Arterial compliance and endothelium-dependent vasodilation are independently related to coronary risk in the elderly: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study

Background: Measurements of both arterial compliance and endothelium‐dependent vasodilation have previously been related to coronary risk factors, but not in the same study. In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, we studied the interplay between arterial compliance and endothelium‐dependent vasodilation on coronary risk. Methods: In the population‐based PIVUS study (1016 subjects aged 70 years), arterial compliance was determined by ultrasound in the carotid artery, by pulse wave analysis (augmentation index) and the stroke volume to pulse pressure ratio by echocardiography, while endothelium‐dependent vasodilation (EDV) was assessed by the invasive forearm technique with acetylcholine , brachial artery ultrasound [flow‐mediated dilatation (FMD)] and pulse wave analysis with terbutaline provocation [change in reflection index (RI)]. Results: Factor analysis disclosed three major factors. The first factor was reflecting the three arterial compliance methods, the second factor was reflecting EDV and the change in RI, while the third factor mainly was reflecting FMD. All these three factors were independently related to the Framingham risk score in multiple regression analysis (P<0·0001, P = 0·0002 and P = 0·0046, respectively). Conclusions: In conclusion, both arterial compliance and endothelium‐dependent vasodilation were independently related to the Framingham risk score, suggesting that it is worthwhile to evaluate the parallel use of these two vascular characteristics in a prospective fashion.     

Atherosclerosis measured by whole body magnetic resonance angiography and carotid artery ultrasound is related to arterial compliance,but not to endothelium‐dependent vasodilation – the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study

Background: Arterial compliance and endothelium‐dependent vasodilation are two characteristics of the vessel wall. In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, we studied the relationships between arterial compliance and endothelium‐dependent vasodilation versus atherosclerosis as measured with two imaging modalities. Methods: In the population‐based PIVUS study (1016 subjects aged 70), arterial compliance was determined by ultrasound in the carotid artery and the stroke volume to pulse pressure ratio by echocardiography, while endothelium‐dependent vasodilation was assessed by the invasive forearm technique with acetylcholine and brachial artery ultrasound. Intima‐media thickness was evaluated by ultrasound in the carotid artery (n = 954). Stenosis in the carotid, aorta, renal, upper and lower leg arteries were determined by magnetic resonance angiography in a random subsample of 306 subjects. Results: After adjustments for gender, Framingham risk score, obesity, myocardial infarction and stroke, distensibility in the carotid artery and the stroke volume to pulse pressure ratio were both significantly related to a weighted index of stenosis in the five arterial territories evaluated by magnetic resonance angiography (p<0·02 for both). Distensibility in the carotid artery (P = 0·021), but not the stroke volume to pulse pressure ratio (P = 0·08), was also significantly related to intima‐media thickness. Conclusion: In the elderly population, atherosclerosis is mainly related to arterial compliance, but not to endothelium‐dependent vasodilation in peripheral conduit or resistance vessels.     

Brachial artery hyperaemic blood flow velocity in relation to established indices of vascular function and global atherosclerosis: the Prospective Investigation of the Vasculature in Uppsala Seniors study

Background: Systolic to diastolic blood flow velocity (SDFV) ratio in the brachial artery recently proved to be related to cardiovascular risk and carotid atherosclerosis. We hypothesized that the SDFV ratio was related to established markers of vascular function and global atherosclerosis. Methods: Established markers of endothelial function in forearm resistance vessels, flow‐mediated vasodilation and arterial stiffness were assessed in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study including 1016 individuals aged 70. Whole‐body magnetic resonance angiography was performed in a random 306 of the participants. Atherosclerotic lesions were summarized in a total atherosclerotic score (TAS). Before and during hyperaemia of the brachial artery, systolic and diastolic blood flow velocities were measured by Doppler. Results: The SDFV ratio was positively related to endothelium‐independent vasodilatation, while inverse relations were found to flow‐mediated dilation, common carotid artery distensibility and the stroke volume to pulse pressure ratio. Endothelium‐dependent vasodilatation and total peripheral resistance index were not significantly related to the SDFV ratio. The SDFV ratio (P = 0·015) and the blood flow increase (BFI) during hyperaemia (P = 0·020) were both significantly related to TAS after gender adjustment. When adjusted for the Framingham risk score, both the SDFV ratio (P = 0·057) and BFI (P = 0·078) lost somewhat in significance. Conclusion: The SDFV ratio was related to established markers of both vasodilation and arterial compliance, and to global atherosclerosis. Future larger studies have to evaluate whether the SDFV ratio is related to global atherosclerosis independently of traditional risk factors.     

