Original Article
Association between Myocardial Oxygen Supply and Demand and Myocardial Injury in Patients with End-Stage Kidney Disease
2024 Volume 31 Issue 5 Pages 540-549
Details
2024 Volume 31 Issue 5 Pages 540-549
Aim: In patients with end-stage kidney disease (ESKD), it is unclear whether an imbalance between myocardial oxygen supply and demand leads to myocardial injury (MI). This study clarifies the association between the balance of the rate pressure product (RPP), consisting of the systolic blood pressure multiplied by the pulse rate (PR), a marker for myocardial oxygen demand, and hemoglobin (Hb), a marker for oxygen supply, with MI.
Methods: A total of 283 consecutive unselected patients for hemodialysis were enrolled in this retrospective, cross-sectional study, and were divided into four groups according to Hb levels (high or low) and RPP. Potential imbalances between myocardial oxygen supply and demand were defined as patients with simultaneous high RPP and low Hb levels. The odds ratio (OR) for MI, defined as cardiac troponin T (cTnT) of ≥ 0.15 ng/mL was investigated using logistic regression analysis between the four patient groups.
Results: The mean age was 68.7 years, 71.3% were men, and 52.6% had diabetes. The mean Hb level was 9.0 g/dL, and 20.5% of patients were latently diagnosed with MI. The median RPP and cTnT level was 12,144 and 0.083 ng/mL, respectively. When exposed to simultaneous high RPP with low Hb, OR significantly increased compared with that of the well-balanced group (RPP ＜12,500 and Hb ≥ 9.0 g/dL; OR 3.63, p＜0.05). Similar results were obtained in multivariate analysis after adjusting for confounding variables. These associations were enhanced or weakened when the Hb cut-off level became lower (Hb=8 g/dL) or higher (Hb=10 g/dL).
Conclusions: As the myocardial oxygen supply and demand balance in patients with ESKD is potentially associated with MI, appropriate management for blood pressure, PR, and anemia may prevent MI.
See editorial vol. 31: 522-523
The mechanism for cardiorenal syndrome is not yet elucidated; however, cardiovascular medicine involving ischemic heart disease for patients with chronic kidney disease (CKD) has evolved1-3). Early trials of CKD treatments revealed the benefits of lipid-lowering therapies in reducing atherosclerotic events4, 5), indicating arterial atheroma as an important modifiable pathophysiological process. However, such treatments are less effective in patients with advanced stages of CKD, including end-stage kidney disease (ESKD)6-8), suggesting that the main mechanism for ischemic heart disease differs between the early and late phases of CKD. Type 2 myocardial infarction caused by disturbances in the myocardial oxygen supply and demand balance, independent of coronary stenotic lesions, is more common in patients with advanced CKD than type 1 myocardial infarction, which results from the complete occlusion by thrombi formed due to vulnerable plaque rupture9). Independent of coronary atheroma lesions, disturbance in the myocardial oxygen balance may play an important role in refractory cardiovascular events in patients with ESKD.
The rate pressure product (RPP), consisting of the systolic blood pressure (SBP) multiplied by the pulse rate (PR), is an index of myocardial oxygen consumption10, 11). It is an indicator of loading intensity and stress during exercise to disclose coronary heart disease occurrences in real-world clinical settings. An increase in RPP, a marker of future cardiovascular events, is strongly associated with cardiovascular events in patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention12), who are susceptible to myocardial oxygen supply and demand imbalances. Hemoglobin (Hb) in red blood cells is circulated by the cardiovascular system. It delivers oxygen to the periphery where it is released and diffused into cells, including cardiac cells13). Therefore, the oxygen transport ability is impaired in patients with anemia and low Hb levels.
In the clinical setting, RPP is an easy and good surrogate marker for myocardial oxygen demand. Similarly, Hb is a simple surrogate marker for tissue oxygen supply. However, imbalances in these markers induce myocardial damage, which is ambiguous. Therefore, we hypothesized that imbalances in these two markers may lead to myocardial damage in patients with ESKD with a vulnerable heart susceptible to oxygen balance.
