Hemodynamic profiles in cardiac amyloidosis (CA) patients differ from traditional heart failure phenotypes. Stressed blood volume is a main determinant of intravascular pressures and affect cardiac filling pressures. We hypothesized that estimated stressed blood volume (eSBV) may help us better understand hemodynamic derangements in patients with CA and its relation to adverse outcomes. We reviewed 462 consecutive patients who underwent right heart catheterization at a tertiary care institution for eSBV based on basic hemodynamic measurements. Median eSBV was used to stratify for high versus low eSBV. The primary outcome was all-cause mortality of high versus low eSBV in CA patients with left ventricular ejection fraction (LVEF) >40% or LVEF ≤ 40%. In our final cohort of 388 patients, of which 225 (58%) had transthyretin CA and 163 (42%) had light-chain CA, the median eSBV was 2,191 ml/70 kg. Among those with LVEF > 40%, 42 (16.6%) patients with high eSBV, while 27 (10.7%) patients with low eSBV developed adverse events (log-rank p = 0.018). Higher eSBV was independently associated with a higher risk of all-cause mortality (HR 1.84, 95% cardiac index 1.12 to 3.01, p = 0.015) even after adjustments for traditional cardiovascular risk factors, LVEF, and NT-proBNP (HR 2.19, 95% cardiac index 1.19 to 4.03, p = 0.012). Conversely, high eSBV did not predicted poor outcome in the LVEF ≤ 40% cohort. In conclusion, eSBV is an independent predictor of all-cause mortality in patients with CA and LVEF > 40% even after adjustment for traditional cardiovascular risk factors. Modelling eSBV through integrating established invasive hemodynamic parameters may become a valuable asset in the contemporary heart failure unit to guide treatment decision-making and prognosis.
Graphical abstract
Estimation of stressed blood volume as a surrogate for cardiac preload was held in 388 patients with cardiac amyloidosis. Caption: Patients were further stratified based on their LVEF. In cardiac amyloidosis patients with an LVEF > 40%, high estimated stressed blood volume is an independent predictor of all-cause mortality even after adjustment for traditional cardiovascular risk factors. Abbreviations: CA = cardiac amyloidosis; eSBV = estimated stressed blood volume; LVEF = left ventricular ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction.
Cardiac amyloidosis (CA) is caused by progressive infiltration of amorphous, fibrillar proteinaceous material in the myocardial extracellular space, leading to a restrictive cardiomyopathy phenotype. , Transthyretin (TTR), light-chain (AL), or non-TTR/AL amyloidogenic precipitants accumulate throughout the myocardial extracellular space and vasculature, which alters normal physiologic hemodynamics. Over time, this results in stiffer atria and ventricles and a less compliant arterial and venous capacitance systems, the latter predominantly featuring in AL-CA.
Invasive hemodynamic profiling of various heart failure (HF) phenotypes was first described in 1976 by Forrester and Diamond. Although CA hemodynamics are largely underrepresented in HF trials, hemodynamic alterations and their prognostic value in CA patients have recently been reconsidered. Also, the degree of amyloid infiltration directly determines the severity of the restrictive phenotype, which is reflected by the hemodynamic profile. Hence, the hemodynamic phenotype should correlate with outcomes, since the degree of infiltration correlates with outcomes. Furthermore, the majority of CA patients (irrespective of CA subtype) features elevated left- and right-sided cardiac filling pressures at rest, which advocates using higher hemodynamic cutoffs compared with patients with nonamyloid HF to predict clinical outcome.
The total blood volume (TBV) of the circulatory system can be divided, functionally, into unstressed and stressed blood components. Stressed blood volume (not TBV) is a main determinant of intravascular pressures. Alternations of TBV and venous tone (either through venoconstriction or venodilation) affect stressed blood volume, which accordingly, further determine cardiac filling pressures. Given the aforementioned myocardial and vascular repercussions of longstanding amyloid deposition, venous compliance and capacitance may be reduced, which along with increased sympathetic tone present in all forms of HF, may lead to alternations of the stressed blood volume portion TBV in patients with CA. As we hypothesized that estimated stressed blood volume (eSBV) may help us better understand hemodynamic derangements in patients with CA, the goals of our analysis were : to describe eSBV in CA patients and its correlation with traditional hemodynamic parameters ; to assess how eSBV in CA patients relate to clinical outcomes.
