Abstract
Background
Multiple factors, including hypertension, affect left ventricular remodeling in hemodialysis (HD) patients. Therefore, this retrospective study used left ventricular global longitudinal strain (GLS), an excellent method for detecting mild left ventricular systolic dysfunction, to compare left ventricular systolic function in HD patients with preserved left ventricular ejection fraction (LVEF) and patients with hypertensive left ventricular hypertrophy (HLVH).
Methods
Participants were aged 60 years or older and had an LVEF of 60% or higher. We compared 20 HD patients (HD group) with 20 HLVH patients matched for age and sex (HLVH group) and 20 healthy control individuals (C group). GLS decline was defined as a GLS value greater than the GLS reference value, which was the mean value of + 2×standard deviation in the C group.
Results
LVEF was not significantly different between the 3 groups, but GLS was significantly worse in the HD group (-15.8%±1.4%) than in the C group (-19.3%±1.1%, p < 0.01) and HLVH group (-17.0%±1.4%, p < 0.05). Relative wall thickness (RWT) and left ventricular mass index (LVMI) were significantly higher in the HLVH and HD groups than in the C group (p < 0.01), and hemoglobin (Hb) levels were significantly lower in the HD group than in the C and HLVH groups (p < 0.01). The frequency of GLS decline (i.e., GLS > -17.0%) was significantly higher in the HD group than in the HLVH group (p < 0.01). Multiple regression analysis of the 3 groups showed that increased RWT and LVMI and decreased Hb were significantly associated with GLS decline (p < 0.01).
Conclusions
HD patients with preserved LVEF have a significantly greater decline in GLS than HLVH patients. Increased RWT and LVMI with renal anemia may contribute to GLS decline in HD patients with LVEF.
Clinical trial number
2023-01-02.
Keywords: Two-dimensional speckle tracking, Left ventricular global longitudinal strain, Hemodialysis, Hypertensive left ventricular hypertrophy
Background
Left ventricular ejection fraction (LVEF) is generally calculated from two-dimensional (2D) echocardiography by using the displacement of wall motion in the direction of the left ventricular short axis and is most frequently used as a regulatory index of left ventricular systolic function (systolic dysfunction), although it is affected by the pre- and afterload of the left ventricle [1]. Other measurement approaches on left ventricular systolic function are 2D speckle tracking echocardiography, which is evaluated by the strains of longitudinal, circumferential and short axis directions of left ventricular chamber. More recently, automatic measurement of left ventricular global longitudinal strain (GLS) has become possible, and the reproducibility of its measurement is high. It represents the longitudinal strain of the internal oblique muscle on the endocardial side of the left ventricle. Because strain has been reported to indicate myocardial contractility independent of left ventricular loading [2], it may be a useful index in diseases that cause left ventricular remodeling because of myocardial loading. GLS measurements are more reproducible than LVEF measurements [3]. Furthermore, LVEF has been reported to be less sensitive than GLS in detecting left ventricular systolic dysfunction in heart failure with preserved ejection fraction (HFpEF), hypertensive left ventricular hypertrophy (LVH), and chronic kidney disease (CKD), whereas GLS detects subtle left ventricular systolic dysfunction in these disorders even when LVEF is in the normal range [4–7]. Moreover, unlike LVEF, GLS has been reported to be effective for early detection of left ventricular dysfunction and for predicting HFpEF prognosis [8].
Left ventricular remodeling with left ventricular diastolic disorder occurs because of aging [9–11], and GLS levels, especially in the endocardial layer, tend to worsen in healthy individuals over 60 years of age [12]. Regarding sex differences in GLS, healthy men with a large body surface area (BSA) may exhibit low GLS values [13–16]. Thus, GLS is an important method for early detection of decreased systolic function, but the reference value of GLS varies depending on sex, age, and echocardiography model.
LVH is observed in more than 70% of patients with end-stage renal disease (ESRD) at the introduction of renal replacement therapy [17, 18]. LVH due to end-stage renal failure is synergistically related to renal anemia, CKD-mineral bone disease (CKD-MBD), and hypertension, whereas hypertensive LVH (HLVH) is related only to hypertension [17–19]. Furthermore, ESRD features not only left ventricular pressure overload but also chronic volume overloading on the left ventricle due to fluid retention, which increases left ventricular remodeling, resulting in left ventricular systolic dysfunction. Therefore, we hypothesized that left ventricular remodeling is more frequent in hemodialysis (HD) patients than in HLVH patients and results in lower GLS even if the LVEF is within the normal range.
