Abstract
Serum sodium is an established prognostic marker in heart failure (HF) patients and is associated with an increased risk of morbidity and mortality. We sought to study the prognostic value of serum sodium in left ventricular assist device (LVAD) patients and whether hyponatremia reflects worsening HF or an alternative mechanism. We identified HF patients that underwent LVAD implantation between 2008 and 2019. Hyponatremia was defined as Na ≤134 mEq/L at 3 months after implantation. We assessed for differences in hyponatremia before and after LVAD implantation. We also evaluated the association of hyponatremia with all-cause mortality and recurrent HF hospitalizations. There were 342 eligible LVAD patients with a sodium value at 3 months. Among them, there was a significant improvement in serum sodium after LVAD implantation compared to preoperatively (137.2 vs. 134.7 mEq/L, P < 0.0001). Patients with and without hyponatremia had no significant differences in echocardiographic and hemodynamic measurements. In a multivariate analysis, hyponatremia was associated with a markedly increased risk of all-cause mortality (HR 3.69, 95% CI, 1.93–7.05, P < 0.001) when accounting for age, gender, co-morbidities, use of loop diuretics, and B-type natriuretic peptide levels. Hyponatremia was also significantly associated with recurrent HF hospitalizations (HR 2.11, 95% CI, 1.02–4.37, P = 0.04). Hyponatremia in LVAD patients is associated with significantly higher risk of all-cause mortality and recurrent HF hospitalizations. Hyponatremia may be a marker of ongoing neurohormonal activation that is more sensitive than other lab values, echocardiography parameters, and hemodynamic measurements.
Introduction
Advanced heart failure (HF) patients have an estimated mortality greater than 50% at 1 year and hyponatremia is among the most consistent and powerful predictors of worse survival.1,2 Continuous-flow left ventricular assist devices (LVAD) have become an established therapy for advanced HF with over 20,000 implants worldwide since 2008 with studies of LVAD therapy consistently demonstrating improvements in morbidity and mortality.3–7
Hyponatremia is defined as serum sodium (Na) ≤134 mEq/L. Hyponatremia is present in about 10–20% of chronic HF patients and has increased frequency during admission for decompensated heart failure.8–10 Lower serum sodium is a poor prognostic marker in HF patients, being associated with increased in-hospital mortality, long-term mortality, and HF hospitalizations.10–14
Left ventricular assist device patients have clinical characteristics that are different than advanced HF patients not treated with mechanical support.15,16 Notable differences include improvements in functional status, hemodynamic and neurohormonal profiles, and end-organ function in LVAD supported patients.17–19 Consequently, the prevalence and clinical relevance of hyponatremia in LVAD patients may be markedly different from HF patients. In this study, we sought to determine the epidemiology, associated clinical characteristics, and prognostic value of hyponatremia in LVAD patients.
Methods
Study Population
We identified patients that underwent durable, continuous flow LVAD implantation between May 9, 2008, and March 31, 2019, at our institution via query of the Northwestern Mechanical Circulatory Support (MCS) database. To minimize confounding by perioperative factors and to better address the long-term consequences of hyponatremia in LVADs, we studied only patients that survived to 3 months on continued LVAD support with a measured serum sodium value at that time. Exclusion criteria included patients that had repeat LVAD implantation (i.e. pump exchange) or who were implanted at age <18 years old.
Data Collection and Definitions
The Northwestern University Institutional Review Board approved the conduct of this study. Clinical data, including patient demographics, medications, clinical characteristics, laboratory values, and outcomes, were abstracted from the Northwestern MCS database within Northwestern University’s Research Electronic Data Capture (REDCap) repository. The Northwestern MCS database was retrospectively populated until January 2016 and prospectively populated from this time onward.
Study groups were defined by the presence of hyponatremia (serum Na ≤ 134 mEq/L) or absence of hyponatremia (serum Na ≥ 135 mEq/L) at 3 months postimplant. Serum sodium was also evaluated as a continuous variable. Comparisons were made between sodium values preoperatively and at 3-months after LVAD implantation. Furthermore, a multivariate analysis assessed significant preoperative predictors of hyponatremia after LVAD implantation.
In the baseline characteristics, right ventricular (RV) failure during implant hospitalization was defined as need for inotrope >14 days postimplant, nitric oxide >48 hours postimplant, or need for right ventricular assist device (RVAD). We also evaluated transthoracic echocardiogram and right heart catheterization measurements at 3 months postimplant when available. Pulmonary artery pulsatility index was defined as (pulmonary artery systolic pressure-pulmonary artery diastolic pressure)/right atrial pressure.
Outcomes
The primary outcome was time to all-cause mortality. Secondary outcomes included frequency of recurrent all-cause and HF hospitalizations. Additional secondary outcomes included stroke, all-cause bleeding, gastrointestinal bleeding, drive-line infection, and pump thrombosis. All-cause hospitalization, HF hospitalization, all-cause bleeding, and gastrointestinal bleeding events were adjudicated based on documentation from the treating clinical team in the electronic health record. A stroke was defined as a new acute neurologic deficit with corresponding imaging abnormality and included both ischemic and hemorrhagic strokes. Driveline infection was defined by microbiological culture data with organisms affecting skin or tissue surrounding driveline and requiring antimicrobial therapy.
