Gout. Hyperuricemia and cardiovascular disease: how strong is the evidence for a causal link?

An association between high levels of serum urate and cardiovascular disease has been proposed for many decades. However, it was only recently that compelling basic science data, small clinical trials, and epidemiological studies have provided support to the idea of a true causal effect. In this review we present recently published data that study the association between hyperuricemia and selected cardiovascular diseases, with a final conclusion about the possibility of this association being causal.     

An Examination of the Relationship Between Resting Heart Rate Variability and Heart Rate Reactivity to a Mental Arithmetic Stressor

Resting heart rate variability can be an index of sympathetic or parasympathetic dominance, according to the frequency of the variability studied. Sympathetic dominance of this system has been linked to increased risk of cardiovascular disease (CVD). Similarly, rapid and dramatic increases in heart rate reactivity to a stressor task have also been suggested as indicating increased risk of CVD via atherogenesis. Although both of these variables have been related to the development of cardiovascular disease, and both may be related to increased sympathetic activity or parasympathetic withdrawal, most research studies have tended to focus on either variable independently of the other. In order to investigate whether these two indices of stressor reactivity were related in relatively young and healthy subjects, resting heart rate variability data were collected from 80 volunteers for 20 minutes. In addition, heart rate reactivity data were collected during a 2-minute mental arithmetic stressor, which has been previously shown to induce significant increases in heart rate. After classifying subjects according to whether their heart rate variability data were above or below the mean for their gender, heart rate reactivity data were examined via MANOVA to detect significant differences between subject groups. Females showed significant effects, and males showed nonsignificant trends, but these two sets of data were in different directions, suggesting that gender may be a confounding factor in the relationship between heart rate reactivity and heart rate variability.     

Total sleep deprivation alters cardiovascular reactivity to acute stressors in humans

Exaggerated cardiovascular reactivity to mental stress (MS) and cold pressor test (CPT) has been linked to increased risk of cardiovascular disease. Recent epidemiological studies identify sleep deprivation as an important risk factor for hypertension, yet the relations between sleep deprivation and cardiovascular reactivity remain equivocal. We hypothesized that 24-h total sleep deprivation (TSD) would augment cardiovascular reactivity to MS and CPT and blunt the MS-induced forearm vasodilation. Because the associations between TSD and hypertension appear to be stronger in women, a secondary aim was to probe for sex differences. Mean arterial pressure (MAP), heart rate (HR), and muscle sympathetic nerve activity (MSNA) were recorded during MS and CPT in 28 young, healthy subjects (14 men and 14 women) after normal sleep (NS) and 24-h TSD (randomized, crossover design). Forearm vascular conductance (FVC) was recorded during MS. MAP, FVC, and MSNA (n = 10) responses to MS were not different between NS and TSD (condition × time, P > 0.05). Likewise, MAP and MSNA (n = 6) responses to CPT were not different between NS and TSD (condition × time, P > 0.05). In contrast, increases in HR during both MS and CPT were augmented after TSD (condition × time, P ≤ 0.05), and these augmented HR responses persisted during both recoveries. When analyzed for sex differences, cardiovascular reactivity to MS and CPT was not different between sexes (condition × time × sex, P > 0.05). We conclude that TSD does not significantly alter MAP, MSNA, or forearm vascular responses to MS and CPT. The augmented tachycardia responses during and after both acute stressors provide new insight regarding the emerging links among sleep deprivation, stress, and cardiovascular risk.     

Positive Fluorescent Treponemal Antibody Reactions in Diabetes

In a survey of 129 diabetic patients and 142 normal individuals, a significantly higher percentage of positive reactions in the fluorescent treponemal antibody-200 (FTA-200) test was found among diabetic patients than in the normal population. Absorption of all FTA-200-reactive sera with an extract of Reiter's treponeme eliminated most of the positive reactions in sera from diabetic patients, and three of the five positive reactions detected in sera from apparently normal subjects. On immunoelectrophoresis, precipitin bands developed most frequently between the Reiter sorbent and sera from diabetic patients positive in the FTA-200 test. Serum components responsible for FTA reactivity and precipitin reactions against the sorbent were resistant to treatment with mercaptoethanol, suggesting antibody of the IgG class. Cross-reacting antibodies produced in response to normal treponemal flora, and perhaps acquiring enhanced reactivity by means of nonspecific interacting substances in sera peculiar to the altered physiological state of diabetes, are suggested as possible causes of positive reactions of unabsorbed sera. No correlation could be made between age of the diabetic patient, treatment or duration of the disease, and FTA or precipitin reactivity of the patient's serum.     

