Authors: Hubert Lee (Department of Neurosurgery and Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA), Uzair Ahmed (Department of Neurosurgery and Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA), Teresa Bell‐Stephens (Department of Neurosurgery and Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA), Gary K. Steinberg (Department of Neurosurgery and Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA)
Categories: Original Research, cerebral revascularization, hypertension, moyamoya disease, prevalence
Source: Stroke: Vascular and Interventional Neurology
Authors: Hubert Lee, Uzair Ahmed, Teresa Bell‐Stephens, Gary K. Steinberg
Hypertension is often codiagnosed in patients with moyamoya disease (MMD), a progressive intracranial steno‐occlusive vasculopathy; this has principally been attributed to renal artery stenosis (up to 10%). Susceptibility MMD genes, including ring finger protein 213/mysterin and GUCY1A3, have also been linked to extracranial vascular disease and increased systolic blood pressure. We aimed to define the prevalence of systemic hypertension in MMD patients and characterize its evolution after cerebral revascularization.
Patients with MMD treated with extracranial‐intracranial bypass from 2014 to 2018 were retrospectively enrolled. Blood pressure measurements and antihypertensive agent use were recorded pre‐ and postoperatively. Hypertension was defined according to the 2020 International Society of Hypertension Guidelines (adults) and 2017 American Academy of Pediatrics Guidelines (children). Multivariate logistic regression was performed for clinical and radiographic predictors of hypertension.
A total of 242 adult and 51 pediatric patients underwent revascularization. Preoperatively, 146 adult and 20 pediatric patients met the diagnostic criteria for hypertension resulting in prevalences of 60.3% and 39.2% respectively. In adults, this was significantly associated with age (odds ratio [OR] 1.05 [95% CI, 1.02–1.09]), body mass index (OR, 1.08 [95% CI, 1.03–1.13]), hyperlipidemia (OR, 2.57 [95% CI, 1.09–6.04]), kidney disease (OR, 18.98 [95% CI, 1.80–200.47]), and symptomatic presentation (OR, 8.88 [95% CI, 1.16–68.06]). After a mean follow‐up of 34.3±18.1 months in adults (33.8±14.9 months – children), patients with hypertension decreased by 15.3% (1.9% – pediatrics) and 31.8% (17.7% – children) experienced improvement in hypertensive status with normalization of blood pressure or reduced need for antihypertensive agents. Posterior circulation involvement was a negative predictor for response of hypertensive status to revascularization (OR, 0.10 [95% CI, 0.01–0.79]).
Hypertension is prevalent among adult and pediatric patients with MMD with contributions from known vascular risk factors. Its association with symptomatic presentation and observed improvement following revascularization suggests blood pressure changes, in part, are a compensatory physiological response to increased intracranial vascular resistance.
Moyamoya disease (MMD) is a progressive intracranial arteriopathy typically characterized by stenosis or occlusion of the terminal internal carotid artery and its proximal branches giving rise to collaterals with the angiographic appearance of a “puff of smoke” at the skull base. ^1^ It commonly presents with ischemic stroke in children, and adults present with either hemorrhage or ischemia more frequently depending on the geographic region. ^2^ Patients with MMD have been observed to exhibit hypertension, particularly in children with renal artery stenosis. ^3^ , ^4^ , ^5^ , ^6^ However, case reports and cohort studies of pediatric patients with hypertension and MMD demonstrate a renovascular etiology is not always present and in one series, accounted for only 8% of cases. ^3^ , ^7^ , ^8^ The mechanism of essential hypertension in MMD is not understood but recently identified susceptibility genes for MMD in genetic linkage analysis of familial MMD have been associated with other intracranial and extracranial vascular disease. ^6^ , ^9^ , ^10^
One such gene is ring finger protein 213/mysterin on susceptibility locus 17q25.3 with the polymorphic variant, p.R4810k, strongly associated with MMD in East Asian populations. ^11^ , ^12^ It has a high prevalence among Japanese (90%) and Korean (75%–79%) patients with MMD in whom those with homozygous genotype demonstrate earlier age of disease onset, symptomatic disease, cerebral infarction on presentation, and cognitive impairment. ^12^ Approximately 1%–2% of individuals in the general Japanese and Korean population are carriers of this variant without evidence of disease. ^10^ , ^11^ p.R4810k is hypothesized to play a role in vascular maintenance, through regulation of lipotoxicity and inflammation, and has been associated with intracranial artery stenosis unrelated to MMD, pulmonary artery hypertension, coronary artery disease, and systemic hypertension. ^9^ , ^10^ , ^13^ , ^14^ , ^15^ , ^16^ Mutations in GUCY1A3, a gene that encodes the soluble guanylate cyclase alpha subunit and is involved in nitric oxide signaling, have also been implicated in the development of MMD. ^17^ How this loss of function predisposes individuals to MMD is not fully elucidated, but those who harbor GUCY1A3 mutations are noted to develop hypertension, with marked early onset, thought to arise from impaired vascular smooth muscle cell relaxation. ^17^ The concurrent finding of elevated blood pressure (BP) among these patients with MMD with an underlying genetic variant suggests a shared signaling pathway may contribute to the clinical manifestation of these phenotypes.
