Effects of a comprehensive lifestyle intervention on cardiovascular health: the TANSNIP-PESA trial.

AIMS: To investigate the effectiveness of a 3-year worksite lifestyle intervention on cardiovascular metrics and to study whether outcomes are influenced by baseline subclinical atherosclerosis (SA) by non-invasive imaging. METHODS AND RESULTS: A randomized controlled trial was performed to compare a lifestyle intervention with standard of care in asymptomatic middle-aged subjects, stratified by SA. The intervention consisted of nine motivational interviews during the first year, followed by three further sessions between Years 1 and 3. The primary outcome was the change in a pre-specified adaptation of the Fuster-BEWAT score (Blood pressure, Exercise, Weight, Alimentation, and Tobacco) between baseline and follow-up Years 1-3. A total of 1020 participants (mean age 50 ± 4 years) were enrolled, of whom 510 were randomly assigned to the intervention and 510 to the control group. The baseline adapted Fuster-BEWAT score was 16.2 ± 3.7 points in the intervention group and 16.5 ± 3.5 points in the control group. At Year 1, the score improved significantly in intervention participants compared with controls [estimate 0.83 (95% CI 0.52-1.15) points]. However, intervention effectiveness decreased to non-significant levels at Year 3 [0.24 (95% CI -0.10 to 0.59) points]. Over the 3-year period, the intervention was effective in participants having low baseline SA [0.61 (95% CI 0.30-0.93) points] but not in those with high baseline SA [0.19 (95% CI -0.26 to 0.64) points]. CONCLUSION: In middle-aged asymptomatic adults, a lifestyle intervention was associated with a significant improvement in cardiovascular health and behavioural metrics. The effect attenuated after 1 year as the intensity of the intervention was reduced. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02561065).

Bone marrow activation in response to metabolic syndrome and early atherosclerosis.

AIMS: Experimental studies suggest that increased bone marrow (BM) activity is involved in the association between cardiovascular risk factors and inflammation in atherosclerosis. However, human data to support this association are sparse. The purpose was to study the association between cardiovascular risk factors, BM activation, and subclinical atherosclerosis. METHODS AND RESULTS: Whole body vascular 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) was performed in 745 apparently healthy individuals [median age 50.5 (46.8-53.6) years, 83.8% men] from the Progression of Early Subclinical Atherosclerosis (PESA) study. Bone marrow activation (defined as BM 18F-FDG uptake above the median maximal standardized uptake value) was assessed in the lumbar vertebrae (L3-L4). Systemic inflammation was indexed from circulating biomarkers. Early atherosclerosis was evaluated by arterial metabolic activity by 18F-FDG uptake in five vascular territories. Late atherosclerosis was evaluated by fully formed plaques on MRI. Subjects with BM activation were more frequently men (87.6 vs. 80.0%, P = 0.005) and more frequently had metabolic syndrome (MetS) (22.2 vs. 6.7%, P < 0.001). Bone marrow activation was significantly associated with all MetS components. Bone marrow activation was also associated with increased haematopoiesis-characterized by significantly elevated leucocyte (mainly neutrophil and monocytes) and erythrocyte counts-and with markers of systemic inflammation including high-sensitivity C-reactive protein, ferritin, fibrinogen, P-selectin, and vascular cell adhesion molecule-1. The associations between BM activation and MetS (and its components) and increased erythropoiesis were maintained in the subgroup of participants with no systemic inflammation. Bone marrow activation was significantly associated with high arterial metabolic activity (18F-FDG uptake). The co-occurrence of BM activation and arterial 18F-FDG uptake was associated with more advanced atherosclerosis (i.e. plaque presence and burden). CONCLUSION: In apparently healthy individuals, BM 18F-FDG uptake is associated with MetS and its components, even in the absence of systemic inflammation, and with elevated counts of circulating leucocytes. Bone marrow activation is associated with early atherosclerosis, characterized by high arterial metabolic activity. Bone marrow activation appears to be an early phenomenon in atherosclerosis development.[Progression of Early Subclinical Atherosclerosis (PESA); NCT01410318].

