Multiple biomarker assessment in primary prevention of cardiovascular disease

There is room for improving current risk stratification tools for the primary prevention of cardiovascular disease (CVD). disease (CVD). Integrating the measurement of multiple biomarkers into a single risk assessment algorithm, a strategy increasingly being used in acute cardiovascular care settings, also has promise for primary prevention. A number of novel biomarkers, including natriuretic peptides, sensitive cardiac troponins, and high-sensitivity C-reactive protein, have successfully been incorporated into multimarker panels that can improve traditional CVD risk assessment measures, and new markers emerge regularly. Targeting the appropriate populations that are most likely to benefit from more advanced screening will be key to the success of a multimarker approach to preventing CVD. Studies evaluating specific combinations of biomarkers (with or without noninvasive tests of subclinical CVD), cost-effectiveness, and clinical outcomes are needed before a multiple biomarker approach to primary prevention of CVD can be widely advocated and implemented.     

Natriuretic Peptides and Assessment of Cardiovascular Disease Risk in Asymptomatic Persons

Current tools for cardiovascular disease (CVD) risk assessment in asymptomatic individuals are imperfect. Preventive measures aimed only at individuals deemed high risk by current algorithms neglect large numbers of low-risk and intermediate-risk individuals who are destined to develop CVD and who would benefit from early and aggressive treatment. Natriuretic peptides have the potential both to identify individuals at risk for future cardiovascular events and to help detect subclinical CVD. Choosing the appropriate subpopulation to target for natriuretic peptide testing will help maximize the performance and the cost effectiveness. The combined use of multiple risk markers, including biomarkers, genetic testing, and imaging or other noninvasive measures of risk, offers promise for further refining risk assessment algorithms. Recent studies have highlighted the utility of natriuretic peptides for preoperative risk stratification; however, cost effectiveness and outcomes studies are needed to affirm this and other uses of natriuretic peptides for cardiovascular risk assessment in asymptomatic individuals.     

Atherosclerotic plaque biomarkers: beyond the horizon of the vulnerable plaque

Cardiovascular disease (CVD) is the number one cause of death globally, and the majority of CVD is caused by atherosclerosis. Atherosclerosis is a systemic inflammatory disease that leads to myocardial infarction, stroke and lower limb ischemia. Pathological studies have given insight to development of atherosclerosis and the importance of local plaque vulnerability, leading to thrombus formation and cardiovascular events. Due to the burden of cardiovascular disease, identification of patients at risk for cardiovascular events and treatment stratification is needed. The predictive power of classical risk factors is limited, especially in patients with manifest atherosclerosis. Imaging modalities have focused on the characteristics of the vulnerable plaque. However, it has become evident that not all so-called vulnerable plaques lead to rupture and subsequent thrombosis. The latter obviously limits the positive predictive value for imaging assessment of plaques and patients at risk. Serum biomarkers have also been studied extensively, but have very limited application in a clinical setting for risk stratification. In line with the important relation between vulnerable plaques and cardiovascular events, plaque biomarker studies have been initiated. These longitudinal studies are based on the concept, that a vulnerable plaque contains predictive information for future cardiovascular events, also in other territories of the vascular tree. Results look promising and plaque markers can be used to develop imaging modalities to identify patients at risk, or to monitor treatment effect. Plaque biomarker studies do not challenge the definition of the vulnerable plaque, but use its concept in favor of prediction improvement for vascular patients.     

Prediction and classification of cardiovascular disease risk in older adults with diabetes

Aims/hypothesis

We sought to derive and validate a cardiovascular disease (CVD) prediction algorithm for older adults with diabetes, and evaluate the incremental benefit of adding novel circulating biomarkers and measures of subclinical atherosclerosis.

Methods

As part of the Cardiovascular Health Study (CHS), a population-based cohort of adults aged ≥65 years, we examined the 10 year risk of myocardial infarction, stroke and cardiovascular death in 782 older adults with diabetes, in whom 265 events occurred. We validated predictive models in 843 adults with diabetes, who were followed for 7 years in a second cohort, the Multi-Ethnic Study of Atherosclerosis (MESA); here 71 events occurred.