There is a paucity of existing literature on systemic hypertension in MMD, with most reports arising from East Asian populations and involving pediatric patients with renal artery stenosis. BP management is critical in optimizing outcomes for patients with MMD treated with extracranial‐to‐intracranial (ECIC) bypass, both in the preoperative and postoperative periods to ensure adequate cerebral blood flow through collaterals and the resulting vascular graft. The objectives of this current study are to characterize the prevalence of systemic hypertension, its associated clinical and radiologic risk factors, and the effect of blood flow augmentation postoperatively among patients with MMD undergoing cerebral revascularization.
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Consecutive patients with MMD treated with an ECIC bypass from December 2014 to December 2018 were retrospectively enrolled from a prospectively maintained database at Stanford Medicine, a tertiary care neurosurgical center. MMD was diagnosed based on 6‐vessel digital subtraction cerebral angiography and disease severity assessed by magnetic resonance imaging (MRI) with perfusion before and after acetazolamide administration. Patients with MMD and moyamoya syndrome were not differentiated, and both were included in the current study's population. The ECIC bypasses performed consisted of indirect and direct bypasses, the latter of which used the superficial temporal artery, posterior auricular artery, or occipital artery as a donor. Previously prescribed antihypertensive agents were withheld during the immediate postoperative period and reintroduced, if required, as BP parameters were relaxed and vasopressors weaned. Following hospital discharge, clinical surveillance occurred at 6‐month intervals for 1 year, then annually. Both pediatric and adult patients with unilateral or bilateral disease were included if they returned for at least 1 clinical follow‐up 6 months postoperatively or later. Appropriate institutional review board approval was obtained for the recruitment and conducting of this study.
For each patient, data were collected regarding their clinical presentation, neuroimaging, surgical details, and postoperative course. Clinical characteristics included age, sex, ethnicity, presence of cardiovascular risk factors (diabetes, coronary artery disease, hyperlipidemia, kidney disease), presence of thyroid disease, smoking status, alcohol consumption, family history of MMD, body mass index (BMI), BP, use of antihypertensive medications or statins, and preoperative symptoms. Systolic BP (SBP) and diastolic BP (DBP), in addition to the number of antihypertensive medications used, were documented at presentation and for each postoperative follow‐up. A localized neurological deficit on presentation was classified as a transient ischemic attack if it resolved within 24 hours without a corresponding T2 fluid‐attenuated inversion recovery hyperintensity on MRI. In contrast, a stroke was defined as localized neurological deficit accompanied by a T2 fluid‐attenuated inversion recovery lesion within an attributable territory. Preoperative digital subtraction cerebral angiographies and MRIs were reviewed recording the location and laterality of stenoocclusion, severity of stenoocclusion (based on the Suzuki Grading System), presence of collateral circulation, presence of ischemia, and cerebrovascular reserve status. The bypass parameters including laterality, direct versus indirect, and first‐time versus revision procedure were obtained from surgical operative notes.
