Effect of Intensive Blood Pressure Control on Troponin and Natriuretic Peptide Levels: Findings From SPRINT.

BACKGROUND: Given the important role of cardiac injury and neurohormonal activation in the pathways leading from hypertension to heart failure and strong associations observed between hypertension and its sequelae on hs-cTnT (high-sensitivity cardiac troponin T) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, we hypothesized that intensive systolic blood pressure (SBP) lowering would decrease levels of hs-cTnT and NT-proBNP. METHODS: hs-cTnT and NT-proBNP were measured at baseline and 1 year from stored specimens in SPRINT (Systolic Blood Pressure Intervention Trial). Changes in biomarkers were evaluated continuously on the log scale and according to categories (≥50% increase, ≥50% decrease, or <50% change). The effect of intensive SBP lowering on continuous and categorical changes in biomarker levels were assessed using linear and multinomial logistic regression models, respectively. The association between changes in biomarkers on heart failure and death was assessed using multivariable-adjusted Cox proportional hazards models. RESULTS: Randomization to intensive SBP lowering (versus standard SBP management) resulted in a 3% increase in hs-cTnT levels over 1-year follow-up (geometric mean ratio, 1.03 [95% CI, 1.01-1.04]) and a higher proportion of participants with ≥50% increase (odds ratio, 1.47 [95% CI, 1.13, 1.90]). In contrast, randomization to intensive SBP lowering led to a 10% decrease in NT-proBNP (geometric mean ratio, 0.90 [95% CI, 0.87-0.93]) and a lower probability of ≥50% increase in NT-proBNP (odds ratio, 0.57 [95% CI, 0.46-0.72]). The association of randomized treatment assignment on change in hs-cTnT was completely attenuated after accounting for changes in estimated glomerular filtration rate over follow-up, whereas the association of treatment with NT-proBNP was completely attenuated after adjusting for change in SBP. Increases in hs-cTnT and NT-proBNP from baseline to 1 year were associated with higher risk for heart failure and death, with no significant interactions by treatment assignment. CONCLUSIONS: Intensive SBP lowering increased hs-cTnT, mediated by the effect of SBP lowering on reduced kidney filtration. In contrast, intensive SBP lowering decreased NT-proBNP, a finding that was explained by the decrease in SBP. These findings highlight the importance of noncardiac factors influencing variation in cardiac biomarkers and raise questions about the potential role of hs-cTnT as a surrogate marker for heart failure or death in SBP-lowering studies.

High-Sensitivity Cardiac Troponins I and T and Cardiovascular Outcomes: Findings from the Systolic Blood Pressure Intervention Trial (SPRINT).

BACKGROUND: Cardiac troponins are associated with adverse cardiovascular disease (CVD) outcomes. The value of high-sensitivity cardiac troponin I (hs-cTnI) independently and in concert with troponin T (hs-cTnT) in the management of hypertension has not been well studied. METHODS: We assessed the utility of hs-cTnI independently and with hs-cTnT in identifying the highest risk individuals in the Systolic Blood Pressure Intervention Trial (SPRINT). Among 8796 eligible SPRINT participants, hs-cTnI was measured at baseline and 1 year. The association of baseline level and 1-year change in hs-cTnI with CVD events and all-cause death was evaluated using adjusted Cox regression models. We further assessed the complementary value of hs-cTnI and hs-cTnT by identifying concordant and discordant categories and assessing their association with outcomes. RESULTS: hs-cTnI was positively associated with composite CVD risk [myocardial infarction, other acute coronary syndrome, stroke, or cardiovascular death: hazard ratio 1.23, 95% confidence interval 1.08-1.39 per 1-unit increase in log(troponin I)] independent of traditional risk factors, N-terminal pro-B-type natriuretic peptide, and hs-cTnT. Intensive blood pressure lowering was associated with greater absolute risk reduction (4.5% vs 1.7%) and lower number needed to treat (23 vs 59) for CVD events among those with higher baseline hs-cTnI (≥6 ng/L in men, ≥4 ng/L in women). hs-cTnI increase at 1 year was also associated with increased CVD risk. hs-cTnI and hs-cTnT were complementary, and elevations in both identified individuals with the highest risk for CVD and death. CONCLUSIONS: Baseline levels and change in hs-cTnI over 1 year identified higher-risk individuals who may derive greater cardiovascular benefit with intensive blood pressure treatment. hs-TnI and hs-TnT have complementary value in CVD risk assessment. ClinicalTrials.gov Registration Number: NCT01206062.

Changes in Natriuretic Peptide Levels and Subsequent Kidney Function Decline in SPRINT.

