Abstract
Iron insufficiency has been associated with heart failure, but the impact of a reduction of hemoglobin content in the erythrocytes as estimated by mean corpuscular hemoglobin concentration (MCHC) to myocardial structure, performance and long-term clinical outcomes has not been well-established. We examined hematologic data and long-term outcomes of 197 ambulatory patients with chronic systolic and symptomatic heart failure who underwent comprehensive echocardiographic evaluation. We observed that relative hypochromia (defined as low MCHC) was associated with higher natriuretic peptide levels (NT-proBNP, r= −0.40, p<0.0001) and lower estimated glomerular filtration rate (eGFR; r=0.45, p<0.0001), and correlated modestly with indices of left and right ventricular diastolic dysfunction (all p<0.05), but were not related to left ventricular ejection fraction (LVEF, r= 0.17, p=0.079). After 5 years of follow-up, lower MCHC levels were associated with higher risk of death, transplant, or heart failure hospitalization after adjusting for age, LVEF, eGFR and New York Heart Association class (Hazard ratio 1.34, 95% confidence interval 1.04–1.72, p=0.025), particularly in those with above-median hemoglobin (>13.8 g/dL; Hazard ratio: 2.02, 95% confidence interval 1.44–2.81, p<0.0001). Taken together, our observations imply physicians should take notice of the presence of relative hypochromia particularly in the absence of anemia in the setting of chronic systolic heart failure.
Keywords: Congestive heart failure, Hypochromia, Echocardiography, Prognosis
Anemia is prevalent in heart failure, and the presence of anemia may contribute to functional impairment and poor long-term prognosis1. While the majority of cases were attributed to anemia of chronic disease2, iron deficiency remains one of the most treatable yet under-appreciated conditions. Recently, large series of patients have identified a substantial subset of both anemic and non-anemic patients with heart failure having functional iron deficiency (defined by ferritin and transferrin saturation levels)3, 4, and the presence of functional iron deficiency also portends poor prognosis4, 5. Furthermore, intravenous iron supplementation has been associated with improvement in functional capacity, cardiac function, and reduction in adverse outcomes6. These findings have generated substantial interest in targeting functional iron deficiency as therapy for advanced heart failure7.
It is interesting to note that the majority of patients have their mean corpuscular volumes within the normal range (normocytic)2. Two commonly available indices in the complete blood count are closely related to overall assessment of iron deficiency in patients without inherited hemoglobinopathies. Mean corpuscular hemoglobin concentration (MCHC) is the relative amount of hemoglobin content in erythrocytes, and has served as one of several hematologic indices related to iron stores8, 9. Recent studies have suggested MCHC to be a reliable surrogate of attenuated functional iron status4. Low MCHC therefore represents a gross estimate of the presence of relative hypochromia. In evaluating patients undergoing dialysis with iron repletion, MCHC provides relatively robust prediction of response8. Another marker, red cell distribution width (RDW), has been studied extensively in the heart failure population as one of the strongest predictors of adverse outcomes10, 11. Representing the degree of variation in erythrocyte sizes, RDW is also closely associated with iron deficiency12 and impaired iron mobilization10. Both values are routinely reported in standard complete blood count reports, and their relationships to myocardial structure, performance and long-term clinical outcomes have not been established in patients with chronic systolic heart failure regardless of anemia status.
METHODS
The Assessment of Doppler Echocardiography Prognosis and Therapy study is a single-center, prospective cohort study of patients with chronic systolic heart failure (>6 months duration, left ventricular ejection fraction ≤35%, New York Heart Association class II–IV) that has been previously described13. In this analysis, we identified complete blood count measurements within 90 days of echocardiography in 197 patients enrolled in the study. These subjects were followed for up to 5 years to identify the primary end-points of time to first death, transplant, or heart failure hospitalization. We excluded patients with a history of active gastrointestinal bleeding during this period or other active hematologic disorders. Estimated glomerular filtration rate (eGFR) was calculated based on serum creatinine levels using the standard 4-variable Modification of Diet in Renal Disease equation. Measurements of aminoterminal proB-type natriuretic peptide (NT-proBNP) and cystatin C14, myeloperoxidase15, and high-sensitivity C-reactive protein16 have been described previously.
