The study, part of the ongoing Regensburg Trial on TMVR Techniques in Mitral Regurgitation (RETORT-MR), enrolled 311 patients with severe mitral regurgitation between December 2017 and March 2024. All were considered clinically well compensated before their procedure, meaning they showed no obvious signs of hypervolemia or congestion on physical examination. The researchers calculated each patient’s estimated plasma volume status, or ePVS, a surrogate marker that quantifies the proportional deviation of actual plasma volume from the ideal value. The calculation relies on Hakim’s formula, which derives actual plasma volume from the hematocrit and body weight using sex-dependent constants, and compares it against ideal plasma volume estimates established by Longo and colleagues. Because it requires nothing more than a complete blood count and a scale, the ePVS can be computed in any clinic within minutes, at essentially no cost.

The median ePVS in the cohort was -3.8 percent, with an interquartile range spanning -10.3 to +3.6 percent, indicating that most patients carried slightly less plasma volume than the theoretical ideal. Using receiver operating characteristic analysis anchored to one-year mortality, the investigators identified an optimal cut-off of +0.36 percent for ePVS and 2794 pg/mL for NT-proBNP, the established blood biomarker of myocardial wall stress. Fifty-one patients died during a median follow-up of twelve months, with a median time to death of 422 days. When the cohort was split at these thresholds, the differences in survival were stark and statistically unmistakable.

Patients whose preprocedural ePVS exceeded the cut-off had a Kaplan-Meier estimated mortality of 14.4 percent at one year, compared with just 4.7 percent among those below the threshold. By five years, the gap had widened dramatically: 63.0 percent of patients with elevated ePVS had died, versus 26.0 percent of those with lower values, a difference the log-rank test flagged as highly significant. Elevated NT-proBNP told a similar story, with one-year mortality of 14.6 percent versus 3.5 percent. Crucially, both markers survived multivariable adjustment for competing risk factors. Elevated ePVS carried a hazard ratio of 2.38 for all-cause mortality, while elevated NT-proBNP carried a hazard ratio of 4.30, confirming that each independently predicted death after the procedure.

Perhaps the most striking finding emerged when the two biomarkers were combined into a single trichotomous congestion variable. Patients with both markers above their cut-offs faced a hazard ratio of 14.27 for mortality compared with those in whom neither was elevated, a nearly fifteen-fold increase in risk. Even one elevated marker alone conferred a hazard ratio of 6.67. Kaplan-Meier curves for the three groups separated in a clean, stepwise fashion, with one-year mortality climbing from 1.9 percent in the double-negative group to 8.2 percent with one marker elevated and 21.5 percent with both. Five-year mortality followed the same gradient, reaching 64.8 percent in the doubly elevated group. The authors argue this reflects the integration of two fundamentally different congestion phenotypes into one comprehensive risk picture.

That pathophysiological distinction is central to the study’s significance. NT-proBNP is released by cardiac muscle cells in response to end-diastolic wall stress caused by pressure or volume overload inside the heart, and it is tightly linked to cardiac function. In this cohort, patients with elevated NT-proBNP indeed showed the expected signature of advanced myocardial disease: a higher prevalence of heart failure with reduced ejection fraction, lower left ventricular ejection fractions, reduced tricuspid annular plane systolic excursion, and more frequent secondary mitral regurgitation. Elevated ePVS, by contrast, was not associated with impaired systolic function. Instead, it marked a composite phenotype dominated by intravascular volume expansion, hemodilution, renal dysfunction, and systemic congestion. Patients with high ePVS were slightly older, had significantly lower estimated glomerular filtration rates, lower body mass index, lower hemoglobin and hematocrit, and required higher doses of loop diuretics.

A critical methodological question was whether ePVS simply repackages anemia, which is itself a known predictor of poor outcomes in heart failure. Because hematocrit is a direct component of the ePVS formula, the researchers built nested multivariable Cox models comparing ePVS against hematocrit, both as a continuous variable and as a sex-specific dichotomized variable. The results were decisive: hematocrit alone was not independently associated with mortality and did not improve model fit, whereas ePVS remained significant even when hematocrit was included, and adding ePVS significantly improved model fit in likelihood-ratio tests. Time-dependent reclassification analyses using integrated discrimination improvement showed that ePVS added significant prognostic information at a two-year horizon. This suggests the prognostic power lies not in anemia itself but in the multifactorial processes of plasma volume expansion and pseudoanemia that ePVS captures.

The findings held across both major etiologies of mitral regurgitation. In patients with primary, or degenerative, mitral regurgitation, elevated ePVS carried a univariable hazard ratio of 6.26, while in those with secondary or mixed disease the hazard ratio was 2.95, both statistically significant. The combined ePVS and NT-proBNP variable also stratified mortality in both subgroups. Regarding cardiovascular death specifically, of the 51 total deaths, 26 were cardiovascular in origin, and elevated ePVS maintained its independent association with cardiovascular mortality in multivariable models, with a hazard ratio of 2.66. Interestingly, only NT-proBNP, not ePVS alone, predicted rehospitalization for heart failure, which the authors interpret as evidence that ePVS marks a subtler, subclinical form of congestion that drives progressive organ dysfunction and death rather than acute decompensation requiring readmission.

The clinical implications are considerable. M-TEER candidates are a heterogeneous, high-risk population in whom traditional risk assessment has struggled to identify who will benefit most and who will deteriorate despite a technically successful procedure. The study found that, alongside the biomarkers, only a reduced left ventricular ejection fraction, severe preprocedural tricuspid regurgitation, and severe residual mitral regurgitation after the procedure remained independently associated with mortality, underscoring that optimal heart failure therapy and excellent procedural results remain essential. But the ePVS offers something those measures do not: a zero-cost, universally available window into subclinical intravascular congestion in patients who appear clinically dry. The authors caution that the estimated plasma volume depends on multiple variables and provides only limited information about true quantitative plasma volume, so it should not dictate therapy on its own.

Limitations temper the enthusiasm appropriately. RETORT-MR is a single-center study with a relatively small cohort, a low absolute number of deaths, and a substantial proportion of patients lost to follow-up, all of which constrain statistical power, particularly for the reclassification analyses and cause-specific mortality. The authors themselves emphasize that the results warrant validation in larger cohorts with more adverse events. Nevertheless, the consistency of the signal across etiologies, its independence from hematocrit and established covariates, and the sheer magnitude of the combined-marker hazard ratio make a compelling case. If confirmed, a calculation performable from a routine blood draw could become a standard element of preprocedural evaluation, flagging the silent fluid overload that today’s stethoscopes cannot hear and tomorrow’s outcomes depend on.

Subject of Research: Prognostic value of estimated plasma volume status in patients undergoing transcatheter edge-to-edge mitral valve repair

Article Title: The estimated plasma volume status is an independent predictor for mortality in patients undergoing transcatheter mitral valve repair

Article References: The estimated plasma volume status is an independent predictor for mortality in patients undergoing transcatheter mitral valve repair. (n.d.). https://doi.org/10.1007/s00392-026-03021-2

Image Credits: AI Generated

DOI: 10.1007/s00392-026-03021-2

Keywords: M-TEER, mitral regurgitation, ePVS, NT-proBNP, congestion, heart failure, plasma volume status, mortality prediction, biomarkers, transcatheter valve repair, risk stratification, cardiology