Comparison of Blood Volume Profiles in Heart Failure With Preserved and Reduced Ejection Fractions: Sex Makes a Difference.

BACKGROUND: Blood volume (BV) profiles vary markedly in patients with heart failure (HF), but how HF phenotypes and patient sex impact volume profiles remain to be explored. The aim of the study was to differentiate BV, plasma volume, and red blood cell mass profiles by phenotypes of preserved and reduced left ventricular ejection fractions and assess the impact of patient sex on profile heterogeneity. METHODS: Retrospective analysis of clinical and BV data was undertaken in patients with chronic New York Heart Association II-III heart failure. BV was quantitated using the nuclear medicine indicator-dilution methodology. RESULTS: A total of 530 BV analyses (360 HF with reduced ejection fraction and 170 HF with preserved ejection fraction) were identified in 395 unique patients. Absolute BV was greater in HF with reduced ejection fraction (6.7±1.8 versus 5.9±1.6 liters: P<0.001); however, large variability in frequency distribution of volume profiles was observed in both phenotypes (-22% deficit to +109% excess relative to normal volumes). HF with reduced ejection fraction was characterized by a higher prevalence of BV expansion ≥+25% of normal (39% versus 26%; P=0.003), and HF with preserved ejection fraction was characterized a by more frequent normal BV (42% versus 24%; P<0.001). Male sex in both phenotypes was associated with a larger absolute BV (7.0±1.6 versus 5.1±1.3 liters; P<0.001) and higher frequency of large BV and plasma volume expansions above normal (both P<0.001), while females in both phenotypes demonstrated a higher prevalence of normal BV and plasma volume (both P<0.001). CONCLUSIONS: Findings support significant differences in BV, plasma volume, and red blood cell mass profile distributions between heart failure phenotypes, driven in large part by sex-specific factors. This underscores the importance of identifying and distinguishing individual patient volume profiles to help guide volume management strategies.

Patient Sex Impacts Volume Phenotypes and Hemodynamics in Chronic Heart Failure: A Multicenter Analysis.

BACKGROUND: Quantitative methods have shown clinically significant heterogeneity in blood volume (BV) profiles in patients with chronic heart failure (HF). How patients' sex might impact this volume heterogeneity and its relationship to cardiac hemodynamics remains to be defined. METHODS: Retrospective analysis of clinical and quantitative BV, plasma volume (PV) and red blood cell (RBC) mass data was undertaken across 3 medical centers. BV was quantitated using nuclear medicine I-131-labeled plasma albumin indicator-dilution methodology with cardiac hemodynamics obtained within 24 hours. RESULTS: In an analysis of 149 males and 106 females, absolute BV was greater, on average, in males (6.9 ± 1.7 vs 5.0 ± 1.2 liters; P < 0.001); however, a wide range in BVs was demonstrated in both sexes (2.9-14.5 liters). Male sex was associated with higher prevalence of large (+ 25% of normal) BV and PV expansions (36% vs 15% and 51% vs 21%, respectively; both P < 0.001). In contrast, female sex was associated with higher prevalence of normal total BV (44% vs 27%; P = 0.005), PV (54% vs 27%; P < 0.001), hypovolemia (23% vs 11%; P = 0.005), and true anemia (42% vs 26%; P < 0.001). Cardiac hemodynamics differed by sex, but only modest associations were demonstrated between volume profiles and cardiac filling pressures. CONCLUSIONS: Findings support unique intravascular volume profiles reflecting sex-specific differences in the prevalence and distributions of total BV, PV and RBC mass profiles in patients with chronic HF. This underscores the importance of recognizing patients' sex as a significant factor influencing volume homeostasis, which needs to be taken into account to individualize volume-management strategies effectively.

Blood volume phenotypes and patient sex in resistant hypertension.

