Angiopathy refers to any disease affecting the blood vessels, encompassing arteries, veins, and capillaries, which can lead to weakening, narrowing, or blockage that disrupts normal blood flow and potentially causes tissue damage or organ dysfunction.[1] It is broadly classified into two main types: microangiopathy, which involves damage to small blood vessels such as capillaries, resulting in thickening and weakening of vessel walls that may cause bleeding, protein leakage into tissues, and slowed circulation; and macroangiopathy, characterized by the accumulation of fats and blood clots in larger blood vessels, leading to obstruction and reduced blood flow.[1][2]Common causes of angiopathy include chronic conditions like diabetes, which damages vessel linings through prolonged high blood sugar levels, hypertension that exerts excessive pressure on vessel walls, and elevated cholesterol levels that promote plaque buildup in arteries.[2] Genetic factors can also predispose individuals to certain forms, while specific subtypes such as diabetic microangiopathy often manifest in the eyes (retinopathy), kidneys (nephropathy), and nerves (neuropathy).[2] Macroangiopathy is frequently associated with atherosclerosis and increases the risk of serious complications, including coronary artery disease affecting the heart, cerebrovascular disease leading to strokes in the brain, and peripheral vascular disease impacting the limbs.[1]Angiopathy's clinical significance lies in its role as a key contributor to cardiovascular and cerebrovascular events, with symptoms varying by the affected vessels and organs, such as vision impairment from retinal damage or leg pain from reduced limb circulation.[2]Diagnosis typically involves imaging techniques like angiography or ultrasound, alongside blood tests to identify underlying risk factors, while management focuses on controlling causes through lifestyle modifications, medications to lower blood pressure or cholesterol, and in severe cases, surgical interventions to restore blood flow.[2] Early detection and treatment are crucial to prevent progression to life-threatening conditions like heart attacks or ischemic strokes.[1]
Overview
Definition
Angiopathy is a generic term derived from the Greek words "angeion," meaning vessel, and "pathos," meaning disease or suffering, referring to any pathological condition affecting the blood vessels.[3] It encompasses a broad range of disorders involving the arteries, veins, and capillaries, characterized by damage, dysfunction, or rupture of these vascular structures.[1][4]Unlike vasculitis, which specifically involves inflammation of the blood vessel walls leading to swelling and potential narrowing, angiopathy is a more inclusive term that does not require an inflammatory component and can arise from various mechanisms such as degeneration or deposition of abnormal substances.[5] Similarly, it differs from arteriosclerosis, which denotes the thickening and hardening of arterial walls, often due to plaque buildup, without necessarily implying broader vascular involvement.[6] Angiopathy thus serves as an umbrella category for vascular pathologies beyond these specific processes.The scope of angiopathy includes both systemic forms, affecting multiple organs through widespread vascular impairment, and organ-specific manifestations, such as those confined to the brain or kidneys. Common presentations often emphasize involvement of small vessels, where damage can lead to fragility, leakage, or occlusion, though larger vessels may also be affected; this distinction is further categorized as microangiopathy for small vessels and macroangiopathy for larger ones.[1][7]
Epidemiology
Angiopathy encompasses a range of vascular disorders affecting millions worldwide, primarily driven by its association with common conditions like diabetes and aging. Diabetic angiopathy, a major subtype, impacts approximately 30-40% of individuals with long-term diabetes, manifesting as microvascular complications such as retinopathy, nephropathy, and neuropathy, or macrovascular issues like peripheral artery disease and accelerated atherosclerosis.[8] As of 2024, approximately 589 million adults (aged 20-79 years) are living with diabetes globally, translating to tens of millions affected by diabetic angiopathy, underscoring its substantial public health burden.[9]Cerebral amyloid angiopathy (CAA), another prominent form, shows a prevalence of 20-30% in autopsy studies of individuals over age 60, rising sharply with advancing age to 43-58% in those over 90.[10] In patients with Alzheimer's disease, CAA prevalence reaches 80-90%, highlighting its overlap with neurodegenerative conditions.[11] Incidence rates for angiopathy are increasing globally, fueled by aging populations and the diabetes epidemic; for instance, macrovascular complications are the leading cause of death in people with diabetes, accounting for approximately 70% of mortality in those with type 2 diabetes.[12]Demographic patterns reveal higher occurrence in older adults, with CAA typically emerging after age 55 and diabetic angiopathy predominantly linked to type 2 diabetes, which comprises over 90% of cases.