N-Terminal Pro-B-Type Natriuretic Peptide and Risk for Diabetes Mellitus and Metabolic Syndrome.

CONTEXT: Natriuretic peptide concentrations are inversely associated with risk of diabetes mellitus and may be protective from metabolic dysfunction. OBJECTIVE: We studied associations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) with incident diabetes, metabolic syndrome (MetS), and MetS components. DESIGN/SETTING/PARTICIPANTS: 2,899 participants with baseline (2003-2007) and follow-up (2013-2016) examinations and baseline NT-proBNP measurement in the REasons for Geographic And Racial Differences in Stroke study. Logistic regression models were fitted to incident MetS, MetS components, and diabetes; covariates included demographics, risk and laboratory factors. MAIN OUTCOME MEASURES: Incident diabetes, defined as fasting glucose ≥126 mg/dL, random glucose ≥200 mg/dL, or use of insulin or hypoglycemic drugs at follow-up but not baseline. Incident MetS, in participants with ≥3 harmonized criteria at follow-up and <3 at baseline. RESULTS: 310 participants (2,364 at risk) developed diabetes and 361 (2,059 at risk) developed MetS over mean 9.4 years follow-up. NT-proBNP was inversely associated with odds of incident diabetes (fully-adjusted OR per-SD higher log NT-proBNP 0.80, 95% CI 0.69-0.93) and MetS in the highest vs. lowest quartile only (fully-adjusted OR 0.59, 95% CI 0.37-0.92); the linear association with incident MetS was not statistically significant. NT-proBNP was inversely associated with incident dysglycemia in all models (fully-adjusted OR per-SD log NT-proBNP 0.65, 95% CI 0.53-0.79), but not with other MetS components. Effect modification by sex, race, age, or BMI was not observed. CONCLUSIONS: NT-proBNP was inversely associated with odds of diabetes, MetS, and the MetS dysglycemia component. The metabolic implications of B-type natriuretic peptides appear important for glycemic homeostasis.

Interleukin-6, Diabetes, and Metabolic Syndrome in a Biracial Cohort: The Reasons for Geographic and Racial Differences in Stroke Cohort.

OBJECTIVE: Black Americans have a greater risk of type 2 diabetes than White Americans. The proinflammatory cytokine interleukin-6 (IL-6) is implicated in diabetes pathogenesis, and IL-6 levels are higher in Black individuals. This study investigated associations of IL-6 with incident diabetes and metabolic syndrome in a biracial cohort. RESEARCH DESIGN AND METHODS: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study enrolled 30,239 Black and White adults age ≥45 years in 2003-2007, with a follow-up ∼9.5 years later. Baseline plasma IL-6 was measured in 3,399 participants at risk of incident diabetes and 1,871 at risk of metabolic syndrome. Relative risk (RR) by IL-6 was estimated with modified Poisson regression for both groups. RESULTS: Incident diabetes occurred in 14% and metabolic syndrome in 20%; both rates rose across IL-6 quartiles. There was a three-way interaction of IL-6, race, and central adiposity for incident diabetes (P = 8 × 10-5). In Black participants with and without central adiposity, RRs were 2.02 (95% CI 1.00-4.07) and 1.66 (1.00-2.75) for the fourth compared with first IL-6 quartile, respectively. The corresponding RRs were 1.73 (0.92-3.26) and 2.34 (1.17-4.66) in White participants. The pattern was similar for IL-6 and metabolic syndrome. CONCLUSIONS: Although IL-6 was higher in Black than in White participants and those with central adiposity, the association of IL-6 with diabetes risk was statistically significant only among White participants without central adiposity. The association with metabolic syndrome risk was similarly stronger in low-risk groups. The results support the concept of interventions to lower inflammation in diabetes prevention, but to reduce race disparities, better biomarkers are needed.

Plasma Pro-Enkephalin A and Incident Cognitive Impairment: The Reasons for Geographic and Racial Differences in Stroke Cohort.

Background Cardiovascular disease is a risk factor for cognitive impairment. Evidence links both lower and higher concentration of the circulating opioid pro-enkephalin A (PENK-A) with stroke risk. We studied the association of plasma PENK-A with incident cognitive impairment. Methods and Results REGARDS (Reasons for Geographic and Racial Differences in Stroke) is a prospective cohort study of 30 239 adults enrolled from 2003 to 2007. Baseline PENK-A was measured in a nested case-control study of 462 participants who developed cognitive impairment over 4.7 years, and 556 controls. Logistic regression and spline plots adjusted for confounders estimated odds ratios (ORs) of cognitive impairment by baseline PENK-A. Interaction terms tested for differences in associations by age, sex, and race. Baseline PENK-A was comparable between cases and controls. There were significant differences in the association of PENK-A with cognitive impairment by sex and age (adjusted P=0.003 and 0.06, respectively). In women but not men, spline plots showed that higher and lower PENK-A were associated with decreased odds of cognitive impairment (ORs for 10th and 90th percentiles versus median, 0.65 [95% CI, 0.43-0.96] and 0.64 [95% CI, 0.41-0.99]), with no difference by age. In men ≥65 years of age but not younger men, higher PENK-A was associated with decreased odds for cognitive impairment (OR for fourth versus first quartile 0.47 [95% CI, 0.22-0.99]); this pattern was not confirmed with spline plotting. Conclusions High and low levels of circulating opioid PENK-A were associated with decreased odds of future cognitive impairment in specific subgroups. Additional research is warranted to understand the biology underlying this association and the observed differences by sex.