The relationship of blood volume (BV) to systemic blood pressure (BP) is not well defined in resistant hypertension (RH). The goal of this study was to examine the extent to which systemic BP stratified by patient sex would impact BV phenotypes. A retrospective analysis of clinical and quantitative BV data was undertaken in a cohort of ambulatory patients with a history of controlled and uncontrolled RH. We analyzed 253 unique BVs with 54% of patients above goal BP of <150 mmHg. BV phenotypes were highly variable but no correlation of systolic BP to absolute BV or percentage deviation from normal volume was identified in either sex. Males demonstrated overall larger absolute BVs with higher prevalence of large plasma volume (PV) expansion; females were overall more hypovolemic by total BV but with a higher frequency of normal PV than males. Females trended towards more RBC mass deficit (true anemia) (49% vs. 38%. P  = 0.084) while more males demonstrated RBC mass excess (erythrocythemia) (21% vs. 11%, P  = 0.029). Importantly, a significant portion (52%) of patients with true anemia identified by BVA would go undetected by hemoglobin measurement alone. BV phenotypes are highly diverse in patients with RH. However, absolute BV or variability in BV phenotypes even when stratified by patient sex did not demonstrate an association with systemic BP. BV phenotyping provides a key to optimizing clinical management by identifying RBC mass profiles particularly distinguishing true anemia, dilutional anemia, and erythrocythemia and the contribution of PV expansion. Findings support the clinical utility of BV phenotyping in RH.

MANP in Hypertension With Metabolic Syndrome: Proof-of-Concept Study of Natriuretic Peptide-Based Therapy for Cardiometabolic Disease.

Hypertension and metabolic syndrome frequently coexist to increase the risk for adverse cardiometabolic outcomes. To date, no drug has been proven to be effective in treating hypertension with metabolic syndrome. M-atrial natriuretic peptide is a novel atrial natriuretic peptide analog that activates the particulate guanylyl cyclase A receptor. This study conducted a double-blind, placebo-controlled trial in 22 patients and demonstrated that a single subcutaneous injection of M-atrial natriuretic peptide was safe, well-tolerated, and exerted pleiotropic properties including blood pressure-lowering, lipolytic, and insulin resistance-improving effects. (MANP in Hypertension and Metabolic Syndrome [MANP-HTN-MS]; NCT03781739).

Measurement of Blood Volume in Patients with Heart Failure: Clinical Relevance, Surrogates, Historical Background and Contemporary Methodology.

The development of clinical congestion resulting from volume overload, either by renal fluid retention or redistribution of blood volume from venous reservoirs, is a recurrent scenario in patients with chronic heart failure (HF). As a result, the treatment of congestion, most commonly by initiating aggressive diuretic therapy, is a front-line issue in the management of patients with HF. However, the association of clinical congestion and volume overload with physical signs and symptoms, as well as other surrogates of volume assessment, has limitations in accuracy and, therefore, reliability to direct appropriate interventions. The ability to quantitate intravascular volume and identify the variability in volume profiles among patients with HF can uniquely inform individualized volume management and aid in risk stratification. This tool is provided by contemporary nuclear medicine-based BVA-100 methodology, which uses the well-established indicator-dilution principle and is a requested topic for discussion in this review.

Serial blood volume measurements in patients with compensated chronic heart failure: How do volume profiles change over time?

