Chiadi E. Ndumele

Markers of inflammation and coronary artery calcification: a systematic review.

OBJECTIVES The goal of this systematic review is to assess the cross-sectional relationship of inflammatory markers with the presence and extent of coronary artery calcium (CAC) to identify asymptomatic individuals with a higher risk of coronary heart disease (CHD). BACKGROUND Markers of subclinical inflammation and subclinical atherosclerosis have both been used to improve detection of individuals at high risk of developing cardiovascular disease. CAC has emerged as a surrogate maker for underlying coronary atherosclerosis, and has been shown to predict future CHD events. Although inflammation is intimately associated with atherosclerosis, and levels of inflammatory markers predict cardiovascular risk, the relationship of subclinical inflammatory markers with the burden of coronary atherosclerosis is not clear. METHODS Medline and Pub Med databases were searched for all studies assessing the relationship of inflammatory markers with CAC published till July 2007. RESULTS We found 12 studies that met our criteria. CRP, fibrinogen, metallic metalloproteinase-9 (MMP-9), monocyte chemotactic protein 1 (MCP-1), resistin, lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), IL-6, tumor necrosis factor alpha (TNF-alpha) and beta-fibroblast growth factor (bFGF) were used as inflammatory markers. There was a wide variation among studies with regards to population size, inclusion criterias, age range and techniques. It was observed that in almost all studies the relationship between inflammatory markers and CAC was weak, and was mostly found upon univariate analysis in women. However, this association was lost after correction for obesity and BMI. The data on the relationship of inflammation and CAC with progression of atherosclerosis is scarce and did not show any predictive benefits for future CHD. CONCLUSION Variable associations between CAC and inflammatory markers were identified. In most studies where a positive relationship was found, this relationship disappeared after appropriate correction for the presence of traditional risk factors. Our data suggests that an approach in which inflammatory markers are used to further characterize risk in individuals with an established coronary artery disease burden is more warranted than using biomarkers as sole risk predictors of future CHD events. Large, well-planned comprehensive studies are required to identify the combined role of measuring inflammatory markers in assessment of atherosclerotic disease.

NH2-Terminal Pro–Brain Natriuretic Peptide and Risk of Diabetes

Brain natriuretic peptide (BNP) has an established role in cardiovascular disease (CVD). However, recent animal studies suggest direct metabolic effects of BNP. To determine the association of BNP with the risk of diabetes, we conducted a prospective analysis of participants from the Atherosclerosis Risk in Communities (ARIC) study. We included 7,822 men and women without history of diabetes, CVD, or reduced kidney function at baseline. At baseline, NH2-terminal (NT)-proBNP, a cleavage product of BNP, was inversely associated with adiposity, fasting glucose, insulin, and cholesterol but positively associated with blood pressure and C-reactive protein levels. During a median follow-up of 12 years, 1,740 participants reported a new diagnosis of diabetes or medication use for diabetes. Baseline quartiles of NT-proBNP were inversely associated with diabetes risk, even after multivariable adjustment including fasting glucose. The adjusted HRs for diabetes were 1.0 (reference), 0.84 (95% CI 0.74–0.96), 0.79 (95% CI 0.68–0.90), and 0.75 (95% CI 0.64–0.87) for the 1st, 2nd, 3rd, and 4th quartiles of baseline NT-proBNP, respectively (P for trend <0.001). This inverse association was robust across sex, race, and obesity subgroups. Our results extend animal studies and support a direct and important metabolic role of BNP in humans.

mActive: A Randomized Clinical Trial of an Automated mHealth Intervention for Physical Activity Promotion

