Cardiovascular Diabetology Research Articles

Development of a core outcome set for cardiovascular diabetology: a methodological framework.

Cardiovascular diabetology is an emergent field focusing on all aspects of diabetes/cardiovascular interrelationship and metabolic syndrome. High-quality evidence needs to be provided to determine the efficacy and safety of interventions in cardiovascular diabetology. The heterogeneity of outcomes among trials limits the comparison of results, and some outcomes are not always meaningful to end-users. The cardiovascular diabetology core outcome set (COS) study aims to develop a COS of interventions for cardiovascular diabetology. In this paper, we introduce the methodological framework for developing the COS. The COS development will include the following steps: (a) establish the COS groups of stakeholders, including international steering committee, Delphi survey group, and consensus meeting group; (b) systematic reviews of outcomes used in trials of cardiovascular diabetology; (c) semistructured interview of stakeholders for outcomes of cardiovascular diabetology; (d) generate a list of candidate outcomes and determine the original outcome pool; (e) Delphi survey with stakeholders of cardiovascular diabetology to select potential core outcomes; and (f) review and endorse the cardiovascular diabetology COS by expert consensus meeting. This current study reports the methodological framework to develop a COS in cardiovascular diabetology and will provide evidence for the future development of COS in cardiovascular diabetology.

Right Ventricular Dysfunction and Exercise Impairment in Patients with Heart Failure, Insulin Resistance, and Diabetes Mellitus: Insights from the T.O.S.CA. Registry (Cardiovascular Diabetology 2022).

Insulin resistance (IR) and type 2 diabetes mellitus (T2D) are known to affect the progression of chronic heart failure (CHF), but little evidence exists about the impact of IR and T2D on right ventricular dysfunction and exercise tolerance. Insights from the T.O.S.C.A. Registry: Echocardiographic hallmarks and cardiopulmonary exercise test (CPET) results were evaluated at baseline and after an average time of 36 months. T2D patients exhibited a greater intraventricular septum (IVS) thickness (11 ± 2 mm, 10 ± 2 mm, 10 ± 2 mm, in T2D, IR, and EU, respectively; p<.05) and LV wall thickness (0.34 ± 0.1, 0.32 ± 0.1, and 0.32 ± 0.1, in T2D, IR, and EU, respectively; p<.05). Moreover, T2D patients exhibited worse LV filling dynamics with larger left atrial volume index compared to IR and EU. Right ventricle dysfunction, expressed as a lower TAPSE/PASP ratio, was found in T2D [0.52(0.32-0.72)] than in EU and IR [0.60(0.30-0.90); p<.05]. T2D patients showed a significantly lower VO2 max peak when compared to IR and EU patients (15.8 ± 3.8 vs. 16.5 ± 4.3 vs. 18.4 ± 4.3 ml/Kg/min; p<.003), with an inverse relationship between the HOMAIR classes and VO2 max. Right ventricle structure and function deteriorated more rapidly in T2D, as suggested by more relevant deterioration in TAPSE/PASP ratio (-10% in EU patients, -14% in IR patients, -21% in T2D; p<.05). The study findings suggest that the right ventricle structure, function, and cardiopulmonary performance deteriorate with IR and, more evidently, due to chronic exposure to hyperglycemia in T2D. Impaired exercise tolerance, poor cardiorespiratory fitness, diastolic dysfunction, and left atrial enlargement predispose patients to poor quality of life, suboptimal adherence to physical activity, and an overall increase in the risk of all-cause and cardiovascular mortality. In addition, chronic hyperglycemia accelerates the progression of these alterations, especially in patients with poor glycemic control over time. Highly selective and even more non-selective sodium glucose transporter type 2 inhibitors and glucagon-like peptide 1 receptor agonists should be considered as the first-line therapy for improving CV outcomes in T2D and CHF. Further studies are needed to understand the role of these molecules in treating pre-clinical conditions, such as IR and metabolic syndrome.