Systemic expression of cutaneous basophil hypersensitivity.

Guinea pigs primed for cutaneous basophil hypersensitivity (CBH) with several soluble proteins or with sheep erythrocytes developed a systemic, delayed-onset, maculopapular rash when challenged parenterally with specific antigen. The rash was most readily induced 5 to 7 days after immunization, at a time when local CBH skin test reactivity was also optimal. Miscroscopically, the rash resembled local CBH skin test reactions, being comprised of a papillary dermal infiltrate of basophils and lymphocytes and a striking dilatation and compaction of superficial venules. In addition to the systemic rash, animals expressing systemic CBH (SCBH) exhibited a striking eosinophilia at 24 hr which gave way to basophilia at 48 hr. Focal collections of eosinophils, and of smaller numbers of basophils, were found in the lungs and spleen; both eosinophils and basophils infiltrated the medulla of the thymus. Thus, basophil-rich infiltrations are favored in the skin even after systemic challenge with antigen and occur only to a much smaller extent in other organs where eosinophils may predominate. These differences in the response of various organs to challenge with parenteral antigen suggest that as yet unidentified local factors play a determinative role in regulating the inflammatory response. The pathogenesis of SCBH is not yet established, but it shares many of the properties of local CBH: histology, carrier specificity, development early after sensitization in the absence of detectable antibodies. Passive transfer has not been accomplished with serum alone but has been achieved irregularly with cells plus serum. SCBH may serve as a useful model for several disease states in man characterized by a systemic rash and eosinophilia, including certain types of drug reaction.     

Invasive and noninvasive techniques for analysis of cardiovascular effects of sleep apnea]

There is increasing epidemiological and experimental evidence that Sleep Disordered Breathing (SDB) is associated with cardiovascular disease such as hypertension, ischaemic heart disease, heart failure and stroke. Due to the high prevalence of SDB in the general population (5% to 10%) there is increasing demand for cost-effective and reliable diagnostic tools for the assessment of cardiovascular function during sleep in patients with SDB. The first part of this review focuses on our present knowledge about the association between SDB and cardiovascular disease. In the second part various methods for the assessment of cardiac function, blood pressure, sympathetic activity, as well as vascular and cerebrovascular function in patients with SDB are discussed. Current developments such as ECG analysis for SDB screening or arterial tonometry are introduced. Further improvements in the diagnostic tools for the investigation of cardiovascular function in patients with SDB may to advantage be coupled with epidemiological studies. This approach may demonstrate the predictive value or superiority of a specific diagnostic parameter in the diagnosis of SDB and its cardiovascular consequences.     

The Association between Neuroticism and Heart Rate Variability Is Not Fully Explained by Cardiovascular Disease and Depression

Neuroticism is associated with cardiovascular disease, autonomic reactivity, and depression. Here we address the extent to which neuroticism accounts for the excess heart disease risk associated with depression and test whether cardiac autonomic tone plays a role as mediator. Subjects were derived from a nationally representative sample (n = 1,255: mean age 54.5, SD = 11.5). Higher neuroticism was associated with reduced heart rate variability equally under rest and stress. The baseline structural equation model revealed significant paths from neuroticism to heart rate variability, cardiovascular disease and depression, and between depression and cardiovascular disease, controlling for age, sex, height, weight, and BMI. Dropping both the neuroticism to heart rate variability, and neuroticism to heart disease paths significantly reduced the model fit (p < .001 in each case). We conclude that neuroticism has independent associations with both autonomic reactivity and cardiovascular disease, over and above its associations with depression and other related variables.     

