The purpose of this study is to evaluate the effect of the (angiotensin-converting enzyme) ACE inhibitor lisinopril on hemoglobin, hematocrit, and erythropoietin levels in patients with secondary polycythemia due to high-oxygen-affinity hemoglobin variants, oxygen-sensing pathway mutations, or other unexplained and potentially irreversible forms of erythrocytosis. This study aims to determine whether ACE inhibition can effectively reduce excessive erythrocytosis by modulating erythropoietin production.

Demonstrating that ACE inhibitor therapy with lisinopril lowers hemoglobin, hematocrit, and erythropoietin levels could introduce a novel therapeutic approach for the management of secondary polycythemia due to high-oxygen-affinity hemoglobin variants, oxygen-sensing pathway mutations, or other unexplained and potentially irreversible forms of erythrocytosis, potentially reducing reliance on repeated phlebotomies and lowering thrombotic risk.

Inclusion Criteria:

• Hemoglobin in Men: >16.5 g/dL (10.3 mmol/L).
• Hemoglobin in Women >16.0 g/dL (10.0 mmol/L).
• BMI 18-40 kg/m2.

Exclusion Criteria:

• Positive JAK2 gene linked to Polycythemia Vera.
• Current smoker or previous heavy smoker (>15 pack years) who quit less than 12 months prior to enrollment.
• Resting SpO₂ ≤ 94% on room air.
• Current or recent (within the past 6 months) use of testosterone or androgen supplementation.
• Any confounding respiratory or renal disease, including diagnosed or suspected sleep apnea, or stage 3 and up of chronic kidney disease.
• Any confounding hematologic disease that may alter hemoglobin level.
• Currently treated with ACE inhibitors.
• Currently treated with potassium-sparing diuretics.
• Currently on SGLT2 or use within 4 weeks prior to screening.
• Baseline systolic blood pressure ≤90 mmHg.
• Baseline systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg.
• Occupational exposure associated with chronically elevated COHb (auto repair, etc.).
• History of anaphylaxis or angioedema.
• Pregnant or breastfeeding.