RATIONALE & OBJECTIVE: Novel approaches to the assessment of kidney disease risk during hypertension treatment are needed because of the uncertainty of how intensive blood pressure (BP) lowering impacts kidney outcomes. We determined whether longitudinal N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements during hypertension treatment are associated with kidney function decline. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 8,005 SPRINT (Systolic Blood Pressure Intervention Trial) participants with NT-proBNP measurements at baseline and 1 year. EXPOSURE: 1-year change in NT-proBNP categorized as a ≥25% decrease, ≥25% increase, or <25% change (stable). OUTCOME: Annualized change in estimated glomerular filtration rate (eGFR) and ≥30% decrease in eGFR. ANALYTICAL APPROACH: Linear mixed-effect and logistic regression models were used to evaluate the association of changes in NT-proBNP with subsequent annualized change in eGFR and ≥30% decrease in eGFR, respectively. Analyses were stratified by baseline chronic kidney disease (CKD) status. RESULTS: Compared with stable 1-year NT-proBNP levels, a ≥25% decrease in NT-proBNP was associated with a slower decrease in eGFR in participants with CKD (adjusted difference, 1.09%/y; 95% CI, 0.35-1.83) and without CKD (adjusted difference, 0.51%/y; 95% CI, 0.21-0.81; P = 0.4 for interaction). Meanwhile, a ≥25% increase in NT-proBNP in participants with CKD was associated with a faster decrease in eGFR (adjusted difference, -1.04%/y; 95% CI, -1.72 to -0.36) and risk of a ≥30% decrease in eGFR (adjusted odds ratio, 1.44; 95% CI, 1.06-1.96); associations were stronger in participants with CKD than in participants without CKD (P = 0.01 and P < 0.001 for interaction, respectively). Relationships were similar irrespective of the randomized BP arm in SPRINT (P > 0.2 for interactions). LIMITATIONS: Persons with diabetes and proteinuria >1 g/d were excluded. CONCLUSIONS: Changes in NT-proBNP during BP treatment are independently associated with subsequent kidney function decline, particularly in people with CKD. Future studies should assess whether routine NT-proBNP measurements may be useful in monitoring kidney risk during hypertension treatment. PLAIN-LANGUAGE SUMMARY: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker in the blood that reflects mechanical stress on the heart. Measuring NT-proBNP may be helpful in assessing the risk of long-term losses of kidney function. In this study, we investigated the association of changes in NT-proBNP with subsequent kidney function among individuals with and without chronic kidney disease. We found that increases in NT-proBNP are associated with a faster rate of decline of kidney function, independent of baseline kidney measures. The associations were more pronounced in individuals with chronic kidney disease. Our results advance the notion of considering NT-proBNP as a dynamic tool for assessing kidney disease risk.

Longitudinal Changes in Cardiac Troponin and Risk of Heart Failure Among Black Adults.

BACKGROUND: Among Black adults, high-sensitivity cardiac troponin I (hs-cTnI) is associated with heart failure (HF) risk. The association of longitudinal changes in hs-cTnI with risk of incident HF, HF with reduced and preserved ejection fraction (HFrEF and HFpEF, respectively), among Black adults is not well-established. METHODS AND RESULTS: This study included Black participants from the Jackson Heart Study with available hs-cTnI data at visits 1 (2000-2004) and 2 (2005-2008) and no history of cardiovascular disease. Cox models were used to evaluate associations of categories of longitudinal change in hs-cTnI with incident HF risk. Among 2423 participants, 11.6% had incident elevation in hs-cTnI at visit 2, and 16.9% had stable or improved elevation (≤50% increase in hs-cTnI), and 4.0% had worsened hs-cTnI elevation (>50% increase). Over a median follow-up of 12.0 years, there were 139 incident HF hospitalizations (64 HFrEF, 58 HFpEF). Compared with participants without an elevated hs-cTnI, those with incident, stable or improved, or worsened hs-cTnI elevation had higher HF risk (adjusted hazard ratio 3.20 [95% confidence interval, 1.92-5.33]; adjusted hazard ratio 2.40, [95% confidence interval, 1.47-3.92]; and adjusted hazard ratio 8.10, [95% confidence interval, 4.74-13.83], respectively). Similar patterns of association were observed for risk of HFrEF and HFpEF. CONCLUSIONS: Among Black adults, an increase in hs-cTnI levels on follow-up was associated with a higher HF risk. LAY SUMMARY: The present study included 2423 Black adults from the Jackson Heart Study with available biomarkers of cardiac injury and no history of cardiovascular disease at visits 1 and 2. The majority of participants did not have evidence of cardiac injury at both visits (67.5%), 11.6% had evidence of cardiac injury only on follow-up, 14.5% had stable elevations, 4.0% had worsened elevations, and 2.4% had improved elevations of cardiac injury biomarkers during follow-up. Compared with participants without evidence of cardiac injury, those with new, stable, and worsened levels of cardiac injury had a higher risk of developing heart failure. TWEET: Among Black adults, persistent or worsening subclinical myocardial injury is associated with an elevated risk of HF.

Associations of liver fat content with cardiometabolic phenotypes and outcomes in a multi-ethnic population: Results from the Dallas Heart Study.