Among patients with chronic heart failure (HF) intravascular volume profiles vary significantly despite similar clinical compensation. However, little is known regarding changes in blood volume (BV) profiles over time. The objective of this analysis was to identify the extent and character of changes in volume profiles over time. A prospective analysis was undertaken in patients who were hospitalized and treated for fluid overload. Quantitative BV analyses were obtained in a compensated state at hospital discharge (baseline) and follow-up at 1, 3, and 6 mo. Data were available on 10 patients who remained stable without rehospitalization or medication change over a 6-mo period. Baseline BV profiles were highly variable at hospital discharge with an average deviation of +28% above normal in 6 patients and normal BV in 4 patients. Over the follow-up period, the median change in BV was -201 mL [-3% (-6, +3%)] from baseline with profiles remaining in the same volume category in 9 out of 10 patients. Crossover from normal BV to mild contraction (-13% of normal) occurred in one patient. Red blood cell mass demonstrated the largest change over 6 mo [median -275 (-410, +175) mL] with a deviation from normal of -14 (-20, +8) % (reflecting mild anemia). These findings suggest that BV profiles in clinically compensated patients with HF do not change substantially over a 6-mo period regardless of baseline expanded or normal BV. This lack of change in volume profiles particularly from an expanded BV has implications for long-term volume management, clinical outcomes, and also our understanding of volume homeostasis in HF.NEW & NOTEWORTHY The novel findings of this study demonstrate that blood volume profiles while highly variable in clinically compensated patients with HF on stable medical therapy do not change substantially over a 6-mo period regardless of baseline expanded or normal blood volumes. This lack of change in volume profiles particularly from an expanded blood volume has implications for long-term volume management and also for how we understand the pathophysiology of volume homeostasis in chronic HF.

Differences in red blood cell mass profiles impact intravascular volume and outcome risk in chronic heart failure.

AIMS: To identify different red blood cell mass (RBCM) profiles, separate from haemoglobin concentrations, and their impact on blood volume expansion and clinical outcomes in chronic heart failure. METHODS AND RESULTS: RBCM was measured at hospital discharge using standardized nuclear medicine indicator-dilution methodology in patients following diuretic treatment for clinical congestion. Individual RBCM phenotypes were prospectively identified and analysed for heart failure-related mortality or first rehospitalization over 1 year. Of 132 patients, 42 (32%) demonstrated normal RBCM, 36 (27%) RBCM deficit (true anaemia), and 54 (41%) RBCM excess (erythrocythemia). Dilutional 'anaemia' defined by haemoglobin <12 g/dL with normal or an excess in RBCM with plasma volume expansion was identified in 37 (28%) patients. There were 61 composite outcome events, which included 38 deaths (29% of cohort) occurring over the 1 year follow-up period [14/36 (39%) in RBCM deficit, 12/42 (29%) in normal RBCM, and 12/54 (22%) in RBCM excess subgroups]. By Kaplan-Meier and multivariate analyses, RBCM excess was independently associated with the best event-free survival while RBCM deficit (true anaemia) the poorest outcomes; both compared with normal RBCM (P < 0.001). Dilutional 'anaemia' demonstrated a lower risk compared with true anaemia (P = 0.03). CONCLUSIONS: Markedly different RBCM profiles are identifiable among comparably compensated heart failure patients, and this variability carries significant implications for post-hospital outcomes. Novel to this analysis and in contrast to RBCM deficit is the independent association of RBCM excess with better event-free survival compared with normal RBCM. The distinction of RBCM profiles to guide risk stratification and individualized patient management strategies warrants further study.

Blood volume and chronic kidney disease in heart failure - Can volume expansion help balance the Cardio-Renal Axis for better clinical outcomes?

Intravascular volume is largely regulated by the kidneys but how differences in intravascular volume profiles interact with chronic kidney disease (CKD) to influence outcomes in chronic heart failure (HF) has not been explored. Our hypothesis was that a greater degree of volume expansion (VE) would moderate the impact of CKD on HF-related clinical outcomes. Quantitative blood volume (BV) data were available in 137 patients at the time of hospital discharge using a nuclear medicine radiolabeled albumin indicator-dilution technique. The study patients were stratified by the cohort median glomerular filtration rate (GFR, 44 ml/min/1.73 m2 ). An a priori cut-point of ≥+25% above normal BV was then used to further stratify the two GFR subgroups and prospectively analyzed for 1-year HF-related mortality or 1st re-hospitalization. Persistent BV expansions ≥+25% were present in 51% of the cohort. In the subgroup with GFR above the median (N = 68) greater or lesser BV expansion from +25% did not differentiate outcomes. However, in the subgroup with GFR below the median (N = 69), BV expansion-stratified risk (log-rank p = 0.022) with <+25% VE associated with poorer outcomes, while VE ≥ + 25% was associated with lower risk and comparable to GFR above the median. In patients with chronic HF, significant intravascular VE and CKD are common co-existing conditions. The presence of larger VE, however, appears to be a factor mitigating the impact of declining renal function on clinical outcomes, and as an element of volume pathophysiology warrants further study.