Results

The best fitting standard model included age, smoking, systolic blood pressure, total and HDL-cholesterol, creatinine and the use of glucose-lowering agents; however, this model had a C statistic of 0.64 and poorly classified risk in men. Novel biomarkers did not improve discrimination or classification. The addition of ankle–brachial index, electrocardiographic left ventricular hypertrophy and internal carotid intima–media thickness modestly improved discrimination (C statistic 0.68; p?=?0.002) and classification (net reclassification improvement [NRI] 0.12; p?=?0.01), mainly in those remaining free of CVD. Results were qualitatively similar in the MESA, with a change in C statistic from 0.65 to 0.68 and an NRI of 0.09 upon inclusion of subclinical disease measures.

Conclusions/interpretation

Standard clinical risk factors and novel biomarkers poorly discriminate and classify CVD risk in older adults with diabetes. The inclusion of subclinical atherosclerotic measures modestly improves these features, but to develop more robust risk prediction, a better understanding of the pathophysiology and determinants of CVD in this patient group is needed.     

On the value of doing nothing: anger and cardiovascular disease in clinical practice

Type A behavior, anger, and hostility have all been described as psychosocial risk factors or potential risk factors for cardiovascular disease (CVD). However, in the populations evaluated, the methods used to measure these traits and the endpoints used to determine outcomes have varied widely. The results of these studies have also been quite disparate. The present article reviews data from all the existing quantitative (meta-analytic) and qualitative systematic review articles that cover this topic, using the Database of Abstracts of Reviews of Effects (DARE) criteria. We conclude that the existing data do not support a meaningful clinical relationship between current measurements of these traits and the development of CVD.     

Progrediente Nierenerkrankungen

In recent years many publications have dealt with new diagnostic, prognostic and predictive biomarkers (BM). Prognostic BMs do not necessarily represent pathophysiologically relevant disease processes but they are often used to establish or improve risk prediction models. Good models estimate the risk of clinically relevant endpoints and take important aspects, such as competing risks into consideration. They are developed in representative cohorts ideally established for this purpose and validated in independent populations; their quality is assessed by statistical parameters describing discrimination and calibration. For the prediction of risk of chronic renal disease progression only few models meet all these criteria. In contrast validated risk estimators, such as the Framingham risk score, are available in cardiovascular medicine. It has been shown that in these models the addition of new BMs does not usually increase the predictive power in general but only in subgroups of the population (e.?g. those with intermediate risk). Predictive biomarkers support therapeutic decisions and are marketed as companion diagnostics. They reflect the molecular pathophysiology of the disease as well as the mode of action of the medication used. Because our knowledge on these processes in the field of chronic renal disease is increasing and new drugs will enter the market, it can therefore be assumed that more predictive biomarkers will become available. Before these can be utilized in clinical practice they have to gain acceptance by clinicians as well as healthcare economists. Examples from other disciplines show that this is most likely for BMs that enter the market at the same time as a new drug.     

Gaining Efficiency in Clinical Trials With Cardiac Biomarkers: JACC Review Topic of the Week

The momentum of cardiovascular drug development has slowed dramatically. Use of validated cardiac biomarkers in clinical trials could accelerate development of much-needed therapies, but biomarkers have been used less for cardiovascular drug development than in therapeutic areas such as oncology. Moreover, there are inconsistences in biomarker use in clinical trials, such as sample type, collection times, analytical methods, and storage for future research. With these needs in mind, participants in a Cardiac Safety Research Consortium Think Tank proposed the development of international guidance in this area, together with improved quality assurance and analytical methods, to determine what biomarkers can reliably show. Participants recommended the development of systematic methods for sample collection, and the archiving of samples in all cardiovascular clinical trials (including creation of a biobank or repository). The academic and regulatory communities also agreed to work together to ensure that published information is fully and clearly expressed.     

