Aldosterone-induced vasculopathy

Aldosterone antagonists reduce mortality in chronic heart failure (CHF). An obvious question to ask is how do they do this. The prevailing hypothesis is that most of the adverse effects of aldosterone stem from its ability to produce a vasculopathy. This vasculopathy is characterised by a reduction in vascular nitric oxide and may be produced by aldosterone's ability to generate superoxide radicals which degrade endogenous NO. The consequences of this "aldosterone-induced vasculopathy" are that it produces tissue ischaemia/infarction and injury, which then repairs itself by producing fibrosis. "Aldosterone-induced vasculopathy" may be the main mechanism why aldosterone promotes widespread tissue injury and ultimately cardiac death.     

Mitochondrial vasculopathy

Mitochondrial disorders(MIDs)are usually multisystem disorders(mitochondrial multiorgan disorder syndrome)either on from onset or starting at a point during the disease course.Most frequently affected tissues are those with a high oxygen demand such as the central nervous system,the muscle,endocrine glands,or the myocardium.Recently,it has been shown that rarely alsothe arteries may be affected(mitochondrial arteriopathy).This review focuses on the type,diagnosis,and treat-ment of mitochondrial vasculopathy in MID patients.A literature search using appropriate search terms was carried out.Mitochondrial vasculopathy manifests as either microangiopathy or macroangiopathy.Clinical manifestations of mitochondrial microangiopathy include leukoencephalopathy,migraine-like headache,stroke-like episodes,or peripheral retinopathy.Mitochondrial macroangiopathy manifests as atherosclerosis,ectasia of arteries,aneurysm formation,dissection,or spontan-eous rupture of arteries.The diagnosis relies on the documentation and confirmation of the mitochondrial metabolic defect or the genetic cause after exclusion of non-MID causes.Treatment is not at variance compared to treatment of vasculopathy due to non-MID causes.Mitochondrial vasculopathy exists and manifests as micro-or macroangiopathy.Diagnosing mitochondrial vasculopathy is crucial since appropriate treatment may prevent from severe complications.     

Cardiac allograft vasculopathy

Cardiac transplantation has emerged as a valuable therapy for various end-stage cardiac disorders. Cardiac allograft vasculopathy (CAV), an unusually accelerated and diffuse form of obliterative coronary arteriosclerosis, determines long-term function of the transplanted heart. Cardiac allograft vasculopathy is a complicated interplay between immunologic and nonimmunologic factors resulting in repetitive vascular injury and a localized sustained inflammatory response. Dyslipidemia, oxidant stress, immunosuppressive drugs, and viral infection appear to be important contributors to disease development. Endothelial dysfunction is an early feature of CAV and progresses over time after transplantation. Early identification of CAV is essential if long-term prognosis is to be improved. Annual coronary angiography is performed for diagnostic and surveillance purposes. Intravascular ultrasound is a more sensitive diagnostic tool for early disease stages and has revealed that progressive luminal narrowing in CAV is in part due to negative vascular remodeling. Because of the diffuse nature of CAV, percutaneous and surgical revascularization procedures have a limited role. Prevention of CAV progression is a primary therapeutic goal.     

Cardiac transplant vasculopathy

STUDY OBJECTIVE: Coronary allograft vasculopathy (CAV) remains the major factor limiting long-term survival after heart transplantation. The purpose of this article is to review for the nontransplant physician the concept of CAV as a disease entity after heart transplantation. DESIGN: A MEDLINE search from 1985 to 1999 was performed. Data on cardiac transplant vasculopathy were divided into pathology, pathophysiology, presentation, diagnosis, and treatment. RESULTS: CAV manifests as a unique and unusually aggressive form of coronary artery disease that differs from traditional atherosclerosis. It is believed to be caused by immunologic mechanisms that combine with nonimmunologic factors to cause endothelial injury, resulting in smooth muscle proliferation and intimal thickening. This intimal hyperplasia leads to coronary obstruction, which ultimately results in allograft failure. Diagnosis of CAV can be difficult because transplant recipients have denervated hearts and rarely present with chest pain. Various noninvasive screening methods have not proved reliable. Therefore, most transplant centers perform periodic coronary angiography for routine CAV surveillance. Treatment of CAV involves modification of risk factors and the use of pharmacologic agents that alter vascular physiology. Revascularization procedures continue to play a role as palliative therapy, but are limited in their effectiveness by the diffuse nature of this disease. CONCLUSION: Cardiac transplant vasculopathy continues to play a major dilemma regarding posttransplant care. Further research is needed to develop successful preventive and therapeutic strategies that may alter the course of this disease.     