AIMS: To evaluate the associations between liver fat content and cardiometabolic parameters to explore potential threshold values that define metabolically healthy liver fat content, and to examine the association of liver fat content with cardiovascular events as well as its longitudinal progression. METHODS: Participants in the Dallas Heart Study underwent clinical evaluation, including laboratory testing, and liver fat quantification by magnetic resonance spectroscopy (MRS) at baseline (N = 2287) and at follow-up (N = 343) after a mean of 7.3 years. Cardiovascular events were adjudicated (>12 years). RESULTS: The mean age at study entry was 44 years, 47% of participants were men, and 48% were African American. The following cardiometabolic biomarkers worsened across liver fat quintiles (P < 0.0001): body mass index (BMI); waist circumference; prevalence of hypertension; prevalence of diabetes; cholesterol, triglyceride, high-sensitivity C-reactive protein (CRP), leptin and fasting glucose levels; homeostatic model assessment of insulin resistance index (HOMA-IR); coronary artery calcium score; visceral adipose tissue; abdominal subcutaneous adipose tissue; and lower body subcutaneous adipose tissue. Cardiovascular events were comparable across groups defined by tertile of baseline liver fat content. Change in BMI (R = 0.40), waist circumference (R = 0.35), CRP (R = 0.31), alanine aminotransferase (R = 0.27), HOMA-IR (R = 0.26), aspartate transaminase (R = 0.15) and triglycerides (R = 0.12) significantly correlated with change in liver fat content (P < 0.01 for all). CONCLUSION: Clinically relevant metabolic abnormalities were higher across quintiles of liver fat, with increases noted well within normal liver fat ranges, but cardiovascular events were not associated with liver fat content. Longitudinal changes in metabolic parameters, especially adiposity-related parameters, were correlated with change in liver fat content.

Kidney tubule health, mineral metabolism and adverse events in persons with CKD in SPRINT.

BACKGROUND: Measures of kidney tubule health are risk markers for acute kidney injury (AKI) in persons with chronic kidney disease (CKD) during hypertension treatment, but their associations with other adverse events (AEs) are unknown. METHODS: Among 2377 Systolic Blood Pressure Intervention Trial (SPRINT) participants with CKD, we measured at baseline eight urine biomarkers of kidney tubule health and two serum biomarkers of mineral metabolism pathways that act on the kidney tubules. Cox proportional hazards models were used to evaluate biomarker associations with risk of a composite of pre-specified serious AEs (hypotension, syncope, electrolyte abnormalities, AKI, bradycardia and injurious falls) and outpatient AEs (hyperkalemia and hypokalemia). RESULTS: At baseline, the mean age was 73 ± 9 years and mean estimated glomerular filtration rate (eGFR) was 46 ± 11 mL/min/1.73 m2. During a median follow-up of 3.8 years, 716 (30%) participants experienced the composite AE. Higher urine interleukin-18, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin (NGAL) and monocyte chemoattractant protein-1 (MCP-1), lower urine uromodulin (UMOD) and higher serum fibroblast growth factor-23 were individually associated with higher risk of the composite AE outcome in multivariable-adjusted models including eGFR and albuminuria. When modeling biomarkers in combination, higher NGAL [hazard ratio (HR) = 1.08 per 2-fold higher biomarker level, 95% confidence interval (CI) 1.03-1.13], higher MCP-1 (HR = 1.11, 95% CI 1.03-1.19) and lower UMOD (HR = 0.91, 95% CI 0.85-0.97) were each associated with higher composite AE risk. Biomarker associations did not vary by intervention arm (P > 0.10 for all interactions). CONCLUSIONS: Among persons with CKD, several kidney tubule biomarkers are associated with higher risk of AEs during hypertension treatment, independent of eGFR and albuminuria.

Association of Baseline and Longitudinal Changes in Body Composition Measures With Risk of Heart Failure and Myocardial Infarction in Type 2 Diabetes: Findings From the Look AHEAD Trial.

BACKGROUND: Intentional weight loss is associated with lower risk of heart failure (HF) and atherosclerotic cardiovascular disease among patients with type 2 diabetes. However, the contribution of baseline measures and longitudinal changes in fat mass (FM), lean mass (LM), and waist circumference (WC) to the risk of HF and myocardial infarction (MI) in type 2 diabetes is not well established. METHODS: Adults from the Look AHEAD trial (Action for Health in Diabetes) without prevalent HF were included. FM and LM were predicted using validated equations and compared with dual-energy x-ray absorptiometry measurements in a subgroup. Adjusted Cox models were used to evaluate the associations of baseline and longitudinal changes in FM, LM, and WC over 1- and 4-year follow-up with risk of overall HF, HF with preserved ejection fraction (EF; EF ≥50%), HF with reduced EF (EF <50%), and MI. RESULTS: Among 5103 participants, there were 257 incident HF events over 12.4 years of follow-up. Predicted and measured FM/LM were highly correlated (R2=0.87-0.90; n=1369). FM and LM decreased over 4-year follow-up with greater declines in the intensive lifestyle intervention arm. In adjusted analysis, baseline body composition measures were not significantly associated with HF risk. Decline in FM and WC, but not LM, over 1 year were each significantly associated with lower risk of overall HF (adjusted hazard ratio per 10% decrease in FM, 0.80 [95% CI, 0.68-0.95]; adjusted hazard ratio per 10% decrease in WC, 0.77 [95% CI, 0.62-0.95]). Decline in FM was significantly associated with lower risk of both HF subtypes. In contrast, decline in WC was significantly associated with lower risk of HF with preserved EF but not HF with reduced EF. Similar patterns of association were observed for 4-year changes in body composition and HF risk. Longitudinal changes in body composition were not significantly associated with risk of MI. CONCLUSIONS: In adults with type 2 diabetes, a lifestyle intervention is associated with significant loss of FM and LM. Declines in FM and WC, but not LM, were each significantly associated with lower risk of HF but not MI. Furthermore, decline in WC was significantly associated with lower risk of HF with preserved EF but not HF with reduced EF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00017953.

