Calcification Of Large Arteries Research Articles

Quantitative Abdominal Arterial Calcification Correlates with Kidney Transplant Waitlist Mortality

Introduction: The scarcity of available organs for kidney transplantation has resulted in a substantial waiting time for patients with end-stage kidney disease. This prolonged wait contributes to an increased risk of cardiovascular mortality. Calcification of large arteries is a high-risk factor in the development of cardiovascular diseases, and it is common among candidates for kidney transplant. The aim of this study was to correlate abdominal arterial calcification (AAC) score value with mortality on the waitlist. Methods: We modified the coronary calcium score and used it to quantitate the AAC. We conducted a retrospective clinical study of all adult patients who were listed for kidney transplant, between 2005 and 2015, and had abdominal computed tomography scan. Patients were divided into two groups: those who died on the waiting list group and those who survived on the waiting list group. Results: Each 1,000 increase in the AAC score value of the sum score of the abdominal aorta, bilateral common iliac, bilateral external iliac, and bilateral internal iliac was associated with increased risk of death (HR 1.034, 95% CI: 1.013, 1.055) (p = 0.001). This association remained significant even after adjusting for various patient characteristics, including age, tobacco use, diabetes, coronary artery disease, and dialysis status. Conclusion: The study highlights the potential value of the AAC score as a noninvasive imaging biomarker for kidney transplant waitlist patients. Incorporating the AAC scoring system into routine imaging reports could facilitate improved risk assessment and personalized care for kidney transplant candidates.

Calcification of the abdominal aorta is an under-appreciated cardiovascular disease risk factor in the general population.

Calcification of large arteries is a high-risk factor in the development of cardiovascular diseases, however, due to the lack of routine monitoring, the pathology remains severely under-diagnosed and prevalence in the general population is not known. We have developed a set of machine learning methods to quantitate levels of abdominal aortic calcification (AAC) in the UK Biobank imaging cohort and carried out the largest to-date analysis of genetic, biochemical, and epidemiological risk factors associated with the pathology. In a genetic association study, we identified three novel loci associated with AAC (FGF9, NAV9, and APOE), and replicated a previously reported association at the TWIST1/HDAC9 locus. We find that AAC is a highly prevalent pathology, with ~ 1 in 10 adults above the age of 40 showing significant levels of hydroxyapatite build-up (Kauppila score > 3). Presentation of AAC was strongly predictive of future cardiovascular events including stenosis of precerebral arteries (HR~1.5), myocardial infarction (HR~1.3), ischemic heart disease (HR~1.3), as well as other diseases such as chronic obstructive pulmonary disease (HR~1.3). Significantly, we find that the risk for myocardial infarction from elevated AAC (HR ~1.4) was comparable to the risk of hypercholesterolemia (HR~1.4), yet most people who develop AAC are not hypercholesterolemic. Furthermore, the overwhelming majority (98%) of individuals who develop pathology do so in the absence of known pre-existing risk conditions such as chronic kidney disease and diabetes (0.6% and 2.7% respectively). Our findings indicate that despite the high cardiovascular risk, calcification of large arteries remains a largely under-diagnosed lethal condition, and there is a clear need for increased awareness and monitoring of the pathology in the general population.

Arterial Calcification and Its Association With Stroke: Implication of Risk, Prognosis, Treatment Response, and Prevention.

Stroke is a leading cause of death worldwide. Vascular calcification (VC), defined as deposition of calcium-phosphate complexes in the vessels, is considered as the characteristic of vascular aging. Calcifications at different vessel layers have different implications. Intimal calcification is closely related to atherosclerosis and affects plaque stability, while medial calcification can cause arterial stiffening and reduce compliance. Accumulating evidence suggested that arterial calcifications, including calcifications in the intracranial artery, coronary artery, and carotid artery, are associated with the risk, prognosis, and treatment response of stroke. VC can not only serve as a marker of atherosclerosis, but cause cerebral hemodynamic impairment. In addition, calcifications in large arteries are associated with cerebral small vessel disease. In this review, we summarize the findings of recently published studies focusing on the relationship between large artery calcification and the risk, prognosis, treatment response, and prevention of stroke and also discuss possible mechanisms behind those associations.