Deciphering Serology to Understand the Ecology of Infectious Diseases in Wildlife

The ecology of infectious disease in wildlife has become a pivotal theme in animal and public health. Studies of infectious disease ecology rely on robust surveillance of pathogens in reservoir hosts, often based on serology, which is the detection of specific antibodies in the blood and is used to infer infection history. However, serological data can be inaccurate for inference to infection history for a variety of reasons. Two major aspects in any serological test can substantially impact results and interpretation of antibody prevalence data: cross-reactivity and cut-off thresholds used to discriminate positive and negative reactions. Given the ubiquitous use of serology as a tool for surveillance and epidemiological modeling of wildlife diseases, it is imperative to consider the strengths and limitations of serological test methodologies and interpretation of results, particularly when using data that may affect management and policy for the prevention and control of infectious diseases in wildlife. Greater consideration of population age structure and cohort representation, serological test suitability and standardized sample collection protocols can ensure that reliable data are obtained for downstream modeling applications to characterize, and evaluate interventions for, wildlife disease systems.     

Active specific immunotherapy with Newcastle-diseasevirus-modified autologous tumor cells following resection of liver metastases in colorectal cancer

Summary A group of 23 colorectal cancer patients were treated by a new type of active specific immunotherapy (ASI) following complete surgical resection of liver metastases (R0 resection). For ASI treatment we used a vaccine consisting of 1 × 10⁷ autologous, irradiated (200 Gy) metastases-derived tumor cells incubated with 32 hemagglutination units (HU) of Newcastle disease virus (NDV). The adjuvant vaccine therapy was started 2 weeks after surgery and was repeated five times at 14-days intervals followed by one boost 3 months later. The delayed-type hypersensitivity (DTH) skin reactions to the vaccine were measured as well as the DTH reactions to a challenge test of 1 × 10⁷ non-virus-modified autologous tumor cells from liver metastases or 1 × 10⁷ autologous normal liver cells. In addition 32 HU NDV alone and a standard antigen test (Merieux test) were applied pre- and post-vaccination. The vaccination was well tolerated. In 13 of 23 patients an increasing reactivity against the vaccine was observed during the vaccination procedure. Nine patients (40%) experienced an increased DTH reactivity against autologous tumor cells following vaccination, while 17% or fewer showed an increased reactivity to Merieux test antigens, NDV, or normal liver cells. The increased antitumor response was not correlated to responsiveness to NDV alone, autologous liver cells, enzymes and culture medium used for vaccine preparation or standard antigens (Merieux test). After a follow-up of at least 18 months 61% of the vaccinated patients developed tumor recurrence in comparison to 87% of a matched control groups from the same institution that had been only surgically treated. The results of this phase II trial are encouraging and should stimulate further prospective randomized studies.     

Influence of hypercapnic vasodilation on cerebrovascular autoregulation and pial arteriolar bed resistance in piglets.

Changes in both pial arteriolar resistance (PAR) and simulated arterial-arteriolar bed resistance (SimR) of a physiologically based biomechanical model of cerebrovascular pressure transmission, the dynamic relationship between arterial blood pressure and intracranial pressure, are used to test the hypothesis that hypercapnia disrupts autoregulatory reactivity. To evaluate pressure reactivity, vasopressin-induced acute hypertension was administered to normocapnic and hypercapnic (N = 12) piglets equipped with closed cranial windows. Pial arteriolar diameters were used to compute arteriolar resistance. Percent change of PAR (%DeltaPAR) and percent change of SimR (%DeltaSimR) in response to vasopressin-induced acute hypertension were computed and compared. Hypercapnia decreased cerebrovascular resistance. Indicative of active autoregulatory reactivity, vasopressin-induced hypertensive challenge resulted in an increase of both %DeltaPAR and %DeltaSimR for all normocapnic piglets. The hypercapnic piglets formed two statistically distinct populations. One-half of the hypercapnic piglets demonstrated a measured decrease of both %DeltaPAR and %DeltaSimR to pressure challenge, indicative of being pressure passive, whereas the other one-half demonstrated an increase in these percentages, indicative of active autoregulation. No other differences in measured variables were detectable between regulating and pressure-passive piglets. Changes in resistance calculated from using the model mirrored those calculated from arteriolar diameter measurements. In conclusion, vasodilation induced by hypercapnia has the potential to disrupt autoregulatory reactivity. Our physiologically based biomechanical model of cerebrovascular pressure transmission accurately estimates the changes in arteriolar resistance during conditions of active and passive cerebrovascular reactivity.     