[13] Risk is elevated in certain groups, including those with the APOE-ε4 genotype and Europeans, where CAA pathology shows comparable prevalence to East Asians at around 23% in moderate-to-severe forms among the elderly.[14] Men and individuals with comorbid diabetes face heightened susceptibility to CAA progression.[15]As of 2025, trends indicate a continued rise in angiopathy incidence, paralleling projections of 853 million adults with diabetes by 2050, particularly in low- and middle-income regions where underdiagnosis exacerbates the issue.[9] Aging demographics further amplify this, with global life expectancy gains leading to more elderly individuals at risk for CAA and related cerebrovascular events.[16]
Classification
By vessel caliber
Angiopathy is classified by vessel caliber into macroangiopathy and microangiopathy, providing a structural basis for understanding the scale of vascular involvement in various diseases.[17]Macroangiopathy affects large and medium-sized arteries, such as the aorta, coronary arteries, renal arteries, basilar arteries, and peripheral arteries.[17] It is primarily characterized by atherosclerosis, which results in vessel wall thickening, luminal narrowing, thrombosis, or aneurysm formation.[18] A representative example is atherosclerotic macroangiopathy, where plaque buildup progressively obstructs blood flow in major conduits.[18]In contrast, microangiopathy involves smaller vessels, including arterioles, capillaries, and venules.[17] Key features include thickening of the basement membrane, endothelial cell dysfunction, and increased vascular permeability leading to leakage.[19] Hyaline microangiopathy exemplifies this, marked by hyaline deposition in arteriolar walls, often seen in conditions like hypertension or diabetes.[20]The impacts of these forms differ significantly in scope. Macroangiopathy typically causes ischemia in large vascular territories, such as myocardial infarction due to coronary arteryocclusion.[21]Microangiopathy, however, leads to more diffuse organ damage across affected tissues, as in retinopathy where capillary leakage and ischemia impair retinal function.[19] Diabetic angiopathy serves as a common example encompassing both types.[17]
By underlying condition
Angiopathy can be classified based on the underlying medical conditions that precipitate vascular damage, each involving distinct pathophysiological triggers and preferential involvement of specific vessel types. This categorization highlights how systemic diseases contribute to angiopathic changes, often exacerbating microvascular or macrovascular integrity in targeted organs.[22]Diabetic angiopathy arises from prolonged hyperglycemia, which induces oxidative stress, advanced glycation end products, and inflammation, leading to endothelial dysfunction and damage primarily in retinal, renal, and peripheral vessels. In the retina, this manifests as microaneurysms and capillary non-perfusion, contributing to diabetic retinopathy; in the kidneys, it causes glomerular basement membrane thickening and mesangial expansion in diabetic nephropathy; and in peripheral arteries, it accelerates atherosclerosis and stenosis, increasing risks of limb ischemia. These changes are vessel-caliber specific but unified by metabolic derangements in diabetes mellitus.[22][23][24]Amyloid angiopathy involves the deposition of amyloid proteins, such as amyloid-beta in cerebral amyloid angiopathy (CAA), within the walls of cerebral vessels, resulting in vessel wall weakening, fragility, and increased susceptibility to hemorrhage or ischemia. CAA predominantly affects leptomeningeal and cortical arteries, sparing systemic vessels, and is strongly associated with aging and Alzheimer's disease pathology. The amyloid accumulation disrupts vascular smooth muscle cells and the extracellular matrix, promoting microbleeds and lobar intracerebral hemorrhages.[10][25][26]Hypertensive angiopathy develops from chronic hypertension, which imposes mechanical stress on arterioles, leading to hyalinization—a glassy thickening of the vessel wall due to plasma protein leakage and smooth muscle cell loss. This primarily impacts small renal and cerebral arterioles, reducing lumen diameter and impairing autoregulation, which can precipitate hypertensive encephalopathy or nephrosclerosis. Unlike other forms, it favors penetrating arterioles over larger vessels, distinguishing it from caliber-based classifications.[27][28][29]Other conditions associated with angiopathy include sickle cell vasculopathy, radiation-induced angiopathy, and thrombotic microangiopathies such as hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). In sickle cell disease, polymerized hemoglobin S causes red blood cell sickling and adhesion to endothelium, resulting in vaso-occlusion and chronic vasculopathy affecting cerebral, pulmonary, and peripheral vessels, with a predilection for large intracranial arteries in stroke-prone cases. Radiation-induced angiopathy emerges years after therapeutic irradiation, involving endothelial injury, fibrosis, and accelerated atherosclerosis in irradiated vascular beds, such as carotid arteries following neck radiation. Thrombotic microangiopathies like HUS and TTP feature microvascular thrombosis and endothelial damage from complement dysregulation or ADAMTS13 deficiency, primarily targeting renal and cerebral capillaries, leading to hemolytic anemia and organ ischemia. Each of these demonstrates unique vessel tropism, such as the cerebral focus in CAA versus the systemic microvasculature in TTP/HUS.[30][31][32][33][34][35]