Fluid Volume Homeostasis in Heart Failure: A Tale of 2 Circulations.

Fluid volume homeostasis in health and heart failure (HF) requires a complex interaction of 2 systems, the intravascular and interstitial-lymphatic circulations. With the development of HF both the intravascular and interstitial compartments undergo variable degrees of volume remodeling which can include significant expansion. This reflects the impact of multiple pathophysiologic mechanisms on both fluid compartments which initially play a compensatory role to stabilize intravascular circulatory integrity but with progression in HF can evolve to produce the various manifestations of volume overload and clinical HF congestion. The intent of this review is to help enhance recognition of the pathophysiologic and clinical importance of the interlinked roles of these 2 circulatory systems in volume regulation and chronic HF. It would also be hoped that a better understanding of the interacting functions of the intravascular and interstitial-lymphatic fluid compartments can potentially aid development of novel management strategies particularly addressing the generally undertargeted interstitial-lymphatic system and help bring such approaches forward through a more integrated view of these 2 circulatory systems.

Quantitative Blood Volume Analysis and Hemodynamic Measures of Vascular Compliance in Patients With Worsening Heart Failure.

BACKGROUND: The role of blood volume (BV) expansion vs a change in vascular compliance in worsening heart failure (HF) remains under debate. We aimed to assess the relationship between BV and resting and stress hemodynamics in worsening HF and to further elucidate the significance of BV in cardiac decompensation. METHODS AND RESULTS: Patients with worsening HF underwent radiolabeled indicator-dilution BV analysis and cardiac catheterization. Intravascular volumes and resting/stress hemodynamics were recorded. Provocative stress maneuvers included change in systolic blood pressure (ΔSBP) from lying to standing and Valsalva and intracardiac pressure changes with leg raise. Correlation between BV and invasive hemodynamics were assessed by linear regression. Of 27 patients with worsening HF, patients' characteristics included mean age 61 ± 12 years, 70% male, 19% Black, and mean ejection fraction 29% ± 15%. Of the patients, 13 (48%) had hypervolemia as measured by total BV, which weakly correlated with ΔSBP by position (R2 = 0.009) and Valsalva (R2 = 0.003) and with right atrial (R2 = 0.049) and pulmonary capillary wedge (R2 = 0.047) pressure changes during leg raise. CONCLUSIONS: In patients with worsening HF, BV mildly correlated with intracardiac pressures at rest. Provocative maneuvers intended to test vascular compliance did not correlate with BV, indicating that compliance may serve as a stand-alone metric in HF.

Blood volume expansion, normovolemia, and clinical outcomes in chronic human heart failure: more is better.

Expansion in blood volume (BV) is a well-recognized response to arterial underfilling secondary to impaired cardiac output in heart failure (HF). However, the effectiveness of this response in terms of outcomes remains inadequately understood. Prospective analysis was undertaken in 110 patients with HF hospitalized and treated for fluid overload. BVs were measured in a compensated state at the hospital discharge using the indicator-dilution methodology. Data were analyzed for composite 1-year HF-related mortality/first rehospitalization. Despite uniform standard of care, marked heterogeneity in BVs was identified across the cohort. The cohort was stratified by BV expansion greater than or equal to +25% above normal (51% of cohort), mild-moderate expansion (22%), and normal BV (27%). Kaplan-Meier (K-M) survival estimates and regression analyses revealed BV expansion (greater than or equal to +25%) to be associated with better event-free survival relative to normal BV (P = 0.038). Increased red blood cell mass (RBCm; RBC polycythemia) was identified in 43% of the overall cohort and 70% in BV expansion greater than or equal to +25%. K-M analysis demonstrated polycythemia to be associated with better outcomes compared with normal RBCm (P < 0.002). Persistent BV expansion to include RBC polycythemia is common and, importantly, associated with better clinical outcomes compared with normal total BV or normal RBCm in patients with chronic HF. However, compensatory BV expansion is not a uniform physiological response to the insult of HF with marked variability in BV profiles despite uniform standard of care diuretic therapy. Therefore, recognizing the variability in volume regulation pathophysiology has implications not only for impact on clinical outcomes and risk stratification but also potential for informing individualized volume management strategies.NEW & NOTEWORTHY The novel findings of this study demonstrate that intravascular volume profiles among the patients with chronic heart failure (HF) vary substantially even with similar clinical compensation. Importantly, a profile of blood volume (BV) expansion (compared with a normal BV) is associated with lower HF mortality/morbidity. Furthermore, RBC polycythemia is common and independently associated with improved outcomes. These observations support BV expansion with RBC polycythemia as a compensatory mechanism in chronic HF.

