Coronary Flow Reserve Is Impaired in Young Men With Familial Hypercholesterolemia

Objectives. We sought to investigate whether functional abnormalities in coronary vasomotion exist in young adults by studying 15 men (age 31 ± 8 years [mean ± SD]) with familial hypercholesterolemia (FH) and a matched group of 20 healthy control subjects.

Background. Precursors of morphologic coronary artery disease are known to be present in adolescents and young adults with a high risk factor profile.

Methods. Myocardial blood flow was measured at the basal state and during dipyridamole-induced hyperemia using positron emission tomography and oxygen-15–labeled water.

Results. Serum total and low density lipoprotein cholesterol concentrations were higher in the patients than in the control subjects (mean ± SD): 7.7 ± 1.9 versus 5.3 ± 1.5 mmol/liter (298 ± 73 vs. 205 ± 58 mg/dl) and 6.1 ± 1.8 versus 3.5 ± 1.4 mmol/liter (236 ± 70 vs. 135 ± 54 mg/dl), respectively (both p < 0.001). The baseline myocardial blood flow was similar in the patients and control subjects: 0.92 ± 0.24 versus 0.83 ± 0.13 ml/g per min, respectively (p = 0.21). A significant increase in flow was observed in both groups after dipyridamole infusion, but the flow at maximal vasodilation was 29% lower in the patients: 3.19 ± 1.59 versus 4.49 ± 1.27 ml/g per min (p = 0.011). Consequently, coronary flow reserve (the ratio of hyperemia flow to basal flow) was 35% lower in the patients than in the control subjects: 3.5 ± 1.6 versus 5.4 ± 1.5 (p = 0.0008). Total coronary resistance during hyperemia was higher in the patients than in the control subjects: 36 ± 25 versus 21 ± 10 mm Hg/min per g per ml (p = 0.045). Coronary flow reserve was inversely associated with serum total cholesterol concentration: r = −0.43 (p = 0.009).

Conclusions. Coronary flow reserve is reduced in young men with FH, and, consequently, coronary resistance during hyperemia is increased. The results demonstrate very early impairment of coronary vasomotion in hypercholesterolemic patients.

(J Am Coll Cardiol 1996;28:1705–11)     

Relation of apolipoprotein E polymorphism to markers of early atherosclerotic changes in young adults--the Cardiovascular Risk in Young Finns Study.

BACKGROUND: Carotid artery intima-media thickness (IMT), which is measured by ultrasound, is used in the assessment of early atherosclerotic changes, and has been associated with apolipoprotein E (APOE) polymorphism in many studies comprising elderly subjects. However, results are still inconclusive and data relating to young adults are missing. Whether common APOE polymorphism is related to carotid IMT was studied in a population of young adults. Also brachial flow-mediated dilatation (FMD) and carotid artery compliance (CAC) were determined to clarify their relation to this genetic factor. METHODS AND RESULTS: A total of 1,188 young adults (aged 24-39 years) participating in the Cardiovascular Risk in Young Finns Study with complete data of common APOE polymorphism underwent a carotid and brachial ultrasound. Patients' lipid levels and blood pressure were also examined. There was no significant association between the APOE phenotypes and carotid IMT, brachial FMD or CAC either in young men or in young women. The results were similar for systolic and diastolic blood pressure. In the same population, the well-known association between APOE phenotypes and lipids was seen. CONCLUSIONS: Common APOE polymorphism does not seem to be an independent genetic determinant of carotid IMT, brachial FMD or CAC.     

Comparison of extracapsular pseudotumors seen in magnetic resonance imaging and in revision surgery of 167 failed metal-on-metal hip replacements

Background and purpose

Magnetic resonance imaging (MRI) is important for detecting extracapsular pseudotumors, but there is little information on the accuracy of MRI and appropriate intervals for repeated imaging. We evaluated the sensitivity and specificity of MRI for detecting pseudotumors in 155 patients (167 hips) with metal-on-metal (MoM) hip arthroplasties that failed due to adverse reactions to metal debris (ARMD).

Methods

Preoperative MRIs were performed with two 1.5 T MRI scanners and graded by a senior musculoskeletal radiologist using a previously described MRI pseudotumor grading system. Revision findings were retrieved from surgical notes, and pseudotumors were retrospectively graded as fluid-filled, mixed-type, or solid.

Results

The sensitivity of MRI was 71% and the specificity was 87% for detecting extracapsular pseudotumors. The sensitivity was 88% (95% CI: 70–96) when MRI was performed less than 3 months before the revision surgery. Interestingly, when the time that elapsed between MRI and revision was more than 1 year, the sensitivity calculated was only 29% (95% CI: 14–56). Comparison between MRI and revision classifications gave moderate agreement (Cohen’s kappa = 0.4).