Von Recklinghausen's vasculopathy

Vasculopathy in the syndrome of Von Recklinghausen's neurofibromatosis is a well known but clinically underestimated phenomenon. Its manifestations have included renovascular hypertension, occlusive cerebrovascular disease and visceral ischemia. The progressive arterial disease may involve small vessels on a regular basis and large vessels in a variety of angiographic patterns. A young neurofibromatosis patient is described with an aneurysm of the superior mesenteric artery complicating renovascular hypertension associated with aortic coarctation and renal artery stenosis. This unique angiographic demonstration illustrates the therapeutic dilemmas posed by the vascular disease associated with Von Recklinghausen's neurofibromatosis.     

Antiphospholipid arterial vasculopathy

We describe 3 relatively young patients who developed arterial occlusions in a limb requiring amputation. All 3 had antiphospholipid antibodies (APLA). In one, these appeared as part of the clinical and serologic spectrum of systemic lupus erythematosus and in the other 2 as a component of a primary antiphospholipid syndrome. Their arterial angiograms showed gradual narrowing of the arterial lumen and the histopathologic study showed striking intimal and medial proliferation as well as some increase in thickness of the adventitia. There was little evidence of thrombosis but in the 2 patients who were amputated early there was mononuclear cell infiltrate of the large arteries and in all 3 there was also leukocytoclastic vasculitis in the skin and/or muscle. We believe this represents a new form of vasculopathy, probably related to the presence of APLA, possibly triggered by the occurrence of vasculitis.     

Cardiac allograft vasculopathy

Cardiac allograft vasculopathy (CAV) is an accelerated form of coronary artery disease affecting both intramyocardial and epicardial coronary arteries and is observed in patients during long-term survival after cardiac transplantation. We report a case of CAV complicated with silent transmural myocardial infarction and massive left ventricular thrombus formation associated with silent pericarditis and with ischemic and non-ischemic scar tissue, as detected by cardiac magnetic resonance imaging (CMRI). The authors suggest CMRI as an additional technique along with echocardiography during follow-up of heart transplant recipients. CMRI may contribute to the early identification of areas of myocardial wall abnormalities suggestive of CAV, thus guiding diagnosis and prompt percutaneous treatment.     

Cocaine-induced thrombotic vasculopathy

Cocaine has been associated with a number of cutaneous manifestations, and most reports in the literature have described cocaine-induced vasculitis. However, not all reactive patterns secondary to cocaine use are vasculitic in nature. Recently, there has been a disturbing trend of "cutting" cocaine with pharmacologically active substances, the most common being levamisole. This agent is known to cause serious adverse effects including agranulocytosis and cutaneous eruptions. The authors describe a 52-year-old woman who acutely developed an extensive bullous rash in the lower extremities after she snorted cocaine. The clinical, hematological and serological findings were suggestive of levamisole-induced vasculitis, but histopathology of the skin showed thrombogenic vasculopathy with no inflammatory infiltrate. A skin biopsy is an essential component in the diagnosis of cocaine-related syndromes and can aid in the distinction from true autoimmune vasculitis.     

Transplant coronary vasculopathy

Opinion statement  

Evolution and diabetic vasculopathy

Evolution of blood sugar, glycation, receptor for advanced glycation end‐products and diabetic vasculopathy.