After informed consent, comprehensive transthoracic echocardiography was performed using commercially available HDI 5000 (Phillips Medical Systems, N.A., Bothell, Washington) or Acuson Sequoia (Siemens Medical Solutions USA Inc., Malvern, Pennsylvania) machines by research sonographer as previously described13. Left ventricular ejection fraction was measured using the modified Simpson’s method. Pulse wave Doppler of mitral inflow at the tip of the mitral leaflets was used to calculate E wave velocity, A wave velocity and A wave duration, and the ratio E/A was calculated. Pulse wave Doppler of the pulmonary vein flow was used to measure the peak systolic velocity (S wave), peak diastolic velocity (D wave) and the S/D ratio was calculated. The isovolumetric relaxation was determined as the difference between the aortic valve closing click and the onset of diastolic mitral flow measured by Doppler. Tissue Doppler imaging of the mitral annulus in the septal and lateral positions was used to measure E′, A′ and S wave, and the E/E′ ratio was calculated using the lateral annulus as previously described13.
Complete blood count with differential analysis was performed at the Cleveland Clinic Reference Laboratory utilizing a Sysmex XE-2100 automated hematology analyzer and leukocyte differential counter (Sysmex America, Inc., Mundelein IL). Anemia was defined as hemoglobin <12g/dL for men and <11g/dL for women. Indices of anemia included red blood cell count, hemoglobin, hematocrit, MCHC (ratio of Hgb to Hct), and RDW. There is not a formal definition of hypochromia in the absence of anemia and the normal range of MCHC is 32–36 g/dL, hence in this study “relative hypochromia” is quantified by MCHC considered as a continuous variable. The normal range of RDW is 12–16%.
Continuous variables were summarized as mean ± standard deviation if normally distributed, and as median and interquartile range if non-normally distributed. Normality was assessed by the Shapiro-Wilk W test. Categorical variables were summarized as proportions and frequencies. Spearman’s rank correlation method was used as a nonparametric measure of association for correlations between MCHC, RDW, and clinical and echocardiographic indices. The Wilcoxon rank-sum or Kruskal-Wallis tests were used to compare differences in MCHC across categorical variables. The Cox proportional hazards model was used to assess the clinical risk associated with increasing continuous standardized increments of natural logarithm-transformed MCHC. The optimal receiver operating characteristic (ROC) curve cutoff value for prediction of adverse clinical events was chosen as the value maximizing sensitivity plus specificity for MCHC. The proportional hazards assumption was verified with log(time) vs. log[−log(survival)] plots. Kaplan-Meier survival plots were calculated from baseline to time of all-cause mortality, cardiac transplantation or heart failure hospitalization. All p-values reported are from two-sided tests and a p-value <0.05 was considered statistically significant. Statistical analyses were performed using JMP 9.0 (SAS Institute, Cary, NC).
RESULTS
Table 1 illustrates the baseline characteristics of the study cohort, which was typical of a cohort of patients with chronic systolic heart failure (mean left ventricular ejection fraction 25 ± 6%, median NT-proBNP = 1,341 pg/ml). In our study cohort, 62 (32%) had chronic kidney disease Stage 3 or higher, and the large majority were non-anemic. With anemia defined as Hb <12 g/dL for males and <11 for females, 174 subjects or 88% were non-anemic (mean Hb of 13.8±1.8 g/dL and a mean Hct of 41±4.9%).
Table 1.