RF10 | PMON242 Free Testosterone is an Independent Predictor of Metabolic Syndrome Severity in U.S. Adolescent Girls Ages 12-19, National Health and Nutrition Examination Survey (NHANES) 2013-2016

Abstract Background Metabolic syndrome (MetS) affects ∼10% of U.S. adolescents, especially those with obesity. Adolescent obesity is associated with adolescent hyperandrogenemia (HA), while adult HA is associated with increased risk of MetS in both asymptomatic women and women with polycystic ovary syndrome (Torchen et al, Obesity [Silver Spring] 2020). Yet, the relationship between HA and severity of MetS during adolescence remains unclear. We investigated whether free testosterone (T) concentrations independently predict MetS severity in adolescent girls. Methods We performed a weighted analysis using data from the National Health and Nutrition Examination Survey (NHANES) for 2013–2016, utilizing a cross-sectional study design. In particular, we analyzed data from a nationally-representative sample of 230 girls aged 12-19 years. We performed regression analysis to evaluate whether free T (independent variable) predicted MetS Severity Z-score (outcome). In a multiple regression model, we adjusted for total percent body fat, age (months), and menarche status (premenarcheal vs. postmenarcheal). Free T was calculated (Vermuelen equation) from total T and sex hormone binding globulin (SHBG). MetS severity was determined by a calculator validated for children (Gurka et al, Metabolic Syndrome Severity Calculator, doi: 10.5281/zeondo.2542213; Gurka et al, Cardiovascular Diabetology 2012) using reported fasting labs and anthropometric parameters. As secondary analyses, we (1) repeated the above analysis substituting SHBG for free T in the primary cohort, and (2) repeated the above analysis substituting total T for tree T in an expanded cohort (n=251). Results In the primary cohort, MetS z-score was -0.27 (-0.41 to -0.13) [mean (95% CI)]; free T 4.0 pg/ml (3.7–4.3); total T 28.7 ng/dL (27.1–30.3); SHBG 60.8 nmol/L (54.0–67.6); total percent body fat 34.5% (33.3–35.6). In simple regression analyses, free T (R=0.11) and percent body fat (R=0.57) each predicted MetS z-score (p&amp;lt;0.001 for each), but age (p=0.68) and menarche status (p=0.18) did not. Our adjusted regression model accounted for 60% of the variance in MetS z-score (R2=0.60). Higher free T and percent body fat were independently associated with higher MetS z-score, while younger age was independently associated with higher MetS z-score (p&amp;lt;0.001 for each). When substituting SHBG and total T for free T, model R2 values were 0.61 and 0.59, respectively, with only percent body fat and age being significant independent predictors of MetS z-score in each model (SHBG, p=0.06; total T, p=0.90). Conclusion We conclude that free T is an independent predictor of MetS severity in a nationally-representative sample of adolescent girls aged 12 to 19 years. Total T was not an independent predictor of MetS severity, suggesting that the relationship between free T and MetS z-score may partly reflect obesity-associated reductions in SHBG levels. These data suggest that HA may contribute to MetS severity in adolescent girls. Presentation: Saturday, June 11, 2022 1:06 p.m. - 1:11 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Research status and trends of the diabetic cardiomyopathy in the past 10 years (2012-2021): A bibliometric analysis.

Diabetic cardiomyopathy is one of the most life-threatening diabetic complications. However, the previous studies only discuss a particular aspect or characteristic of DCM, the current state and trends were explored by limited research. We aimed to perform a systemically bibliometric study of DCM research progress status in the past decade, visualize the internal conceptual structure and potential associations, and further explore the prospective study trends. Articles related to DCM published from January 2012 to December 2021 were collected in the Web of Science core collection (WoSCC) database on June 24, 2022. We exported all bibliographic records, including titles, abstracts, keywords, authorship, institutions, addresses, publishing sources, references, citation times, and year of publication. In addition, the journal Impact Factor and Hirsch index were obtained from the Journal Citation Report. We conducted the data screening, statistical analysis, and visualization via the Bibliometrix R package. VOS viewer software was employed to generate the collaboration network map among countries and institutions for better performance in visualization. In total, 1,887 original research articles from 2012 to 2021 were identified. The number of annual publications rapidly increased from 107 to 278, and a drastic increase in citation times was observed in 2017-2019. As for global contributions, the United States was the most influential country with the highest international collaboration, while China was the most productive country. Professor Cai Lu was the most prolific author. Shandong University published the most articles. Cardiovascular Diabetology journal released the most DCM-related articles. "Metabolic Stress-induced Activation of FoxO1 Triggers Diabetic Cardiomyopathy in Mice" Battiprolu PK et al., J Clin Invest, 2012. was the most top-cited article regarding local citations. The top three keywords in terms of frequency were apoptosis, oxidative stress, and fibrosis. The analysis of future topic trends indicated that "Forkhead box protein O1," "Heart failure with preserved ejection fraction," "Dapagliflozin," "Thioredoxin," "Mitochondria dysfunction," "Glucose," "Pyroptosis," "Cardiac fibroblast" and "Long non-coding RNA" could be promising hotspots. This study provides meaningful insights into DCM, which is expected to assist cardiologists and endocrinologists in exploring frontiers and future research directions in the domain through a refined and concise summary.