Pathophysiology
General mechanisms
Angiopathy encompasses a range of vascular disorders characterized by damage to blood vessel walls, with endothelial dysfunction serving as a central initiating mechanism across various forms. The endothelium, the inner lining of blood vessels, maintains vascular homeostasis through regulation of vasodilation, permeability, and anti-thrombotic properties; however, initial injury often arises from oxidative stress, where excessive reactive oxygen species (ROS) production—primarily from sources like NADPH oxidase, mitochondria, and uncoupled endothelial nitric oxide synthase (eNOS)—impairs endothelial function.[36] This oxidative burden reduces nitric oxide (NO) bioavailability, as ROS scavenges NO and promotes eNOS uncoupling, leading to diminished vasodilation and heightened vasoconstriction.[36] Consequently, increased endothelial permeability occurs due to disruption of cell-cell junctions and glycocalyx degradation, allowing plasma components to infiltrate the vessel wall and exacerbate injury.[36]Inflammatory cascades amplify endothelial damage, transforming acute injury into chronic vascular remodeling. Following initial endothelial activation, cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and IL-6 are released by endothelial cells, macrophages, and vascular smooth muscle cells (VSMCs), activating pathways like NF-κB and JAK-STAT that further upregulate adhesion molecules including vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1).[37] These molecules facilitate leukocyte adhesion and transmigration into the subendothelial space, where recruited monocytes and neutrophils release additional proinflammatory mediators, promoting oxidative stress and matrix metalloproteinase (MMP) activity that degrades extracellular matrix (ECM).[37] This inflammatory milieu drives VSMC proliferation and migration, contributing to vessel wall thickening through ECM deposition and intimal expansion.[37]Hemodynamic factors, including shear stress and hypertension, impose mechanical forces that perpetuate vascular injury. Disturbed or low shear stress at arterial bifurcations and curvatures induces proinflammatory gene expression in endothelial cells, fostering monocyte adhesion and plaque formation, while high shear stress can protect against atherosclerosis but may lead to endothelial denudation if excessive.[38]Hypertension exacerbates this by impairing eNOS expression and NO production, resulting in endothelial dysfunction and increased vascular stiffness; chronic exposure promotes fibrosis through VSMC hypertrophy and ECM accumulation, potentially culminating in vessel rupture under sustained pressure.[38]Thrombotic tendencies emerge as a downstream consequence, heightening the risk of acute vascular occlusion. Endothelial injury exposes subendothelial collagen and von Willebrand factor, triggering platelet activation via glycoprotein Ib/IX/V receptors and subsequent aggregation through fibrinogen binding to GP IIb/IIIa, amplified by release of thromboxane A2 and ADP.[39] This process promotes fibrin deposition via tissue factor activation and coagulation cascade initiation, forming stable thrombi that can occlude vessels or embolize distally, particularly in inflamed or dysfunctional endothelium.[39]The progression of angiopathy follows a model from early endothelial dysfunction to advanced structural remodeling. Initial oxidative and inflammatory insults lead to a proinflammatory state, reprogramming VSMCs from a contractile to synthetic phenotype via pathways such as TGF-β/Smad and Rho/ROCK, enabling their migration and proliferation into the intima.[40] This culminates in neointima formation and intimal hyperplasia, characterized by excessive ECM deposition and vessel narrowing; persistent stimuli may induce further calcification or fibrosis, reducing lumen patency and perpetuating ischemia.[40] While these mechanisms are shared, manifestations differ between micro- and macrovasculature due to scale-dependent hemodynamics.[40]
Type-specific pathology