To clarify this hypothesis, we performed a retrospective observational study to compare GLS in HD patients with an LVEF of at least 60% and patients with HLVH with an LVEF of at least 60% who had no symptoms of heart failure. In addition, we analyzed factors that contribute to GLS decline in these patients. We evaluated GLS by extracting archived echocardiographic image data, and to minimize the impact of age and sex on GLS, we matched HD and HLVH patients according to age and sex. The study aimed to inform the use of GLS in daily clinical practice.
Methods
Participants and study design
From among all eligible patients who underwent echocardiography at our hospital by the end of December 2022 and had an LVEF of at least 60%, we enrolled 20 patients (10 men and 10 women) with HD (HD group) and 20 patients (10 men and 10 women) with HLVH (HLVH group). All patients were aged 60 years or older and retrospectively met the enrollment conditions. Data were extracted from the archived echocardiography image data from regularly performed echocardiography evaluations. To determine the GLS reference value for this study, we also enrolled 20 consecutive control individuals (10 men and 10 women) aged 60 years or older with an LVEF of at least 60% (C group).
The HD group was selected from patients who had undergone HD 3 times a week for 4 h or longer at a time, had no symptoms of heart failure for more than 6 months and had a Kt/V 1.4 or higher, an index of dialysis efficiency, using high-flux HD or hemodiafiltration and controlled renal anemia using intravenous iron and erythropoietin-stimulating agents (ESA); the HLVH group was selected from patients who had taken antihypertensive drugs for more than 1 year, had no symptoms of heart failure, had undergone echocardiography, and had LVH with a left ventricular mass index (LVMI) of greater than 115 g/m2 if male and greater than 95 g/m2 if female; and the C group was selected from individuals with no history of hypertension or diabetes in whom echocardiography had been performed to test cardiac function before surgery or because of electrocardiogram abnormalities, but in whom echocardiography was normal cardiac systolic function and the blood pressure conditions were defined as individuals with systolic blood pressure of less than 140 mmHg and diastolic blood pressure of less than 90 mmHg at the time of echocardiography and not taking antihypertensive drugs. In the HLVH and C groups, the estimated glomerular filtration rate (eGFR) classification of renal function had to be G1 to G3 (eGFR ≥ 30 mL/min/m2). The exclusion criteria were chronic atrial fibrillation, valvular heart disease, and coronary artery disease. GLS was measured with automatic analysis software. The reference value for GLS was defined as the mean value + 2×standard deviation (SD) of the C group, and a GLS decline was defined as a GLS value greater than the reference value.
Echocardiography
In the HD group, echocardiography was performed within 1 day after HD. Left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), and LVEF were calculated by the biplane modified Simpson method by using apical 2-chamber and 4-chamber planes [14]. Relative wall thickness (RWT) was calculated by using wall thickness in the left ventricular morphological index with the equation RWT = (2 × PWth) / LVEDd (where PWth is the posterior wall thickness and LVEDd is left ventricular end-diastolic diameter). LVMI was calculated with the Cube formula method by using the equation LVMI = {0.8 × 1.04 × [(IVSth + LVEDd + PWth)3 - LVEDd3] + 0.6}/BSA (where IVSth is the interventricular septal wall thickness and BSA is body surface area). Wall thickening was assumed to be present if the RWT was greater than 0.42 and the patient had LVH (men > 115 g/m2; women > 95 g/m2) [14, 20]. Left atrial volume index (LAVI) was calculated by the biplane modified Simpson method by using apical 2- and 4-chamber sections. Left atrial volume (LAV) was corrected for BSA [14]. The maximum early velocity of ventricular inflow (E) and maximum atrial systolic velocity of left ventricular inflow (A) were measured, and the ratio of the two was calculated. A sample volume was placed on each valve annulus on the ventricular septal side and the lateral side of the 4-chamber cross section and measured, and the ratio of E to the mean value of the maximum early annular velocity (e’), i.e., E/e’, was calculated. Abnormal findings were defined as E/e’ greater than 14 and LAVI greater than or equal to 35 mL/m2 [21].
Echocardiography indices included LVEF as an index of left ventricular systolic function; E/A, E/e’, and LAVI as indices of left ventricular diastolic function; RWT and LVMI as indices of left ventricular morphology; and left ventricular end-diastolic volume index (LVEDVI) as an index of left ventricular expansion.
Echocardiographic evaluation was performed after hemodialysis with the primary aim of assessing postdialytic left ventricular volume, although this may have led to misleading strain and hemodynamic values due to changes in vascular volume after dialysis.
