2023 Volume 30 Issue 9 Pages 1198-1209
Aims: We aimed to assess the prognostic impact of hyperhomocysteinemia (HHcy) on the recurrent vascular event risk in stroke patients with or without chronic kidney disease (CKD).
Methods: In this prospective observational study, 621 patients (mean age, 69.5 years; male, 62.2%) with ischemic stroke or transient ischemic attack were consecutively enrolled within 1 week of onset and followed-up for 1 year. HHcy was defined as elevated levels of fasting total homocysteine ＞15 µmol/L. CKD was defined as an estimated glomerular filtration rate of ＜60 mL/min/1.73 m2 or a history of renal replacement therapy. The primary outcome was a composite of major adverse cardiovascular events (MACEs), including nonfatal stroke, nonfatal acute coronary syndrome, major peripheral artery disease, and vascular death.
Results: The prevalence of HHcy was 18.5%. Patients with HHcy were more likely to have intracranial (37.4% versus 24.8%; p=0.008) and extracranial (20.9% versus 13.0%; p=0.037) artery stenosis than were those without HHcy. At 1 year, patients with HHcy were at a greater risk of MACE than were those without HHcy (annual rate, 17.8% versus 10.4%; log-rank p=0.033). In the Cox proportional hazard regression models, HHcy was independently associated with an increased risk of MACE in patients with CKD (adjusted hazard ratio [HR], 2.06; 95% confidence interval [CI], 1.02-4.20), whereas HHcy was not predictive of MACE in those without CKD (adjusted HR, 1.00; 95% CI, 0.30-3.32).
Conclusions: Elevated levels of serum homocysteine can be an important modifiable risk factor in stroke patients with CKD, but not in those without CKD.
Clinical trial registration
The TWMU Stroke Registry is registered at UMIN000031913 (https://upload.umin.ac.jp).
The residual risk of vascular events after a stroke is substantial despite the aggressive management of traditional risk factors such as hypertension, diabetes mellitus, dyslipidemia, and atrial fibrillation1). Given that 60–80% of ischemic strokes are due to traditional risk factors2), non-traditional risk factors may still play important roles in risk prediction as well as in secondary prevention. Hyperhomocysteinemia (HHcy) is recognized as one of the non-traditional vascular risk factors, and previous epidemiological studies have indicated significant associations of HHcy with incident stroke and coronary artery disease3, 4). However, there are few data regarding the residual HHcy-associated risk in stroke patients.
Serum homocysteine (Hcy) levels are closely related to the renal function, and patients with chronic kidney disease (CKD) are more likely to have HHcy5). Accordingly, we speculated that the prognostic impact of HHcy may differ between patients with and without CKD. Therefore, when investigating the relations between HHcy and vascular diseases, there may be a need to categorize patients according to the presence or absence of CKD. In the present study, we aimed to assess the prognostic role of HHcy in ischemic stroke or transient ischemic attack patients with and without CKD.
This was a single-center prospective observational study, in which Japanese patients with acute ischemic stroke or transient ischemic attack hospitalized at our center within 1 week of onset were consecutively enrolled. The study adhered to the ethical principles of the 1975 Declaration of Helsinki, as well as the Ethical Guidelines for Epidemiological Research by the Japanese government and the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. The study protocol was approved by the ethics committee of Tokyo Women’s Medical University (TWMU) Hospital (approval no. 2955-R2). Written informed consent was obtained from all the patients. The TWMU Stroke Registry is registered at UMIN000031913 (https://upload.umin.ac.jp). The data that support the findings of this study are available from the corresponding author upon reasonable request.
Between December 2013 and January 2020, 887 patients were enrolled in the study. After excluding 9 patients who met the exclusion criteria (e.g., stroke mimics as final diagnosis, enrolled more than 1 week after stroke onset, lack of data because of transfer to another hospital, or duplicate registration) and 257 patients without data regarding baseline Hcy levels, the data of 621 patients were included in the present analysis (Fig.1).