Variability of serum levels of tumor necrosis factor-alpha, interleukin 6, and soluble interleukin 6 receptor over 2 years in young women

Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), and soluble interleukin 6 receptor (sIL-6R) have been studied as risk factors of cardiovascular disease in longitudinal studies. However, it is unknown about their long-term intra-individual variations and whether single measurements of these cytokines and receptor are reliable biomarkers in epidemiological studies. In this study, serum levels of TNF-alpha, IL-6, and sIL-6R were assayed by ELISAs in 36 young, healthy women from whom three blood samples were collected at 12-month intervals over 2 years, and the intraclass correlation coefficients (ICC) were estimated. The ICC of 0.73 (95% CI=0.49-0.79) for TNF-alpha was comparable to those of other commonly used biomarkers, justifying its use in epidemiological studies. The ICC of 0.48 (95% CI=0.25-0.58) for IL-6 was not optimal. However, IL-6 has been demonstrated as a consistent risk factor for cardiovascular disease, suggesting it could still be a useful biomarker if its disease association is substantial. The ICC of 0.36 (95% CI=0.10-0.47) for sIL-6R was relatively low, and multiple samples would need to be collected in prospective studies for this receptor.     

我国心血管专科临床科研数据中心的建设与思考

中国是心血管疾病的数据大国,但是从数据质量和临床科研上讲,并非强国。为了提高心血管数据在临床质量评估和科研中的应用,我院心内科开始了心血管专科临床科研数据中心的尝试和建设。通过借鉴美国相关经验,以及对我国心血管临床质量评估以及科研需求的深入调研,我们建设了以心血管专科临床数据仓库以及心血管注册数据中心为核心的心血管专科临床科研数据中心。在此基础上,进一步探索并建设了自定义科研表单,多维度组合筛选,基于随访策略的心血管随访管理,基于个性化诊疗计划的心血管病人院后管理,相关性分析及不良心血管事件模式发现等应用和工具,有助于提升心血管专科的临床流程效率,临床质量评估和科研水平,同时为建立全国性的心血管疾病注册数据库打下了基础。     

Virtual Reality Cue Reactivity Assessment: A Case Study in a Teen Smoker

Cigarette smoking in adolescents is a major public health problem. To address the increasing need for efficacious assessment and treatment methods, we developed and tested a novel virtual reality cue reactivity assessment system. A case study of a controlled virtual reality cue reactivity trial with a 17-year-old adolescent cigarette smoker is presented. During the trial, the participant was exposed to virtual reality (VR) smoking cues and VR neutral cues and assessments of subjective craving and skin conductance response (SCR) were recorded. Upon exposure to VR smoking cues, craving increased. A novel methodology for collecting and analyzing SCR in VR was developed and explored to expand the role of physiological variables in VR research. SCR data indicated specific reactions to smoking cue stimuli, with the subject experiencing increased reactivity to smoking cues (i.e., cigarettes) compared to food or drinks. Based on this case study, further research using VR cue reactivity assessment in adolescent smokers is warranted. The impact of VR in drug research and future applications in research are also discussed.     

