Elizabeth Ellins

Endothelial Function Predicts Progression of Carotid Intima-Media Thickness

Background— Endothelial dysfunction develops early and has been shown to predict the development of clinical complications of atherosclerosis. However, the relationship between early endothelial dysfunction and the progression of arterial disease in the general population is unknown. We investigated endothelial dysfunction, risk factors, and progression of carotid intima-media thickness (cIMT) in late-middle-aged individuals at low to intermediate cardiovascular risk in a prospective study between 1997 and 2005. Methods and Results— Brachial artery flow-mediated dilatation and cIMT were measured in 213 nonsmoking British civil servants recruited from a prospective cohort (Whitehall II study). Participants (age, 45 to 66 years) were free of clinical cardiovascular disease and diabetes mellitus. Risk factors and Framingham Risk Score were determined at baseline. cIMT was repeated 6.2±0.4 years later. At baseline, age, blood pressure, low-density lipoprotein cholesterol, and Framingham Risk Score correlated with cIMT. However, only flow-mediated dilatation, not risk factors or Framingham Risk Score, was associated with average annual progression of cIMT. This relationship remained significant after adjustment for risk factors whether entered as separate variables or as Framingham Risk Score. Further adjustment for waist circumference, triglycerides, and employment grade had no significant effect. Conclusions— Systemic endothelial function was associated with progression of preclinical carotid arterial disease over a 6-year period and was more closely related to cIMT changes than conventional risk factors. Thus, the relationship between endothelial dysfunction and adverse outcome is likely to be due not only to destabilization of established disease in high-risk populations but also to its impact on the evolution of the atherosclerotic substrate. Flow-mediated dilatation testing provides an integrated vascular measure that may aid the prediction of structural disease evolution and represents a potential short- to intermediate-term outcome measure for evaluation of preventive treatment strategies.

Mineral Metabolism and Vascular Damage in Children on Dialysis

Cardiovascular disease is increasingly recognized as a life-limiting problem in young patients with chronic kidney disease, but there are few studies in children that describe its determinants. We studied the association of intact parathyroid hormone (iPTH) levels and their management on vascular structure and function in 85 children, ages 5-18 years, who had received dialysis for > or =6 months. Compared to controls, dialysis patients had increased carotid intima-media thickness and pulse-wave velocity. All vascular measures positively correlated with serum phosphorus levels, while carotid intima-media thickness and cardiac calcification score also correlated with iPTH levels. Patients with mean time-integrated iPTH levels less than twice the upper limit of normal (n = 41) had vascular measures that were comparable to age-matched controls, but those with iPTH levels greater than twice the upper limit of normal (n = 44) had greater carotid intima-media thickness, stiffer vessels, and increased cardiac calcification than controls. Patients with increased carotid intima-media thickness had stiffer vessels and a greater prevalence of cardiac calcification. There was a strong dose-dependent correlation between vitamin D and all vascular measures, and calcium intake from phosphate binders weakly correlated with carotid intima-media thickness. In conclusion, both iPTH level and dosage of vitamin D are associated with vascular damage and calcification in children on dialysis.

Low-Dose Sodium Nitrite Attenuates Myocardial Ischemia and Vascular Ischemia-Reperfusion Injury in Human Models

OBJECTIVES The aim of this study was to assess the potential benefits of inorganic nitrite in 2 clinical models: stress-induced myocardial ischemia and whole-arm ischemia-reperfusion. BACKGROUND Inorganic nitrite, traditionally considered a relatively inert metabolite of nitric oxide, may exert vasomodulatory and vasoprotective effects. Despite promising results from animal models, few have shown effectiveness in human model systems, and none have fully translated to the clinical setting. METHODS In 10 patients with inducible myocardial ischemia, saline and low-dose sodium nitrite (NaNO₂) (1.5 μmol/min for 20 min) were administered in a double-blind fashion during dobutamine stress echocardiography, at separate visits and in a random order; long-axis myocardial function was quantified by peak systolic velocity (Vs) and strain rate (SR) responses. In 19 healthy subjects, flow-mediated dilation was assessed before and after whole-arm ischemia-reperfusion; nitrite was given before ischemia or during reperfusion. RESULTS Comparing saline and nitrite infusions, Vs and SR at peak dobutamine increased in regions exhibiting ischemia (Vs from 9.5 ± 0.5 cm/s to 12.4 ± 0.6 cm/s, SR from -2.0 ± 0.2 s(-1) to -2.8 ± 0.3 s(-1)), whereas they did not change in normally functioning regions (Vs from 12.6 ± 0.4 cm/s to 12.6 ± 0.6 cm/s, SR from -2.6 ± 0.3 s(-1) to -2.3 ± 0.1 s(-1)) (p < 0.001, analysis of variance). With NaNO2, the increment of Vs (normalized for increase in heart rate) increased only in poorly functioning myocardial regions (+122%, p < 0.001). Peak flow-mediated dilation decreased by 43% after ischemia-reperfusion when subjects received only saline (6.8 ± 0.7% vs. 3.9 ± 0.7%, p < 0.01); administration of NaNO2 before ischemia prevented this decrease in flow-mediated dilation (5.9 ± 0.7% vs. 5.2 ± 0.5%, p = NS), whereas administration during reperfusion did not. CONCLUSIONS Low-dose NaNO₂ improves functional responses in ischemic myocardium but has no effect on normal regions. Low-dose NaNO₂ protects against vascular ischemia-reperfusion injury only when it is given before the onset of ischemia.

