Atherosclerotic plaques occur in absence of intima-media thickening in both systemic sclerosis and systemic lupus erythematosus: a duplexsonography study of carotid and femoral arteries and follow-up for cardiovascular events

Introduction

The objective of this cross-sectional and retrospective cohort study was (1) to determine the usefulness of intima-media thickness (IMT) in contrast to plaque assessment, (2) to examine the value of additive femoral artery sonography and (3) to identify potential risk factors for atherosclerosis and incident cardiovascular events in systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) patients.

Methods

In this study, 90 SSc and 100 SLE patients were examined by duplexsonography. IMT was measured in common carotid and common femoral arteries, plaques were assessed in common, internal and external carotid and common, proximal superficial and deep femoral arteries. Different definitions of pathological IMT (pIMT) were compared with the presence of plaque. Results were evaluated in relation to traditional and non-traditional risk factors for baseline atherosclerosis (logistic regression) and their predictive value for cardiovascular events during follow-up (cox regression).

Results

Definite atherosclerosis occurred frequently without signs of subclinical atherosclerosis in both diseases: pIMT >0.9 mm was present in only 17/59 (28.9%) SSc and 13/49 (26.5%) SLE patients with already present atherosclerotic plaques. Using age-adjusted pIMT definitions, this rate was even lower (5.1-10.3% in SSc, 14.3-26.5% in SLE). Plaques were located only at the carotid or only at the femoral arteries in 26 (13.7%) and 24 (12.6%) patients, respectively. Age and nicotine pack-years were independently associated with atherosclerotic plaques in SLE and SSc patients, as well as the cumulative prednisolone dose in SSc subgroup, and ssDNA positive SLE patients had a lower risk for atherosclerotic plaque. During follow-up (available for 129/190 (67.9%) patients, 650 person-years), cardiovascular events occurred more often in patients with coronary heart disease (adjusted-hazards ratio (HR) 10.19, 95% confidence interval (CI) 3.04 to 34.17, P <0.001), male patients (adjusted-HR 8.78, 95% CI 2.73 to 28.19, P <0.001) and in patients with coexistent carotid and femoral plaques (adjusted-HR 5.92, 95% CI 1.55 to 22.67, P = 0.009). Patients with solely carotid or femoral plaque were not at higher risk.

Conclusion

Atherosclerotic plaque lesions can be found frequently in absence of intima-media thickening in both SSc and SLE patients. As well as routine sonography of carotid arteries, the sonography of femoral arteries is recommended to identify additional atherosclerotic lesions and to detect patients at a high risk for cardiovascular events.     

The use of digital subtraction angiography in diseases of the arteries of the pelvis and lower limbs

The diagnostic potentialities of digital subtraction angiography (DSA) in diseases of the pelvic arteries and lower limbs were studied. Intravenous (iv) and intraarterial (ia) DSA were performed in 613 patients, among them were patients with obliterating atherosclerosis and endarteritis, thromboembolism, aneurysms and arteriovenous fistulas. Iv DSA provided good information for the solution of therapeutic and tactical problems in pelvic, femoral and popliteal arterial lesions but in 16% of the cases it gave no opportunity to assess the status of the crural arteries. Ia DSA was shown to be no inferior to routine arteriography in the visualization of the lower limb arteries. This method is economical, well tolerated by patients, permits the intensification of examination of patients with acute and chronic arterial pathology. It can be employed under outpatient conditions and in the early postoperative period.     

Evidence for greater burden of peripheral arterial disease in lower extremity arteries of spinal cord-injured individuals