Study flow chart
All cases of stroke or transient ischemic attack were diagnosed by board-certified stroke neurologists based on neurological and radiological findings. Upon admission, the neurological symptoms were assessed using the National Institutes of Health Stroke Scale score. The patient data collected included demographic data, clinical symptoms during the qualifying event, medical histories (hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, chronic heart failure, CKD, stroke, and current smoking), medications, investigations (including blood tests, brain and cerebral artery imaging, 24-hour Holter electrocardiogram, and ultrasonic echocardiography), management (medical treatment, revascularization procedure, and surgery), and the occurrence of clinical events after the qualifying event using a structured case report form. The etiologies of ischemic stroke were classified into small vessel disease, atherothrombosis, cardioembolism, other determined causes, and undetermined causes, according to the Trial of Org 10172 in Acute Stroke Treatment classification6).
HHcyFasting blood samples were used for plasma Hcy measurement. Total Hcy levels were measured using high-performance liquid chromatography. HHcy was defined as serum Hcy concentrations of ＞15 µmol/L at baseline7).
Renal DiseaseThe estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease formula with the Japanese coefficient. CKD was defined as an eGFR of ＜60 mL/min/1.73 m2 or a history of renal replacement therapy, including hemodialysis and renal transplantation.
Evaluation of Atherosclerotic DiseaseThe intracranial arteries were examined using time-of-flight magnetic resonance angiography (n=593) and/or computed tomography angiography (n=128). The narrowest diameter of each stenosed vessel was measured and divided by the diameter of the normal vessel proximal to the lesion or distal to the lesion if the proximal artery was diseased. Significant intracranial artery stenosis (ICAS) was defined as ＞50% stenosis or occlusion.
Extracranial carotid atherosclerosis was evaluated using ultrasonography (n=593) and/or computed tomography angiography (n=72) and/or time-of-flight magnetic resonance angiography (n=65). We defined significant extracranial artery stenosis (ECAS) as atherosclerotic stenosis of ＞50% or occlusion according to the European Carotid Surgery Trial criteria8).
Aortic atherosclerosis was evaluated using transesophageal echocardiography (n=180). Mobile plaques were diagnosed as mobile components that swung on their peduncles. An ulcerative plaque was diagnosed as a discrete indentation of the luminal surface of the plaque with a base width, as well as a maximum depth, of ≥2 mm. Complex aortic atheroma was defined as any plaque with a thickness of ≥4 mm or ulceration or mobile components9).
Follow-Up and OutcomesPatients visited our center after 3 months and thereafter every 1 year for 3 years after enrollment. This study reports 1-year outcomes. At follow-up visits, the findings from physical examinations, treatments, any clinical events, and modified Rankin Scale scores were recorded. If the patient could not be reached for follow-up, a relative or caregiver was interviewed via telephone. The primary outcome was a composite of major adverse cardiovascular events (MACEs), including nonfatal stroke (ischemic or hemorrhagic), nonfatal acute coronary syndrome, major peripheral artery disease, and vascular death. Vascular death was defined as fatal acute coronary artery disease, fatal stroke, and other cardiovascular deaths. Secondary outcomes included any stroke and stroke subtypes (ischemic or hemorrhagic).
Statistical AnalysisQuantitative variables are expressed as means (standard deviations) for normally distributed data or medians (interquartile ranges) for non-normally distributed data. Qualitative variables are presented as frequencies (percentages). The study participants were divided into HHcy and non-HHcy groups, and between-group comparisons were performed using a t-test or the Mann-Whitney U test for quantitative variables and the χ2 test for qualitative variables, as appropriate. The event rates were estimated using the Kaplan-Meier method, and inter-group differences were assessed using the log-rank test. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Age, sex, and the medical histories with p values of ＜0.05 in the univariable analysis were entered into the multivariable model. Subgroup analysis was performed for those with and without CKD separately. In addition, we divided patients into 3 groups according to the tertile of Hcy levels in those with CKD (tertile 1, ＜10.66 µmol/L; tertile 2, 10.66–14.81 µmol/L; tertile 3, ＞14.81 µmol/L) and without CKD (tertile 1, ＜7.20 µmol/L; tertile 2, 7.20–9.87 µmol/L; tertile 3, ＞9.87 µmol/L) separately. Then, we examined the associations of Hcy levels with the 1-year MACE risk. The data for the patients with no information at 1 year were censored at the time of the last available follow-up. For a given outcome, the patients who died of causes other than the outcome were censored at the time of death. Events that occurred after 1 year of follow-up were not included in the current analysis. For all analyses, statistical significance was set at p＜0.05.