Overview: Studies on Spontaneous Hypertension - Development from Animal Models Toward Man

The development of genetic rat models for research on hypertension, stroke and other cardiovascular diseases (CVD) such as spontaneously hypertensive rats (SHR) and strokeprone SHR (SHRSP) have contributed not only to the elucidation of the pathogenesis of hypertension-related CVD but also to their prediction and prevention. Since both genetic and environmental factors are involved in the pathogenesis of CVD as extensively studied so far on these models, the detection of the early pathogenic mechanisms related to the genetic factors and the control of environmental factors such as dietary improvement are useful as predictive and preventive measures against CVD. Sympathetic overresponsiveness, early development of cardiovascular hypertrophy, increased salt sensitivity and membrane or transport abnormalities in vascular smooth muscle cells (VSMC) from SHR and SHRSP, possibly related to the pathogenesis of hypertension, are so far regarded as predictors for hypertension partly applicable to human hypertension. Genetic pathogenic mechanisms of stroke in SHRSP which have been proven to be greatly influenced also by dietary factors are hypertension-induced VSMC degeneration and necrosis of intracerebral arteries due to local nutritional disturbance. One of predictors of stroke related to the pathogenic mechanisms is reduction of regional cerebral blood flow. On the other hand, the control of environmental factors, especially nutrition and diets such as intakes of animal and vegetable proteins, some amino acids and fatty acids, potassium, calcium, magnesium, dietary fibers, etc., have been experimentally demonstrated to be effective for the prevention of CVD in these genetic models, and the applicability of these experimental findings to the CVD prevention in man is now supported from our world-wide epidemiological studies (WHO CARDIAC Study).     

Oxidative stress biomarkers in type 2 diabetes mellitus for assessment of cardiovascular disease risk

Aims

Type-2 Diabetes Mellitus (T2DM) is one of the most prevalent and progressive metabolic conditions affecting approximately 8.5% of the global population. Individuals with T2DM have a significantly increased risk of developing chronic conditions such as cardiovascular disease (CVD) and its associated complications, therefore, it is of great importance to establish strategies for combatting T2DM and its associated chronic conditions. Current literature has identified several biomarkers that are known to play a key role in the pathogenesis of CVD. Many of these biomarkers affecting CVD are influenced by an increase in oxidative stress as seen in T2DM. The purpose of this review is to analyse and correlate the oxidative stress-related biomarkers that have been identified in the literature to provide an updated summary of their significance in CVD risk factors.

Oxidative stress and vascular disease

Growing evidence indicates that chronic and acute overproduction of reactive oxygen species (ROS) under pathophysiologic conditions is integral in the development of cardiovascular diseases (CVD). These ROS can be released from nicotinamide adenine dinucleotide (phosphate) oxidase, xanthine oxidase, lipoxygenase, mitochondria, or the uncoupling of nitric oxide synthase in vascular cells. ROS mediate various signaling pathways that underlie vascular inflammation in atherogenesis: from the initiation of fatty streak development through lesion progress to ultimate plaque rupture. Various animal models of oxidative stress support the notion that ROS have a causal role in atherosclerosis and other cardiovascular diseases. Human investigations also support the oxidative stress hypothesis of atherosclerosis. Oxidative stress is the unifying mechanism for many CVD risk factors, which additionally supports its central role in CVD. Despite the demonstrated role of antioxidants in cellular and animal studies, the ineffectiveness of antioxidants in reducing cardiovascular death and morbidity in clinical trials has led many investigators to question the importance of oxidative stress in human atherosclerosis. Others have argued that the prime factor for the mixed outcomes from using antioxidants to prevent CVD may be the lack of specific and sensitive biomarkers by which to assess the oxidative stress phenotypes underlying CVD. A better understanding of the complexity of cellular redox reactions, development of a new class of antioxidants targeted to specific subcellular locales, and the phenotype-genotype linkage analysis for oxidative stress will likely be avenues for future research in this area as we move toward the broader use of pharmacological and regenerative therapies in the treatment and prevention of CVD.     