Interpretation

A recent MRI predicts the presence of a pseudotumor well, but there is more discrepancy when the MRI examination is over a year old, most likely due to the formation of new pseudotumors. 1 year could be a justifiable limit for considering a new MRI if development of ARMD is suspected. MRI images over a year old should not be used in decision making or in planning of revision surgery for MoM hips.Metal-on-metal (MoM) hip replacements have been widely used for the treatment of hip osteoarthritis, particularly in young and active patients (Bozic et al. 2009). During the last few years, an increased risk of developing soft tissue reactions linked to increased wear of MoM articulation has been reported (Pandit et al. 2008, Kwon et al. 2010, Langton et al. 2011). An umbrella term “adverse reaction to metal debris” (ARMD) has been used to describe these tissue reactions, which include metallosis, aseptic lymphocytic vasculitis-associated lesions, and the fluid-filled or solid extracapsular lesions often referred to as pseudotumors (Langton et al. 2011). Most patients have high blood metal ions and many experience pain in the groin and thigh region, but ARMD may also be found in patients presenting with no clinical symptoms and normal whole-blood metal ion levels (Hart et al. 2011, Wynn-Jones et al. 2011). Asymptomatic extracapsular pseudotumors have been reported to increase and decrease in size with occasional remission of small masses, and they may involve the abductor and iliopsoas muscles (Almousa et al. 2013). Revision surgeries because of pseudotumors have been reported to have significantly poorer outcome than hip revisions for other reasons (Grammatopolous et al. 2009). Imaging is therefore needed to identify these patients for closer follow-up or revision surgery. Preoperative magnetic resonance imaging (MRI) is also of importance for surgeons to visualize the location and dimensions of the pseudotumor for optimal resection (Liddle et al. 2013).MRI and ultrasonography are the main imaging modalities for assessment of ARMD lesions. Modern MRI techniques allow good visibility in the hip region, even though intracapsular lesions cannot be reliably assessed in some cases due to metal artifacts. To our knowledge, only 1 study has compared pseudotumors seen in MRI with those actually found in revision surgery (Liddle et al. 2013).The main aim of this study was to evaluate the ability of preoperative MRI to detect extracapsular pseudotumors encountered in revision surgery and to assess appropriate intervals for repeated imaging, when development/progression of soft tissue pathologies is suspected. A secondary aim was to ascertain whether pseudotumors fall into the same categories in both MRI and revision surgery classifications.     

Does Bone Resorption Stimulate Periosteal Expansion? A Cross‐Sectional Analysis of β‐C‐telopeptides of Type I Collagen (CTX), Genetic Markers of the RANKL Pathway,and Periosteal Circumference as Measured by pQCT

We hypothesized that bone resorption acts to increase bone strength through stimulation of periosteal expansion. Hence, we examined whether bone resorption, as reflected by serum β‐C‐telopeptides of type I collagen (CTX), is positively associated with periosteal circumference (PC), in contrast to inverse associations with parameters related to bone remodeling such as cortical bone mineral density (BMD_C). CTX and mid‐tibial peripheral quantitative computed tomography (pQCT) scans were available in 1130 adolescents (mean age 15.5 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC). Analyses were adjusted for age, gender, time of sampling, tanner stage, lean mass, fat mass, and height. CTX was positively related to PC (β = 0.19 [0.13, 0.24]) (coefficient = SD change per SD increase in CTX, 95% confidence interval)] but inversely associated with BMD_C (β = –0.46 [–0.52,–0.40]) and cortical thickness [β = –0.11 (–0.18, –0.03)]. CTX was positively related to bone strength as reflected by the strength‐strain index (SSI) (β = 0.09 [0.03, 0.14]). To examine the causal nature of this relationship, we then analyzed whether single‐nucleotide polymorphisms (SNPs) within key osteoclast regulatory genes, known to reduce areal/cortical BMD, conversely increase PC. Fifteen such genetic variants within or proximal to genes encoding receptor activator of NF‐κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) were identified by literature search. Six of the 15 alleles that were inversely related to BMD were positively related to CTX (p < 0.05 cut‐off) (n = 2379). Subsequently, we performed a meta‐analysis of associations between these SNPs and PC in ALSPAC (n = 3382), Gothenburg Osteoporosis and Obesity Determinants (GOOD) (n = 938), and the Young Finns Study (YFS) (n = 1558). Five of the 15 alleles that were inversely related to BMD were positively related to PC (p < 0.05 cut‐off). We conclude that despite having lower BMD, individuals with a genetic predisposition to higher bone resorption have greater bone size, suggesting that higher bone resorption is permissive for greater periosteal expansion. © 2014 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.     