Short-Term Progression of Multiterritorial Subclinical Atherosclerosis.

BACKGROUND: Atherosclerosis progression predicts cardiovascular events; however, progression of multiterritorial subclinical atherosclerosis is incompletely understood. OBJECTIVES: This study sought to study short-term progression of atherosclerosis using different noninvasive imaging techniques and their relationship with cardiovascular risk. METHODS: The study included 3,514 PESA (Progression of Early Subclinical Atherosclerosis) study participants (45.7 ± 4.2 years of age; 63% men). Participants underwent 2-dimensional vascular ultrasound (2DVUS) of abdominal aorta, carotid, iliac, and femoral territories to determine a plaque number score; 3DVUS to quantify carotid and femoral plaque volume; and coronary artery calcium score (CACS) at baseline and 2.8 years later. The authors calculated the rate of new disease incidence and changes in disease extent. Logistic regression models were used to evaluate associations of progression rates with baseline cardiovascular risk factors and estimated 10-year risk. RESULTS: Imaging detected short-term (3-year) atherosclerosis progression in 41.5% of participants (26.4% by 2DVUS, 21.3% by 3DVUS, and 11.5% by CACS), particularly in peripheral territories examined by vascular ultrasound. New atherosclerosis onset accounted for approximately one-third of total progression, also more frequently by 2DVUS and 3DVUS (29.1% and 16.6%, respectively), than by CACS (2.9%). Participants with baseline disease by all 3 modalities (n = 432) also showed significant atherosclerosis progression (median: 1 plaque [interquartile range (IQR): -1 to 3 plaques] by 2DVUS; 7.6 mm3 [IQR: -32.2 to 57.6 mm3] by 3DVUS; and 21.6 Agatston units [IQR: 4.8 to 62.6 Agatston units] by CACS). Age, sex, dyslipidemia, hypertension, smoking, and family history of premature cardiovascular disease contributed to progression, with dyslipidemia the strongest modifiable risk factor. Although disease progression correlated with cardiovascular risk, progression was detected in 36.5% of participants categorized as low risk. CONCLUSIONS: With this multimodal and multiterritorial approach, the authors detected short-term progression of early subclinical atherosclerosis in a substantial proportion (41.5%) of apparently healthy middle-aged men and women, more frequently by peripheral 2D/3DVUS than by CACS. Disease progression, as defined in this study, correlated with almost all cardiovascular risk factors and estimated risk. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318).

Does Socioeconomic Status Influence the Risk of Subclinical Atherosclerosis?: A Mediation Model.

BACKGROUND: Socioeconomic status (SES)-education, income level, and occupation-is associated with cardiovascular risk. OBJECTIVES: This study aimed to investigate the association between SES and subclinical atherosclerosis and the potential mechanisms involved. METHODS: SES, lifestyle habits (smoking, dietary patterns, physical activity, and hours of sleep), traditional risk factors, and subclinical atherosclerosis extent were prospectively assessed in 4,025 individuals aged 40 to 54 years without known cardiovascular disease enrolled in the PESA (Progression of Early Subclinical Atherosclerosis) study. After factors associated with atherosclerosis were identified, a multiple mediation model was created to quantify the effect of SES on subclinical atherosclerosis as explained by lifestyle behaviors. RESULTS: Although education level was significantly associated with the presence of atherosclerosis, no differences were found according to income level in this population. Participants with lower education presented with a higher risk of generalized atherosclerosis than those with higher education (odds ratio: 1.46; 95% confidence interval: 1.15 to 1.85; p = 0.002). Lifestyle behaviors associated with both education level and atherosclerosis extent were: smoking status, number of cigarettes/day, and dietary pattern, which explained 70.5% of the effect of SES on atherosclerosis. Of these, tobacco habit (smoking status 35% and number of cigarettes/day 32%) accounted for most of the explained differences between groups, whereas dietary pattern did not remain a significant mediator in the multiple mediation model. CONCLUSIONS: Despite the relative economic homogeneity of the cohort, lower education level is associated with increased subclinical atherosclerosis, mainly mediated by the higher and more frequent tobacco consumption. Smoking cessation programs are still needed, particularly in populations with lower education level.