Statistical Analysis
Continuous variables were compared using Student’s two-sample t-test or paired t-test. Categorical variables were compared using χ2 test. Univariate Cox regression analyses were done to compare groups. Baseline characteristics that were significantly different between groups and additional prespecified covariates (age, gender, B-type natriuretic peptide, estimated glomerular filtration rate) based on theoretical likelihood of being significantly associated with exposure and the outcome were included in adjusted Cox regression analyses. In addition, Kaplan-Meier survival analysis with log rank test was used. A competing risks analysis using the cumulative incidence function as described by Fine and Gray was used to account for the possible competing outcomes in LVAD patients: all-cause death or heart transplantation.20 Additionally, a recurrent event analysis as described by Andersen and Gill was used to assess the association between recurrent all-cause and HF hospitalizations.21
All analyses were done using SAS Enterprise Guide version 7.1 (SAS Institute, Cary, North Carolina). Two-sided p-values <0.05 were considered statistically significant for analyses.
Results
Patient Characteristics
A total of 342 patients underwent continuous-flow LVAD implantation at our institution between May 2008 and March 2019, remained on LVAD support, and had a sodium value measured at 3 months postimplant. The mean 3-month Na value was 137.2 ± 2.2 mEq/L. There were 55 patients (16%) with hyponatremia (Na ≤ 134 mEq/L) and 287 patients (84%) without hyponatremia (Na ≥ 135 mEq/L). Median follow-up time was 10 months.
The baseline characteristics of each group are shown in Table 1. The groups were significantly different in terms of etiology of cardiomyopathy, body-mass index, presence of diabetes mellitus, peripheral vascular disease (PVD), chronic obstructive lung disease (COPD), LVAD strategy (bridge-to-transplant versus destination therapy), and use of loop diuretics at 3 months postimplant. There were no significant differences between groups in LVAD type (HeartMate II, HeartMate III, or Heartware HVAD), RV failure during implant hospitalization, or lab values other than sodium.
Table 1.
Baseline Characteristics
| Variable | Entire Cohort (n = 342) | Na ≤ 134 mEq/L (n = 55) | Na ≥ 135 mEq/L (n = 287) | p-value |
|---|---|---|---|---|
|
| ||||
| Age (years) | 57.0 (46.0, 66.0) | 58.0 (43.0, 68.0) | 57.0 (46.0, 65.0) | 0.51 |
| Gender: Male | 267 (78%) | 47 (85%) | 220 (77%) | 0.15 |
| Race: White | 186 (54%) | 30 (55%) | 156 (54%) | 0.98 |
| Etiology: NICM | 210 (61%) | 29 (53%) | 181 (63%) | 0.15 |
| Body mass index (kg/m2) | 27.4 (23.2, 31.7) | 28.7 (23.6, 32.9) | 27.0 (22.9, 31.4) | 0.12 |
| Diabetes mellitus | 117 (34%) | 28 (51%) | 89 (31%) | 0.004 |
| Hypertension | 177 (52%) | 32 (58%) | 145 (51%) | 0.30 |
| Dyslipidemia | 172 (50%) | 30 (55%) | 142 (49%) | 0.49 |
| Chronic kidney disease | 135 (39%) | 24 (44%) | 111 (39%) | 0.49 |
| Peripheral vascular disease | 22 (7%) | 7 (13%) | 15 (6%) | 0.05 |
| Chronic obstructive lung disease | 61 (18%) | 15 (27%) | 46 (16%) | 0.05 |
| Prior stroke | 38 (11%) | 7 (13%) | 31 (11%) | 0.68 |
| LVAD strategy | 0.04 | |||
| Bridge-to-transplant | 180 (53%) | 22 (40%) | 158 (55%) | |
| Destination therapy | 162 (47%) | 33 (60%) | 129 (45%) | |
| LVAD type | 0.83 | |||
| Heartmate II | 125 (37%) | 20 (36%) | 105 (37%) | |
| Heartmate III | 32 (9%) | 4 (7%) | 28 (10%) | |
| Heartware HVAD | 185 (54%) | 31 (56%) | 154 (54%) | |
| RV failure during implant hospitalization | 31 (9%) | 5 (9%) | 26 (9%) | 0.99 |
| Medications | ||||
| Loop diuretic | 213 (62%) | 43 (80%) | 170 (59%) | 0.005 |
| Thiazide diuretic | 12 (4%) | 3 (6%) | 9 (3%) | 0.38 |
| Beta-blocker | 150 (44%) | 18 (33%) | 132 (46%) | 0.09 |
| ACE inhibitor or Angiotensin receptor blocker | 164 (48%) | 25 (46%) | 139 (48%) | 0.77 |
| Mineralocorticoid receptor antagonist | 178 (52%) | 33 (61%) | 145 (51%) | 0.15 |
| Lab values at 3 months postimplant | ||||
| Sodium (mEq/L) | 137 (136, 139) | 133 (131, 134) | 138 (136, 140) | <0.001 |
| B-type natriuretic peptide (pg/mL) | 257 (152, 441) | 224.5 (133, 421.5) | 277.5 (161, 444) | 0.40 |
| Creatinine (mg/dL) | 1.1 (0.9, 1.4) | 1.1 (0.9, 1.4) | 1.1 (0.9, 1.4) | 0.60 |
| Estimated GFR (mL/min) | 86.5 (64.6, 106.6) | 81.1 (62.1, 103.8) | 87.9 (64.9, 106.7) | 0.30 |
| BUN/Creatinine ratio | 16.4 (13.5, 21.3) | 17.5 (13.9, 22.0) | 16.4 (13.5, 21.0) | 0.18 |
| Albumin (g/dL) | 3.7 (3.3, 4.1) | 3.6 (3.2, 4.0) | 3.7 (3.3, 4.1) | 0.26 |
Baseline characteristics of entire cohort and groups based on presence and absence of hyponatremia. Numbers are represented as n (%) or median (interquartile range).
