Association between bone mineral metabolism and vascular calcification in end-stage renal disease

Background Development of vascular calcification is accelerated in patients with end-stage renal disease. In addition to traditional risk factors of cardiovascular disease (CVD) abnormal bone and mineral metabolism together with many other factors contribute to the excess cardiovascular burden in patients on dialysis. Aortic calcification score and coronary calcification score are predictive of CVD and mortality. The aim of this study was to evaluate the possible relationship between arterial calcification and bone metabolism. Methods Thirty two patients on dialysis were included. All patients underwent a bone biopsy to assess bone histomorphometry and a 18F-NaF PET scan. Fluoride activity was measured in the lumbar spine (L1 – L4) and at the anterior iliac crest. Arterial calcification scores were assessed by computerized tomography for quantification of coronary artery calcification score and lateral lumbar radiography for aortic calcification score. Results This study group showed high prevalence of arterial calcification and 59% had verified CVD. Both CAC and AAC were significantly higher in patients with verified CVD. Only 22% had low turnover bone disease. There was a weak association between fluoride activity, which reflects bone turnover, measured in the lumbar spine, and CAC and between PTH and CAC. There was also a weak association between erosion surfaces and AAC. No significant association was found between calcification score and any other parameter measured. Conclusions The results in this study highlight the complexity, when evaluating the link between bone remodeling and vascular calcification in patients with multiple comorbidities and extensive atherosclerosis. Several studies suggest an impact of bone turnover on development of arterial calcification and there is some evidence of reduced progression of vascular calcification with improvement in bone status. The present study indicates an association between vascular calcification and bone turnover, even though many parameters of bone turnover failed to show significance. In the presence of multiple other factors contributing to the development of calcification, the impact of bone remodeling might be diminished. Trial registration The study is registered in ClinicalTrials.gov protocol registration and result system, ID is NCT02967042. Date of registration is 17/11/2016.

Case Report: A Novel Genetic Mutation Causes Idiopathic Infantile Arterial Calcification in Preterm Infants

Idiopathic infantile arterial calcification (IIAC), also known as generalized arterial calcification of infancy (GACI), is a heritable ectopic mineralization disorder that results in diffuse arterial calcifications and or stenosis, which are attributed to mutations in the ENPP1 gene. In this case study, we report the development of IIAC in a 2-month-old male preterm infant. The patient presented with severe hypertension and seizures, which revealed diffused calcifications and c.130C > T and c.1112A > T mutations in the ENPP1 gene. With biphosphonate, antihypertensive, and control epilepsy therapy, his blood pressure was maintained at 110–120/50–60 mmHg. Intellectual motor development retardation was anticipated in this patient. To the best of our knowledge, this is the first case in which a novel c.130C > T mutation in the ENPP1 gene has been identified, and the administration of bisphosphonates to patients with IIAC has been assessed.

Therapy of Pseudoxanthoma Elasticum: Current Knowledge and Future Perspectives

Pseudoxanthoma elasticum (PXE) is a rare, genetic, metabolic disease with an estimated prevalence of between 1 per 25,000 and 56,000. Its main hallmarks are characteristic skin lesions, development of choroidal neovascularization, and early-onset arterial calcification accompanied by a severe reduction in quality-of-life. Underlying the pathology are recessively transmitted pathogenic variants of the ABCC6 gene, which results in a deficiency of ABCC6 protein. This results in reduced levels of peripheral pyrophosphate, a strong inhibitor of peripheral calcification, but also dysregulation of blood lipids. Although various treatment options have emerged during the last 20 years, many are either already outdated or not yet ready to be applied generally. Clinical physicians often are left stranded while patients suffer from the consequences of outdated therapies, or feel unrecognized by their attending doctors who may feel uncertain about using new therapeutic approaches or not even know about them. In this review, we summarize the broad spectrum of treatment options for PXE, focusing on currently available clinical options, the latest research and development, and future perspectives.

CT perfusion: stroke, seizure or both?

An 88-year-old male with a history of hypertension, ischaemic heart disease and Bell’s palsy presented with symptoms and signs of an acute ischaemic stroke. National Institutes of Health Stroke Scale (NIHSS) was 19 at presentation, indicative of potential large vessel occlusion. The initial CT scan revealed evidence of small vessel disease and arterial calcification. As there were no contraindications, he received thrombolytic treatment. CT angiography and CT perfusion imaging were performed in preparation for possible thrombectomy. There was no evidence of a large vessel thrombus, and changes on CT perfusion were suggestive of seizure activity, with relative hyperperfusion on the cerebral hemisphere of interest. Post thrombolysis, his NIHSS was 5. An MR scan revealed evidence of bilateral thalamic infarcts. After a period of rehabilitation, he was discharged home and independently mobile but with cognitive impairment.Acute stroke care increasingly uses multimodal imaging to confirm the clinical diagnosis and help optimise initial emergency management. Such imaging is useful in determining whether the presentation is a vascular event or stroke mimic. Moreover, seizures complicate and mimic acute strokes, which can lead to therapeutic uncertainty. This case highlights the increasingly sophisticated investigation of patients presenting with suspected acute stroke, with the attendant need for accurate interpretation by experienced clinicians.