Methods
Study population
Consecutive patients diagnosed with CA at a tertiary care institution between January 2001 and August 2021 were screened for participation. Patient characteristics have been previously described by Martens et al, whereas the median duration between right heart catheterization (RHC) and diagnosis of CA was 0 days (−8 to 0 days). The diagnosis of TTR CA (ATTR-CA) was either established from routine tissue biopsy or a standardized noninvasive assessment in both the outpatient and inpatient cohort. The indication for RHC were in descending order of frequency: part of a procedure with concomitant endomyocardial biopsy (EMB), RHC for acute on chronic HF with need for invasive hemodynamic monitoring, part of an evaluation for pulmonary hypertension, part of an evaluation for idiopathic cardiomyopathy/dyspnea (without EMB), as part of an evaluation of bridging to advanced therapies (eg, LVAD or heart transplant), and as an evaluation of progressive cardio-renal syndrome. When an EMB was performed, confirmation of TTR deposition in tissue specimen was found by either immunogold electron microscopy, immunohistochemistry, or mass spectrometry. Alternatively, noninvasive diagnosis of ATTR-CA was established through all the following : signs and symptoms of HF supported with an echocardiogram or cardiac magnetic resonance imaging consistent with or suggestive of CA ; grade 2 or 3 cardiac uptake on a technetium pyrophosphate scan confirmed by single-photon emission computerized tomography/computerized tomography; and absence of a detectable monoclonal protein on serum or urine immunofixation electrophoresis or serum free light chain assay. The diagnosis of AL-CA was established through multimodality imaging (eg, echocardiography or cardiac magnetic resonance imaging) supported with abnormal serum or urine immunofixation electrophoresis or abnormal serum free light chain assay, with ultimate confirmation based on the presence of light chain amyloid deposits on biopsy (either cardiac or extracardiac biopsy).
Data synthesis
Patient demographics, comorbidities, medical history, laboratory features, medical therapies, electrocardiogram, echocardiogram, pressures, and cardiac output from RHC and technetium pyrophosphate scans were all retrieved from the prospectively maintained REDCap database. Patients were stratified based on EF.
Outcomes
The primary outcome was all-cause mortality, comparing patients with high versus low eSBV in CA patients with left ventricular ejection fraction (LVEF) >40% or LVEF ≤ 40%. Uni- and multivariable analysis for the primary endpoint of all-cause mortality where enclosed in the survival analysis.
Hemodynamic measurements and definitions
RHC was performed according to institutional standards, at baseline in the catheterization laboratory at rest and in the supine position. A balloon-tipped, fluid-filled catheter was used to obtain mean right atrial pressure (RAP), right ventricular pressures, pulmonary artery systolic and diastolic pressures, as well as pulmonary capillary wedge pressure (PCWP). All measurements were obtained at end expiration under steady state conditions. PCWP was measured at the end of expiration after a spontaneous breathing cycle. Cardiac output was measured using thermodilution, and cardiac index (CI) was calculated as cardiac output divided by body surface area. Stroke volume index (SVi) was derived from CI using instantaneous heart rate. Systolic and diastolic blood pressures were obtained using a digital sphygmomanometer at the time of the procedure.
Estimation of stressed blood volume
TBV is functionally divided into UBV and SBV pools: TBV = UBV + SBV. Direct measurement of UBV and SBV necessitates thorough experimental maneuvers, which are not readily applicable to humans. As such, we applied a simulation-based method for estimating SBV based on widely used models of the cardiovascular system. In brief, the systemic and pulmonary circulations are represented by series of resistors and capacitors, whereas the cardiac chambers are featured by individual time-varying elastances. ,,,, The nonlinear, time-varying differential equations governing this model can be solved by numeric integration. For estimation of the SBV, the measured values of heart rate, cardiac output, RAP, PCWP, systolic PAP, diastolic PAP, systolic and diastolic aortic pressures, and LVEF for a given patient and condition were provided to the model. The algorithm unbiasedly searches the multidimensional space composed of the model parameters to optimize the agreement of all hemodynamic parameter measurements with the model output. The algorithm is implemented in the real-time simulation (retrieved online from http://harvi.online , Harvi Dynamics Inc). Aside from heart rate, each of the other 8 variables represents a measured parameter that must be matched by the output of the model on a patient-by-patient basis. Model parameter values that are optimized include RV and left ventricular end-systolic elastances and diastolic stiffness constants, systemic and PA compliances and characteristic impedances, and, finally, eSBV. To account for differences in patient sizes, all eSBV values are presented as milliliters per 70 kg body weight. TBV was estimated using body weight, as described previously (detailed description of SBV measurement is provided in the Supplementary Materials ). Unstressed blood volume was calculated as the difference of TBV and eSBV.
Statistical analysis
Continuous variables are summarized as mean ± standard deviation if normally distributed and median (interquartile range) if not normally distributed. Chi-square analysis was used to compare categorical variables. Mann–Whitney U test was used for continuous variables as appropriate. Spearman analysis was performed to assess nonparametric correlations between eSBV and other hemodynamic parameters. Ordinal regression was used to determine relation between functional status and hemodynamic variables, with the reporting of a standardized estimate ( Z scores) to allow unitless strength comparison between hemodynamic variables using different units and thus measurement scale. Survival analysis was established by Kaplan–Meier analysis and univariable and multivariable Cox proportional hazard models for primary outcome. Multivariable survival models included adjustments for covariates such as age, sex, hypertension, body mass index, LVEF, and NT-proBNP. All analyses were performed with R (RStudio 2024.09.1 + 394) and SPSS (SPSS, Chicago, IL, version 29.0.2.0), and a two-sided p value <0.05 was considered statistically significant.