ACE, angiotensin-converting enzyme; BUN, blood urea nitrogen; GFR, glomerular filtration rate; LVAD, left ventricular assist device; NICM, nonischemic cardiomyopathy.
Comparison of Preimplant and 3-month Sodium Values
Mean serum sodium values significantly improved from preimplant to 3 months after LVAD implantation (134.7 ± 4.5 vs. 137.2 ± 3.3 mEq/L, P < 0.0001). Hyponatremia was present in 156 (46%) of patients before LVAD implantation compared to 55 (16%) of patients at 3 months after surgery.
There was no significant difference in the proportion of patients with hyponatremia at 3 months based on the presence of hyponatremia before LVAD implantation (Table 2). Of the 156 patients with hyponatremia preoperatively, 31 (20%) patients had hyponatremia at 3 months and 125 (80%) patients did not. Similarly, of the 186 patients without hyponatremia preoperatively, 24 (13%) patients had hyponatremia at 3 months and 162 (87%) patients did not. In other words, having hyponatremia preoperatively was not significantly associated with hyponatremia at 3 months postimplant.
Table 2.
Comparison of hyponatremia preoperatively and 3 months post-LVAD implantation
| Sodium at 3 months post-VAD | |||
|---|---|---|---|
|
| |||
| Na ≤ 134 mEq/L (n = 55) | Na ≥ 135 mEq/L (n = 287) | ||
| Preoperative sodium | Na ≤ 134 mEq/L (n = 156) | 31 | 125 |
| Na ≥ 135 mEq/L (n = 186) | 24 | 162 | |
Hyponatremia was more common in patients before left ventricular assist device (LVAD) implantation compared to 3-months postimplant. However, having hyponatremia preimplant was not significantly associated with hyponatremia at 3 months postimplant (P = 0.081).
Preoperative Predictors of Hyponatremia After LVAD Implantation
In a multivariate analysis to identify preoperative predictors of hyponatremia at 3 months after LVAD implantation, preoperative sodium value (HR 0.88, 95% CI 0.81–0.95, P = 0.001) and diabetes mellitus (HR 2.36, 95% CI, 1.11–5.02, P = 0.03) were significantly associated (Table 3).
Table 3.
Preoperative predictors of hyponatremia after LVAD implantation
| Variable | Hazard Ratio | 95% CI | p-value |
|---|---|---|---|
|
| |||
| Age at implant (per year) | 1.01 | 0.98–1.05 | 0.43 |
| Gender male | 1.82 | 0.65–5.08 | 0.25 |
| Race (vs. white) | |||
| Black | 1.00 | 0.38–2.59 | 0.99 |
| Other/unknown | 1.42 | 0.59–3.42 | 0.43 |
| Preoperative body-mass index | 1.04 | 0.98–1.10 | 0.23 |
| Etiology ischemic heart disease (vs. NICM) | 1.16 | 0.52–2.62 | 0.72 |
| Diabetes mellitus | 2.36 | 1.11–5.02 | 0.03 |
| Hypertension | 1.07 | 0.51–2.23 | 0.86 |
| Chronic obstructive lung disease | 2.07 | 0.88–4.83 | 0.09 |
| Peripheral vascular disease | 1.68 | 0.49–5.77 | 0.41 |
| INTERMACS class (vs. 1) | |||
| 2 | 0.73 | 0.29–1.86 | 0.51 |
| 3 | 0.73 | 0.24–2.22 | 0.58 |
| ≥4 | 0.19 | 0.02–1.84 | 0.15 |
| Preoperative sodium value | 0.88 | 0.81–0.95 | 0.001 |
| Preoperative BNP (per 100 pg/mL) | 1.01 | 0.98–1.05 | 0.51 |
| Preoperative estimated GFR | 1.01 | 1.00–1.03 | 0.14 |
Multivariate Cox regression model demonstrated diabetes mellitus and preoperative sodium values were significantly associated with hyponatremia after LVAD implantation after adjusting for co-variates shown.
BNP, B-type natriuretic peptide; GFR, glomerular filtration rate; LVAD, left ventricular assist device; NICM, nonischemic cardiomyopathy.
Evaluation of Echocardiogram and Right Heart Catheterization Data
In patients with and without hyponatremia at 3 months after LVAD implantation, there were no significant differences in echocardiographic parameters including chamber size, function, and valvular disease (Table 4). Similarly, right heart catheterization hemodynamic measurements including ventricular filling pressures, pulmonary artery pressures, cardiac output, right atrial pressure/pulmonary capillary wedge ratio, and pulmonary artery pulsatility index were not significantly different between groups (Table 5).
Table 4.
