Diffuse Arteriopathy Research Articles

Long-term Outcomes After Surgical Intervention for Congenital Supravalvar Aortic Stenosis in Children

BackgroundPrimary supravalvar aortic stenosis (SVAS) is a rare congenital cardiovascular condition that can coexist with Williams-Beuren syndrome, coronary artery involvement, aortic coarctation, and pulmonary artery stenosis. SVAS repair can be achieved with low perioperative mortality, but long-term survival remains less well understood. We used the Pediatric Cardiac Care Consortium, a multicenter United States-based registry for pediatric cardiac operations, to assess long-term outcomes after SVAS repair. MethodsWe used Kaplan-Meier plots and Cox proportional hazards regression to examine factors associated with postdischarge deaths. These included sex, age-group, weight z-score, coexisting conditions (Williams-Beuren syndrome, coronary artery involvement, coarctation, and pulmonary artery stenosis), surgical techniques, and era, defined as early (1982-1995) or late (1996-2003). Survival was assessed by matching with the National Death Index through 2021. ResultsOf 333 patients who met inclusion criteria, 313 (94.0%) survived to discharge and 188 (60.1%) had identifiers for National Death Index matching. Over a median follow-up of 25.2 years (interquartile range, 21.1-29.4 years), 17 deaths occurred. The 30-year survival after discharge from SVAS repair was 88.7% (95% CI, 82.9%-94.8%). Infantile surgery and non-Williams-Beuren syndrome were associated with decreased 30-year survival. From the various repairs, the 2-sinus technique had better outcomes compared with all other types, except the 3-sinus technique (nonsignificant difference). Adjusted analysis revealed infantile age and type of repair as associated with postdischarge probability of death. ConclusionsThese data demonstrate favorable long-term outcomes after SVAS repair, except for the infantile group that was associated with more diffuse arteriopathy. As techniques continue to evolve, future studies are warranted to investigate their long-term outcomes.

Caractéristiques clinicopathologiques et résultats postopératoires de l’entérite radio-induite : une étude rétrospective de 41 patients

Surgery is required in patients with symptoms of chronic radiation-induced enteritis (CRE) resistant to medical therapy. The study aimed to correlate histopathologic features of CRE to the clinical presentation and the postoperative recurrence. All patients with small bowel resection performed for CRE between 2006 and 2017 were studied. Histological data were retrospectively correlated to initial clinical data and to postoperative recurrence of CRE (occlusion, need for parenteral nutrition) observed during a median follow-up of 32 months. Forty-one patients were studied (39 women and 2 men, median age 62 yo at time of radiation for pelvic cancer, 80% gynecologic). Median time to surgery after radiation was 3 years. Ileocaecal resections (80% of patients) removed 60cm (median length). Histologically, a diffuse obliterative arteriopathy was present in 24 (59%) patients, highly associated to amyotrophy, villous atrophy and ulceration observed in 66, 63 and 34% of patients respectively (P<.05). Diffuse arteriopathy was uncorrelated with patient's age and vascular risk factor (tobacco, diabetes, hypertension, dyslipidemia). Median time to surgery after radiation was longer in patients presenting with obliterative arteriopathy (13 years vs. 2.6 years, P=0.0002). During follow-up, half of the patients had a recurrence of CRE, uncorrelated to the arteriopathy. Radiation-induced enteritis requiring late surgery after radiation presented histologically with a diffuse obliterative arteriopathy and ischemic features. In our center, half of the patients were cured by surgery. The arterial injury was not a risk factor for postoperative recurrence.

LIMITED PROGNOSTIC ABILITY OF SPECT IN THE HEART TRANSPLANT POPULATION: ANALYSIS FROM A SINGLE LARGE-VOLUME CENTER

Survival after heart transplant has greatly improved, with a median survival now ~13 years. Cardiac allograft vasculopathy (CAV), characterized by diffuse arteriopathy, is a major source of morbidity and mortality. SPECT MPI is used for CAV surveillance, but its accuracy in diagnosis of CAV is

MR Imaging Diagnosis of ACTA2

Smooth muscle alpha-2 actin (ACTA2) mutations are associated with diffuse smooth-muscle dysfunction syndrome and produce distinct imaging features. Clinical manifestations include intrathoracic large-vessel disease, nonreactive mydriasis, bladder hypotonia, and intestinal dysmotility. ACTA2 mutations are associated with childhood stroke due to diffuse cerebral arteriopathy distinct from moyamoya disease. Recognition of this syndrome has important clinical and prognostic implications. The purpose of this article is to review the unique imaging phenotypes associated with ACTA2 mutations, including vascular and nonvascular abnormalities.

