Cerebral small vessel disease (cSVD) is a pathological process that affects the small arteries, arterioles, capillaries, and venules of the brain. Neuroimaging markers including white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMB), and enlarged perivascular spaces (PVS) are commonly used to evaluate the severity of cSVD [1]. These representative SVD markers, along with composite scores that combine them, are associated with stroke incidence, recurrence, and mortality [2,3,4]. However, their cumulative impact on long-term functional outcomes, especially in patients with spontaneous intracerebral hemorrhage (sICH), remains underexplored. In this issue of Hypertension Research, Ikeda et al. addressed this gap and provided new insights by investigating the long-term impact of cSVD on patients with sICH in the HAGAKURE-ICH study [5].

This single-center prospective cohort study followed 155 patients with sICH who underwent MRI to assess SVD markers, over a median period of 2.1 years. Among these patients, 98 had severe SVD burden (SVD score ≥ 3). Over the follow-up period, the study reported stroke recurrence and mortality rates of 2.2 and 8.3 per 100 patient-years, respectively. Regarding functional prognosis, 51.8% of patients showed improvement, 29.1% remained stable, and 19.1% experienced a decline. Severe SVD burden, particularly moderate-to-severe WMH, was significantly associated with poorer functional prognosis (odds ratio [OR] 2.54; 95% confidence interval [CI] 1.02–6.54; p = 0.048), underscoring the cumulative impact of SVD on the long-term prognosis of patients with sICH.

cSVD has a significant impact on stroke outcomes, particularly in patients with sICH. A meta-analysis examining the relationship between cSVD markers or total cSVD burden and stroke prognosis demonstrated that WMH, lacunes, CMB, and total cSVD burden are associated with a substantially increased risk of worse functional outcomes, mortality, and stroke recurrence [4]. While few studies have evaluated long-term prognosis, a five-year follow-up study of patients with ICH found that severe white matter lesions, CMB, and cumulative cSVD score were associated with poor long-term outcomes in sICH [6]. The results of these studies support the current research findings, indicating that WMH, CMB, and total SVD score are among the markers associated with poor prognosis [5].

A distinctive and significant aspect of this study was the definition of functional outcomes based on changes in the modified Rankin Scale (mRS). Severe SVD burden was significantly associated with functional decline over the two-year follow-up period. Notably, among patients with severe SVD burden who experienced a worsening of mRS score by two points or more, no cases of stroke recurrence were observed. Although the underlying mechanisms are likely multifactorial, particularly in elderly populations, these findings suggest that SVD burden itself may be intrinsically linked to functional prognosis.

The underlying pathophysiology of cSVD involves a complex interplay of endothelial dysfunction, blood-brain barrier disruption, chronic inflammation, white matter changes, and vascular alterations such as arteriolosclerosis [3]. These pathological processes contribute to several key mechanisms by which cSVD affects stroke outcomes. Impaired cerebral blood flow regulation due to endothelial dysfunction and arteriolosclerosis can lead to inadequate brain perfusion [7]. Chronic hypoxia and endothelial dysfunction in cSVD create a vulnerable brain environment, where even minor insults may cause significant damage [8]. cSVD disrupts white matter tracts and neural networks, inhibiting functional recovery by impairing the brain’s ability to recruit alternative pathways or reorganize post-stroke [9]. Pre-existing low-grade inflammation in cSVD may exacerbate the inflammatory cascade triggered by acute stroke, leading to more extensive tissue damage [10]. Additionally, the reduced cognitive reserve associated with cSVD may limit the ability of the brain to compensate for stroke-related damage. Each of these factors may profoundly influence the cumulative disease burden (Table 1).

In conclusion, cSVD plays a crucial role in determining functional outcomes following stroke, particularly sICH. Understanding the complex interplay between cSVD pathology, acute stroke injury, and recovery processes is essential for the development of more effective prevention and treatment strategies. Future research should focus on elucidating the mechanisms underlying the relationship between cSVD and stroke outcomes as well as identifying novel therapeutic targets to mitigate the impact of cSVD on brain health and function.