Echocardiogram measurements
| Variable | Na ≤ 134 mEq/L (n = 40) | Na ≥ 135 mEq/L (n = 218) | p-value |
|---|---|---|---|
|
| |||
| LV end-diastolic diameter (cm) | 5.8 ± 1.2 | 5.9 ± 1.3 | 0.90 |
| LV end-diastolic diameter index (cm/m2) | 2.9 ± 0.6 | 2.9 ± 0.6 | 0.90 |
| RV dilated (Y/N) | 28 (70%) | 137 (63%) | 0.67 |
| RV dilatation severity | 0.89 | ||
| Mild | 7 (25%) | 41 (30%) | |
| Mild-moderate | 0 (0%) | 3 (2%) | |
| Moderate | 11 (39%) | 42 (31%) | |
| Moderate-severe | 1 (4%) | 3 (2%) | |
| Severe | 4 (14%) | 18 (13%) | |
| Indeterminate | 5 (18%) | 30 (22%) | |
| RV systolic function reduced (Y/N) | 32 (80%) | 162 (74%) | 0.70 |
| RV dysfunction severity | 0.77 | ||
| Mild | 8 (25%) | 53 (33%) | |
| Mild-moderate | 1 (3%) | 1 (1%) | |
| Moderate | 12 (38%) | 50 (31%) | |
| Moderate-severe | 2 (6%) | 10 (6%) | |
| Severe | 6 (19%) | 32 (20%) | |
| Indeterminate | 3 (9%) | 16 (10%) | |
| LA volume (mL) | 79.6 ± 38.3 | 84.0 ± 37.4 | 0.57 |
| LA volume index (mL/m2) | 39.7 ± 16.4 | 42.2 ± 18.2 | 0.50 |
| RA dilated (Y/N) | 17 (43%) | 90 (41%) | 0.41 |
| Mitral regurgitation (at least moderate) | 3 (8%) | 20 (9%) | 0.90 |
| Aortic regurgitation (at least moderate) | 1 (3%) | 4 (2%) | 0.52 |
| Tricuspid regurgitation (at least moderate) | 5 (13%) | 19 (9%) | 0.84 |
| Tricuspid regurgitant peak velocity (m/s) | 2.2 ± 0.8 | 2.2 ± 0.8 | 0.97 |
Transthoracic echocardiogram measurements when available at 3 months after implant in LVAD patients with and without hyponatremia. There are no significant differences between groups. LA, left atrium; LV, left ventricular; RV, right ventricle; RA, right atrium.
Table 5.
Right heart catheterization measurements
| Variable | Na ≤ 134 mEq/L (n = 26) | Na ≥ 135 mEq/L (n = 153) | p-value |
|---|---|---|---|
|
| |||
| RA pressure (mm Hg) | 10.2 ± 5.7 | 9.5 ± 4.9 | 0.52 |
| RV systolic pressure (mm Hg) | 36.5 ± 13.4 | 36.0 ± 11.2 | 0.83 |
| PA systolic pressure (mm Hg) | 37.5 ± 14.1 | 35.8 ± 11.2 | 0.51 |
| PA diastolic pressure (mm Hg) | 16.7 ± 7.6 | 16.8 ± 7.0 | 0.96 |
| PA mean pressure (mm Hg) | 24.9 ± 8.9 | 24.8 ± 8.1 | 0.95 |
| PCWP (mm Hg) | 14.5 ± 6.4 | 14.5 ± 6.7 | 0.99 |
| PA oxygen saturation (%) | 62.3 ± 10.0 | 65.4 ± 7.3 | 0.07 |
| Thermodilution cardiac index (L/m/m2) | 2.7 ± 0.6 | 2.6 ± 0.7 | 0.51 |
| RA pressure/PCWP | 0.7 ± 0.2 | 0.7 ± 0.2 | 0.66 |
| Pulmonary artery pulsatility index | 3.0 ± 3.1 | 3.0 ± 3.1 | 0.98 |
Right heart catheterization measurements when available at 3 months after implant in LVAD patients with and without hyponatremia. There are no significant differences between groups. Pulmonary artery pulsatility index = (pulmonary artery systolic pressure – pulmonary artery diastolic pressure)/right atrial pressure.
PA, pulmonary artery; PCWP, pulmonary capillary wedge pressure; RA, right atrial; RV, right ventricular.
Hyponatremia and All-Cause Mortality
In this cohort, 67 (20%) deaths occurred. There were 20 (36%) deaths in the hyponatremia group and 47 (16%) deaths in patients without hyponatremia. In an unadjusted Cox regression model, LVAD patients with hyponatremia had a significantly shorter time to all-cause mortality compared to those without hyponatremia (Figure 1A). Furthermore, when adjusting for competing risks, LVAD patients with hyponatremia had a significantly increased cumulative incidence of mortality compared to patients without hyponatremia (Figure 1B). In a multivariate analysis accounting for baseline differences between groups, LVAD patients with hyponatremia remained at markedly increased risk of mortality (HR 3.69, 95% CI, 1.93–7.05, P < 0.001) when accounting for age, gender, co-morbidities, use of loop diuretics, and BNP values (Table 6).
Figure 1.
Left ventricular assist device patients with hyponatremia (Na ≤ 134 mEq/L) at 3 months had significantly increased risk of time to all-cause mortality compared with patients without hyponatremia in (A) a Kaplan-Meier survival analysis and (B) an analysis accounting for competing risks of death, heart transplantation, and continued LVAD support.