P4643Pulmonary hypertension incidence is higher than systemic arterial hypertension in children after aortic coarctation repair

Abstract Introduction Coarctation of the aorta (CoA) is characterized by diffuse arteriopathy which can persist to upward of the aortic isthmus, even after successful surgical correction. This arteriopathy can also occur in the pulmonary vasculature, leading to pulmonary hypertension (PH), a strong risk factor of poor prognosis in CoA population. Purpose The purpose of this study was to determine the incidence of systemic and pulmonary hypertension in a CoA paediatric population after surgical repair, as well as the impact of PH in right ventricular function. Methods This cross-sectional study included children after successful surgical repair of the CoA in a tertiary centre [1996, 2009] up to the first year of age. Children with other cardiac structural lesions or recoarctation were excluded. Systemic arterial hypertension was defined as blood pressure in the 95th percentile or higher. PH was considered if the estimated pulmonary systolic arterial pressure (PSAP) was higher than 30mmHg. Pulse wave velocity, ambulatory 24 hours blood pressure monitoring, echocardiographic assessment of right ventricle (RV) and blood tests were performed 11±4 years after surgical procedure. Echocardiographic variables were normalized and evaluated by z-scores. One sample t test or sign test was used to estimate the deviation of measured/observed values from the normality/expected values (defined by z-score=0). Results We included 38 children with a mean age of 12±4 years (63% male). Late arterial hypertension was diagnosed in 29% of the children and PH incidence was 68% with a mean PSAP of 37±5mmHg. The mean of A' wave (z-score: 0.34±0.93, p=0.030) and median of E/E' ratio (z-score: 0.46 [−1.32; 3.68], p=0.004) z-scores were increased comparing with expected normal values in paediatric population. Moreover, E' wave (z-score: −0.35±0.98, p=0.034) and RV index of myocardial performance (z-score: −0.20±0.41, p=0.006) were decreased. Regarding RV systolic function, TAPSE z-score was significantly increased (z-score: 2.06±2.33, p&lt;0.001), being outside the z-score normal range. Conclusion Children submitted to CoA surgical repair before the first year of life showed a higher PH incidence than late systemic hypertension occurrence. Also, they already present with significant RV functional abnormalities when compared to the normal paediatric population. These abnormalities can underlie pulmonary vascular remodelling after left ventricular pressure overload in CoA population that seems irreversible after pressure overload relief. Acknowledgement/Funding AFF are supported by FCT (SFRH/BD/138925/2018)

Abstract TP500: Cerebrovascular Artery Size is Age- and Sex-Dependent

Introduction: Arteriopathy is a leading cause of pediatric stroke. Cerebral arteriopathies may be diffuse, such as in radiation or moyamoya arteriopathies, limiting contralateral normal comparisons. Normative data for comparison and identification of diffuse arteriopathy is not currently available. Cerebral blood flow has been shown to vary based on age and sex; therefore, we aimed to determine potential age- and sex-related differences in cerebral artery size. Method: Healthy children and young adults aged 4 - 40 years were recruited to undergo 3D time-of-flight magnetic resonance angiography (MRA). Motion-degraded studies were excluded. The mean diameters of segments of the internal carotid artery (ICA), middle cerebral artery (MCA), anterior cerebral artery (ACA), basilar artery (BA) and ophthalmic artery (OA) were manually determined using a double-oblique technique. Mixed model regression of vessel diameters determined significance of age and sex. Results: MRAs of 22 children (ages 4-21 years; 12 male) and 13 adults (ages 22-38 years; 9 male) were analyzed. On mixed model regression, younger participants maintained larger diameters for ICA (p=0.03), MCA (p&lt;0.001), ACA (p&lt;0.001) and BA (all p=0.007) without difference between sexes. OA diameter did not differ with regards to age or sex. Conclusion: Normal cerebral artery size in vessels contributing to brain perfusion is largest in younger children and diminishes with age, likely reflecting higher cerebral blood flows observed in younger children. Age-specific normative data is needed to identify diffuse cerebral arteriopathy in children and young adults.