Among the 621 patients included in the analysis (mean age, 69.5 years; male, 62.2%), the mean Hcy level was 11.8±9.4 µmol/L. Further, 115 (18.5 %) and 268 (43.1 %) patients had HHcy and CKD, respectively. In the groups of patients with and without CKD, the mean Hcy levels were 14.5±9.8 µmol/L and 9.7±8.6 µmol/L, and 88 (32.8 %) and 27 (7.6 %) had HHcy, respectively.
Table 1 shows the baseline characteristics of all patients. Patients with HHcy were more likely to be male and have hypertension, chronic heart failure, and CKD than were those without HHcy. The serum levels of high-density lipoprotein cholesterol and the eGFR were lower, and the levels of low-density lipoprotein cholesterol was higher in those with HHcy than in those without HHcy. There was no significant association between HHcy and ischemic stroke subtypes. The baseline characteristics of patients with and without CKD are provided in Supplemental Table 1 and Supplemental Table 2.
| Non-HHcy (n= 506) | HHcy (n= 115) | p value | |
|---|---|---|---|
| Age, y | 70±14 | 67±15 | 0.059 |
| Male | 303 (59.9) | 83 (72.8) | 0.009 |
| Medical history | |||
| Hypertension | 341 (67.4) | 96 (84.2) | 0.002 |
| Diabetes mellitus | 183 (36.3) | 51 (37.8) | 0.11 |
| Dyslipidemia | 224 (44.2) | 65 (56.5) | 0.018 |
| Atrial fibrillation | 98 (19.4) | 21 (18.4) | 0.82 |
| Chronic heart failure | 51 (10.1) | 26 (22.6) | ＜0.001 |
| Chronic kidney disease | 180 (35.6) | 88 (76.5) | ＜0.001 |
| Stroke | 97 (19.3) | 26 (22.6) | 0.43 |
| Current smoking | 84 (16.7) | 24 (20.9) | 0.30 |
| Laboratory data | |||
| eGFR | 66±21 | 37±28 | ＜0.001 |
| LDL-c, mg/dL | 118±36 | 106±32 | 0.001 |
| HDL-c, mg/dL | 57±17 | 51±18 | 0.002 |
| Triglycerides, mg/dL | 130±92 | 129±79 | 0.92 |
| HbA1c, % | 6.9±6.0 | 6.3±1.2 | 0.30 |
| NIHSS | 2 (1–5) | 2 (1–5) | 0.88 |
| Stroke subtypes | 0.19 | ||
| Small vessel disease | 107 (21.1) | 20 (17.4) | |
| Atherothrombosis | 97 (19.1) | 32 (27.8) | |
| Cardioembolism | 114 (22.4) | 29 (25.2) | |
| Other causes | 33 (6.5) | 4 (3.5) | |
| Undetermined causes | 155 (30.8) | 30 (26.1) |
Figures are expressed as n (%), mean±standard deviation, or median (interquartile range).
Chronic kidney disease was defined as an eGFR ＜60 mL/min/1.73 m2 or a history of renal replacement therapy.
