Proposed section structure
1. Highlights
2. Clinical background and unmet need
3. Why atrial functional mitral regurgitation matters in HFpEF
4. PRAISE-MR study design and methods
5. Primary and secondary results
6. Safety and tolerability
7. Mechanistic and clinical interpretation
8. Strengths, limitations, and generalizability
9. Implications for practice and research
10. Funding, registration, and references
Highlights
PRAISE-MR tested a phenotype-focused strategy in heart failure with preserved ejection fraction (HFpEF), targeting patients with at least moderate atrial functional mitral regurgitation (AFMR), a subgroup with high symptom burden and adverse exercise hemodynamics.
Compared with standard of care, sacubitril/valsartan improved the 6-month exercise mean pulmonary artery pressure to cardiac output slope, with an adjusted between-group difference of -0.93 mmHg/L/min (95% CI, -1.80 to -0.07; p=0.035).
Benefits extended beyond invasive physiology surrogates: peak oxygen consumption improved, Kansas City Cardiomyopathy Questionnaire scores increased, NT-proBNP fell, left atrial volume decreased, and the exercise-related increase in MR severity was attenuated.
The trial supports the idea that HFpEF is not a single disease entity and that response to therapy may depend on a clinically recognizable structural phenotype, in this case left atrial remodeling with secondary MR.
Clinical background and unmet need
Therapeutic progress in HFpEF has lagged behind that in heart failure with reduced ejection fraction (HFrEF), largely because HFpEF encompasses multiple pathobiologic phenotypes rather than one dominant syndrome. Although sodium-glucose cotransporter-2 inhibitors have established outcome benefits across much of the HFpEF spectrum, there remains substantial residual morbidity, particularly among patients with severe exercise intolerance, pulmonary vascular congestion during effort, and atrial myopathy.
AFMR is increasingly recognized as an important and underappreciated component of this phenotype. Unlike ventricular functional MR, which is driven mainly by left ventricular remodeling and papillary muscle displacement, AFMR arises from left atrial enlargement, annular dilation, impaired atrial function, and often atrial fibrillation, while left ventricular systolic function remains preserved. This structural context is common in HFpEF. Clinically, AFMR may intensify symptoms during exertion because regurgitation worsens dynamically, raising left atrial pressure, worsening pulmonary venous congestion, and contributing to abnormal pulmonary artery pressure responses during exercise.
That pathophysiology provides a compelling rationale for testing therapies that reduce filling pressures, favor reverse chamber remodeling, and possibly blunt dynamic MR during stress. Sacubitril/valsartan has already shown favorable effects on natriuretic peptides and structural remodeling in heart failure, and in HFrEF it has been associated with reduction in secondary MR. Whether a similar benefit might emerge in HFpEF with AFMR had remained uncertain.
Why atrial functional mitral regurgitation matters in HFpEF
AFMR is not merely an echocardiographic bystander. In HFpEF, the left atrium often becomes enlarged and dysfunctional due to chronically elevated filling pressures, atrial fibrillation, or both. The mitral annulus enlarges, leaflet coaptation becomes incomplete, and regurgitation develops despite preserved leaflet morphology and preserved left ventricular ejection fraction. During exercise, further rises in left atrial pressure and annular distortion can magnify the regurgitant burden.
This matters because many patients with HFpEF feel relatively stable at rest yet become markedly dyspneic with activity. Resting echocardiography can underestimate the hemodynamic burden of the disease. By combining cardiopulmonary exercise testing and simultaneous echocardiography, PRAISE-MR focused on a clinically relevant endpoint: the mPAP/CO slope during exercise. This variable captures how steeply pulmonary artery pressure rises as cardiac output increases. A steeper slope indicates inefficient pulmonary vascular and left heart reserve, and has been linked to exertional intolerance and worse prognosis in heart failure syndromes.
PRAISE-MR study design and methods
PRAISE-MR was a multicenter, randomized, open-label trial with blinded primary endpoint assessment. Eighty-four patients with symptomatic HFpEF and at least moderate AFMR documented within the previous year were assigned to sacubitril/valsartan (n=41) or standard of care (n=43). The open-label design is important to note, but blinded adjudication of the primary endpoint reduces some risk of ascertainment bias for the physiologic outcome.
The primary outcome was change over 6 months in the exercise mPAP/CO slope, assessed using cardiopulmonary exercise testing with simultaneous echocardiography, often referred to as CPETecho. This is a sophisticated but highly informative phenotyping tool because it integrates symptoms, exercise capacity, and dynamic valve-hemodynamic interactions.