Vascular Inflammation in Subclinical Atherosclerosis Detected by Hybrid PET/MRI.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease, but data on arterial inflammation at early stages is limited. OBJECTIVES: The purpose of this study was to characterize vascular inflammation by hybrid 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI). METHODS: Carotid, aortic, and ilio-femoral 18F-FDG PET/MRI was performed in 755 individuals (age 40 to 54 years; 83.7% men) with known plaques detected by 2-/3-dimensional vascular ultrasound and/or coronary calcification in the PESA (Progression of Early Subclinical Atherosclerosis) study. The authors evaluated the presence, distribution, and number of arterial inflammatory foci (increased 18F-FDG uptake) and plaques with or without inflammation (coincident 18F-FDG uptake). RESULTS: Arterial inflammation was present in 48.2% of individuals (24.4% femorals, 19.3% aorta, 15.8% carotids, and 9.3% iliacs) and plaques in 90.1% (73.9% femorals, 55.8% iliacs, and 53.1% carotids). 18F-FDG arterial uptakes and plaques significantly increased with cardiovascular risk factors (p < 0.01). Coincident 18F-FDG uptakes were present in 287 of 2,605 (11%) plaques, and most uptakes were detected in plaque-free arterial segments (459 of 746; 61.5%). Plaque burden, defined by plaque presence, number, and volume, was significantly higher in individuals with arterial inflammation than in those without (p < 0.01). The number of plaques and 18F-FDG uptakes showed a positive albeit weak correlation (r = 0.25; p < 0.001). CONCLUSIONS: Arterial inflammation is highly prevalent in middle-aged individuals with known subclinical atherosclerosis. Large-scale multiterritorial PET/MRI allows characterization of atherosclerosis-related arterial inflammation and demonstrates 18F-FDG uptake in plaque-free arterial segments and, less frequently, within plaques. These findings suggest an arterial inflammatory state at early stages of atherosclerosis. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318).

Normal LDL-Cholesterol Levels Are Associated With Subclinical Atherosclerosis in the Absence of Risk Factors.

BACKGROUND: Absence of cardiovascular risk factors (CVRFs) is traditionally considered low risk for atherosclerosis; however, individuals without CVRFs, as currently defined, still have events. OBJECTIVES: This study sought to identify predictors of subclinical atherosclerosis in CVRF-free individuals. METHODS: Participants from the PESA (Progression of Early Subclinical Atherosclerosis) study (n = 4,184) without conventional CVRFs were evaluated (n = 1,779; 45.0 ± 4.1 years, 50.3% women). CVRF freedom was defined as no current smoking and untreated blood pressure <140/90 mm Hg, fasting glucose <126 mg/dl, total cholesterol <240 mg/dl, low-density lipoprotein cholesterol (LDL-C) <160 mg/dl, and high-density lipoprotein cholesterol ≥40 mg/dl. A subgroup with optimal CVRFs (n = 740) was also defined as having blood pressure <120/80 mm Hg, fasting glucose <100 mg/dl, glycosylated hemoglobin <5.7%, and total cholesterol <200 mg/dl. We evaluated ultrasound-detected carotid, iliofemoral, and abdominal aortic plaques; coronary artery calcification; serum biomarkers; and lifestyle. Adjusted odds ratios (with 95% confidence interval) and ordinal logistic regression models were used. RESULTS: Subclinical atherosclerosis (plaque or coronary artery calcification) was present in 49.7% of CVRF-free participants. Together with male sex and age, LDL-C was independently associated with atherosclerosis presence and extent, in both the CVRF-free and CVRF-optimal groups (odds ratio [×10 mg/dl]: 1.14 to 1.18; p < 0.01 for all). Atherosclerosis presence and extent was also associated in the CVRF-free group with glycosylated hemoglobin levels. CONCLUSIONS: Many CVRF-free middle-aged individuals have atherosclerosis. LDL-C, even at levels currently considered normal, is independently associated with the presence and extent of early systemic atherosclerosis in the absence of major CVRFs. These findings support more effective LDL-C lowering for primordial prevention, even in individuals conventionally considered at optimal risk. (Progression of Early Subclinical Atherosclerosis [PESA] Study; NCT01410318).