MO905: Calcification of Branches is Superior to Abdominal Aortic Calcification in Predicting Mortality of Hemodialysis Patients

Abstract BACKGROUND AND AIMS Vascular calcification (VC) is considered to be an important initiating risk factor of cardiovascular events, which contributes to the leading cause of death in maintenance hemodialysis (MHD) patients. VC has a high incidence and has been reported to predict the mortality of MHD patients. Inspired by an extreme example of VC in dialysis patients, calciphylaxis (which involves extensive calcification of small- and medium- arteries with poor prognosis), we hypothesized that VC of branches was a better predictor of mortality than abdominal aortic calcification. Therefore, a cohort study based on MHD patients was constructed to investigate the distribution characteristics of VC, compare the predictive value of VC on mortality among different arteries, and explore a comprehensive model predicting mortality. METHOD A total of 1583 patients in our Blood Purification Center from January 2015 to September 2017 were screened, and 237 eligible patients were finally included. Abdominal-pelvic computed tomography images were collected and an open-source software 3D Slicer (version 4.11) was used to calculate the calcification volume in abdominal aorta, celiac trunk, superior and inferior mesenteric artery, renal artery, common iliac artery and internal iliac artery. Demographic and clinical data including medical history and some laboratory indexes were collected. Patients were followed-up until all-cause death or September 2020. Cause of death and survival time were recorded in detail. The area under the curve (AUC) of Time-dependent receiver operating curves (ROC) was calculated to evaluate the predictive value of arterial calcification. 80% of cases were randomly assigned to the training dataset and the remaining were assigned to the validation dataset. Lasso regression was performed to screen variables. Cox proportional hazards regression was performed to construct the predicting model and nomogram. C-index, calibration and decision curve analysis were used to evaluate the comprehensive model. SPSS software (version 26.0) and R software (version 4.1.2) perform statistical analysis. RESULTS The prevalence of total VC is 95.36%. Among the abdominal arteries, abdominal aortic calcification is the most prevalent (88.61%), followed by calcification of internal iliac artery (85.65%) and common iliac artery (80.17%). Median survival time was 37.00 (1.00–70.00) months. The 1-year survival rate, 3-year survival rate and 5-year survival rate were 73.42%, 50.01% and 35.43%, respectively. Cardiovascular disease accounts for 54.01% of the death cause. AUC of Time-dependent ROC by internal iliac artery and mesenteric artery calcification for predicting mortality is significantly higher than that of other arterial calcification. Internal iliac artery calcification (IIAC) was screened out as the most representative predictor for all-cause death among the calcification of arterial calcification by lasso regression. When analyzing IIAC and other clinical data, age (hazard ratio 1.03, P < 0.001), serum albumin level (hazard ratio 0.919, P < 0.001) and IIAC (hazard ratio 1.36, P = 0.003) were independent factor of mortality in HD patients. The nomogram based on Cox proportional hazards model is shown in Figure 1. C-index of the model was 74.09%. Decision curves of Cox proportional hazards model from training dataset and validation dataset showed the reliable predictive value of Cox model (Figure 2). CONCLUSION This is the first study evaluating the calcification volume of abdominal aortic branches and comparing their predictive values. In conclusion, calcification of abdominal aortic branches, especially internal iliac artery, is a better predictor for mortality of HD patients than abdominal aortic calcification. Our concern with calcification of large arteries in MHD patients needs to be shifted to smaller branch arteries.

Investigation of large artery calcification in non-­contrast computed tomography with small vessel ­disease, large ­artery atherosclerosis and stroke subtype in ­ischaemic stroke patients

Strokes are the second leading cause of death worldwide. Arterial calcification has been associated with an increased frequency of stroke. Arterial calcification increases vessel stiffness, which has been indicated to be linked with cerebral small vessel disease.[1,2][1] However the relation of

Investigation of large artery calcification in non-­contrast computed tomography with small vessel ­disease, large ­artery atherosclerosis and stroke subtype in ­ischaemic stroke patients

Strokes are the second leading cause of death worldwide. Arterial calcification has been associated with an increased frequency of stroke. Arterial calcification increases vessel stiffness, which has been indicated to be linked with cerebral small vessel disease.[1,2][1] However the relation of

Study on the Prevalence of Vascular Calcification in Different Types of Arteries and Influencing Factors in Maintenance Peritoneal Dialysis Patients