Diabetes mellitus is still an illness that leads to earlier death than in individuals who do not have this condition. The life expectancy in patients with diabetes is approximately 10 years shorter than in the non‐diabetes population. The top three causes of death in diabetes patients are malignant neoplasm, infectious disease and vascular derangement. Even before being fatal, diabetes patients often suffer from decreased quality of life due to vascular complications; for example, retinopathy can cause blindness. Nephropathy can render patients to undergo hemodialysis. In more than half of diabetes patients, signs of neuropathy are evident before symptoms become noticed. Accordingly, to know how blood vessels are impaired under diabetic conditions is important for both the extension of vital prognosis and the improvement of quality of life in diabetes patients.As is diabetes itself, diabetic vasculopathy is a multifactorial disease that is caused by a variety of environmental and genetic factors. To screen those factors, we initially carried out an in vitro approach, in which pericytes and endothelial cells, the constituents of small vessels, were cultured under various chemical or physical environments. The rationale behind this approach was based on the pathological features of the early phase of diabetic retinopathy; that is, pericyte loss and focal angiogenesis. Several substances or physical conditions, such as endothelial growth factor and hypoxia, caused the increase in both pericytes and endothelial cells. Some other factors, such as high concentration of glucose, caused the decrease in both cell types. There is only one condition that consistently elicits the decrease in pericytes on one hand and the increase in endothelial cells on the other hand. It is advanced glycation end‐products (AGEs), and we thus regard it as the major environmental cause of diabetic vasculopathy. AGEs is a general term of heterogenous compounds that are yielded through non‐enzymatic glycation of macromolecules, including proteins, deoxyribonucleic acids, ribonucleic acids and lipids. The reducing carbonyl terminus of glucose can interact with the amino groups of proteins, nucleic acids and lipids, forming reversible Schiff base and Amadori rearrangement products, which further undergo irreversible chemical reactions, eventually yielding AGEs.Our subsequent in vivo approach using gene‐manipulated animals showed that the major cellular device that responds to AGEs is the receptor for AGEs (RAGE). RAGE was first described in 1992 as a cell‐surface protein belonging to the immunoglobulin superfamily ¹ . We found that when overexpressed in diabetic animals, the indices of retinopathy and nephropathy were aggravated ² . On the contrary, RAGE‐null mice did not develop diabetic nephropathy ³ .These observations suggested AGEs and RAGE could be potential molecular targets for overcoming diabetic vascular complications. Prototype chemicals used for trials against AGEs, such as aminoguanidine, which covalently binds Amadori intermediates, and AGEs breakers, which were expected to decompose pre‐existing AGEs, were likely to have stoichiometric problems, purportedly giving little or marginal effects. We found that low‐molecular weight AGEs could antagonize the action of physiologically occurring AGEs molecules ⁴ . This suggests that signaling ligands could possess considerable size with plural binding sites for oligomerizing RAGE molecules to transduce signals, and that rational drug design against RAGE could be possible. The amino acid residues on human RAGE protein that are essential for ligand recognition have been identified ⁵ .Diabetic vasculopathy only develops in mammals, whereas diabetes‐like conditions are observed among a wide range of species. One may ask; how such diversity has emerged? One answer can be it is the result of evolution.Sugar species that flow in the blood stream differ among vertebrates, insects and plants (Figure 1). Vertebrates, including humans, circulate glucose as blood sugar through their vascular system. Blood sugars that insects and plants use are trehalose and sucrose, respectively. Neither trehalose nor sucrose have any carbonyl group, which if present can cause glycation. Drosophila melanogaster mutants manifesting higher blood trehalose levels are reported, but are known to have a rather longer lifespan. Glucose consists of six carbon atoms, and, therefore, they automatically form a ring structure, because of intra‐atomic bond angles. However, when glucose transits between its two ring forms, namely, α and β anomers, it transiently gives rise to the straight‐chain structure, whose carbonyl terminus then shows a reducing, glycating activity. This is the reason why glycation takes place in vessels of vertebrates. Dr Tarui remarked in his book ⁶ that diabetes might be a disease that is fated to have a risk of developing complications in vertebrates, which have glucose in their closed circulation system.Open in a separate windowFigure 1Evolution of blood sugar, glycation, receptor for advanced glycation end‐products (RAGE) gene and diabetic vasculopathy. +, presence; −, absence. Illustrations were purchased from PIXTA. [Colour figure can be viewed at wileyonlinelibrary.com]Dr Szwergold and Dr Miller ⁷ wondered why birds can live healthy lives with chronic hyperglycemia that would be fatal to humans, and analyzed the RAGE gene, Ager, in various mammalian and avian species. Their study showed that there are definitive homologies for the RAGE gene in humans, mice, rats, cattle, opossums and platypuses, whereas such alignments are absent from chickens, turkeys and zebra finch genomes. Accordingly, it might be reasonable to posit that the presence or absence of the RAGE gene could be a determinant of the predisposition or resistance to diabetic vasculopathy (Figure 1).During the course of our study, we encountered an unusual observation. There were much fewer pups in the cage of RAGE‐null mice than in that of wild‐type animals. The RAGE‐null mothers did not appear to be skilled at parenting, and even committed infanticide. This seemed to be a physiologically important issue, but continued to be an enigma for a long time. Our research group, grown by 2019 to become a Japan–Russia–USA international collaboration team, finally clarified that RAGE proteins expressed on vascular cells are essential for transporting oxytocin into the brain parenchyma to elicit maternal bonding behavior ⁸ . Oxytocin was found to bind the V domain of RAGE protein, but at a distinct site from AGEs, neither inducing nor inhibiting intracellular signals, suggesting that targeting RAGE to overcome diabetic vasculopathy and maintaining RAGE function for parental bonding and nurturing could go together ⁸ .In most likelihood, diabetes and its vasculopathy would have been beyond expectation of evolution. Our ancestors must have used glucose principally as the fuel molecule, because it yields energy very efficiently. AGEs are formed as we age, at an accelerated rate under the diabetic condition, but are almost negligible at reproductive age, the period evolution concerns. Obviously, diabetes abuses RAGE. It was probably gifted to mammals primarily as a device for parental bonding and nurturing, and numerous other socially interactive behaviors. During evolution, mammals have endowed RAGE with another benefit as an additional device for innate immunity to combat a variety of communicable and non‐communicable diseases ⁹ . Patients with type 2 diabetes are characterized by an undermined immune response to both natural infections and vaccination, and RAGE signaling has been implicated as a therapeutic target to improve outcomes after recent severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection ^{10 , 11} . We cannot reverse the clock of evolution, although should make proper use of the yin and yang of RAGE, and other molecules that have evolved.     

