The goal of this clinical trial is to learn whether valsartan can slow the progression of atrial functional mitral regurgitation (AFMR) in adults with preserved left ventricular ejection fraction. The study will also evaluate the safety and tolerability of valsartan in this population.

The main questions it aims to answer are:

• Does treatment with valsartan reduce the progression of atrial functional mitral regurgitation compared with placebo?
• Does valsartan have favorable effects on mitral valve leaflet remodeling and related cardiac structure and function?
• Is valsartan safe and well tolerated in patients with atrial functional mitral regurgitation who do not currently require angiotensin-converting enzyme inhibitors or angiotensin receptor blockers?

Researchers will compare valsartan to a placebo (a look-alike substance with no active drug) to see if valsartan reduces the progression of atrial functional mitral regurgitation and improves clinical and imaging outcomes.

Participants will:

• Take valsartan or placebo twice daily for 12 months, with dose adjustments based on blood pressure, kidney function, and tolerance
• Undergo 3D echocardiography at baseline, 6 months, and 12 months
• Complete a 6-minute walk test at baseline and 12 months
• Complete the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline, 6 months, and 12 months
• Undergo 24-hour ambulatory blood pressure monitoring at 1 month
• Have regular safety monitoring, including phone follow-up at 7 days, blood tests at 1 month, and blood pressure checks after dose adjustments

Atrial functional mitral regurgitation (AFMR) is a common and increasingly recognized condition, particularly among older adults, women, patients with atrial fibrillation, and those with heart failure with preserved ejection fraction (HFpEF). AFMR is associated with significant morbidity and mortality, including recurrent hospitalizations and reduced quality of life. Current treatment options remain limited and are mainly focused on managing symptoms and associated conditions, with no therapy specifically targeting the underlying mechanisms of AFMR progression.

The pathophysiology of AFMR is characterized by left atrial dilation, which leads to stretching of the mitral annulus and inadequate leaflet adaptation in the absence of significant left ventricular dilation or systolic dysfunction. Although mitral valve leaflets have the capacity to adapt by increasing their surface area in response to annular dilation, this compensatory mechanism is often insufficient, resulting in progressive mitral regurgitation. Experimental and observational data suggest that activation of the renin-angiotensin-aldosterone system may contribute to maladaptive leaflet remodeling, fibrosis, and thickening.

Angiotensin receptor blockers (ARBs) have been shown in preclinical and observational studies to reduce fibrosis and promote more favorable tissue remodeling in cardiac structures, including valvular tissue. However, the potential role of ARBs in slowing the progression of AFMR has not been specifically evaluated in a randomized clinical trial. Valsartan, a commonly used ARB, may promote more adequate mitral leaflet adaptation and reduce structural maladaptive changes, thereby limiting AFMR progression.

The VALORIA study is a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the effect of valsartan on the progression of AFMR.

The study will enroll 50 adult participants with at least moderate atrial functional mitral regurgitation, a left ventricular ejection fraction of 50% or greater, and no current indication for treatment with angiotensin-converting enzyme inhibitors or ARBs.

Participants will be randomized in a 1:1 ratio to receive either valsartan or placebo for a total duration of 12 months.

Participants assigned to the active treatment arm will receive valsartan at an initial dose of 40 mg twice daily, with planned titration up to a maximum of 160 mg twice daily based on tolerance, blood pressure, renal function, and potassium levels. Participants in the placebo group will follow an identical dosing and titration schedule. Dose adjustments will be guided by a standardized follow-up algorithm and predefined safety criteria, including hypotension, worsening renal function, or hyperkalemia.

All participants will undergo a comprehensive clinical and imaging evaluation at baseline. Three-dimensional transthoracic echocardiography will be performed at baseline, 6 months, and 12 months to assess mitral regurgitation severity, mitral annular geometry, and mitral leaflet morphology. Functional capacity will be evaluated using the 6-minute walk test at baseline and at 12 months. Health-related quality of life will be assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline, 6 months, and 12 months.

Blood pressure will be monitored regularly throughout the study, including 24-hour ambulatory blood pressure monitoring at 1 month. Safety assessments will include a telephone follow-up at 7 days after treatment initiation, laboratory testing (serum creatinine and electrolytes) at 1 month, and additional blood pressure measurements after each dose adjustment.

The primary objective of the VALORIA study is to determine whether treatment with valsartan reduces the progression of atrial functional mitral regurgitation compared with placebo over a 12-month period. Secondary objectives include evaluating the effects of valsartan on mitral valve leaflet remodeling, cardiac structure and function, exercise capacity, and quality of life, as well as assessing the safety and tolerability of valsartan in this patient population.

By specifically targeting the structural mechanisms underlying AFMR, the VALORIA study aims to provide novel evidence to support a disease-modifying pharmacologic approach for this common and clinically significant condition.

Inclusion Criteria:

1. No evidence of mitral organic disease
2. At least moderate left atrial dilatation (left atrial volume index ≥34 mL/m²)
3. Normal (≥ 50%) left ventricular ejection fraction and
4. At least moderate MR grade by multiparametric assessment.

Exclusion Criteria:

1. Inability to provide informed consent
2. Indication for or ongoing treatment with ACEI/ARB
3. History of hypotension
4. Hypertension (>140/90 mmHg) *
5. Planned cardiac surgery (CABG or valve)
6. Ongoing or planned pregnancy
7. Chronic renal failure with eGFR < 30 mL/min/1.73m2
8. Neurocognitive disorder
9. History of hyperkalemia
10. Medication interacting with valsartan