Future Cardiac Allograft Vasculopathy in Heart Transplant Recipients is Predicted by Class II Human Leukocyte Antigen Eplet Mismatch Score

Background: Many heart transplant patients develop a decline in cardiac function over time that is poorly understood. An important association of this is the development of cardiac allograft vasculopathy (CAV), a diffuse arteriopathy that may relate to subclinical chronic rejection. Conventional organ matching has limited sensitivity to predict development of donor-specific antibodies. Using the HLAMatchmaker matching algorithms, it is now possible to assess compatibility at the fundamental epitope (eplet) level. This study investigated whether recipient–donor eplet mismatch at time of transplant predicts development of CAV.

Cervical artery tortuosity is associated with intracranial aneurysm.

Background Intracranial aneurysms may be associated with an underlying arteriopathy, leading to arterial wall fragility. Arterial tortuosity is a major characteristic of some connective tissue disease. Aim To determine whether intracranial aneurysm is associated with an underlying arteriopathy. Methods Using a case-control design, from May 2012 to May 2013, we selected intracranial aneurysm cases and controls from consecutive patients who had conventional cerebral angiography in our center. Cases were patients with newly diagnosed intracranial aneurysm. Controls were patients who had diagnostic cerebral angiography and free of aneurysm. The prevalence of tortuosity, retrospectively assessed according to standard definitions, was compared between cases and controls and, association between tortuosity and some aneurysm characteristics was examined, in cases only. Results About 659 arteries from 233 patients (112 cases and 121 controls) were examined. Tortuosity was found in 57 (51%) cases and 31 (26%) controls (adjusted OR = 2.71; 95%CI, 1.53-4.80). The same trend was found when looking at each tortuosity subtype (simple tortuosity, coil, kink) or at carotid or vertebral territory separately. In contrast, no association between tortuosity and rupture status, aneurysm number or neck size was found. Conclusions Cervical artery tortuosity is significantly associated with intracranial aneurysm, although not related to main aneurysm characteristics. Our results support the presence of an underlying diffuse arteriopathy in intracranial aneurysm patients.

Anatomical findings after amplatzer occluder to treat aortic regurgitation on left ventricular assist device patient

A 57-years-old woman, with HeartMate II left ventricular assist device (LVAD) as a bridge to transplant for a coronary arteries disease presented 6 months after implantation with severe haemolysis, new-onset aortic insufficiency (AI) and pulmonary oedema. On the transoesophageal echocardiography (TEE,) the aortic valve showed increased thickening, valve leaflet fusion without opening and moderate to severe central regurgitation. Despite diffuse arteriopathy, a 25-mm Amplatzer Cribiform septal occlude was delivered across the aortic valve via a percutaneously placed 9-F TorqVue catheter. With TEE guidance, the device was positioned across the valve, resulting in decreased AI without mitral obstruction. A transthoracic echocardiography performed two weeks later demonstrated decreased end diastolic left ventricular diameter and disappearance of aortic regurgitation. The haemolysis ceased and clinical status improved. 4 months later, the patient again developed severe haemolysis leading to global heart failure without AI. Thrombosis in the device was suspected and emergency cardiac transplantation was undertaken. During the procedure, after cardiectomy, the aortic valve was checked (figure) and found totally closed and watertight when submitted to the water test; the aortic leaflets disappeared under layers of fibrosis. The Amplatzer was complety endothelialized on both the aortic and the ventricular side without thrombus apposition or obstruction of ostial coronary arteries. The left ventricular output chamber was free without anomaly of mitral valve motion. Trans-catheter closure of the native aortic valve with an Amplatzer occluder can offer an easy way to treat new-onset severe AI on LVAD patients. ![Figure][1] Figure 1. Amplatzer on aortic valve [1]: pending:yes

Rapamycin Inhibits Smooth Muscle Cell Proliferation and Obstructive Arteriopathy Attributable to Elastin Deficiency

