White matter hyperintensity (WMH) is an important risk factor for cognitive dysfunction (Hu et al., 2021) and neuropsychiatric symptoms (Clancy et al., 2021) worldwide. Two meta-analyses have indicated a strong relationship between high blood pressure (BP) and the severity of WMH, especially in elderly individuals (Alateeq et al., 2021; Wilkinson and Webb, 2022). After adjusting for age, hypertension was the strongest risk factor for the development of WMH (Liao et al., 1996; Basile et al., 2006). Patients with uncontrolled hypertension have a higher risk of severe WMH and also face a higher risk of WMH progression compared with those who accepted hypertension prevention or treatment (Dufouil et al., 2001; Verhaaren et al., 2013). Additionally, patients with hypertension tend to have early occurrence of WMH (de Leeuw et al., 2002).

Relatively fewer studies have focused on the threshold of BP control in patients with WMH. An observational study revealed that a systolic blood pressure (SBP) higher than 160 mmHg or lower than 140 mmHg was associated with higher risk of WMH progression compared to an SBP between 140 and 160 mmHg in patients over 80 years old (Peng et al., 2014), indicating that an excessively high or low SBP contributes to the development of WMH in special populations. Previously reported studies used the traditional SBP threshold of <140 mmHg, and had a mean SBP over 130 mmHg after treatment (de Leeuw et al., 2002; Dufouil et al., 2005). In 2019, the Systolic Blood Pressure Intervention Trial (SPRINT), a multicenter randomized controlled study (RCT) with a 4-year follow-up (Nasrallah et al., 2019), included 670 patients older than 50 years without a history of diabetes and stroke who were randomly classified into two groups: (1) the intensive intervention group with an SBP less than 120 mmHg and (2) the standard treatment group with an SBP less 140 mmHg. The results of this study showed that among hypertensive adults, targeting SBP of less than 120 mmHg was significantly associated with a slower development of WMH (Nasrallah et al., 2019). However, at the end of intervention, the mean SBP was 120.7 mmHg in the intensive treatment group vs. 134.9 mmHg in the standard treatment group (Nasrallah et al., 2019). In 2020, a longitudinal study enrolled 505 community-dwelling and cognitively normal elderly individuals and measured BP values three times in a sitting position. The study revealed that a low SBP, defined as an SBP ≤110 mmHg, was independently associated with the severe periventricular WMH in patient with controlled hypertension but not in those without hypertension (Kim et al., 2020). High SBP variability was also shown to have a strong relationship with WMH severity and development (Zhang et al., 2022). Therefore, what is the optimal mean SBP and SBP variability that should be targeted to stop or slow the development of WMH?

