Abstract
Background
Anemia caused by left ventricular outflow tract obstruction in patients with hypertrophic obstructive cardiomyopathy (HOCM) has been reported, however, large clinical studies confirming this association are lacking. The objective of the present study was to investigate the relationship between left ventricular outflow tract (LVOT) pressure gradient and hemoglobin in patients with hypertrophic cardiomyopathy (HCM).
Methods
Patient demographics, laboratory and echocardiography data from 310 patients diagnosed with HCM from our hospital who had undergone echocardiography from July 2014 to March 2019 were collected from medical records. Patients were classified into HOCM and non-HOCM groups.
Results
Compared to the non-HOCM group, patients in the HOCM group had a lower hemoglobin level (112.2 ± 16.7 vs. 132.9 ± 22.2 g/L, p < 0.001). In addition, significant negative correlations between hemoglobin and LVOT pressure gradient were found in males (r = -0.568, p < 0.001) and females (r = -0.589, p < 0.001). Receiver operating characteristic curve analysis revealed that the best cut-off value for hemoglobin to predict HOCM in male patients was 128 g/L with 74.19% sensitivity and 75.51% specificity (area under the curve: 0.763, p < 0.001). For female patients, the cut-off value was 125 g/L, with a sensitivity and specificity of 89.39% and 48.48%, respectively (area under the curve: 0.718, p < 0.001).
Conclusions
Our results indicate that hemoglobin level is inversely proportional to the LVOT gradient pressure and has value for predicting outflow tract obstruction in patients with HCM.
Keywords: Bernoulli equation, Continuity equation, Dynamic obstruction, Hemolytic anemia, Left ventricular outflow tract pressure gradient
INTRODUCTION
Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased left ventricular wall thickness that cannot solely be explained by abnormal loading conditions.1 It is not a rare condition and with the development of echocardiographic and genetic diagnoses, a much higher prevalence of HCM has been revealed. The minimal prevalence of HCM gene carriers is estimated to be 1 in 200 people or greater,2 2.5-fold more common than reported in the original Coronary Artery Risk Development in Young Adults (CARDIA) study.3
Medical treatment for HCM depends on whether there is left ventricular outflow tract obstruction (LVOTO). Arterial and venous dilators, including nitrate and phosphodiesterase type 5 inhibitors, and inotropic drugs (such as digoxin) should be used with caution in patients with hypertrophic obstructive cardiomyopathy (HOCM) to avoid exacerbating outflow obstruction.1 Therefore, when HCM is suspected, it is important to identify the presence or absence of LVOTO since it is crucial to guide treatment. Echocardiography is most often used to diagnose HOCM, but it is often inconvenient and time-consuming. Most hospitals require that patients wait 3-5 days for an echocardiographic examination, with the longest wait reaching 1-2 weeks; moreover, some hospitals do not have the capability to perform echocardiography.
Anemia caused by LVOTO in patients with HOCM has previously been reported.4-8 However, no large clinical studies have confirmed the relationship between the two conditions. Therefore, in this study we investigated the relationship between LVOT pressure gradient and hemoglobin level in patients with HCM and sought to determine whether hemoglobin level has predictive value for HOCM.
METHODS
Study participants
This cross-sectional study enrolled 310 patients diagnosed with HCM from the Jiading District Central Hospital who had undergone echocardiography from July 2014 to March 2019.
Diagnostic criteria
The diagnostic criteria were based on the detection of a maximum left ventricular wall thickness ≥ 15 mm by echocardiography, in the absence of other accountable cardiac or systemic diseases.1 HOCM was defined as an instantaneous peak Doppler LVOT gradient ≥ 30 mmHg at rest.1 All interrogations were acquired using a standardized clinical protocol inclusive of continuous-wave Doppler interrogation of LVOT flow from the apical long-axis view. Measurements of left ven-tricular wall thickness were performed at end-diastole, in the short-axis view. Resting LVOT peak velocity was measured using continuous-wave Doppler echocardiography, and the LVOT pressure gradient was estimated using a simplified Bernoulli equation. Left ventricular ejection fraction (LVEF) was measured using a modified biplanar Simpson’s method. The degree of mitral regurgitation (MR) was evaluated by effective regurgitant orifice area (EROA). Mild MR was defined as an EROA < 20 mm2; moderate as an EROA between 20-39 mm2; and severe as an EROA ≥ 40 mm2.9 Complete blood count and biochemical blood work were performed within 24 hours of admission.