Predicting Subclinical Atherosclerosis in Low-Risk Individuals: Ideal Cardiovascular Health Score and Fuster-BEWAT Score.

BACKGROUND: The ideal cardiovascular health score (ICHS) is recommended for use in primary prevention. Simpler tools not requiring laboratory tests, such as the Fuster-BEWAT (blood pressure [B], exercise [E], weight [W], alimentation [A], and tobacco [T]) score (FBS), are also available. OBJECTIVES: The purpose of this study was to compare the effectiveness of ICHS and FBS in predicting the presence and extent of subclinical atherosclerosis. METHODS: A total of 3,983 participants 40 to 54 years of age were enrolled in the PESA (Progression of Early Subclinical Atherosclerosis) cohort. Subclinical atherosclerosis was measured in right and left carotids, abdominal aorta, right and left iliofemoral arteries, and coronary arteries. Subjects were classified as having poor, intermediate, or ideal cardiovascular health based on the number of favorable ICHS or FBS. RESULTS: With poor ICHS and FBS as references, individuals with ideal ICHS and FBS showed lower adjusted odds of having atherosclerotic plaques (ICHS odds ratio [OR]: 0.41; 95% confidence interval [CI]: 0.31 to 0.55 vs. FBS OR: 0.49; 95% CI: 0.36 to 0.66), coronary artery calcium (CACS) ≥1 (CACS OR: 0.41; 95% CI: 0.28 to 0.60 vs. CACS OR: 0.53; 95% CI: 0.38 to 0.74), higher number of affected territories (OR: 0.32; 95% CI: 0.26 to 0.41 vs. OR: 0.39; 95% CI: 0.31 to 0.50), and higher CACS level (OR: 0.40; 95% CI: 0.28 to 0.58 vs. OR: 0.52; 95% CI: 0.38 to 0.72). Similar levels of significantly discriminating accuracy were found for ICHS and FBS with respect to the presence of plaques (C-statistic: 0.694; 95% CI: 0.678 to 0.711 vs. 0.692; 95% CI: 0.676 to 0.709, respectively) and for CACS ≥1 (C-statistic: 0.782; 95% CI: 0.765 to 0.800 vs. 0.780; 95% CI: 0.762 to 0.798, respectively). CONCLUSIONS: Both scores predict the presence and extent of subclinical atherosclerosis with similar accuracy, highlighting the value of the FBS as a simpler and more affordable score for evaluating the risk of subclinical disease.

The Importance of Breakfast in Atherosclerosis Disease: Insights From the PESA Study.

BACKGROUND: Daily habits, including the number and quality of eating occasions, are potential targets for primary prevention strategies with large health impacts. Skipping breakfast is considered a frequent and unhealthy habit associated with an increased cardiovascular (CV) risk. OBJECTIVES: The study sought to explore the association between different breakfast patterns and CV risk factors and the presence, distribution, and extension of subclinical atherosclerosis. METHODS: Cross-sectional analysis was performed within the PESA (Progression of Early Subclinical Atherosclerosis) study, a prospective cohort of asymptomatic (free of CV events at baseline) adults 40 to 54 years of age. Lifestyle and multivascular imaging data along with clinical covariates were collected from 4,052 participants. Multivariate logistic regression models were used in the analysis. RESULTS: Three patterns of breakfast consumption were studied: high-energy breakfast, when contributing to >20% of total daily energy intake (27% of the population); low-energy breakfast, when contributing between 5% and 20% of total daily energy intake (70% of the population); and skipping breakfast, when consuming <5% of total daily energy (3% of the population). Independent of the presence of traditional and dietary CV risk factors, and compared with high-energy breakfast, habitual skipping breakfast was associated with a higher prevalence of noncoronary (odds ratio: 1.55; 95% confidence interval: 0.97 to 2.46) and generalized (odds ratio: 2.57; 95% confidence interval: 1.54 to 4.31) atherosclerosis. CONCLUSION: Skipping breakfast is associated with an increased odds of prevalent noncoronary and generalized atherosclerosis independently of the presence of conventional CV risk factors. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318).