Metformin in cardiovascular diabetology: a focused review of its impact on endothelial function.

As a first-line treatment for diabetes, the insulin-sensitizing biguanide, metformin, regulates glucose levels and positively affects cardiovascular function in patients with diabetes and cardiovascular complications. Endothelial dysfunction (ED) represents the primary pathological change of multiple vascular diseases, because it causes decreased arterial plasticity, increased vascular resistance, reduced tissue perfusion and atherosclerosis. Caused by “biochemical injury”, ED is also an independent predictor of cardiovascular events. Accumulating evidence shows that metformin improves ED through liver kinase B1 (LKB1)/5'-adenosine monophosphat-activated protein kinase (AMPK) and AMPK-independent targets, including nuclear factor-kappa B (NF-κB), phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt), endothelial nitric oxide synthase (eNOS), sirtuin 1 (SIRT1), forkhead box O1 (FOXO1), krüppel-like factor 4 (KLF4) and krüppel-like factor 2 (KLF2). Evaluating the effects of metformin on endothelial cell functions would facilitate our understanding of the therapeutic potential of metformin in cardiovascular diabetology (including diabetes and its cardiovascular complications). This article reviews the physiological and pathological functions of endothelial cells and the intact endothelium, reviews the latest research of metformin in the treatment of diabetes and related cardiovascular complications, and focuses on the mechanism of action of metformin in regulating endothelial cell functions.

Bibliometric Study of Sodium Glucose Cotransporter 2 Inhibitors in Cardiovascular Research.

BackgroundAn increasing number of studies have shown that sodium glucose cotransporter 2 (SGLT2) inhibitors, initially used as antidiabetic agents, have cardiovascular (CV) benefits. However, few bibliometric analyses have examined this field systematically. Our study aimed to visualize the publications to determine the trends and hotspots in CV research on SGLT2 inhibitors.MethodsPublications on SGLT2 inhibitors in cardiovascular research were retrieved from the Web of Science Core Collection. Microsoft Excel 2019, VOSviewer, and CiteSpace V were used to analyze and plot the references.ResultsOn July 3, 2020, 1509 records of CV research on SGLT2 inhibitors published from 2013 to 2020 were retrieved. Nearly half were authored by American scholars, and most were published in Diabetes Obesity Metabolism, Cardiovascular Diabetology, and Diabetes Therapy. The USA was the leading driving force, with a strong academic reputation in this area. Inzucchi SE published the most related articles, while Neal B was cited the most frequently. All the top 10 co-cited references were in the leading co-cited journal, The New England Journal of Medicine. “Atherosclerotic cardiovascular event” was the leading research hotspot. The keywords “cardiac metabolism,” “heart failure hospitalization,” and “heart failure with preserved ejection fraction” appeared most recently as research frontiers.ConclusionMost studies focused on clinical trial outcomes, such as cardiovascular death and heart failure (HF) hospitalization. The mechanisms of SGLT2 inhibitors, especially those related to cardiac metabolism, may soon become hotspots and should be closely monitored.

Role of interleukin-15 in cardiovascular diseases.

Interleukin (IL)‐15 is a recently identified cytokine, which belongs to the interleukin‐2(IL‐2) family, and plays an important role in innate and adaptive immunoreaction. Given the fact that the structure of IL‐15 is partially similar to IL‐2, they share some common biological effects, including immunoregulation. IL‐2 was proven to protect cardiac function in mouse myocardial infarction models. Cardiovascular diseases (CVDs) dominate the cause of mortality worldwide. Besides atherosclerosis, inflammation is also widely involved in the pathogenesis of many CVDs including hypertension, heart failure (HF) and aneurysm. IL‐15, as a pro‐inflammatory cytokine, is up‐regulated in some cardiovascular diseases, such as myocardial infarction and atherosclerosis. The current understanding of IL‐15, including its signal pathway and cellular function, was described. Furthermore, IL‐15 has a protective effect in myocardial infarction and myocarditis by decreasing cardiomyocyte death and improving heart function. The inhibited effect of IL‐15 in ductus arteriosus (DA) should be focused on. IL‐15 promoted atherogenesis. IL‐15 may be a good target in treatment of cardiovascular diabetology. Finally, future research direction of IL‐15 deserves attention. Since IL‐15 plays several roles in CVDs, understanding the role of the IL‐15/IL‐15R system may provide a scientific basis for the development of new approaches that use IL‐15 for the treatment of CVDs.