Currently, whether diastolic blood pressure (DBP) plays an important role in the development and progression of WMH remains controversial (Zhang et al., 2020; Wilkinson and Webb, 2022). Several studies have supported a stronger association between DBP and WMH, compared to SBP. In 2011, a Northern Manhattan study (Marcus et al., 2011) including 1,290 stroke-free participants analyzed the association of two recorded BP values with changes in WMH from baseline to the last MRI scan and showed that the baseline DBP value and the longitudinal increase in DBP were independently associated with a greater increase in WMH volume (Marcus et al., 2011). Further literature from the Northern Manhattan study also indicated that DBP was associated with the region-specific load of WMH. Compared to patients with a DBP higher than 90 mmHg, those with a DBP between 80 and 89 mmHg presented a WMH volume in the anterior periventricular region that was approximately 12% lower and a WMH volume in the posterior periventricular region that was 9% lower; however, SBP values were not significantly associated with the regional location of WMH (Caunca et al., 2020). The mean age of the participants in these two studies was 64 ± 8 years, ranging from 40 to 90 years (Marcus et al., 2011; Caunca et al., 2020). A previous meta-analysis showed that the association of DBP with WMH was closer than that of SBP with WMH, and the risk of WMH progression in patients under 70 years old was higher than that in patients over 70 years old when the DBP was increased (Zhang et al., 2020). Data from a prospective, community-based, multicenter cohort study (UK Biobank) of midlife patients between 40 to 69 years old also revealed that although WMH was more strongly associated with current SBP control, past DBP control had a stronger association with WMH load compared to past SBP control, especially in patients under 50 years old (Wartolowska and Webb, 2021). These studies indicated a more important role of DBP in the occurrence and development of WMH in midlife patients, in whom WMH starts to appear earlier among those with hypertension (de Leeuw et al., 2002). Although, low DBP, defined as a DBP <60 mmHg, did not show an association with WMH severity (Kim et al., 2020). As an important factor that determines organ perfusion, a low DBP was reported to be the only independent risk factor associated with periprocedural stroke or death (de Waard et al., 2017) and was associated with an increased risk of cardiovascular events (Stensrud and Strohmaier, 2017; Böhm et al., 2018; Tsujimoto and Kajio, 2018). Greater DBP variability and a low DBP have also been confirmed as risk factors for cognitive decline in later life (average 62.5 years old) (Lee et al., 2020; Peters and Xu, 2022; Zhang et al., 2022). However, the optimal control thresholds for the mean DBP and DBP variability in patients with WMH still remains unclear.

To provide more evidence for SBP and DBP control in patients with WMH, this study mainly focused on longitudinal SBP and DBP data from baseline to the final MRI scan. Second, in this study, we aimed to determine the optimal threshold of mean SBP and DBP, and BP variability associated with a lower risk of WMH progression.

In this retrospective study, both SBP and DBP values were strongly associated with the severity of WMH. A mean SBP value lower than 130 mmHg, a mean DBP value lower than 80 mmHg were associated with a lower risk of WMH progression, but only mean SBP was significant after adjusted for age, education level, diabetes mellitus, hyperhomocysteinemia, smoking status, stroke, kidney dysfunction, and etiology of hospitalization. Although longitudinal SBP variability and DBP variability were associated with the severity of WMH, but were not related to risk of WMH progression.

In the SPRINT study (Nasrallah et al., 2019), intensive SBP control of lower than 120 mmHg was significantly associated with a smaller increase in mean WMH volume compared with standard SBP control of lower than 140 mmHg, although no change in cognitive decline was observed (Liao et al., 1996). At the end of the intervention, the mean SBP value was 120.7 mmHg in the intensive treatment group vs. 134.9 mmHg in the standard treatment group. In our study, the mean longitudinal SBP value was 129.04 ± 8.34 mmHg in the WMH absence group, 131.65 ± 9.96 mmHg in the mild WMH group, and 140.68 ± 11.27 mmHg in the moderate to severe WMH group (Nasrallah et al., 2019). Patients with a mean SBP value lower than 130 mmHg showed a significantly lower risk of WMH progression compared to those with SBP values of 130–140, 140–150, and ≥ 150 mmHg. This evidence confirmed a positive effect of the intensive reduction of the mean SBP to a value lower than 130 mmHg to reduce the risk of WMH progression. As an SBP lower than 110 mmHg has also been reported to be associated with more severe periventricular WMH in patients with a history of hypertension (de Waard et al., 2017), the control of mean SBP between 110 mmHg and 130 mmHg seems to be the optimal target threshold, although further study is still needed.