Data availability
The data, analytic methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedures. There are restrictions related to the availability of some of the clinical data generated in the present study because we do not have permission in our informed consent from research subjects to share data outside our institution without their authorizations. The authors had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis, and may agree to make aggregate data available upon reasonable request.
This study has been approved by our Institutional Review Board, and written informed consent was waived as all procedures were performed as part of the routine clinical care. The manuscript was designed according to the Strengthening the Reporting of Observational Studies in Epidemiology statement for observational studies.
Results
Patient population
Between January 2001 and August 2021, a total of 1,556 patients received a diagnosis of CA, of whom 466 underwent RHC at baseline (33%). For this analysis, we included 388 patients. Figure 1 outlines a STROBE diagram illustrating the patient flow throughout the study. Table 1 provides the baseline characteristics of patients with CA stratified by high versus low eSBV. Cohorts for high and low eSBV were created based on the median eSBV of the total cohort. There were no significant differences in baseline characteristics between patients with high eSBV compared with low eSBV. Patients with low eSBV were more likely to receive beta-blocker therapy (59%). Yet, nearly half of the cohort featured prior diagnosis of atrial fibrillation. Only one in five patients did not receive maintenance diuretic therapy. Subsequently, distinctive cohorts were defined based on EF strata. Both LVEF > 40% and LVEF ≤ 40% cohorts featured different phenotypical background as outlined in Supplemental Tables 1 and 2 .
STROBE diagram displaying patient selection for different phases of the study.
Table 1
Baseline characteristics stratified by low and high eSBV in the total cohort
| Parameters | Total ( N = 388) | Low eSBV/70 kg ( N = 195) | High eSBV/70 kg ( N = 193) | p value |
|---|---|---|---|---|
| Demographics | ||||
| Age, years | 71 ± 10 | 70 ± 10 | 72 ± 10 | 0.576 |
| Male | 297 (77%) | 151 (77%) | 146 (76%) | 0.138 |
| Ethnicity | ||||
| Black | 81 (21%) | 40 (21%) | 41 (21%) | 0.844 |
| White | 295 (76%) | 148 (76%) | 147 (76%) | 0.844 |
| Other | 12 (3%) | 7 (4%) | 5 (3%) | 0.844 |
| History of smoking | 210 (54%) | 104 (54%) | 106 (56%) | 0.154 |
| Type of cardiac amyloidosis | ||||
| ATTR-CA | 225 (58%) | 118 (60%) | 107 (54%) | 0.237 |
| AL-CA | 163 (42%) | 77 (40%) | 86 (46%) | 0.237 |
| Comorbidities | ||||
| Hypertension | 247 (64%) | 117 (60%) | 130 (67%) | 0.693 |
| Dyslipidemia | 240 (62%) | 119 (61%) | 121 (63%) | 0.104 |
| Diabetes | 102 (26%) | 48 (25%) | 54 (28%) | 0.318 |
| CAD | 182 (47%) | 93 (48%) | 89 (50%) | 0.132 |
| Stroke | 46 (12%) | 26 (13%) | 20 (10%) | 0.305 |
| Atrial fibrillation | 209 (54%) | 106 (55%) | 103 (53%) | 0.176 |