In diabetic microangiopathy, advanced glycation end-products (AGEs) formed through chronic hyperglycemia cross-link proteins such as collagen in the extracellular matrix, leading to structural alterations including increased stiffness and thickness of the basement membrane.[41] This process is mediated by AGE-receptor interactions that upregulate pathways like TGF-β and PKC, promoting excessive matrix protein accumulation.[41] In the glomeruli, this manifests as glomerular basement membrane thickening, a hallmark of diabetic nephropathy, with uneven expansion observed via transmission electron microscopy in experimental models after prolonged AGE exposure.[42] Similarly, in the retina, AGE-induced cross-linking causes capillary basement membrane expansion, contributing to pericyte loss and vascular permeability changes central to diabetic retinopathy pathogenesis.[43]Cerebral amyloid angiopathy (CAA) features progressive deposition of amyloid-beta (Aβ) peptides, predominantly Aβ40, in the tunica media and adventitia of small- to medium-sized leptomeningeal and cortical arteries, resulting in vessel wall weakening and fragility.[44] This deposition disrupts smooth muscle cells and elastic lamina, predisposing to microaneurysms, ischemia, and recurrent lobar intracerebral hemorrhages, often in occipital and parietal regions.[44] CAA subtypes include sporadic forms, the most common and associated with aging and the APOE ε4 allele, which exacerbate vascular amyloid burden, and hereditary variants such as those linked to APP gene mutations (e.g., Dutch-type with E693Q), characterized by earlier onset and more severe deposition around age 50.[44][45]Hypertensive angiopathy involves distinct acute and chronic vascular changes in arterioles. In the acute phase, particularly during malignant hypertension, fibrinoid necrosis occurs as plasma proteins and fibrin infiltrate the vessel wall of subcortical penetrating arterioles, causing eosinophilic deposition, inflammation, and wall weakening that heightens intracerebral hemorrhage risk.[29] In the chronic phase, sustained hypertension induces hyperplastic arteriolosclerosis, marked by concentric smooth muscle cell proliferation and fibrous tissue layering, producing an "onion-skin" appearance on histological sections that narrows the lumen and impairs cerebral perfusion.[46]Thrombotic microangiopathy (TMA) is characterized by primary endothelial injury in small vessels, triggered by toxins such as Shiga toxin from Escherichia coli or immune-mediated mechanisms like complement dysregulation and autoantibodies.[47] This injury activates platelets and the coagulation cascade, forming platelet-fibrin microthrombi that occlude arterioles and capillaries, leading to ischemic organ damage, particularly in the kidneys.[47] Peripheral blood smears reveal schistocytes from mechanical red blood cell fragmentation, with levels ≥1% supporting the diagnosis alongside thrombocytopenia and hemolysis.[47]Histological confirmation of CAA relies on special stains, with Congo red demonstrating amyloid deposits as apple-green birefringent material under polarized light in vessel walls, often complemented by beta-amyloid immunohistochemistry for specificity.[10]
Causes and Risk Factors
Primary causes
Angiopathy encompasses a range of vascular disorders characterized by pathological changes in blood vessel walls, and its primary causes include metabolic, genetic, toxic/iatrogenic, infectious, and idiopathic factors.In metabolic causes, chronic hyperglycemia in diabetes mellitus is a leading initiator, activating the polyol pathway where aldose reductase converts glucose to sorbitol, depleting NADPH and promoting oxidative stress through reactive oxygen species accumulation, which damages endothelial cells and leads to microvascular angiopathy.[48] This pathway's overactivation in hyperglycemic conditions exacerbates vascular complications by fostering advanced glycation end-products and inflammation in vessel walls.[49]Oxidative stress from hyperglycemia further impairs nitric oxide bioavailability, contributing to endothelial dysfunction central to diabetic angiopathy.[50]Genetic causes of angiopathy include mutations in the amyloid precursor protein (APP) gene, which underlie hereditary cerebral amyloid angiopathy (CAA) by altering amyloid-beta processing and triggering early-onset deposition in cerebral vessel walls.[51] These APPmutations, such as those at the Dutch (E693Q) or Arctic sites, promote fibrillar amyloid accumulation in leptomeningeal and cortical vessels, often manifesting in the fourth to sixth decades with hemorrhagic strokes.[52] Heterozygous APP variants disrupt proteolytic cleavage, leading to toxic amyloid-beta oligomers that compromise vascular integrity.[53]Toxic and iatrogenic causes include radiation therapy, which induces endothelial apoptosis through direct DNA damage and oxidative bursts, resulting in accelerated atherosclerosis and microangiopathy in irradiated tissues.[54]Ionizing radiation activates pro-apoptotic pathways in endothelial cells, increasing adhesion molecule expression and leukocyte interactions that initiate vessel wall injury.[55] Chemotherapy agents like cisplatin contribute via vascular toxicity, causing endothelial damage and persistent hypertension through oxidative stress and reduced nitric oxide production.[56]Cisplatin's platinum-based mechanism leads to severe ischemic events, including angina, by promoting thrombosis and vessel narrowing.