World Health Organization hemoglobin thresholds were used to classify anemia in individuals living at sea level: pregnant women, 100 g/L; non-pregnant women, 120 g/L; and men, 130 g/L.10 Echocardiography and laboratory studies were retrieved from digital archives, collected by independent observers. The exclusion criteria included congenital heart disease, valvular heart disease, connective tissue disease, infective endocarditis or other infection, the presence of tumors, and anemia due to the other causes such as preexisting anemia, chronic renal dysfunction, iron deficiency, vitamin B12 and folate deficiency.
Statistical analysis
SPSS version 24.0 (IBM Co., Armonk, New York), STATA/SE version 15.0 (StataCorp, College Station, Texas), and MedCalc version 15.8 (MedCalc Software, Mariakerke, Belgium) were used for statistical analysis. Clinical variables were expressed as a percentage (%) for categorical variables and mean ± standard deviation (SD) for normally distributed continuous variables, or, in cases of skewed distribution, median with interquartile range. To compare continuous variables, the unpaired two-tailed t-test or Mann-Whitney U-test was used, to compare categorical variables, the chi-square test or Fisher’s exact test (as appropriate) was used. Correlations between numerical variables were assessed using Pearson’s correlation analysis or Spearman’s test. Receiver operating characteristic (ROC) curves were plotted to examine the sensitivity and specificity of hemoglobin levels to detect HOCM. Areas under the curves (AUCs) and optimal cut-off values were calculated, and an AUC value > 0.65 was considered to be a reasonable model for prediction. Multivariate linear regression analysis was used to assess the association between hemoglobin level and LVOT pressure gradient. A p-value of < 0.05 was considered to be statistically significant.
This study was approved by the local institutional review board and conducted in accordance with the Declaration of Helsinki.
RESULTS
Patient characteristics
A total of 310 patients with HCM were enrolled, of whom 97 had HOCM. The HOCM patient group had a lower percentage of males and a higher percentage of MR compared to those without HOCM (Table 1). The mean age, lactate dehydrogenase level, LVOT pressure gradient, and left atrial dimension (LAD) were all higher in the patients with HOCM. Conversely, the hemoglobin level was lower in the patients with HOCM. There were no significant differences between the groups in hypertension, blood pressure, heart rate, diabetes mellitus, atrial fibrillation, syncope, creatinine, brain natriuretic peptide, high-sensitivity cardiac troponin T, fasting blood glucose, interventricular septal thickness, posterior wall thickness, LVEF, or concomitant medications (Table 1).
Table 1. Baseline characteristics of the hypertrophic cardiomyopathy patients with and without left ventricular outflow tract obstruction.
| Characteristic | HOCM | p value | |
| Yes (n = 97) | No (n = 213) | ||
| Age (years) | 66 ± 13 | 62 ± 14 | 0.041 |
| Male | 31 (32.0%) | 147 (69.0%) | < 0.001 |
| Hypertension | 46 (47.4%) | 94 (44.1%) | 0.589 |
| SBP (mmHg) | 129 ± 20 | 133 ± 22 | 0.129 |
| DBP (mmHg) | 76 ± 13 | 75 ± 12 | 0.632 |
| Heart rate (beats/min) | 84 ± 17 | 81 ± 17 | 0.116 |
| Diabetes mellitus | 16 (16.5%) | 49 (23.0%) | 0.192 |
| Atrial fibrillation | 24 (24.7%) | 61 (28.6%) | 0.476 |
| Syncope | 8 (8.2%) | 17 (8.0) | 0.936 |
| Hemoglobin (g/L) | 112.2 ± 16.7 | 132.9 ± 22.2 | < 0.001 |
| LDH (U/L) | 258 (211/299) | 220 (193/259) | 0.001 |
| Creatinine (umol/l) | 76.2 ± 21.6 | 79.8 ± 20.0 | 0.161 |
| BNP (pg/ML) | 666 (239/1208) | 472 (168/1091) | 0.143 |