Arterial stiffness and inflammatory response to psychophysiological stress

The processes through which psychological stress influences cardiovascular disease are poorly understood, but may involve activation of hemodynamic, neuroendocrine and inflammatory responses. We assessed the relationship between carotid arterial stiffness and inflammatory responses to acute psychophysiologic stress. Participants were 155 healthy men and women aged 55.3, SD 2.7 years. Blood samples for the assessment of plasma fibrinogen, tumor necrosis factor (TNF) alpha and interleukin (IL) 6 were drawn at baseline, immediately following standardized behavioral tasks, and 45 min later. Carotid artery stiffness was measured ultrasonically three years later, and blood pressure and heart rate responses were recorded. The tasks induced substantial increases in blood pressure and heart rate, together with increased fibrinogen, TNFalpha and IL-6 concentration. Carotid stiffness was positively associated with body mass, waist/hip ratio, blood pressure, low density lipoprotein cholesterol, and C-reactive protein, and inversely with high density lipoprotein and grade of employment. Baseline levels of inflammatory variables were not related to carotid artery stiffness. But carotid stiffness was greater in participants with larger fibrinogen (p=0.037) and TNFalpha (p=0.036) responses to psychophysiological stress. These effects were independent of age, gender, grade of employment, smoking, body mass, waist/hip ratio, systolic and diastolic pressure, high and low density lipoprotein cholesterol, and C-reactive protein. There were no associations between carotid stiffness and stress responses in IL-6, blood pressure, or heart rate. We conclude that individual differences in inflammatory responses to psychophysiological stress are independently related to structural changes in artery walls that reflect increased cardiovascular disease risk.

Endothelial Dysfunction and Cytomegalovirus Replication in Pediatric Heart Transplantation

Background— Cardiac allograft vasculopathy is the major limiting factor to the long-term success of pediatric heart transplantation. Cytomegalovirus (CMV) has been shown to be a significant risk factor for the development of cardiac allograft vasculopathy. Recent work has demonstrated CMV DNA in leukocytes in the absence of direct allograft infection, suggesting that vascular changes may not be limited to the allograft. Method and Results— Systemic arterial endothelial function was assessed with high-resolution ultrasound to determine brachial artery flow-mediated dilation in 50 pediatric heart transplant recipients (8 to 17 years of age; 27 male). Patients were separated into 2 groups according to CMV status: those without evidence of CMV replication after transplantation (n=38; 19 male) and patients with evidence of viremia after transplantation (n=12; 8 male). No patient had detectable viremia at the time of study. Flow-mediated dilation was significantly impaired in patients with evidence of CMV replication after transplantation (6.64±1.12%, mean±SE) compared with those without (9.48±0.56%; P=0.02). This difference remained after adjustment for age, time since transplantation, and medication. Pretransplantation recipient and donor CMV status and traditional CMV risk were not associated with flow-mediated dilation. Conclusions— CMV replication after cardiac transplantation is associated with chronic endothelial dysfunction in the systemic circulation in children. The implication for both systemic and coronary vascular health requires prospective evaluation.

Lipoprotein-apheresis reduces circulating microparticles in individuals with familial hypercholesterolemia

Lipoprotein-apheresis (apheresis) removes LDL-cholesterol in patients with severe dyslipidemia. However, reduction is transient, indicating that the long-term cardiovascular benefits of apheresis may not solely be due to LDL removal. Microparticles (MPs) are submicron vesicles released from the plasma membrane of cells. MPs, particularly platelet-derived MPs, are increasingly being linked to the pathogenesis of many diseases. We aimed to characterize the effect of apheresis on MP size, concentration, cellular origin, and fatty acid concentration in individuals with familial hypercholesterolemia (FH). Plasma and MP samples were collected from 12 individuals with FH undergoing routine apheresis. Tunable resistive pulse sensing (np200) and nanoparticle tracking analysis measured a fall in MP concentration (33 and 15%, respectively; P < 0.05) pre- to post-apheresis. Flow cytometry showed MPs were predominantly annexin V positive and of platelet (CD41) origin both pre- (88.9%) and post-apheresis (88.4%). Fatty acid composition of MPs differed from that of plasma, though apheresis affected a similar profile of fatty acids in both compartments, as measured by GC-flame ionization detection. MP concentration was also shown to positively correlate with thrombin generation potential. In conclusion, we show apheresis nonselectively removes annexin V-positive platelet-derived MPs in individuals with FH. These MPs are potent inducers of coagulation and are elevated in CVD; this reduction in pathological MPs could relate to the long-term benefits of apheresis.

Where Are We Heading with Noninvasive Clinical Vascular Physiology? Why and How Should We Assess Endothelial Function?