Baseline Subject Characteristics (n=197).
| Variable | Value |
|---|---|
| Demographics: | |
| Age (years) | 57 ± 13 |
| Male gender, n (%) | 151 (77%) |
| Body mass index (kg/m2) | 28 ± 6 |
| African American, n (%) | 36 (18%) |
| Caucasian, n (%) | 160 (81%) |
| Heart failure history: | |
| Ischemic etiology, n (%) | 81 (41%) |
| New York Heart Association class III/IV, n (%) | 85 (43%) |
| Co-morbidities: | |
| Hypertension, n (%) | 103 (53%) |
| Diabetes mellitus, n (%) | 45 (23%) |
| Hyperlipidemia, n (%) | 102 (55%) |
| Chronic Kidney Disease Stage ≥3, n (%) | 62 (32%) |
| Echocardiographic indices: | |
| Left ventricular mass index (g/m2) | 157 ± 48 |
| Left ventricular end-diastolic volume, indexed (mL/m2) | 114 ± 39 |
| Left ventricular ejection fraction (%) | 25 ± 6 |
| Diastolic stage III, n (%) | 63 (34%) |
| Medications: | |
| Angiotensin converting enzyme inhibitor and/or angiotensin receptor blocker, n (%) | 182 (94%) |
| Beta-blockers, n (%) | 110 (56%) |
| Spironolactone, n (%) | 51 (27%) |
| Loop diuretics, n (%) | 159 (82%) |
| Digoxin, n (%) | 123 (66%) |
| Laboratory data: | |
| Estimated glomerular filtration rate (mL/min/1.73m2) | 72 ± 26 |
| Serum creatinine (mg/dL) | 1.3 ± 0.9 |
| Cystatin C (ng/mL) | 1.22 [1.01, 1.63] |
| Blood urea nitrogen (mg/dL) | 25 ± 14 |
| High-sensitivity C-reactive protein (ng/mL) | 3.40 [1.55, 7.32] |
| Aminoterminal pro-B-type natriuretic peptide (pg/mL) | 1341 [449, 3431] |
| Hemoglobin (g/dL) | 13.8 ± 1.8 |
| Hematocrit (%) | 41.0 ± 4.9 |
| Mean corpuscular hemoglobin concentration (g/dL) | 33.6 ± 1.2 |
| Red cell distribution width (%) | 14.7 + 2.1 |
Table 2 illustrates the relationship between red cell indices with clinical and laboratory data. MCHC was inversely correlated with RDW (r= −0.57, p<0.0001). Lower MCHC and higher RDW were associated with lower hemoglobin levels and more impaired renal function. Both MCHC and RDW correlated with NT-proBNP and high-sensitivity C-reactive protein but not with myeloperoxidase.
Table 2.
Univariate correlations between mean corpuscular hemoglobin concentration (MCHC, g/dL) and red cell distribution width (%) and clinical indices.
| MCHC (g/dL) | Red cell distribution width (%) | |||
|---|---|---|---|---|
| Variable | Spearman’s r | p-value | Spearman’s r | p-value |
| Demographics: | ||||
| Age (years) | −0.12 | 0.087 | 0.12 | 0.103 |
| Mean arterial pressure (mmHg) | 0.03 | 0.759 | −0.08 | 0.307 |
| Body mass index (kg/m2) | 0.03 | 0.684 | 0.01 | 0.922 |
| Laboratory data: | ||||
| Estimated glomerular filtration rate (mL/min/1.73m2) | 0.35 | <0.0001 | −0.46 | <0.0001 |
| Cystatin C (mg/L) | −0.52 | <0.0001 | 0.51 | <0.0001 |
| NT-proBNP (pg/mL) | −0.39 | <0.0001 | 0.50 | <0.0001 |
| High-sensitivity C-reactive protein (mg/L) | −0.36 | <0.001 | 0.42 | <0.0001 |
| Myeloperoxidase (pM) | −0.06 | 0.503 | 0.10 | 0.280 |
Table 3 illustrates the relation between MCHC and RDW and echocardiographic indices. Both MCHC and RDW had a modest relation to left ventricular ejection fraction (MCHC: r=0.20, p=0.006; RDW: r=−0.29, p<0.0001), but did not correlate with any measures of left ventricular structure. Lower MCHC and higher RDW were correlated with indices of more severe left ventricular diastolic dysfunction (Table 3). Higher RDW (but not MCHC) was modestly associated with more severe right ventricular systolic dysfunction. However, both measures were related to estimated right-sided pressures but only modestly to right ventricular diastolic indices (Table 3).