Abbreviations: eGFR = estimated glomerular filtration rate; HDL-c = high-density lipoprotein cholesterol; HHcy = hyperhomocysteinemia; LDL- c = low-density lipoprotein cholesterol; NIHSS = National Institute of Health Stroke Scale.
| Non-HHcy (n= 180) | HHcy (n= 88) | p value | |
|---|---|---|---|
| Age, y | 74±11 | 68±14 | ＜0.001 |
| Male | 110 (61.8) | 60 (69.0) | 0.25 |
| Medical history | |||
| Hypertension | 132 (74.1) | 77 (88.5) | 0.005 |
| Diabetes mellitus | 80 (44.9) | 44 (50.0) | 0.048 |
| Dyslipidemia | 94 (52.8) | 50 (56.8) | 0.54 |
| Atrial fibrillation | 53 (29.6) | 19 (21.8) | 0.18 |
| Chronic heart failure | 30 (16.8) | 25 (28.4) | 0.030 |
| Stroke | 45 (25.4) | 23 (26.1) | 0.90 |
| Current smoking | 21 (11.9) | 15 (13.6) | 0.25 |
| Laboratory data | |||
| eGFR | 44±13 | 26±19 | ＜0.001 |
| LDL-c, mg/dL | 115±37 | 105±34 | 0.036 |
| HDL-c, mg/dL | 56±18 | 49±17 | 0.013 |
| Triglycerides, mg/dL | 126±82 | 134±85 | 0.44 |
| HbA1c, % | 6.6±1.5 | 6.3±1.3 | 0.093 |
| NIHSS | 2 (1–5) | 3 (1–6) | 0.91 |
| Stroke subtypes | 0.47 | ||
| Small vessel disease | 33 (18.4) | 12 (13.6) | |
| Atherothrombosis | 32 (17.9) | 24 (27.3) | |
| Cardioembolism | 55 (30.6) | 26 (29.6) | |
| Other causes | 7 (3.9) | 3 (3.4) | |
| Undetermined causes | 53 (29.4) | 23 (26.1) |
Figures are expressed as n (%), mean±standard deviation, or median (interquartile range).
Chronic kidney disease was defined as an eGFR ＜60 mL/min/1.73 m2 or a history of renal replacement therapy.
Abbreviations: eGFR = estimated glomerular filtration rate; HDL-c = high-density lipoprotein cholesterol; HHcy = hyperhomocysteinemia; LDL-c = low-density lipoprotein cholesterol; NIHSS = National Institute of Health Stroke Scale
| Non-HHcy (n= 326) | HHcy (n= 27) | p value | |
|---|---|---|---|
| Age, y | 67±14 | 61±16 | 0.026 |
| Male | 192 (58.9) | 23 (85.2) | 0.004 |
| Medical history | |||
| Hypertension | 209 (64.1) | 19 (70.3) | 0.51 |
| Diabetes mellitus | 103 (31.8) | 7 (25.9) | 0.52 |
| Dyslipidemia | 130 (39.9) | 15 (55.6) | 0.12 |
| Atrial fibrillation | 44 (13.5) | 2 (7.4) | 0.33 |
| Chronic heart failure | 20 (6.1) | 1 (3.7) | 0.58 |
| Stroke | 52 (16.1) | 3 (11.1) | 0.48 |
| Current smoking | 63 (19.4) | 9 (33.3) | 0.10 |
| Laboratory data | |||
| eGFR | 78±15 | 76±14 | 0.50 |
| LDL-c, mg/dL | 121±36 | 112±27 | 0.19 |
| HDL-c, mg/dL | 57±17 | 54±18 | 0.44 |
| Triglycerides, mg/dL | 133±97 | 112±52 | 0.28 |
| HbA1c, % | 7.0±7.4 | 6.1±0.9 | 0.093 |
| NIHSS | 4 (1–5) | 2 (1–4) | 0.18 |
| Stroke subtypes | 0.61 | ||
| Small vessel disease | 74 (22.7) | 8 (29.6) | |
| Atherothrombosis | 64 (19.6) | 8 (29.6) | |
| Cardioembolism | 59 (18.1) | 3 (11.1) | |
| Other causes | 26 (8.0) | 1 (3.7) | |
| Undetermined causes | 103 (31.3) | 7 (25.9) |
Figures are expressed as n (%), mean±standard deviation, or median (interquartile range).
Chronic kidney disease was defined as an eGFR ＜60 mL/min/1.73 m2 or a history of renal replacement therapy.