Relation of Intravascular Volume Profiles to Heart Failure Progression and Clinical Outcomes.

Heart failure (HF) commonly progresses over time and identifying differences in volume profiles may help stratify risk and guide therapy. The aim of this study was to assess the pathophysiologic and prognostic roles of volume profiles for HF progression in stable ambulatory and hospitalized patients. HF patients who had undergone quantitative intravascular volume analysis (185 outpatients and 139 inpatients) were retrospectively assessed for the combined end point of HF-related hospital admissions (outpatients), HF-readmissions (inpatients), and overall all-cause mortality. After multivariate Cox regression analysis, greater total blood volume expansion was associated with higher risk of HF-admission in previously stable outpatients (HR: 1.023, CI 1.005 to 1.043; p = 0.013) while in more advanced HF (inpatients) total blood volume expansion was associated with lower risk for HF-readmission and mortality (HR: 0.982, CI 0.967 to 0.997; p = 0.017). Secondary analysis suggests that subclinical plasma volume expansion was a driving factor for the detrimental association in outpatients (HR: 1.018, CI 0.997 to 1.036; p = 0.054), while an increase in red blood cell mass was central to the beneficial association in advanced HF (HR: 0.979, CI 0.968 to 0.991; p <0.001). In conclusion, understanding differences in plasma volume and red blood cell mass profiles can provide insight into the pathophysiology and progression of HF.

Contributions of cardiac dysfunction and volume status to central haemodynamics in chronic heart failure.

AIMS: Elevated cardiac filling pressures producing clinical congestion in heart failure (HF) patients may be secondary to intravascular volume expansion or abnormalities in cardiac diastolic properties. The objective of this study was to assess the extent to which measures of myocardial function and intravascular volume correlate with haemodynamic abnormalities in chronic HF. METHODS AND RESULTS: Subjects underwent invasive haemodynamic assessment, measurement of total blood volume (TBV) using radiolabel indicator-dilution methodology, and echocardiography to evaluate cardiac structure and function. Patients were divided into those with hypervolaemia (defined as TBV > +8% above referenced normal volume) and normal volume ('euvolaemia') (TBV ≤ + 8%). Of 66 patients, 39 (59%) were hypervolaemic and 27 (41%) normal TBV. Central venous pressure (CVP, P = 0.01) and pulmonary capillary wedge pressure (PCWP, P < 0.001) were higher in hypervolaemic compared with euvolaemic patients; however, 15% of hypervolaemic patients displayed normal pressures. Of euvolaemic patients, 70% displayed elevated CVP and 63% elevated PCWP. PCWP was moderately correlated with TBV (r = 0.42), left ventricular diastolic function (e' velocity, r = -0.44), and left atrial strain (r = -0.47). In multivariable regression TBV, left ventricular e', and left atrial strain were independently associated with PCWP (all P < 0.05). CONCLUSIONS: While hypervolaemic patients displayed elevations in filling pressures, a substantial proportion (15%) had normal pressures, and of all subjects with elevated filling pressures nearly one third had normal TBVs. Importantly, of patients with normal volumes, a majority (>60%) display elevated filling pressures. Combined analysis of volume, pressure, and cardiac function may be helpful to guide comprehensive assessments of HF status.