Clinical impact of Bachmann's bundle pacing defined by electrocardiographic criteria on atrial arrhythmia outcomes.

AIMS: Evaluate whether Bachmann's bundle pacing (BBp) defined by electrocardiographic (ECG) criteria is associated with less atrial fibrillation/tachycardia (AF/AT) compared with anatomically defined right atrial septal pacing (RASp) and right atrial appendage pacing (RAAp). METHODS AND RESULTS: This is a retrospective study comparing BBp with non-specific RASp and RAAp on new incidence, burden, and recurrence of AF/AT. We included patients who underwent atrial lead placement between 2006 and 2019 and received > 20% atrial pacing. BBp was defined by paced P-wave morphology and fluoroscopic lead position. Compared with RASp (n = 107) and RAAp (n = 108), AF/AT burden was lower in the BBp (n = 134) group by repeated measures ANOVA (P < 0.001). Over 2-year follow-up, AF/AT burden increased in the RASp (P < 0.01) and RAAp (P < 0.01) groups but did not significantly change in the BBp group (P = 0.91). Atrial arrhythmia burden was lower in the BBp group than the RASp and RAAp groups at 12-15, 18-21, and 24-27 months (P < 0.05) after pacemaker placement. Risk of AF/AT recurrence was lower in BBp than RASp (HR 0.43; P < 0.01) and RAAp patients (HR 0.29, P < 0.01). Risk of de novo AF/AT was also lower in BBp than in RASp (OR 0.12; P < 0.01) and RAAp patients (OR 0.20, P < 0.01). CONCLUSION: Bachmann's bundle pacing defined using P-wave criteria was associated with decreased atrial arrhythmia burden, recurrence, and de novo incidence compared with right atrial septal pacing and right atrial appendage pacing.

Atrial fibrillation and risk of incident heart failure with reduced versus preserved ejection fraction.

OBJECTIVE: Associations between atrial fibrillation (AF) and heart failure (HF) have been established. We compared the extent to which AF is associated with each primary subtype of HF, with reduced (HFrEF) versus preserved ejection fraction (HFpEF). METHODS: We included 25 787 participants free of baseline HF from the REGARDS (REasons for Geographic And Racial Differences in Stroke) cohort. Baseline AF was ascertained from ECG and self-reported history of physician diagnosis. Incident HF events were determined from physician-adjudicated review of hospitalisation medical records and HF deaths. Based on left ventricular ejection fraction (LVEF) at the time of HF event, HFrEF, HFpEF, and mid-range HF were defined as LVEF <40%, ≥50% and 40%-49%, respectively. Multivariable Cox proportional-hazards models examined the association between AF and HF. The Lunn-McNeil method was used to compare associations of AF with incident HFrEF versus HFpEF. RESULTS: Over a median of 9 years of follow-up, 1109 HF events occurred (356 HFpEF, 388 HFrEF, 77 mid-range and 288 unclassified). In a model adjusted for sociodemographics, cardiovascular risk factors, and incident coronary heart disease, AF was associated with increased risk of all HF events (HR 1.67, 95% CI 1.38 to 2.01). The associations of AF with HFrEF versus HFpEF events did not differ significantly (HR 1.87 (95% CI 1.38 to 2.54) and HR 1.65 (95% CI 1.20 to 2.28), respectively; p value for difference=0.581). These associations were consistent in sex and race subgroups. CONCLUSIONS: AF is associated with both HFrEF and HFpEF events, with no significant difference in the strength of association among these subtypes.

Pro-neurotensin/Neuromedin N and Hypertension Risk: A Prospective Study.