Patients with elastin deficiency attributable to gene mutation (supravalvular aortic stenosis) or chromosomal microdeletion (Williams syndrome) are characterized by obstructive arteriopathy resulting from excessive smooth muscle cell (SMC) proliferation, mural expansion, and inadequate vessel size. We investigated whether rapamycin, an inhibitor of the cell growth regulator mammalian target of rapamycin (mTOR) and effective against other SMC proliferative disorders, is of therapeutic benefit in experimental models of elastin deficiency. As previously reported, Eln(-/-) mice demonstrated SMC hyperplasia and severe stenosis of the aorta, whereas Eln(+/-) mice exhibited a smaller diameter aorta with more numerous but thinner elastic lamellae. Increased mTOR signaling was detected in elastin-deficient aortas of newborn pups that was inhibited by maternal administration of rapamycin. mTOR inhibition reduced SMC proliferation and aortic obstruction in Eln(-/-) pups and prevented medial hyperlamellation in Eln(+/-) weanlings without compromising aortic size. However, rapamycin did not prolong the survival of Eln(-/-) pups, and it retarded the somatic growth of juvenile Eln(+/-) and Eln(+/+) mice. In cell cultures, rapamycin inhibited prolonged mTOR activation and enhanced proliferation of SMC derived from patients with supravalvular aortic stenosis and with Williams syndrome. mTOR inhibition may represent a pharmacological strategy to treat diffuse arteriopathy resulting from elastin deficiency.

A case with unusual stroke and fulminant outcome in a Hispanic male

Patient: Male, 42Final Diagnosis: Moyamoya disease (MMD)Symptoms: Aphasia • concentration difficulty • dysarthria • personality changeMedication: —Clinical Procedure: —Specialty: RadiologyObjective:Rare diseaseBackground:Moyamoya disease (MMD) was first described in 1957 as “hypoplasia of the bilateral internal carotid arteries.” The characteristic appearance of the associated network of abnormally dilated collateral vessels on angiography was later likened to “something hazy, like a puff of cigarette smoke,” which, in Japanese, is Moyamoya. This paper describes the fulminant course of the disease in a Hispanic male involving the corpus callosum.Case Report:A 42-year-old Hispanic male with progressive aphasia, slow mentation, and sudden onset of sensorimotor symptoms with gait disturbance was found to have multiple intracranial supratentorial infarcts of variable stages of evolution involving, but not limited to, the anterior corpus callosum, followed by rapid development of further infarcts. Angiography demonstrated right ACA occlusion, left supraclinoid ICA occlusion with a Moyamoya pattern of collateralization, and diffuse arteriopathy. A fulminant course ensued and the patient did not survive the acute phase of ischemic disease.Conclusions:Moyamoya disease may rarely present in North American Hispanic males, with advanced atypical clinical and imaging features involving the anterior corpus callosum and having a fulminant course.

Ulcérations digitales révélant un carcinome bronchique

Digital ulcers usually reflect focal ischemia due to a microangiopathy, its causes are diverse. In women, it first suggests a connective tissue disease whereas in men, a diffuse arteriopathy. Acral ischemia till necrosis is a rare form of a paraneoplasia. We report about a man with a metastatic lung cancer revealed by digital ulcers. In front of digital necrosis, haemopathy or cancer must be searched in the absence of iatrogenic cause, occupational diseases, atherosclerosis or systemic disease.

Spontaneous Post-Partum Cervical Carotid Artery Dissection in a Patient with Reversible Cerebral Vasoconstriction Syndrome

Post-partum cervicocephalic artery dissection (pp-CAD) is a rare and poorly understood condition. To our knowledge, only 21 cases have been reported. Reversible cerebral segmental vasoconstriction (RCSV) was first described by Call and Fleming in 1988, and its association with pp-CAD has only been reported in three cases. However, in those cases it is unclear whether the pp-CAD may have been caused by straining during labor and therefore merely coincidental to the intracranial arteriopathy. We describe a 41-year-old right-handed African-American woman who developed the syndrome of pp-CAD (headaches, trace subarachnoid hemorrhage and diffuse cerebral arteriopathy on angiogram) two weeks after delivery. In this unique case, the patient had fortuitously undergone an MR study twice over a four day period which included the carotid bifurcations. During that time the patient was an inpatient, on bed rest and subject to continuous cardiac monitoring. The interval studies documented a true spontaneous right internal carotid artery dissection occurring without obvious cause. The patient had noted moderate right neck pain developing between the two MR studies but experienced no neurological deficits. Subsequent conventional angiography confirmed the presence of postpartum cerebral arteriopathy and the cervical dissection. The patient was managed conservatively with antiplatelet medication and had an otherwise uneventful course. We hypothesize whether transient arterial wall abnormalities, postpartum hormonal changes or subtle connective tissue aberrations play a similar role in the pathogenesis of these two associated conditions.