Association of Intensive Lifestyle Intervention, Fitness, and Body Mass Index With Risk of Heart Failure in Overweight or Obese Adults With Type 2 Diabetes Mellitus: An Analysis From the Look AHEAD Trial.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with a higher risk for heart failure (HF). The impact of a lifestyle intervention and changes in cardiorespiratory fitness (CRF) and body mass index on risk for HF is not well established. METHODS: Participants from the Look AHEAD trial (Action for Health in Diabetes) without prevalent HF were included. Time-to-event analyses were used to compare the risk of incident HF between the intensive lifestyle intervention and diabetes support and education groups. The associations of baseline measures of CRF estimated from a maximal treadmill test, body mass index, and longitudinal changes in these parameters with risk of HF were evaluated with multivariable adjusted Cox models. RESULTS: Among the 5109 trial participants, there was no significant difference in the risk of incident HF (n=257) between the intensive lifestyle intervention and the diabetes support and education groups (hazard ratio, 0.96 [95% CI, 0.75-1.23]) over a median follow-up of 12.4 years. In the most adjusted Cox models, the risk of HF was 39% and 62% lower among moderate fit (tertile 2: hazard ratio, 0.61 [95% CI, 0.44-0.83]) and high fit (tertile 3: hazard ratio, 0.38 [95% CI, 0.24-0.59]) groups, respectively (referent group: low fit, tertile 1). Among HF subtypes, after adjustment for traditional cardiovascular risk factors and interval incidence of myocardial infarction, baseline CRF was not significantly associated with risk of incident HF with reduced ejection fraction. In contrast, the risk of incident HF with preserved ejection fraction was 40% lower in the moderate fit group and 77% lower in the high fit group. Baseline body mass index also was not associated with risk of incident HF, HF with preserved ejection fraction, or HF with reduced ejection fraction after adjustment for CRF and traditional cardiovascular risk factors. Among participants with repeat CRF assessments (n=3902), improvements in CRF and weight loss over a 4-year follow-up were significantly associated with lower risk of HF (hazard ratio per 10% increase in CRF, 0.90 [95% CI, 0.82-0.99]; per 10% decrease in body mass index, 0.80 [95% CI, 0.69-0.94]). CONCLUSIONS: Among participants with type 2 diabetes mellitus in the Look AHEAD trial, the intensive lifestyle intervention did not appear to modify the risk of HF. Higher baseline CRF and sustained improvements in CRF and weight loss were associated with lower risk of HF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00017953.

Racial Differences in Malignant Left Ventricular Hypertrophy and Incidence of Heart Failure: A Multicohort Study.

BACKGROUND: A malignant subphenotype of left ventricular hypertrophy (LVH) has been described, in which minimal elevations in cardiac biomarkers identify individuals with LVH at high risk for developing heart failure (HF). We tested the hypothesis that a higher prevalence of malignant LVH among blacks may contribute to racial disparities in HF risk. METHODS: Participants (n=15 710) without prevalent cardiovascular disease were pooled from 3 population-based cohort studies, the ARIC Study (Atherosclerosis Risk in Communities), the DHS (Dallas Heart Study), and the MESA (Multi-Ethnic Study of Atherosclerosis). Participants were classified into 3 groups: those without ECG-LVH, those with ECG-LVH and normal biomarkers (hs-cTnT (high sensitivity cardiac troponin-T) <6 ng/L and NT-proBNP (N-terminal pro-B-type natriuretic peptide) <100 pg/mL), and those with ECG-LVH and abnormal levels of either biomarker (malignant LVH). The outcome was incident HF. RESULTS: Over the 10-year follow-up period, HF occurred in 512 (3.3%) participants, with 5.2% in black men, 3.8% in white men, 3.2% in black women, and 2.2% in white women. The prevalence of malignant LVH was 3-fold higher among black men and women versus white men and women. Compared with participants without LVH, the adjusted hazard ratio for HF was 2.8 (95% CI, 2.1-3.5) in those with malignant LVH and 0.9 (95% CI, 0.6-1.5) in those with LVH and normal biomarkers, with similar findings in each race/sex subgroup. Mediation analyses indicated that 33% of excess hazard for HF among black men and 11% of the excess hazard among black women was explained by the higher prevalence of malignant LVH in blacks. Of black men who developed HF, 30.8% had malignant LVH at baseline, with a corresponding population attributable fraction of 0.21. The proportion of HF cases occurring among those with malignant LVH, and the corresponding population attributable fraction, were intermediate and similar among black women and white men and lowest among white women. CONCLUSIONS: A higher prevalence of malignant LVH may in part explain the higher risk of HF among blacks versus whites. Strategies to prevent development or attenuate risk associated with malignant LVH should be investigated as a strategy to lower HF risk and mitigate racial disparities.