Table 6.
Multivariate Cox regression model for all-cause mortality
| Variable | Hazard Ratio | 95% CI | p-value |
|---|---|---|---|
|
| |||
| Hyponatremia (Na ≤ 134 mEq/L) | 3.69 | 1.93–7.05 | <0.001 |
| B-type natriuretic peptide (per 100 pg/mL) | 1.08 | 1.02–1.14 | 0.006 |
| Age at implant (per year) | 1.04 | 1.00–1.08 | 0.04 |
| Gender male | 1.31 | 0.44–3.89 | 0.63 |
| LVAD indication (bridge-to-transplant) | 0.83 | 0.35–1.96 | 0.67 |
| Loop diuretic use | 0.48 | 0.24–0.96 | 0.04 |
| Preoperative body-mass index | 0.96 | 0.91–1.02 | 0.15 |
| Diabetes mellitus | 0.88 | 0.48–1.61 | 0.68 |
| Chronic obstructive lung disease | 0.67 | 0.33–1.38 | 0.28 |
| Peripheral vascular disease | 3.35 | 1.39–8.08 | 0.007 |
| Estimated GFR | 1.00 | 0.99–1.02 | 0.65 |
Multivariate Cox regression model adjusting for covariates shown demonstrated hyponatremia was significantly associated with all-cause mortality.
GFR, glomerular filtration rate; LVAD, left ventricular assist device.
In evaluating serum sodium at 3 months as a continuous variable, a univariate analysis demonstrated higher sodium values had a significantly lesser association with mortality (HR 0.90, 95% CI, 0.84–0.97, P = 0.005). A multivariate analysis indicated that higher sodium values remained significantly less associated with mortality when accounting for other relevant co-variates (HR 0.89, 95% CI, 0.82–0.96, P = 0.004) (Table 7).
Table 7.
Multivariate regression model for all-cause mortality
| Variable | Hazard ratio | 95% CI | p-value |
|---|---|---|---|
|
| |||
| Sodium (per 1 mEq/L) | 0.89 | 0.82–0.96 | 0.004 |
| B-type natriuretic peptide (per 100 pg/mL) | 1.08 | 1.02–1.14 | 0.009 |
| Age at implant (per year) | 1.04 | 1.00–1.08 | 0.03 |
| Gender male | 1.45 | 0.49–4.32 | 0.50 |
| LVAD indication (bridge-to-transplant) | 0.71 | 0.31–1.62 | 0.41 |
| Loop diuretic use | 0.62 | 0.31–1.23 | 0.17 |
| Preoperative body-mass index | 0.97 | 0.91–1.02 | 0.23 |
| Diabetes mellitus | 0.89 | 049–1.63 | 0.71 |
| Chronic obstructive lung disease | 0.64 | 0.31–1.33 | 0.23 |
| Peripheral vascular disease | 3.50 | 1.46–8.38 | 0.005 |
| Estimated GFR | 1.01 | 0.99–1.02 | 0.44 |
Multivariate Cox regression model adjusting for covariates shown demonstrated lower serum sodium was significantly associated with all-cause mortality.
GFR, glomerular filtration rate; LVAD, left ventricular assist device.
Hyponatremia and Secondary Outcomes
Hyponatremia was significantly associated with frequency of HF hospitalizations considered as a recurrent event (HR 2.11, 95% CI, 1.02–4.37, P = 0.04). However, hyponatremia was not significantly associated with recurrent all-cause hospitalizations (HR 1.18, 95% CI, 0.81–1.73, P = 0.39).
Patients with hyponatremia did not have a significantly different incidence of other adverse events when compared with patients without hyponatremia including stroke (11% vs. 9%, P = 0.72), any bleeding (13% vs. 14%, P = 0.81), GI bleeding (13% vs. 11%, P = 0.19), LVAD thrombosis (4% vs. 4%, P = 0.94), or driveline infection (7% vs. 5%, P = 0.39).
Discussion
In this single-center study of LVAD patients who remain on mechanical circulatory support at 3 months postimplant, our findings demonstrate that: (1) hyponatremia (defined as serum Na ≤ 134 mmol/L) improves with LVAD therapy though remains prevalent after LVAD implantation, (2) hyponatremia is associated with increased risk of all-cause mortality, and (3) hyponatremia is associated with recurrent HF hospitalizations.
Up to 50% of advanced HF patients undergoing LVAD implantation reportedly have hyponatremia, which is consistent with the findings in our study.22,23 In our cohort, 16% of LVAD patients had hyponatremia at 3 months after implant. Interestingly, the patients with hyponatremia preoperatively were not significantly more likely to have hyponatremia 3 months after LVAD implantation. Thus, although hyponatremia often improves after LVAD implantation, the condition remains present or newly develops in a subset of LVAD patients.
The importance of hyponatremia in LVAD patients is underscored by our study’s findings that LVAD patients with hyponatremia at 3 months postimplant had markedly increased risk of all-cause mortality with a hazard ratio of 3.69 (95% CI 1.93–7.05) when accounting for age, co-morbidities, certain laboratory values, and use of loop diuretics. Similarly, a lower serum sodium level evaluated continuously was significantly associated with a higher risk of all-cause mortality. A competing risks analysis that accounted for the possibility of heart transplantation in addition to death also demonstrated hyponatremia was associated with all-cause mortality. Moreover, LVAD patients with hyponatremia were twice as likely to have recurrent HF hospitalizations compared to patients without hyponatremia.