GLS evaluation method
GLS analysis of the stored image data of extracted cases was performed by the 2D speckle tracking method, and data were compared between the 3 groups. For GLS, strain was analyzed on the left long axis by using a 2D speckle tracking method with AutoSTRAIN (Philips) on 3 cross sections: apical long axial cross section (A3c), 4-chamber cross section (A4c), and 2-chamber cross section (A2c). In GLS analysis, when the left ventricular endocardial side is traced at the end of the systolic phase, the region of interest corresponding to the myocardial width is automatically set, a 6-segment time-strain curve is automatically constructed, and the strain value is calculated. GLS was calculated by averaging each GLS value obtained from the 3 apical cross Sect. [14] (Fig. 1).
Fig. 1.
Measurement of global longitudinal strain. Global longitudinal strain (GLS) analysis of the stored image data of extracted cases was performed on the left long axis by the two-dimensional (2D) speckle tracking method with AutoSTRAIN (Philips). Three cross sections were evaluated: apical long axial cross-section (A3c), 4-chamber cross-section (A4c), and 2-chamber cross-section (A2c). GLS, global longitudinal strain
Blood and biochemical evaluations
In each patient, blood had been sampled on the day of the echocardiography examination or within 1 week of the date of the examination. In HD patients, we used the values before dialysis.
Statistical analysis
Numerical data are expressed as mean ± SD, and categorical data are expressed as percentages. For multi-group comparisons, one-way analysis of variance (ANOVA) was used to assess the differences between the 3 groups, and if a significant difference (p < 0.05) was found, a multiple comparison test was performed with a Bonferroni test. The unpaired t test was used to compare 2 groups of continuous variables, and a chi-square test was used to analyze the difference in frequency between categories. The relationship between GLS and each index was evaluated by simple regression analysis and Pearson’s correlation coefficient. Multiple linear regression analysis was performed for indices that showed a significant difference (p < 0.05) in relation to GLS by single regression analysis. We excluded IVSth, PWth, and left ventricular end-systolic volume index (LVESVI) beforehand to avoid collinear effects. A variance inflation factor was calculated to evaluate the effect of multicollinearity on the selected items and was confirmed to be less than 5. The criterion for statistical significance was a p value of less than 0.05.
Results
Comparison of clinical and echocardiographic characteristics between the 3 groups
Table 1 shows the clinical background, echocardiogram indices, and blood test data of the 3 groups. There were no significant differences in age, blood pressure, or LVEF between the 3 groups. IVSth and PWth were significantly higher (p < 0.01) in the HLVH and HD groups than in the C group and were also significantly higher in the HLVH group than in the HD group (p < 0.05). RWT and LVMI, calculated by using wall thickness in the left ventricular morphology indices, were significantly higher in the HLVH and HD groups than in the C group. LVEDVI, which is associated with left ventricular volume, was significantly higher in the HD group than in the C group. E/A and E/e’, both indices of left ventricular diastolic function, were not significantly different between the 3 groups, but LAVI was significantly higher in the HLVH group than in the C group and showed an increasing trend in the HD group. Hb values were significantly lower in the HD group than in the C and HLVH groups, but there was no significant difference in eGFR between the C and HLVH groups. All patients in the HD group were receiving intravenous iron and erythropoietin stimulating agents. Ferritin was 212 ± 137ng/mL, TSAT (transferrin saturation, i.e., Fe/TIBC; total iron binding capacity) was 29 ± 9%. Moreover, all patients in the HD group had ferritin levels ≧ 100 ng/mL and TSAT ≧ 20%. However, 3 out of 20 patients (15%) in the HD group had Hb levels between 9 g/dL and 10 g/dL (the other patients had Hb levels between 10 and 13 g/dL). 80% of the patients (16/20) in the HD group in this study had hemodiafiltration, and the rest (4/20) had high-flux hemodialysis.
Table 1.