Endothelial vasodilatory function is related to the proportions of saturated fatty acids and alpha-linolenic acid in young men,but not in women

BACKGROUND: Fatty acid composition of serum lipids is associated with cardiovascular disease. As attenuated endothelium-dependent vasodilation (EDV) is an early event in atherosclerosis, we investigated the relationships between endothelial vasodilatory function and the proportion of serum fatty acids, reflecting dietary fat quality, in 74 healthy men and women, aged 20-30 years. DESIGN: Endothelium-dependent vasodilation and endothelium-independent vasodilation (EIDV) was studied in the forearm during local administration of methacholine (2 and 4 micro g min-1) and nitroprusside (5 and 10 micro g min-1). Forearm blood flow was determined with venous occlusion plethysmography. An endothelial function index was calculated as the EDV/EIDV ratio. RESULTS: The endothelial function index was inversely related to the total proportion of saturated fatty acids (r = -0.41, P < 0.05), in particular lauric and myristic acid (r = -0.37 and r = -0.36, respectively, P < 0.05 for both), and was positively related to the proportion of alpha-linolenic acid (r = 0.45, P < 0.01) in men only. Total serum nonesterified fatty acid (NEFA) concentration was not significantly related to endothelial vasodilatory function. By multiple stepwise regression analysis, including age, blood pressure, body mass index, and serum cholesterol, triglyceride and NEFA as confounders, myristic acid and alpha-linolenic acid were independent predictors of the endothelial function index in men only (r = -0.39 and r = 0.47, respectively, P < 0.01 for both). CONCLUSIONS: We conclude that serum fatty acid composition predicts endothelial vasodilatory dysfunction independently of serum NEFA and cholesterol levels in young, healthy men in their third decade of life, whereas fatty acid composition seems to be less important in women at this age. As a result of the large number of analyses performed, these findings need to be verified by other studies.     

Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein(a) level.

Familial hypercholesterolemia is associated with premature atherosclerosis. Since endothelial dysfunction is an early event in atherogenesis, we used a noninvasive method to assess endothelial function in the systemic arteries of 30 children aged 7-17 yr (median 11) with familial hypercholesterolemia (2 homozygotes, 28 heterozygotes, total cholesterol 240-696 mg/dl) and 30 healthy age- and sex-matched controls. Using high resolution ultrasound, the diameter of the superficial femoral artery was measured at rest, in response to reactive hyperemia (with increased flow causing endothelium-dependent dilation), and after sublingual glyceryltrinitrate (causing endothelium-independent vasodilation). Flow-mediated dilation was present in the controls (7.5 +/- 0.7%) but was impaired or absent in the hypercholesterolemic children (1.2 +/- 0.4%, P < 0.0001). Total cholesterol was inversely correlated with flow-mediated dilation (r = -0.61, P < 0.0001). In the hypercholesterolemic children, flow-mediated dilation was inversely related to the lipoprotein(a) level (r = -0.61, P = 0.027) but not to other lipid fractions. Glyceryltrinitrate-induced dilation was present in all subjects but was lower in the hypercholesterolemia group (10.0 +/- 0.6% vs 12.4 +/- 0.8%, P = 0.023). Thus, impaired endothelium-dependent dilation is present in children with familial hypercholesterolemia as young as 7 yr of age and the degree of impairment is related to the lipoprotein(a) level.     

The inverse association of plasma lipoprotein(a) concentrations with apolipoprotein(a) isoform size is not due to differences in Lp(a) catabolism but to differences in production rate.