Regression of Atherosclerosis

Atherosclerotic cardiovascular disease (CVD) is a complex disorder that leads to premature death and hospitalization. Several drugs have been, or are currently being tested for their ability to reduce cardiovascular mortality and/or promote regression of atherosclerotic lesions. In addition to "hard end point" clinical trials in which total and cardiovascular mortality as well as risk of incident myocardial infarction are considered as outcomes, trials with surrogate end points using imaging biomarkers can rapidly assess the efficacy of new cardiovascular drugs. Low-density lipoprotein-based therapies with statins have been shown to promote atherosclerosis regression, and several other drugs targeting high-density lipoproteins or inflammation/oxidation are currently being tested in both outcomes and imaging trials in which atherosclerosis regression is anticipated. In this review, we focus on the latest progress in CVD and highlight novel drugs that tackle atherosclerosis as well as the currently used and upcoming imaging techniques to optimally measure atherosclerosis progression.     

Usefulness of aortic root dimension in persons > or = 65 years of age in predicting heart failure, stroke, cardiovascular mortality, all-cause mortality and acute myocardial infarction (from the Cardiovascular Health Study)

Echocardiographic measures of left ventricular (LV) function and structure as well as left atrial size have been reported to predict adverse cardiovascular disease (CVD) outcomes. Although anatomic changes of the aortic root are likely to reflect effects of hypertension and atherosclerosis, few data are available on the predictive value of aortic root dimension (ARD) for outcome in free-living populations. The purpose of this investigation was to determine whether in a cohort of patients aged > or = 65 years ARD was associated with traditional coronary heart disease (CHD) risk factors and with 10-year incident CVD outcomes. In the National Heart, Lung, and Blood Institute-sponsored Cardiovascular Health Study, 3,933 free-living black and white men and women > or = 65 years of age without prevalent CVD had 2-dimensional directed M-mode echocardiographic measurements of ARD as part of a comprehensive evaluation. ARD was associated with age and gender (greater in men) but not race. ARD was also positively associated with diastolic blood pressure, LV hypertrophy, major electrocardiographic abnormalities, and other echocardiographic measures, including LV mass, ventricular septal and posterior wall thickness, and LV dimension. After adjustment for other known risk factors, high ARD was associated with an increased risk for incident congestive heart failure (CHF) in men (hazard ratio for upper compared with all other quintiles 1.47, p = 0.014), stroke in men and women (hazard ratio 1.39 per cm, p = 0.015), CVD mortality in men and women (hazard ratio 1.48 per cm, p = 0.007), and total mortality in men and women taking antihypertensive medications (hazard ratio 1.46 per cm, p = 0.007), but not with incident myocardial infarction (MI) (hazard ratio 0.89, p = 0.39). In conclusion, in a cohort of patients aged > or = 65 years without clinical CVD at baseline, ARD was associated with several CHD risk factors and measures of subclinical disease and was predictive of incident CHF, stroke, CVD mortality, and all-cause mortality, but not of incident MI.     

Combining serum biomarkers: the association of C-reactive protein, insulin sensitivity, and homocysteine with cardiovascular disease history in the general US population.

BACKGROUND: Elevated levels of serum biomarkers such as C-reactive protein (CRP) and homocysteine have been independently associated with cardiovascular risk. However, the prevalence of concurrent elevations of these biomarkers in the general population is unknown, as is their association with cardiovascular disease (CVD). METHODS: Data from adults (n = 4900) in the National Health and Nutrition Examination Survey were used to investigate the relationship between combinations of serum biomarkers of inflammation (CRP), atherosclerosis (homocysteine), and insulin sensitivity [homeostatic model assessment (HOMA) fasting insulin] and CVD. Using SUDAAN, logistic regression models were constructed to examine the relationships between elevated serum biomarkers (CRP, homocysteine, HOMA, or insulin), singly or in combination, and having a history of heart failure, myocardial infarction (MI), stroke, or any CVD, while controlling for age, race, sex, obesity, smoking, cholesterol level, diabetes history, hypertension history, exercise level, and dietary fiber intake. RESULTS: After adjustment for covariates, there was a significant relationship between concomitant elevations of CRP plus homocysteine and a history of MI [odds ratio (OR) 2.21], heart failure (OR 2.14), and any CVD (OR 1.87) that was stronger than the relationship between individual biomarkers alone and a history of CVD. In addition, combinations of elevated CRP plus HOMA and CRP plus insulin, remained significantly related to having a history of any CVD. CONCLUSION: Recent scientific evidence and the present findings demonstrate the possibility for improving cardiovascular risk stratification through the concurrent evaluation of multiple biomarkers. In particular, these findings demonstrate the need to evaluate the combination of CRP and homocysteine prospectively as predictors of CVD.     