The purpose of this study was to clarify the distribution of RPP and Hb in patients with ESKD. When high RPP combined with low Hb was defined as an imbalance of myocardial oxygen supply and demand, its association with troponin T concentration was examined. We believe that the outcomes may guide the management of Hb and blood pressure or PR to prevent myocardial injury (MI), independently of coronary artery disease.
This was a hospital-based, single-center, retrospective, cross-sectional study. The eligibility criteria included 327 consecutive unselected patients with ESKD who started hemodialysis (HD) at Toho University Ohashi Medical Center from December 2010 to November 2021. The exclusion criteria were: (1) the presence of myocardial infarction or ACS at the initiation of HD; (2) death during hospitalization for HD initiation; and (3) missing data for Hb and cardiac troponin T (cTnT). Of the 327 patients, three patients had ACS at admission, one died during hospitalization, and 40 patients had incomplete Hb and cTnT data. Therefore, a total of 283 patients were included in the study (Fig.1).
ESKD, end-stage kidney disease; Hb, hemoglobin; cTnT, cardiac troponin T
The study adhered to the principles of the Declaration of Helsinki. The Ethics Committee for Clinical Research at the Toho University Ohashi Medical Center approved the study protocol (Permission no. H23013_H22026_H21078). Consent was not required from individual patients. However, we posted a notice before initiating the study, indicating that the patients can object to using their data through the opt out policy.
Data CollectionThe clinical diagnosis of the underlying kidney disease, the presence of diabetes, preexisting cardiovascular disease, and medications used at HD initiation were obtained from the patients’ medical records. Immediately before the first HD session, blood pressure and heart rate were routinely recorded in the supine position after at least five minutes of rest, and blood samples were collected. Whole blood was used for blood counts and serum samples for biochemical assays. The estimated glomerular filtration rate (eGFR) was calculated using the modified three-variable equation for Japanese adults proposed by the Japanese Society for Nephrology: eGFR (mL/min per 1.73 m2)=194´ serum creatinine (mg/dL)−1.094´ age (years)−0.287 ([if female]´ 0.739)14).
Serum total calcium was adjusted for albumin following the formula (Payne’s) of the Japanese Society for Dialysis Therapy guideline for hypoalbuminemia (serum albumin ＜4.0 g/dL): corrected calcium (mg/dL)=total serum calcium (mg/dL)＋(4−serum albumin [mg/dL]).
At discharge, the body mass index (BMI) was calculated as weight (kg) divided by the square of height (m2). Body weight change was computed as the weight difference between HD initiation and discharge. The percent body weight change was estimated as the body weight difference divided by the body weight at discharge. The presence or absence of cardiac disease was determined by reviewing the patients’ medical records. Cardiac diseases were defined as any heart failure requiring hospitalization and ischemic heart diseases, including myocardial infarction and ACS, which require coronary revascularization therapy.
Measurement of cTnTBlood sampling for cTnT was performed immediately before the first HD session. Serum cTnT levels were measured using a high-sensitivity method (Troponin T hs STAT Elecsys; Roche, Mannheim, Germany). According to the K/DOQI guidelines15), screening for ischemic heart disease is recommended at the initiation of renal replacement therapy with routine cTnT measurements.
Imbalance between Myocardial Oxygen Supply and DemandTo our knowledge, no studies have explored Hb levels affecting myocardial oxygenation in patients with ESKD. Therefore, we decided to select a Hb level of 9.0 g/dL, which is based on the median Hb level of 9.1 g/dL in our patients. RPP was selected as the marker of oxygen and calculated by multiplying SBP by PR at the initiation of HD. The patients were divided into four groups according to Hb levels (high or low) and median RPP level. Potential imbalances between myocardial oxygen supply and demand were defined as patients with simultaneous low Hb and high RPP levels (Supplemental Fig.1).
Definition for oxygen supply and demand
The study outcome was the presence or absence of MI. Based on diagnostic approaches for ischemic heart disease16), MI was identified as an elevated cTnT without clinical evidence of acute myocardial ischemia (acute myocardial infarction or ACS), as judged by two physicians based on the Fourth Universal Definition of Myocardial Infarction17). Following our previous study, as the cTnT level is affected by renal function, a cut-off value of 0.15 ng/mL was selected for MI, which included patients with stage 5 CKD18).