The systemic implication of novel non-statin therapies in cardiovascular diabetology: PCSK9 as a case model.

PCSK9, like other novel non-statin drugs were primarily developed to help patients achieve low-density lipoprotein cholesterol targets, especially in patients with dyslipidemia not achieving lipid goals with statins due to poor tolerance or inadequate response. PCSK9 inhibitors, in addition to modulating lipid metabolism, improve mortality outcomes in cardiovascular disease. These benefits are markedly pronounced in patients with type 2 diabetes mellitus. However, these benefits do not come without associated risk. Multiple trials, studies, and case reports have attempted to explain observed outcomes with PCSK9 expression and administration of PCSK9 inhibitors from multiple perspectives, such as their effects on insulin sensitivity and glucose tolerance, changes in renal physiology, thyroid physiology, vascular tone, intestinal regulation of lipids, and improved cardiovascular function. These agents represent an opportunity for physicians to exercise prudence by using appropriate clinical judgement when managing comorbidities in the hyperglycemic patient, a concept that extends to other novel non-statin drugs.

Plasma irisin is elevated in type 2 diabetes and is associated with increased E-selectin levels

BackgroundIrisin is a hormone released mainly from skeletal muscle after exercise which increases adipose tissue energy expenditure. Adipocytes can also release irisin after exercise, acting as a local adipokine to induce white adipose tissue to take on a brown adipose tissue-like phenotype, suggesting that irisin and its receptor may represent a novel molecular target for the treatment of obesity and obesity-related diabetes. Previous reports provide conflicting evidence regarding circulating irisin levels in patients with type 2 diabetes (T2DM).MethodsThis study investigated plasma irisin concentrations in 79 T2DM individuals, assessing potential associations with measures of segmental body composition, markers of endothelial dysfunction and peripheral blood mononuclear cell telomere length (TL).ResultsResting, overnight-fasted plasma irisin levels were significantly higher in this group of T2DM patients compared with levels we previously reported in healthy volunteers (p < 0.001). Moreover, plasma irisin displayed a positive correlation with body mass index (p = 0.04), body fat percentage (p = 0.03), HbA1c (p = 0.03) and soluble E-selectin (p < 0.001). A significant negative association was observed between plasma irisin and visceral adiposity (p = 0.006) in T2DM patients. Multiple regression analysis revealed that circulating soluble E-selectin levels could be predicted by plasma irisin (p = 0.004). Additionally, cultured human umbilical vein endothelial cells (HUVEC) exposed to 200 ng/ml irisin for 4 h showed a significant fourfold increase in E-selectin and 2.5-fold increase in ICAM-1 gene expression (p = 0.001 and p = 0.015 respectively), and there was a 1.8-fold increase in soluble E-selectin in conditioned media (p < 0.05).ConclusionThese data suggest that elevated plasma irisin in T2DM is associated with indices of adiposity, and that irisin may be involved in pro-atherogenic endothelial disturbances that accompany obesity and T2DM. Accordingly, irisin may constitute a potentially novel therapeutic opportunity in the field of obesity and cardiovascular diabetology.

Acknowledgement of manuscript reviewers 2014

Contributing reviewersThe editors of Cardiovascular Diabetology would like to thank all our reviewers who have contributed to the journal in Volume 13 (2014).

Diabetes to cardiovascular disease: Is depression the potential missing link?

The etiopathological consequences of diabetes and its imperative sequels have been explored extensively in the scientific arena of cardiovascular diabetology. Innumerable risk covariates and confounders have been delineated for the primary and secondary prevention of diabetes and cardiovascular diseases (CVD). However, an intricate interaction of depression on them has been largely overlooked. Depression influences and participates in each and every step that worsens the diabetic state for developing cardiovascular complications. The dilemma is that it coexists, remains silent and generally not considered as relevant clinical parameter amenable to intervention. In this review, it is highlighted that depression has strong association and linkages with both diabetes and CVD and it should be considered and diagnosed at every stage of the diabetes to CVD continuum. Careful attention to the diagnosis and management of these disease states would contribute in lessening the CVD burden of the society.

Interpretation of cardiovascular outcome trials in type 2 diabetes needs a multiaxial approach.