Randomized controlled trials have consistently demonstrated the prognostic value of serum sodium in chronic HF patients.8,14 For example, in the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbation of Chronic Heart Failure (OPTIMECHF) study, admission hyponatremia was associated with increased HF hospitalizations and 60-day mortality.12 Likewise, the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV) study showed admission hyponatremia was associated with 60-day mortality.24 In addition, multiple, large observational cohort studies have shown the association between hyponatremia and mortality in HF patients, including incorporation into prognostic models.8,14 The Heart Failure Survival Score (HFSS) and UK-HEART models validated lower serum sodium being associated with 1- and 5-year mortality respectively in outpatients with chronic HF.25,26 A prior study in LVAD patients showed hyponatremia 1 month after device implantation was not significantly associated with all-cause mortality.27 At that time point, LVAD patients may still be affected by operative factors and be undergoing adjustments of pump parameters and medical management. These factors may be less relevant 3 months after LVAD implantation when hyponatremia is significantly associated with mortality as demonstrated in the current study.
Mechanistically, hyponatremia in HF is typically dilutional in etiology and occurs in the setting of impairments in effective circulating volume and increased neurohormonal activation.8,14,28–30 Other factors including the use of diuretic therapy, particularly thiazide-like diuretics may also contribute to hyponatremia in HF via alternate mechanisms.8 Regardless, the underlying mechanisms of neurohormonal upregulation and/or need for sequential nephron blockade in HF patients reflect the basis for use of serum sodium as a marker of more progressive disease.
In our analysis, diabetes mellitus was a significant predictor of hyponatremia after LVAD implantation. Diabetes mellitus has been associated with an increased risk of adverse clinical outcomes including morality in LVAD patients.31–33 Thus, the presence of diabetes mellitus and postimplant hyponatremia may identify a common cohort of LVAD patients at higher risk of adverse outcomes. However, diabetes mellitus mechanistically contributes to HF via several mechanisms including increased neurohormonal activation, which may partly account for the association with hyponatremia in LVAD patients.34
Although many HF patients treated with LVAD therapy have an improvement in hemodynamic and neurohormonal profiles that translate to improvements in sodium levels, we show in this study that a subset of patients exhibits persistent hyponatremia and new-onset hyponatremia.1,15,19 These patients are at markedly higher risk of all-cause mortality and recurrent HF hospitalizations, suggesting lower serum sodium may be reflective of ongoing neurohormonal activation. Similarly, a previous study in LVAD patients also suggested hyponatremia after device implantation is significantly associated with HF hospitalizations.27 Moreover, patients with hyponatremia are more likely to be on loop diuretics, which could also be consistent with signs and symptoms of heart failure in the setting of ongoing neurohormonal activation. Interestingly, LVAD patients with hyponatremia did not have increased natriuretic peptide levels, more RV dysfunction at baseline, or significant differences in echocardiographic or hemodynamic measurements 3 months after implant. Thus, decreased serum sodium may be a particularly sensitive marker of ongoing neurohormonal activation in LVAD patients who are at risk for adverse clinical outcomes and which other conventional testing may not reliably identify.
Furthermore, hyponatremia may identify patients with a relatively higher comorbidity (e.g., diabetes mellitus, COPD, PVD) burden that may also contribute to an increased risk of mortality.32,35 Although treatment with an LVAD reliably improves the clinical HF syndrome, LVAD patients may experience residual HF, potentially related to mechanisms of inadequate LV unloading, late right ventricular dysfunction, or less commonly pump malfunction.7,36–39 Other LVAD-related adverse events, which are largely unrelated to neurohormonal activation, were not associated with hyponatremia. Future investigation should further evaluate risk factors and mechanisms of hyponatremia in LVAD patients. These further investigations with larger sample sizes can also elucidate differences in patients with persistent hyponatremia versus new-onset hyponatremia after LVAD implantation.
The current study has potential limitations. First, this was a single-center, observational study with a limited sample size that could have affected the ability to detect significant differences in baseline characteristics and secondary outcomes. Confounding may have been present from unmeasured covariates. Larger, multi-center studies are warranted to validate the results of this study. Also, although the association between hyponatremia and recurrent HF hospitalizations supports the likelihood that neurohormonal activation is indeed the main driving mechanism, we did not directly measure circulating neurohormonal levels. It thus remains plausible that overlapping drivers of hyponatremia could be present to account for its association with significantly increased mortality. Finally, our study was limited to LVAD patients that were alive on continued mechanical circulatory support at 3 months, thereby excluding patients that died, underwent heart transplantation, or had device explant before this.
Conclusions
In this study, we show that in LVAD patients, hyponatremia at 3 months is significantly associated with all-cause mortality and recurrent HF hospitalizations. These findings suggest that hyponatremia in LVAD patients may be a marker of ongoing neurohormonal activation associated with adverse clinical outcomes that were not otherwise attributable to differences in other lab values, echocardiographic parameters, and hemodynamic measurements. Further investigation in larger populations are warranted to provide additional insights into the clinical relevance and mechanisms of this finding. Subsequent studies can evaluate whether more aggressive treatment with neurohormonal blockade or adjustment to LVAD parameters may improve outcomes in these patients.