Spinal cord injury leads to increased risk for cardiovascular disease and results in greater risk of death. Subclinical markers of atherosclerosis have been reported in carotid arteries of spinal cord-injured individuals (SCI), but the development of lower extremity peripheral arterial disease (PAD) has not been investigated in this population. The purpose of this study was to determine the effect of spinal cord injury on ankle-brachial index (ABI) and intima-media thickness (IMT) of upper-body and lower-extremity arteries. We hypothesized that the aforementioned measures of lower-extremity PAD would be worsened in SCI compared with controls and that regular participation in endurance exercise would improve these in both groups. To test these hypotheses, ABI and IMT were determined in 105 SCI and compared with 156 able-bodied controls with groups further subdivided into physically active and sedentary. ABIs were significantly lower in SCI versus controls (0.96 ± 0.12 vs. 1.06 ± 0.07, P < 0.001), indicating a greater burden of lower-extremity PAD. Upper-body IMTs were similar for brachial and carotid arteries in controls versus SCI. Lower extremity IMTs revealed similar thicknesses for both superficial femoral and popliteal arteries, but when normalized for artery diameter, individuals with SCI had greater IMT than controls in the superficial femoral (0.094 ± 0.03 vs. 0.073 ± 0.02 mm/mm lumen diameter, P < 0.01) and popliteal (0.117 ± 0.04 vs. 0.091 ± 0.02 mm/mm lumen diameter, P < 0.01) arteries. The ABI and normalized IMT of SCI compared with controls indicate that subclinical measures of lower-extremity PAD are worsened in individuals with SCI. These findings should prompt physicians to consider using the ABI as a screening method to detect lower-extremity PAD in SCI.     

Mass ratios of magnesium to calcium and phosphorus in the arteries of Japanese and Thai

To elucidate quantitative changes of Ca, P, and Mg in the arteries with aging, the authors investigated changes of the mass ratios of Mg to Ca and P in the arteries of Japanese and Thai by inductively coupled plasma-atomic emission spectrometry. The arteries of Japanese that were used were the thoracic and abdominal aortas, coronary, common iliac, internal iliac, external iliac, and femoral arteries, in which very high accumulations of Ca and P occurred in old age. The arteries of Thai that were used were the abdominal aorta, ramifying site of the abdominal aorta, coronary, common iliac, internal iliac, and external iliac arteries. It was found that there were extremely significant correlations both between Ca and Mg contents and between P and Mg contents in all of the arteries of the Japanese and the Thai. With regard to the mass ratio, the mass ratios of Mg to Ca ranged from 1.5% to 2.1% in the six arteries of the Japanese, except for the thoracic aorta at 3.1%, at an advanced stage of atherosclerosis, being similar to each other. In the arteries of the Thai, the mass ratios of Mg to Ca ranged from 1.9% to 3.0%, except for the coronary artery at 0.5%, at an advanced stage of atherosclerosis. The mass ratios of Mg to P ranged from 2.5% to 2.7% in the six arteries of the Japanese, except for the coronary artery at 1.8%, at an advanced stage of atherosclerosis. With regard to the arteries of the Thai, the mass ratios of Mg to P ranged from 1.9% to 3.3%, except for the coronary artery at 0.7%, at an advanced stage of atherosclerosis. These results revealed that both the mass ratios of Mg to Ca and Mg to P were almost similar among the arteries of Japanese and Thai, except for the coronary arteries. Therefore, these results suggested that the inorganic deposits in the coronary arteries of Japanese and Thai were similar to those in the intimal tunica of the thoracic aorta, whereas in the other arteries, they were similar to those in the middle tunica of the thoracic aorta.     

Aneurysms after microvascular anastomoses. Incidence and pathogenesis in experimental animals.

This study has demonstrated that aneurysms occur in about 50 percent of the rat femoral arteries subjected to microvascular anastomosis. These aneurysms are consistent histologically--being characterized by medial necrosis, loss of elastic lamellae, and subintimal hyperplasia. Mechanical trauma is implicated as a factor in their pathogenesis, though further study in necessary to define the exact etiology.     

Mechanical instability of normal and aneurysmal arteries

Tortuous arteries associated with aneurysms have been observed in aged patients with atherosclerosis and hypertension. However, the underlying mechanism is poorly understood. The objective of this study was to determine the effect of aneurysms on arterial buckling instability and the effect of buckling on aneurysm wall stress. We investigated the mechanical buckling and post-buckling behavior of normal and aneurysmal carotid arteries and aorta’s using computational simulations and experimental measurements to elucidate the interrelationship between artery buckling and aneurysms. Buckling tests were done in porcine carotid arteries with small aneurysms created using elastase treatment. Parametric studies were done for model aneurysms with orthotropic nonlinear elastic walls using finite element simulations. Our results demonstrated that arteries buckled at a critical buckling pressure and the post-buckling deflection increased nonlinearly with increasing pressure. The presence of an aneurysm can reduce the critical buckling pressure of arteries, although the effect depends on the aneurysm’s dimensions. Buckled aneurysms demonstrated a higher peak wall stress compared to unbuckled aneurysms under the same lumen pressure. We conclude that aneurysmal arteries are vulnerable to mechanical buckling and mechanical buckling could lead to high stresses in the aneurysm wall. Buckling could be a possible mechanism for the development of tortuous aneurysmal arteries such as in the Loeys–Dietz syndrome.     