| Hs-ctnt (ug/L) | 0.08 (0.02/0.21) | 0.05 (0.02/0.23) | 0.508 |
| FBG (mmol/L) | 5.0 (4.4/6.2) | 5.1 (4.6/6.2) | 0.532 |
| Echocardiography | |||
| LVOT pressure gradient (mmHg) | 65.0 (45.0/82.0) | 22.0 (12.6/24.0) | < 0.001 |
| IVST (mm) | 19.8 ± 3.4 | 20.3 ± 3.6 | 0.257 |
| LAD (mm) | 48.1 ± 7.2 | 46.1 ± 6.6 | 0.014 |
| PWT (mm) | 11.6 ± 1.8 | 11.3 ± 1.8 | 0.17 |
| LVEF (%) | 65.8 ± 5.5 | 64.2 ± 9.8 | 0.07 |
| Mitral regurgitation | 90 (92.8%) | 122 (57.3%) | < 0.001 |
| Mild | 35 (36.1%) | 122 (57.3%) | 0.002 |
| Moderate | 35 (36.1%) | 0 (0.0%) | < 0.001 |
| Severe | 20 (20.6%) | 0 (0.0%) | < 0.001 |
| Concomitant medications | |||
| ACEI or ARB | 23 (23.7%) | 35 (16.4%) | 0.128 |
| DHP-CCB | 21 (21.6%) | 38 (17.8%) | 0.428 |
| NDHP-CCB | 7 (7.2%) | 7 (3.3%) | 0.143 |
| β-blockers | 33 (34.0%) | 62 (29.1%) | 0.384 |
| Diuretics | 18 (18.6%) | 29 (13.6%) | 0.261 |
| Nitrates | 5 (5.2%) | 7 (3.3%) | 0.526 |
Data presented are the number (percentage) of patients for categorical variables, mean values ± standard deviation for continuous variables, or, in case of skew distribution, median values (1st/3rd quartile).
ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blocker; BNP, B-type natriuretic peptide; DBP, diastolic blood pressure; DHP-CCB, dihydropyridine calcium channel blocker; FBG, fasting blood glucose; HOCM, hypertrophic obstructive cardiomyopathy; Hs-ctnt, high-sensitivity troponin; IVST, inter-ventricular septal thickness; LAD, left atrial dimension; LDH, lactate dehydrogenase; LVEF, left ventricular ejection fraction; LVOT, left ventricular outflow tract; NDHP-CCB, non-dihydropyridine calcium channel blocker; PWT, posterior wall thickness; SBP, systolic blood pressure.
Male and female results grouped by anemia status
To explore correlations between hemoglobin and other factors in males and females, we divided the patients into anemia and non-anemia groups by sex [male (n = 178); female (n = 132)]. The proportion of male patients in this study population was higher than that of female patients (57.4% vs. 42.6%). In both male and female patients, the mean age and heart rate were higher in the anemia group, however the mean age was not significantly different between the two groups for females (Table 2). The blood pressure was lower in the anemia group for male patients, but there were no significant differences between the two groups for females. The hemoglobin level in the anemia group was significantly lower than that in the non-anemia group, while the LVOT pressure gradient was significantly higher than that in the non-anemia group for both male and female patients. There were no statistically significant differences in the remaining related factors between the two groups both for male and female patients (Table 2). The hemoglobin level in the male patients was significantly higher than that in the female patients (135 ± 22 vs. 115 ± 18 g/L; p < 0.001). Figure 1 shows that the patients with HOCM had lower hemoglobin levels in both male and female groups. Figure 2A shows significant negative correlations between hemoglobin and LVOT pressure gradient in the male patients (r = -0.568, p < 0.001) and female patients (r = -0.589, p < 0.001). To further explore the relationship between LVOT pressure gradient and age, sex, MR, hemoglobin, and other parameters in the study population, multivariate linear regression analysis was performed. The regression model had statistical significance (p < 0.001, R2 = 0.527) and the effects of the variables included in the LVOT pressure gradient model, age, hemoglobin, and MR were statistically significant. However, the other parameters were not statistically significant (Table 3).