Background We hypothesized that a fully automated mobile health (mHealth) intervention with tracking and texting components would increase physical activity. Methods and Results mActive enrolled smartphone users aged 18 to 69 years at an ambulatory cardiology center in Baltimore, Maryland. We used sequential randomization to evaluate the interventions 2 core components. After establishing baseline activity during a blinded run‐in (week 1), in phase I (weeks 2 to 3), we randomized 2:1 to unblinded versus blinded tracking. Unblinding allowed continuous access to activity data through a smartphone interface. In phase II (weeks 4 to 5), we randomized unblinded participants 1:1 to smart texts versus no texts. Smart texts provided smartphone‐delivered coaching 3 times/day aimed at individual encouragement and fostering feedback loops by a fully automated, physician‐written, theory‐based algorithm using real‐time activity data and 16 personal factors with a 10 000 steps/day goal. Forty‐eight outpatients (46% women, 21% nonwhite) enrolled with a mean±SD age of 58±8 years, body mass index of 31±6 kg/m2, and baseline activity of 9670±4350 steps/day. Daily activity data capture was 97.4%. The phase I change in activity was nonsignificantly higher in unblinded participants versus blinded controls by 1024 daily steps (95% confidence interval [CI], −580 to 2628; P=0.21). In phase II, participants receiving texts increased their daily steps over those not receiving texts by 2534 (95% CI, 1318 to 3750; P<0.001) and over blinded controls by 3376 (95% CI, 1951 to 4801; P<0.001). Conclusions An automated tracking‐texting intervention increased physical activity with, but not without, the texting component. These results support new mHealth tracking technologies as facilitators in need of behavior change drivers. Clinical Trial Registration URL: http://ClinicalTrials.gov/. Unique identifier: NCT01917812.

The association of Framingham and reynolds risk scores with incidence and progression of coronary artery calcification in MESA (multi-ethnic study of atherosclerosis)

OBJECTIVES The purpose of this study was to compare the association of the Framingham risk score (FRS) and Reynolds risk score (RRS) with subclinical atherosclerosis, assessed by incidence and progression of coronary artery calcium (CAC). BACKGROUND The comparative effectiveness of competing risk algorithms for identifying subclinical atherosclerosis is unknown. METHODS MESA (Multi-Ethnic Study of Atherosclerosis) is a prospective cohort study of 6,814 participants free of baseline cardiovascular disease. All participants underwent risk factor assessment, as well as baseline and follow-up CAC testing. We assessed the performance of the FRS and RRS to predict CAC incidence and progression using relative risk and robust linear regression. RESULTS The study population included 5,140 individuals (mean age 61 ± 10 years, 47% males, mean follow-up: 3.1 ± 1.3 years). Among 53% of subjects (n = 2,729) with no baseline CAC, 18% (n = 510) developed incident CAC. Both the FRS and RRS were significantly predictive of incident CAC (relative risk: 1.40 [95% confidence interval (CI): 1.29 to 1.52] and 1.41 [95% CI: 1.30 to 1.54] per 5% increase in risk, respectively) and CAC progression (mean CAC score change: 6.92 [95% CI: 5.31 to 8.54] and 6.82 [95% CI: 5.51 to 8.14] per 5% increase). Discordance in risk category classification (<10% or >10% per 10-year coronary heart disease risk) occurred in 13.7%, with only the RRS consistently adding predictive value for incidence and progression of CAC. These subclinical atherosclerosis findings are supported by a coronary heart disease events analysis over a mean follow-up of 5.6 ± 0.7 years. CONCLUSIONS Both the RRS and FRS predict onset and progression of subclinical atherosclerosis. However, the RRS may provide additional predictive information when discordance between the scoring systems exists.