Comparison of clinical and echocardiographic characteristics between the 3 groups
| C group | HLVH group | HD group | p value | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| N (male: female) | 20 (10:10) | 20 (10:10) | 20 (10:10) | (3 groups) | ||||||
| Age (years) | 73 | ± | 11 | 73 | ± | 8 | 74 | ± | 6 | 0.895 |
| Systolic BP (mmHg) | 133 | ± | 13 | 143 | ± | 24 | 138 | ± | 18 | 0.251 |
| Diastolic BP (mmHg) | 76 | ± | 10 | 77 | ± | 14 | 77 | ± | 12 | 0.988 |
| Antihypertensive drugs (%) | 0 | 100* | 85* | < 0.001 | ||||||
| BSA (m2) | 1.60 | ± | 0.24 | 1.66 | ± | 0.18 | 1.50 | ± | 0.14# | 0.038 |
| LVEF (%) | 65 | ± | 4 | 64 | ± | 2 | 63 | ± | 3 | 0.191 |
| IVSth (mm) | 10.5 | ± | 0.9 | 13.3 | ± | 1.0* | 12.1 | ± | 1.7*, # | < 0.001 |
| PWth (mm) | 10.5 | ± | 0.9 | 13.3 | ± | 1.0* | 12.1 | ± | 1.7*, # | < 0.001 |
| LVEDd (mm) | 43.2 | ± | 3.9 | 44.9 | ± | 4.0 | 43.3 | ± | 5.3 | 0.407 |
| RWT | 0.49 | ± | 0.05 | 0.60 | ± | 0.07* | 0.56 | ± | 0.09* | < 0.001 |
| LVEDVI (mL/m2) | 40 | ± | 7 | 43 | ± | 11 | 50 | ± | 10* | 0.004 |
| LVESVI (mL/m2) | 14 | ± | 3 | 16 | ± | 4 | 18 | ± | 3* | 0.001 |
| LVMI (g/m2) | 96 | ± | 13 | 138 | ± | 24* | 129 | ± | 29* | < 0.001 |
| Normal geometry (%) | 5 | 0* | 0* | 0.014 | ||||||
| Concentric remodeling (%) | 75 | 0* | 20* | < 0.001 | ||||||
| Concentric hypertrophy (%) | 20 | 100* | 80* | < 0.001 | ||||||
| Eccentric hypertrophy (%) | 0 | 0 | 0 | |||||||
| E/A | 0.68 | ± | 0.19 | 0.64 | ± | 0.27 | 0.64 | ± | 0.20 | 0.784 |
| E/e’ | 8.7 | ± | 3.0 | 9.1 | ± | 3.3 | 10.3 | ± | 3.2 | 0.283 |
| LAVI (mL/m2) | 24 | ± | 6 | 32 | ± | 10* | 28 | ± | 8 | 0.015 |
| Hb (g/dL) | 13.1 | ± | 1.6 | 13.6 | ± | 1.8 | 10.7 | ± | 1.2*, # | < 0.001 |
| eGFR (mL/min/1.73m2) | 66 | ± | 15 | 65 | ± | 15 | 5 | ± | 1 | NA |
Data are expressed as mean ± SD
*p < 0.05 compared with C group; #p < 0.05 compared with HLVH group; NA, comparison of estimated glomerular filtration rates not available
C, control; HLVH, hypertensive left ventricular hypertrophy; HD, hemodialysis; BP, blood pressure; BSA, body surface area; LVEF, left ventricular ejection fraction; IVSth, intraventricular septal thickness; PWth, posterior wall thickness; LVEDd, left ventricular end-diastolic diameter; RWT, relative wall thickness; LVEDVI, left ventricular end-diastolic volume index; LVESVI, left ventricular end-systolic volume index; LVMI, left ventricular mass index; E/A, ratio of peak velocities of early (E) to atrial systolic (A) transmitral flow; E/e’, ratio of peak velocity of early transmitral flow (E) to early mitral annular velocity (e’); LAVI, left atrial volume index; Hb, hemoglobin; eGFR, estimated glomerular filtration rate
The serum calcium (Ca), phosphorus (P), and intact PTH levels in the HD group were 9.2 ± 0.6 mg/dL, 4.7 ± 0.6 mg/dL, and 133.0 ± 76.9 pg/mL, respectively, and the calcium-phosphorus (Ca×P) product was 43.5 ± 6.7. Serum phosphorus levels and calcium-phosphorus products in all patients were controlled below 6 and 55, respectively.
Left ventricular morphological distribution
In the HLVH group, LVH was concentric in all participants. In the HD group, 4 patients (20%) had concentric left ventricular remodeling, and 16 patients (80%) had concentric LVH and no eccentric LVH (Table 1).
Number and types of antihypertensive drugs between HLVH and HD groups (Table 2).
Table 2.
Number and types of antihypertensive drugs between hypertensive left ventricular hypertrophy and Hemodialysis groups
| Number | Types | HLVH group (n = 20) |
HD group (n = 20) |
|---|---|---|---|
| 0 | 0 | 3 | |
| 1 | ARB | 0 | 1 |
| 1 | CCB | 3 | 3 |
| 2 | ARB + CCB | 13 | 12 |
| 3 | ARB + CCB + βB | 4 | 1 |
HLVH, hypertensive left ventricular hypertrophy; HD, hemodialysis; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; βB, β-blocker
The majority of patients in both the HLVH and HD groups were taking two antihypertensive drugs, angiotensin II receptors (ARBs) and calcium channel blockers (CCBs), with 13 patients (65%) and 12 patients (60%), respectively. There was no statistically significant difference in the number and the types of antihypertensive drugs between the HLVH group and the HD group (p = 0.211).