[57]Infectious causes are rare but can mimic angiopathy through vasculitides induced by bacteria or viruses, particularly in immunocompromised individuals. Cytomegalovirus (CMV) infection, for instance, triggers endothelial inflammation and vasculopathy in such patients, leading to vessel wall necrosis resembling primary angiopathy.[58] CMV primarily affects small vessels, causing cerebral or retinal lesions via direct viral endothelial invasion and immune-mediated damage.[59] Other agents, like certain bacteria, may provoke similar inflammatory vasculitides through molecular mimicry.[60]Idiopathic or sporadic forms, such as age-related CAA, occur without identifiable triggers and predominate in the elderly, with amyloid-beta deposition in cerebral vessels increasing markedly after age 60.[10] This sporadic CAA arises from age-associated failures in amyloid clearance, leading to insidious vascular fragility without genetic predisposition.[61]Prevalence rises to over 50% in those over 90, driven by cumulative proteolytic imbalances in the brain's microvasculature.[62]
Risk factors
Risk factors for angiopathy encompass both non-modifiable and modifiable elements that contribute to the development and progression of vascular damage across various forms, including cerebral amyloid angiopathy (CAA), atherosclerotic, and diabetic angiopathy. Non-modifiable factors include advanced age, family history of vascular disease, and certain genetic predispositions. Advanced age is a primary risk factor, with the prevalence of CAA rising significantly after age 60; for instance, autopsy studies indicate a prevalence of 5-9% in individuals aged 60-69 years, increasing to 43-58% in those over 90 years.[63] Family history of vascular disease, such as atherosclerosis or stroke, elevates susceptibility through shared genetic and environmental influences inherited across generations.[64] Genetic factors, notably the APOE ε4 allele, are strongly associated with increased risk and severity of CAA, as carriers exhibit higher amyloid deposition in cerebral vessels.[65]Modifiable risk factors play a critical role in accelerating angiopathy, particularly through lifestyle and metabolic influences. Smoking substantially heightens the risk, approximately doubling the likelihood of atherosclerosis by promoting endothelial dysfunction and vasoconstriction induced by nicotine and other tobacco components.[66]Dyslipidemia, characterized by elevated low-density lipoprotein (LDL) cholesterol levels, fosters plaque formation in arterial walls, directly contributing to macrovascular angiopathy.[67]Obesity exacerbates risk via insulin resistance, which impairs vascular endothelial function and promotes inflammatory pathways leading to angiopathy in conditions like diabetes.[68]Disease-related factors further compound vulnerability. Uncontrolled hypertension markedly increases the risk of stroke-associated angiopathy, with relative risks ranging from 2 to 4 times higher compared to normotensive individuals, due to chronic shear stress on vessel walls.[69]Chronic kidney disease (CKD) is linked to accelerated vascular calcification and endothelial injury, heightening angiopathy incidence independently of other comorbidities.[70]Lifestyle choices beyond smoking and obesity, such as sedentary behavior and diets high in salt and sugar, intensify endothelial stress and inflammation, thereby elevating angiopathy risk through sustained metabolic derangements.[71] Notably, interactions among risk factors amplify effects; for example, the combination of diabetes and hypertension synergistically accelerates macroangiopathy progression by enhancing oxidative stress and plaque instability.[68]
Clinical Features
Symptoms
Symptoms of angiopathy depend on the affected vessels, organs, and whether the pathology leads to ischemia (reduced blood flow) or hemorrhage (vessel rupture). Ischemic manifestations are common in both macroangiopathy and microangiopathy, presenting as pain, weakness, or functional impairment due to inadequate tissueperfusion.[72]In macroangiopathy, such as coronary artery disease or peripheral artery disease, patients typically experience angina—characterized by chest pressure, tightness, or pain that may radiate to the arms, neck, or jaw, often triggered by exertion—and shortness of breath or fatigue. Peripheral involvement leads to intermittent claudication, manifesting as cramping, pain, numbness, or weakness in the legs during walking, along with cold extremities and slow-healing sores.[73][64]Microangiopathy often affects smaller vessels in specific organs, causing organ-specific symptoms. Retinopathy results in blurred vision, floaters, or fluctuating visual acuity, potentially progressing to dark spots or vision loss. Renal microangiopathy presents with leg or ankle swelling (edema), foamy urine due to proteinuria, high blood pressure, fatigue, nausea, and loss of appetite in later stages. Neuropathy associated with microvascular damage causes tingling, burning pain, or numbness in the hands and feet, increasing risk for injuries. Cardiac small vessel disease may mimic macroangiopathy with angina-like chest discomfort and tiredness.[74][75][76][72]Hemorrhagic angiopathy, as seen in cerebral amyloid angiopathy, features acute onset of severe headache, confusion, seizures, focal neurological deficits like hemiparesis or weakness, and in severe cases, coma or progressive dementia with memory loss. Systemic symptoms in advanced angiopathy include generalized fatigue and unintentional weight loss, often from multi-organ involvement. Presentations can be chronic and insidious, with gradual symptom progression, or acute, resembling stroke with sudden deficits.[77][78]