Until now, the association between DBP and WMH has remained controversial. Two studies using the data from the Northern Manhattan study revealed a significant association between DBP and WMH progression (Marcus et al., 2011) and the region-specific load of WMH in the anterior periventricular region and the posterior periventricular region (Caunca et al., 2020), while a nonsignificant association was observed between SBP and both WMH progression and region distribution (Marcus et al., 2011; Caunca et al., 2020). To better reflect patients’ BP control status between baseline and the last MRI scans, we collected in our study more detailed BP records every year, including inpatient records, outpatient visit records, community monitoring records, and home monitoring records. The results of the study also showed a significant association between DBP and the severity of WMH, which was consistent with the Northern Manhattan study. A trend of elevated risk of WMH progression with increasing DBP levels was also observed in this study. The mean longitudinal DBP value was 78.08 ± 4.64 mmHg in the WMH absence group, 77.91 ± 5.11 mmHg in the mild WMH group, and 83.38 ± 6.65 mmHg in the moderate to severe WMH group. A mean DBP value lower than 80 mmHg was evidently associated with a higher risk of WMH progression in unadjusted analysis, but the association was nonsignificant after adjusting for age, education, diabetes mellitus, hyperhomocysteinemia, smoking, stroke, kidney dysfunction, and etiology of hospitalization. The DBP variability was not correlated with WMH progression before or after adjustment. A DBP value lower than 60 mmHg has been reported to increase the risk of faster cognitive decline (Razay et al., 2009), periprocedural stroke and death (de Waard et al., 2017), and cardiovascular events (Stensrud and Strohmaier, 2017; Böhm et al., 2018; Tsujimoto and Kajio, 2018) but not the severity of WMH (Kim et al., 2020). A DBP value between 60 and 80 mmHg seems to be the optimal threshold in patients with hypertension.

In our study, SBP SD, SBP CV, DBP SD, and DBP CV was not associated with the risk of WMH progression. Although SBP SD >11.1 mmHg and an SBP CV of >12.24% was associated with the risk WMH progression, but this was not significant after adjusting for age, education level, diabetes mellitus, hyperhomocysteinemia, smoking status, stroke, kidney dysfunction, and the etiology for hospitalization. Previous studies had reported an independent association between 24 h BP variability and WMH volumes/severity (van Middelaar et al., 2019; Zhang et al., 2022). There were several explanations that may be associated with the different result of our study and previous studies. Firstly, the mean age of the patients were about 70–80 years old or elder (Liu et al., 2016; van Middelaar et al., 2019; Zhang et al., 2022). However, the mean age of patients in our study was 61.79 ± 8.11 in total. Older population may be more sensitive to BP variability. Besides, in previous studies, the evaluation of MWH mainly focused on the severity or volume of the last visit (van Middelaar et al., 2019; Zhang et al., 2022), which was different from a dynamic progression of WMH in our study. Thirdly, the frequency and time interval of BP recording in our study was not that regular comparing to other studies. Further studies are still needed.

Subgroup analysis in our study revealed that the risk of WMH progression was significantly reduced when the SBP value was lower than 130 mmHg and the DBP value was lower than 80 mmHg in patients younger than 70 years old and patients with a history of stroke. This was consistent with a previous meta-analysis that indicated a higher risk of WMH progression in patients under 70 years old than in patients over 70 years old when their DBP increased (Verhaaren et al., 2013; Zhang et al., 2020). A clinical registry study (PORTYWHITE) involving neurology outpatients aged 18–55 years with vascular WMH on MRI and a score of II or III on the Fazekas scale revealed that although patients tended to be concentrated in the oldest age groups (age ≥ 45 years), patients without a stroke history were younger and had a lower burden of WMH and fewer vascular risk factors; however, hypertension was still the most frequent vascular risk factor (Viana-Baptista et al., 2019). In patients between 40 and 69 years old, past DBP control showed the strongest association with WMH risk when comparing the current DBP level and past SBP control, especially in patients under 50 years old (Wartolowska and Webb, 2021). These findings may also demonstrate potential greater benefits of strict BP control in younger patients and patients with a history of stroke, especially DBP control. In elderly patients or patients with multiple diseases, excessive lowering of SBP and DBP should be carefully considered. Our study excluded patients with large-area stroke but included patients with minor stroke and lacunes. Data from the framework of the international multisite MRI-Genetics Interface Exploration (MRI-GENIE) study showed that a higher WMH burden was associated with increased stroke severity and depended on stroke lesion locations (Bonkhoff et al., 2022). The presence of lacunes at the initial visit was a strong predictor of WMH progression (Jiang et al., 2022). For stroke type, patients with small artery occlusion had significantly higher WMH volumes compared to those with other stroke subtypes (Giese et al., 2020). The relationship between WMH and large artery sclerosis could not exclude multitype target organ damage caused by similar vascular risk factors, as earlier studies failed to determine the association between intracranial large-artery stenosis and WMH (Park et al., 2015).