Table 2. Baseline characteristics of the hypertrophic cardiomyopathy patients with and without anemia.
| Characteristic | Male | Female | ||||
| Anemia (n = 64) | Non-anemia (n = 114) | p value | Anemia (n = 81) | Non-anemia (n = 51) | p value | |
| Age (years) | 65 ± 14 | 59 ± 14 | 0.006 | 68 ± 12 | 64 ± 13 | 0.062 |
| Hypertension | 24 (37.5%) | 49 (43.0%) | 0.48 | 43 (53.1%) | 24 (47.1%) | 0.50 |
| SBP (mmHg) | 127 ± 21 | 135 ± 20 | 0.012 | 129 ± 25 | 132 ± 20 | 0.398 |
| DBP (mmHg) | 72 ± 13 | 78 ± 12 | 0.001 | 74 ± 14 | 74 ± 10 | 0.903 |
| Heart rate (beats/min) | 89 ± 20 | 76 ± 15 | < 0.001 | 86 ± 16 | 77 ± 17 | 0.002 |
| Diabetes mellitus | 14 (21.9%) | 24 (21.1%) | 0.90 | 16 (19.8%) | 11 (21.6%) | 0.80 |
| Atrial fibrillation | 15 (23.4%) | 34 (29.8%) | 0.36 | 22 (27.2%) | 14 (27.5%) | 0.97 |
| Creatinine (umol/l) | 83.6 ± 21.3 | 84.3 ± 17.3 | 0.80 | 73.3 ± 22.5 | 68.4 ± 15.7 | 0.19 |
| FBG (mmol/L) | 5.2 ± 1.6 | 5.7 ± 2.1 | 0.18 | 6.3 ± 2.6 | 5.7 ± 1.6 | 0.16 |
| Hemoglobin (g/L) | 110.9 ± 13.3 | 148.5 ± 12.9 | < 0.001 | 104.0 ± 12.6 | 132.5 ± 9.2 | < 0.001 |
| MCV (fL) | 90.8 ± 6.5 | 92.2 ± 4.5 | 0.14 | 90.1 ± 9.4 | 89.6 ± 5.8 | 0.75 |
| MCH (pg) | 30.1 ± 2.4 | 31.0 ± 1.6 | 0.12 | 29.4 ± 3.6 | 29.6 ± 2.6 | 0.64 |
| Serum iron (umol/L) | 23.2 ± 5.4 | 22.3 ± 5.9 | 0.35 | 22.3 ± 5.1 | 21.6 ± 5.7 | 0.49 |
| Ferritin (ug/L) | 197.8 (90.5/271.0) | 166.2 (69.0/233.6) | 0.12 | 191.0 (117.6/247.0) | 207.9 (154.3/275.1) | 0.22 |
| Vitamine B12 (pg/ml) | 556.5 (353.5/737.5) | 562.0 (341.0/740.0) | 0.85 | 543.0 (362.3/728.3) | 612.0 (389.5/747.0) | 0.47 |
| Folate (ng/ml) | 10.9 (6.4/15.8) | 10.7 (6.3/14.7) | 0.78 | 10.0 (7.1/15.2) | 11.6 (6.6/14.7) | 0.53 |
| LVOT pressure gradient (mmHg) | 68.0 (27.0/87.0) | 25.0 (17.5/35.5) | < 0.001 | 61.2 (33.0/76.3) | 37.5 (20.8/52.0) | 0.002 |
DBP, diastolic blood pressure; FBG, fasting blood glucose; LVOT, left ventricular outflow tract; MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume; SBP, systolic blood pressure.
Figure 1.
Comparison of hemoglobin levels between male and female patients with or without hypertrophic obstructive cardiomyopathy (HOCM).
Figure 2.
(A) Association between hemoglobin and left ventricular outflow tract pressure gradient in patients with hypertrophic cardiomyopathy by sex. (B) The red blood cells are destroyed into fragmented red blood cells by mechanical shear forces when blood flow is obstructed in the narrow outflow tract. This figure shows the mechanism of dynamic obstruction of outflow tract in patients with hypertrophic obstructive cardiomyopathy (HOCM).