There are several invasive and noninvasive methods available to the clinical researcher for the assessment of endothelial function. The first investigations in humans involved invasive pharmacological vascular function testing, which have been used to gain a detailed understanding of the mechanisms involved in the pathogenesis of endothelial dysfunction and atherosclerosis as well as novel targets for intervention. Techniques for endothelial function testing have evolved over time from these invasive methods, which, by their nature, are restricted to small studies in the research laboratory, to more standardized noninvasive methods, which are suitable for use in large prospective cohort studies and clinical trials. This paper describes currently available methods for assessment of endothelial function and their potential application in cardiovascular research and clinical practice.

Ethnic Differences in Carotid Intima-Media Thickness Between UK Children of Black African-Caribbean and White European Origin

Background and Purpose— UK black African-Caribbean adults have higher risks of stroke than white Europeans and have been shown to have increased carotid intima-media thickness (cIMT). We examined whether corresponding ethnic differences in cIMT were apparent in childhood and, if so, whether these could be explained by ethnic differences in cardiovascular risk markers. Methods— We conducted a 2-stage survey of 939 children (208 white European, 240 black African-Caribbean, 258 South Asian, 63 other Asian, 170 other ethnicity), who had a cardiovascular risk assessment and measurements of cIMT at mean ages of 9.8 and 10.8 years, respectively. Results— Black African-Caribbean children had a higher cIMT than white Europeans (mean difference, 0.014 mm; 95% CI, 0.008–0.021 mm; P<0.0001). cIMT levels in South Asian and other Asian children were however similar to those of white Europeans. Among all children, cIMT was positively associated with age, systolic and diastolic blood pressure and inversely with combined skinfold thickness and serum triglyceride. Mean triglyceride was lower among black African-Caribbeans than white Europeans; blood pressure and skinfold thickness did not differ appreciably. However, adjustment for these risk factors had little effect on the cIMT difference between black African-Caribbeans and white Europeans. Conclusions— UK black African-Caribbean children have higher cIMT levels in childhood; the difference is not explained by conventional cardiovascular risk markers. There may be important opportunities for early cardiovascular prevention, particularly in black African-Caribbean children.

ORIGINAL RESEARCH—PEYRONIE'S DISEASE: Systemic Vascular Endothelial Dysfunction in Peyronie's Disease

INTRODUCTION Many patients with Peyronies disease (PD) have one or more risk factors (RFs) for atherosclerosis and endothelial dysfunction. It is well recognized that such RFs commonly lead to the development of systemic vascular abnormalities. While not necessarily so, this may implicate vascular dysfunction in its pathogenesis. The cause of PD remains obscure despite intense research over the years and investigating the role of vascular dysfunction in the pathogenesis of PD is a novel approach worth undertaking. AIM To test our hypothesis that PD is associated with systemic vascular changes even in the absence of RFs for atherosclerosis and endothelial dysfunction. METHODS Vascular function was assessed using high-resolution brachial artery ultrasound in 23 PD patients (aged 30-65 years) without RFs for endothelial dysfunction and atherosclerosis, and 23 age-matched healthy controls. Endothelium-dependent, flow-mediated brachial artery dilation was measured in response to increased shear stress (reactive hyperemia induced by 5 minutes of forearm ischemia). This response was contrasted with that of 400 microg sublingual glyceryl trinitrate, an endothelium-independent vasodilator. Anthropometric characteristics, blood pressure, fasting lipids, and glucose were also measured. MAIN OUTCOME MEASURE Endothelium-dependent, flow-mediated brachial artery dilation and glyceryl trinitrate-induced endothelium-independent vasodilation. RESULTS Endothelium-dependent flow-mediated dilation (FMD) was impaired in PD patients compared to controls (5.62 +/- 0.58% vs. 7.46 +/- 0.56%, P = 0.03). In contrast, responses to glyceryl trinitrate were similar in PD patients and controls as were blood pressure, lipid, and glucose values. FMD remained impaired after multivariable adjustment for potential confounders. CONCLUSION Patients with Peyronies disease have evidence of systemic vascular changes in the way of systemic conduit artery endothelial impairment even in the absence of RFs for atherosclerosis and endothelial dysfunction. These wider vascular abnormalities in PD are likely to be of clinical relevance and require further study.

Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy

Mutations in prominin 1 (PROM1) have been shown to result in retinitis pigmentosa, macular degeneration and cone-rod dystrophy. Because of the putative role of PROM1 in hippocampal neurogenesis, we examined two kindreds with the same R373C PROM1 missense mutation using our established paradigm to study brain structure and function. As the protein encoded by PROM1, known as CD133, is used to identify stem/progenitor cells that can be found in peripheral blood and reflect endothelial reparatory mechanisms, other parameters were subsequently examined that included measures of vascular function, endothelial function and angiogenic capacity. We found that aspects of endothelial function assayed ex vivo were abnormal in patients with the R373C PROM1 mutation, with impaired adhesion capacity and higher levels of cellular damage. We also noted renal infections, haematuria and recurrent miscarriages possibly reflecting consequences of abnormal tubular modelling. Further studies are needed to confirm these findings.