Cyclosporin A-related cerebral vasculopathy

The use of cyclosporin A has been associated with several side-effects, including neurotoxicity. The mechanism of toxicity is not well known. We report two patients treated with cyclosporin A who developed lesions in the cerebral white matter associated with abnormally elevated cerebral blood flow velocities on transcranial doppler ultrasound and abnormal vascular appearance on magnetic resonance angiography. Bone Marrow Transplantation (2000) 26, 801-804.     

Mechanisms of transplant vasculopathy

Cardiac allograft vasculopathy is a diffuse, obliterative form of arteriosclerosis that is characterized by the production of a neointima rich in vascular smooth muscle cells that progressively obstructs the lumen. Pathophysiologically, after heart transplantation, alloantigens (e. g. on donor endothelial cells) are presented by antigen presenting cells to the T-cells of the body's immune system. With the appropriate costimulatory signal, this signal pattern generates a differentiated T-cell, B-cell, and inflammatory cell response whereas without the second signal, the immune cells undergo apoptosis. In case of immune cell proliferation and differentiation, a coordinated pattern of cytokine release is initiated. Cells of innate immunity, monocyte-derived macrophages, are involved in this process. The inflammatory response culminates in rolling, sticking, and diapedesis through the coronary vascular endothelium and migration and phenotype switch of medial smooth muscle cells mediated by generation of growth-promoting cytokines.     

Chemokines and transplant vasculopathy

Transplant vasculopathy (TV) remains the leading cause of late death among heart transplant recipients. Transplant vasculopathy is characterized by progressive neointimal proliferation, leading to ischemic failure of the allograft. Multiple experimental and clinical studies have shown that injury to the graft at various stages of transplantation can be a risk factor for development of transplant vasculopathy. The hallmark of cardiac allograft injury is the infiltration of leukocytes. Recruitment of leukocytes requires intercellular communication between infiltrating cells, endothelium, parenchymal cells, and components of extracellular matrix. These events are mediated via the generation of adhesion molecules, cytokines, and chemokines. The chemokines, by virtue of their specific cell receptor expression, can selectively mediate the local recruitment/activation of distinct leukocytes/cells, allowing for migration across the endothelium and beyond the vascular compartment. This report provides a comprehensive review of the chemokines that participate in the development of transplant vasculopathy.     

