Microangiopathy

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Microangiopathy (also known as microvascular disease, small vessel disease (SVD) or microvascular dysfunction) is a disease of the microvessels, small blood vessels in the microcirculation. [1] It can be contrasted to macroangiopathies such as atherosclerosis, where large and medium-sized arteries (e.g., aorta, carotid and coronary arteries) are primarily affected. [2]

Contents

Microangiopathy
MVD001.jpg
A case of conjunctival microangiopathy (red dashed-square) secondary to diabetes demonstrating a microaneurysm (orange arrow), vessel dilatation (blue arrows), and vascular tortuosity (yellow arrow).
MVD002.jpg
Examples of microvascular diseases.

Small vessel diseases (SVDs) affect primarily organs that receive significant portions of cardiac output such as the brain, the kidney, and the retina. Thus, SVDs are a major etiologic cause in debilitating conditions such as renal failure, blindness, lacunar infarcts, and dementia. [3]

Types

Microangiopathies are involved in a variety of different diseases including:

Pathophysiology

The main target of small vessel diseases is the endothelium, which plays a key role in vascular homeostasis. [3] The pathogenesis of SVDs in various organs is characterized by endothelial dysfunction, capillary rarefaction, microthrombi and microvascular remodeling. [15]

Diabetic microangiopathy, which is the most common cause of microangiopathy, is more prevalent in the kidney, retina and vascular endothelium since glucose transport in these sites isn’t regulated by insulin and these tissues cannot stop glucose from entering cells when blood sugar levels are high. [16] Among all biochemical mechanisms involved in diabetic vascular damage such as the polyol pathway and the renin–angiotensin system (RAS), the advanced glycation end products (AGEs) pathway appears to be the most important in the pathogenesis and progression of microvascular complications. [17]

Chronic high blood sugar levels lead to the attachment of sugar molecules to various proteins, including collagen, laminin, and peripheral nerve proteins. This process, called glycosylation, creates advanced glycation end products (AGEs). AGEs formation cross-links these proteins, making them resistant to degradation. This leads to accumulation of AGEs, thickening of the basement membrane, narrowing the blood vessels, reducing blood flow to the tissues and causing ischemic injury. [18] [19]

In addition, oxidative stress, caused by AGEs and the other pathways, causes apoptosis of pericytes and podocytes in the retina and the kidneys respectively leading to capillary wall fragility and increased vascular leakage. This results in local swelling (e.g. macular edema) and impaired tissue function. [20]

Microvascular diseases as a multisystem disorder

Some researchers have suggested that SVD may be a multisystem disorder, meaning that it can affect multiple organs in the body, including the heart and brain. This is supported by multiple studies stating that cardiac pathologies are more prevalent in patients with pathological evidence of cerebrovascular SVD and vice versa. [15] [21]

Coronary microvascular diseases (CMDs) can be caused by: [5]

On the other hand, Cerebral SVD encompasses a range of vascular pathologies including arteriosclerosis-related CSVD, where lipohyalinosis causes stenosis of the lumen of the arterioles and amyloid-related CSVD, characterized by the build-up of β-amyloid deposits in small- and medium-caliber cerebral vessels. [6]

The vascular anatomy of the heart and brain is similar in that conduit arteries are distributed on the surface of these organs with tissue perfusion achieved through deep penetrating arteries. Both coronary and cerebral microvascular diseases do share some common risk factors such as hypertension. Why some patients with microvascular angina subsequently develop vascular cognitive impairment and others do not is an unanswered question. Potential underpinning mechanisms include premature vascular aging and clustering of vascular risk factors leading to an accelerated cardiovascular risk. [21]

Diagnosis

The diagnosis of microangiopathies can be based on direct visualization of the microcirculation, imaging modalities (e.g. MRI), conventional testings (e.g. ophthalmoscopy for diabetic retinopathy) or other diagnostic measures (e.g. blood smear for schistocytes in thrombotic microangiopathies). [6] [8] [16]