Table 3. Multivariable linear regression analysis of the LVOT pressure gradient.
| Variables | β | Standard error | Standardized β | 95% CI | p value |
| Age | -0.559 | 0.226 | -0.257 | -1.009 – -1.08 | < 0.001 |
| Hb | -1.308 | 0.170 | -0.788 | -1.646 – -0.969 | < 0.001 |
| MR | 20.96 | 6.870 | 0.247 | 7.289 – 34.630 | 0.003 |
| Syncope | 4.190 | 7.454 | 0.047 | -10.641 – 19.022 | 0.562 |
| Male | 11.835 | 6.909 | 0.180 | -1.913 – 25.583 | 0.901 |
| Hypertension | 2.036 | 5.888 | 0.031 | -9.678 – 13.751 | 0.730 |
| Diabetes | -8.837 | 7.686 | -0.099 | -24.130 – 6.456 | 0.254 |
| HS-ctnt | -0.153 | 1.527 | -0.008 | -3.191 – 2.886 | 0.921 |
| BNP | -0.002 | 0.003 | -0.061 | -0.008 – 0.004 | 0.522 |
| Creatinine | -0.012 | 0.142 | -0.008 | -0.294 – 0.269 | 0.931 |
| IVST | -0.802 | 0.813 | -0.096 | -2.419 – 0.815 | 0.327 |
| PWT | 2.046 | 1.550 | 0.114 | -1.039 – 5.130 | 0.191 |
BNP, B-type natriuretic peptide; CI, confidence interval; Hb, hemoglobin; Hs-ctnt, high-sensitivity troponin; IVST, inter-ventricular septal thickness; LVOT, left ventricular outflow tract; MR, mitral regurgitation; PWT, posterior wall thickness.
Ability of hemoglobin to predict obstruction
ROC curve analysis was used to evaluate the ability of hemoglobin to predict HOCM. The cut-off value of 1/hemoglobin was 0.0078 L/g (hemoglobin = 128 g/L), with a sensitivity and specificity of 1/hemoglobin in predicting HOCM of 74.19% and 75.51%, respectively. The positive predictive value was 36.50%, negative predictive value was 93.04%, and further ROC curve analysis demonstrated an AUC of 0.763 (p < 0.001) for male patients (Figure 3A). For female patients, the cut-off value of 1/hemoglobin was 0.008 L/g (hemoglobin = 125 g/L), with a sensitivity and specificity of 89.39% and 48.48%, respectively. The positive predictive value was 62.5%, negative predictive value was 83.33%, and the AUC was 0.718 (p < 0.001) (Figure 3B).
Figure 3.
The ROC curve of 1/HB (hemoglobin) to predict hypertrophic obstructive cardiomyopathy (HOCM) in male (A) and female (B) patients.
DISCUSSION
Little is known about the association between LVOT gradient pressure and hemoglobin levels in patients with HCM. To the best of our knowledge, this is the first study to explore this association. Our results revealed a significant negative correlation between hemoglobin and LVOT pressure gradient in patients with HCM. We also found that LVOT gradient pressure was useful for assessing the severity of hemolytic anemia (Table 3). Moreover, the cut-off value of hemoglobin to predict HOCM was 128 g/L for males and 125 g/L for females (Figure 3). The hemoglobin level had predictive value for the risk of LVOTO in the patients with HCM. HCM is the most common cause of sudden cardiac death (SCD) and is associated with cardiomyopathy, especially in young athletes. The largest review of SCD in 1866 athletes over 27 years revealed 251 cases (13%) diagnosed with HCM.11 LVOTO is a major hallmark of HCM that is caused by systolic anterior motion of the mitral apparatus towards the hypertrophied septum (Figure 2B). Therefore, LVOTO is dynamic and the severity of obstruction depends mainly on cardiac contractility and loading conditions. LOVTO is defined as an instantaneous peak Doppler LVOT pressure gradient ≥ 30 mmHg at rest, is present in approximately one third of patients with HCM, and constitutes a diagnosis of HOCM. A series of studies have reported a significant association between LVOTO and SCD.12-14 In addition, the presence of dynamic LVOTO is related to symptomatic status, such as chest pain, heart failure, development of atrial fibrillation, embolic complications, and even syncope. Thus, rapid identification of obstruction or non-obstruction forms of HCM is crucial for clinicians because treatment decisions largely depend on the presence or absence of obstruction.