Machine learning for detection of stenoses and aneurysms: application in a physiologically realistic virtual patient database

This study presents an application of machine learning (ML) methods for detecting the presence of stenoses and aneurysms in the human arterial system. Four major forms of arterial disease—carotid artery stenosis (CAS), subclavian artery stenosis (SAS), peripheral arterial disease (PAD), and abdominal aortic aneurysms (AAA)—are considered. The ML methods are trained and tested on a physiologically realistic virtual patient database (VPD) containing 28,868 healthy subjects, adapted from the authors previous work and augmented to include disease. It is found that the tree-based methods of Random Forest and Gradient Boosting outperform other approaches. The performance of ML methods is quantified through the \(F_1\) score and computation of sensitivities and specificities. When using six haemodynamic measurements (pressure in the common carotid, brachial, and radial arteries; and flow-rate in the common carotid, brachial, and femoral arteries), it is found that maximum \(F_1\) scores larger than 0.9 are achieved for CAS and PAD, larger than 0.85 for SAS, and larger than 0.98 for both low- and high-severity AAAs. Corresponding sensitivities and specificities are larger than 90% for CAS and PAD, larger than 85% for SAS, and larger than 98% for both low- and high-severity AAAs. When reducing the number of measurements, performance is degraded by less than 5% when three measurements are used, and less than 10% when only two measurements are used for classification. For AAA, it is shown that \(F_1\) scores larger than 0.85 and corresponding sensitivities and specificities larger than 85% are achievable when using only a single measurement. The results are encouraging to pursue AAA monitoring and screening through wearable devices which can reliably measure pressure or flow-rates.

     

Transascending aortic intraaortic balloon insertion with delayed sternal closure: A retrospective analysis

Intraaortic balloon pumping (IABP) is an established therapeutic adjunct in the treatment of postcardiotomy/infarction low cardiac output states. Although the common femoral or iliac arteries are the preferred sites for balloon insertion, severe arterial occlusive disease may preclude entry by these methods. To circumvent this problem, alternative methods of insertion utilizing transthoracic approaches have evolved. In our institution, direct (transaortic) IABP insertion, combined with delayed sternal closure to avoid cardiac compression and possible tamponade, was performed in 28 adult postcardiotomy patients (mean age 60.4 +/- 3 years). The severity of generalized atherosclerosis was reflected in an overall survival rate of 28.6%. Retrospective analyses of the clinical courses of these patients revealed that the transaortic approach allowed utilization of larger and more effective balloons. Successful insertion of 30 and 40 ml balloons was accomplished in 27 of 28 (96%) of these patients, and one patient with a hypoplastic aorta required a 20 ml balloon. There were no complications directly attributable to this alternative site of balloon insertion, and tamponade was avoided. Delayed sternal closure was accomplished within 48 to 96 hours. We concluded that when severe peripheral vascular occlusive disease prevents insertion of intraaortic balloons via the femoral or iliac arteries in patients with low cardiac output, the alternative transaortic approach is indicated. Combined with delayed sternal closure in patients with postcardiotomy dilatation, additional benefits accrue.     

A stepwise method for the isolation of endothelial cells and smooth muscle cells from individual canine coronary arteries

Methods for the stepwise isolation of endothelial cells and smooth muscle cells from individual canine coronary arteries are described. Both cell types can be isolated in pure culture with high yields. Dogs are a common species used in the study of atherosclerosis and coronary artery disease. Capacity to isolate endothelial cells and smooth muscle cells from individual canine coronary arteries should prove useful in the study of coronary artery disease.     