For assessment of the morphological and functional aspects of microcirculation, nailfold videocapillaroscopy (NVC) can be used, in which videocapillaroscopy is performed at the nailfold, where capillaries are arranged with the longitudinal axis parallel to the skin surface, so that they can be examined along their entire length. [8]

NVC has been largely used not only for investigating peripheral microangiopathy, but also as a sort of "window" to systemic microvascular dysfunction. Although its main application is within the connective tissue diseases such as systemic scleroderma and dermatomyositis, it has been employed in non-rheumatic diseases with microvascular involvement such as diabetes mellitus, essential hypertension and COVID-19 infection. [8]

Nailfold capillaroscopy MVD003.png
Nailfold capillaroscopy
Capillaroscopic findings in patients with mild COVID-19 Enlarged loops (Black arrow) Microhemorrhages (Red arrow) Microthrombosis (Green arrow) MVD004.jpg
Capillaroscopic findings in patients with mild COVID-19
  1. Enlarged loops (Black arrow)
  2. Microhemorrhages (Red arrow)
  3. Microthrombosis (Green arrow)

Optical coherence tomography angiography (OCTA) is another imaging modality that offers high-resolution visualization of the retinal capillary network and can be used to evaluate microcirculation in conditions such as diabetic retinopathy. [22] Many studies have demonstrated that evaluation of the retinal microvascular changes using OCTA or other methods such as fluorescein angiography may reflect the systemic microvascular functions as in patients with coronary microvascular disease, cerebral small vessel diseases or systemic sclerosis (The potential of retinal microvascularopathy as a biomarker for assessing microvascular status of other circulations). [23] [24]

Unlike the retinal microcirculation, the coronary microvasculature cannot be directly imaged. Instead, a number of different tests can be used to measure how much blood is flowing through the coronary microvasculature. These tests can be used to assess how well the coronary microvasculature is functioning and to diagnose coronary microvascular disease. [5] They include non-invasive measures such as cardiac MRI and invasive measures such as intracoronary Doppler wire. [25]

Similarly, CSVD is typically recognized on both brain magnetic resonance imaging (MRI) and computed tomography (CT) scans, but MRI has greater sensitivity and specificity. Neuroimaging of CSVD primarily involves visualizing radiological phenotypes of CSVD such as recent subcortical infarcts or cerebral microbleeds (CMBs). [6]

Treatment

Treatment options of microangiopathies can be directed at:

A better understanding of the mechanisms leading to damage of small blood vessels may be associated with novel therapeutic approaches, the safety and efficacy of some of which will need to be further investigated. Examples include calcium dobesilate and aldose reductase inhibitors in diabetic microangiopathies and endothelin receptor antagonists for pulmonary hypertension. [16] [21] [27] [28]

Related Research Articles

Angiopathy is the generic term for a disease of the blood vessels. The best known and most prevalent angiopathy is diabetic angiopathy, a common complication of chronic diabetes.

<span class="mw-page-title-main">Capillary</span> Smallest type of blood vessel

A capillary is a small blood vessel, from 5 to 10 micrometres in diameter, and is part of the microcirculation system. Capillaries are microvessels and the smallest blood vessels in the body. They are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the site of the exchange of many substances from the surrounding interstitial fluid, and they convey blood from the smallest branches of the arteries (arterioles) to those of the veins (venules). Other substances which cross capillaries include water, oxygen, carbon dioxide, urea, glucose, uric acid, lactic acid and creatinine. Lymph capillaries connect with larger lymph vessels to drain lymphatic fluid collected in microcirculation.