Incorporation of Biomarkers Into Risk Assessment for Allocation of Antihypertensive Medication According to the 2017 ACC/AHA High Blood Pressure Guideline: A Pooled Cohort Analysis.

BACKGROUND: Risk for atherosclerotic cardiovascular disease was a novel consideration for antihypertensive medication initiation in the 2017 American College of Cardiology/American Heart Association Blood Pressure (BP) guideline. Whether biomarkers of chronic myocardial injury (high-sensitivity cardiac troponin T ≥6 ng/L] and stress (N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥100 pg/mL) can inform cardiovascular (CV) risk stratification and treatment decisions among adults with elevated BP and hypertension is unclear. METHODS: Participant-level data from 3 cohort studies (Atherosclerosis Risk in Communities Study, Dallas Heart Study, and Multiethnic Study of Atherosclerosis) were pooled, excluding individuals with prevalent CV disease and those taking antihypertensive medication at baseline. Participants were analyzed according to BP treatment group from the 2017 American College of Cardiology/American Heart Association BP guideline and those with high BP (120 to 159/<100 mm Hg) were further stratified by biomarker status. Cumulative incidence rates for CV event (atherosclerotic cardiovascular disease or heart failure), and the corresponding 10-year number needed to treat to prevent 1 event with intensive BP lowering (to target systolic BP <120 mm Hg), were estimated for BP and biomarker-based subgroups. RESULTS: The study included 12 987 participants (mean age, 55 years; 55% women; 21.5% with elevated high-sensitivity cardiac troponin T; 17.7% with elevated NT-proBNP) with 825 incident CV events over 10-year follow-up. Participants with elevated BP or hypertension not recommended for antihypertensive medication with versus without either elevated high-sensitivity cardiac troponin T or NT-proBNP had a 10-year CV incidence rate of 11.0% and 4.6%, with a 10-year number needed to treat to prevent 1 event for intensive BP lowering of 36 and 85, respectively. Among participants with stage 1 or stage 2 hypertension recommended for antihypertensive medication with BP <160/100 mm Hg, those with versus without an elevated biomarker had a 10-year CV incidence rate of 15.1% and 7.9%, with a 10-year number needed to treat to prevent 1 event of 26 and 49, respectively. CONCLUSIONS: Elevations in high-sensitivity cardiac troponin T or NT-proBNP identify individuals with elevated BP or hypertension not currently recommended for antihypertensive medication who are at high risk for CV events. The presence of nonelevated biomarkers, even in the setting of stage 1 or stage 2 hypertension, was associated with lower risk. Incorporation of biomarkers into risk assessment algorithms may lead to more appropriate matching of intensive BP control with patient risk.

High-Phosphate Diet Induces Exercise Intolerance and Impairs Fatty Acid Metabolism in Mice.

BACKGROUND: Inorganic phosphate (Pi) is used extensively as a preservative and a flavor enhancer in the Western diet. Physical inactivity, a common feature of Western societies, is associated with increased cardiovascular morbidity and mortality. It is unknown whether dietary Pi excess contributes to exercise intolerance and physical inactivity. METHODS: To determine an association between Pi excess and physical activity in humans, we assessed the relationship between serum Pi and actigraphy-determined physical activity level, as well as left ventricular function by cardiac magnetic resonance imaging, in DHS-2 (Dallas Heart Study phase 2) participants after adjusting for relevant variables. To determine direct effects of dietary Pi on exercise capacity, oxygen uptake, serum nonesterified fatty acid, and glucose were measured during exercise treadmill test in C57/BL6 mice fed either a high-Pi (2%) or normal-Pi (0.6%) diet for 12 weeks. To determine the direct effect of Pi on muscle metabolism and expression of genes involved in fatty acid metabolism, additional studies in differentiated C2C12 myotubes were conducted after subjecting to media containing 1 to 3 mmol/L Pi (pH 7.0) to simulate in vivo phosphate conditions. RESULTS: In participants of the DHS-2 (n=1603), higher serum Pi was independently associated with reduced time spent in moderate to vigorous physical activity ( P=0.01) and increased sedentary time ( P=0.004). There was no association between serum Pi and left ventricular ejection fraction or volumes. In animal studies, compared with the control diet, consumption of high-Pi diet for 12 weeks did not alter body weight or left ventricular function but reduced maximal oxygen uptake, treadmill duration, spontaneous locomotor activity, fat oxidation, and fatty acid levels and led to downregulation of genes involved in fatty acid synthesis, release, and oxidation, including Fabp4, Hsl, Fasn, and Pparγ, in muscle. Similar results were recapitulated in vitro by incubating C2C12 myotubes with high-Pi media. CONCLUSIONS: Our data demonstrate a detrimental effect of dietary Pi excess on skeletal muscle fatty acid metabolism and exercise capacity that is independent of obesity and cardiac contractile function. Dietary Pi may represent a novel and modifiable target to reduce physical inactivity associated with the Western diet.