Arterial calcification, atherosclerosis and osteoporosis: only clinical associations or a genetic platform?

The review is devoted to the comorbidity of two multifactorial diseases — atherosclerosis and osteoporosis. Numerous epidemiological, experimental and clinical studies have confirmed the relationship between these diseases based on common risk factors and pathogenetic mechanisms. At the same time, to assess the associations between osteoporosis and atherosclerosis-related cardiovascular diseases, the following surrogate markers are used: vascular calcification, vascular stiffness, bone mineral density. It is known that atherosclerosis and osteoporosis depend on the human genotype, and they are caused by the interaction between the environment and genes. The modifiable risk factors for these diseases are largely similar, and the common features of atherosclerosis and osteoporosis pathogenesis make it possible to formulate the concept of a unified genetic basis of their development. Advances in molecular technology have made it possible to conduct a genome-wide association study (GWAS) and successfully identify genetic markers associated with both atherosclerosis and osteoporosis. The review aim was to describe the genes associated with developing atherosclerosis, arterial calcification and osteoporosis, as well as to provide information on the current understanding of the general genetic basis for plaque formation, vascular calcium deposition, and a decrease in bone mass. The analysis of publications from the PubMed, Medline, Web of Science and Cochrane Library databases since 2000 have been carried out. The article describes the genetic markers associated with atherosclerosis and osteoporosis, as well as considers the achievements in studying genetics of osteoporosis and atherosclerosis-related cardiovascular diseases. In addition, modern approaches and directions for further research of these diseases was established. The review can be useful for medical practitioners to clarify various genetic associations and mechanisms that lead to this comorbidity.

Carotid plaque thickness is increased in chronic kidney disease and associated with carotid and coronary calcification

Background Chronic kidney disease accelerates both atherosclerosis and arterial calcification. The aim of the present study was to explore whether maximal carotid plaque thickness (cPTmax) was increased in patients with chronic kidney disease compared to controls and associated with cardiovascular disease and severity of calcification in the carotid and coronary arteries. Methods The study group consisted of 200 patients with chronic kidney disease stage 3 from the Copenhagen Chronic Kidney Disease Cohort and 121 age- and sex-matched controls. cPTmax was assessed by ultrasound and arterial calcification by computed tomography scanning. Results Carotid plaques were present in 58% of patients (n = 115) compared with 40% of controls (n = 48), p = 0.002. Among participants with plaques, cPTmax (median, interquartile range) was significantly higher in patients compared with controls (1.9 (1.4–2.3) versus 1.5 (1.2–1.8) mm), p = 0.001. Cardiovascular disease was present in 9% of patients without plaques (n = 85), 23% of patients with cPTmax 1.0–1.9 mm (n = 69) and 35% of patients with cPTmax >1.9 mm (n = 46), p = 0.001. Carotid and coronary calcium scores >400 were present in 0% and 4%, respectively, of patients with no carotid plaques, in 19% and 24% of patients with cPTmax 1.0–1.9 mm, and in 48% and 53% of patients with cPTmax >1.9 mm, p<0.001. Conclusions This is the first study showing that cPTmax is increased in patients with chronic kidney disease stage 3 compared to controls and closely associated with prevalent cardiovascular disease and severity of calcification in both the carotid and coronary arteries.

Risk factors for spinal cord ischemia in frozen elephant trunk–induced upper spinal cord ischemia in patients with combination of degenerative arch aneurysms and peripheral artery diseases: a possible mechanism