<span class="mw-page-title-main">Retinopathy</span> Damage to the retina of the eyes

Retinopathy is any damage to the retina of the eyes, which may cause vision impairment. Retinopathy often refers to retinal vascular disease, or damage to the retina caused by abnormal blood flow. Age-related macular degeneration is technically included under the umbrella term retinopathy but is often discussed as a separate entity. Retinopathy, or retinal vascular disease, can be broadly categorized into proliferative and non-proliferative types. Frequently, retinopathy is an ocular manifestation of systemic disease as seen in diabetes or hypertension. Diabetes is the most common cause of retinopathy in the U.S. as of 2008. Diabetic retinopathy is the leading cause of blindness in working-aged people. It accounts for about 5% of blindness worldwide and is designated a priority eye disease by the World Health Organization.

<span class="mw-page-title-main">Diabetic retinopathy</span> Diabetes-induced damage to the retina of the eye

Diabetic retinopathy, is a medical condition in which damage occurs to the retina due to diabetes. It is a leading cause of blindness in developed countries.

<span class="mw-page-title-main">Arteriole</span> Small arteries in the microcirculation

An arteriole is a small-diameter blood vessel in the microcirculation that extends and branches out from an artery and leads to capillaries.

<span class="mw-page-title-main">Endothelium</span> Layer of cells that line the inner surface of blood vessels

The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel wall.

Microvascular angina (MVA), previously known as cardiac syndrome X, also known as coronary microvascular dysfunction(CMD) or microvascular coronary disease is a type of angina (chest pain) with signs associated with decreased blood flow to heart tissue but with normal coronary arteries.

<span class="mw-page-title-main">Conjunctiva</span> Part of the eye; protective outer layer covering the sclera

In the anatomy of the eye, the conjunctiva is a thin mucous membrane that lines the inside of the eyelids and covers the sclera. It is composed of non-keratinized, stratified squamous epithelium with goblet cells, stratified columnar epithelium and stratified cuboidal epithelium. The conjunctiva is highly vascularised, with many microvessels easily accessible for imaging studies.

<span class="mw-page-title-main">Pericyte</span> Cells associated with capillary linings

Pericytes are multi-functional mural cells of the microcirculation that wrap around the endothelial cells that line the capillaries throughout the body. Pericytes are embedded in the basement membrane of blood capillaries, where they communicate with endothelial cells by means of both direct physical contact and paracrine signaling. The morphology, distribution, density and molecular fingerprints of pericytes vary between organs and vascular beds. Pericytes help to maintain homeostatic and hemostatic functions in the brain, one of the organs with higher pericyte coverage, and also sustain the blood–brain barrier. These cells are also a key component of the neurovascular unit, which includes endothelial cells, astrocytes, and neurons. Pericytes have been postulated to regulate capillary blood flow and the clearance and phagocytosis of cellular debris in vitro. Pericytes stabilize and monitor the maturation of endothelial cells by means of direct communication between the cell membrane as well as through paracrine signaling. A deficiency of pericytes in the central nervous system can cause increased permeability of the blood–brain barrier.

Diabetic angiopathy is a form of angiopathy associated with diabetic complications. While not exclusive, the two most common forms are diabetic retinopathy and diabetic nephropathy, whose pathophysiologies are largely identical. Other forms of diabetic angiopathy include diabetic neuropathy and diabetic cardiomyopathy.

<span class="mw-page-title-main">Thrombotic microangiopathy</span> Medical condition

Thrombotic microangiopathy (TMA) is a pathology that results in thrombosis in capillaries and arterioles, due to an endothelial injury. It may be seen in association with thrombocytopenia, anemia, purpura and kidney failure.

Neovascularization is the natural formation of new blood vessels, usually in the form of functional microvascular networks, capable of perfusion by red blood cells, that form to serve as collateral circulation in response to local poor perfusion or ischemia.