Secondary endpoints included peak oxygen consumption, Kansas City Cardiomyopathy Questionnaire score, NT-proBNP, left atrial volume and function, and AFMR severity at rest and during exercise. Together these outcomes provide a multidimensional view of response: physiology, symptoms, biomarkers, chamber remodeling, and valvular behavior.
The intervention was pragmatic. Patients randomized to sacubitril/valsartan underwent titration toward target dosing, while the comparator arm received standard-of-care management. At 6 months, 60% of patients in the active-treatment arm reached target dose, with symptomatic hypotension being the main limiting factor.
Primary and secondary results
The central finding was a significant improvement in exercise pulmonary hemodynamics with sacubitril/valsartan. The adjusted between-group difference in change in the mPAP/CO slope was -0.93 mmHg/L/min, with a 95% confidence interval from -1.80 to -0.07 and p=0.035. In practical terms, this suggests a flatter rise in pulmonary artery pressure for a given increase in cardiac output during exercise, consistent with reduced left-sided filling pressure transmission and improved pulmonary vascular-left heart coupling during exertion.
This physiologic signal was accompanied by better functional capacity. Peak VO2 increased by 0.9 mL/kg/min in the sacubitril/valsartan group, whereas it declined by 0.6 mL/kg/min with standard care, a between-group difference that was statistically significant (p=0.002). In HFpEF trials, even modest changes in peak VO2 can be clinically meaningful, especially when they align with symptom improvement and hemodynamic changes.
Patient-reported health status also improved. The median increase in Kansas City Cardiomyopathy Questionnaire score was 10 points with sacubitril/valsartan versus 2 points with standard care (p=0.002). A 5-point change is often considered clinically relevant; therefore, the observed improvement suggests that the physiologic benefits were translated into tangible symptom or quality-of-life gains.
Biomarker and remodeling findings further support a treatment effect. NT-proBNP decreased significantly in the sacubitril/valsartan arm compared with standard care (p<0.001), indicating reduced myocardial wall stress or improved loading conditions. Left atrial volume also declined significantly (p<0.001), a particularly notable result in an AFMR-centered trial because the left atrium is central to the mechanism of disease.
Perhaps the most conceptually important secondary observation was that sacubitril/valsartan significantly blunted the dynamic increase in MR during exercise (p=0.020). This aligns the trial’s mechanistic thesis with its outcome pattern: improve atrial loading and remodeling, and the valve behaves better under stress. That finding may be more relevant than rest MR changes alone, because many symptoms in HFpEF emerge during exertion rather than at baseline.
Although the abstract does not provide a full numerical breakdown for every echocardiographic parameter, the overall pattern is coherent: improved exercise hemodynamics, improved objective functional capacity, improved patient-reported status, reduced neurohormonal activation, reduced left atrial enlargement, and less exercise-provoked MR severity.
Safety and tolerability
The major tolerability issue was symptomatic hypotension, which limited dose escalation and likely explains why only 60% of patients achieved target dose. This is clinically unsurprising in HFpEF populations, who are often older, more preload sensitive, and exposed to multiple antihypertensive or diuretic therapies. The abstract does not report excess renal dysfunction, hyperkalemia, angioedema, or severe adverse events, so no firm conclusions should be drawn beyond the stated observation regarding blood pressure tolerance.
From a practical standpoint, the titration data matter. A benefit signal was observed despite incomplete achievement of target dose in 40% of treated patients. That suggests either that moderate dosing may still be effective in this phenotype or that responders may be identifiable even when full titration is not possible. However, this remains speculative until fuller trial reporting is available.
Mechanistic and clinical interpretation
The trial is notable because it moves beyond the broad question of whether sacubitril/valsartan works in “HFpEF” and instead asks whether it may work in a biologically enriched HFpEF phenotype. This approach is consistent with lessons from prior HFpEF research, where averaged treatment effects may obscure benefit in subgroups defined by specific structural or hemodynamic features.
The biological plausibility is strong. Neprilysin inhibition augments endogenous natriuretic peptides, promoting natriuresis, vasodilation, and antifibrotic signaling, while valsartan blocks angiotensin II type 1 receptor-mediated vasoconstrictive and profibrotic pathways. In a patient with atrial remodeling, elevated filling pressures, and dynamic MR, these effects could plausibly reduce left atrial pressure, favor reverse atrial remodeling, lower annular stretch, and reduce regurgitant burden during exercise. The observed reduction in NT-proBNP and left atrial volume is consistent with this framework.
