Lydia Project

Objective: Inflammation drives cardiovascular disease, anti-inflammatory approaches may be beneficial. Short-chain fatty acids (SCFA) are bacterial metabolites with anti-inflammatory properties affecting host immune homeostasis including regulatory T cells (Treg). We investigated effects of the SCFA propionate (administered in drinking water, NaCl as control) in two mouse models, namely hypertensive heart disease (wild-type NMRI (WT), angiotensin (Ang)II infusion 1.44 mg/kg/d s.c. for 14 days) and atherosclerosis (Apolipoprotein E knockout (ApoE), AngII infusion 0.72 mg/kg/d s.c. for 28 days), respectively. Results: Propionate attenuated cardiac hypertrophy and fibrosis in both models significantly. Susceptibility to cardiac ventricular arrhythmias was significantly reduced in propionate-treated WT mice. Aortic atherosclerotic lesion area was significantly reduced in propionate-treated ApoE (27.6±8 vs. 7.9±2.4%). Treatment reduced splenic effector memory (CD4+ CD44+ CD62L-) T cell frequencies (WT: 30.5±4.6 vs. 19.1±1.6; ApoE: 41.1±3.1 vs. 32.7±1.4%) and splenic Th17 cells (WT: 1.0±0.2 vs. 0.6±0.1; ApoE: 1.3±0.1 vs. 0.9±0.1%) in both models, indicating beneficial effects on systemic inflammation. Similarly, propionate reduced cardiac immune cell infiltration (CD4+, CD8+, F4/80+) in WT mice. Propionate improved vascular dysfunction and moderately reduced blood pressure in both models. Organ-protective actions of propionate (cardiac inflammation and fibrosis) were abrogated in Treg-depleted (antiCD25-treated) AngII-infused WT mice, suggesting a central role for Treg. To verify our findings in a human cohort, we re-analyzed clinical and metagenomic data from a recent randomized controlled trial investigating the effect of a 90-day synbiotic intervention in 84 subjects with metabolic syndrome including healthy controls. Interestingly, in synbiotic-treated subjects an increased capacity for SFCA production was significantly correlated to blood pressure reduction. Conclusion: Data underscore the importance of SCFA for cardiovascular health and suggest that lifestyle modifications leading to augmented SCFA production could be a beneficial non-pharmacological add-on strategy for cardiovascular disease.

Background: Aortic stiffness and left ventricular (LV) remodeling increases with age and accumulated CVD risk factors, which vary by race. We hypothesized that childhood risk factors are longitudinally associated with adult aortic stiffness and LV remodeling and that these associations vary by race in the biracial (black vs. white) Bogalusa Heart Study cohort. Methods: Participants sampled had at least three Study visits over the life course, ultrasound as young adults for aorta-femoral pulse wave velocity (afPWV), and echocardiographic LV mass (n=1081, 24-44 years old, 31% black, 57% female, and mean follow-up 27 years). Demographic, anthropometric, blood pressure, lipid, glucose and tobacco exposure data were extracted from each visit. Given variable visit intervals and number, separate growth mixed models were used to compute total area under the curve for risk factor traits on the primary outcomes of interest, a) afPWV or b) LV mass indexed to height 2.7 (LVMI). Childhood trait to adult afPWV and LVMI associations, adjusted for cumulative trait levels, were examined with multivariable-adjusted linear regression. Significant race by trait interaction terms (p<0.001) led to race-specific reporting. Results: Adult afPWV and LVMI were higher in black (5.4±1.2 m/s and 36.3±11.4 g/m 2.7 ) than white (5.2±1.1 and 33.8±9.2) participants (p=0.01). Higher adult afPWV was associated with childhood low density lipoprotein cholesterol (LDL-C, β 0.13;p<0.001) and mean arterial pressure (MAP, 0.1;p=0.02). By race, higher afPWV was associated with childhood LDL-C in blacks (0.17;p<0.01) and whites (0.1;p<0.01) while MAP was associated only in whites (0.08;p=0.04). Adult LVMI was associated with childhood BMI (0.3; p<0.001), triglycerides (TG, -0.08; p=0.04), and afPWV (0.10, p<0.01). By race, higher LVMI was associated with childhood BMI in blacks (0.27; p<0.001) and whites (0.34;p<0.001), while LDL-C (0.1; p=0.02), TG (-0.14; p<0.01), Glucose (0.12; p<0.01), and afPWV(0.11,p<0.01) were associated only in whites. Conclusions: Adult aortic stiffness and LV remodeling were associated with childhood traits, even after adjustment for cumulative trait levels. These associations appear to vary by race.