<span class="mw-page-title-main">Cotton wool spots</span> Medical condition of the eye

Cotton wool spots are opaque fluffy white patches on the retina of the eye that are considered an abnormal finding during a funduscopic exam. Cotton wool spots are typically a sign of another disease state, most common of which is diabetic retinopathy. The irregularly shaped white patches are a result of ischemia, or reduced blood flow and oxygen, in the retinal nerve fiber layer, which is located in the distribution of the capillaries of the superficial layer of the retina. These areas with reduced blood flow reflect the obstruction of axoplasmic flow due to mechanical or vascular causes and the consequential accumulation as a result of decreased axonal transport. This reduced axonal transport can then cause swelling or bulging on the surface layer of the retina, increasing the potential for nerve fiber damage.

<span class="mw-page-title-main">Diabetic cardiomyopathy</span> Medical condition

Diabetic cardiomyopathy is a disorder of the heart muscle in people with diabetes. It can lead to inability of the heart to circulate blood through the body effectively, a state known as heart failure(HF), with accumulation of fluid in the lungs or legs. Most heart failure in people with diabetes results from coronary artery disease, and diabetic cardiomyopathy is only said to exist if there is no coronary artery disease to explain the heart muscle disorder.

<span class="mw-page-title-main">Complications of hypertension</span>

Complications of hypertension are clinical outcomes that result from persistent elevation of blood pressure. Hypertension is a risk factor for all clinical manifestations of atherosclerosis since it is a risk factor for atherosclerosis itself. It is an independent predisposing factor for heart failure, coronary artery disease, stroke, kidney disease, and peripheral arterial disease. It is the most important risk factor for cardiovascular morbidity and mortality, in industrialized countries.

Complications of diabetes are secondary diseases that are a result of elevated blood glucose levels that occur in diabetic patients. These complications can be divided into two types: acute and chronic. Acute complications are complications that develop rapidly and can be exemplified as diabetic ketoacidosis (DKA), hyperglycemic hyperosmolar state (HHS), lactic acidosis (LA), and hypoglycemia. Chronic complications develop over time and are generally classified in two categories: microvascular and macrovascular. Microvascular complications include neuropathy, nephropathy, and retinopathy; while cardiovascular disease, stroke, and peripheral vascular disease are included in the macrovascular complications.

<span class="mw-page-title-main">Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations</span> Medical condition

Retinal vasculopathy with cerebral leukocencephalopathyand systemic manifestations is an inherited condition resulting from a frameshift mutation in the C-terminal region of the TREX1 gene.

Optical coherence tomography angiography (OCTA) is a non-invasive imaging technique based on optical coherence tomography (OCT) developed to visualize vascular networks in the human retina, choroid, skin and various animal models. OCTA may make use of speckle variance optical coherence tomography.

Retinal vessel analysis is a non-invasive method to examine the small arteries and veins in the retina which allows to draw conclusions about the morphology and the function of small vessels elsewhere in the human body. Retinal vessel analysis is conducted mainly by ophthalmologists, cardiologists, neurologists and other medical specialities dealing with vascular diseases.

Sickle cell retinopathy can be defined as retinal changes due to blood vessel damage in the eye of a person with a background of sickle cell disease. It can likely progress to loss of vision in late stages due to vitreous hemorrhage or retinal detachment. Sickle cell disease is a structural red blood cell disorder leading to consequences in multiple systems. It is characterized by chronic red blood cell destruction, vascular injury, and tissue ischemia causing damage to the brain, eyes, heart, lungs, kidneys, spleen, and musculoskeletal system.