Patients with hypertension tend to develop lower myelin content, have more severe brain microstructure impairment (Laporte et al., 2023a), have a higher risk of perivascular inflammation (Solé-Guardia et al., 2023), have lower cerebrovascular density, and have lower branch numbers (Zhang et al., 2021), which are potential mechanisms of WMH (Ungvari et al., 2021). Data from the Baltimore Longitudinal Study of Aging (BLSA) and the Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing (GESTALT) studies analyzed the association between hypertension and myelin content measured by Diffusion tensor imaging (DTI) and showed that patients with hypertension presented lower myelin content and higher impairment to the brain microstructure, especially in the corpus callosum, fronto-occipital fasciculus, temporal lobes, internal capsules, and corona radiata (Laporte et al., 2023a). Additionally, elevated arterial stiffness was associated with lower microstructural integrity of white matter, and this association was also stronger and significant in the splenium of the corpus callosum and internal capsules, which have been reported to be sensitive to elevated arterial stiffness (Laporte et al., 2023b). Controlling arterial stiffness may represent a therapeutic target in maintaining the health of white matter tissue in the cerebral normative aging (Laporte et al., 2023b). Patients with a history of hypertension also have two times the risk of perivascular inflammation both in white matter with hyperintensity and normal-appearing white matter, indicating that neurovascular inflammation is involved in the etiology of WMH (Solé-Guardia et al., 2023). This evidence indicated that patients with hypertension are potentially susceptible to the development of WMH and that early prevention and intervention of hypertension is helpful to stop or delay WMH development.

This study had several differences and limitations compared with other studies. The first was that we used the Fazekas scale to semi-quantitatively analyze severity and WMH progression rather than WMH volume. As the Fazekas scale is a commonly used tool both in the clinic and in clinical studies, it may be easier and applicable to help clinicians understand the severity of WMH and the velocity of WMH progression. The second was that we did not analyze a lower SBP of <120 mmHg or < 110 mmHg and DBP <60 mmHg as there were very few patients with a mean SBP of lower than 120 mmHg and DBP lower than 70 mmHg in our study. The third limitation of the retrospective study was that the total number of blood pressure records and the time interval between blood pressure measurements, which might differ among different patients as the number of hospitalizations and outpatient visits were different. These blood pressure records may not be adequate to represent the patients’ average daily control of blood pressure.

In this longitudinal retrospective study, both SBP and DBP had a strong relationship with the severity of WMH. A target mean SBP lower than 130 mmHg and a mean DBP lower than 80 mmHg were associated with a lower risk of WMH progression. An SBP SD value <11.1 mmHg and an SBP CV value <12.24% were associated with lower risk of WMH progression, but DBP variability was not.

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

All procedures were performed in accordance with relevant named guidelines and regulations and were approved by the ethics committee of the Dalian Central Municipal Hospital. Written informed consent was not required to participate in this study in accordance with the local legislation and institutional requirements.

SL: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Writing – original draft. MW: Data curation, Formal analysis, Supervision, Validation, Visualization, Writing – original draft. DG: Data curation, Investigation, Validation, Writing – original draft. YL: Data curation, Investigation, Validation, Writing – original draft. XZ: Data curation, Investigation, Validation, Writing – original draft. HL: Data curation, Investigation, Validation, Writing – original draft. CJ: Investigation, Validation, Writing – original draft. XN: Investigation, Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Project administration, Resources, Writing – review & editing. JL: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Writing – review & editing.