Objective: To investigate the occurrence of vascular calcification (VC) in different types of arteries in patients with maintenance peritoneal dialysis (PD) patients and its influencing factors. Methods: This study enrolled PD patients with stable status who has received PD treatment for more than 6 months in Peking University People’s Hospital. We used plain X-ray films of abdomen, pelvis, and hands to quantitatively evaluate VC of large artery (abdominal aorta, iliac artery), medium artery (femoral artery, radial artery), and small artery (finger arteries). Two radiologists read and scored radiographs blindly. Demographic data, clinical characteristics, Charlson comorbidity index (CCI), baseline and time-average laboratory indices including parameters of calcium phosphorus metabolism, serum albumin, PD adequacy were collected. A logistic regression model was used to estimate the influencing factors of different sites of VC. Results: (1) 154 PD patients were enrolled in this study: seventy-eight males, mean age was 60.4 ± 13.9 years, and median PD duration was 24 (16.39) months. The major primary disease was diabetic nephropathy (39%). (2) Among the 154 PD patients, the proportion of calcification of large artery was the highest (found in 100 patients, accounting for 64.9%); then the medium artery (66, 42.9%); and 15 of small artery, accounting for 9.7%. (3) Logistic regression showed that older age, longer dialysis duration, lower baseline serum intact parathyroid hormone (iPTH), and higher CCI scores were independent risk factors of large artery calcification (p < 0.05), and higher CCI scores, higher baseline serum triglycerides (TG), lower baseline serum iPTH, and time-average iPTH were independent risk factors of medium and small arteries. Conclusions: In PD patients, the occurrence of large artery calcification was higher than others. Among different sites of VC, the abdominal aortic calcification was most likely to occur, and the proportion of small artery calcification was low. Calcification of medium and small arteries can exist alone without calcification of large artery. Large artery calcification was more likely to occur in patients with older age, longer dialysis duration, lower baseline serum iPTH levels and higher CCI scores. Patients with higher CCI scores, higher baseline TG and lower baseline iPTH, and time-average iPTH were more likely to develop small and medium artery calcification.

Vitamin K Antagonists, Non-Vitamin K Antagonist Oral Anticoagulants, and Vascular Calcification in Patients with Atrial Fibrillation.

Background Vitamin K antagonists (VKAs) are associated with coronary artery calcification in low-risk populations, but their effect on calcification of large arteries remains uncertain. The effect of non–vitamin K antagonist oral anticoagulants (NOACs) on vascular calcification is unknown. We investigated the influence of use of VKA and NOAC on calcification of the aorta and aortic valve. Methods In patients with atrial fibrillation without a history of major adverse cardiac or cerebrovascular events who underwent computed tomographic angiography, the presence of ascending aorta calcification (AsAC), descending aorta calcification (DAC), and aortic valve calcification (AVC) was determined. Confounders for VKA/NOAC treatment were identified and propensity score adjusted logistic regression explored the association between treatment and calcification (Agatston score > 0). AsAC, DAC, and AVC differences were assessed in propensity score–matched groups. Results Of 236 patients (33% female, age: 58 ± 9 years), 71 (30%) used VKA (median duration: 122 weeks) and 79 (34%) used NOAC (median duration: 16 weeks). Propensity score–adjusted logistic regression revealed that use of VKA was significantly associated with AsAC (odds ratio [OR]: 2.31; 95% confidence interval [CI]: 1.16–4.59; p = 0.017) and DAC (OR: 2.38; 95% CI: 1.22–4.67; p = 0.012) and a trend in AVC (OR: 1.92; 95% CI: 0.98–3.80; p = 0.059) compared with non-anticoagulation. This association was absent in NOAC versus non-anticoagulant (AsAC OR: 0.51; 95% CI: 0.21–1.21; p = 0.127; DAC OR: 0.80; 95% CI: 0.36–1.76; p = 0.577; AVC OR: 0.62; 95% CI: 0.27–1.40; p = 0.248). A total of 178 patients were propensity score matched in three pairwise comparisons. Again, use of VKA was associated with DAC ( p = 0.043) and a trend toward more AsAC ( p = 0.059), while use of NOAC was not (AsAC p = 0.264; DAC p = 0.154; AVC p = 0.280). Conclusion This cross-sectional study shows that use of VKA seems to contribute to vascular calcification. The calcification effect was not observed in NOAC users.