Abbreviations: eGFR = estimated glomerular filtration rate; HDL-c = high-density lipoprotein cholesterol; HHcy = hyperhomocysteinemia; LDL-c = low-density lipoprotein cholesterol; NIHSS = National Institute of Health Stroke Scale
The data on medication use at discharge and surgery are presented in Supplemental Table 3. The usage rates of antiplatelet and anticoagulant agents were 73.8% and 31.6% in the non-HHcy group and 73.9% and 29.6% in the HHcy group, respectively.
| Non-HHcy (n = 506) | HHcy (n = 115) | p value | |
|---|---|---|---|
| Antiplatelet agent, | 374 (73.8) | 85 (73.9) | 0.97 |
| Single | 215 (42.4) | 46 (40.0) | 0.63 |
| Dual or triple | 159 (31.4) | 39 (33.9) | 0.61 |
| Anticoagulant agent | 160 (31.6) | 34 (29.6) | 0.68 |
| Warfarin | 49 (9.7) | 20 (17.4) | 0.024 |
| Direct oral anticoagulant agent | 106 (20.9) | 13 (11.3) | 0.013 |
| Antihypertensive agent | 254 (50.5) | 78 (68.4) | ＜0.001 |
| Lipid lowering agent | 333 (65.7) | 71 (61.7) | 0.43 |
| Statin | 322 (63.5) | 67 (58.3) | 0.30 |
| Others | 30 (5.9) | 16 (13.9) | 0.006 |
| Glucose lowering agent or insulin | 143 (28.2) | 31 (27.0) | 0.78 |
| Carotid endarterectomy | 6 (1.2) | 0 | 0.12 |
| Carotid artery stent | 14 (2.8) | 2 (1.7) | 0.51 |
Figures are expressed as n (%).
Abbreviation: HHcy = hyperhomocysteinemia
Fig.2 illustrates the prevalence of atherosclerotic diseases. HHcy was significantly associated with the prevalence of ICAS and ECAS, whereas no differences were observed for the prevalence of coronary artery disease or aortic atherosclerosis. For patients with CKD, HHcy was significantly associated with the ICAS prevalence.
Abbreviations: CKD=chronic kidney disease; HHcy=hyperhomocysteinemia.
＊p＜0.01
†p＜0.05
Among the 621 patients, vascular events occurred in 71 patients within 1 year (event rate, 11.5%; 95% CI, 9.2–14.2%). As shown in Fig.3 and Table 2, according to the Kaplan-Meier method, the rate of MACE was significantly higher in patients with HHcy than in patients without HHcy (annual rate, 17.8% versus 10.4%; log-rank p=0.033). There was a significant association of HHcy with the MACE rate in patients with CKD (annual rate, 19.8% versus 10.0%; log-rank p=0.029), but not in those without CKD (annual rate, 11.3% versus 10.8%; log-rank p=0.93). When patients were stratified by the tertile of Hcy levels, higher Hcy levels were still significantly associated with the higher MACE rate in those with CKD (annual rate, 5.8%, 13.1%, and 20.7% in the tertile 1, tertile 2, and tertile 3 groups, respectively; log-rank p=0.016). On the other hand, such an association was not found in those without CKD (annual rate, 10.4%, 12.7%, and 9.5% in the tertile 1, tertile 2, and tertile 3 groups, respectively; log-rank p=0.79) (Supplemental Fig.1). In the Cox proportional hazard regression models, HHcy patients with CKD had a higher risk of MACE than did non-HHcy patients with CKD (adjusted HR, 2.06; 95% CI, 1.02–4.20), but those without CKD did not (adjusted HR, 1.00; 95% CI, 0.30–3.32). After a further adjustment for eGFR values, there was a nearly significant association of HHcy with the MACE risk in patients with CKD (adjusted HR, 2.32; 95% CI, 0.95–5.68; p=0.064).