References

  1. ↑ "microangiopathy" at Dorland's Medical Dictionary
  2. ↑ Kumar, Vinay; Abbas, Abul K.; Aster, Jon C.; Perkins, James A.; Robbins, Stanley L.; Cotran, Ramzi S. (2015). Robbins and Cotran pathologic basis of disease (Ninth ed.). Philadelphia, Pa: Elsevier; Saunders. ISBN   978-1-4557-2613-4.
  3. 1 2 Hakim, Antoine M. (24 September 2019). "Small Vessel Disease". Frontiers in Neurology. 10: 1020. doi: 10.3389/fneur.2019.01020 . ISSN   1664-2295. PMC   6768982 . PMID   31616367. Creative Commons by small.svg  This article incorporates text available under the CC BY 4.0 license.
  4. ↑ Sugimoto, Kazuhiro; Murakami, Hiroshi; Deguchi, Takahisa; Arimura, Aiko; Daimon, Makoto; Suzuki, Susumu; Shimbo, Takuro; Yagihashi, Soroku (2019). "Cutaneous microangiopathy in patients with type 2 diabetes: Impaired vascular endothelial growth factor expression and its correlation with neuropathy, retinopathy and nephropathy". Journal of Diabetes Investigation. 10 (5): 1318–1331. doi:10.1111/jdi.13020. ISSN   2040-1116. PMC   6717820 . PMID   30719863.
  5. 1 2 3 Camici, Paolo G.; Crea, Filippo (22 February 2007). "Coronary microvascular dysfunction". The New England Journal of Medicine. 356 (8): 830–840. doi:10.1056/NEJMra061889. ISSN   1533-4406. PMID   17314342.
  6. 1 2 3 4 Litak, Jakub; Mazurek, Marek; Kulesza, Bartłomiej; Szmygin, Paweł; Litak, Joanna; Kamieniak, Piotr; Grochowski, Cezary (20 December 2020). "Cerebral Small Vessel Disease". International Journal of Molecular Sciences. 21 (24): 9729. doi: 10.3390/ijms21249729 . ISSN   1422-0067. PMC   7766314 . PMID   33419271. Creative Commons by small.svg  This article incorporates text available under the CC BY 4.0 license.
  7. ↑ Pereira Fontes, Carla; Fonseca, Samuel (2021). "Pseudothrombotic Microangiopathy as a Rare Presentation of Cobalamin Deficiency". Cureus. 13 (8): e17184. doi: 10.7759/cureus.17184 . ISSN   2168-8184. PMC   8439408 . PMID   34540418.
  8. 1 2 3 4 Gualtierotti, Roberta; Fox, Sharon E.; Da Silva Lameira, Fernanda; Giachi, Andrea; Valenti, Luca; Borghi, Maria Orietta; Meroni, Pier Luigi; Cugno, Massimo; Peyvandi, Flora (28 May 2023). "Nailfold Videocapillaroscopic Alterations as Markers of Microangiopathy in COVID-19 Patients". Journal of Clinical Medicine. 12 (11): 3727. doi: 10.3390/jcm12113727 . ISSN   2077-0383. PMC   10253962 . PMID   37297922. Creative Commons by small.svg  This article incorporates text available under the CC BY 4.0 license.
  9. ↑ Prommer, Hans-Ulrich; Maurer, Johannes; von Websky, Karoline; Freise, Christian; Sommer, Kerstin; Nasser, Hamoud; Samapati, Rudi; Reglin, Bettina; Guimarães, Pedro; Pries, Axel Radlach; Querfeld, Uwe (28 March 2018). "Chronic kidney disease induces a systemic microangiopathy, tissue hypoxia and dysfunctional angiogenesis". Scientific Reports. 8 (1): 5317. Bibcode:2018NatSR...8.5317P. doi:10.1038/s41598-018-23663-1. ISSN   2045-2322. PMC   5871820 . PMID   29593228.
  10. ↑ Franzeck, U. K.; Haselbach, P.; Speiser, D.; Bollinger, A. (1993). "Microangiopathy of cutaneous blood and lymphatic capillaries in chronic venous insufficiency (CVI)". The Yale Journal of Biology and Medicine. 66 (1): 37–46. ISSN   0044-0086. PMC   2588834 . PMID   8256463.