| Pacemaker | 104 (27%) | 59 (30%) | 45 (23%) | 0.533 |
| ICD | 53 (14%) | 33 (17%) | 20 (11%) | 0.616 |
| BMI > 30 (kg/m 2) | 98 (26%) | 53 (28%) | 45 (24%) | 0.195 |
| Weight, kg | 79 ± 18 | 79 ± 18 | 79 ± 18 | 0.584 |
| Heart failure measurements | ||||
| NYHA class | 0.465 | |||
| I | 11 (3%) | 3 (2%) | 8 (5%) | |
| II | 114 (32%) | 57 (32%) | 57 (32%) | |
| III | 208 (59%) | 108 (60%) | 100 (57%) | |
| IV | 22 (6%) | 11 (6%) | 11 (6%) | |
| cTnI (ng/ml) | 0.10 ± 0.14 | 0.106 ± 0.12 | 0.10 ± 0.16 | 0.615 |
| NT-proBNP (ng/ml) | 7,471 ± 10,791 | 8,172 ± 12,178 | 6,812 ± 9,293 | 0.293 |
| Medications | ||||
| MRA | 101 (26%) | 46 (24%) | 55 (28%) | 0.458 |
| Diuretic | 320 (83%) | 158 (81%) | 162 (84%) | 0.288 |
| Digoxin | 46 (12%) | 24 (12%) | 22 (11%) | 0.096 |
| ACE/ARB | 149 (39%) | 79 (41%) | 70 (37%) | 0.400 |
| Beta-blocker | 137 (54%) | 115 (59%) | 97 (50%) | 0.887 |
| CCB | 35 (9%) | 15 (8%) | 20 (11%) | 0.274 |
| Echocardiographic measurements | ||||
| LVEF, % | 46 ± 14 | 47 ± 14 | 46 ± 13 | 0.389 |
| LAVi, ml/m 2 | 48 ± 23 | 47 ± 25 | 49 ± 21 | 0.368 |
| LVEDV, ml | 93 ± 35 | 90 ± 31 | 96 ± 39 | 0.276 |
| LVESV, ml | 50 ± 25 | 46 ± 20 | 54 ± 28 | 0.170 |
| GLS, % | −9.3 ± 3.7 | −9.2 ± 3.7 | −9.4 ± 3.7 | 0.336 |
| Hemodynamic measurements | ||||
| eSBV, ml/70 kg | 2,191 ± 2,660 | 1,753 ± 1,227 | 2,575 ± 1,431 | <0.001 |
| eUBV, ml | 2,548 ± 962 | 3,075 ± 5,755 | 2,082 ± 5,134 | <0.001 |
| eTBV, ml | 4,692 ± 5,517 | 4,733 ± 5,387 | 4,669 ± 4,717 | 0.493 |
| HR, bpm | 79 ± 15 | 79 ± 15 | 79 ± 15 | 0.954 |
| Systolic BP, mm Hg | 119 ± 21 | 118 ± 21 | 120 ± 21 | 0.255 |
| Diastolic BP, mm Hg | 75 ± 13 | 73 ± 12 | 76 ± 13 | 0.072 |
| RAP, mm Hg | 12 ± 6 | 11 ± 5 | 13 ± 6 | <0.001 |
| PASP, mm Hg | 48 ± 15 | 46 ± 15 | 50 ± 14 | 0.023 |
| PADP, mm Hg | 23 ± 7 | 21 ± 7 | 24 ± 7 | 0.023 |
| mPAP, mm Hg | 30 ± 10 | 29 ± 10 | 32 ± 10 | 0.001 |
| PCWP, mm Hg | 21 ± 7 | 20 ± 7 | 22 ± 7 | 0.007 |
| PVR, WU | 2.9 ± 5.7 | 2.5 ± 1.5 | 3.3 ± 7.9 | 0.927 |
| SVR, mm Hg/min per ml | 1,524 ± 540 | 1,523 ± 495 | 1,526 ± 582 | 0.698 |
| DPG, mm Hg | 1.9 ± 6.1 | 1.5 ± 5.7 | 2.3 ± 6.6 | 0.896 |
| TPG, mm Hg | 11.9 ± 19.8 | 10.3 ± 5.7 | 13.4 ± 27.5 | 0.718 |
| RAP/PCWP ratio | 0.56 ± 0.25 | 0.53 ± 0.26 | 0.57 ± 0.25 | 0.175 |
| API | 2.39 ± 1.89 | 2.57 ± 2.20 | 2.21 ± 1.31 | 0.289 |
| PAPi | 2.8 ± 2.2 | 2.9 ± 2.4 | 2.6 ± 1.9 | 0.100 |
| LVCPO, Watt | 0.90 ± 0.37 | 0.87 ± 0.35 | 0.92 ± 0.40 | 0.713 |
| RVCPO, Watt | 0.31 ± 0.14 | 0.29 ± 0.12 | 0.33 ± 0.15 | 0.091 |
| PAC, ml/mm Hg | 2.4 ± 2.0 | 2.2 ± 1.7 | 2.5 ± 2.2 | 0.178 |
| SAC, ml/mm Hg | 1.6 ± 4.7 | 1.8 ± 6.4 | 1.3 ± 0.8 | 0.421 |
| CO/70 kg, L/min | 4.5 ± 1.7 | 4.4 ± 1.4 | 4.6 ± 1.9 | 0.996 |
| CI/70 kg, L/min/m 2 | 2.2 ± 0.6 | 2.2 ± 0.6 | 2.2 ± 0.6 | 0.833 |
| PP (mm Hg) | 44 ± 15 | 45 ± 16 | 44 ± 15 | 0.969 |
| PPP (%) | 37 ± 8 | 37 ± 9 | 36 ± 8 | 0.623 |
| LV E es | 2.00 ± 1.17 | 2.12 ± 1.26 | 1.88 ± 1.07 | 0.021 |
| Alpha-LV | 0.040 ± 0.017 | 0.040 ± 0.016 | 0.042 ± 0.019 | 0.353 |
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