Sex and Race Differences in Lifetime Risk of Heart Failure With Preserved Ejection Fraction and Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Lifetime risk of heart failure has been estimated to range from 20% to 46% in diverse sex and race groups. However, lifetime risk estimates for the 2 HF phenotypes, HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), are not known. METHODS: Participant-level data from 2 large prospective cohort studies, the CHS (Cardiovascular Health Study) and MESA (Multiethnic Study of Atherosclerosis), were pooled, excluding individuals with prevalent HF at baseline. Remaining lifetime risk estimates for HFpEF (EF ≥45%) and HFrEF (EF <45%) were determined at different index ages with the use of a modified Kaplan-Meier method with mortality and the other HF subtype as competing risks. RESULTS: We included 12 417 participants >45 years of age (22.2% blacks, 44.8% men) who were followed up for median duration of 11.6 years with 2178 overall incident HF events with 561 HFrEF events and 726 HFpEF events. At the index age of 45 years, the lifetime risk for any HF through 90 years of age was higher in men than women (27.4% versus 23.8%). Among HF subtypes, the lifetime risk for HFrEF was higher in men than women (10.6% versus 5.8%). In contrast, the lifetime risk for HFpEF was similar in men and women. In race-stratified analyses, lifetime risk for overall HF was higher in nonblacks than blacks (25.9% versus 22.4%). Among HF subtypes, the lifetime risk for HFpEF was higher in nonblacks than blacks (11.2% versus 7.7%), whereas that for HFrEF was similar across the 2 groups. Among participants with antecedent myocardial infarction before HF diagnosis, the remaining lifetime risks for HFpEF and HFrEF were up to 2.5-fold and 4-fold higher, respectively, compared with those without antecedent myocardial infarction. CONCLUSIONS: Lifetime risks for HFpEF and HFrEF vary by sex, race, and history of antecedent myocardial infarction. These insights into the distribution of HF risk and its subtypes could inform the development of targeted strategies to improve population-level HF prevention and control.

Long-Term Association of Low-Density Lipoprotein Cholesterol With Cardiovascular Mortality in Individuals at Low 10-Year Risk of Atherosclerotic Cardiovascular Disease.

BACKGROUND: The associations of low-density lipoprotein cholesterol (LDL-C) with cardiovascular disease (CVD) and coronary heart disease mortality in an exclusively low estimated 10-year risk group are not well delineated. We sought to determine the long-term associations of various LDL-C and non-high-density lipoprotein cholesterol (HDL-C) thresholds and CVD and coronary heart disease mortality in a large, low 10-year risk cohort. METHODS: The study sample included participants of the CCLS (Cooper Center Longitudinal Study) without a history of CVD or diabetes mellitus and defined as low risk (<7.5%) for 10-year atherosclerotic CVD events at baseline based on Pooled Cohort Risk Assessment Equations. The associations of fasting LDL-C and non-HDL-C with CVD mortality were tested with Cox proportional hazards models. RESULTS: In 36 375 participants (72% men, median age 42) followed for a median of 26.8 years, 1086 CVD and 598 coronary heart disease deaths occurred. Compared with LDL-C <100 mg/dL, LDL-C categories 100 to 129 mg/dL, 130 to 159 mg/dL, 160 to 189.9 mg/dL, and ≥190 mg/dL were associated with a significantly higher risk of CVD death, with hazard ratios of 1.4 (95% CI, 1.1-1.7), 1.3 (95% CI, 1.1-1.6), 1.9 (95% CI, 1.5-2.4), and 1.7 (95% CI, 1.3-2.3), and mean reductions in years free of CVD death of 1.8, 1.1, 4.3, and 3.9, respectively. After adjustment for atherosclerotic CVD risk factors, LDL-C categories 160 to 189 mg/dL and ≥190 mg/dL remained independently associated with CVD mortality, with hazard ratios of 1.7 (95% CI, 1.4-2.2) and 1.5 (95% CI, 1.2-2.1), respectively. In multivariable-adjusted models using non-HDL-C <130 mg/dL as the reference, non-HDL-C 160 to 189 mg/dL, 190 to 219 mg/dL, and ≥220 mg/dL were significantly associated with CVD death, with hazard ratios of 1.3 (95% CI, 1.1-1.6), 1.8 (95% CI, 1.4-2.2), and 1.5 (95% CI, 1.2-2.0), respectively. Restricting the cohort to those with 10-year risk <5% did not diminish the associations of LDL-C and non-HDL-C with CVD mortality. CONCLUSIONS: In a low 10-year risk cohort with long-term follow-up, LDL-C and non-HDL-C ≥160 mg/dL were independently associated with a 50% to 80% increased relative risk of CVD mortality. These findings may have implications for future cholesterol treatment paradigms.