  11. ↑ Lambova, Sevdalina Nikolova (10 February 2023). "Microangiopathy in Rheumatic Diseases". Life. 13 (2): 491. doi: 10.3390/life13020491 . ISSN   2075-1729. PMC   9965541 . PMID   36836847.
  12. ↑ Martinelli, Anthony W.; Dunn, William; McClure, Mark E.; Walker, Ieuan; Stewart, Andrew; Karia, Sumit; Preston, Stephen D.; Thiru, Sathia; Torpey, Nicholas; Ojha, Sanjay; Symington, Emily; Nathan, James A. (November 2022). "A Case of Thrombotic Microangiopathy and Acute Sarcoidosis". Chest. 162 (5): e245–e248. doi:10.1016/j.chest.2022.06.023. ISSN   0012-3692. PMC   9752182 . PMID   36344132.
  13. ↑ Koike, Haruki; Katsuno, Masahisa (5 February 2019). "Ultrastructure in Transthyretin Amyloidosis: From Pathophysiology to Therapeutic Insights". Biomedicines. 7 (1): 11. doi: 10.3390/biomedicines7010011 . ISSN   2227-9059. PMC   6466231 . PMID   30764529.
  14. ↑ Cesarone, M. R.; Belcaro, G.; Geroulakos, G.; Griffin, M.; Ricci, A.; Brandolini, R.; Pellegrini, L.; Dugall, M.; Ippolito, E.; Candiani, C.; Simeone, E.; Errichi, B. M.; Di Renzo, A. (April 2003). "Flight microangiopathy on long-haul flights: prevention of edema and microcirculation alterations with Venoruton". Clinical and Applied Thrombosis/Hemostasis. 9 (2): 109–114. doi: 10.1177/107602960300900203 . ISSN   1076-0296. PMID   12812378. S2CID   1605773.
  15. 1 2 Feuer, Daniel S.; Handberg, Eileen M.; Mehrad, Borna; Wei, Janet; Merz, C. Noel Bairey; Pepine, Carl J.; Keeley, Ellen C. (2022). "Microvascular dysfunction as a systemic disease: A review of the evidence". The American Journal of Medicine. 135 (9): 1059–1068. doi:10.1016/j.amjmed.2022.04.006. ISSN   0002-9343. PMC   9427712 . PMID   35472396.
  16. 1 2 3 4 5 6 7 Khalil, H. (November 2017). "Diabetes microvascular complications-A clinical update". Diabetes & Metabolic Syndrome. 11 (Suppl 1): S133–S139. doi:10.1016/j.dsx.2016.12.022. ISSN   1878-0334. PMID   27993541.
  17. ↑ Mengstie, Misganaw Asmamaw; Chekol Abebe, Endeshaw; Behaile Teklemariam, Awgichew; Tilahun Mulu, Anemut; Agidew, Melaku Mekonnen; Teshome Azezew, Muluken; Zewde, Edgeit Abebe; Agegnehu Teshome, Assefa (15 September 2022). "Endogenous advanced glycation end products in the pathogenesis of chronic diabetic complications". Frontiers in Molecular Biosciences. 9: 1002710. doi: 10.3389/fmolb.2022.1002710 . ISSN   2296-889X. PMC   9521189 . PMID   36188225.
  18. ↑ Cecil, Russell La Fayette; Goldman, Lee; Schafer, Andrew I. (2012). Goldman's Cecil medicine (24th ed.). Philadelphia: Elsevier/Saunders. ISBN   978-1-4377-1604-7.
  19. ↑ Somboonwong, Juraiporn; Yusuksawad, Mariem; Keelawat, Somboon; Thongruay, Sirima; Poumsuk, Ubon (2016). "Minimization of the Risk of Diabetic Microangiopathy in Rats by Nigella sativa". Pharmacognosy Magazine. 12 (Suppl 2): S175–S180. doi: 10.4103/0973-1296.182169 . ISSN   0973-1296. PMC   4883076 . PMID   27279704.