Hypertension was defined separately in adult and pediatric (≤18 years) patients according to the 2020 International Society of Hypertension Global Hypertension Practice Guidelines and 2017 American Academy of Pediatrics Clinical Practice Guidelines respectively. ^18^ , ^19^ In adults, a diagnosis of hypertension was established if one or more of the following were (1) SBP≥140 mm Hg, (2) DBP≥90 mm Hg, and (3) use of any antihypertensive medication. ^18^ Similar criteria were applied in pediatric patients with BP thresholds adjusted based on age, sex, and height using the 95th percentile for those aged 1–13 years. ^19^ In pediatric patients over the age of 13 years, SBP≥130 mm Hg or SBP≥80 mm Hg were defined as hypertensive. In the postoperative period, hypertensive status was considered improved if there was a decrease in BP to normal values accompanied by no change or a reduction in the number of antihypertensive agents required. To account for patients managed with permissive hypertension to maintain adequate cerebral blood flow through the bypass graft or those presenting with medication‐achieved normotension, the use of fewer antihypertensive medications while maintaining a similar BP, or without a rise above the hypertensive threshold if previously normotensive, was also deemed a postoperative improvement.
Adult and pediatric data were analyzed separately. The associations between clinical characteristics and radiographic features were compared between patients with MMD with preoperative hypertension and normotension, as well as those with and without postoperative improvements in hypertensive status through univariate analysis. Due to low frequencies and concern regarding insufficient power, P values were not calculated for the pediatric data, which alternatively were analyzed descriptively. Smoking and alcohol consumption were also excluded from the pediatric analysis as, to be expected, no patients in this subgroup participated in these activities. For the adult data, 2‐sided Student's t test and chi‐square or Fisher exact tests were used for continuous and categorical variables respectively. A conservative P value threshold of <0.20 was used to select variables for inclusion in multivariate analysis. These variables then underwent logistic regression by stepwise backward selection retaining only those that remained significant (P<0.05). The resulting relationships of these predictors to preoperative hypertension and postoperative improvements in hypertensive status were summarized as odds ratios (ORs) with corresponding 95% CIs. Statistical analyses were performed using SAS Studio software (2021, OnDemand for Academics, SAS Institute Inc., Cary, NC, USA).
Of the 319 patients with MMD who underwent cerebral revascularization surgery within the recruitment period, 242 adults and 51 children were included in our analysis. Twenty‐six patients were excluded as they were lost to follow‐up, 12 of whom had died before their 6‐month postoperative clinical assessment. Data for race were missing for 10 patients and Suzuki Grading of moyamoya angiopathy severity was not available in 1 patient. The mean age in adults was 39.7±10.7 years and 9.7±4.7 years in pediatric patients where a majority were female in both populations (77.7% and 56.9% respectively) (Tables 1 and 2). Hyperlipidemia was the most prevalent comorbidity (33.1%) in adults, whereas kidney disease (5%) and a family history of MMD (0.8%) were rare. No pediatric patients harbored a diagnosis of diabetes, coronary artery disease, hyperlipidemia, or kidney disease. Nearly all adults were symptomatic on presentation (96.7%) and a high frequency was observed in children (84.3%). The most common symptom was ischemic stroke (58.3% – adults, 54.9% – pediatrics), matched by headache (58.3%) in adults, and followed closely by transient ischemic attack (57.4% – adults, 39.2% – pediatrics). Correspondingly, MRI fluid‐attenuated inversion recovery hyperintensities were found in at least one hemisphere in 85.5% of adult and 66.7% of pediatric patients. Bilateral intracranial circulation involvement was present in 57.9% of adults with a majority classified with an angiographic severity of Suzuki Grade 3 (right: 26.1%, 26%), and 4 (right: 15.4%, 17.4%). A similar distribution of angiographic findings was observed in pediatric patients with 51% having bilateral Suzuki Grade 3 (right: 21.6% 11.8%) and 4 (right: 15.7%, 25.5%). Most patients, 64% (adults) and 72.5% (children), harbored abnormal cerebrovascular reserve as demonstrated on MRI following acetazolamide challenge. Direct bypasses were performed in 195 adult (80.6%, the remaining underwent indirect bypass) and 26 pediatric (51%) initial revascularization procedures compared with 73 (73.7% – adult) and 11 (40.7% – pediatric) second procedures for bilateral MMD.