Diuresis-Related Weight Loss Reflects Interstitial Compartment Decongestion with Minimal Impact on Intravascular Volume Expansion or Outcomes in Post-Acute Heart Failure: Metrics of Decongestion and Volume Status.

BACKGROUND: Findings from heart failure (HF) studies linking diuresis-related weight loss to clinical decongestion and outcomes are mixed. Differential responses of interstitial and intravascular volume compartments to diuretic therapy and heterogeneity in volume profiles may confound the clinical interpretation of weight loss in patients with HF. METHODS AND RESULTS: Data were prospectively collected in hospitalized patients requiring diuresis. Plasma volume (PV) was measured using I-131-labelled albumin indicator-dilution methodology. The cohort was stratified by tertiles of weight loss and analyzed for interstitial fluid loss relative to changes in PV and HF-related morality or first rehospitalization. Among 92 patients, the admission PV was expanded +42% (4.7 ± 1.2 L) above normal with significant variability (14% normal PV, 18% mild-moderate expansion, and 68% with large PV expansion [>+25% above normal]). With diuresis there were proportional decreases in interstitial volume (-6.5 ± 4.4%) and PV (-7.5 ± 11%); however, absolute decreases in the PV (-254 mL, interquartile range -11 to -583 mL) were less than 10% of interstitial volume loss (-5040 mL, interquartile range -2800 to -7989 mL); greater interstitial fluid loss did not translate into better outcomes (log-rank P = .430). CONCLUSIONS: Diuresis-related decreases in weight reflect fluid loss from the interstitial compartment with only minor changes in the PV and without an impact on outcomes. Further, the degree of PV expansion at hospital admission does not drive the magnitude of the diuresis response, even with a wide spectrum of body weights; interstitial fluid overload is preferentially targeted and PV relatively preserved. Therefore, greater interstitial fluid loss reflects clinical decongestion, but not better outcomes, and a limited association with intravascular volume profiles potentially confounding weight loss as a prognostic metric in HF.

Plasma Volume Status and Its Association With In-Hospital and Postdischarge Outcomes in Decompensated Heart Failure.

BACKGROUND: Prior analyses suggest an association between formula-based plasma volume (PV) estimates and outcomes in heart failure (HF). We assessed the association between estimated PV status by the Duarte-ePV and Kaplan Hakim (KH-ePVS) formulas, and in-hospital and postdischarge clinical outcomes, in the ASCEND-HF trial. METHODS AND RESULTS: The KH-ePVS and Duarte-ePV were calculated on admission. We assessed associations with in-hospital worsening HF, 30-day composite cardiovascular mortality or HF rehospitalization and 180-day all-cause mortality. There were 6373 (89.2%), and 6354 (89.0%) patients who had necessary characteristics to calculate KH-ePVS and Duarte-ePV, respectively. There was no association between PV by either formula with in-hospital worsening HF. KH-ePVS showed a weak correlation with N-terminal prohormone BNP, and with measures of decongestion such as body weight change and urine output (r < 0.3 for all). Duarte-ePV was trending toward an association with worse 30-day (adjusted odds ratio 1.07, 95% confidence interval [CI] 1.00-1.15, P = .058), but not 180-day outcomes (adjusted hazard ratio 1.03, 95% CI 0.97-1.09, P = .289). A continuous KH-ePVS of >0 (per 10-unit increase) was associated with improved 30-day outcomes (adjusted odds ratio 0.75, 95% CI 0.62-0.91, P = .004). The continuous KH-ePVS was not associated with 180-day outcomes (adjusted hazard ratio 1.05, 95% CI 0.98-1.12, P = .139). CONCLUSIONS: Baseline PV estimates had a weak association with in-hospital measures of decongestion. The Duarte-ePV trended toward an association with early clinical outcomes in decompensated HF, and may improve risk stratification in HF.