Complications
Angiopathy, characterized by damage to blood vessels of varying calibers, leads to severe long-term consequences when untreated, primarily through ischemia, hemorrhage, and organ dysfunction across multiple systems. These complications arise from the progressive narrowing, weakening, or occlusion of arteries, veins, and capillaries, often exacerbating underlying conditions like diabetes or amyloid deposition.[10]In the cardiovascular system, coronary macroangiopathy predisposes individuals to myocardial infarction due to atherosclerotic plaque rupture and thrombosis, which can result in acute ischemia and necrosis of heart muscle. Untreated, this evolves into heart failure through ventricular remodeling and reduced cardiac output, with recurrent ischemic events further impairing myocardial function.[79][80]Neurological complications are prominent in cerebral amyloid angiopathy (CAA), where amyloid-beta deposition in cortical and leptomeningeal vessels causes vessel fragility and recurrent lobar hemorrhages. These hemorrhages often lead to stroke, with ischemic or hemorrhagic types contributing to acute neurological deficits and long-term disability. Additionally, CAA-related vascular damage promotes cognitive decline and dementia through chronic microbleeds and white matter injury, while the risk of recurrent hemorrhages remains elevated, affecting up to 23% of patients. Mortality following CAA-related intracerebral hemorrhage is substantial, with 1-year rates around 20% in affected cohorts.[10][81][82][83]Renal involvement in diabetic nephropathy, a form of microangiopathy, progresses to end-stage kidney disease characterized by glomerulosclerosis and tubulointerstitial fibrosis, ultimately necessitating dialysis for survival as glomerular filtration rate falls below 15 mL/min/1.73 m². This advanced stage reflects irreversible nephron loss from hyperglycemia-induced endothelial dysfunction and proteinuria. Diabetic nephropathy accounts for a leading proportion of end-stage renal disease cases globally.[75][84]Ocular complications from diabetic microangiopathy manifest as proliferative retinopathy, where retinal ischemia triggers neovascularization and subsequent vitreous hemorrhage or tractional retinal detachment. These events distort the vitreoretinal interface, leading to severe vision impairment or complete blindness if the macula or optic nerve is involved. Diabetic retinopathy remains the primary cause of preventable blindness in working-age adults.[85][86]Multi-organ effects are evident in peripheral vascular disease, a macroangiopathy often linked to atherosclerosis, which causes critical limb ischemia and non-healing ulcers, culminating in amputation to prevent sepsis or gangrene. In severe cases, such as chronic limb-threatening ischemia, amputation rates are heightened, particularly in comorbid diabetes. Overall, angiopathic complications contribute to elevated mortality, with CAA-related events exemplifying a 20-30% 1-year post-hemorrhage risk in vulnerable populations.[87][88][83]
Diagnosis
Clinical evaluation
Clinical evaluation of angiopathy begins with a detailed history to identify underlying risk factors and symptom patterns suggestive of vascular involvement. Clinicians inquire about the duration of diabetes, as prolonged hyperglycemia exceeding 10 years significantly increases the risk of microvascular and macrovascular complications.[89] Control of hypertension is assessed, given its role as a major modifiable risk factor accelerating vessel wall damage.[89] Family history of vascular diseases, such as premature cardiovascular events, is explored to gauge genetic predisposition.[90] Recent symptoms, including transient ischemic attacks (TIAs) characterized by brief episodes of focal neurological deficits, or intermittent claudication presenting as exertional leg pain relieved by rest, are probed to correlate with potential ischemic events.[89]The physical examination focuses on systemic signs of vascular compromise, starting with vital signs, particularly blood pressure measurement to detect hypertension that exacerbates angiopathy.[91] Peripheral pulses are palpated at key sites, including femoral, popliteal, posterior tibial, and dorsalis pedis arteries; diminished or absent pulses indicate arterial insufficiency.[90] The ankle-brachial index (ABI), a non-invasive ratio of ankle to brachial systolic blood pressure (normal 0.9–1.3), is routinely calculated to quantify lower extremity perfusion and screen for peripheral macroangiopathy, with values below 0.9 suggesting obstructive disease.