Hypertension in Chronic Kidney Disease - Role of Arterial Calcification and Impact on Treatment.

Hypertension contributes to the progression of kidney diseases as well as to the occurrence of cardiovascular events such as myocardial infarction, heart failure and stroke. The prevalence of hypertension is elevated in patients with kidney disease, and increases progressively as glomerular filtration rate falls. A better understanding of the mechanisms leading to hypertension in renal diseases has been gained in recent years; in this article we will review the pathogenesis of hypertension in chronic kidney disease (CKD) with a special focus on vascular calcification because calcification is associated with an increased incidence of cardiovascular morbidity in CKD patients. Although calcification of large arteries and blood pressure increase with age, few studies have specifically investigated a possible connection between these two factors as determinants of the severity of hypertension in CKD. Finally, we will review the trends in hypertension treatment in CKD patients. Expanded understanding of the role of CKD as both a cause and a target of hypertension highlights key points of pathophysiology of hypertension and may contribute to the identification of new strategies for its prevention and treatment.

Large artery calcification on dialysis patients is located in the intima and related to atherosclerosis.

Vascular calcification (VC) has a significant effect in cardiovascular diseases on dialysis patients. However, VC is assessed with x-ray-based techniques, which do not inform about calcium localization (intima, media, atherosclerosis-related). The aim of this work is to study VC and its related factors using arterial ultrasound to report the exact location of calcium. This was an observational, cross-sectional, case-control study that included 232 patients in dialysis and 208 age- and sex-matched controls with normal kidney function. Demographic data and laboratory values were collated. Carotid, femoral, and brachial ultrasounds were performed to assess VC and atherosclerosis burden using a standardized protocol. Cardiovascular risk factors were predominantly found in controls, although the burden of atherosclerosis was higher in the dialysis group. VC was significantly more prevalent in the group of patients on dialysis than control subjects, and in both groups the most prevalent pattern of VC was linear calcification located in the intima of the artery wall. Age and undergoing dialysis (with or without previous cardiovascular diseases) were positively and significantly associated with linear calcification. Conversely, the absence of atherosclerosis and low levels of C-reactive protein and phosphorus significantly impeded the development of linear calcification. VC in large, conduit arteries is more prevalent in patients on dialysis than controls and is predominantly located in a linear fashion in the intima of the arteries.

The pathobiology of isolated systolic hypertension

Central artery stiffening with aging is the driving force that results in increased pulse pressure (PP) and ultimately the development of isolated systolic hypertension (ISH). Since diastolic blood pressure (DBP) rises with increased small arterial and arteriolar resistance and falls with increased large artery stiffness, DBP displays a J-curve pattern of CV risk; thus, PP is a stronger risk factor than systolic blood pressure (SBP) in patients with ISH when DBP is <70 mmHg. ISH can develop from either “burned-out” diastolic hypertension or de novo, secondary to increased arterial stiffness without going through a preliminary phase of essential hypertension. De novo ISH, the most frequent form of ISH, has multiple etiologies, which include a variety of conditions that impair synthesis of elastin protein and increase large artery calcification. The projected increase in ISH with aging of the US population and the often found resistance of ISH to antihypertensive therapy represent a potential worsening public health problem.