Angioid streaks leading to the discovery of a new mutation in pseudoxanthoma elasticum

AbstractPurpose Discovery of angioid streaks can lead to the diagnosis of pseudoxanthoma elasticum (PXE), an unusual autosomal recessive genetic disorder. We report a new functional pathogenic mutation associated to phenotypic manifestations of the disease.Methods A 35‐year old female was admitted for an etiologic work‐up of a diffuse juvenile arteriopathy. Fundus examination evidenced typical peripapillary angioid streaks that led to the diagnosis of PXE, confirmed by genetic analysis of the ABCC6 gene. Our patient was compound heterozygote for two heterozygous mutations: one at exon 24 (c.3421C&gt;T, R1141X), the other at exon 17 (c.2153A&gt;G, D718G) not described before. Among her siblings, her brother and one sister were compound heterozygotes for the two mutations and had vascular symptoms and angioid streaks as well. Her mother was heterozygous for the D718G mutation while her father was heterozygous for the R1141X mutation. Both were asymptomatic.Results ABCC6 gene implication in PXE was first described in 2000. Pathological mutations are mostly located from exons 23 to 29. The R1141X mutation is already known to be associated with a strong increase in the prevalence of coronary artery disease. Our results highlight that the D718G mutation is functional and may have a pathogenic role mainly due to its segregation with the disease and genetic arguments (Grantham’s distance, damaging role related in the Polyphen tool online).Conclusion Diagnosis of angioid streaks can lead to the diagnosis of PXE confirmed by genetic analysis. Examination of our patients allowed us to describe for the first time a new mutation of the ABCC6 gene (D718G), associated with the classical and recurrent R1141X mutation and with phenotypic manifestations of PXE.

E-007 Spontaneous post-partum cervical carotid artery dissection in a patient with reversible cerebral vasoconstriction syndrome

Postpartum cervicocephalic artery dissection (pp-CAD) is a rare and poorly understood condition. To our knowledge, only 21 cases have been reported. Reversible cerebral segmental vasoconstriction was first described by Call...

Drug eluting versus bare metal stents in cardiac allograft vasculopathy

Cardiac allograft vasculopathy (CAV) is a distinct pathological condition characterized by diffuse and progressive arteriopathy and it is an important determinant of long-term graft survival. Definitive CAV treatment is retransplantation but palliation with stenting might temporarily alleviate it. The benefit of drug eluting stents (DES) over bare metal stents (BMS) in the treatment of such lesions is debatable. We therefore sought to do a literature search to review the available evidence comparing DES to BMS. We conducted Pub Med, EMBASE, Cochrane database review, Web of Science search of studies comparing DES with BMS in CAV. Available studies were retrospective in nature with either direct comparison groups (n = 5) or historical controls (n = 1). The main outcomes analyzed were in stent restenosis (ISR) during follow-up and clinical outcomes. A total of 312 patients from six studies were included in the review (1995-2007). Most commonly used DES were sirolimus eluting stent. DES appeared to reduce the long-term risk of ISR compared with BMS. Three of the five studies showed a statistically significant reduction in ISR at 12 months while the one study assessing ISR at 6 months showed no significant difference. Clinical endpoints such as death and major adverse cardiac events were not statistically different. DES appear to reduce the incidence of ISR in CAV as compared with BMS. Prospective randomized clinical trials are needed to determine the clinical benefit of DES beyond a reduction in ISR.

Profil étiologique des nécroses digitales des membres supérieurs : analyse de 25 observations

To investigate the etiologies of the upper limb digital necrosis based on a retrospective analysis of 25 cases. We retrospectively reviewed the medical records of patients treated for digital necrosis of the upper limb in four departments of internal medicine from January 1997 to December 2003. There were 16 women and nine men, mean age 55 years. Eleven patients were smokers. Raynaud's phenomenon was noted in 12 cases. Connective tissue diseases were the most common cause (nine cases), all of them were women. The second cause was atherosclerosis (five cases) and Buerger's disease (five cases). In the other cases, the following diagnoses were found: vasculitis (three cases) and neoplasm (two cases). No cause could be identified in one female smoker. Digital necrosis is a common symptom, revealing a vascular pathology. Its causes are diverse. In women, it first suggests a connective tissue disease whereas in men, a diffuse arteriopathy. The etiological diagnosis strategy should consider drug intake, anamnesis and Raynaud's phenomenon history. However, in all cases the etiology investigations should not delay the treatment in order to preserve functional prognosis.