In cardiovascular (CV) diabetology a "one-size fits-all" approach needs caution as vasculopathy and CV manifestations in patients with type 2 diabetes (T2D) with short disease duration are different as compared to those with longer duration. This is of relevance when interpreting results of CV outcome trials as responses to any intervention aimed to reduce CV risk might be different in patients with established vasculopathy as compared to those without, where also the duration of the intervention may play a role. Additionally, the mode-of-action of the intervention and its assumed time to peak CV risk modulation need to be taken into account: an intervention with possibly immediate effects, like on blood pressure or other direct functional dynamic parameters such as endothelial function or renal hemodynamics, could likely provide a meaningful impact on CV outcomes over a shorter time span than interventions that primarily target pathways that work on atherosclerotic processes, organ-remodelling, or vessel integrity. We are now faced with CV outcome results to interpret from a plethora of outcomes trials in T2D, some of which are testing the CV risk modulation predominantly beyond glucose lowering, e.g., as is the case for several trials testing the newer therapy classes di-peptidyl peptidase-4 inhibitors, glucagon-like protein-1 receptor analogues and sodium glucose co-transporter-2 inhibitors, and this paper reviews the data that support a call for a multiaxial approach to interpret these results.

Annual acknowledgement of manuscript reviewers

Contributing reviewersThe Editors of Cardiovascular Diabetology wish to thank all reviewers, both Editorial Board Members and external referees, who contributed to the journal in 2013 (Volume 12), and whose enthusiastic support in providing the essential service of peer review continues to improve the scientific quality of the journal and enable its goals to be achieved.

Annual acknowledgement of manuscript reviewers

Contributing reviewersThe Editors of Cardiovascular Diabetology wish to thank all reviewers, both Editorial Board Members and external referees, who contributed to the journal in 2012 (Volume 11), and whose enthusiastic support in providing the essential service of peer review continues to improve the scientific quality of the journal and enable its goals to be achieved.

Joint ESC/EASD Guidelines on Diabetes, where are we Now and where should we Go?

Patients with diabetes and prediabetes are at high risk for micro- and macrovascular complications. A multifactorial management strategy improves their prognosis considerably. Of concern is that these patients often fall between two specialties: cardiovascular medicine and diabetology. Practice guidelines for this patient category have been issued in collaboration between the European Society of Cardiology and the European Association for the Study of Diabetes to ascertain management according to the best available evidence. This article discusses why and for whom such guidelines are important.

Blood Pressure Variability

A series of articles1–4⇓⇓⇓ published recently in The Lancet and Lancet Neurology raise an interesting issue that has implications for both the clinical management of hypertension and future research in hypertension, particularly in the development and use of different classes of blood pressure (BP)–lowering drugs. These studies, which were led by Peter Rothwell at the John Radcliffe Hospital in Oxford, United Kingdom, suggest that, whereas there is undoubted and well-proven benefit in the current practice of reducing mean BP to prevent cardiovascular events, there may be additional benefit in also reducing BP variability (BPV), especially to prevent stroke. The studies suggest, moreover, that different classes of drugs are superior to others in reducing BPV (calcium channel blockers being best and the β-blocker atenolol being worst). However, these articles, by virtue of their sheer volume (≈50 pages of printed text and many pages of supplementary web appendix data), could overwhelm all but the most stoic readers, and misinterpretation of the data could lead to confusion and have an adverse effect on clinical practice. It is important, therefore, to assess the scientific reality and determine how attention to BPV might benefit patients with hypertension. In the first analysis, systolic BPV between visits and maximum BP reached in 4 cohorts of patients with previous transient ischemic attacks were strong predictors for subsequent stroke.1 In treated hypertensive patients in the Anglo-Scandinavian Cardiac Outcome Trial-Blood Pressure Lowering Arm systolic BPV between visits was also a strong predictor of stroke and coronary events independent of mean clinic or ambulatory BP measurement (ABPM). BPV on ABPM was a weaker predictor overall but was related to visit-to-visit variability. Traditional measures of variability, such as SD and coefficient of variation (CV), were used in these analyses, but one of the problems encountered in the …