Obesity, Subclinical Myocardial Injury, and Incident Heart Failure

OBJECTIVES The study sought to evaluate the association of obesity with a novel biomarker of subclinical myocardial injury, cardiac troponin T measured with a new high-sensitivity assay (hs-cTnT), among adults without clinical cardiovascular disease (CVD). BACKGROUND Laboratory evidence suggests a relationship between obesity and myocardial injury that may play a role in the development of heart failure (HF), but there is limited clinical data regarding this association. METHODS We evaluated 9,507 participants in the ARIC (Atherosclerosis Risk in Communities) study without baseline CVD (Visit 4, 1996 to 1999). We assessed the cross-sectional association of body mass index (BMI) with high (≥14 ng/l) and measurable (≥3 ng/l) hs-cTnT levels after multivariable regression. We further evaluated the independent and combined associations of BMI and hs-cTnT with incident HF. RESULTS Higher BMI was independently associated with a positive, linear increase in the likelihood of high hs-cTnT, with severe obesity (BMI >35 kg/m(2)) associated with an odds ratio of 2.20 (95% confidence interval: 1.59 to 3.06) for high hs-cTnT after adjustment. Over 12 years of follow-up, there were 869 incident HF events. Obesity and hs-cTnT were both independently associated with incident HF, and individuals with severe obesity and high hs-cTnT had a greater than 9-fold higher risk of incident HF (hazard ratio: 9.20 [95% confidence interval: 5.67 to 14.93]) than individuals with normal weight and undetectable hs-cTnT. CONCLUSIONS Among individuals without CVD, higher BMI has an independent, linear association with subclinical myocardial injury, as assessed by hs-cTnT levels. Obesity and hs-cTnT provide independent and complementary prognostic information regarding the risk of incident HF.

Liver enzymes, race, gender and diabetes risk: the Atherosclerosis Risk in Communities (ARIC) Study.

To examine the associations of the liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase(AST), and gamma‐glutamyl transferase (GGT) with diabetes risk and to determine whether associations differ by race and/or gender. We hypothesized that all liver enzymes would be associated with diabetes risk and that associations would differ by race and gender.

Obesity and Subtypes of Incident Cardiovascular Disease

Background Obesity is a risk factor for various subtypes of cardiovascular disease (CVD), including coronary heart disease (CHD), heart failure (HF), and stroke. Nevertheless, there are limited comparisons of the associations of obesity with each of these CVD subtypes, particularly regarding the extent to which they are unexplained by traditional CVD mediators. Methods and Results We followed 13 730 participants in the Atherosclerosis Risk in Communities (ARIC) study who had a body mass index ≥18.5 and no CVD at baseline (visit 1, 1987–1989). We compared the association of higher body mass index with incident HF, CHD, and stroke before and after adjusting for traditional CVD mediators (including systolic blood pressure, diabetes mellitus, and lipid measures). Over a median follow‐up of 23 years, there were 2235 HF events, 1653 CHD events, and 986 strokes. After adjustment for demographics, smoking, physical activity, and alcohol intake, higher body mass index had the strongest association with incident HF among CVD subtypes, with hazard ratios for severe obesity (body mass index ≥35 versus normal weight) of 3.74 (95% CI 3.24–4.31) for HF, 2.00 (95% CI 1.67–2.40) for CHD, and 1.75 (95% CI 1.40–2.20) for stroke (P<0.0001 for comparisons of HF versus CHD or stroke). Further adjustment for traditional mediators fully explained the association of higher body mass index with CHD and stroke but not with HF (hazard ratio 2.27, 95% CI 1.94–2.64). Conclusions The link between obesity and HF was stronger than those for other CVD subtypes and was uniquely unexplained by traditional risk factors. Weight management is likely critical for optimal HF prevention, and nontraditional pathways linking obesity to HF need to be elucidated.

N-Terminal Pro-Brain Natriuretic Peptide and Heart Failure Risk Among Individuals With and Without Obesity: The Atherosclerosis Risk in Communities (ARIC) Study.