Improving the power of genetic association tests with imperfect phenotype derived from electronic medical records

To reduce costs and improve clinical relevance of genetic studies, there has been increasing interest in performing such studies in hospital-based cohorts by linking phenotypes extracted from electronic medical records (EMRs) to genotypes assessed in routinely collected medical samples. A fundamental difficulty in implementing such studies is extracting accurate information about disease outcomes and important clinical covariates from large numbers of EMRs. Recently, numerous algorithms have been developed to infer phenotypes by combining information from multiple structured and unstructured variables extracted from EMRs. Although these algorithms are quite accurate, they typically do not provide perfect classification due to the difficulty in inferring meaning from the text. Some algorithms can produce for each patient a probability that the patient is a disease case. This probability can be thresholded to define case–control status, and this estimated case–control status has been used to replicate known genetic associations in EMR-based studies. However, using the estimated disease status in place of true disease status results in outcome misclassification, which can diminish test power and bias odds ratio estimates. We propose to instead directly model the algorithm-derived probability of being a case. We demonstrate how our approach improves test power and effect estimation in simulation studies, and we describe its performance in a study of rheumatoid arthritis. Our work provides an easily implemented solution to a major practical challenge that arises in the use of EMR data, which can facilitate the use of EMR infrastructure for more powerful, cost-effective, and diverse genetic studies.     

Polyphenols and prevention of cardiovascular diseases

PURPOSE OF REVIEW: Polyphenols are the most abundant dietary antioxidants and research on their role in the prevention of degenerative diseases has developed quickly over these last few years. This paper reviews the recent studies on the prevention of cardiovascular diseases by polyphenols, focusing on human studies. RECENT FINDINGS: A large number of recent intervention studies have shown that several biomarkers of cardiovascular risk are influenced by the consumption of polyphenol-rich foods. Effects on biomarkers of oxidative stress, lipemia and inflammation appear so far inconclusive. More consistent effects have been observed on endothelial function and haemostasis and support a reduction of risk by polyphenols in agreement with the few epidemiological studies already published. All clinical studies have used foods or beverages containing a mixture of different polyphenols and the exact nature of the most active compounds remains largely unknown. Absorption, metabolism and elimination vary widely between polyphenols. These data on bioavailability should be taken into account to improve the experimental design and the interpretation of the observed effects. SUMMARY: Future intervention studies should include a detailed assessment of the bioavailability of polyphenols. Beyond clinical trials carried out with polyphenol-rich foods, more studies with pure polyphenols will also be needed to establish their role in the prevention of cardiovascular diseases.     

PETscan: measuring incidence of disease phenotypes to prioritize genetic studies in companion animals

Reliable incidence measurement of diseases is necessary for identification of hereditary diseases in companion animal populations. The data collection system ‘PETscan’ was developed to facilitate standardized registration of diagnoses in veterinary practice. In the development, we attempted to counter challenges known from other primary practice data systems. PETscan includes a comprehensive list of potential diagnoses and supports the veterinary professionals in the diagnostic process. Demographics, individual data and standardized diagnostic data are collected through practice management software in a central database for epidemiological analysis. A preliminary data analysis from PETscan showed specific health issues in four canine breeds. As a real‐time prospective monitoring tool, PETscan summaries can objectively assess the incidence of disorders in companion animal populations and can be used to prioritize disease–gene identification studies and evaluate the effects of breeding strategies, for example, after implementation of a new DNA test in the breeding strategy.     

Plasma homocysteine concentrations are positively associated with hostility and anger

Homocysteine is a sulphur amino acid that is positively associated with risk of vascular disease. Very few behavioral or psychological factors have been studied in relationship to homocysteine levels, despite the fact that several psychological factors have also been linked with risk for cardiovascular disease. One psychological attribute showing a strong association with risk is hostility, which is prospectively predictive of future cardiovascular disease endpoints. Another related psychological factor is anger expression; coronary heart disease risk is associated with both heightened expression and inhibition of anger. The purpose of this study was to test the relationship of hostility and anger expression with homocysteine concentrations in a sample of healthy, middle-aged men and women. Participants completed the Cook-Medley hostility questionnaire, the Speilberger Anger Expression questionnaire, and had blood taken for the assessment of plasma homocysteine concentrations. Results indicated positive and significant associations between hostility and homocysteine levels for all participants, and positive and significant correlations between anger-in and homocysteine levels for men only. These data are among the first to test the relationship between homocysteine and psychological risk factors for cardiovascular diseases, and suggest one potential mechanism for the increased cardiovascular risk associated with hostility and anger expression.     