Subclinical Atherosclerosis Burden by 3D Ultrasound in Mid-Life: The PESA Study.

BACKGROUND: Detection of subclinical atherosclerosis improves risk prediction beyond cardiovascular risk factors (CVRFs) and risk scores, but quantification of plaque burden may improve it further. Novel 3-dimensional vascular ultrasound (3DVUS) provides accurate volumetric quantification of plaque burden. OBJECTIVES: The authors evaluated associations between 3DVUS-based plaque burden and CVRFs and explored potential added value over simple plaque detection. METHODS: The authors included 3,860 (92.2%) PESA (Progression of Early Subclinical Atherosclerosis) study participants (age 45.8 ± 4.3 years; 63% men). Bilateral carotid and femoral territories were explored by 3DVUS to determine the number of plaques and territories affected, and to quantify global plaque burden defined as the sum of all plaque volumes. Linear regression and proportional odds models were used to evaluate associations of plaque burden with CVRFs and estimated 10-year cardiovascular risk. RESULTS: Plaque burden was higher in men (63.4 mm3 [interquartile range (IQR): 23.8 to 144.8 mm3] vs. 25.7 mm3 [IQR: 11.5 to 61.6 mm3] in women; p < 0.001), in the femoral territory (64 mm3 [IQR: 27.6 to 140.5 mm3] vs. 23.1 mm3 [IQR: 9.9 to 48.7 mm3] in the carotid territory; p < 0.001), and with increasing age (p < 0.001). Age, sex, smoking, and dyslipidemia were more strongly associated with femoral than with carotid disease burden, whereas hypertension and diabetes showed no territorial differences. Plaque burden was directly associated with estimated cardiovascular risk independently of the number of plaques or territories affected (p < 0.01). CONCLUSIONS: 3DVUS quantifies higher plaque burden in men, in the femoral territory, and with increasing age during midlife. Plaque burden correlates strongly with CVRFs, especially at the femoral level, and reflects estimated cardiovascular risk more closely than plaque detection alone. (Progression of Early Subclinical Atherosclerosis [PESA] Study; NCT01410318).

A 30-month worksite-based lifestyle program to promote cardiovascular health in middle-aged bank employees: Design of the TANSNIP-PESA randomized controlled trial.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death worldwide. With atherosclerosis as the underlying cause for many CVD events, prevention or reduction of subclinical atherosclerotic plaque burden (SAPB) through a healthier lifestyle may have substantial public health benefits. OBJECTIVE: The objective was to describe the protocol of a randomized controlled trial investigating the effectiveness of a 30-month worksite-based lifestyle program aimed to promote cardiovascular health in participants having a high or a low degree of SAPB compared with standard care. METHODS: We will conduct a randomized controlled trial including middle-aged bank employees from the Progression of Early Subclinical Atherosclerosis cohort, stratified by SAPB (high SAPB n=260, low SAPB n=590). Within each stratum, participants will be randomized 1:1 to receive a lifestyle program or standard care. The program consists of 3 elements: (a) 12 personalized lifestyle counseling sessions using Motivational Interviewing over a 30-month period, (b) a wrist-worn physical activity tracker, and (c) a sit-stand workstation. Primary outcome measure is a composite score of blood pressure, physical activity, sedentary time, body weight, diet, and smoking (ie, adapted Fuster-BEWAT score) measured at baseline and at 1-, 2-, and 3-year follow-up. CONCLUSIONS: The study will provide insights into the effectiveness of a 30-month worksite-based lifestyle program to promote cardiovascular health compared with standard care in participants with a high or low degree of SAPB.