Background Degenerative aortic arch aneurysms are known to develop through a pathological process of arterial atherosclerosis, which could be accompanied by peripheral artery diseases and resultant development of intrapelvic collateral arteries to the ischemic lower limbs. The aim of this study was to investigate the relationship between peripheral collateral circulation and postoperative paraplegia after total arch repair with a frozen elephant trunk in patients with degenerative aortic arch aneurysms and peripheral artery diseases. Methods Between October 2014 and March 2020, 27 patients (20 men; 69.8 ± 7.7 years old) underwent total arch repair with a frozen elephant trunk. Two of the 27 patients developed paraplegia postoperatively. The patients were divided into two groups, spinal cord ischemia (SCI) group (2 patients) and no-SCI group (25 patients). The aortic shagginess score, arterial calcification (subclavian artery; hypogastric artery) score, and the number of hypogastric artery branches, assessed using preoperative contrast-enhanced computed tomography images, were compared between the two groups. Results The ankle brachial artery pressure index (i.e., lower side value each patient) was lower in the SCI group than that in the no-SCI group (0.64, 0.71, and 1.09±0.07, respectively). There was no difference between the two groups in the arterial calcification scores or the aortic shagginess score. The number of hypogastric artery branches was greater in the SCI group than in the no-SCI group (66, 66, and 30.7±7.5, respectively). Conclusions Enhanced collateral circulation to the ischemic lower limbs in patients with combination of degenerative aortic arch aneurysms and peripheral artery diseases may be involved in paraplegia the upper thoracic spinal cord injury after total arch repair with a frozen elephant trunk.

Abstract 16747: Rapidly Lethal Dilated Cardiomyopathy Secondary To Generalized Arterial Calcification Of Infancy

Case Presentation: A previously healthy 3-month-old infant presented with cardiorespiratory arrest, from which she was successfully resuscitated. A dilated cardiomyopathy with severely depressed systolic function was diagnosed. ECG showed high voltage QRS complexes and generalized alteration of repolarization. In the following 12 hours, she suffered 2 other cardiac arrests, recuperated with defibrillation. Hemodinamic stability was achieved but brain death was diagnosed 36 hours after the onset of symptoms. Autopsy showed striking calcification of the right and left coronary arteries, with narrowing of the arterial lumen, causing extensive subendocardial infarction. Calcification also affected the aorta, pulmonary arteries, thyroid, kidney and other splanchnic arteries. Generalized arterial calcification of infancy (GACI) was diagnosed and a genetic study found two biallelic variants in ABCC6 gene: p.Arg1114Cys and p.Trp38Ser, both previously described in elastic pseudoxanthoma (PXE), but not in GACI. Genotyping of the healthy parents confirmed genetic segregation with biallelic variants. Discussion: GACI is an extremely rare genetic disease characterized by widespread arterial calcification and narrowing of large and medium-sized vessels. The usual clinical presentation is heart failure in fetal life or in the first months of infancy. In most cases it is lethal, with death occurring within a few hours or days after the onset of symptoms, although clinical involvement is highly variable and cases with long survival have been described. GACI is an autosomal recessive disease secondary to biallelic variants in the ENPP1 gene (67% of cases) and in the ABCC6 gene (9%). The variants found in our patient had not been previously described in GACI, just in PXE, a much milder disease with usually normal lifespan. This case confirms that both entities reflect two extremes of a clinical spectrum of ectopic calcification instead of two different disorders. The aim of presenting this case is to remind clinicians of this rare etiology in neonates or infants with dilated cardiomyopathy. In case of death, autopsy should always be requested. When this condition is diagnosed, genetic study will be positive in 75% of cases, allowing prenatal counseling.

Is It Good to Have a Stiff Aorta with Aging? Causes and Consequences

Aortic stiffness increases with advancing age more than doubling during the human lifespan and is a robust predictor of cardiovascular disease (CVD) clinical events independent of traditional risk factors. The aorta increases in diameter and length to accommodate growing body size and cardiac output in youth, but in middle- and older age the aorta continues to remodel to a larger diameter thinning the pool of permanent elastin fibers increasing intramural wall stress resulting in the transfer of load bearing onto stiffer collagen fibers. While aortic stiffening in early middle-age may be a compensatory mechanism to normalize intramural wall stress and therefore theoretically 'good' early in the lifespan, the negative clinical consequences of accelerated aortic stiffening beyond middle-age far outweigh any earlier physiological benefit. Indeed, aortic stiffness and the loss of the "Windkessel effect" with advancing age results in elevated pulsatile pressure and flow in downstream microvasculature that is associated with subclinical damage to high flow, low resistance organs such as brain, kidney, retina and heart. The mechanisms of aortic stiffness include alterations in extracellular matrix proteins (collagen deposition, elastin fragmentation), increased vasodilator tone (oxidative stress and inflammation-related reduced vasodilators and augmented vasoconstrictors; enhanced sympathetic activity), arterial calcification, vascular smooth muscle cell stiffness and extracellular matrix glycosaminoglycans. Given the rapidly aging population of the U.S., aortic stiffening will likely contribute to substantial CVD burden over the next 2-3 decades unless new therapeutic targets and interventions are identified to prevent the potential avalanche of clinical sequelae related to age-related aortic stiffness.