[92] Fundoscopic examination is performed to identify diabetic retinopathy, a marker of widespread microvascular disease.[91] Neurological assessment evaluates for deficits such as sensory loss, motor weakness, or cognitive impairment, which may reflect cerebral or peripheral involvement.[10]In cases of suspected cerebral amyloid angiopathy (CAA) with stroke-like presentation, the National Institutes of HealthStroke Scale (NIHSS) is briefly applied to quantify neurological deficits and gauge stroke severity, aiding in urgent triage.[93]Red flags during evaluation include sudden onset of symptoms, such as severe headache or focal deficits suggesting hemorrhage, in contrast to gradual progression indicative of chronic ischemia.[10]Differential diagnosis involves distinguishing angiopathy from primary vasculitis, which features systemic inflammation and multi-organ involvement absent in degenerative angiopathies, or from embolic events, typically presenting with abrupt, multifocal deficits without underlying chronic vessel pathology.[94]
Imaging and laboratory tests
Diagnosis of angiopathy relies on a combination of imaging and laboratory tests to confirm vascular pathology, assess extent of involvement, and guide management, often prompted by clinical suspicion of cerebrovascular, diabetic, or atherosclerotic disease.[95]In cerebral amyloid angiopathy (CAA), magnetic resonance imaging (MRI) with gradient-echo or susceptibility-weighted sequences is the primary modality, detecting cerebral microbleeds as hypointense lesions indicative of hemosiderin deposition from prior hemorrhages.[95] These sequences enhance sensitivity for identifying lobar microbleeds, a hallmark of CAA, distinguishing it from other causes of intracranial hemorrhage.[96] For macroangiopathy, such as atherosclerotic stenosis, duplex ultrasound is the initial non-invasive imaging test for carotid arteries, providing velocity-based assessment of stenosis degree with high sensitivity and specificity; computed tomography (CT) angiography is used for detailed visualization of luminal narrowing when ultrasound is inconclusive or for procedural planning, with high accuracy for detecting stenoses greater than 50%.[97][98] In diabetic retinopathy, a form of microvascular angiopathy, fluorescein angiography reveals retinal non-perfusion areas, microaneurysms, and neovascularization through dye leakage patterns, aiding in staging and treatment planning.[99]Laboratory evaluations focus on underlying risk factors and end-organ effects. Hemoglobin A1c (HbA1c) testing assesses long-term glycemic control in diabetic angiopathy, with levels above 6.5% correlating with increased microvascular and macrovascular complications.[100] A lipid panel, including total cholesterol, LDL, HDL, and triglycerides, identifies dyslipidemia as a contributor to atherosclerotic angiopathy, where elevated LDL promotes plaque formation.[17] Urinalysis detects proteinuria or microalbuminuria, signaling renal angiopathy in diabetic kidney disease, with persistent albumin excretion over 30 mg/day indicating early vascular damage.[17]Biopsy of affected vessel walls is rarely performed due to invasiveness but can confirm amyloid deposition in CAA via Congo red staining, which exhibits apple-green birefringence under polarized light, or immunohistochemistry for beta-amyloid.[10] Such sampling is typically reserved for atypical cases or when non-invasive methods are inconclusive.[101]Advanced imaging like positron emission tomography (PET) with amyloid tracers (e.g., Pittsburgh compound B) quantifies amyloid burden in CAA, showing increased vascular retention compared to controls, though primarily used in research settings for its moderate diagnostic accuracy.[102][103]The Boston criteria version 2.0 provide a non-invasive framework for diagnosing probable CAA, requiring age ≥50 years, clinical presentation with spontaneous intracerebral hemorrhage or cognitive impairment, and MRI evidence of ≥2 lobar microbleeds or other supportive features like cortical superficial siderosis, achieving improved sensitivity over prior versions without sacrificing specificity.[104]
Management
Treatment approaches
Treatment approaches for angiopathy are tailored to the underlying etiology, such as diabetes or cerebral amyloid deposition, and focus on mitigating vascular damage, preventing progression, and addressing complications like stenosis or hemorrhage. In diabetic angiopathy, which encompasses both microvascular and macrovascular involvement, therapies emphasize multifactorial risk management to preserve vascular integrity.[105] For cerebral amyloid angiopathy (CAA), treatments prioritize hemorrhage risk reduction while cautiously managing comorbidities.[106]Pharmacological interventions form the cornerstone for diabetic angiopathy. Glycemic control is achieved through agents like metformin or insulin, which reduce microvascular complications such as retinopathy and nephropathy by maintaining HbA1c below 7% in most patients.[8] Antihypertensives, particularly angiotensin-converting enzyme (ACE) inhibitors like ramipril, are recommended for patients with diabetic nephropathy to slow progression to end-stage renal disease, targeting blood pressure below 130/80 mmHg.