Effects of Weight-Loss Medications on Cardiometabolic Risk Profiles: A Systematic Review and Network Meta-analysis.

BACKGROUND & AIMS: We performed a systematic review and network meta-analysis to evaluate the overall and comparative effects of weight-loss medications approved by the Food and Drug Administration for long-term use on cardiometabolic risk profiles of obese adults. METHODS: We performed a systematic literature review through February 28, 2017 to identify randomized clinical trials of the effects of Food and Drug Administration-approved weight-loss medications (ie, orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate, and liraglutide) administered to obese adults for 1 year or more, compared with placebo or another active agent. Outcomes of interest included changes in blood glucose (fasting blood glucose [FBG] and hemoglobin A1c), cholesterol profile (low-density lipoprotein and high-density lipoproteins), blood pressure (BP; systolic/diastolic), and waist circumference (WC). We performed pair-wise and network meta-analyses with outcomes reported as weighted and standardized mean differences. Quality of evidence was rated using GRADE (Grading of Recommendations Assessment, Development and Evaluation). RESULTS: In a meta-analysis of 28 randomized controlled trials (29,018 participants; median body mass index, 36.1 kg/m2), we associated weight-loss medications with a modest decrease in FBG (weighted mean difference, 4.0 mg/dL; 95% confidence interval, -4.4 to -3.6 mg/dL) and WC (weighted mean difference, reduction of 3.3 cm; 95% confidence interval, -3.5 to -3.1 cm), without clinically meaningful changes in systolic/diastolic BP or cholesterol profile vs placebo (standardized mean difference <0.2); effects varied among drugs. Phentermine-topiramate use was associated with a substantial decrease in WC and a modest decrease in FBG, hemoglobin A1c, and BP, and had minimal effect on cholesterol. Liraglutide use was associated with a substantial decrease in FBG, hemoglobin A1c, and WC, and a minimal effect on BP and cholesterol. Naltrexone-bupropion use was associated with moderate increase in high-density lipoprotein cholesterol, but had a minimal effect on FBG and WC. Orlistat use was associated with a decrease in low-density lipoprotein and high-density lipoprotein cholesterol. No drug improved all cardiometabolic risk factors. CONCLUSIONS: In a systematic review and network meta-analysis, we found Food and Drug Administration-approved weight-loss medications to have only modest positive effects on cardiometabolic risk profile. Further research is needed to evaluate the long-term cardiometabolic benefits of these medications. PROSPERO: CRD42016039486.

Sex-Based Differences in Cardiometabolic Biomarkers.

BACKGROUND: Few data are available comparing cardiovascular disease (CVD) biomarker profiles between women and men in the general population. We analyzed sex-based differences in multiple biomarkers reflecting distinct pathophysiological pathways, accounting for differences between women and men in CVD risk factors, body composition, and cardiac morphology. METHODS: A cross-sectional analysis was performed using data from the Dallas Heart Study, a multiethnic population-based study. Associations between sex and 30 distinct biomarkers representative of 6 pathophysiological categories were evaluated using multivariable linear regression adjusting for age, race, traditional CVD risk factors, kidney function, insulin resistance, MRI and dual-energy x-ray absorptiometry measures of body composition and fat distribution, and left ventricular mass. RESULTS: After excluding participants with CVD, the study population included 3439 individuals, mean age 43 years, 56% women, and 52% black. Significant sex-based differences were seen in multiple categories of biomarkers, including lipids, adipokines, and biomarkers of inflammation, endothelial dysfunction, myocyte injury and stress, and kidney function. In fully adjusted models, women had higher levels of high-density lipoprotein cholesterol and high-density lipoprotein particle concentration, leptin, d-dimer, homoarginine, and N-terminal pro B-type natriuretic peptide, and lower levels of low-density lipoprotein cholesterol, adiponectin, lipoprotein-associated phospholipase A2 mass and activity, monocyte chemoattractant protein-1, soluble endothelial cell adhesion molecule, symmetrical dimethylarginine, asymmetrical dimethylarginine, high-sensitivity troponin T, and cystatin C. CONCLUSIONS: Biomarker profiles differ significantly between women and men in the general population. Sex differences were most apparent for biomarkers of adiposity, endothelial dysfunction, inflammatory cell recruitment, and cardiac stress and injury. Future studies are needed to characterize whether pathophysiological processes delineated by these biomarkers contribute to sex-based differences in the development and complications of CVD.

Multimodality Strategy for Cardiovascular Risk Assessment: Performance in 2 Population-Based Cohorts.