Association Between a Social-Business Eating Pattern and Early Asymptomatic Atherosclerosis.

BACKGROUND: The importance of a healthy diet in relation to cardiovascular health promotion is widely recognized. Identifying specific dietary patterns related to early atherosclerosis would contribute greatly to inform effective primary prevention strategies. OBJECTIVES: This study sought to quantify the association between specific dietary patterns and presence and extent of subclinical atherosclerosis in a population of asymptomatic middle-aged adults. METHODS: The PESA (Progression of Early Subclinical Atherosclerosis) study enrolled 4,082 asymptomatic participants 40 to 54 years of age (mean age 45.8 years; 63% male) to evaluate the presence of subclinical atherosclerosis in multiple vascular territories. A fundamental objective of this cohort study was to evaluate the life-style-related determinants, including diet, on atherosclerosis onset and development. We conducted a cross-sectional analysis of baseline data, including detailed information on dietary habits obtained as part of the overall life-style and risk factor assessment, as well as a complete vascular imaging study that was performed blinded to the clinical information. RESULTS: Most PESA participants follow a Mediterranean (40% of participants) or a Western (41%) dietary pattern. A new pattern, identified among 19% of participants, was labeled as a social-business eating pattern, characterized by a high consumption of red meat, pre-made foods, snacks, alcohol, and sugar-sweetened beverages and frequent eating-out behavior. Participants following this pattern presented a significantly worse cardiovascular risk profile and, after adjustment for risk factors, increased odds of presenting subclinical atherosclerosis (odds ratio: 1.31; 95% confidence interval: 1.06 to 1.63) compared with participants following a Mediterranean diet. CONCLUSIONS: A new social-business eating pattern, characterized by high consumption of red and processed meat, alcohol, and sugar-sweetened beverages, and by frequent snacking and eating out as part of an overall unhealthy life-style, is associated with an increased prevalence, burden, and multisite presence of subclinical atherosclerosis. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318).

Prevalence, Vascular Distribution, and Multiterritorial Extent of Subclinical Atherosclerosis in a Middle-Aged Cohort: The PESA (Progression of Early Subclinical Atherosclerosis) Study.

BACKGROUND: Data are limited on the presence, distribution, and extent of subclinical atherosclerosis in middle-aged populations. METHODS AND RESULTS: The PESA (Progression of Early Subclinical Atherosclerosis) study prospectively enrolled 4184 asymptomatic participants 40 to 54 years of age (mean age, 45.8 years; 63% male) to evaluate the systemic extent of atherosclerosis in the carotid, abdominal aortic, and iliofemoral territories by 2-/3-dimensional ultrasound and coronary artery calcification by computed tomography. The extent of subclinical atherosclerosis, defined as presence of plaque or coronary artery calcification ≥1, was classified as focal (1 site affected), intermediate (2-3 sites), or generalized (4-6 sites) after exploration of each vascular site (right/left carotids, aorta, right/left iliofemorals, and coronary arteries). Subclinical atherosclerosis was present in 63% of participants (71% of men, 48% of women). Intermediate and generalized atherosclerosis was identified in 41%. Plaques were most common in the iliofemorals (44%), followed by the carotids (31%) and aorta (25%), whereas coronary artery calcification was present in 18%. Among participants with low Framingham Heart Study (FHS) 10-year risk, subclinical disease was detected in 58%, with intermediate or generalized disease in 36%. When longer-term risk was assessed (30-year FHS), 83% of participants at high risk had atherosclerosis, with 66% classified as intermediate or generalized. CONCLUSIONS: Subclinical atherosclerosis was highly prevalent in this middle-aged cohort, with nearly half of the participants classified as having intermediate or generalized disease. Most participants at high FHS risk had subclinical disease; however, extensive atherosclerosis was also present in a substantial number of low-risk individuals, suggesting added value of imaging for diagnosis and prevention. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01410318.