Type 1 diabetes linked PTPN22 gene polymorphism is associated with the frequency of circulating regulatory T cells

Dysfunction of FOXP3-positive regulatory T cells (Tregs) likely plays a major role in the pathogenesis of multiple autoimmune diseases including type 1 diabetes (T1D). Whether genetic polymorphisms associated with the risk of autoimmune diseases affect Treg frequency or function is currently unclear. Here, we analysed the effect of T1D-associated major HLA class II haplotypes and seven single nucleotide polymorphisms in six non-HLA genes [INS (rs689), PTPN22 (rs2476601), IL2RA (rs12722495 and rs2104286), PTPN2 (rs45450798), CTLA4 (rs3087243), and ERBB3 (rs2292239)] on peripheral blood Treg frequencies. These were determined by flow cytometry in 65 subjects who had progressed to T1D, 86 islet autoantibody-positive at-risk subjects, and 215 islet autoantibody-negative healthy controls. The PTPN22 rs2476601 risk allele A was associated with an increase in total (p = 6 × 10⁻⁶) and naïve (p = 4 × 10⁻⁵) CD4+CD25+CD127lowFOXP3+ Treg frequencies. These findings were validated in a separate cohort comprising ten trios of healthy islet autoantibody-negative children carrying each of the three PTPN22 rs2476601 genotypes AA, AG, and GG (p = 0.005 for total and p = 0.03 for naïve Tregs, respectively). In conclusion, our analysis implicates the autoimmune PTPN22 rs2476601 risk allele A in controlling the frequency of Tregs in human peripheral blood.     

Carbohydrate intake, serum lipids and apolipoprotein E phenotype show association in children

Aim:  To study the association between carbohydrate intake and serum lipids in children, and influence of apolipoprotein E phenotype (apoE) on the association.
Subjects/methods:  A total of 644 children from a prospective, randomized atherosclerosis prevention trial (STRIP) participated in this longitudinal study at age 5 (n = 644), 7 (n = 585) and 9 (n = 550) years. ApoE phenotype, fasting triglyceride, total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol concentrations and 4-day food records were analysed.
Results:  An increase in the total carbohydrate intake by 1 E% (percentage of total daily energy intake) associated with a decrease in HDL cholesterol by 0.006 mmol/L (p < 0.001) when adjusted for saturated, monounsaturated and polyunsaturated fatty acid, age, gender, body mass index and STRIP study group. The inverse association between total carbohydrate intake and HDL cholesterol was evident in children with apoE3 (p < 0.001) or apoE4 (p < 0.001), but not in those with apoE2 (p = 0.78). An increase in total carbohydrate intake by 1 E% increased triglycerides by 0.02 mmol/L (p < 0.001) independently of apoE phenotype, while 1 E% increase in sucrose intake increased triglycerides by 0.01 mmol/L (p < 0.001).
Conclusion:  Carbohydrate intake has a relatively small effect on serum lipids in children. Children with the apoE3 or E4 but not with E2 phenotype show reduction in HDL cholesterol with increasing carbohydrate intake indicating that genetic and environmental factors interact with children's lipoprotein metabolism.     

Influence of Body Mass Index and Smoking on the Long-Term Survival of Patients With Renal Cell Cancer

BackgroundSmoking and obesity are known risk factors for renal cell carcinoma (RCC). We determined the influence of smoking, body mass index (BMI), and symptoms on the survival of patients with RCC.Patients and MethodsIn this retrospective study, the relative overall survival (OS) up to 25 years was calculated among 948 Finnish patients with RCC diagnosed between 1964 and 1997 using a Bayesian univariate analysis and the life-table method.ResultsObese patients had better OS than did normal or underweight patients (median, 5.9 years, 3.4 years, and 12 months, respectively), with lower stage and more asymptomatic tumors at diagnosis and fewer relapses during surveillance. Clinical presentation of the tumor was a stronger prognostic factor than BMI; however, asymptomatic patients with a low BMI had poorer survival compared with normal or overweight patients. There was no difference in tumor stage or presentation at diagnosis between the nonsmokers and smokers; however, the smokers had more relapses with shorter disease-free intervals (DFIs) than did the nonsmokers. The OS was poorer in the smokers (4.2 years compared with 6.6 years in nonsmokers), but no difference was observed in cancer-specific survival (CSS).ConclusionOverweight patients have better survival, with more asymptomatic or local tumors. The clinical presentation was a stronger prognostic factor than BMI. Additionally, survival is poorer in smokers, even if there is no difference in tumor stage or symptoms.