The choice of exercise mPAP/CO slope as the primary endpoint is also important. Many conventional HFpEF studies rely heavily on resting measurements, which can miss the pathophysiologic signature of exertional congestion. By contrast, PRAISE-MR tested whether therapy improves what patients experience most acutely: breathlessness and circulatory inefficiency during activity. The concordance between the hemodynamic endpoint and peak VO2 and KCCQ strengthens confidence that the findings are not merely statistical artifacts.
The results also invite comparison with prior sacubitril/valsartan studies. In PARAGON-HF, the overall primary endpoint was narrowly missed, although subgroup signals suggested potential heterogeneity of benefit. PRAISE-MR does not contradict that history; rather, it refines it by suggesting one phenotype in which therapeutic benefit may be more pronounced. Similarly, data in HFrEF have shown that sacubitril/valsartan may reduce secondary MR, and PRAISE-MR extends that concept to an atrial rather than ventricular MR substrate.
Strengths, limitations, and generalizability
The strengths of PRAISE-MR include randomized allocation, multicenter conduct, blinded primary endpoint assessment, and a highly relevant mechanistic phenotype. The use of CPETecho is a major strength because it captures dynamic abnormalities not apparent at rest. The inclusion of objective functional, biomarker, and structural secondary outcomes provides internal consistency across domains.
The limitations are equally important. First, the sample size was small, with 84 participants. This restricts precision, limits subgroup analysis, and increases the possibility that effect size estimates are unstable. Second, the trial was open-label, which may influence subjective outcomes such as quality-of-life scores, though it is less likely to explain the directional consistency seen in objective measures. Third, the follow-up period was only 6 months, so the study cannot determine whether these improvements translate into fewer hospitalizations, less progression of valvular disease, or improved survival.
Fourth, the comparator was standard of care rather than placebo, and the abstract does not detail background therapies in depth. Contemporary HFpEF care is evolving rapidly, especially with SGLT2 inhibitor use; whether the same benefit would be seen on top of fully optimized modern therapy needs clarification. Fifth, because AFMR is a specialized imaging diagnosis and exercise echo expertise is not universally available, external validity may depend on center experience.
Finally, the publication date and citation establish the trial’s existence, but the abstract alone does not provide funding details or a ClinicalTrials.gov identifier. Those should be reviewed in the full publication before making judgments about sponsorship, protocol deviations, or prespecified analyses.
Implications for practice and research
PRAISE-MR should not be interpreted as definitive evidence to broadly prescribe sacubitril/valsartan for all HFpEF patients with mitral regurgitation. Instead, it is best viewed as an important proof-of-concept trial supporting phenotype-directed therapy. For clinicians, the study reinforces several practical lessons.
First, AFMR in HFpEF deserves active recognition rather than passive notation on the echo report. It may identify patients with disproportionate exercise symptoms, left atrial disease, and potentially modifiable hemodynamic abnormalities. Second, stress-based assessment can be highly informative when resting findings seem insufficient to explain symptoms. Third, sacubitril/valsartan may be a reasonable therapeutic consideration in carefully selected symptomatic patients with HFpEF and AFMR, especially when blood pressure permits, although this remains an evidence-informed rather than guideline-mandated decision pending larger trials.
For researchers, the next step is clear: larger, placebo-controlled trials powered for clinical events are needed. These studies should incorporate contemporary background therapy, prespecify AF rhythm status, quantify rest versus exercise MR behavior, and assess whether improvements in exercise hemodynamics translate into reductions in hospitalization and progression to valve intervention. It will also be useful to identify imaging or biomarker signatures that predict response, such as degree of left atrial dysfunction, annular dilation, pulmonary vascular reserve, or natriuretic peptide profile.
Conclusion
PRAISE-MR adds a clinically meaningful piece to the HFpEF puzzle. In symptomatic HFpEF patients with at least moderate AFMR, sacubitril/valsartan improved exercise pulmonary hemodynamics, increased peak VO2, enhanced health status, lowered NT-proBNP, reduced left atrial volume, and attenuated the dynamic worsening of MR during exercise over 6 months compared with standard care. The study is small and not designed to answer outcome questions, but its message is important: targeting a specific structural-hemodynamic HFpEF phenotype may uncover benefits that broader trials dilute. If confirmed in larger placebo-controlled studies, AFMR could become one of the more actionable phenotypes in HFpEF management.
Funding and registration
Funding source and ClinicalTrials.gov registration number were not provided in the abstract supplied here. These details should be verified in the full Circulation publication.
References
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