Abbreviation: HHcy=hyperhomocysteinemia
| All patients (n= 621) | Event rate, n (%/year) |
Log rank p value |
Adjusted HR (95% CI)＊ | p value＊ | |
|---|---|---|---|---|---|
| Non-HHcy (n= 506) | HHcy (n= 115) | ||||
| Primary outcome | |||||
| MACE | 51 (10.4) | 20 (17.8) | 0.033 | 1.62 (0.91–2.88) | 0.098 |
| Secondary outcome | |||||
| Any stroke | 45 (9.2) | 15 (13.2) | 0.18 | 1.55 (0.81–2.97) | 0.18 |
| Ischemic stroke | 42 (8.5) | 13 (11.4) | 0.31 | 1.38 (0.70–2.74) | 0.35 |
| Hemorrhagic stroke | 3 (0.6) | 2 (1.9) | 0.22 | 5.05 (0.65–39.1) | 0.12 |
| Patients with chronic kidney disease (n= 268) | Event rate, n (%/year) |
Log rank p value |
Adjusted HR (95% CI) ＊ | p value＊ | |
| Non-HHcy (n= 180) | HHcy (n= 88) | ||||
| Primary outcome | |||||
| MACE | 17 (10.0) | 17 (19.8) | 0.029 | 2.06 (1.02–4.20) | 0.044 |
| Secondary outcome | |||||
| Any stroke | 13 (7.5) | 13 (15.0) | 0.059 | 2.17 (0.96–4.88) | 0.062 |
| Ischemic stroke | 13 (7.5) | 11 (12.7) | 0.17 | 1.78 (0.76–4.16) | 0.18 |
| Hemorrhagic stroke | 0 | 2 (2.4) | 0.047 | - | 1.00 |
| Patients without chronic kidney disease (n= 353) | Event rate, n (%/year) |
Log rank p value |
Adjusted HR (95% CI) ＊ | p value＊ | |
| Non-HHcy (n= 326) | HHcy (n= 27) | ||||
| Primary outcome | |||||
| MACE | 34 (10.8) | 3 (11.3) | 0.93 | 1.00 (0.30–3.32) | 0.99 |
| Secondary outcome | |||||
| Any stroke | 32 (10.2) | 2 (7.4) | 0.69 | 0.75 (0.18–3.20) | 0.70 |
| Ischemic stroke | 29 (9.2) | 2 (7.4) | 0.80 | 1.26 (0.30–5.37) | 0.76 |
| Hemorrhagic stroke | 3 (1.0) | 0 | 0.62 | - | 0.99＊ |
Adjusted for age, sex, and the variables with p values of ＜0.05 in the univariate analysis.
Abbreviations: CI = confidence interval; HHcy = hyperhomocysteinemia; HR = hazard ratio; MACE = major adverse cardiovascular event.
Patients were divided into 3 groups according to the tertile of homocysteine levels in those with chronic kidney disease (tertile 1, ＜10.66 µmol/L; tertile 2, 10.66–14.81 µmol/L; tertile 3, ＞14.81 µmol/L) and without chronic kidney disease (tertile 1, ＜7.20 µmol/L; tertile 2, 7.20–9.87 µmol/L; tertile 3, ＞9.87 µmol/L).
This study found that HHcy was associated with an increased prevalence of atherosclerotic stenosis in cervicocephalic arteries, rather than coronary or aortic atherosclerosis. Furthermore, HHcy was associated with a higher 1-year rate of MACE. Of note, the HHcy-related residual risk was found in patients with CKD, but not in those without CKD. This may suggest that HHcy is an important non-traditional risk factor particularly in stroke patients with CKD.
HHcy can promote atherosclerosis by endothelial oxidative damage via the suppression of nitric oxide and vascular smooth muscle proliferation10). Previous clinical studies found a higher prevalence of atherosclerotic diseases in HHcy than non-HHcy patients3, 11-15). In our study, HHcy was significantly related with ICAS and ECAS, but not coronary and aortic atherosclerosis. In an in vivo study, cerebral arterioles were more sensitive to HHcy and more likely to be affected by endothelial dysfunction than were aorta in mice16, 17). Moreover, in clinical studies, the relative risk for stroke was higher than that for coronary artery disease in HHcy patients compared to non-HHcy patients3, 4). Therefore, it is possible that the influence of HHcy on atherosclerotic diseases differs by vascular domains and that cerebral arteries may be susceptible to the Hcy toxicity.