Table 3.
Univariate correlations between mean corpuscular hemoglobin concentration (MCHC) and red cell distribution width (RDW) and echocardiographic indices.
| MCHC (g/dL) | RDW (%) | |||
|---|---|---|---|---|
| Variable | Spearman’s r | p-value | Spearman’s r | p-value |
| Echocardiographic indices: | ||||
| Left ventricular Structure: | ||||
| LV mass index (g/m2) | −0.01 | 0.865 | 0.15 | 0.041 |
| LV end-systolic dimension (cm) | −0.02 | 0.773 | 0.11 | 0.135 |
| LV end-systolic volume, indexed (mL/m2) | −0.05 | 0.513 | 0.12 | 0.126 |
| LV end-diastolic dimension (cm) | 0.04 | 0.598 | 0.05 | 0.517 |
| LV end-diastolic volume, indexed (mL/m2) | −0.02 | 0.773 | 0.06 | 0.402 |
| Left Ventricular Systolic Function: | ||||
| LV ejection fraction (%) | 0.20 | 0.006 | −0.29 | <0.0001 |
| Left Ventricular Diastolic Function: | ||||
| Mitral E wave | −0.33 | <0.0001 | 0.36 | <0.0001 |
| Mitral deceleration time (ms) | 0.28 | <0.001 | −0.36 | <0.0001 |
| Pulmonary vein S/D ratio | 0.26 | <0.001 | −0.39 | <0.0001 |
| Mitral E/Ea ratio | −0.37 | <0.0001 | 0.32 | <0.0001 |
| Left atrial volume index (mL/m2) | −0.22 | 0.008 | 0.44 | <0.0001 |
| RV Systolic Function: | ||||
| RV systolic wave (cm/s) | 0.08 | 0.280 | −0.22 | 0.004 |
| Right Tei index | −0.07 | 0.443 | 0.22 | 0.017 |
| RV Diastolic Function: | ||||
| Tricuspid E wave | −0.10 | 0.195 | 0.12 | 0.124 |
| Tricuspid deceleration time (ms) | 0.15 | 0.066 | −0.12 | 0.162 |
| Hepatic vein S/D ratio | 0.23 | 0.010 | −0.24 | 0.005 |
| Tricuspid E/Ea ratio | −0.12 | 0.125 | 0.14 | 0.063 |
| RA volume index (mL/m2) | −0.22 | 0.005 | 0.30 | <0.001 |
| Estimated Right-sided Pressures: | ||||
| Tricuspid regurgitation area (cm2) | −0.32 | <0.0001 | 0.43 | <0.0001 |
| Tricuspid regurgitation jet velocity (cm/s) | −0.25 | <0.001 | 0.34 | <0.0001 |
| RV systolic pressure (mmHg) | −0.26 | 0.001 | 0.35 | <0.0001 |
There were a total of 79 events (all-cause mortality, cardiac transplantation or heart failure hospitalization) in our study cohort over the course of 5-year follow-up. Both lower MCHC (Hazard ratio 1.57, 95% confidence interval 1.26 – 1.95, p<0.0001) and higher RDW (Hazard ratio 1.57, 95% confidence interval 1.30 – 1.87, p<0.0001) were associated with an increased risk of all-cause mortality, cardiac transplantation or heart failure hospitalization at 5 years (Figure 1A and 1B). Following adjustment for age, left ventricular ejection fraction, eGFR and New York Heart Association class, both MCHC and RDW remained a significant predictor of adverse outcomes at 5 years (Table 4). MCHC remained a significant predictor of adverse clinical outcomes following adjustment with RDW (Hazard ratio 1.32, 95% confidence interval 1.02 – 1.69, p=0.033) and other clinical parameters (Figure 2). The prognostic value of MCHC was stronger in, and largely confined to, patients with hemoglobin above median level of 13.8 mg/dL (Hazard ratio 2.02, 95% confidence interval: 1.44 – 2.81, p<0.0001; 38 events).
Figure 1.