[105] Statins, such as atorvastatin at high-intensity doses (40-80 mg daily), are used for lipid control in macrovascular disease, aiming for LDL cholesterol below 70 mg/dL to lower atherosclerosis risk.[105] Antiplatelet therapy with aspirin (75-162 mg daily) is standard for secondary prevention in macroangiopathy with atherosclerotic cardiovascular disease (ASCVD), though dual therapy with low-dose rivaroxaban (2.5 mg twice daily) may be considered for stable coronary or peripheral artery disease if bleeding risk is low.[105] In CAA, antiplatelets like aspirin are often avoided due to heightened intracerebral hemorrhage risk, unless required for specific indications like recent coronary stenting, with decisions guided by multidisciplinary assessment.[106]Specific therapies target organ-specific manifestations. For diabetic retinopathy, a microvascular complication, intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents such as ranibizumab or aflibercept are first-line for center-involved macular edema, administered every 4-8 weeks to improve visual acuity.[107]Interventional procedures address macrovascular stenosis in angiopathy. Endovascular angioplasty with or without stenting is recommended for peripheral artery disease (PAD) complicating diabetic foot ulcers, particularly when ankle-brachial index is below 0.5 or ulcers fail to heal after 4-6 weeks of conservative care, aiming to restore inline flow to the affected limb.[108] For proliferative diabetic retinopathy, panretinal laser photocoagulation reduces severe vision loss risk by targeting ischemic areas.[107]Supportive measures manage advanced complications. Dialysis is indicated for renal failure in diabetic nephropathy when glomerular filtration rate falls below 15 mL/min/1.73 m², providing renal replacement therapy to sustain life.[8] Post-stroke rehabilitation, including physical and occupational therapy, is essential following macrovascular events like ischemic stroke in angiopathy, improving functional recovery through multidisciplinary programs.[109]The American Diabetes Association (ADA) guidelines recommend comprehensive screening and treatment for diabetic angiopathy, including annual retinal exams for retinopathy, blood pressure monitoring with ACE inhibitor initiation for albuminuria, and statin therapy for all patients over 40 with additional ASCVD risk factors, integrated with SGLT2 inhibitors like empagliflozin for cardioprotection in type 2 diabetes.[105]
Prognosis and prevention
The prognosis of angiopathy varies widely depending on the underlying cause, affected vascular bed, and patient-specific factors such as age and comorbidities. In diabetic macroangiopathy, cardiovascular complications are associated with reduced long-term survival, with five-year mortality rates reaching approximately 30-50% in patients experiencing events like major amputations or diabetic foot ulcers.[110] For cerebral amyloid angiopathy (CAA), the annual recurrence rate of intracerebral hemorrhage is around 5-10%, increasing to 14% per year in carriers of the APOE ε4 allele, which exacerbates vascular fragility and hemorrhage risk.[111][112]Several factors influence angiopathy outcomes, with early diagnosis and intervention playing a pivotal role in improving prognosis. For instance, effective blood pressure control can substantially reduce the risk of recurrent intracerebral hemorrhage by lowering systolic targets to under 140 mmHg, thereby mitigating vascular stress and hemorrhage progression. Conversely, advanced age and comorbidities like hypertension or diabetes worsen prognosis by accelerating endothelial damage and complication rates.[113][114]Prevention of angiopathy emphasizes lifestyle modifications and targeted screening to address modifiable risk factors. Smoking cessation is critical, as it reduces endothelial dysfunction and progression of peripheral arterial disease, while regular exercise and adherence to a Mediterranean diet lower cardiovascular event risks by improving vascular health and lipid profiles. In diabetic patients, annual screening for retinopathy via dilated eye exams and kidney function tests enables early detection of microangiopathy, preventing advancement to macrovascular complications. Vaccination against infections such as influenza and pneumococcus is recommended for those at risk of vasculitis-related angiopathy, as it curbs inflammatory triggers that exacerbate vascular injury.[115][116][117][118]Public health initiatives, particularly diabetes management programs incorporating multifactorial interventions like glycemic control and lifestyle education, have demonstrated reductions in the risk of progression to nephropathy and retinopathy by approximately 50% in controlled cohorts.[119] Emerging approaches as of 2025 include gene therapy trials for hereditary forms, such as antisense oligonucleotide treatments targeting amyloid precursor protein in Dutch-type CAA, showing promise in halting vascular amyloid deposition in early-phase studies.[120][121]