What dishwashers and humans have in common

One answer to the title question could be that both ‘species’, dishwashers and humans, can be protected from unwanted calcification by the anticalcifying properties of small double-phosphate molecules, diphosphonates or pyrophosphates, respectively. More than 40 years ago, we started to realize that there are compounds present in many biological fluids capable of inhibiting precipitation of calcium phosphates [1]. These compounds have been identified as inorganic pyrophosphates (P–O–P) and have been demonstrated to slow the transformation of amorphous calcium phosphate into its crystalline form while inhibiting crystal aggregation. This observation led to the development of diphosphonates, in which the P–O–P bond is replaced by a P–C–P bond and, subsequently, to the development of bone scanning agents and bisphosphonates. While excellent evidence has since accrued that diphosphonate detergents protect dishwashers from premature calcification and ‘sudden death’—and, thus, contribute to longevity—this evidence is still weak and just starting to accumulate in mammals and human beings. The paper by O'Neill, Sigrist and McIntyre in this issue of Nephrology Dialysis Transplantation is one step forward in exploring the potential clinical role of endogenous pyrophosphates in human disease scenarios and, consequently, addresses the patient population at highest risk for unwanted calcification, i.e. individuals suffering from advanced chronic kidney disease (CKD) [2]. The authors measured plasma pyrophosphate concentrations in 115 individuals in CKD stages 4–5D and correlated these levels with the degree and change in large artery calcification which was quantitatively detected at the superficial femoral artery by computed tomography (CT). CT imaging was obtained at baseline and after 1 year. An inverse association was found between baseline calcification score and pyrophosphate levels; also, an inverse, though non-significant trend regarding calcification progression and pyrophosphate levels was reported. In the past and over many years, this group of investigators has led the path towards this current and sig

Arterial Calcification in Race Horses

Calcification of large arteries has been sporadically reported in horses. The pathogenesis is still unknown, but recent studies in humans suggest that this is a regulated biomineralizing process. This study surveyed the prevalence, distribution, and severity of vascular calcification in Thoroughbred and Standardbred racehorses. Histopathologic, ultrastructural imaging, and energy dispersive X-ray elemental analyses were used to examine the lesions. Calcification of the tunica media, predominantly the pulmonary artery, was found in 82% of horses (83/101). Young adult horses (mean [SD] age in years, 4.44 +/- 2.17) of both breeds and sexes were similarly affected. Lesions appeared as white-to-yellowish, hard, and gritty plaques of variable size. On microscopic examination, elastic fibers within the tunica media were thinned, fragmented, and calcified, and surrounded by dense collagen matrix. Elemental analysis showed distinct peaks for calcium and phosphorus, consistent with hydroxyapatite mineral. The frequent occurrence of calcification in the tunica media of large pulmonary arteries of young racing horses indicates the need to investigate its pathogenesis and potential clinical implications.

Is there a role for reactive oxygen species in arterial medial elastocalcinosis?

Isolated systolic hypertension results from a gradual stiffening of large arteries, to which medial elastocalcinosis (calcification of elastic lamellae) contributes. There is compelling evidence that reactive oxygen species (ROS) are associated with several disease processes affecting the cardiovascular system, including hypertension. The present study was designed to investigate whether the inhibition of ROS production by alpha-lipoic acid can prevent vascular calcification. Sprague–Dawley rats were treated with warfarin (20 mg/kg/day) and vitamin K (15 mg/kg/day) (WVK) for 4 weeks to induce large artery calcification. Subgroups received either a normal diet or a diet supplemented with lipoic acid (1000 mg/kg/day). The WVK treatment produced a small elevation of aortic superoxide levels that did not reach statistical significance. Alpha-lipoic acid reduced the elevation below baseline levels. In rats treated with alpha-lipoic acid, the WVK-induced elevation of pulse wave velocity (an index of arterial stiffness), left ventricular hypertrophy, and aortic, femoral and carotid elastocalcinosis were not prevented. Although a contribution of oxidative stress has been suggested in the aging cardiovascular system, this alteration does not appear to contribute to the calcification process and the subsequent stiffening of large arteries in the animal model tested.

Vascular calcification in patients with end-stage renal disease.

Vascular calcification is the most common type of extra-osseous calcification in end-stage renal disease (ESRD), manifesting as both medial and intimal calcification of large arteries. It is highly prevalent, often progressive and is associated with reduced arterial elasticity and increased mortality. Risk factors for calcification in ESRD include age, duration of dialysis, diabetes mellitus, most probably an elevated calcium-phosphorus product (Ca x P) level, the dose of calcium-containing phosphate binders and the induction of the systemic inflammatory response. Uraemic calcification was thought to be a largely physico-chemical process facilitated by elevated Ca x P (i.e. "metastatic" calcification). It is now well established, however, that vascular smooth muscle cells actively take up phosphate to form bioapatite. This process is associated with a phenotypic transformation of vascular smooth muscle cells during which they express osteoblast markers. In addition to phosphate, various other factors are likely to increase bioapatite formation, e.g. lipids and inflammatory cytokines. There have also been relatively new insights relating to the role of endogenous inhibitors of calcification [i.e. matrix Gla protein and fetuin-A (alpha(2)-Heremans-Schmid glycoprotein)], in particular the downregulation of fetuin-A in systemic inflammation. Decreased serum fetuin-A has been shown to be associated with a reduced capacity to inhibit calcium phosphate precipitation in vitro and is predictive of mortality in dialysis patients. These new insights into pathogenesis may lead to better prevention and treatment of calcification (e.g. with calcimimetics, anti-cytokines, etc.). However, the only preventive approach to have been established prospectively to date is the replacement of calcium-containing phosphate binders with sevelamer HCl, a non-calcaemic phosphate binder. Yet, it remains unclear whether sevelamer HCl reduces vascular calcification by preventing episodes of hypercalcaemia and/or by reducing low-density lipoprotein (LDL)-cholesterol levels.