Statistical AnalysesWe descriptively analyzed continuous variables by the mean, standard deviation, and median (quartiles) for nonnormal distribution parameters, and the categorical variables by numbers (proportions). Univariate and multivariate logistic regression models were used to verify the association between exposure (imbalance between myocardial oxygen supply and demand) and the outcome (MI). The association between cTnT and disturbance in the myocardial oxygen balance was assessed using multivariate logistic regression analysis by comparing four patient groups (high or low levels of Hb and RPP: high or low RPP and high or low Hb group, Supplemental Fig.1) based on an RPP of 12,500 as the median value and a Hb of 9.0 g/dL. A similar analysis was performed using Hb levels of 8.0 g/dL or 10.0 g/dL as a subanalysis for defining the optimal Hb level for preventing MI. Statistical significance was set at P＜0.05. All statistical analyses were performed using JMP for Windows version 16 (IBM, New York, NY, USA).
The mean age was 68.7 years, 71.3% were men, and 52.6% had diabetes. The mean Hb level was 9.0±1.6 g/dL, and the median RPP was 12,144. The RPP distribution is shown in Supplemental Fig.2. This RPP value is similar to that of a previous study from Japan19). The median cTnT level was 0.083, and 20.5% of patients were latently diagnosed with MI in this study (Table 1).
Distribution of RPP
| Available data | Total |
RPP＜12500 n=152 |
RPP ≥ 12500 n=131 |
P-value |
Hb＜9 n=125 |
Hb ≥ 9 n=158 |
P-value | |
|---|---|---|---|---|---|---|---|---|
| Age, years | 283 | 68.7±14.0 | 71.0±12.9 | 66.1±14.8 | ＜0.005 | 68.2±14.3 | 69.1±13.8 | 0.55 |
| Men, % | 283 | 71.3 | 71.7 | 70.9 | 0.89 | 70.4 | 72.1 | 0.79 |
| Diabetes, % | 283 | 52.6 | 50.0 | 55.7 | 0.34 | 48.8 | 55.7 | 0.28 |
| BMI, kg/m2 | 283 | 24.1±4.9 | 23.7±4.9 | 24.5±4.9 | 0.16 | 24.5±4.8 | 23.7±5.0 | 0.07 |
| Body weight change, kg | 240 | 5.5±6.3 | 4.9±6.1 | 6.2±6.4 | ＜0.05 | 5.9±6.1 | 5.1±6.4 | 0.084 |
| % Body weight change | 240 | 9.3±9.7 | 8.2±8.5 | 10.5±10.9 | ＜0.05 | 10.0±9.8 | 8.7±9.7 | 0.12 |
| Smoking, % | 282 | 63.8 | 67.5 | 59.5 | 0.15 | 61.6 | 65.6 | 0.53 |
| Primary disease, % | 283 | 0.25 | 0.86 | |||||
| Diabetic nephropathy | 124 | 43.8 | 38.1 | 50.3 | 40.8 | 46.2 | ||
| Glomerulonephritis | 62 | 21.9 | 23.0 | 20.6 | 23.2 | 20.8 | ||
| Nephrosclerosis | 25 | 8.8 | 11.8 | 5.3 | 9.6 | 8.2 | ||
| PCK | 6 | 2.1 | 2.6 | 1.5 | 1.6 | 2.5 | ||
| Others | 22 | 7.7 | 8.5 | 6.8 | 8.0 | 7.5 | ||
| Unknown | 44 | 15.5 | 15.7 | 15.2 | 16. | 14.5 | ||
| Cardiac diseases, % | 283 | 29.3 | 32.2 | 25.9 | 0.29 | 25.6 | 32.2 | 0.23 |
| Systolic BP, mmHg | 283 | 157.6±23.9 | 143.7±17.3 | 173.7±20.0 | ＜0.0001 | 155.8±25.5 | 159.0±22.5 | 0.20 |
| Diastolic BP, mmHg | 283 | 80.1±14.5 | 72.9±10.8 | 88.4±13.8 | ＜0.0001 | 79.9±14.9 | 80.2±14.2 | 0.94 |