A possible balance of phosphorus accumulations among bone, cartilage, artery, and vein in single human individuals

To elucidate relationships between the decrease of mineral contents in human bones and the accumulation of minerals in the other human tissues, the contents of phosphorus in human bones, arteries, veins, and cartilages in 27 subjects (17 men and 10 women) were analyzed by inductively coupled plasma-atomic emission spectrometry. These were resected from subjects who died in the age range 40–98 yr. Calcanei were chosen for analysis of mineral contents in contrast to arteries such as the femoral, popliteal, and common carotid arteries, veins such as superior and inferior venae cavae, internal jugular, and femoral veins, and pubic symphyses. It was found that the content of phosphorus in calcanei was in agreement with that in both the pubic symphysis and the arteries such as femoral, popliteal, and common carotid arteries, but it was not in agreement with that in the veins such as superior and inferior venae cavae, internal jugular, and femoral veins. This suggests that phosphorus released from bones is accompanied by accumulations of phosphorus in the artery and cartilage.     

Global revascularization: the role of the cardiologist

There are compelling reasons for cardiologists to undertake a more global approach to patients with peripheral vascular diseases: atherosclerosis is a 'systemic' disease frequently causing both coronary and peripheral vascular problems in the same patient; coronary artery disease is the most common cause of morbidity and mortality in patients with peripheral vascular disease; and peripheral vascular disease negatively impacts the management of angina pectoris and congestive heart failure. There are four major areas of special interest to the cardiologist: (1) iliac arteries (vascular access), (2) renal arteries (hypertension and volume overload), (3) subclavian arteries (coronary steal with a left internal mammary artery [LIMA] graft), and (4) carotid arteries (stroke). Technical skills necessary to perform coronary angioplasty are transferable to the peripheral vasculature. However, an understanding of the natural history of peripheral disease, patient and lesion selection criteria, and knowledge of other treatment alternatives are essential to performing these procedures safely and effectively. Appropriate preparation and training, and a team approach, including an experienced vascular surgeon, are both desirable and necessary before interventional cardiologists who are inexperienced in the treatment of peripheral vascular disease attempt percutaneous peripheral angioplasty. There are inherent advantages for patients when the cardiologist performing the procedure is also a clinician. Judgments regarding the indications, timing, and risk/benefit ratio of procedures are enhanced by a long-term relationship between physician and patient. Finally, in view of the increased incidence of coronary artery disease in patients with atherosclerotic peripheral vascular disease, the participation of a cardiologist in their care seems appropriate.     

TNF-alpha is necessary for induction of coronary artery inflammation and aneurysm formation in an animal model of Kawasaki disease

Kawasaki disease is the most common cause of multisystem vasculitis in childhood. The resultant coronary artery lesions make Kawasaki disease the leading cause of acquired heart disease in children in the developed world. TNF-alpha is a pleiotropic inflammatory cytokine elevated during the acute phase of Kawasaki disease. In this study, we report rapid production of TNF-alpha in the peripheral immune system after disease induction in a murine model of Kawasaki disease. This immune response becomes site directed, with migration to the coronary arteries dependent on TNF-alpha-mediated events. Production of TNF-alpha in the heart is coincident with the presence of inflammatory infiltrate at the coronary arteries, which persists during development of aneurysms. More importantly, inflammation and elastin breakdown in the coronary vessels are completely eliminated in the absence of TNF-alpha effector functions. Mice treated with the TNF-alpha-blocking agent etanercept, as well as TNFRI knockout mice, are resistant to development of both coronary arteritis and coronary aneurysm formation. Taken together, TNF-alpha is necessary for the development of coronary artery lesions in an animal model of Kawasaki disease. These findings have important implications for potential new therapeutic interventions in children with Kawasaki disease.     