BACKGROUND: Neurotensin, a neuropeptide with direct cardiac effects, has been associated with prospective risk of hypertension-related conditions through measurement of its precursor, pro-neurotensin/neuromedin N (pro-NT/NMN). Its association with incident hypertension has not been evaluated. METHODS: From 2003 to 2007, the REasons for Geographic And Racial Differences in Stroke (REGARDS) study enrolled 30,239 Black or White adults age ≥45. Pro-NT/NMN was measured in 1,692 participants without baseline hypertension (self-reported antihypertensive use or blood pressure ≥140/90 mm Hg) who underwent follow-up assessment in 2013-2016. A sensitivity analysis was conducted using a lower threshold (≥130/80 mm Hg) to define hypertension. Three robust Poisson regression models were fitted to risk of incident hypertension, adding demographics, cardiometabolic risk factors, and dietary covariates. RESULTS: Six hundred and fourteen participants developed hypertension over 9.4 years of follow-up. Pro-NT/NMN ranged from 14 to 1,246 pmol/l, with median [interquartile range] 154 [112, 206] pmol/l. Pro-NT/NMN was not associated with hypertension overall (fully adjusted incidence rate ratio per SD increment log pro-NT/NMN 1.03, 95% confidence interval 0.95-1.11). Results of sensitivity analysis did not differ substantially. CONCLUSIONS: Baseline pro-NT/NMN was not associated with incident hypertension. This may be a result of neurotensin's long-term interactions with other molecular regulators of blood pressure, such as the renin-angiotensin-aldosterone system.

Pro-Neurotensin/Neuromedin N and Risk of Incident Metabolic Syndrome and Diabetes Mellitus in the REGARDS Cohort.

CONTEXT: The peptide neurotensin is implicated in insulin resistance, diabetes mellitus (DM), and cardiovascular disease. OBJECTIVE: We studied the association of neurotensin's stable precursor, pro-neurotensin/neuromedin N (pro-NT/NMN) with incident metabolic syndrome (MetS) and DM. METHODS: We included 3772 participants from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study who completed the baseline exam (2003-2007), the follow-up exam (2013-2016), and had pro-NT/NMN measured by immunoassay. Weighted logistic regression models were fitted to incident DM, incident MetS, and each MetS component, separately, incorporating demographics, metabolic risk factors, homeostasis model of insulin resistance (HOMA-IR), and diet scores. Incident MetS was defined by 3 or more harmonized criteria at follow-up in those with fewer than 3 at baseline. Incident DM was defined by use of hypoglycemic drugs/insulin, fasting glucose 126 mg/dL or greater, or random glucose 200 mg/dL or greater in those without these at baseline. RESULTS: Median (IQR) plasma pro-NT/NMN was 160 pmol/L (118-218 pmol/L). A total of 564 (of 2770 without baseline MetS) participants developed MetS, and 407 (of 3030 without baseline DM) developed DM. Per SD higher log-pro-NT/NMN, the demographic-adjusted odds ratio (OR) and 95% CI of incident MetS was 1.22 (1.11-1.35), 1.16 (1.00-1.35) for incident low high-density lipoprotein (HDL), and 1.25 (1.11-1.40) for incident dysglycemia. The association of pro-NT/NMN with MetS was attenuated in the model adding HOMA-IR (OR per SD log-pro-NT/NMN 1.14; 95% CI, 1.00-1.30). There was no association with incident DM (OR per SD log-pro-NT/NMN 1.06; 95% CI, 0.94-1.19). CONCLUSION: Pro-NT/NMN was associated with MetS and 2 components, dysglycemia and low HDL, likely explained by insulin resistance.

N-Terminal Pro-B-Type Natriuretic Peptide and Longitudinal Risk of Hypertension.

BACKGROUND: Hypertension is a common condition that increases risk for future cardiovascular disease. N-terminal B-type natriuretic peptide (NT-proBNP) is higher in individuals with hypertension, but studies of its association with hypertension risk have been mixed. METHODS: The REasons for Geographic And Racial Differences in Stroke (REGARDS) study enrolled 30,239 U.S. Black or White adults aged ≥45 years from 2003 to 2007. A subcohort included 4,400 participants who completed a second assessment in 2013-2016. NT-proBNP was measured by immunoassay in 1,323 participants without baseline hypertension, defined as blood pressure ≥140/90 or self-reported antihypertensive prescriptions. Two robust Poisson regression models assessed hypertension risk, yielding incidence rate ratios (IRRs): Model 1 included behavioral and demographic covariates and Model 2 added risk factors. A sensitivity analysis using a less conservative definition of hypertension (blood pressure ≥130/80 or self-reported antihypertensive prescriptions) was conducted. RESULTS: Four hundred and sixty-six participants developed hypertension after mean follow-up of 9.4 years. NT-proBNP was not associated with hypertension (Model 2 IRR per SD log NT-proBNP 1.01, 95% confidence interval 0.92-1.12), with no differences by sex, body mass index, age, or race. Similar findings were seen in lower-threshold sensitivity analysis. CONCLUSIONS: NT-proBNP was not associated with incident hypertension in REGARDS; this did not differ by race or sex.

Pro-neurotensin/neuromedin N and risk of ischemic stroke: The REasons for Geographic And Racial Differences in Stroke (REGARDS) study.