Perspectives on cardiac allograft vasculopathy

Allograft arteriopathy, the slowly progressive, diffuse, atherosclerosis noted often after heart transplant, and also called chronic rejection, is the most common cause of late cardiac graft failure and patient death. The process is multifactorial, rooted in both immune and nonimmune factors that can be coupled to passenger atherosclerosis moved with the donor heart, as well as initially nondiseased endothelium. Great insight has emerged from experimental models and intravascular ultrasound study of patients, but treatments are still crude and produce less than optimal results. Nonetheless, it has been demonstrated that diltiazem, pravastatin, ganciclovir, newer immunosuppressive agents, and photophoresis may be helpful. In the future, better control of the allograft immunologic response will likely be the key to attenuating development of this form of atherosclerosis.     

视网膜血管病变与脑血管病

视网膜血管病变与脑血管病的关系日益受到重视.多数研究显示,视网膜血管病变可反映脑血管病变,从而帮助我们更直接地了解脑血管病.视网膜血管病变与脑血管病的发病风险、转归以及认知损害密切相关.     

Vascular remodeling in transplant vasculopathy

As therapeutic strategies to prevent acute rejection progressively improve, transplant vasculopathy (TV) constitutes the single most important limitation for long-term functioning of solid organ allografts. In TV, allograft arteries characteristically develop severe, diffuse intimal hyperplastic lesions that eventually compromise luminal flow and cause ischemic graft failure. Traditional immunosuppressive strategies that check acute allograft rejection do not prevent TV; indeed 50% of transplant recipients will have significant disease within five years of organ transplantation, and 90% will have significant TV a decade after their surgery. TV can involve the entire length of the transplanted arterial bed, including penetrating intraorgan arterioles. Indeed, the luminal narrowing of such penetrating vessels may be the most functionally significant because arterioles represent the major contributors to tissue vascular resistance. Because of the diffuseness of TV involvement in the allograft vascular bed, the only currently definitive therapy requires re-transplantation. Nevertheless, as we better understand the pathogenesis and critical mediators of these lesions, pharmacological advances can be anticipated. Other articles in this thematic review series focus on the specifics of the inciting injury, the cytokines and chemokines that drive TV development, and the nature of the recruited cells in TV lesions, as well as the pathogenic similarities between TV and other vascular lesions such as atherosclerosis. This review focuses on the mechanisms of vascular wall remodeling in TV, including the intimal accumulation of smooth muscle-like cells and associated extracellular matrix, medial smooth muscle cell degeneration, and adventitial fibrosis. A brief overview highlights the aneurysmal changes that can accrue when vessel wall inflammation has a cytokine profile distinct from the typical proinflammatory interferon-gamma-dominated milieu.     

Is scleroderma a vasculopathy?

Described as an autoimmune collagen vascular disease, the most striking feature of scleroderma may be a systemic vasculopathy. This vasculopathy includes characteristic noninflammatory macrovascular and microvascular changes with dramatic and possibly occlusive formation of a thickened neointima. Scleroderma vessels also have an unusual endothelial phenotype, with loss of normal markers including vascular endothelial (VE)-cadherin. These endothelial cells express type 1 interferon and regulator of G protein signaling 5 (RGS5), two molecules associated with vascular rarefaction. These genes may be important because tissue is hypoxic with high levels of vascular endothelial growth factor (VEGF), especially early in the disease. The combination of VEGF and rarefaction is not necessarily paradoxical. VEGF-mediated angiogenesis creates labile vessels that may not survive unless the vessel acquires a smooth muscle coat. The combination of interferon and RGS5 is consistent with an antiangiogenic phenotype. We offer a hypothesis that places vascular injury at the center of this disease and also suggest possible clinical approaches for arresting and/or reversing the disease.     

Juvenile dermatomyositis with gingival vasculopathy

Clinical Rheumatology -