| Heart rate, bpm | 283 | 80.0±14.0 | 72.0±10.0 | 89.4±12.1 | ＜0.0001 | 81.9±14.8 | 78.5±13.2 | 0.07 |
| RPP | 283 | 12144 | 10611 | 14850 | ＜0.0001 | 12019 | 12280 | 0.75 |
| (10540, 14688) | (9435, 11530) | (13635, 16748) | (10578, 14916) | (10434, 14350) | ||||
| Hb, g/dL | 283 | 9.0±1.6 | 9.0±1.5 | 9.1±1.6 | 0.59 | 7.6±1.0 | 10.1±1.0 | ＜0.0001 |
| Albumin, g/dL | 283 | 3.1±0.5 | 3.0±0.6 | 3.1±0.5 | 0.39 | 2.9±0.5 | 3.2±0.6 | ＜0.005 |
| Creatinine, mg/dL | 283 | 10.1±3.6 | 9.9±3.4 | 10.4±3.9 | 0.47 | 10.6±4.3 | 9.7±3.0 | 0.22 |
| Fe, μg/dL | 267 | 62.3±37.8 | 60.5±37.3 | 64.4±38.4 | 0.31 | 58.2±35.5 | 65.5±39.3 | 0.09 |
| TSAT, % | 262 | 28.5±17.5 | 28.0±17.1 | 29.2±18.1 | 0.65 | 28.6±18.6 | 28.5±16.7 | 0.63 |
| Ferritin, ng/dL | 260 | 266.9±282.5 | 277.3±328.0 | 254.2±214.8 | 0.70 | 240.2±315.3 | 301.1±230.8 | ＜0.0005 |
| CRP, mg/dL | 281 | 0.2 (0.06, 1.3) | 0.34 (0.06, 1.5) | 0.1 (0.06, 1.0) | ＜0.05 | 0.4 (0.1, 2.2) | 0.1 (0.04, 0.7) | ＜0.005 |
| cTnT, ng/mL | 283 | 0.08 (0.05, 0.1) | 0.07 (0.05, 0.1) | 0.08 (0.06, 0.1) | 0.076 | 0.08 (0.05, 0.1) | 0.07 (0.05, 0.1) | 0.12 |
| Medications | ||||||||
| ESA, % | 283 | 78.8 | 77.6 | 80.1 | 0.66 | 72.8 | 83.5 | ＜0.05 |
| Iron, % | 283 | 23.3 | 25.0 | 21.3 | 0.48 | 16.8 | 28.4 | ＜0.05 |
| CCB, % | 283 | 81.9 | 81.5 | 82.4 | 0.87 | 80.8 | 82.9 | 0.64 |
| RAS inhibitor, % | 283 | 64.3 | 63.8 | 64.8 | 0.90 | 56.8 | 70.2 | ＜0.05 |
| BB, % | 283 | 33.2 | 38.8 | 26.7 | ＜0.05 | 32.0 | 34.1 | 0.70 |
Values for continuous variables are given as mean±SD or median (25% tile, 75% tile).
Values for categorical variables are presented as percentages.
P values for differences between RPP ≥ 12500 or ＜12500 and Hb ＜9 or ≥ 9, respectively.
RPP, rate pressure product (systolic blood pressure＊ heart rate); Hb, hemoglobin; BMI, body mass index; PCK, polycystic kidney disease; BP, blood pressure; TSAT, transferrin saturation; CRP, C-reactive protein; cTnT, cardiac troponin T; ESA, erythropoiesis-stimulating agent; CCB, calcium channel blocker; RAS, renin-angiotensin-aldosterone system; BB, beta-blocker; OR, odds ratio; CI, confidence interval
The median values of RPP were 14,850 and 10,611 in the high RPP and low RPP groups, respectively, whereas the mean age was 66.1 and 71.0, respectively which is significantly difference between two groups. . The median C-reactive protein (CRP) was significantly lower in the high RPP group than in the low RPP group. Body weight change was significantly higher, and the use of beta-blockers was remarkably lower in the high RPP group compared with those of the low RPP group. No other significant differences between the two groups were observed, except for blood pressure and heart rate (Table 1). Serum albumin was lower, and CRP was higher in the low Hb group than in the high Hb group.