Background —Obesity is a risk factor for heart failure (HF), but is associated with lower N-terminal of pro-Brain Natriuretic Peptide (NT-proBNP) levels. It is unclear whether the prognostic value and implications of NT-proBNP levels for HF risk differ across body mass index (BMI) categories. Methods and Results —We followed 12,230 ARIC participants free of prior HF at baseline (visit 2, 1990-1992) with BMI ≥18.5 kg/m2. We quantified and compared the relative and absolute risk associations of NT-proBNP with incident HF across BMI categories. There were 1,861 HF events during a median 20.6 years of follow-up. Despite increased HF risk in obesity, a weak inverse association was seen between baseline BMI and NT-proBNP levels (r = -0.10). Nevertheless, higher baseline NT-proBNP was associated with increased HF risk in all BMI categories. NT-proBNP improved HF risk prediction overall and even among those with severe obesity (BMI ≥35 kg/m2; improvement in c-statistic +0.032 [95% CI 0.011-0.053]). However, given higher HF rates among those with obesity, at each NT-proBNP level, higher BMI was associated with greater absolute HF risk. Indeed, among those with NT-proBNP 100 to 10% if severely obese. Conclusions —Despite its inverse relationship with BMI, NT-proBNP provides significant prognostic information regarding the risk of developing HF even among individuals with obesity. Given the higher baseline HF risk among persons with obesity, even slight elevations in NT-proBNP may have implications for increased absolute HF risk in this population.Background— Obesity is a risk factor for heart failure (HF) but is associated with lower N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. It is unclear whether the prognostic value and implications of NT-proBNP levels for HF risk differ across body mass index (BMI) categories. Methods and Results— We followed up 12 230 ARIC participants free of prior HF at baseline (visit 2, 1990–1992) with BMI ≥18.5 kg/m2. We quantified and compared the relative and absolute risk associations of NT-proBNP with incident HF across BMI categories. There were 1861 HF events during a median 20.6 years of follow-up. Despite increased HF risk in obesity, a weak inverse association was seen between baseline BMI and NT-proBNP levels (r=−0.10). Nevertheless, higher baseline NT-proBNP was associated with increased HF risk in all BMI categories. NT-proBNP improved HF risk prediction overall, even among those with severe obesity (BMI ≥35 kg/m2; improvement in C statistic, 0.032; 95% confidence interval, 0.011–0.053). However, given the higher HF rates among those with obesity, at each NT-proBNP level, higher BMI was associated with greater absolute HF risk. Indeed, among those with NT-proBNP of 100 to <200 pg/mL, the average 10-year HF risk was <5% among normal-weight individuals but >10% among the severely obese. Conclusions— Despite its inverse relationship with BMI, NT-proBNP provides significant prognostic information on the risk of developing HF even among individuals with obesity. Given the higher baseline HF risk among persons with obesity, even slight elevations in NT-proBNP may have implications for increased absolute HF risk in this population.

Six-Year Change in High-Sensitivity Cardiac Troponin T and Risk of Subsequent Coronary Heart Disease, Heart Failure, and Death.

IMPORTANCE High-sensitivity cardiac troponin T (hs-cTnT) is a biomarker of cardiovascular risk and could be approved in the United States for clinical use soon. However, data linking long-term temporal change in hs-cTnT to outcomes are limited, particularly in primary prevention settings. OBJECTIVE To examine the association of 6-year change in hs-cTnT with incident coronary heart disease (CHD), heart failure (HF), and all-cause mortality. DESIGN, SETTING, AND PARTICIPANTS This prospective observational cohort study, performed from January 1, 1990, to December 31, 2011, included 8838 participants with biracial representation from the Atherosclerosis Risk in Communities Study who were initially free of CHD and HF and who had hs-cTnT measured twice, 6 years apart. Data analysis was performed from October 28, 2014, to March 9, 2016. MAIN OUTCOME AND MEASURES Risk factor and temporal hs-cTnT data were collected. Using Cox proportional hazards regression, we examined the association of hs-cTnT change with subsequent CHD, HF, and death during a maximum of 16 years. Improvement in discrimination was determined by the Harrell C statistic. RESULTS Of the 8838 participants (mean age, 56 years; 5215 female [59.0%]; 1891 black [21.4%]) there were 1157 CHD events, 965 HF events, and 1813 deaths overall. Incident detectable hs-cTnT (baseline, <0.005 ng/mL; follow-up, ≥0.005 ng/mL) was independently associated with subsequent CHD (hazard ratio [HR], 1.4; 95% CI, 1.2-1.6), HF (HR, 2.0; 95% CI, 1.6-2.4), and death (HR, 1.5; 95% CI, 1.3-1.7), relative to an hs-cTnT level less than 0.005 ng/mL at both visits. In addition, HRs as high as 4 for CHD and death and 8 for HF were recorded among individuals with the most marked hs-cTnT increases (eg, baseline, < 0.005 ng/mL; follow-up, ≥0.014 ng/mL). Risk for subsequent outcomes was lower among those with relative hs-cTnT reductions greater than 50% from baseline. Furthermore, information on hs-cTnT change improved discrimination for HF and death when added to a model that included traditional risk factors, N-terminal pro-brain natriuretic peptide, and baseline hs-cTnT level. Among individuals with adjudicated HF hospitalizations, hs-cTnT change appeared to be similarly associated with HF with reduced and preserved ejection fraction. CONCLUSIONS AND RELEVANCE Temporal increases in hs-cTnT, suggestive of progressive myocardial damage, are independently associated with incident CHD, death, and, above all, HF. Serial determination of hs-cTnT trajectory adds clinically relevant information to baseline testing and may be useful in prognostic assessments and the targeting of prevention strategies to high-risk individuals, especially among persons with stage A or B HF.