Lipoprotein(a) (Lp[a]) is an atherogenic lipoprotein which is similar in structure to low density lipoproteins (LDL) but contains an additional protein called apolipoprotein(a) (apo[a]). Apo(a) is highly polymorphic in size, and there is a strong inverse association between the size of the apo(a) isoform and the plasma concentration of Lp(a). We directly compared the in vivo catabolism of Lp(a) particles containing different size apo(a) isoforms to establish whether there is an effect of apo(a) isoform size on the catabolic rate of Lp(a). In the first series of studies, four normal subjects were injected with radio-labeled S1-Lp(a) and S2-Lp(a) and another four subjects were injected with radiolabeled S2-Lp(a) and S4-Lp(a). No significant differences in fractional catabolic rate were found between Lp(a) particles containing different apo(a) isoforms. To confirm that apo(a) isoform size does not influence the rate of Lp(a) catabolism, three subjects heterozygous for apo(a) were selected for preparative isolation of both Lp(a) particles. The first was a B/S3-apo(a) subject, the second a S4/S6-apo(a) subject, and the third an F/S3-apo(a) subject. From each subject, both Lp(a) particles were preparatively isolated, radiolabeled, and injected into donor subjects and normal volunteers. In all cases, the catabolic rates of the two forms of Lp(a) were not significantly different. In contrast, the allele-specific apo(a) production rates were more than twice as great for the smaller apo(a) isoforms than for the larger apo(a) isoforms. In a total of 17 studies directly comparing Lp(a) particles of different apo(a) isoform size, the mean fractional catabolic rate of the Lp(a) with smaller size apo(a) was 0.329 +/- 0.090 day-1 and of the Lp(a) with the larger size apo(a) 0.306 +/- 0.079 day-1, not significantly different. In summary, the inverse association of plasma Lp(a) concentrations with apo(a) isoform size is not due to differences in the catabolic rates of Lp(a) but rather to differences in Lp(a) production rates.     

To test,or not to test: that is the question for the future of lipoprotein(a)

Introduction: Lipoprotein(a) [Lp(a)] is a potent, highly heritable and common risk factor for atherosclerotic cardiovascular disease (ASCVD). Evidence for a causal association between elevated Lp(a) and ASCVD has been provided by large epidemiological investigations that have demonstrated a curvilinear association with increased risk, as well as from genetic examinations and cellular and transgenic animal studies. Although there are several therapies available for lowering Lp(a), none are selective for Lp(a) and there is no clinical trial data that has specifically shown that lowering Lp(a) reduces the risk of ASCVD. Hence, screening for elevated Lp(a) is not routinely incorporated into clinical practice.

Areas covered: This paper reviews the current evidence supporting the causal role of Lp(a) in the primary and secondary prevention of ASCVD, screening approaches for high Lp(a), current guidelines on testing Lp(a), and barriers to the routine screening of elevated Lp(a) in clinical practice.

Expert opinion: At present, there is a moderate level of evidence supporting the routine screening of elevated Lp(a). Current guidelines recommend testing for elevated Lp(a) in individuals at intermediate or high risk of ASCVD.     

The excision of polydnavirus sequences from the genome of the wasp Cotesia congregata (Braconidae, Microgastrinae) is developmentally regulated but not strictly restricted to the ovaries in the adult

Cotesia congregata polydnavirus (CcPDV) is essential for the successful parasitism of Manduca sexta larvae by the braconid wasp Cotesia congregata. In the absence of PDV, parasitoid eggs are encapsulated. Molecular analysis has demonstrated that polydnavirus sequences are integrated in the wasp chromosomes, and an ultrastructural analysis has shown that PDV replication occurs in the calyx region in the ovaries of the wasp. The bracovirus sequences appear to be excised from the wasp genome in the calyx cells where the virus replicates. Following excision of the virus sequences, the flanking sequences are rejoined. We analysed the production of two polydnavirus circles during wasp development and in different body parts of the adults of both sexes. Our study indicates that the excision of viral sequences is developmentally regulated, beginning in the pupal stage. In the adult wasp, excision occurs ubiquitously. However, regulation in the adult seems to occur only in diploid individuals, as no excision is detected in haploid males produced from virgin females.     

The susceptibility of lipoprotein(a) to copper oxidation is correlated with the susceptibility of autologous low density lipoprotein to oxidation

OBJECTIVES: Lipoprotein(a) [Lp(a)] can be oxidized by copper in vitro in a way comparable to low-density lipoprotein (LDL). We sought to determine whether the susceptibility of Lp(a) to oxidation is correlated with the susceptibility of autologous heterogeneous LDL, with apolipoprotein(a) [apo(a)] molecular size, or with both factors. DESIGN AND METHODS: We examined shifts in electrophoretic mobility of Lp(a) and LDL caused by copper oxidation in plasma samples from 81 healthy men. The effect of copper oxidation on different-sized apo(a) was also evaluated. RESULTS: There was a close correlation between the relative electrophoretic mobilities of oxidized Lp(a) and oxidized LDL in subjects, especially with small-sized apo(a) (n = 25, r = 0.72, p < 0.0001). Oxidative processes in Lp(a) resulted in the degradation of large-, but not small-sized apo(a). CONCLUSIONS: The susceptibility of Lp(a) to oxidation is correlated with that of autologous LDL. Large-sized apo(a) may be involved in the Lp(a) oxidation.     