The Odds Ratio (OR) Associated with MIIn the unadjusted model (Table 2), five parameters were significantly associated with MI. Diabetes mellitus, body weight change, RPP, and CRP level showed a positive association, whereas serum albumin level showed a negative association with a cTnT level of ≥ 0.15. Further, we found that the Hb level was not associated with cTnT ≥ 0.15.
| Available data | OR | 95%CI | P-value | |
|---|---|---|---|---|
| Age, years | 283 | 0.98 | 0.96–1.00 | 0.27 |
| Men | 283 | 1.69 | 0.86–3.53 | 0.12 |
| Diabetes | 283 | 2.61 | 1.42–4.97 | ＜0.005 |
| BMI, kg/m2 | 283 | 1.05 | 0.99–1.11 | 0.056 |
| Body weight change, kg | 240 | 1.08 | 1.03–1.14 | ＜0.0005 |
| % Body weight change | 240 | 1.04 | 1.01–1.08 | ＜0.005 |
| Smoking | 282 | 0.63 | 0.35–1.14 | 0.12 |
| Cardiac diseases | 283 | 1.35 | 0.72–2.48 | 0.33 |
| Systolic BP, mmHg | 283 | 1.00 | 0.99–1.02 | 0.15 |
| Diastolic BP, mmHg | 283 | 1.01 | 0.99–1.03 | 0.22 |
| Heart rate, bpm | 283 | 1.01 | 0.99–1.03 | 0.10 |
| RPP, 100 | 283 | 1.00 | 1.00–1.01 | ＜0.05 |
| Hemoglobin, g/dL | 283 | 0.87 | 0.72–1.04 | 0.13 |
| Albumin, g/dL | 283 | 0.48 | 0.29–0.79 | ＜0.005 |
| Creatinine, mg/dL | 283 | 0.97 | 0.89–1.05 | 0.52 |
| Fe, μg/dL | 283 | 0.99 | 0.98–1.00 | 0.40 |
| TSAT, % | 262 | 0.99 | 0.97–1.01 | 0.63 |
| Ferritin, ng/dL | 260 | 1.00 | 0.99–1.00 | 0.10 |
| CRP, mg/dL | 281 | 1.11 | 1.01–1.22 | ＜0.05 |
| ESA | 283 | 0.45 | 0.24–0.88 | ＜0.05 |
| Iron supplement | 283 | 0.38 | 0.15–0.84 | ＜0.05 |
| CCB | 283 | 1.47 | 0.68–3.56 | 0.33 |
| RAS inhibitor | 283 | 0.73 | 0.40–1.34 | 0.31 |
| BB | 283 | 1.29 | 0.70–2.35 | 0.39 |
cTnT, cardiac troponin T; BMI, body mass index; BP, blood pressure; RPP, rate pressure product (systolic blood pressure＊ heart rate); TSAT, transferrin saturation; CRP, C-reactive protein; ESA, erythropoiesis-stimulating agent; CCB, calcium channel blocker; RAS, renin-angiotensin- aldosterone system; BB, beta-blocker; OR, odds ratio; CI, confidence interval.
The four multiple logistic regression analysis models are shown in Table 3. For combination analysis, compared with that of the well-balanced group (RPP ＜12,500 and Hb ≥ 9.0 g/dL), the OR increased when exposed to high RPP or low Hb; however, these were not significant in the unadjusted model (Model 1). A synergistic increase in the OR was observed when exposed to high RPP and low Hb compared with that of the well-balanced group (OR 3.63, p＜0.05). A multivariate analysis of Models 2, 3, and 4 provided similar results. After adjusting for age, male sex, and diabetes (Model 2), Model 2 adjustments plus malnutrition inflammation markers of serum albumin and CRP (Model 3), and Model 2 adjustments plus body weight markers of BMI and % body weight change (Model 4), a significantly increased OR was found in the unbalanced group compared with the well-balanced group (Table 3). The influences of blood pressure medication and renal anemia were confirmed in Models 5 and 6 (Supplemental Table 1).