NT-proBNP and Heart Failure Risk Among Individuals With and Without Obesity: The ARIC Study

Background —Obesity is a risk factor for heart failure (HF), but is associated with lower N-terminal of pro-Brain Natriuretic Peptide (NT-proBNP) levels. It is unclear whether the prognostic value and implications of NT-proBNP levels for HF risk differ across body mass index (BMI) categories. Methods and Results —We followed 12,230 ARIC participants free of prior HF at baseline (visit 2, 1990-1992) with BMI ≥18.5 kg/m2. We quantified and compared the relative and absolute risk associations of NT-proBNP with incident HF across BMI categories. There were 1,861 HF events during a median 20.6 years of follow-up. Despite increased HF risk in obesity, a weak inverse association was seen between baseline BMI and NT-proBNP levels (r = -0.10). Nevertheless, higher baseline NT-proBNP was associated with increased HF risk in all BMI categories. NT-proBNP improved HF risk prediction overall and even among those with severe obesity (BMI ≥35 kg/m2; improvement in c-statistic +0.032 [95% CI 0.011-0.053]). However, given higher HF rates among those with obesity, at each NT-proBNP level, higher BMI was associated with greater absolute HF risk. Indeed, among those with NT-proBNP 100 to 10% if severely obese. Conclusions —Despite its inverse relationship with BMI, NT-proBNP provides significant prognostic information regarding the risk of developing HF even among individuals with obesity. Given the higher baseline HF risk among persons with obesity, even slight elevations in NT-proBNP may have implications for increased absolute HF risk in this population.Background— Obesity is a risk factor for heart failure (HF) but is associated with lower N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. It is unclear whether the prognostic value and implications of NT-proBNP levels for HF risk differ across body mass index (BMI) categories. Methods and Results— We followed up 12 230 ARIC participants free of prior HF at baseline (visit 2, 1990–1992) with BMI ≥18.5 kg/m2. We quantified and compared the relative and absolute risk associations of NT-proBNP with incident HF across BMI categories. There were 1861 HF events during a median 20.6 years of follow-up. Despite increased HF risk in obesity, a weak inverse association was seen between baseline BMI and NT-proBNP levels (r=−0.10). Nevertheless, higher baseline NT-proBNP was associated with increased HF risk in all BMI categories. NT-proBNP improved HF risk prediction overall, even among those with severe obesity (BMI ≥35 kg/m2; improvement in C statistic, 0.032; 95% confidence interval, 0.011–0.053). However, given the higher HF rates among those with obesity, at each NT-proBNP level, higher BMI was associated with greater absolute HF risk. Indeed, among those with NT-proBNP of 100 to <200 pg/mL, the average 10-year HF risk was <5% among normal-weight individuals but >10% among the severely obese. Conclusions— Despite its inverse relationship with BMI, NT-proBNP provides significant prognostic information on the risk of developing HF even among individuals with obesity. Given the higher baseline HF risk among persons with obesity, even slight elevations in NT-proBNP may have implications for increased absolute HF risk in this population.