Plasma β-Amyloid 1-40 Is Associated With the Diffuse Small Vessel Disease Subtype

The underlying mechanisms of small vessel disease (SVD) subtypes are diffuse arteriopathy (diffuse-SVD) or microatheroma (focal-SVD). Endothelial dysfunction by beta-amyloid peptide (Abeta) deposition has been associated with lacunar infarcts and leukoaraiosis, but its specific relationship with SVD subtypes is unknown. We hypothesized that plasma Abeta levels can play a different role in SVD subtypes in patients with acute lacunar stroke. We studied 149 patients with acute ischemic stroke of SVD etiology according to Trial Of Org 10172 In Acute Stroke Treatment criteria and 25 age-matched control subjects. Patients were classified into focal-SVD: 39 patients with isolated lacunar infarct without leukoaraiosis and diffuse-SVD: 110 patients with an isolated lacunar infarct with leukoaraiosis or with multiple lacunar infarcts with or without leukoaraiosis. Baseline data included vascular risk factors and extensive laboratory tests, including plasma Abeta levels. Median [quartiles] Abeta(1-40) levels (40.4 [35.1, 50.5] versus 55.1 [42.3, 69.6] pg/mL), but not Abeta(1-42) levels, were significantly higher in the diffuse-SVD group than in focal-SVD group (P<0.001) and control subjects (P<0.001). No differences in Abeta(1-40) levels were found between focal-SVD and control subjects. Logistic regression analysis showed that age (OR, 1.06; 95% CI, 1.01 to 1.12), history of hypertension (OR, 3.5; 95% CI, 1.3 to 9.2), and plasma beta-amyloid(1-40) levels over the median value (OR, 17.3; 95% CI, 3.0 to 99 for the third quartile and OR, 6.0; 95% CI, 1.6 to 23 for the fourth quartile) were independently associated with the diffuse-SVD subtype. Plasma beta-amyloid(1-40) levels are independently associated with the diffuse-SVD subtype. These results are consistent with the pathophysiological role of fraction Abeta(1-40) in disrupting endothelial vascular function.

小児高安大動脈炎で複数の脳動脈炎を伴い出血性脳梗塞をきたした１例

高安大動脈炎は大動脈と第1次分枝の原因不明な非特異的炎症性疾患で8∼35%に脳卒中を合併する．また小児の脳卒中も10万人に2.7人の頻度で日常経験することは少ない． 今回我々は高安大動脈炎で脳動脈炎を伴い，脳卒中をきたした小児例を経験したので報告する．症例は3歳男児．全身痙攣にて発症し，頭部CTで左側頭葉脳内出血・くも膜下出血を認め，脳血管撮影では左半球の複数脳動脈の壁不整を認めた．胸腹部3DCTAで大動脈弓と第1次分枝及び胸部大動脈の拡張・壁肥厚，腎動脈狭窄を認め，高安大動脈炎に伴う脳動脈炎・出血性脳梗塞と診断した．脳梗塞は保存的に治療．高安大動脈炎はプレドニゾロンとメソトレキセート投与により改善し，ほぼ神経学的欠落症状なく退院した． 高安大動脈炎に伴う脳動脈炎は非常に稀であるが，小児脳卒中の鑑別診断の1つとして考慮すべき疾患と考えられた．早期診断・早期治療により良好な経過が得られた．

Genes, endothelial function and cerebral small vessel disease in man

Cerebral small vessel disease results from ischaemia in the perforating arteries supplying the white matter and deep grey matter nuclei. It results in both focal lacunar infarction and more diffuse areas of chronic ischaemia (leukoaraiosis). Two subtypes may exist. One subtype (isolated lacunar infarction) is associated with single or a few larger lacunar infarcts without leukoaraiosis, and may result from microatheroma in the larger perforating arteries. The second subtype (ischaemic leukoaraiosis) results in multiple small lacunar infarcts with leukoaraiosis secondary to a diffuse arteriopathy affecting the smaller perforating arteries, usually occurring in the presence of hypertension. In this subtype, chronic hypoperfusion and impaired cerebral autoregulation have been reported. A number of lines of evidence support a pathogenic role of endothelial activation and dysfunction. Genetic predisposition has also been implicated. Associations with genes involved in endothelial function, including those regulating the renin-angiotensin system, endothelial nitric oxide and homocysteine levels, have been reported. However, not all results have been replicated and there are few robust replicable associations. Larger studies are required to determine definitively which associations represent important risk factors.