Lower wall shear rate of the common carotid artery in treated type 2 diabetes mellitus with metabolic syndrome

Arterial sites with low wall shear stress (WSS) are more prone to the development of atherosclerotic plaques, as was observed in carotid arteries in subjects with atherosclerosis risk factors. Type 2 diabetes mellitus (DM), hypertension, hyperlipidemia and other components of the metabolic syndrome, are associated with high risk for symptomatic cerebrovascular disease. It was shown by others that untreated type 2 DM is associated with lower WSS in common carotid arteries. However, the cardiovascular risk of type 2 DM could be modified by therapy. The aim of our study was to test the hypothesis that treated type 2 DM subjects with metabolic syndrome still have lower WSS in common carotid arteries than healthy controls. We enrolled 26 compensated DM subjects with metabolic syndrome, treated by metformin, statins and ACEI for more than 6 months, and 22 aged-comparable healthy controls. Wall shear rate (WSR) was used as a measure of WSS. A linear 3-11 MHz probe was used to measure blood velocity and internal diameter in the common carotid arteries. We compared observed values of WSR adjusted for age by ANCOVA. Wall shear rate was significantly lower in DM group than in control subjects: peak (systolic) values of wall shear rate were 410+/-130 s(-1) vs. 487+/-111 s(-1) (p<0.005). DM subjects had significantly lower WSR, because of both thinner lumen and slower blood flow velocities. Lower WSR was accompanied by higher IMT (0.73+/-0.12 mm vs. 0.64+/-0.11 mm, p<0.001). Treated subjects with compensated type 2 DM with metabolic syndrome still have atherogenic hemodynamic profile. These findings might help to understand faster progression of atherosclerosis in diabetic subjects with metabolic syndrome despite up-to-date medication.     

Extracellular vesicle signalling in atherosclerosis

Atherosclerosis is a major cardiovascular disease and in 2016, the World Health Organisation (WHO) estimated 17.5 million global deaths, corresponding to 31% of all global deaths, were driven by inflammation and deposition of lipids into the arterial wall. This leads to the development of plaques which narrow the vessel lumen, particularly in the coronary and carotid arteries. Atherosclerotic plaques can become unstable and rupture, leading to myocardial infarction or stroke. Extracellular vesicles (EVs) are a heterogeneous population of vesicles secreted from cells with a wide range of biological functions. EVs participate in cell-cell communication and signalling via transport of cargo including enzymes, DNA, RNA and microRNA in both physiological and patholophysiological settings. EVs are present in atherosclerotic plaques and have been implicated in cellular signalling processes in atherosclerosis development, including immune responses, inflammation, cell proliferation and migration, cell death and vascular remodeling during progression of the disease. In this review, we summarise the current knowledge regarding EV signalling in atherosclerosis progression and the potential of utilising EV signatures as biomarkers of disease.     

The role of cytokines in the development of atherosclerosis

Atherosclerosis contributes to the development of many cardiovascular diseases, which remain the leading cause of death in developed countries. Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries. It is caused by dyslipidemia and mediated by both innate and adaptive immune responses. Inflammation is a key factor at all stages of atherosclerosis progression. Cells involved in pathogenesis of atherosclerosis were shown to be activated by soluble factors, cytokines, that strongly influence the disease development. Pro-inflammatory cytokines accelerate atherosclerosis progression, while anti-inflammatory cytokines ameliorate the disease. In this review, we discuss the latest findings on the role of cytokines in the development and progression of atherosclerosis.     

Curvature and tortuosity of the superficial femoral artery: a possible risk factor for peripheral arterial disease.

Atherosclerosis in the superficial femoral artery (SFA) resulting in peripheral arterial disease is more common in men than women and shows a predilection for the region of the adductor canal. Blood flow patterns are related to development of atherosclerosis, and we investigated if curvature and tortuosity of the femoral artery differed between young men and women and if differences resulted in adverse flow patterns. Magnetic resonance imaging (MRI) and computational fluid dynamics (CFD) were combined in 18 young adult volunteers (9 men) to assess the relationship of flow features to likely sites of future atherosclerosis formation. Subjects underwent MRI of the right SFA, three-dimensional vascular geometry was reconstructed, and measures of tortuosity and curvature were calculated. Tortuosity and curvature were significantly greater for men than women, and this was related to increased body surface area, body mass index, or weight in men. In both sexes, "tortuosity" increased from the midthigh to the popliteal fossa. The greatest curvature was found within the distal quarter of the SFA. CFD modeling was undertaken on MRI-based reconstructions of the SFA. Wall shear stresses (WSS) were extracted from the computations. WSS showed greater spatial variation in the men than in the women, and the men exhibited lower mean WSS. These data indicate that sex differences related to body size and anatomical course of the femoral artery may contribute to the enhanced risk of focal atherosclerosis in the adductor canal.     