Inflammation and Cardiovascular Disease: From Pathogenesis to Therapeutic Target

Atherosclerosis represents the most common pathological substrate of coronary heart disease (CHD), and the characterization of the disease as a chronic low-grade inflammatory condition is now largely accepted. A number of mediators of inflammation have been widely studied, both as surrogate biomarkers and as causal agents, in the pathophysiological network of atherogenesis and plaque vulnerability. The epidemiological observation that biomarkers of inflammation are associated with clinical cardiovascular risk supports the theory that targeted anti-inflammatory treatment appears to be a promising strategy in reducing residual cardiovascular risk on the background of traditional medical therapy. A large number of randomized controlled trials have shown that drugs commonly used in cardiovascular disease (CVD), such as statins, may be effective in the primary and secondary prevention of cardiovascular events through an anti-inflammatory effect. Moreover, several anti-inflammatory drugs are being tested for their potential to reduce residual cardiovascular risk on the background of validated medical therapy for atherosclerotic disease. In this paper, we review relevant evidence with regard to the relationship between inflammation and CVD, from pathogenesis to therapeutic strategies.     

Anxiety associations with cardiac symptoms,angiographic disease severity,and healthcare utilization: The NHLBI-sponsored Women's Ischemia Syndrome Evaluation

Background

Anxiety is common among patients presenting with suspected coronary artery disease (CAD). In a sample of women with signs and symptoms of ischemia, we examined three anxiety markers as predictors of CAD endpoints including: 1) cardiac symptom indicators; 2) angiographic CAD severity; and 3) healthcare utilization (cardiac hospitalizations and 5-year cardiovascular [CVD] healthcare costs).

Methods

Participants completed a baseline protocol including coronary angiogram, cardiac symptoms, psychosocial measures and a median 5.9-year follow-up to track hospitalizations. We calculated CVD costs based on cardiac hospitalizations, treatment visits, and CVD medications. Anxiety measures included anxiolytic medication use, Spielberger Trait Anxiety Inventory (STAI) scores, and anxiety disorder treatment history.

Results

The sample numbered 514 women with anxiety measure data and covariates (mean age = 57.5 [11.1]). One in five (20.4%) women reported using anxiolytic agents. Anxiety correlated with cardiac symptom indicators (anxiolytic use with nighttime angina and nitroglycerine use; STAI scores and anxiety disorder treatment history with nighttime angina, shortness of breath, and angina frequency). Anxiety disorder treatment history (but not STAI scores or anxiolytics) predicted less severe CAD. Anxiolytic use (but not STAI scores or anxiety disorder treatment history) predicted hospitalizations for chest pain and coronary catheterization (HRs = 2.0, 95% CIs = 1.1–4.7). Anxiety measures predicted higher 5-year CVD costs (+ 9.0–42.7%) irrespective of CAD severity.

Conclusions

Among women with signs and symptoms of myocardial ischemia, anxiety measures predict cardiac endpoints ranging from cardiac symptom severity to healthcare utilization. Based on these findings, anxiety may warrant greater consideration among women with suspected CAD.     