Although echocardiography is the gold standard for the diagnosis of HOCM it is not convenient, and more importantly, is sometimes not reliable because of the dynamic nature of the obstruction. Since the obstruction in HOCM is largely variable from hour to hour, it is possible for the LVOT gradient pressure to appear normal, while a short time later, a moderate to severe obstruction may be detected in a stable patient.15 Therefore, it is clinically imperative to find simple and stable markers to assist echocardiography in the diagnosis of HOCM.
Yosuke reported a patient with HOCM complicated with refractory hemolytic anemia, in whom the anemia was dramatically improved after the outflow obstruction had been relieved.16 Hemolytic anemia results when red blood cells are destroyed by mechanical shear forces when blood flows through the narrow outflow tract in patients with HOCM (Figure 2B). Ding et al. found that human blood may be hemolyzed within 0.04 to1.5 seconds of exposure to a shear stress range of 25 to 320 Pa.17 Therefore, the more severe the outflow obstruction, the more hemoglobin is destroyed. In this study, we used the continuity equation and Bernoulli equation to explain the mechanism of dynamic obstruction of the outflow tract in HOCM. According to the continuity equation, the flow of blood through any of the flow cross-sections in the lumen is equal, as the flow area on either flow cross-section is inversely proportional to the flow rate (S1V1 = S2V2) (Figure 2B). According to the Bernoulli equation, the sum of the kinetic energy, potential energy, and pressure energy per unit volume of fluid is equal to a constant at different sections of the same flow tube (1/2 ρV2 + ρgh + P = Constant). When blood flows through the narrow outflow tract, the flow rate will increase. When the flow rate is increased, the pressure energy will decrease accordingly, thus forming a pressure gradient at the mitral and outflow tract that pulls the leaflets anteriorly to the basal septum, leading to both LVOTO and malcoaptation of the mitral leaflets. Reduced hemoglobin leads to tachycardia and increased ventricular contractility to meet oxygen requirements of the peripheral tissues. However, an increase in heart rate leads to a shortened diastolic phase, and a decrease in the volume of the left ventricle causes the interventricular septum to move closer to the mitral. The increased myocardial contractility increases the rate of blood flow, thus worsening the outflow tract obstruction in patients with HOCM. Therefore, we believe this leads to a vicious cycle of obstruction, anemia, worsened obstruction, worsened anemia, etc. Therefore, the heart rate-lowering therapy may effective. What’s more, the study by Seda et al. showed that an effective HR lowering in patients with heart failure with reduced ejection fraction can lead to improvements in diastolic function.18
In this study, the prevalence of male patients with HCM was higher than that of females (Table 2), which us consistent with a study by Maro et al.19 The reason for this finding remains unclear, however it might reflect bias in echocardiography and hormonal modifiers. However, the proportion of males in the HOCM group was lower than that of females (Table 1), which may be explained by lower baseline hemoglobin levels in females.
Approximately 90% of patients with HOCM have a significant improvement in syncope after the outflow obstruction is relieved.20 However, we found no significant difference in the proportion of syncope between the HOCM and non-HOCM groups (Table 1). This may be because patients with occult obstruction were included in our non-HOCM group; moreover, the relatively small sample size may have influenced this finding.
Our results indicate that the lower the hemoglobin level, the more likely the patient has outflow obstruction with suspected HCM. If electrocardiogram findings show a variable combination of left ventricular hypertrophy, ST- and T-wave abnormalities, and pathological Q-waves), drugs that will aggravate outflow obstruction should be avoided.
The present study has several limitations. First, the number of patients who were included in the non-HOCM group may have included individuals with occult obstruction, and the sample size of patients with HOCM was small. Second, this was a prospective cross-sectional study, and large-scale studies are needed to identify the usefulness of hemoglobin levels in predicting HOCM in patients with suspected HCM.
CONCLUSIONS
Our results indicate that hemoglobin level is inversely proportional to LVOT gradient pressure, and that hemoglobin has a value in predicting whether the outflow tract is obstructed in patients with HCM.
CONFLICT OF INTEREST
All the authors declare no conflict of interest.
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