BACKGROUND: Current strategies for cardiovascular disease (CVD) risk assessment among adults without known CVD are limited by suboptimal performance and a narrow focus on only atherosclerotic CVD (ASCVD). We hypothesized that a strategy combining promising biomarkers across multiple different testing modalities would improve global and atherosclerotic CVD risk assessment among individuals without known CVD. METHODS: We included participants from MESA (Multi-Ethnic Study of Atherosclerosis) (n=6621) and the Dallas Heart Study (n=2202) who were free from CVD and underwent measurement of left ventricular hypertrophy by ECG, coronary artery calcium, N-terminal pro B-type natriuretic peptide, high-sensitivity cardiac troponin T, and high-sensitivity C-reactive protein. Associations of test results with the global composite CVD outcome (CVD death, myocardial infarction, stroke, coronary or peripheral revascularization, incident heart failure, or atrial fibrillation) and ASCVD (fatal or nonfatal myocardial infarction or stroke) were assessed over >10 years of follow-up. Multivariable analyses for the primary global CVD end point adjusted for traditional risk factors plus statin use and creatinine (base model). RESULTS: Each test result was independently associated with global composite CVD events in MESA after adjustment for the components of the base model and the other test results (P<0.05 for each). When the 5 tests were added to the base model, the c-statistic improved from 0.74 to 0.79 (P=0.001), significant integrated discrimination improvement (0.07, 95% confidence interval [CI] 0.06-0.08, P<0.001) and category free net reclassification improvement (0.47; 95% CI, 0.38-0.56; P=0.003) were observed, and the model was well calibrated (χ2=12.2, P=0.20). Using a simple integer score counting the number of abnormal tests, compared with those with a score of 0, global CVD risk was increased among participants with a score of 1 (adjusted hazard ratio, 1.9; 95% CI, 1.4-2.6), 2 (hazard ratio, 3.2; 95% CI, 2.3-4.4), 3 (hazard ratio, 4.7; 95% CI, 3.4-6.5), and ≥4 (hazard ratio, 7.5; 95% CI, 5.2-10.6). Findings replicated in the Dallas Health Study were similar for the ASCVD outcome. CONCLUSIONS: Among adults without known CVD, a novel multimodality testing strategy using left ventricular hypertrophy by ECG, coronary artery calcium, N-terminal pro B-type natriuretic peptide, high-sensitivity cardiac troponin T, and high-sensitivity C-reactive protein significantly improved global CVD and ASCVD risk assessment.

The Evolving Role of Cardiorespiratory Fitness and Exercise in Prevention and Management of Heart Failure.

PURPOSE OF REVIEW: This paper highlights the dynamic relationship between cardiorespiratory fitness (CRF) and heart failure (HF). As heart failure with preserved ejection fraction (HFpEF) surpasses heart failure with reduced ejection fraction (HFrEF) in prevalence, our void in understanding how to treat this syndrome becomes less justifiable. As such, significant attention has been given to the role that obesity and physical inactivity play, as both risk factors for heart failure, and therapeutic targets for its treatment. RECENT FINDINGS: Previous findings have shown that low CRF, obesity, and physical inactivity are all risk factors for HF. More recently, it has been discovered that these factors are even more significant when applied to HFpEF, even after accounting for traditional cardiovascular risk factors. As such, new investigations have attempted to discover whether improvements in CRF could be utilized as a tool for prevention of HF. In addition, small studies have shown that interventions to improve CRF in patients with HF could improve both quality of life and fitness. The role of CRF, PA, and obesity in the development of HF is now well established; however, our ability to attenuate that risk is yet to be determined. Observational data have signaled a correlation between improvements in PA, CRF and lower risk of HF however, large randomized controlled trials are still required to truly determine whether exercise training could be used in the prevention and treatment of HF, particularly HFpEF.

Invited Commentary: Searching for the Perfect Measure of Diastolic Dysfunction-A Futile Exercise?

Heart failure with preserved ejection fraction (HFpEF) is common, recalcitrant to treatment, and associated with poor outcomes. Diastolic dysfunction (DD) is an independent predictor of HFpEF risk, associated clinical manifestations, and long-term outcomes. However, the usefulness of diastolic function assessment is limited by the heterogeneity in the existing definitions of DD. In this issue of the Journal, Rasmussen-Torvik et al. (Am J Epidemiol. 2017;185(12):1221-1227) have highlighted this problem by evaluating the prevalence and concordance of 4 established definitions of DD in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. The authors demonstrate significant variability in prevalence of DD and its association with established risk factors across the different definitions. These findings suggest that the current 1-dimensional approach to HFpEF risk prediction based on noninvasive measures of diastolic function may not be optimal. Perhaps the future of HFpEF risk assessment lies in a multimodality approach that combines the relevant echocardiographic measures of diastolic function with blood-based biomarkers (such as N-terminal prohormone of brain natriuretic peptide (NT-proBNP)) and a measure of functional status (such as exercise capacity).