不典型急性主动脉夹层的预检识别

急性主动脉夹层有相对低的发病率但却有时间依赖性的高病死率,因此早期预检识别和治疗对提高存活率极为重要。掌握其常见临床表现和不典型表现,特别是注意发作的突然性、症状的波动性和疼痛的扩展性是临床识别的关键。这对急诊的分诊及救护工作提出更高的要求。     

An expanded peripheral T cell population to a cytotoxic T lymphocyte (CTL)-defined, melanocyte-specific antigen in metastatic melanoma patients impacts on generation of peptide-specific CTLs but does not overcome tumor escape from immune surveillance in metastatic lesions.

It is not known if immune response to T cell-defined human histocompatibility leukocyte antigen (HLA) class I-restricted melanoma antigens leads to an expanded peripheral pool of T cells in all patients, affects cytotoxic T lymphocyte (CTL) generation, and correlates with anti-tumor response in metastatic lesions. To this end, a limiting dilution analysis technique was developed that allowed us to evaluate the same frequency of peptide-specific T cells as by staining T cells with HLA-peptide tetrameric complexes. In four out of nine patients, Melan-A/Mart-1(27-35)-specific CTL precursors (CTLp) were >/=1/2,000 peripheral blood lymphocytes and found mostly or only in the CD45RO(+) memory T cell subset. In the remaining five patients, a low (<1/40,000) peptide-specific CTLp frequency was measured, and the precursors were only in the CD45RA(+) naive T cell subset. Evaluation of CTL effector frequency after bulk culture indicated that peptide-specific CTLs could be activated in all patients by using professional antigen-presenting cells as dendritic cells, but CTLp frequency determined the kinetics of generation of specificity and the final number of effectors as evaluated by both limiting dilution analysis and staining with HLA-A*0201-Melan-A/Mart-1 tetrameric complexes. Immunohistochemical analysis of 26 neoplastic lesions from the nine patients indicated absence of tumor regression in most instances, even in patients with an expanded peripheral T cell pool to Melan-A/Mart-1 and whose neoplastic lesions contained a high frequency of tetramer-positive Melan-A/Mart-1-specific T cells. Furthermore, frequent lack of a "brisk" or "nonbrisk" CD3(+)CD8(+) T cell infiltrate or reduced/absent Melan-A/Mart-1 expression in several lesions and lack of HLA class I antigens were found in some instances. Thus, expansion of peripheral immune repertoire to Melan-A/Mart-1 takes place in some metastatic patients and leads to enhanced CTL induction after antigen-presenting cell-mediated selection, but, in most metastatic lesions, it does not overcome tumor escape from immune surveillance.     

The "volumetric" pulsatility index as evaluated by spatiotemporal imaging correlation (STIC): a preliminary description of a novel technique, its application to the endometrium and an evaluation of its reproducibility

We propose new volumetric indices derived from three-dimensional (3-D) power Doppler (PD) using spatiotemporal imaging correlation (STIC) to overcome the influence of machine settings and attenuation. In this study, we describe these indices and evaluate their interobserver reliability: two static-3-D and two STIC PD datasets were acquired from 60 women and two observers (blinded analysis) evaluated vascularization index (VI), the flow index (FI) and the vascularization flow index (VFI) of standardized spherical samples of endometrium. Three new indices were determined based on maximum, minimum and mean values (vPI, vRI_max-min, vS/D_max-min) and two indices from frames subjectively defined as systole and diastole (vRI_sys-dia, vS/D_sys-dia). Highest intraclass coefficient correlations (ICCs) were obtained from vPI derived from VI or VFI (0.77-0.76), followed by vRI_max-min (0.72-0.72) and vS/D_max-min (0.52-0.49). ICCs from indices based on subjectively systole and diastole or FI were consistently lower (<0.40). We conclude that the subjective choice of systolic and diastolic frames only lacks reliability but indices based on complete evaluation may reliably be used.