| Model 1 | Model 2 | Model 3 | Model 4 | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| OR | 95% CI | P-value | OR | 95%CI | P-value | OR | 95% CI | P-value | OR | 95% CI | P-value | ||
| RPP＜12500 | Hb ≥9 | 1 | 1 | 1 | 1 | ||||||||
| Hb ＜9 | 1.37 | 0.56-3.39 | 0.47 | 1.45 | 0.58-3.63 | 0.42 | 0.98 | 0.38-2.55 | 0.98 | 1.11 | 0.39-3.14 | 0.83 | |
| RPP≥12500 | Hb ≥9 | 1.63 | 0.70-3.91 | 0.25 | 1.52 | 0.64-3.69 | 0.33 | 1.20 | 0.48-2.99 | 0.68 | 1.45 | 0.56-3.71 | 0.43 |
| Hb ＜9 | 3.63 | 1.59-8.64 | ＜0.005 | 3.92 | 1.65-9.72 | ＜0.005 | 3.07 | 1.24-7.62 | ＜0.05 | 3.07 | 1.17-8.04 | ＜0.05 | |
Model 1: unadjusted
Model 2: Adjusted for age, male sex, and diabetes mellitus
Model 3: Model 2 plus CRP, albumin,
Model 4: Model 2 plus BMI and % body weight change
RPP, rate pressure product; Hb, hemoglobin; CRP, C-reactive protein; BMI, body mass index; OR, odds ratio; CI, confidence interval
| Model 5 | Model 6 | ||||||
|---|---|---|---|---|---|---|---|
| OR | 95%CI | P-value | OR | 95%CI | P-value | ||
| RPP ＜12500 | Hb ≥ 9 | 1 | 1 | ||||
| Hb ＜9 | 1.22 | 0.48–3.09 | 0.66 | 1.41 | 0.56–3.52 | 0.45 | |
| RPP ≥ 12500 | Hb ≥ 9 | 1.53 | 0.63–3.70 | 0.33 | 1.58 | 0.66–3.80 | 0.29 |
| Hb ＜9 | 3.72 | 1.52–9.10 | ＜0.005 | 3.79 | 1.55–9.26 | ＜0.005 | |
Model 5: Adjusted for age, male sex, diabetes mellitus, ESA, and iron
Model 6: Adjusted for age, male sex, diabetes mellitus, CCB, RAS inhibitor, and BB
RPP, rate pressure product; Hb, hemoglobin; ESA, erythropoiesis stimulating agent; CCB, calcium channel blocker; RAS, renin-angiotensin- aldosterone system; BB, beta blocker; OR, odds ratio; CI, confidence interval
Patients with ESKD may have a vulnerable heart susceptible to the disturbance of oxygen supply and demand balance, irrespective of coronary atherosclerotic lesions9). Currently, there are no reliable markers for determining these imbalances. We examined the association between oxygen supply and demand imbalance and MI using two convenient clinical parameters: RPP, an oxygen demand marker, and Hb, an oxygen supply marker in incident dialysis patients. Compared with the well-balanced group, the OR for MI increased upon exposure to increased oxygen demand or decreased supply only (high RPP and high Hb or low RPP and low Hb); however, this was not significant. A synergistic increase in OR was observed in the high RPP and low Hb group compared with those of the well-balanced groups. This association was enhanced or weakened when the Hb cut-off level became lower (Hb 8.0 g/dL) or higher (Hb level 10.0 g/dL) (Supplemental Table 2), suggesting that disturbances in the myocardial oxygen supply and demand may induce relative myocardial ischemia, MI, and elevated cTnT levels. As there was no significant correlation here, increased RPP is not a result of a decreased secondary Hb. Hence, both markers should be managed independently to maintain myocardial oxygen balance.
