his is a single-center, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the effect of Henagliflozin (an SGLT2 inhibitor) on myocardial fibrosis burden in patients with non-obstructive hypertrophic cardiomyopathy (nHCM). The study will use 68 68 Ga/ 18 18 F-FAPI PET/CMR imaging to quantitatively assess changes in active fibroblast activity after 6 months of treatment. A total of 150 eligible adult patients with nHCM (FAPI-positive at baseline, NYHA class I-III) will be enrolled and randomized in a 1:1 ratio to either the Henagliflozin group (10 mg once daily) or the placebo group for a 6-month treatment period. The primary endpoint is the change in myocardial FAPI target-to-background ratio (ΔTBR) at 6 months. Secondary endpoints include changes in FAPI SUVmax, FAPI burden percentage (FAV%), cardiac structure and function parameters, 6-minute walk distance, NYHA classification, NT-proBNP levels, and quality-of-life scores. Exploratory analyses will assess clinical events over 12 months, such as heart failure hospitalization, atrial fibrillation, ventricular arrhythmias, and cardiovascular death. The study employs stratified block randomization based on baseline FAPI burden, central randomization and blinding via IWRS, independent core laboratory imaging evaluation, and an intention-to-treat analytical approach. It aims to provide early evidence for the anti-fibrotic effect of Henagliflozin in nHCM and to validate FAPI-PET/CMR as an imaging biomarker for fibrosis activity.
Aged 18 years or older, regardless of gender.
Confirmed diagnosis of HCM by cardiac magnetic resonance (CMR) or echocardiography (left ventricular wall thickness ≥15 mm, or ≥13 mm in the presence of a family history of HCM).
Exclusion of patients in whom left ventricular hypertrophy is primarily attributable to hypertensive heart disease, as assessed by a cardiology specialist based on clinical and imaging evidence.
Exclusion of other identifiable causes of secondary myocardial hypertrophy (e.g., valvular heart disease, storage cardiomyopathies).
Significant left ventricular outflow tract obstruction (resting or provoked LVOT pressure gradient ≥30 mmHg).
Predominant or persistent hypertensive heart disease;
Severe aortic stenosis or other significant valvular heart disease;
Infiltrative or storage cardiomyopathies (e.g., Fabry disease, amyloidosis);
Parallel
Henagliflozin (SGLT2 Inhibitor)
DrugThis intervention involves the oral administration of Henagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, at a dose of 10 mg once daily for a period of 6 months. Henagliflozin is provided as a film-coated tablet identical in appearance to the matched placebo used in the control arm. The intervention is administered in a double-blind manner as an add-on to stable standard background therapy for non-obstructive hypertrophic cardiomyopathy. This study specifically investigates the potential anti-fibrotic effects of Henagliflozin on active myocardial fibrosis, as quantified by novel FAPI PET/CMR imaging, in a patient population without diabetes mellitus.
Placebo
DrugThis intervention involves the oral administration of a matched placebo tablet once daily for a period of 6 months. The placebo is manufactured to be identical in appearance (size, shape, color, coating), packaging, and administration schedule to the active comparator, Henagliflozin 10 mg tablet. It contains no active pharmaceutical ingredient. The intervention is administered in a double-blind manner as an add-on to stable standard background therapy for non-obstructive hypertrophic cardiomyopathy, serving as the control to isolate and evaluate the specific pharmacological effects of the SGLT2 inhibitor.
Change in Myocardial FAPI Target-to-Background Ratio (ΔTBR)
The primary outcome is the change in myocardial FAPI uptake quantified by the target-to-background ratio (TBR) on FAPI PET/CMR imaging. TBR is calculated as the ratio of the mean standardized uptake value (SUVmean) in the myocardium to that in the ascending aortic blood pool. The difference in TBR from baseline to 6 months post-intervention (ΔTBR) will be compared between the Henagliflozin and placebo groups. This measure directly reflects changes in active fibroblast activity and myocardial fibrosis burden.
Change in Myocardial FAPI Maximum Standardized Uptake Value (ΔSUVmax)
This outcome measures the change in the maximum standardized uptake value of FAPI within the myocardium, reflecting the activity of the most intense focal fibrotic lesion. It is quantified from the same FAPI PET/CMR images used for the primary outcome.
Change in FAPI Activity Volume Percentage (ΔFAV%)
This outcome measures the percentage change in myocardial volume exhibiting active fibrosis. It is calculated by applying a standardized SUV threshold (e.g., SUV ≥ 1.3) to the FAPI PET images to define FAPI-positive voxels and expressing their volume as a percentage of the total left ventricular myocardium volume.
Change in Left Ventricular Ejection Fraction (ΔLVEF)
This outcome assesses the change in global left ventricular systolic function, measured as the percentage of blood ejected from the left ventricle with each contraction, using cardiac magnetic resonance imaging.
Change in Left Ventricular Mass Index (ΔLVMi)
This outcome measures the change in left ventricular myocardial mass, adjusted for body surface area, as an indicator of regression or progression of myocardial hypertrophy, assessed via cardiac magnetic resonance.
Significant Worsening of Cardiac Function or Onset of Heart Failure
This outcome is a composite endpoint capturing clinically meaningful deterioration in heart failure status, defined as any of the following: worsening of NYHA functional class by one or more grades, hospitalization primarily due to heart failure, or a decline in 6-minute walk distance of ≥30 meters from baseline.
New Onset or Recurrence of Atrial Fibrillation/Atrial Flutter
This outcome records the occurrence of newly diagnosed or recurrent episodes of atrial fibrillation or atrial flutter, confirmed by standard 12-lead electrocardiogram, Holter monitoring, or other clinically documented evidence during follow-up.
Sustained or Non-Sustained Ventricular Tachycardia
This outcome captures episodes of ventricular tachycardia, defined as sustained (lasting ≥30 seconds or requiring termination due to hemodynamic compromise) or non-sustained (≥3 consecutive ventricular beats at a rate \>100 bpm, lasting \<30 seconds), documented by ECG or cardiac monitoring.
Sudden Cardiac Death or Cardiac Arrest
This outcome records fatal events adjudicated as sudden cardiac death (unexpected death within 1 hour of symptom onset in a stable patient, or unwitnessed death without other explanation) or non-fatal cardiac arrest requiring resuscitation.
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