Introduction: That adverse health outcomes, including atherosclerosis, are associated with sleep disturbance is well-documented; however, evidence from diverse populations on the magnitude of this association, or investigating sleepiness as an outcome, is scarce. Methods: We examined data from theBogalusa Heart Study, a long-term community-based observational study of a biracial cohort, with first measurements in childhood in 1973. Men and women (n=546) who underwent a measure of carotid intima-media thickness (IMT), calculated as the composite IMT (cIMT), mean of six segments (common and internal carotid, and carotid bifurcation, each left and right), and completed the Epworth Sleepiness Scale (ESS), were included. Multivariable logistic regression was employed to model the association between ordinal self-rated sleepiness and cIMT per standard deviation, adjusted for age, sex, smoking status (at time of IMT measurement), hours of sleep, symptoms of sleep disturbance, and previous heart attack. Based on previous race-specific findings, data were analyzed separately by race. Results: Of whites (n=356), 59.6% were female and 22.5% were current smokers. Mean (SD) age was 43.1 (4.4) years, and cIMT was 0.6 (0.1) mm. Of African-Americans (n=190), 66.8% were female, 34.7% were current smokers. Mean (SD) age was 42.8 (4.6) years, and cIMT was 0.7 (0.2) mm. Multivariate modeling found a significant race-cIMT interaction term (p=0.04). In stratified analyses, the adjusted odds of abnormal sleepiness (vs. normal sleepiness) were 1.40 times greater (95% CI: 1.04-1.90) per 1-SD increase in cIMT in whites, while among black participants, the odds ratio (95% CI) was 1.01 (0.68-1.50). Conclusions: There was a significant association between unfavorable subclinical measures of atherosclerosis and excessive daytime sleepiness among white participants.

Background: Childhood risk factors predict adult onset type 2 diabetes mellitus (T2DM). We developed a novel statistical approach using risk factor patterns to improve prediction. Methods: The cohort included 5269 individuals from the Bogalusa Heart Study, Cardiovascular Risk in Young Finns Study, Childhood Determinants of Adult Health Study, Childhood Cohort Studies in Minneapolis and Cincinnati, and the Muscatine Study. All had 2+ childhood measures of risk factors between ages 3 and 20 in 1970s-90s and reported whether they had T2DM between ages 21 and 63 in 2011-16. We established sex-specific polynomial age patterns to represent standard growth curves for each risk factor and computed the residual from this standard for each observation within ages 3-20. Residuals were regressed on age within each person to get a personal intercept and slope, and then 9 patterns were formed as intercept tertiles crossed with slope tertiles within each intercept tertile. T2DM associations with risk factors were assessed by using either the first childhood measurement or childhood patterns of body mass index (BMI), systolic blood pressure (SBP), and height (HT), with covariates age at first visit, sex, race, and study. Results: Mean age at first measure was 9.2 (SD 3.3) y, 41% male, 85% white, 12% black, with 2-19 repeats of childhood risk factor measures. Risk factor patterns tended to diverge from each other by mid-childhood and measured adult risk factor values were well predicted, diverging widely across the childhood patterns (not shown). After mean follow-up of 29.0 (SD 8.1) y, 282 (5.4%) participants self-reported T2DM. T2DM was predicted by the model including first measures of BMI (positive), SBP (positive), and HT (inverse), but the corresponding pattern model improved prediction probability by 55% (Table). Conclusion: These findings show the value of using multiple risk factor measurements during childhood and the potential for developing risk factor pattern charts to be used as clinical standards for predicting adult T2DM risk.