Among the 293 patients with MMD with adequate clinical follow‐up, preoperative SBP or DBP were elevated in 98 adult and 17 pediatric patients. Antihypertensive medications were used in 37.6% (91) of adults and 7.8% (4) of children, with 48 and 3 patients achieving normotension respectively. The resulting prevalence of preoperative hypertension was 60.3% (146/242) in adults and 39.2% (20/51) in pediatric patients (Table 3). Clinical characteristics significantly associated with hypertension prior to revascularization from univariate analysis included age, BMI, diabetes, coronary artery disease, hyperlipidemia, statin use, kidney disease, and symptomatic presentation. Coronary artery disease was excluded from further analysis due to overall low frequencies (6 versus 0). Following multivariable logistic regression, only the following factors maintained a significant relationship to preoperative hypertension in MMD (Table 4): age, BMI, having a diagnosis of hyperlipidemia (OR, 2.57 [95% CI, 1.09–6.04]) or kidney disease (OR, 18.98 [95% CI, 1.80–200.47]), and presenting with symptoms (OR, 8.88 [95% CI, 1.16–68.06]). Older age (OR, 1.05 [95% CI, 1.02–1.09]) and a higher BMI (OR, 1.08 [95% CI, 1.03–1.13]) rendered a higher risk of having preoperative hypertension.
At the last postoperative follow‐up, 57 adult and 17 pediatric patients had a SBP or DBP above the age‐adjusted hypertensive thresholds with 87 adult and 2 pediatric patients taking at least 1 antihypertensive medication. The overall prevalence of hypertension subsequent to cerebral revascularization was 45% among adults (absolute reduction of 15.3%, 37 patients) and 37.3% among children (absolute reduction of 1.9%, 1 patient). Hypertensive status improved in 77 adult (31.8%) and 9 pediatric (17.7%) patients accompanied by a reduction in the number of antihypertensive medications required in 45 adult (18.6%) and 2 pediatric (3.9%) patients (Table 3). Univariate analysis revealed improvements were more common with older age, a diagnosis of hyperlipidemia, and posterior circulation involvement. Only moyamoya angiopathy involving the posterior circulation remained statistically significant following multivariable logistic regression demonstrating a reduced odds of improved hypertensive status following cerebral revascularization when present on angiography (OR, 0.10 [95% CI, 0.01–0.79]) (Table 5).