Beyond LDL Cholesterol, a New Role for PCSK9

Elevated low-density lipoprotein cholesterol (LDLC) levels in the plasma is the most important causative factor of atherosclerosis and associated ischemic cardiovascular diseases. The LDL receptor (LDLR) is the preferential pathway through which LDLs are cleared from the circulation. LDLs bound to the LDLR are internalized into clathrin-coated pits and subsequently undergo lysosomal degradation, whereas the LDLR is recycled back to the plasma membrane. See accompanying article on page 1333 Familial hypercholesterolemia (FH) is an autosomal dominant disorder associated with elevated LDL levels and premature coronary heart disease. FH is caused primarily by mutations of the LDLR or of apolipoprotein B100 (apoB100), the protein component of LDL that interacts with the LDLR. In 2003, “gain of function” mutations on a newly identified gene, proprotein convertase subtilisin/kexin type 9 ( PCSK9), were associated with FH. In 2005, a causative association was established between “loss of function” mutations in PCSK9 and low LDLC levels in 2% of the African-American population. The coronary heart disease risk in these individuals was reduced by 88%. As a result of these landmark studies (reviewed in Reference 1), PCSK9 became the subject of intensive research to discover the underlying mechanisms. PCSK9 is a serine protease mainly expressed in the liver and the intestine. It acts by reducing the amount of LDLR in hepatocytes. This was demonstrated in vitro and in mouse models …

The Beneficial Effects of a Paleolithic Diet on Type 2 Diabetes and other Risk Factors for Cardiovascular Disease

A 2009 report by Jonsson and colleagues in Cardiovascular Diabetology has highlighted the potential benefits of a Paleolithic diet for patients with type 2 diabetes (T2DM). In a randomized crossover study spanning two consecutive 3-month study periods, a Paleolithic diet improved glycemic control and several cardiovascular risk factors compared to a diabetes diet in a cohort of patients with T2DM.1 Because a Paleolithic diet differs from a traditional diabetes diet, it is worthwhile to consider the potential benefits of this diet for patients with diabetes who are at increased risk for cardiovascular disease.

Weight of Pericardial Fat on Coronaropathy

The regional distribution of adipose tissue (AT) is a major determinant of metabolic and cardiovascular diseases. The mass of fat in the visceral area associates independently of obesity with the development and progression of cardiovascular diseases in a series of clinical and epidemiological studies.1 This led to the concept of a pathophysiological link between abdominal obesity and metabolic syndrome. More recently, fat depots localized around the heart, highly variable among individuals, were proposed to contribute to the pathogenesis of coronaropathy independently of other visceral depots (ie, in the omental and mesenteric area).2,3 The study by Greif et al3a in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology highlights the association between pericardial adipose tissue (PAT) and the number of atherosclerotic plaques evaluated concomitantly by Dual source CT scan. This measurement was qualitatively interpretable in 264 consecutive patients with a large range of age, a normal or moderately increased body mass index (BMI), and no a priori coronary disease. An estimated volume of pericardial fat more than 300 cm3 provided an incremental value for the presence of coronary atherosclerosis (odds ratio 4.1) independently of well known risk factors (hyperglycemia or diabetes, hypercholesterolemia, hypertension, and smoking). Ninety-five percent of patients with PAT volume >300 cm3 had one or more atherosclerotic plaques by ROC estimation. In univariate statistical analysis, PAT …

The Metabolic Syndrome

See related article, pages 1078–1083. The metabolic syndrome is a clustering of metabolic abnormalities, which include insulin resistance or diabetes, obesity, hypertension, and dyslipidemia. Although the mechanisms of the underlying abnormalities remain to be clarified, the pathogenesis includes both genetic predisposition and modifiable risk factors such as sedentary lifestyle and dietary intake. Recent estimates suggest that approximately 24% of US adults have the metabolic syndrome.1 In several studies, the metabolic syndrome has been shown to increase the risk of cardiovascular diseases2; however, the strength of its association with stroke is weaker than that for coronary heart disease.3 In the guidelines for the primary prevention of stroke from the American Heart Association/American Stroke Association, the metabolic syndrome is listed as a less–well-documented risk factor.4 But, given the high prevalence of the metabolic syndrome, studying its association with stroke is certainly relevant for 2 reasons: first, to obtain a better etiologic understanding of the causes of stroke; second, to identify individuals at high risk for stroke. This translates into 2 distinct scientific questions: is the metabolic syndrome by itself a risk factor for stroke?; and can we predict which individuals are at increased risk for stroke based on information about the metabolic syndrome? To answer these questions from observational data, one needs 2 distinct model-building strategies that require differences in assumptions of biological associations and statistical considerations.5,6 In this issue of Stroke ,7 Wang and …