Microvascular changes in the retina as a risk marker for cardiovascular disease

The retinal vasculature can be viewed directly and noninvasively, offering an easily accessible window through which to study the human microcirculation in vivo and, therefore, early processes and pathways in cardiovascular disease (CVD) development. Recent advances in digital retinal photography and image analysis have allowed reliable and objective evaluation of retinal vascular pathologies (eg, retinopathy signs) as well as quantitative assessment of other topographic retinal vascular parameters, including retinal vascular caliber. An expanding series of clinical and epidemiologic studies now show that retinal vascular changes are associated with cardiovascular and metabolic diseases, including hypertension, diabetes, obesity, stroke, coronary heart disease, and heart failure. These data indicate that structural alterations in the retinal vasculature may mirror pathologic processes occurring in the systemic circulation and may represent novel biomarkers for CVD risk. This review summarizes the systemic cardiovascular associations of retinal vascular changes and discusses their clinical and research implications.     

Clinical utility of novel biomarkers for cardiovascular disease risk stratification

Over the past few decades, a number of coronary artery disease (CAD) and cardiovascular disease (CVD) risk factors have been identified. The predictive power of “conventional” risk factors have been validated by observational, prospective and intervention studies. Nevertheless, all attempts to exactly predict the individual risk for CAD have failed, biased by a large number of incorrectly risk-classified subjects. To improve cardiovascular (CV) risk prediction, a large number of genetic and/or non-genetic biomarkers have been discovered and tested against the “classical” risk factors for their power to predict CV risk. Only few of them had a significant improvement over the predictive models. In this paper, the most investigated biomarkers will be discussed and the evidence of their use as predictors of CV will be questioned.     

Arterial Stiffness and Cardiovascular Events in Hypertensives

A major reason for measuring arterial stiffness routinely in clinical practice in hypertensive patients comes from the recent demonstration that arterial stiffness has predictive value for cardiovascular events, which is independent of classical risk scores. In primary prevention, some “imaging biomarkers,” such as arterial stiffness, enhance risk prediction to a higher extent than “circulating biomarkers.” The aim of the present brief review is to address the concept of “surrogate endpoint” and to determine whether aortic stiffness meets the criteria that are requested by international guidelines: (1) Proof of concept: Do novel marker levels differ between subjects with and without outcome? (2) Prospective validation: Does the novel marker predict development of future outcomes in a prospective cohort or nested case-cohort study? (3) Incremental value: Does the novel marker add predictive information to established, standard risk markers? (4) Clinical utility: Does the novel risk marker change predicted risk sufficiently to change recommended therapy? (5) Clinical outcomes: Does use of the novel risk marker improve clinical outcomes, especially when tested in a randomized clinical trial? (6) Cost-effectiveness: Does use of the novel risk marker improve clinical outcomes sufficiently to justify the additional costs? In conclusion, although aortic stiffness meets the first 4 criteria, there is still a need for studies comparing aortic stiffness-guided therapeutic strategies with classic guidelines-guided strategies for preventing cardiovascular events.     

Using adult stem cells to monitor endothelial dysfunction in diabetes mellitus

Diabetes affects approximately 10.5% of adults in the United States and this is projected to nearly double by 2025. Both type 2 diabetes (T2DM) and obesity are associated with endothelial dysfunction, oxidative stress, endothelial cell inflammation, cardiovascular pro-thrombotic states and are the most common causes of endothelial dysfunction, chronic kidney disease (CKD) and cardiovascular disease (CVD). Lately several new diabetes medications have come to clinical use that claim CVD risk improvement, however modalities used to test and monitor CVD risk are not cell based, which bring into question the reproducibility of these studies. Our review is designed to highlight cardiovascular risk reduction with novel diabetes medications while emphasizing cellular outcomes as a biomarker of cardiovascular risk.We are going to highlight studies that comment on peripheral blood derived CD34+ hematopoietic progenitor cells, as biomarkers of endothelial function. CD34+ cells have been extensively investigated by us and several other laboratories for the last two decades, as a viable cardiovascular function biomarker. In this context we will also discuss relevant CVD risk reduction trials that used novel diabetes medications.