Hypertension is common among patients with MMD particularly when presenting with ischemia. The prevalence in our cohort of adult patients with MMD was 60.3%, which is higher than the US national observed occurrence of 45.4% overall, in addition to 22.4% for those age 18 to 39 years and 54.5% for those age 40 to59 years (encompassing our study's mean age of 39.7 years) from the 2017 to2018 National Health and Nutrition Examination Survey. ^20^ , ^21^ This difference persists when the definitions for hypertension are exactly matched, 40.5% (current study) compared with 30.7% (United States overall), by excluding individuals who were normotensive while taking antihypertensive medications in the current study and using thresholds of 140 mm Hg and 90 mm Hg for SBP and DBP respectively. ^20^ The greater frequency observed suggests MMD has an influence on BP, perhaps from a similar pathophysiological change in the peripheral vasculature to that contributing to intracranial stenosis or a physiological response to increased intracranial vascular resistance in order to maintain adequate cerebral blood flow. In a 2020 study by Ma and colleagues that recruited adults with MMD from China, 156 of 542 patients (28.8%) met the diagnostic criteria for hypertension. ^4^ The lower percentage observed in their study may be explained in part by a higher prevalence of hypertension in the general US population than in East Asia. ^22^ This regional difference is preserved despite a theoretically heightened risk of systemic hypertension among Japanese, Korean, and Chinese patients with MMD who are known to harbor mutations in MMD susceptibility genes shown to influence BP. ^9^ , ^10^ , ^17^ A recent European study investigating associations between elevated BP and post‐revascularization outcomes in adult patients with moyamoya angiopathy found a prevalence of systemic hypertension more similar to our current study of 50%. ^23^ Their definition of hypertension differed, however, including only those requiring pharmacological treatment with an antihypertensive. In contrast, the pediatric patients from our study exhibited a lower prevalence of systemic hypertension, 39.2%, compared with adults. Although comparable with Lee and colleagues’ study detecting hypertension in 29% of their Korean pediatric cohort with MMD, the overall lower pediatric prevalence may be the result of absent cardiovascular risk factors and an inherently lower prevalence of critically elevated BP in a younger population. ^3^ , ^19^ , ^24^ This is supported by the diagnosis of hypertension in only 2.3% of 22 224 students between the ages 10 and 17 years screened in a US‐based cohort study using the same updated clinical practice guidelines as our study, equating to about one twentieth the prevalence observed in adults overall. ^24^ No pediatric patients were diagnosed with renal artery stenosis either before or after revascularization surgery, which differs from previous pediatric cohorts with MMD in which 2% to10% were affected. ^3^ , ^7^
Diabetes and hyperlipidemia are well‐known contributors to the development of hypertension in general and together are synergistic in promoting cardiovascular disease. ^25^ , ^26^ , ^27^ After controlling for other common risk factors including age, sex, BMI, cigarette smoking, alcohol consumption, and kidney disease, we found a diagnosis of hyperlipidemia in addition to older age, elevated BMI, kidney disease, and being symptomatic on presentation remained strongly associated with hypertension in patients with MMD. ^27^ A similar higher mean age (43.6±8.5 versus 36.3±9.3 years) and concurrent diabetes (18.6% versus 3.1%) was found by Ma's group in their patients with MMD who had hypertension when comparing univariate analyses performed with respect to hypertensive status. ^4^ Lucia and colleagues did not find any significant associations between age and gender to preoperative systemic hypertension in their adult cohort with MMD; however, their population size was relatively smaller. ^23^ Most studies to date have focused on the influence of elevated BP on the development of moyamoya vasculopathy or the clinical course of this disease. ^4^ , ^28^ , ^29^ In patients with Down syndrome, known to have a higher incidence of moyamoya syndrome, Santoro and colleagues observed a progressive elevation in BP readings at 6 to12 months and 18 to24 months prior to being diagnosed with moyamoya syndrome as compared with controls. ^29^ Although the absolute BP values were within the normal range based on sex, age, and height, the upward trend in close proximity to presentation was significantly associated with the diagnosis of moyamoya, particularly in patients with bilateral anterior or posterior circulation involvement and higher Suzuki grade on angiography. Hypertension in asymptomatic adult patients with MMD has also been shown to promote earlier onset of symptoms with an increase from 0.6% to 5.5% per year in a Japanese cohort, a relationship also observed in our study with nearly all patients with hypertension symptomatic at presentation (98.6%). ^28^ Development of symptoms, whether hemorrhagic or ischemic stroke, is associated with more advanced angiographic changes including major artery occlusion and collateral formation, which may be accelerated by elevations in blood pressure. ^30^ Hypertension is known to alter the intracranial circulation leading to non‐moyamoya ischemic stroke by way of endothelial dysfunction and diminished nitric oxide signaling, in addition to damaging vascular elastin fibers resulting in atheroma formation, stiffened vessels, and impaired cerebral autoregulation. ^31^ A similar process is plausible as contributing to angiographic progression and symptom onset in MMD. Although we did not find the extent of moyamoya vasculopathy correlated with the presence of hypertension, having stenoocclusion in the posterior cerebral arteries was significantly associated with hypertension in Korean pediatric patients with MMD who underwent ECIC bypass. ^3^ This discrepancy could be explained by the low rate of posterior circulation involvement within our cohort or the clinical variable of symptomatic presentation capturing the influence from severe disease.