Natriuretic Peptides to Predict Short-Term Mortality in Patients With Sepsis: A Systematic Review and Meta-analysis.

Data are conflicting regarding the optimal cutoffs of B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) to predict short-term mortality in patients with sepsis. We conducted a comprehensive search of several databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus) for English-language reports of studies evaluating adult patients with sepsis, severe sepsis, and septic shock with BNP/NT-proBNP levels and short-term mortality (intensive care unit, in-hospital, 28-day, or 30-day) published from January 1, 2000, to September 5, 2017. The average values in survivors and nonsurvivors were used to estimate the receiver operating characteristic curve (ROC) using a parametric regression model. Thirty-five observational studies (3508 patients) were included (median age, 51-75 years; 12%-74% males; cumulative mortality, 34.2%). A BNP of 622 pg/mL had the greatest discrimination for mortality (sensitivity, 0.695 [95% CI, 0.659-0.729]; specificity, 0.907 [95% CI, 0.810-1.003]; area under the ROC, 0.766 [95% CI, 0.734-0.797]). An NT-proBNP of 4000 pg/mL had the greatest discrimination for mortality (sensitivity, 0.728 [95% CI, 0.703-0.753]; specificity, 0.789 [95% CI, 0.710-0.867]; area under the ROC, 0.787 [95% CI, 0.766-0.809]). In prespecified subgroup analyses, identified BNP/NT-proBNP cutoffs had higher discrimination if specimens were obtained 24 hours or less after admission, in patients with severe sepsis/septic shock, in patients enrolled after 2010, and in studies performed in the United States and Europe. There was inconsistent adjustment for renal function. In this hypothesis-generating analysis, BNP and NT-proBNP cutoffs of 622 pg/mL and 4000 pg/mL optimally predicted short-term mortality in patients with sepsis. The applicability of these results is limited by the heterogeneity of included patient populations.

Intravascular Volume Modulates the Outcome Predictive Capacity of Clinical Renal Function Biomarkers in Clinically "Euvolemic" Chronic Heart Failure Patients.

BACKGROUND: Cardiorenal interconnections are complex and may in part be mediated by the extent of intravascular volume expansion. The impact of subclinical volume excess on outcomes in heart failure (HF) patients with chronic kidney disease (CKD) has not been examined previously. OBJECTIVES: To assess the impact of volume-kidney interactions on outcomes in clinically "euvolemic" chronic HF patients (NYHA class II) with coexisting CKD. METHODS: Plasma volume (PV) was prospectively measured in 110 stable HF patients with different degrees of renal function using a standardized radiolabeled albumin indicator-dilution technique. To examine the interactive roles of volume expansion and biomarkers of CKD, the cohort was dichotomized by median PV and then further stratified by cohort median serum creatinine, eGFR, and BUN, and analyzed for outcomes of HF-related mortality and 1st hospitalization. RESULTS: PV was expanded above normal in 76% of the cohort. Over 1.5 years of follow-up, sCr and BUN above and eGFR below cohort median stratified higher risks for the composite endpoint only in ambulatory HF patients with a severe degree of PV expansion (median PV expansion ≥+26%; p = 0.02). With less expansion (<+26% expansion), these biomarkers reflecting worse renal function did not discriminate risk (p = 0.578). The percentage of subjects experiencing composite outcome events was, however, comparable for both greater and lesser degrees of PV expansion in HF patients with stable clinical status. CONCLUSIONS: In clinically stable chronic HF patients with coexisting CKD, substantial subclinical PV expansion is common even when patients are considered clinically to be euvolemic, and, importantly, the extent of PV expansion impacts outcomes including early HF mortality. Better kidney function appears to mitigate the effects of excess PV expansion, while less volume expansion appears to limit the risk of worse renal function as reflected by clinical biomarkers of renal function. Thus, the extent of volume expansion impacts the capacity of standard clinical biomarkers of CKD to differentiate outcome risk in ambulatory chronic (NYHA class II) HF patients.