Citations

ABSTRACT Background: Inorganic polyphosphate (polyP) is a procoagulant polyanion. We assessed the impact of polyP inhibition on thrombin generation after trauma using the novel polyP antagonists, macromolecular polyanion inhibitor 8 (MPI 8), and universal heparin reversal agent 8 (UHRA-8). Methods: Plasma thrombin generation (calibrated automated thrombogram, CAT), in 56 trauma patients and 39 controls +/− MPI 8 and UHRA-8 (50 μg/mL), was expressed as lag time (LT, minutes), peak height (PH, nM), and time to peak (ttPeak, minutes), with change in LT (ΔLT) and change in ttPeak (ΔttPeak) quantified. Results expressed in median and quartiles [Q1, Q3], Wilcoxon matched-pairs testing, P < 0.05 significant. Results: Trauma patients had greater baseline PH than controls (182.9 [121.0, 255.2]; 120.5 [62.1, 174.8], P < 0.001). MPI 8 treatment prolonged LT and ttPeak in trauma (7.20 [5.88, 8.75]; 6.46 [5.45, 8.93], P = 0.020; 11.28 [8.96, 13.14]; 11.00 [8.95, 12.94], P = 0.029) and controls (7.67 [6.67, 10.50]; 6.33 [5.33, 8.00], P < 0.001; 13.33 [11.67, 15.33]; 11.67 [10.33, 13.33], P < 0.001). UHRA-8 treatment prolonged LT and ttPeak and decreased PH in trauma (9.09 [7.45, 11.33]; 6.46 [5.45, 8.93]; 14.02 [11.78, 17.08]; 11.00 [8.95, 12.94]; 117.4 [74.5, 178.6]; 182.9 [121.0, 255.2]) and controls (9.83 [8.00, 12.33]; 6.33 [5.33, 8.00]; 16.67 [14.33, 20.00]; 11.67 [10.33, 13.33]; 55.3 [30.2, 95.9]; 120.5 [62.1, 174.8]), all P < 0.001. Inhibitor effects were greater for controls (greater ΔLT and ΔttPeak for both inhibitors, P < 0.001). Conclusion: PolyP inhibition attenuates thrombin generation, though to a lesser degree in trauma than in controls, suggesting that polyP contributes to accelerated thrombin generation after trauma.

Introduction: Severe hypertriglyceridemia (SHTG), defined as plasma triglyceride (TG) level ≥ 500 mg/dl, is a risk factor for cardiovascular disease. In the NHANES dataset (2001 - 2006), the prevalence of SHTG was 1.7%. However, the prevalence of primary SHTG in the community is unknown. We conducted a community-based study to estimate the prevalence of primary SHTG, in Olmsted County, Minnesota. Methods: We used the Rochester Epidemiology Project (REP) records linkage system to identify individuals with TG ≥ 500 mg/dl between 1998-2015. Index date was defined as the first documentation of TG ≥500 mg/dl during the study period. We excluded individuals with mixed hyperlipidemia (TG ≥500 mg/dl and non-high density lipoprotein (HDL) cholesterol ≥190 mg/dl). HTG was defined as secondary in the presence of hypothyroidism, biliary obstruction, nephrotic syndrome, uncontrolled diabetes, pregnancy, liver disease, renal failure, BMI ≥35 and medication use (isotretinoin, tetracyclines, anti-retrovirals). Primary HTG was defined as absence of an identifiable secondary etiology. Characteristics of the primary SHTG individuals were ascertained from the electronic health record. Results: SHTG was identified in 3802 individuals of whom 2511 had mixed hyperlipidemia, 743 had a secondary cause for SHTG and the remaining 548 had primary SHTG. Using the 2015 population census of 151,436 for Olmsted County, the prevalence of SHTG was 2.5%, of secondary SHTG was 0.49% and of primary SHTG was 0.36%. Only half of the primary SHTG group had a diagnosis of dyslipidemia in the electronic health record and 44.3% were on lipid-lowering therapy on index date. Characteristics of individuals with primary SHTG are summarized in Table 1. Conclusions: These data highlight that primary SHTG is relatively common (≈1 in 300, similar to the prevalence of familial hypercholesterolemia), underdiagnosed and undertreated.