| Model 7 | Model 8 | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| OR | 95%CI | P-value | OR | 95%CI | P-value | ||||
| RPP ＜12500 | Hb ≥ 8 | 1 | RPP ＜12500 | Hb ≥ 10 | 1 | ||||
| Hb ＜8 | 2.37 | 0.87–6.45 | 0.089 | Hb ＜10 | 1.08 | 0.35–3.31 | 0.89 | ||
| RPP ≥ 12500 | Hb ≥ 8 | 2.13 | 0.99–4.55 | 0.051 | RPP ≥ 12500 | Hb ≥ 10 | 1.96 | 0.55–6.95 | 0.29 |
| Hb ＜8 | 3.91 | 1.34–11.37 | ＜0.05 | Hb ＜10 | 2.00 | 0.67–5.98 | 0.21 | ||
Adjusted for age, male sex, diabetes mellitus, CRP, and albumin
RPP, rate pressure product; Hb, hemoglobin; CRP, C-reactive protein; OR, odds ratio; CI, confidence interval
The median troponin level of patients (0.083 ng/mL), was higher than the 99th percentile value of 0.014 ng/mL in healthy patients. Here, we discuss the significance of elevated cTnT levels as patients with ACS and myocardial infarction, as well as those who died during hospitalization, were excluded from our study.
The most important factors influencing serum cTnT levels are its blood elimination mechanisms20). Renal troponin excretion in the urine is strongly associated with GFR levels21). In the absence of myocardial damage, elevated cTnT levels are identified due to impaired renal excretion. In contrast, elevated cTnT levels impact death or cardiac death prediction in patients with ESKD. Deegan et al. conducted a prospective study with 73 asymptomatic HD patients and measured their cTnT levels. Among them, 20 patients (27.4%) had cTnT levels of ＞0.1 ng/mL, a cut-off value for ACS diagnosis, and a poor prognosis compared with those having cTnT levels of ＜0.1 ng/mL22). A meta-analysis confirmed the clinical significance of cTnT elevation in HD without any signs of ACS or acute myocardial infarction23) and concluded that patients with ESKD with elevated cTnT levels (＞0.1 ng/mL) have poor survival and a high cardiac death risk despite being asymptomatic. Therefore, the elevated troponin levels in patients with ESKD are not merely due to decreased elimination but also potential myocardial damage. A subanalysis of a cluster-randomized trial24) stated that 29% of acute MI evaluated using high-sensitivity cTnT was observed in patients with suspected ACS with an eGFR of 30 mL/min/1.73 m2 whose percentage is 2–3 times higher than those with an eGFR of ＞60 ml/min/1.73 m2 25). According to diagnostic approaches for patients with acute myocardial ischemia, MI includes elevated cTnT levels over the upper reference limit without any clinical evidence of acute myocardial ischemia16). Based on this exclusion criteria, patients with elevated cTnT levels suffer from MI. However, there is no clear cut-off value for cTnT in ESKD patients with a suspected MI. Based on two studies on ESKD patients with coronary artery disease18, 26), a cTnT of 0.15 ng/mL was defined as a cut-off value for MI in patients with ESKD. However, further verification of the accuracy of this value is required.
Hb and RPP as Markers of Oxygen Supply and DemandPatients suffer from complex conditions where there is a simultaneous increase in oxygen demand and decreased oxygen supply27), predisposing them to ischemic tolerance. Type 2 myocardial infarction is often seen in patients with ESKD9).
RPP is an index of myocardial oxygen demand28) and an increase indicates a higher myocardial oxygen demand, which usually rises or falls as a physiological response. Therefore, there is no clear threshold for excess pathological oxygen demand. In a study of 200 participants without a medical history of hypertension, the average RPP through 24-hour ambulatory monitoring was about 8,100 in men and 8,300 in women29), which is a standard RPP candidate marker. In a study examining increased myocardial oxygen demand and coronary sinus flow, increasing RPP from 9,000 to 15,000 or higher reduced coronary sinus flow in the coronary artery disease group30). This suggests that our selected myocardial oxygen demand threshold (RPP 12,500) was within 9,000 to 15,000 during stress test, and also approximately 4,000 higher than that of the healthy state of 8,000, making it a reasonable cut-off. A prospective study12) indicates that the relative risk for a cardiovascular event was significantly higher in those with an RPP of ＞9,657 than in those with an RPP of ＜9,657. For patients with percutaneous coronary intervention for ACS, our cut-off value for RPP is clinically reasonable for an increase in the myocardial oxygen demand.
