Chronic Exogenous Ketosis in HFpEF

Prior treatment

• Participation in another clinical study with an investigational product in the previous 4 weeks prior to enrollment (or longer if deemed necessary by the investigator).

Other illness

• Cirrhosis or alcohol use disorder (\>14 drinks/week).
• Clinically significant lung disease, defined as severe obstructive lung disease (Gold stage 3), a requirement for supplemental oxygen, or chronic obstructive pulmonary disease with an exacerbation requiring steroids or antibiotics within the last 2 months.
• Type 1 diabetes mellitus
• Angina due to epicardial coronary disease or known presence of clinically-significant, unrevascularized epicardial coronary disease, in the investigator's opinion.
• Conditions that may render the patient unable to complete the study, in the opinion of the investigator.

Lab values

• Contraindications to stress testing, conditions that limit exercise, and other clinically-significant causes of exertional limitation (claudication with peripheral artery disease, atrial fibrillation and heart rate \>110 at rest, systolic blood pressure\>180 mmHg or diastolic blood pressure\>110 mmHg, infiltrative/hypertrophic/inflammatory cardiomyopathy, clinically significant pericardial disease, joint or neuromuscular disease that precludes exercise, acute coronary syndrome within the last 2 months, estimated glomerular filtration rate\<20 mL/min/1.73 m2, and hemoglobin \< 9 mg/dL).
• Prior reduced LVEF to \< 45% by echocardiography or cardiac MRI

Other

• Intentional ketogenic (high fat, low carbohydrate) diet in the last week
• \> Moderate aortic stenosis, \>mild mitral stenosis, \> moderate aortic or mitral regurgitation on screening echocardiogram, or presence of a prosthetic valve in the mitral position.
• Start of a GLP-1 RA within the past 6 months.
• Pregnant women.

• 18 years of age or older
• Stable medical therapy for at least 2 weeks
• New York Heart Association (NYHA) class symptoms II or III
• Left ventricular ejection fraction ≥ 50%
• Evidence for elevated filling pressures as follows (at least one of the following between a-d):
  • Mitral early (E)/mitral septal tissue annular (e') velocity ratio \> 8 on echocardiography in addition to one of the following:
  • Enlarged left atrium (LA\>4.0 cm width or LA volume index \>34 mL/m2)
• Chronic loop diuretic use for control of symptoms
• Elevated natriuretic peptides within the past year (NT-proBNP\>125 pg/ml or BNP\>35 pg/ml)
• Mitral E/e' ratio \> 14 at rest or with exercise on echocardiography
• Elevated invasively-determined filling pressures previously (resting left ventricular end-diastolic pressure \>16 mm Hg or pulmonary capillary wedge pressure \> 14 mmHg; or PCWP or LVEDP ≥ 25 mmHg with exercise)
• Prior episode of acute heart failure requiring IV diuretics with evidence of volume overload on exam or radiology, or evidence of elevated natriuretic peptides.