Kaplan-Meier analysis of 5-year all-cause mortality, cardiac transplantation, or heart failure hospitalization in all subjects stratified according to (A) quartiles of mean corpuscular hemoglobin concentration (MCHC); and (B) quartiles of red cell distribution width (RDW).
Table 4.
Cox proportional hazards analysis of adverse clinical outcomes (5 year death, cardiac transplantation, or heart failure hospitalization) for mean corpuscular hemoglobin concentration (MCHC) and red cell distribution width.
| MCHC (g/dL) * | Red Cell Distribution Width (%) * | |||
|---|---|---|---|---|
| HR (95%CI) | p value | HR (95%CI) | p value | |
| Univariate | 1.57 (1.26–1.95) | <0.0001 | 1.57 (1.30–1.87) | <0.0001 |
| Multivariate ** | 1.34 (1.04–1.72) | 0.025 | 1.34 (1.06–1.67) | 0.017 |
Hazard ratios (HR) per 1 standard deviation (SD) decrement for Ln MCHC (0.036 g/dL) and Ln red cell distribution width (0.133 %-units)
Multivariate adjustments for age (SD=13 years), left ventricular ejection fraction (SD=6 %-units), estimated glomerular filtration rate (SD=26 mL/min/1.73m2), and New York Heart Association functional class
Figure 2.
Five-year adverse event (all-cause mortality, cardiac transplantation or heart failure hospitalization) rate in patients stratified according to optimal cut-off value for mean corpuscular hemoglobin concentration (MCHC, 33.4 g/dL) and red cell distribution width (RDW, 14.1%) levels.
DISCUSSION
Over the past decade, there has been much interest regarding the contribution of anemia and iron deficiency in the disease progression of chronic heart failure1. Often considered a prevalent co-morbid condition associated with chronic inflammation, iron insufficiency (in the presence or absence of overt anemia) has been associated with poorer long-term prognosis1. Recent reports of potential clinical benefit of iron infusion even in patients without overt anemia have raised the possibility that subclinical iron deficiency may be under-appreciated6. Our observation illustrated that in patients with chronic systolic heart failure, the presence of abnormal decrease in the hemoglobin content of the erythrocytes that we referred to as “relative hypochromia” (as reflected by a lower MCHC level) is associated with more advanced left ventricular (and to some degree right ventricular) diastolic dysfunction, higher natriuretic peptide levels, and adverse long-term clinical events. Interestingly, the prognostic value of low MCHC is particularly relevant in those with adequate hemoglobin levels, and abnormal MCHC and RDW values both have additive prognostic significance. These findings are confirmatory to recent reports showing the relationship between relative hypochromia with functional impairment and association with functional iron deficiency in chronic heart failure4, but extend the potential clinical utility of assessing these two otherwise “standard” parameters in hematologic evaluation as part of heart failure risk stratification and therapeutic considerations.
There are multiple contributing factors to relative hypochromia described in the literature. First and foremost, there might be an issue with the availability or incorporation of iron into the hemoglobin within the erythrocyte. Such defects may not be specific to heart failure, but can be present in various hypoxic states such as pulmonary hypertension or sleep apnea. Hypoxia induced factor may also play a role, although difficult to quantify in vivo. The strong association with renal insufficiency (in the form of reduced eGFR, increased cystatin C levels) may also indicate either an insufficiency of or resistance to erythropoietin in the setting of underlying renal dysfunction17 (even though the prognostic value remained significant after adjusting for eGFR). Alternatively, there is a possibility of a dilutional effect, considering the fact that changes in osmotic pressures in the setting of congestion may theoretically affect the relative concentration of hemoglobin within the erythrocyte. That may explain why hypochromia was observed in more advanced diastolic dysfunction and higher natriuretic peptide levels. That being said, red cell volumes and mass are unlikely to change despite reduced overall concentration of erythrocytes in congested states (so-called “pseudo-anemia”), and thus alternative processes that are sensitive to congestion (e.g. erythropoiesis) may be affected.
