transport.
This is not merely "NAD⁺ sparing"—acetoacetate delivery actively restores the NAD⁺/NADH ratio. This is critical for the failing heart, where NAD⁺ depletion impairs sirtuin signaling, mitochondrial biogenesis, and oxidative phosphorylation efficiency.
Recent work by Koay et al. (Circulation Research 2025) demonstrated that the human heart possesses intrinsic ketogenic capacity via HMGCS2, and that NAD⁺ repletion therapy in HFpEF models requires this ketogenic pathway to exert its beneficial effects.3
SNV-801 is designed to deliver acetoacetate directly—providing the myocardium with NAD⁺-regenerating fuel rather than NAD⁺-consuming BHB.
Complementary preclinical studies provide mechanistic context for the clinical observations and demonstrate additional therapeutic potential in acute ischemia:
β-hydroxybutyrate administered at the moment of reperfusion—modeling clinical scenarios such as post-PCI treatment—reduced myocardial infarct size by approximately 50%. The mechanism was traced to mTOR inhibition and activation of cardioprotective autophagy.
In a rat model of post-myocardial infarction heart failure, ketone ester dietary treatment—initiated after established HF—restored cardiac function dramatically.
This study demonstrated that enhanced myocardial ketone body oxidation specifically contributes to the cardioprotective effects of empagliflozin. When ketone metabolism was blocked, the SGLT2i benefit was attenuated—providing causal evidence for the "ketone hypothesis" of SGLT2i cardioprotection.
| Study | Population | Design | n | BHB | ΔCO | ΔLVEF | ΔPCWP | Other |
|---|---|---|---|---|---|---|---|---|
| Nielsen 2019 | HFrEF | RCT X-over | 16 | 3.3 mM | +2.0 L/min | +8 pts | — | SVR −18% |
| Berg-Hansen 2023 | Shock | DB X-over | 12 | KE bolus | — | +4 pts | ↓ bivent | CPO +0.07 W |
| Nielsen 2023 | PAH | RCT X-over | 10 | ~3 mM | +1.2 L/min | — | — | PVR −18% |
| Berg-Hansen 2024 | HFrEF | RCT DB 14d | 24 | 1.5–2.5 | +0.3 L/min | +3 pts | −3 mmHg | BNP −18% |
| Gopalasingam 2024 | HFpEF+T2D | RCT DB 14d | 24 | ~1.0 mM | +0.2 L/min | — | −5 peak | ↓LV stiff |
| Guldbrandsen 2025 | HFrEF | RCT X-over | 12 | BD oral | +0.9 L/min | +3 pts | — | SV +15 mL |
All studies compared exogenous ketone intervention vs. placebo/comparator, on background standard-of-care therapy. X-over = crossover; DB = double-blind.
| Attribute | Profile |
|---|---|
| Mechanism | Oral acetoacetate-releasing prodrug |
| Target Exposure | 1.0–3.5 mM sustained ketosis (therapeutic range) |
| Differentiation | NAD⁺-regenerating (AcAc bypasses BDH1 and restores NAD⁺/NADH ratio) |
| Lead Indication | HFpEF (high unmet need); HFrEF (expansion) |
| Expected Endpoints | Hemodynamic (CO, PCWP); symptom (KCCQ); biomarker (NT-proBNP) |
| Regulatory Path | 505(b)(2) NDA |
The target exposure range (1.0–3.5 mM) represents physiological nutritional ketosis, a metabolic state extensively studied in fasting, ketogenic diet, and supplement contexts. This is distinct from diabetic ketoacidosis (DKA), which requires the triad of ketones typically >10 mM, metabolic acidosis, and hyperglycemia—conditions that do not apply to therapeutic ketone administration in euglycemic patients.
Across the six clinical studies summarized above, encompassing nearly 100 patients with heart failure across a range of acuities, no serious treatment-related adverse events have been reported.
SGLT2 inhibitors have established that mild ketone elevation (0.1–0.3 mM) contributes to cardiovascular benefit. SNV-801 is designed to deliver approximately 10-fold higher ketone exposure, targeting the therapeutic range (1.0–3.5 mM) demonstrated to produce clinically meaningful hemodynamic effects in the randomized trials reviewed above.
This positions SNV-801 as complementary to SGLT2 inhibitor therapy—not competitive with it. SGLT2 inhibitors address volume and neurohormonal pathways; SNV-801 directly addresses the bioenergetic deficit.
Strategic partner for HFpEF Phase 2b trial (~$25M)
6 completed RCTs establish human proof-of-concept. Next step: registration-quality efficacy trial.