Hb is one of the major factors for myocardial oxygen supply as it delivers oxygen to the periphery where it is released and diffused into cells, such as cardiac cells13). Although the absolute Hb value for impaired oxygen delivery to cardiac cells in a normal heart is unclear, a physiological study determined the association of Hb levels with cardiac output31). Figure1 shows that cardiac output begins increasing when Hb is ＜10.0 g/dL, suggesting that myocardial oxygen supply may be impaired if Hb levels are ＜10 g/dL. In addition, in the cohort study of Nishimura et al., they demonstrated that Japanese HD patients with Hb levels of ＜8.5 g/dL at HD initiation have a higher risk of cardiovascular events than new HD patients with Hb levels of ＞8.5 g/dL32). Hence, we hypothesized and defined Hb levels of ＜9.0 g/dL as the threshold for myocardial oxygen supply imbalance. Anemia plays an important role in type 2 myocardial infarction, which causes an imbalance in myocardial oxygen supply and demand, independent of the narrowing of the coronary artery. It is reported as the most frequently observed causal factor33) and is defined as having a level of ＜5.5 mmol/L (8.8 g/dL).
MI in Imbalances between Oxygen Supply and DemandCompared with the well-balanced group (RPP ＜12,500 and Hb ≥ 9.0 g/dL), the OR for MI did not increase only with the impairment of oxygen supply (Hb ＜9.0 g/dL). However, in addition to RPP ＞12,500 with Hb ＜9.0 g/dL, which indicates an imbalance between oxygen supply and demand, the OR significantly increased to 3.07 compared with that of the well-balanced group. These suggest that the combination of impairments in both oxygen supply and demand is associated with MI in patients with ESKD, not oxygen supply or demand alone. Moreover, these associations were strengthened or weakened if Hb and the oxygen supply threshold decreased (Hb ＜8.0 g/dL) or increased (Hb ＜10.0 g/dL), respectively. Hence, a dose–response relationship may exist between the magnitude of the imbalance and MI risk, supporting our hypothesis that an imbalance latently induces MI in patients with ESKD.
In our study, the MI may be induced by endocardial ischemia. An animal study established the occurrence of subendocardial ischemia in increased oxygen requirements combined with mild anemia34). They created aortic stenosis in dogs as an increased myocardial oxygen demand model. Here, subendocardial ischemia was absent with mild anemia alone; however, it appeared that mild anemia was combined with aortic stenosis. Although proving this clinically is impossible, the same cardiac phenomenon may occur in patients with oxygen supply and demand imbalances. If the Hb threshold was 10.0 g/dL, a significantly elevated OR for MI disappeared in the imbalance group. Hence, MI may be minimized by maintaining Hb levels above 10.0 g/dL, despite increased oxygen demand.
This study had several limitations. This was a single-center, retrospective, cross-sectional study with a small sample size. External validity may not be ensured, and the causal effect of the imbalance between oxygen supply and demand on MI may be limited. The lack of confirmation on the narrowing of the coronary artery, the most important oxygen supply marker, is another limitation. However, as precisely confirming the presence of microcirculatory impairment in a real-world clinical setting is impossible, confirming visible narrowing of the coronary artery may provide a partial solution. In this study, cardiac troponin T is used as a marker for MI. Reports suggest that compared with troponin T, troponin I is more useful for the diagnosis of ischemic heart disease in patients with kidney disease35, 36). This study may have resulted in more accurate results if MI had been diagnosed with the use of troponin I. Another limitation is that the proportion of men in our study was higher than that of the annual data of the Japanese Society for Dialysis Therapy37). This difference suggests a limitation in easily applying the results of this study to all HD patients in Japan.
Myocardial oxygen supply and demand imbalance in patients with ESKD is potentially associated with MI. Appropriate management of blood pressure levels, PR, and anemia in patients with ESKD may prevent MI and lead to a better prognosis.
The authors show great appreciation to Naoko Tsuda for their kind assistance with database management.
None of grant support.
None to declare.