The strong correlation between MCHC and RDW deserves some discussion. While the precise mechanisms leading to elevated RDW is unclear, the contribution of elevated RDW to poor long-term outcomes has been described in patients with both acute and chronic heart failure. Recently, a high RDW has been associated with more adverse cardiovascular outcomes including death and heart failure admission (Hazard ratio 1.17) (3), and also was found to be a significant predictor of mortality at 1 year in heart failure patients, independent of BNP levels and nutritional status (4). In our study, we confirmed these findings and demonstrated that there is a strong relation between RDW and MCHC levels. Since both measure have long been associated with underling iron deficiency, our findings might be best explained by the compensatory response of erythrocytosis in the setting of anemia or the immaturity of erythrocytes in the setting of insufficient iron stores. The fact that MCHC and RDW are correlated, and yet independently predictive of adverse long-term outcomes, is intriguing, and may suggest that they present at different stages of erythropoietic dysfunction. Meanwhile, the lack of correlation between both indices with myeloperoxidase argued against enhanced oxidative stress as underlying mechanism.
There are several notable limitations in our single-center observational series of stable ambulatory patients despite the availability of extensive clinical, echocardiographic, and long-term outcome analyses. We included all complete blood count obtained within 90 days of study enrollment in order to maximize our sample size, even though the results are consistent when the timing of complete blood count was restricted to measurements within 30 days (n=168), within 1 day (n=128), and even on the same day (n=107) of enrollment. We also did not have blood iron studies to establish the presence of underlying functional iron deficiency, even though patients with known hematologic disorders or gastrointestinal bleeding were excluded. Nevertheless, prior studies have indicated a close correlation between measures of iron deficiency and MCHC (as well as RDW). In many ways, this is an indirect quantification of the degree of hypochromia observed in the erythrocytes rather than a measure of circulating substrates and iron-carrying capacities. Determination of hypochromia was based on spot check of a single complete blood count performed by automated hematology analyzer. Other disease processes that may directly or indirectly impact on MCHC or RDW cannot be excluded. Enrollment of the study occurred prior to the broad adoption of device therapies or recognition that anemia and iron deficiency could be intricately involved in heart failure pathophysiology. Therefore, the overall prognostic value in the contemporary era of pharmacologic and device therapy will require further investigations. Nevertheless, it is conceivable that abnormalities in MCHC may indicate underlying impaired hematopoiesis, and hence may provide identification of potential candidates for a wide range of interventions related to improving iron incorporation into erythrocytes regardless of anemia status.
What are the clinical implications of these findings? There have been growing interests in the potential role of functional iron deficiency in the pathogenesis and disease progression of heart failure, although specific testing of iron status is often required. Ongoing studies are looking at the potential benefits of iron therapy implied that benefits may include both anemic and non-anemic patients. Using a commonly measure of relative hypochromia in standard complete blood count panel like MCHC may identify a subset of patients that may have underlying impairment of iron incorporation into erythrocytes in the setting of chronic systolic heart failure. Like any other marker of organ dysfunction, the ability of MCHC (in combination with other measures like RDW or hemoglobin) to identify underlying dysfunction in hematopoiesis warrants further investigations. Indeed, the route and timing of iron supplementation is the subject of several ongoing clinical trials, and further analyses in these studies will help to unravel the potential for MCHC as an indicator for therapeutic interventions.
CONCLUSION
In patients with chronic systolic heart failure, relative hypochromia (as reflected by low MCHC levels) is modestly associated with left and right ventricular diastolic dysfunction and predicted adverse long-term clinical events, even independent of hemoglobin levels and RDW. Further studies are warranted to evaluate the potential benefit of therapeutic interventions targeting patients with heart failure and relative hypochromia.
Acknowledgments
Funding Sources: The original Assessment of Doppler Echocardiography Prognosis and Therapy (ADEPT) study was supported by the 2003 American Society of Echocardiography Outcomes Research Award, and GlaxoSmithKline Pharmaceuticals.
Footnotes
DISCLOSURES
Dr Tang has served as consultant for Medtronic Inc and St. Jude Medical, and has received grant support from Abbott Laboratories and the NIH. All others have no relationships to disclose.
References
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