Review and meta-analysis of epidemiological associations between low/moderate doses of ionizing radiation and circulatory disease risks, and their possible mechanisms

Although the link between high doses of ionizing radiation and damage to the heart and coronary arteries has been well established for some time, the association between lower-dose exposures and late occurring cardiovascular disease has only recently begun to emerge, and is still controversial. In this paper, we extend an earlier systematic review by Little et al. on the epidemiological evidence for associations between low and moderate doses of ionizing radiation exposure and late occurring blood circulatory system disease. Excess relative risks per unit dose in epidemiological studies vary over at least two orders of magnitude, possibly a result of confounding and effect modification by well-known (but unobserved) risk factors, and there is statistically significant (p < 0.00001) heterogeneity between the risks. This heterogeneity is reduced, but remains significant, if adjustments are made for the effects of fractionated delivery or if there is stratification by endpoint (cardiovascular disease vs. stroke, morbidity vs. mortality). One possible biological mechanism is damage to endothelial cells and subsequent induction of an inflammatory response, although it seems unlikely that this would extend to low-dose and low-dose-rate exposure. A recent paper of Little et al. proposed an arguably more plausible mechanism for fractionated low-dose effects, based on monocyte cell killing in the intima. Although the predictions of the model are consistent with the epidemiological data, the experimental predictions made have yet to be tested. Further epidemiological and biological evidence will allow a firmer conclusion to be drawn.     

Folate, homocysteine, endothelial function and cardiovascular disease

Evidence reported from numerous clinical studies over the past decade has revealed an association between increased plasma total homocysteine (tHcy) concentrations and cardiovascular disease (CVD). In addition, epidemiological studies have identified an inverse association between blood folate concentrations, folate intake and cardiovascular endpoints, that are independent of homocysteine. Folic acid supplementation can lower plasma tHcy concentrations safely and inexpensively. Furthermore, folic acid can reverse endothelial dysfunction observed in patients with CVD. This reversal in endothelial dysfunction with folic acid has been shown to be independent of plasma tHcy lowering, suggesting that folate has pleiotropic effects on the vasculature other than homocysteine lowering. In vitro evidence demonstrates that 5-methyltetrahydrofolate (5MeTHF) the main circulating metabolite of folate, can increase nitric oxide production and can directly scavenge superoxide radicals. The potential beneficial role of folic acid supplements on vascular disease are currently being tested in randomized placebo controlled studies.     

Carotenoids and cardiovascular disease: what research gaps remain?

PURPOSE OF REVIEW: Dietary and blood carotenoids, including alpha-carotene, beta-carotene, lycopene, lutein/zeaxanthin, and beta-cryptoxanthin, have been examined in a number of epidemiological studies in recent years for the risk of cardiovascular disease. This review assimilated the existing and recent literature on carotenoids and cardiovascular disease and considered what research gaps may remain. RECENT FINDINGS: Numerous large cohort studies have been published in largely American men and women that have examined dietary intake or blood levels of total or individual carotenoids with the risk of various cardiovascular endpoints. Overall, early, promising results have grown increasingly inconsistent over time. More recently, studies examining lycopene and lutein/zeaxanthin have offered more promising data on a possible, but not yet established, inverse association with the risk of cardiovascular disease. Recent epidemiological data on beta-cryptoxanthin and cardiovascular disease are lacking. Primary and secondary prevention trials have extensively examined beta-carotene, but not other carotenoids, for the risk of cardiovascular disease as either the primary or secondary endpoint with largely null results. More recent studies have focused on individual carotenoids in relation to cardiovascular disease and require a more careful evaluation of potential mechanisms of effect. SUMMARY: The promise of early epidemiological studies on carotenoids and cardiovascular disease paved the way to largely disappointing results from several large prevention trials of beta-carotene. Emerging recent evidence of potential cardioprotective effects for lycopene and other carotenoids besides beta-carotene in the diet and blood suggest that there is more to be learned in the story of carotenoids and both atherosclerotic progression and clinically manifested cardiovascular disease.