Comparison of GLS between the 3 groups
GLS was significantly lower in the HLVH and HD groups than in the C group (p < 0.01) and significantly lower in the HD group than in the HLVH group (p < 0.05) (Fig. 2). There was no significant difference in GLS values by sex in any of the groups (C group, -19.6 ± 1.2% in men vs. -19.1 ± 1.0% in women; HLVH group, -17.3 ± 1.6% in men vs. -16.7 ± 1.0% in women; HD group, -15.7 ± 1.1% in men vs. -16.0 ± 1.8% in women).
Fig. 2.
Comparison of global longitudinal strain between the 3 groups. Distribution of global longitudinal strain (GLS) in each group and mean ± SD GLS values are shown. Blue circles, control group; orange circles, hypertensive left ventricular hypertrophy group; and black circles, hemodialysis group. C, control; GLS, global longitudinal strain; HD, hemodialysis; HLVH, hypertensive left ventricular hypertrophy
Comparison of clinical and echocardiographic characteristics of GLS decline (i.e., GLS > -17.0%) in HLVH and HD groups
The GLS reference value was calculated as -17.0% (formula: mean value + 2 × SD of the C group) and was used to assess GLS decline (Table 3). The frequency of GLS decline (i.e., GLS > -17.0%) was significantly higher in the HD group (17/20, 85%) than in the HLVH group (7/20, 35%; p < 0.01). Blood pressure was not significantly different between the HLVH and HD groups. The difference of 21 mmHg of systolic blood pressure between the HLVH and the HD did not reach significance due to the small number of cases (Type II error). IVSth and PWth values indicated significantly thicker walls in the HLVH group than in the HD group (p < 0.01). RWT showed significantly thicker walls in the HLVH group than in the HD group (p < 0.05). LVMI was higher in the HLVH group than in the HD group, but the difference was not significant. E/A was significantly higher in the HD group than in the HLVH group (p < 0.05), and Hb values were significantly lower in the HD group than in the HLVH group (p < 0.05). The eGFR of the seven individuals in the HLVH group ranged from 33 mL/min/m2 to 86 mL/min/m2, with a median of 63 mL/min/m2. One patient had an eGFR of 33 mL/min/m2, while the other had an eGFR of 50 mL/min/m2 or more.
Table 3.
Comparison of clinical and echocardiographic characteristics of global longitudinal strain decline (i.e., global longitudinal strain > -17.0%) in hypertensive left ventricular hypertrophy and Hemodialysis groups
| HLVH group | HD group | p value | |||||
|---|---|---|---|---|---|---|---|
| N (male: female) | 7 (4:3) | 17 (10:7) | 0.001 | ||||
| Age (years) | 73 | ± | 8 | 74 | ± | 5 | 0.665 |
| BSA (m2) | 1.63 | ± | 0.26 | 1.53 | ± | 0.13 | 0.379 |
| Systolic BP (mmHg) | 157 | ± | 32 | 136 | ± | 20 | 0.153 |
| Diastolic BP (mmHg) | 79 | ± | 18 | 78 | ± | 9 | 0.809 |
| LVEF (%) | 63 | ± | 2 | 63 | ± | 3 | 0.905 |
| IVSth (mm) | 14.0 | ± | 1.0 | 12.5 | ± | 1.3 | 0.009 |
| PWth (mm) | 14.0 | ± | 1.0 | 12.5 | ± | 1.3 | 0.009 |
| LVEDd (mm) | 43.4 | ± | 5.2 | 43.5 | ± | 5.3 | 0.986 |
| RWT | 0.65 | ± | 0.06 | 0.58 | ± | 0.08 | 0.038 |
| LVEDVI (mL/m2) | 43 | ± | 16 | 49 | ± | 10 | 0.351 |
| LVESVI (mL/m2) | 16 | ± | 6 | 18 | ± | 4 | 0.379 |
| LVMI (g/m2) | 147 | ± | 31 | 132 | ± | 28 | 0.311 |
| Concentric remodeling (%) | 0 | 18 | 0.235 | ||||
| Concentric hypertrophy (%) | 100 | 82 | 0.235 | ||||
| E/A | 0.48 | ± | 0.08 | 0.61 | ± | 0.18 | 0.016 |
| E/e’ | 10.7 | ± | 4.8 | 10.2 | ± | 3.4 | 0.807 |
| LAVI (mL/m2) | 31 | ± | 6 | 28 | ± | 7 | 0.279 |
| Hb (g/dL) | 13.4 | ± | 1.8 | 10.8 | ± | 1.2 | 0.015 |
| eGFR (mL/min/1.73m2) | 61 | ± | 17 | 5 | ± | 1 | NA |
Data are expressed as mean ± SD
NA: Comparison of eGFRs among eGFR not available
HLVH, hypertensive left ventricular hypertrophy; HD, hemodialysis; BP, blood pressure; BSA, body surface area; LVEF, left ventricular ejection fraction; IVSth, intraventricular septal thickness; PWth, posterior wall thickness; LVEDd, left ventricular end-diastolic diameter; RWT, relative wall thickness; LVEDVI, left ventricular end-diastolic volume index; LVESVI, left ventricular end-systolic volume index; LVMI, left ventricular mass index; E/A, ratio of peak velocities of early (E) to atrial systolic (A) transmitral flow; E/e’, ratio of peak velocity of early transmitral flow (E) to early mitral annular velocity (e’); LAVI, left atrial volume index; Hb, hemoglobin; eGFR, estimated glomerular filtration rate
Distribution of left ventricular morphology in GLS decline (i.e., GLS > -17.0%)
In the patients with GLS decline, concentric LVH was seen in 7/7 (100%) of the HLVH group, concentric left ventricular remodeling was seen in 3/17 (18%) of the HD group, and concentric LVH was seen in 14/17 (82%) of the HD group. The frequency of concentric LVH was not significantly different between the HLVH and HD groups (Table 3).