Introduction: Aldosterone (Aldo) increases sodium and water reabsorption and mediates inflammatory processes. Its relationship to co-morbidities has not been well defined in the general population. Hypothesis: We addressed the hypothesis that plasma aldosterone concentration (PAC) is associated with metabolic and cardiorenal diseases in the general community. Methods: We determined PAC in a general community-based cohort from Olmsted County, MN (n=1,674), and defined correlations with cardiorenal, metabolic diseases and myocardial function and structure. Results: PAC was detected in all subjects and ranged from 2.5 to 91 ng/dl (mean value 6.7 ng/dl, +/- SD 6.6). Multivariate analysis adjusted for age, gender, BMI, ANP and BNP showed highly significant correlations between PAC and hypertension (HTN) (p<.0001, OR=2.28, CI:1.91-2.71), atrial fibrillation (p<.01), chronic kidney disease (CKD) (p<.0001, OR=1.64, CI:1.33-2.02), central obesity (p<.0001, OR=1.61, CI:1.27-2.05), hypertriglyceridemia (p<.003), prevalence of metabolic syndrome (MetS) (p<.0007, OR=1.40, CI=1.15-1.71), obesity (p<.0001, OR=1.48, CI:1.27-1.73), and concentric left ventricular hypertrophy (cLVH) (p=.01). Recognizing that ANP and BNP are known inhibitors of Aldo, we defined the relationship between these cardiac hormones (NTpro-ANP and NT-proBNP) and PAC and observed highly significant inverse relationships with NTpro-ANP (p=0.0009), NTpro-BNP (p=0.0003) in the general population. Conclusions: In conclusion, in the general community, PAC is strongly correlated with renal, metabolic and cardiovascular diseases as well as cardiac remodeling. Specifically, increasing PAC is strongly associated with HTN, CKD, obesity, MetS, cLVH, and lower levels of natriuretic peptides. Our data suggest a key role of Aldo as a possible biomarker and/or mediator of human cardiorenal and metabolic diseases even in the general adult population, prior to overt disease. This study also supports a possible counter regulatory relationship between cardiac natriuretic peptides and PAC. Further studies are warranted to evaluate possible therapeutic interventions targeting Aldo as a strategy to delay disease progression.

Introduction Current evidence suggests that abnormal ventriculo-vascular coupling may contribute to the development of atrial fibrillation (AF) by increasing ventricular filling pressures and consequently, left atrial pressure. Recent investigations have also suggested that inflammation might have a role in the pathophysiology of AF. We hypothesize that autoimmune vasculitis plays a significant role in the pathogenetic mechanism of AF. Methods In this longitudinal cohort study, residents of Olmsted County, MN with first- time diagnosed AF during 1980-2000 and a reference age- and sex-matched control group from the same underlying population and time period were identified and followed until death, or 2000. The relationship between autoimmune vasculitis and first documented AF was analyzed. Results Of a total of 8766 patients (mean age 61.1+14.9 years; 56% women), 691 (7.9%) were diagnosed with autoimmune vasculitis during the 20 year period. The prevalence of autoimmune vasculitis in the AF group was 9.9% and 5.9% in the control group; p <0.001, respectively. After adjusting for CAD and LV dysfunction, the odds of autoimmune vasculitis in AF was 1.7 times higher than in controls (OR 1.69, 95%; CI 1.42 - 2.01, p < 0.0001). AF patients with autoimmune vasculitis had a worse survival compared to controls; p=.0114 (log-rank test). Conclusion Autoimmune vasculitis strongly increases the risk of atrial fibrillation and portends shorter survival in the AF population. These observations may represent one mechanism linking increased arterial stiffness and inflammation in the pathogenesis and prognosis of AF as an age-related disorder.

Abstract Background Although diabetic gastroenteropathy (DGE) is associated with small intestinal bacterial overgrowth (SIBO), most studies have evaluated SIBO with a hydrogen breath test, which may be affected by altered transit in DGE. The risk factors for the consequences of SIBO in DGE are poorly understood. We aimed to evaluate the prevalence of, risk factors for, and gastrointestinal symptoms associated with SIBO in patients with DGE. Methods In 75 patients with DGE and dyspepsia, we tested for SIBO (≥10 5 colony forming units /mL of aerobic and/or anaerobic bacteria in a duodenal aspirate) and assessed gastric emptying (GE) of solids, symptoms during a GE study and during an enteral lipid challenge (300 kcal/2 h), and daily symptoms with a Gastroparesis Cardinal Symptom Index diary for 2 weeks. Symptoms and GE were compared in patients with versus without SIBO. Key Results Of 75 patients, 34 (45%) had SIBO, which was not associated with the use of proton pump inhibitors, daily symptoms, GE, or symptoms during a GE study. During enteral lipid challenge, severe nausea ( p = 0.006), fullness ( p = 0.02) and bloating ( p = 0.009) were each associated with SIBO. Twenty patients (59%) with versus 13 (32%) without SIBO had at least one severe symptom during the lipid challenge ( p = 0.006). Conclusions & Inferences Among patients with DGE 45% had SIBO, which was associated with symptoms during enteral lipid challenge but not with delayed GE, symptoms during a GE study, or daily symptoms. Perhaps bacterial products and even fatty acids are recognized by and activate mast cells that drive the increased lipid sensitivity in SIBO.