The effects of hyperlipidemia and elevations in BMI on hypertension in pediatric and adult patients with MMD have not been previously investigated. They have been identified as risk factors and targeted in the primary prevention of cardiovascular disease in the general population with growing evidence directly linking hyperlipidemia and BMI with development of systemic hypertension. ^26^ , ^27^ , ^32^ , ^33^ High BMI classified as either overweight (24–27.9 kg/m^2^) or obese (≥28 kg/m^2^) were found to be associated with increased odds (OR, 1.70 [95% CI, 1.39–2.09], OR, 2.60 [95% CI, 1.84–3.66] respectively) of hypertension, whereas being underweight was protective (OR, 0.52 [95% CI, 0.29–0.93]). ^32^ Within this large Chinese cohort, having concurrent hyperlipidemia potentiated this risk with a relative excess risk due to interaction of 1.91 in individuals who are overweight and 2.20 for individuals with obesity. A similar dose‐response relationship between BMI and BP was observed in a study of 1.7 million adults with a 0.8 to1.7 mm Hg increase in BP per unit BMI after controlling for sex, age, smoking status, and socioeconomic variables, as well as in nearly 30,000 children aged 6 to14 years old, but in a nonlinear fashion. ^33^ , ^34^ The number of patients diagnosed with hypertension within these studies was comparatively lower (27.9 to 41.6%); however, the mean BMI among adults within the current study was higher at 28.8 kg/m^2^ compared with 24.5 to 24.7 kg/m^2^. ^32^ , ^33^ Although this could explain the difference observed, the magnitude of increased prevalence of hypertension and our finding of a high number of pediatric patients with MMD meeting criteria for hypertensive BP in this study despite not harboring common cardiovascular risk factors suggests an additional contributing mechanism driving hypertension in MMD that differs from benign essential hypertension.
The exact physiology underlying elevations in blood pressure among patients with MMD is unknown; however, genetic predisposition and end‐organ demand likely contribute. The p.R4810k polymorphism of MMD susceptibility gene, ring finger protein 213/mysterin, has been shown through quantitative trait locus analyses to be significantly associated with elevations in SBP among adults having this mutation. ^10^ This mutation is most common among Japanese and Korean individuals and is thought to account for the higher incidence of MMD in Asian populations, in addition to rendering carriers of the mutation without MMD at higher risk of developing hypertension. ^10^ , ^11^ Similarly, GUCY1A3 loss‐of‐function mutations have been found in non‐Asian patients with MMD with early onset disease and concurrent hypertension consistently found in all patients with biallelic involvement. ^17^ These mutations affect differing molecular posttranslational modifications through ubiquitination and the cyclic guanosine monophosphate‐dependent protein kinase pathway respectively, hypothesized to alter vascular tone regulation through nitric oxide and promoting smooth muscle cell proliferation and fibrosis, and ultimately, endothelial dysfunction to precipitate moyamoya vasculopathy. ^9^ It is foreseeable that similar insults to the peripheral vasculature can precipitate hypertension. Elevations in BP may also be a physiological response to maintain cerebral perfusion with progressive intracranial arterial stenosis and subsequent reliance on internal carotid and external carotid collateral flow. Cerebral blood flow typically remains constant despite fluctuations in mean arterial pressure owing to cerebral autoregulation; however, this hemostatic process is impaired in MMD, particularly with angiographically advanced vasculopathy. ^35^ , ^36^ These patients may then be more reliant on hypertension to ensure adequate perfusion especially in the presence of increased intracranial vascular resistance and transit time through collateral circulation. This theory is supported by our finding that 32% of adult and 19% of pediatric patients experienced an improvement in their hypertensive status following revascularization. Santoro and colleagues similarly observed a postoperative reduction in BP returning to normal percentiles within 3 to 6 months. ^29^ Augmentation of cerebral blood flow provided by the ECIC bypass graft may render unnecessary the dependence on increased mean arterial pressure to maintain steady cerebral perfusion. Interestingly, this surgical benefit was nearly absent amongst patients harboring preoperative posterior circulation involvement, which