Relationship between GLS and each index by simple regression analysis of the 3 groups
Table 4 shows the results of the analysis of correlation with GLS by simple regression analysis. Although all patients had an LVEF greater than or equal to 60%, LVEF showed a weak negative correlation with GLS. RWT and LVMI, both left ventricular morphological indices, showed a relatively strong positive correlation with GLS. The association between Hb levels and GLS showed a relatively weak negative correlation. LVEDVI and E/e’ showed a weak positive correlation with GLS. All patients were aged 60 years and older, and no correlation was found between this age distribution and GLS.
Table 4.
Relationship between global longitudinal strain and each index by simple regression analysis of the 3 groups
| r | p value | |
|---|---|---|
| Age (years) | 0.105 | 0.425 |
| BSA (m2) | -0.159 | 0.226 |
| LVEF (%) | -0.394 | 0.002 |
| PWth (mm) | 0.596 | < 0.001 |
| LVEDd (mm) | -0.037 | 0.780 |
| RWT | 0.549 | < 0.001 |
| LVEDVI (mL/m2) | 0.306 | 0.017 |
| LVMI (g/m2) | 0.628 | < 0.001 |
| E/A | -0.197 | 0.132 |
| E/e’ | 0.300 | 0.037 |
| LAVI (mL/m2) | 0.228 | 0.080 |
| Hb (g/dL) | -0.369 | 0.004 |
| eGFR (mL/min/1.73m2) | NA |
IVSth was omitted because it had the same value as PWth
r, Pearson’s correlation coefficient; BSA, body surface area; LVEF, left ventricular ejection fraction; PWth, posterior wall thickness; LVEDd, left ventricular end-diastolic diameter; RWT, relative wall thickness; LVEDVI, left ventricular end-diastolic volume index; LVMI, left ventricular mass index; E/A, ratio of peak velocities of early (E) to atrial systolic (A) transmitral flow; E/e’, ratio of peak velocity of early transmitral flow (E) to early mitral annular velocity (e’); LAVI, left atrial volume index; Hb, hemoglobin; eGFR, estimated glomerular filtration rate
Factors associated with GLS according to multivariate analysis
Table 5 shows the results of multiple regression analysis. The significant indices associated with GLS were RWT, LVMI, LVEF, and Hb values (p < 0.01). In particular, the standard regression coefficient of RWT was higher than that of the other indices and had a high contribution rate: RWT, 32.8%; LVMI, 21.2%; and Hb, 19.7%.
Table 5.
Factors associated with global longitudinal strain according to multivariate analysis
| Model 1 (adjusted R2 = 0.58) |
Model 2 Model 1 + Hb (adjusted R2 = 0.65) |
|||||
|---|---|---|---|---|---|---|
| β | p value | β | p value | |||
| LVEF (%) | -0.260 | 0.005 | -0.222 | 0.009 | ||
| RWT | 0.393 | < 0.001 | 0.435 | < 0.001 | ||
| LVEDVI (mL/m2) | 0.206 | 0.029 | 0.110 | 0.227 | ||
| LVMI (g/m2) | 0.312 | 0.003 | 0.343 | < 0.001 | ||
| E/e’ | 0.128 | 0.157 | -0.001 | 0.993 | ||
| Hb (g/dL) | -0.299 | 0.002 | ||||
β, standard regression coefficient; corrected R2, coefficient of determination adjusted for degrees of freedom; LVEF, left ventricular ejection fraction; RWT, relative wall thickness; LVEDVI, left ventricular end-diastolic volume index; LVMI, left ventricular mass index; E/e’, ratio of peak velocity of early transmitral flow (E) to early mitral annular velocity (e’); Hb, hemoglobin
Correlation between GLS and RWT
RWT made the highest contribution to GLS, and the regression line of GLS and RWT showed that the RWT value was 0.58 when the reference value of GLS was − 17.0% (Fig. 3). Among the patients with an RWT greater than or equal to 0.58, the frequency of GLS decline (i.e., GLS > -17%) was significantly higher in the HD group (9/9, 100%) than in the HLVH group (7/13, 54%; p < 0.05).