Abstract Background Customized and standard automated insulin delivery (AID) systems for use in pregnancies of women with preexisting type 1 diabetes (T1D) are being developed and tested to achieve pregnancy appropriate continuous glucose monitoring (CGM) targets. Guidance on the use of CGM for treatment decisions during pregnancy in the United States is limited. Methods Ten pregnant women with preexisting T1D participated in a trial evaluating at-home use of a pregnancy-specific AID system. Seven-point self-monitoring of blood glucose (SMBG) was compared to the closest sensor glucose (Dexcom G6 CGM) value biweekly to assess safety and reliability based on the 20%/20 mg/dL criteria. Results All participants completed the study with 7 participants satisfying the safety and reliability criteria with a mean absolute relative difference of 10.3%. Three participants did not fulfill the criteria, mainly because the frequency of SMBG did not meet the requirements. Conclusion Dexcom G6 CGM is safe and accurate in the real-world setting for use in pregnant women with preexisting T1D with reduced SMBG testing as part of a pregnancy-specific AID system.

AbstractBackgroundHigher blood pressure (BP) is associated with greater white matter hyperintensity (WMH) volume, but research is limited in recently menopausal and postmenopausal women. Postmenopausal women have a greater burden of WMH than men and premenopausal women, but whether hormone therapy (HT) modifies the association between systolic and diastolic BP (SBP, DBP) and WMH is unknown. We investigated the association of SBP and DBP in recently postmenopausal women who participated in an HT trial with WMH volumes measured 14 years later and explored whether HT modified the results.MethodWomen with good cardiovascular (CV) health, who were previously enrolled in a randomized placebo‐controlled HT trial, the Kronos Early Estrogen Prevention Study (KEEPS), participated in the current observational KEEPS continuation (n = 212; median age = 67; range 58‐72). SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59) and continuation. Antihypertensive users were excluded (baseline, n = 34; continuation, n = 61). Approximately 10 years after the end of KEEPS HT versus placebo 4‐year interventions, automated WMH volumes were measured from 3D‐FLAIR MRI. Associations of KEEPS baseline and continuation SBP and DBP with log WMH volume at KEEPS continuation were tested using linear regression analyses adjusting for covariates in model 1 (age, total intracranial volume, study site) and model 2 (model 1 plus cardiovascular risk factors (CVRF)).ResultHigher KEEPS baseline SBP and DBP were associated with greater WMH volume measured 14 years later, and after adjusting for CVRF (p≤0.01). Similarly, in KEEPS continuation, higher SBP and DBP were associated with greater WMH volume measured concurrently and after adjusting for CVRF (p<0.001). We did not find statistically significant evidence that HT versus placebo modified these associations. Topographically, higher SBP and DBP were associated with greater periventricular WMH in the frontal and parietal lobes after adjusting for age (Figure).ConclusionHigher SBP and DBP in recently menopausal women with good CV health were associated with greater WMH volumes more than a decade later after adjusting for CVRF, independent of randomization to HT. Our results show the importance of blood pressure control in recently menopausal women, that may reduce the white matter injury later in life.