Footnotes
Disclosure: K.G. is on Speakers Bureau for Abbott. J.E.W. is a Consultant for Amgen, Boehringer Ingelheim, and Scientific Advisory Board Member for Cytokinetics; E.E.V. is on Speakers Bureau for Abiomed. F.A. is a Consultant for Amgen. A.S.A. is a Consultant for Edwards Lifesciences and Pfizer. D.T.P. is a Consultant for Abbott, Medtronic, and Abiomed. J.D.R. is a Consultant for Abbott and Medtronic. For the remaining authors, there are no conflicts of interest.
References
- 1.Pinney SP, Anyanwu AC, Lala A, Teuteberg JJ, Uriel N, Mehra MR: Left ventricular assist devices for lifelong support. J Am Coll Cardiol 69: 2845–2861, 2017. [DOI] [PubMed] [Google Scholar]
- 2.Lee WH, Packer M: Prognostic importance of serum sodium concentration and its modification by converting-enzyme inhibition in patients with severe chronic heart failure. Circulation 73: 257–267, 1986. [DOI] [PubMed] [Google Scholar]
- 3.Slaughter MS, Rogers JG, Milano CA, et al. ; HeartMate II Investigators: Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 361: 2241– 2251, 2009. [DOI] [PubMed] [Google Scholar]
- 4.Miller LW, Pagani FD, Russell SD, et al. ; HeartMate II Clinical Investigators: Use of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med 357: 885–896, 2007. [DOI] [PubMed] [Google Scholar]
- 5.Yancy CW, Jessup M, Bozkurt B, et al. : 2013 ACCF/AHA guideline for the management of heart failure: Executive summary: A report of the American College of Cardiology Foundation/ American Heart Association Task Force on practice guidelines. Circulation 128: 1810–1852, 2013. [DOI] [PubMed] [Google Scholar]
- 6.Kirklin JK, Cantor R, Mohacsi P, et al. : First Annual IMACS Report: A global International Society for Heart and Lung Transplantation Registry for Mechanical Circulatory Support. J Heart Lung Transplant 35: 407–412, 2016. [DOI] [PubMed] [Google Scholar]
- 7.Kirklin JK, Pagani FD, Kormos RL, et al. : Eighth annual INTERMACS report: Special focus on framing the impact of adverse events. J Heart Lung Transplant 36: 1080–1086, 2017. [DOI] [PubMed] [Google Scholar]
- 8.Verbrugge FH, Steels P, Grieten L, Nijst P, Tang WH, Mullens W: Hyponatremia in acute decompensated heart failure: Depletion versus dilution. J Am Coll Cardiol 65: 480–492, 2015. [DOI] [PubMed] [Google Scholar]
- 9.Omar HR, Charnigo R, Guglin M: Prognostic significance of discharge hyponatremia in Heart Failure patients with normal admission sodium (from the ESCAPE Trial). Am J Cardiol 120: 607–615, 2017. [DOI] [PubMed] [Google Scholar]
- 10.Bettari L, Fiuzat M, Shaw LK, et al. : Hyponatremia and long-term outcomes in chronic heart failure–an observational study from the Duke Databank for Cardiovascular Diseases. J Card Fail 18: 74–81, 2012. [DOI] [PubMed] [Google Scholar]
- 11.Tepper D, Harris S, Ip R. Characterization and prognostic value of persistent hyponatremia in patients with severe heart failure in the ESCAPE trial. Congest Hear Fail 14: 46, 2008. [Google Scholar]
- 12.Klein L, O’Connor CM, Leimberger JD, et al. ; OPTIME-CHF Investigators: Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure: Results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study. Circulation 111: 2454–2460, 2005. [DOI] [PubMed] [Google Scholar]
- 13.De Luca L, Klein L, Udelson JE, et al. : Hyponatremia in patients with heart failure. Am J Cardiol 96(12A):19L–23L, 2005. [DOI] [PubMed] [Google Scholar]
- 14.Bettari L, Fiuzat M, Felker GM, O’Connor CM: Significance of hyponatremia in heart failure. Heart Fail Rev 17: 17–26, 2012. [DOI] [PubMed] [Google Scholar]
- 15.Brouwers C, de Jonge N, Caliskan K, et al. : Predictors of changes in health status between and within patients 12 months post left ventricular assist device implantation. Eur J Heart Fail 16: 566–573, 2014. [DOI] [PubMed] [Google Scholar]
- 16.Estep JD, Starling RC, Horstmanshof DA, et al. ; ROADMAP Study Investigators: Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients: Results from the ROADMAP study. J Am Coll Cardiol 66: 1747–1761, 2015. [DOI] [PubMed] [Google Scholar]
- 17.Russell SD, Rogers JG, Milano CA, et al. ; HeartMate II Clinical Investigators: Renal and hepatic function improve in advanced heart failure patients during continuous-flow support with the HeartMate II left ventricular assist device. Circulation 120: 2352–2357, 2009. [DOI] [PubMed] [Google Scholar]
- 18.Mehra MR, Goldstein DJ, Uriel N, et al. ; MOMENTUM 3 Investigators: Two-year outcomes with a magnetically levitated cardiac pump in heart failure. N Engl J Med 378: 1386–1395, 2018. [DOI] [PubMed] [Google Scholar]
- 19.James KB, McCarthy PM, Thomas JD, et al. : Effect of the implantable left ventricular assist device on neuroendocrine activation in heart failure. Circulation 92(suppl 9): II191–II195, 1995. [DOI] [PubMed] [Google Scholar]