Fig. 3.
Correlation between global longitudinal strain and relative wall thickness. Regression line obtained from a simple regression analysis of the 3 groups is shown. At a global longitudinal strain decline greater than − 17% (the reference value calculated from the control group), the relative wall thickness was 0.58. Blue circles, control group; orange circles, hypertensive left ventricular hypertrophy group; and black circles, hemodialysis group. C, control; GLS, global longitudinal strain; HD, hemodialysis; HLVH, hypertensive left ventricular hypertrophy
Discussion
The present study compared left ventricular systolic function assessed by GLS in HD patients and HLVH patients aged 60 years and older with LVEF of at least 60% and matched for age and sex. The 4 main results of the study are as follows: (1) GLS in HD patients was significantly worse than in healthy controls and HLVH patients; (2) Hb levels were significantly lower in HD patients than in healthy controls and HLVH patients; (3) in patients with GLS decline (i.e., GLS > -17%), the increase in RWT was significantly greater in HLVH patients than in HD patients; and (4) increased RWT and LVMI (indices of left ventricular morphological remodeling) and decreased Hb levels contributed to GLS decline, as did the decrease in LVEF, even though the study included only patients with an LVEF of at least 60%.
The above results indicate that the decline in GLS (i.e., GLS > -17.0%) in HD patients is related to increased RWT with renal anemia, whereas the decline in GLS in HLVH patients is related to the greater increase in RWT than in HD patients.
Possible causes of greater GLS decline in HD patients than in HLVH patients
Because the reference value of GLS differs slightly depending on age and sex, patients in the study were matched for age and sex, and the reference value of GLS was calculated from the mean and SD values in the C group (mean GLS + 2 × SD). Thus, the reference value was − 17%, meaning that a GLS value greater than − 17% was regarded as a decline in GLS. The HD group had a significantly greater decline in GLS than the HLVH group. Although LVEF was in the normal range in all patients, we hypothesize that the HD patients had already developed subendocardial lesions because they had multiple risk factors, whereas the HLVH patients had not. GLS decline was accompanied by low Hb levels. Studies showed that renal anemia increases LVH in ESRD [17, 22], and Silverberg et al. later referred to this association as the cardio-renal-anemia syndrome [23]. In addition, renal anemia may indicate a substantial amount of myocardial damage on the endocardial side due to insufficient oxygen supply. Other CKD-specific factors, including ESRD, are presumed to be increased activation of the renin-angiotensin system and calcification of the heart valvular membrane and aorta due to CKD-MBD; these factors increase the stiffness of the central arteries, causing more excessive left ventricular afterload, which in turn results in myocardial hypertrophy and fibrosis [19, 24–27]. We hypothesize that volume overload was more involved in GLS decline in HD patients than in HLVH patients. However, future studies need to test this hypothesis because LVEDVI tended to be higher in HD than in HLVH patients but did not statistically reach a significant contributing factor to GLS decline (p = 0.151).
Left ventricular morphological changes and decline in GLS with preserved LVEF
Stokke et al. [28] created a mathematical model of LVEF by assuming that the left ventricle was a truncated ellipsoid with a thickened wall and used this model to examine how GLS affects LVEF. They found that LVEF is less affected by GLS and strongly influenced by global circumferential strain (GCS) of the left ventricle. Furthermore, they clarified that LVEF tends to be maintained as the left ventricular wall thickness increases or as the LVEDV decreases, even if GCS and GLS decrease. This finding indicates that RWT (i.e., the ratio of the left ventricular PWth to the LVEDd) increases. Therefore, we suggest that the significant increase in RWT in HLVH and HD patients with a decline in GLS contributed to preservation of LVEF.
In this study, the HD patients with a significantly smaller BSA had increased LVEDVI, although their LVEDd was similar to that of the C and HLVH groups. According to previous research reports targeting HFpEF and ESRD, the group of patients with decreased GLS but LVEF in the normal range shows a tendency for higher LVEDV or LVEDVI as a result of slight LVEF decrease [4, 7, 29]. In a hypertensive heart disease model with salt-sensitive rats, Ishizu et al. showed that as RWT and LVM increase, GLS decreases first, followed by GCS and LVEF [30]. Therefore, LVEF-preserved GLS decline despite large LVEDVI (indicating left ventricular volume) in the HD group may indicate that the GCS of the entire left ventricle was increased more in the HD group than in the HLVH group or that the LVEF was already on a downward trend despite all patients having an LVEF of 60% or higher. However, this is a topic for future consideration.