AbstractBackgroundHigher blood pressure (BP) is associated with greater white matter hyperintensity (WMH) volume, but research is limited in recently menopausal and postmenopausal women. Postmenopausal women have a greater burden of WMH than men and premenopausal women, but whether hormone therapy (HT) modifies the association between systolic and diastolic BP (SBP, DBP) and WMH is unknown. We investigated the association of SBP and DBP in recently postmenopausal women who participated in an HT trial with WMH volumes measured 14 years later and explored whether HT modified the results.MethodWomen with good cardiovascular (CV) health, who were previously enrolled in a randomized placebo‐controlled HT trial, the Kronos Early Estrogen Prevention Study (KEEPS), participated in the current observational KEEPS continuation (n = 212; median age = 67; range 58‐72). SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59) and continuation. Antihypertensive users were excluded (baseline, n = 34; continuation, n = 61). Approximately 10 years after the end of KEEPS HT versus placebo 4‐year interventions, automated WMH volumes were measured from 3D‐FLAIR MRI. Associations of KEEPS baseline and continuation SBP and DBP with log WMH volume at KEEPS continuation were tested using linear regression analyses adjusting for covariates in model 1 (age, total intracranial volume, study site) and model 2 (model 1 plus cardiovascular risk factors (CVRF)).ResultHigher KEEPS baseline SBP and DBP were associated with greater WMH volume measured 14 years later, and after adjusting for CVRF (p = 0.01). Similarly, in KEEPS continuation, higher SBP and DBP were associated with greater WMH volume measured concurrently and after adjusting for CVRF (p<0.001). We did not find statistically significant evidence that HT versus placebo modified these associations. Topographically, higher SBP and DBP were associated with greater periventricular WMH in the frontal and parietal lobes after adjusting for age (Figure).ConclusionHigher SBP and DBP in recently menopausal women with good CV health were associated with greater WMH volumes more than a decade later after adjusting for CVRF, independent of randomization to HT. Our results show the importance of blood pressure control in recently menopausal women, that may reduce the white matter injury later in life.

Introduction: US rural areas have a disproportionate burden of CVD and hypertension. Physical inactivity is a major risk factor, with 25% prevalence in US adults. However, rural disparities in physical inactivity are incompletely described. The aim was to evaluate differences in prevalence of physical inactivity based on county-level rurality. Methods: We used CDC county-level data for adults aged ≥20 years, 2004–2019, available for 97.6% of US counties (n=3148/3226). CDC defined physical inactivity as self-reported lack of leisure time physical activity in the month preceding the survey. Rurality was based on six categories ordered from least rural (large central metro) to most rural (noncore). We used weighted least squares regression to compare prevalence by rurality level, adjusting for 13 county-level sociodemographic factors; results reported as prevalence ratios (95% CI) with partial F -tests and P -values. Results: In age and sex ratio adjusted analysis (model 1), we observed a gradient in the prevalence of physical inactivity across levels of rurality, with significantly higher rates in small metro (1.03 [1.00–1.06]), micropolitan (1.05 [1.02–1.07]), and noncore (1.05 [1.02–1.08]) compared with large central metro counties ( F -statistic=7.5; P <.001). With further adjustment for other sociodemographic factors (model 2), the relative differences were negated in noncore counties (0.99 [0.97-1.02]), attenuated in intermediate counties, and accentuated in large fringe metro counties (1.06 [1.04-1.08]) ( F -statistic=14.3; P <.001). Further adjustment for obesity (model 3) largely attenuated the association of rurality with physical inactivity, resulting in no significant differences relative to large central metro counties ( F -statistic=4.8; P <.001). Conclusions: County-level rurality was associated with prevalence of physical inactivity. These disparities were largely accounted for by obesity, which may be targeted for intervention.

Introduction: US rural, compared with nonrural, counties have a higher burden of CVD. Obesity is a major CVD risk factor with 40% prevalence in adults. However, the rural-nonrural disparities in obesity are incompletely described. We aimed to evaluate differences in prevalence of obesity by county-level rurality. Methods: We used CDC county-level data for adults aged ≥20 years, 2004–2019, available for 97.6% of US counties (n=3148/3226). CDC defined obesity (body mass index ≥30 kg/m 2 ) using self-reported weight and height. Rurality was based on six levels from large central metro (most urban) to noncore (most rural). We compared prevalence by rurality level using weighted least squares regression, adjusting for 13 county-level sociodemographic measures, and reported prevalence ratios (95% CI). Results: Counties with increasing rurality reflected older populations, as indicated by higher median age (from 35.6 years to 42.4 years). Also, increasing rurality was associated with differences in income and proportion uninsured. In age and sex ratio adjusted analysis (model 1), obesity prevalence was 1.05- to 1.06-fold higher in medium metro, small metro, and micropolitan counties compared with large central metro counties (global test, P <.001). With further adjustment for sociodemographic measures (model 2; model 1 covariates plus race, state, income, proportion uninsured) these relative differences were preserved but attenuated (each 1.03-fold higher), while a greater difference was revealed for large fringe metro (1.06-fold higher) counties. In both models, differences in obesity prevalence between noncore and large central metro counties were minimal. (Table) Conclusion: Counties with intermediate rurality were associated with higher obesity prevalence. The association was partly accounted for by nonmodifiable and modifiable sociodemographic measures, which may be targeted to reduce rural-nonrural disparities in obesity.