A possible balance of calcium accumulations among bone, cartilage, artery, and vein in single human individuals

To elucidate the relationships between the decrease of mineral contents in human bones and the accumulation of minerals in the other human tissues, the relative contents (RCs) of calcium were analyzed by inductively coupled plasma atomic emission spectrometry among human bones, arteries, veins, and cartilages in 27 subjects (17 men and 10 women). These were resected from subjects who died in the age range from 40 to 98 yr old. Calcanei were chosen for analysis of mineral contents in contrast with femoral, popliteal and common carotid arteries, internal jugular veins, and pubic symphysis. It was found that the RCs of calcium in calcanei were agreeable to association with those in both the pubic symphysis and the femoral artery, but they were not agreeable to association with those in the popliteal and common carotid arteries, and the internal jugular veins. This suggests that calcium released from bones is accompanied by accumulations of calcium in the artery and cartilage.     

Ascending aorta to common femoral artery bypass: An unusual but successful method for revascularization of the lower extremity: Report of case

A 61-year-old woman presented with symptoms and signs of severe ischemia in the left leg. Rest pain was present, and the leg was pulseless. The patient reported a complicated history of repeated strokes. Complete evaluation revealed mitral valve disease, atrial fibrillation, and occlusion of the distal aorta and left iliac and femoral arteries. Corrective surgery consisted of mitral valve replacement and concomitant ascending aorta to left common femoral and femoral graft to right femoral artery bypass. Recovery was uneventful. The cardiac and vascular prostheses functioned well and provided complete relief of ischemia.     

Accumulation of calcium and phosphorus accompanied by increase of magnesium and decrease of sulfur in human arteries

To elucidate the accumulation of elements in the arteries with aging, the authors investigated age-related changes of elements in human arteries, such as the thoracic aorta, femoral, basilar, coronary, radial, and common iliac arteries by inductively coupled plasma-atomic emission spectrometry. The subjects consisted of 17 men and 9 women, ranging in age from 55 to 92 yr in the cases of the five arteries, except for the common iliac arteries, in which the subjects consisted of 16 men and 8 women, ranging in age from 65 to 93 yr. It was found that there were significantly direct correlations between calcium and phosphorus contents and between calcium and magnesium contents in all of the six arteries: thoracic aorta, femoral, basilar, coronary, radial, and common iliac arteries. Significantly direct correlations were also found between phosphorus and magnesium contents in the five arteries, except for the basilar artery. In contrast, significantly inverse correlations were found between calcium and sulfur contents and between phosphorus and sulfur contents in the four arteries, except for the coronary and radial arteries. These revealed that the accumulation of calcium and phosphorus in the arteries was accompanied by an increase of magnesium in the arteries and by a decrease of sulfur in the arteries.     

Effects of posture on shear rates in human brachial and superficial femoral arteries

Shear rate is significantly lower in the superficial femoral compared with the brachial artery in the supine posture. The relative shear rates in these arteries of subjects in the upright posture (seated and/or standing) are unknown. The purpose of this investigation was to test the hypothesis that upright posture (seated and/or standing) would produce greater shear rates in the superficial femoral compared with the brachial artery. To test this hypothesis, Doppler ultrasound was used to measure mean blood velocity (MBV) and diameter in the brachial and superficial femoral arteries of 21 healthy subjects after being in the supine, seated, and standing postures for 10 min. MBV was significantly higher in the brachial compared with the superficial femoral artery during upright postures. Superficial femoral artery diameter was significantly larger than brachial artery diameter. However, posture had no significant effect on either brachial or superficial femoral artery diameter. The calculated shear rate was significantly greater in the brachial (73 +/- 5, 91 +/- 11, and 97 +/- 13 s(-1)) compared with the superficial femoral (53 +/- 4, 39 +/- 77, and 44 +/- 5 s(-1)) artery in the supine, seated, and standing postures, respectively. Contrary to our hypothesis, our current findings indicate that mean shear rate is lower in the superficial femoral compared with the brachial artery in the supine, seated, and standing postures. These findings of lower shear rates in the superficial femoral artery may be one mechanism for the higher propensity for atherosclerosis in the arteries of the leg than of the arm.