The tridecapeptide neurotensin has been implicated in the pathogenesis of cardiometabolic disease. Its stable precursor, pro-neurotensin/neuromedin N (pro-NT/NMN), has been associated with composite cardiovascular outcomes including coronary heart disease (CHD) and stroke. The exclusive association of pro-NT/NMN with ischemic stroke has not been evaluated. We conducted a prospective case-cohort study in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. From 2003 to 2007, REGARDS enrolled 30,239 white or black adults aged ⩾ 45 years. Baseline fasting pro-NT/NMN was measured by immunoassay in the analytic sample including 448 incident ischemic stroke cases and 818 random cohort sample participants. A total of 464 ischemic strokes occurred. Risk of stroke was assessed with a Cox proportional-hazards model incorporating demographic covariates and a second adding stroke risk factors. Increased pro-NT/NMN was associated with ischemic stroke in the demographic model overall (hazard ratio (HR) per standard deviation (SD) pro-NT/NMN 1.16, 95% confidence interval (CI) 1.01-1.33) and in men (HR per SD pro-NT/NMN 1.25, 95% CI 1.04-1.50); HRs were attenuated in the risk factor model. Pre-existing diabetes mellitus and CHD were the largest confounders of ischemic stroke risk, each accounting for an estimated 19% of the association of pro-NT/NMN with ischemic stroke observed in the demographic model. There were no significant interactions of race or sex with pro-NT/NMN. Further research on associations of pro-NT/NMN with stroke risk factors such as diabetes mellitus is indicated.

Pro-Neurotensin/Neuromedin N and Risk of Cognitive Impairment in a Prospective Study.

BACKGROUND: The neuropeptide neurotensin (NT) has been linked to cardiometabolic disease. Cardiovascular risk factors are being recognized as risk factors for cognitive impairment. OBJECTIVE: To examine the association of the stable precursor of NT, pro-neurotensin/neuromedin N (pro-NT/NMN), with incident cognitive impairment (ICI). METHODS: We conducted a prospective nested case-control study in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. In 2003-2007, REGARDS enrolled 30,239 Black and White adults aged ≥45 years. ICI was identified using a 3-test cognitive battery administered biannually. Baseline pro-NT/NMN was measured by immunoassay in 393 cases of ICI and 490 controls after 3.4 years follow up. Multivariable logistic regression was used to calculate odds ratios (OR) of ICI by pro-NT/NMN quartiles. Race, age, and sex differences were studied with stratified models and interaction testing. RESULTS: Pro-NT/NMN was higher in Black participants and those with hypertension and diabetes. Women with a 4th versus 1st-quartile pro-NT/NMN had 2.28-fold increased odds of ICI (95% CI 1.08-4.78) after adjusting for risk factors and incident stroke. There was no association of higher pro-NT/NMN quartiles with ICI in the overall group or men. There were no race or age differences in associations. CONCLUSION: In this biracial population-based study, elevated systemic pro-NT/NMN was associated with more than doubled risk of ICI in women but not men. Others reported sex-specific associations in women for cardiovascular mortality and diabetes with higher pro-NT/NMN, supporting a role for future research on sex differences in the neurotensinergic system.

Association of Rurality With Survival and Guidelines-Concordant Management in Early-stage Non-Small Cell Lung Cancer.

BACKGROUND: Rural populations of the United States have not experienced a similar degree of decline in lung cancer mortality recently seen nationwide. Several investigations examining survival differences in rural lung cancer patients have been incongruent. We investigated the association of rural residence with survival outcomes and receipt of guidelines-concordant treatment in early-stage non-small cell lung cancer (NSCLC). METHODS: Retrospective study of National Cancer Data Base patients with NSCLC diagnosed from 2004 to 2015. Comparisons of survival outcomes and guidelines-concordant management with lobectomy or stereotactic body radiation therapy among rural and nonrural patients, classified according to the US Department of Agriculture's Rural-Urban Continuum Codes. RESULTS: We identified 840,566 patients; 18.7% resided in rural areas. Rurality was associated with greater proportions of males, white patients, and higher comorbidities. Larger proportions of rural stage I patients (53.4%) did not undergo guidelines-concordant management with lobectomy or stereotactic body radiation therapy relative to nonrural patients (50.1%, P<0.001). Although rural patients within each stage at diagnosis have a significant disparity in overall survival (OS), stage I NSCLC had the largest absolute difference (nonrural=61.4 mo, rural=50.3 mo, difference of 11.1 mo, P<0.0001). In multivariable Cox regression, rurality was independently associated with impaired survival in both all-stages (hazard ratio=1.08, P<0.001) and stage I NSCLC (hazard ratio=1.09, P<0.001). CONCLUSIONS: Small differences exist in OS among all rural NSCLC patients, but rural patients with stage I NSCLC have a marked disadvantage in OS. Rurality is an independent risk factor for decreased survival in all-stages and stage I NSCLC.