  20. ↑ Madonna, Rosalinda; Balistreri, Carmela Rita; Geng, Yong-Jian; De Caterina, Raffaele (March 2017). "Diabetic microangiopathy: Pathogenetic insights and novel therapeutic approaches". Vascular Pharmacology. 90: 1–7. doi:10.1016/j.vph.2017.01.004. ISSN   1879-3649. PMID   28137665.
  21. 1 2 3 Berry, Colin; Sidik, Novalia; Pereira, Anthony C.; Ford, Thomas J.; Touyz, Rhian M.; Kaski, Juan-Carlos; Hainsworth, Atticus H. (2 February 2019). "Small-Vessel Disease in the Heart and Brain: Current Knowledge, Unmet Therapeutic Need, and Future Directions". Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease. 8 (3): e011104. doi:10.1161/JAHA.118.011104. ISSN   2047-9980. PMC   6405580 . PMID   30712442. Creative Commons by small.svg  This article incorporates text available under the CC BY 4.0 license.
  22. ↑ Le, Patrick H.; Patel, Bhupendra C. (2023). "Optical Coherence Tomography Angiography". StatPearls. StatPearls Publishing. PMID   33085382 . Retrieved 29 September 2023.
  23. ↑ Sideri, Anna-Maria; Kanakis, Menelaos; Katsimpris, Andreas; Karamaounas, Aristotelis; Brouzas, Dimitrios; Petrou, Petros; Papakonstaninou, Evangelia; Droutsas, Konstantinos; Kandarakis, Stylianos; Giannopoulos, Georgios; Georgalas, Ilias (5 May 2023). "Correlation Between Coronary and Retinal Microangiopathy in Patients With STEMI". Translational Vision Science & Technology. 12 (5): 8. doi:10.1167/tvst.12.5.8. ISSN   2164-2591. PMC   10168007 . PMID   37145590.
  24. ↑ Tang, Qian; Zhang, Yanli; Yang, Zhengfang; Li, Siou; Wu, Meini; Guo, Yongming; Zhao, Weina; Yin, Changhao (9 June 2022). "Study on the Interaction between the Characteristics of Retinal Microangiopathy and Risk Factors for Cerebral Small Vessel Disease". Contrast Media & Molecular Imaging. 2022: 9505945. doi: 10.1155/2022/9505945 . ISSN   1555-4309. PMC   9203197 . PMID   35800241.
  25. 1 2 3 4 Taqueti, Viviany R.; Di Carli, Marcelo F. (27 November 2018). "Coronary Microvascular Disease Pathogenic Mechanisms and Therapeutic Options: JACC State-of-the-Art Review". Journal of the American College of Cardiology. 72 (21): 2625–2641. doi:10.1016/j.jacc.2018.09.042. ISSN   0735-1097. PMC   6296779 . PMID   30466521.
  26. 1 2 3 Chojdak-Łukasiewicz, Justyna; Dziadkowiak, Edyta; Zimny, Anna; Paradowski, Bogusław (March 2021). "Cerebral small vessel disease: A review". Advances in Clinical and Experimental Medicine. 30 (3): 349–356. doi: 10.17219/acem/131216 . ISSN   1899-5276. PMID   33768739. S2CID   232365709.
  27. ↑ Zhang, XinYuan; Liu, Wei; Wu, ShanShan; Jin, JingLong; Li, WeiHong; Wang, NingLi (2014-12-20). "Calcium dobesilate for diabetic retinopathy: a systematic review and meta-analysis". Science China Life Sciences. 58 (1): 101–107. doi: 10.1007/s11427-014-4792-1 . ISSN   1674-7305. PMID   25528255.
  28. ↑ Haller, Hermann; Ji, Linong; Stahl, Klaus; Bertram, Anna; Menne, Jan (2017). "Molecular Mechanisms and Treatment Strategies in Diabetic Nephropathy: New Avenues for Calcium Dobesilate—Free Radical Scavenger and Growth Factor Inhibition". BioMed Research International. 2017: 1909258. doi: 10.1155/2017/1909258 . ISSN   2314-6133. PMC   5634607 . PMID   29082239.
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