was a significant negative predictor for postrevascularization BP status improvement. Stenoocclusive changes to the vertebrobasilar system and posterior cerebral arteries have been previously associated with advanced disease evidenced by our findings that this cohort demonstrated higher grade internal carotid artery arteriopathy (Suzuki Grade 6 (right) – 8/18 (44.4%), Suzuki Grade 6 (left) – 5/18 (27.8%)) and a high frequency of ischemic presentation (72.2% versus 58.3% overall). ^37^ , ^38^ The severity of vasculopathy may also extend peripherally, sustaining systemic hypertension despite successful anterior circulation revascularization indirectly supported by findings that posterior circulation arterial flow significantly reduced after direct ECIC bypass. ^39^
Several limitations exist in the current study, principally owing to its retrospective nature. First, although we were able to control for most comorbidities known to promote development of hypertension, several modifiable lifestyle risk factors including diet and level of physical activity were missed as they were not routinely recorded in medical records. ^27^ Their contribution to cases of hypertension is not insignificant accounting for population attributable fractions of 9% and 12% in women and men who consumed fruits and vegetables <5 times daily, as well as 12% and 7% in women and men who participated in <150 minutes of moderate‐to‐vigorous physical activity weekly in a Canadian‐wide study from 2007 to 2015. ^27^ These numbers were surprisingly greater than the population‐attributable fraction for diabetes. The absence of these variables from our analyses may confound the associations identified between clinical and radiographic characteristics to preoperative hypertension. Second, the dosage of antihypertensive medications was not always available, preventing postoperative to preoperative comparison for dose escalation or reduction and limiting our assessment to the number of agents prescribed. The hypertensive status for individuals requiring only a postoperative dose change may not have been accurately captured, leading to misclassification bias. Lastly, this cohort is composed exclusively of surgically treated patients who might harbor particularly advanced MMD given the high percentage of symptomatic presentation. With our finding of a significant association between symptomatic presentation and hypertension, the prevalence identified in this study could overestimate the true number of cases in a population with MMD that includes medically managed patients. Compared with the study by Hirano's group in 2020 that recruited adult patients with asymptomatic (47%), ischemic (40%), and hemorrhagic (13%) MMD treated conservatively and surgically, our cohort exhibited a higher percentage of severe vasculopathy based on a Suzuki Grade ≥4 (43.2% versus 17%). ^28^ However, the frequency of high Suzuki grade in their study was low, even among patients with ischemic and hemorrhagic stroke, showing no significant difference between groups.
Hypertension is prevalent among both adult and pediatric patients with MMD, particularly in those of older age, high BMI, having a concurrent diagnosis of hyperlipidemia or kidney disease, and presenting with neurological deficits or hemorrhage. Although the prevalence appears to follow geographical trends seen with essential hypertension, the overall case numbers are higher when matched for age. The mechanism underlying elevations in BP in MMD is not yet determined; however, contributions from the physiological effect of MMD susceptibility genes on vessel wall function and compensatory peripheral vascular changes to maintain steady cerebral perfusion likely play a role. This supports the theory that MMD, although characterized by local intracranial stenoocclusion, is a disease process with systemic sequelae. Cerebral revascularization appears beneficial in reducing preoperative hypertension in a subset of patients with MMD, although posterior circulation involvement appears to be a risk factor for poor response. Further studies investigating the correlation of postoperative graft patency and degree of recipient territory perfusion may help elucidate this intricate relationship between cerebral blood flow and systemic BP.
This work was supported in part by the Reddy Lee Family Moyamoya Fund, Bernard and Ronni Lacroute, and the William Randolph Hearst Foundation (G.K.S.).
Dr Steinberg is a consultant for Peter Lazic US, SanBio, Surgical Theater, and Zeiss. The other authors have no interests to disclose.