Because multiple regression analysis showed that RWT contributed the most to the decline in GLS, the RWT value at a GLS decline of -17% was obtained from the regression line of simple regression analysis (Fig. 3). This procedure showed that if RWT is 0.58 or higher, GLS may be more likely to decrease, especially in HD patients, so that this value may predict early GLS decline.
Clinical implications
LVH is an independent prognostic factor for a high incidence of cardiovascular events such as coronary artery disease and heart failure [31]. Similarly, HD patients often develop cardiovascular disease because of the rapid increases and decreases in body fluid volume due to HD, and they have a poor prognosis, especially when left ventricular systolic function is reduced with LVH [32].
Recently, attention has been focused on reverse remodeling of the left ventricle, which occurs when pharmacotherapy improves cardiac function and reduces left ventricular volume [33, 34]. If reverse remodeling occurs, the prognosis is considered good. Moreover, early intervention yields reliable results [35]. GLS decline is also a prognostic factor for cardiovascular disease [8, 36, 37] and has been reported to be an indicator for early left ventricular systolic dysfunction [4, 38, 39]. Therefore, GLS should be routinely measured during echocardiography in patients with hypertensive heart disease and ESRD with left ventricular morphology changes.
To suppress GLS decline in hypertensive heart disease and ESRD, it is important to prevent left ventricular remodeling by controlling blood pressure from an early stage in hypertension and CKD and treating renal anemia from an early stage in ESRD. In fact, a meta-analysis that directly compared the effects of antihypertensive agents on the regression of LVH found that renin-angiotensin system inhibitors and calcium channel blockers had the greatest effect [40–42]. Other articles have reported that lowering central blood pressure reduces LVH and lowers B-type natriuretic peptide, an indicator of cardiac impairment [43, 44]. Furthermore, treatment with calcium channel blockers has been reported to improve GLS in HLVH patients [45]. A study in a model of hypertensive heart disease in salt-sensitive rats showed that treatment with angiotensin-converting enzyme inhibitors was effective in preventing heart failure before GCS decreased, even in the GLS-decreased state [46].
Study limitations
This study has some limitations. First, it was a retrospective study with a relatively small number of participants in each group. The numerical limitation of the sample of our study makes careful validity of the results, especially, which may include the small difference with no statistical significance between 3 groups. Second, the reference value for reduced GLS was defined as the control group mean + 2 SD, which may result in selection bias. Association of Cardiovascular Imaging (ASE/EACVI) recommend a reference value of -20% or less for GLS in healthy subjects. However, the reference value for the decline in GLS is not clearly indicated like the reference value for the decline in LVEF [14]. In addition, GLS levels tend to decline in healthy subjects with age [13]. Thus, we have set up a control group with our own criteria for individuals aged 60 years. We would like to increase the number of cases and wait for guidelines to be presented. Third, the automatic analysis software could not evaluate GCS. Only GLS was assessed. However, it is known that global circumferential strain (GCS) plays a more prominent role in the preservation of LVEF [30]. Fourth, because echocardiography was performed after HD, GLS may have been different in the left ventricular volume overloading state before HD. Last, the factor of CKD-MBD (mineral and bone disorder) is directly related to cardiac calcification and afterload. Serum Ca and P in the HD group were controlled, however, we did not measure FGF 23. The FGF23 has been reported to induce LVH and has been attracting attention, so our HD group was not adequately evaluated for CKD-MBD [27]. These issues should be considered in future studies.
Conclusions
This study showed that HD patients with preserved LVEF show significantly more decline in GLS than HLVH patients, suggesting that increased RWT and LVMI with renal anemia may contribute to GLS decline in HD patients with preserved LVEF.
Acknowledgements
We would like to thank all the staff at our HD center for supporting data collection and Yamada Translation Bureau, Inc. for conducting the English language review. We are very grateful for the writing support of Dr. So Nishiyama, Dr. Yume Oshiro, and our former hospital director, Dr. Hiroshige Ohashi.
Author contributions
MO, TN, and TS designed the study. MO, TS, YY, and JY collected the data. MO, TN, and TS analyzed the data. MO wrote the manuscript. All authors read and approved the final manuscript.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
The present study was conducted in accordance with the principles of the Declaration of Helsinki and approved by the Research Ethics Committee of Asahi University Hospital (approval number 2023-01-02).
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
No datasets were generated or analysed during the current study.