HHcy can also cause thrombosis via the activation of platelet generation and deactivation of protein C and thrombomodulin, and consequently vascular events10). In the general population, HHcy increases the risk of incident cerebro- and cardiovascular events3, 4). However, the association between HHcy and residual vascular risk has been controversial among stroke patients; some studies found positive associations, but others did not18-20). The discrepant results may be partly due to differences in age, race, and the prevalence of common risk factors among the studies. Importantly, in our study, HHcy was significantly associated with the MACE risk in patients with CKD, but not in those without CKD. In general, patients with CKD are also more likely to have HHcy than those without CKD, since CKD reduces the clearance of Hcy from the plasma due to the reduced uptake and metabolism of Hcy in the kidney21). Moreover, CKD decreased the conversion of Hcy to methionine22). Previous clinical studies demonstrated that lower methionine, an essential sulfur-based amino acid, increased the risk of stroke23) and acute myocardial infarction24). It is unclear why HHcy independently increases the vascular risk in CKD patients, but not in non-CKD patients. One of explanations may be lower levels of vitamin D in CKD patients. CKD is commonly accompanied with vitamin D insufficiency25). In an experimental study, Hcy impairs mitochondrial function and induces changes in the redox status in heart tissue, which were reverted by the administration of 1,25-dihydroxivitamin D26). Hence, we speculated that the toxicity effects of Hcy might be more exhibited in CKD patients because of their lower vitamin D levels, although the causal association should be assessed in further studies. To date, there were no strong evidences that showed the benefit of homocysteine-lowering therapy in reducing vascular events27, 28). However, given our findings, stroke patients with CKD may be targeted in future studies.
Our study has several limitations. First, because of the single-center design, the generalizability of our results is limited. The annual MACE rate of 11.5% in the entire study population was higher than that reported in previous clinical trials on general stroke populations29, 30). This may be partly due to our continuous enrollment of patients regardless of their age, systemic conditions, or comorbidities, whereas clinical trials typically include patients whose general condition is fair. Moreover, patients were enrolled within 1 week of onset, ensuring that early recurrent vascular events were recorded. It is likely that our patients represent the “real world” stroke cohort rather than those who would be included in clinical trials. Second, the sample size was relatively small, and the number of outcome events was insufficient. Our results should be replicated in larger studies. Third, we did not collect the detailed information on recurrent ischemic strokes, including etiologic subtypes, examination findings or treatments. It would be interesting to see the underlying pathophysiology of recurrent stroke in HHcy patients, which will help optimize their secondary prevention strategies. Fourth, plasma Hcy levels are influenced by measurements such as chromatographic methods (e.g., mass spectrometry, high-performance liquid chromatography, or ion-exchange chromatography) and immunoassays (e.g., fluorescence polarization, chemiluminescence, or enzyme-linked immunoassays). The coefficients of variation for the mean total Hcy level in chromatographic methods and immunoassays are 2.6–7.8% and 3.1–6.2%, respectively31), and these differences may lead to misestimation of the characteristics and predictive value of HHcy. Fifth, we did not evaluate the serum folic acid and vitamin B12 levels and the genetic variants of methylenetetrahydrofolate reductase, all of which are known to affect HHcy concentrations32, 33). Finally, we did not measure the temporal changes in Hcy levels during the follow-up period. Lifestyle factors such as exercise, smoking, and alcohol would largely influence the Hcy concentrations34, 35).
Elevated levels of Hcy are associated with high atherosclerotic burden as well as the risk of vascular events in stroke patients with CKD. HHcy may be a good treatment target that should be addressed in future clinical trials, particularly in patients with CKD.
None.
None.
Dr. Kitagawa reports personal fees from Kyowa Kirin, grants and personal fees from Daiichi Sankyo, grants from Bayer, and grants from Dainihon Sumitomo outside the submitted work.
Other authors have nothing to disclose.