- 20.Fine JP, Gray RJ: A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 94:496–509, 1999. [Google Scholar]
- 21.Andersen PK, Gill RD: Cox’s regression model for counting processes: A large sample study. Ann Stat 10: 1100–1120, 1982. [Google Scholar]
- 22.Mehra MR, Naka Y, Uriel N, et al. ; MOMENTUM 3 Investigators: A fully magnetically levitated circulatory pump for advanced heart failure. N Engl J Med 376: 440–450, 2017. [DOI] [PubMed] [Google Scholar]
- 23.Rogers JG, Pagani FD, Tatooles AJ, et al. : Intrapericardial left ventricular assist device for advanced heart failure. N Engl J Med 376: 451–460, 2017. [DOI] [PubMed] [Google Scholar]
- 24.Gheorghiade M, Gattis WA, O’Connor CM, et al. ; Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF) Investigators: Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: A randomized controlled trial. JAMA 291: 1963–1971, 2004. [DOI] [PubMed] [Google Scholar]
- 25.Aaronson KD, Schwartz JS, Chen TM, Wong KL, Goin JE, Mancini DM: Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 95: 2660–2667, 1997. [DOI] [PubMed] [Google Scholar]
- 26.Kearney MT, Nolan J, Lee AJ, et al. : A prognostic index to predict long-term mortality in patients with mild to moderate chronic heart failure stabilised on angiotensin converting enzyme inhibitors. Eur J Heart Fail 5: 489–497, 2003. [DOI] [PubMed] [Google Scholar]
- 27.Kanelidis AJ, Imamura T, Yang B, et al. : The clinical importance of hyponatremia in patients with left ventricular assist devices. ASAIO J 67: 1012–1017, 2021. [DOI] [PubMed] [Google Scholar]
- 28.Schrier RW, Abraham WT: Hormones and hemodynamics in heart failure. N Engl J Med 341: 577–585, 1999. [DOI] [PubMed] [Google Scholar]
- 29.Bankir L: Antidiuretic action of vasopressin: Quantitative aspects and interaction between V1a and V2 receptor-mediated effects. Cardiovasc Res 51: 372–390, 2001. [DOI] [PubMed] [Google Scholar]
- 30.Dzau VJ, Packer M, Lilly LS, Swartz SL, Hollenberg NK, Williams GH: Prostaglandins in severe congestive heart failure. Relation to activation of the renin–angiotensin system and hyponatremia. N Engl J Med 310: 347–352, 1984. [DOI] [PubMed] [Google Scholar]
- 31.Usoh CO, Sherazi S, Szepietowska B, et al. : Influence of diabetes on outcomes in patients after left ventricular assist device implantation. Ann Thorac Surg 106: 555–560, 2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Asleh R, Briasoulis A, Schettle SD, et al. : Impact of diabetes mellitus on outcomes in patients supported with left ventricular assist devices. Circ Hear Fail 10: e004213, 2017. [DOI] [PubMed] [Google Scholar]
- 33.Lateef N, Usman MS, Colombo PC, et al. : Meta-analysis comparing risk for adverse outcomes after left ventricular assist device implantation in patients with versus without diabetes mellitus. Am J Cardiol 124: 1918–1923, 2019. [DOI] [PubMed] [Google Scholar]
- 34.Dunlay SM, Givertz MM, Aguilar D, et al. ; American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; and the Heart Failure Society of America: Type 2 Diabetes Mellitus and Heart Failure: A Scientific Statement From the American Heart Association and the Heart Failure Society of America: This statement does not represent an update of the 2017 ACC/AHA/HFSA heart failure guideline update. Circulation 140: e294–e324, 2019. [DOI] [PubMed] [Google Scholar]
- 35.Ullah W, Sattar Y, Darmoch F, et al. : The impact of peripheral arterial disease on patients with mechanical circulatory support. Int J Cardiol Hear Vasc 28: 100509, 2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Stulak JM, Davis ME, Haglund N, et al. : Adverse events in contemporary continuous-flow left ventricular assist devices: A multi-institutional comparison shows significant differences. J Thorac Cardiovasc Surg 151: 177–189, 2016. [DOI] [PubMed] [Google Scholar]
- 37.Rich JD, Gosev I, Patel CB, et al. ; Evolving Mechanical Support Research Group (EMERG) Investigators: The incidence, risk factors, and outcomes associated with late right-sided heart failure in patients supported with an axial-flow left ventricular assist device. J Heart Lung Transplant 36: 50–58, 2017. [DOI] [PubMed] [Google Scholar]
- 38.Ali HR, Kiernan MS, Choudhary G, et al. : Right ventricular failure post-implantation of left ventricular assist device: Prevalence, pathophysiology, and predictors. ASAIO J 66: 610–619, 2020. [DOI] [PubMed] [Google Scholar]
- 39.Kapelios CJ, Charitos C, Kaldara E, et al. : Late-onset right ventricular dysfunction after mechanical support by a continuous-flow left ventricular assist device. J Heart Lung Transplant 34: 1604–1610, 2015. [DOI] [PubMed] [Google Scholar]