A new model of isolated systolic hypertension induced by chronic warfarin and vitamin K 1 treatment

Background Isolated systolic hypertension is the predominant form of hypertension in the elderly population. Reduction of arterial compliance appears to contribute to the elevation of pulse pressure (PP) and among potential mechanisms, gradual vascular calcification, fragmentation of elastic lamellae, and augmentation of rigid component like collagen could contribute to increase aortic stiffening. Few experimental models of the disease are currently available. Methods To induce large artery calcification, rats were treated with warfarin and vitamin K 1 (WK) for 4 and 8 weeks, to inhibit the maturation of matrix Gla protein. The impact of chronic PP elevation was determined on large artery and cardiac remodeling and on aortic endothelial function. Results The WK treatment led to aortic medial calcification and a proportional elevation of PP, attributable mainly to a selective elevation of systolic blood pressure. The chronic treatment also increased collagen, whereas elastin decreased in the aorta. Pulse wave velocity, an index of aortic stiffening, increased in rats treated with WK. However, indices of left ventricular and aortic hypertrophy and remodeling remained normal. In addition, the WK treatment did not modify the vasoconstriction to norepinephrine and endothelin-1, and the vasodilatory response to acetylcholine and sodium nitroprusside. Conclusions Chronic treatment with WK represents a new model of isolated systolic hypertension with several characteristics of the human disease. The relative ease to induce calcification in this model may help to foster more fundamental research, which is lacking in this type of hypertension.

In Reply

I thank Dr. Neurath for his comments on blood pressure measurement in the elderly. The term “pseudohypertension” has indeed become a diagnostic term that refers to artifactual hypertension in patients with Mönckeberg's medical calcification of large arteries.1 This process can be diagnosed by radiographic examination of the arms; vascular calcification will be evident. Pseudohypertension may be superimposed on existing hypertension, normotension, or even hypotension and must be diagnosed correctly in order to prevent potentially dangerous overtreatment. Unfortunately, the true prevalence of pseudohypertension remains unknown although it is relatively uncommon. The Osler maneuver has not proved to be reliable, and a high index of clinical suspicion remains the best screening measure.2 There are many other causes of erroneous blood pressure readings, several of which are listed by Dr. Neurath. One of the most common is use of a blood pressure cuff that is too small for the patient's arm. The need for correct blood pressure measuring technique cannot be overemphasized. This includes the palpation of the peripheral pulse (radial or brachial) to avoid the error of the “silent zone” with consequent underestimation of the true intraarterial pressure. The diagnosis of ISH clearly requires multiple measurements on separate visits. The physical examination, chest X-ray, and ECG greatly underestimate the true prevalence of left ventricular hypertrophy. Nevertheless, cardiac ultrasound should be reserved for patients for whom the results are expected to be critical for diagnostic and therapeutic decision making. It is not a routine test. I could not agree more regarding the dangers of too rapid reduction of elevated blood pressure, especially in elderly patients. Rapid reduction is rarely necessary and potentially dangerous. Patients who are anxious and/or in pain may have blood pressure levels truly elevated above their usual baseline. Often the best treatment is relief of the anxiety and/or pain and not direct treatment of the blood pressure numbers. Semantics aside, the most important point of my editorial was that there are now data on which to base the treatment of patients with ISH.3 It is, of course, crucial to determine that the patient does, in fact, have ISH in order to avoid the risks of treatment, however small, for an entity that the patient does not actually have.