Stroke is the 5 th -leading cause of death in the US and the major cause of disability. Many patients who have suffered from strokes are left with permanent neurological deficits, new occupational and social difficulties, and reductions in quality of life that may be idiosyncratic or vary considerably from patient to patient. Solicitation of patient reported outcomes (PROs) in the treatment and recovery from strokes is therefore imperative. We examined a list compiled in 2013 for Stroke by Magin et al. of representative stroke-related, randomized clinical trials published in 10 high-impact journals between 2002 and 2012 to assess whether PROs were collected and which constructs were reported. We categorized PRO measures as stroke-specific (e.g. Stroke Impact Scale), health profile and utility scales (e.g. Beck Depression Scale), or general (e.g. pain visual analog scale). Two reviewers independently abstracted PRO measures from each article and disagreements were resolved by consensus. Fisher’s exact test was used for statistical analyses. Of the 99 articles that met study inclusion criteria, 20% concerned prevention, 22% acute treatment, and 58% rehabilitation. A plurality of trials were European (43%) followed by studies based in the US (25%), Asian countries (10%), and Australia (10%). Altogether, 37% of studies used a PRO of any kind. Stroke-specific PROs were collected in 17% of studies, health profile and utility scales were used in 17%, and general PROs were used in 23%. There were no significant differences in PRO use with regards to year of publication or study location. Health profile and utility scales (p=0.01) and unclassified PROs (p<0.001) were most-commonly reported in rehabilitation trials. Stroke-specific PROs were most commonly published in the journals Brain and Journal of Stroke and Cerebrovascular Diseases (p=0.001). Overall, our review and analysis detected a low prevalence and a large degree of heterogeneity of PRO measures reported in stroke-related clinical trials. Future stroke research must routinely incorporate PROs into the study design to help patients, caregivers, and providers make informed decisions about stroke prevention, treatment, and rehabilitation options that yield outcomes of greatest importance to them.

Introduction: This study investigated the feasibility and accuracy of real-time three-dimensional echocardiography (RT3DE) in assessing the severity of simulated mitral stenosis in a pumped porcine heart model. Hypothesis: RT3DE is accurate for assessing mitral stenosis. Methods: Eight porcine hearts were used to simulate mitral stenosis. Four different sized inner-diameter tubes (9,11,13 and 15mm) were used to create stenotic mitral valve orifice areas. These tubes were inserted into vinyl tubing which was then connected to a pulsatile pump. A balloon was secured to the end of the tubing entering the left ventricle, and the model was sutured at the mitral annulus. The heart was submerged in a water tank and the pump set at 60 bpm with stroke volumes ranging from 30-70 mL in 10 mL increments. At each increment, images were acquired in 2D echo and RT3DE using a GE Vivid 7 ultrasound system. Data were analyzed using GE EchoPAC PC. Results: A comparison of true area and measured orifice areas were analyzed for both 2D echo and RT3DE. Linear regression analysis showed excellent correlation 2D and RT3DE acquired areas and true areas (2D: r 2 =0.9; RT3DE: r 2 =0.9). It was found that while RT3DE presented significantly similar mean values for all areas tested (P<0.05), 2D-measured areas were consistently larger than expected values (P<0.05). Conclusions: RT3DE has the potential to be an accurate, noninvasive diagnostic tool in clinical cardiology that overcomes imaging limitations present in 2D echo.

Background: The modified and original variants of the TICI scale (mTICI and oTICI) define substantial reperfusion in endovascular stroke therapy (EVT) as ≥50% (mTICI) or ≥67% (oTICI) of the downstream territory. Despite recent adoption of the mTICI definition, it remains uncertain which threshold better predicts good clinical outcome after EVT. Methods: The angiography core lab of the IMS III trial evaluated use of the oTICI definition compared to the mTICI technical endpoint. Inclusion criteria were presence of an intracranial ICA or MCA M1 occlusion, active EVT and available 90-day mRS. Two expert readers independently reviewed the complete angiography studies to categorize mTICI 2B results into 50-66% vs. 67-99% reperfusion and differences were resolved by consensus. ROC analysis was performed to determine the optimal threshold for predicting good clinical outcome (mRS 0-2). Safety endpoints were mortality and symptomatic intracranial hemorrhage. Inter-rater agreement was assessed using the kappa statistic. Results: 187 patients met inclusion criteria with mean age 65.7 years and median NIHSS 19 were included, with 56 ICA and 131 M1 occlusions. The mTICI was 0 in 32 patients, 1 in 17, 2A in 69, 2B in 64, and 3 in only 5. Of the 64 mTICI 2B cases, 38 (59%) were adjudicated as oTICI 2B (i.e., 67-99%). There was an increase in good outcomes with greater reperfusion (mTICI 2B, 46%; oTICI 2B, 53%; p<0.0001), although there was no significant pairwise difference between 50-66% vs. 67-99% (p=0.80). For good outcome, the c-statistic was non-significantly higher for mTICI vs. oTICI (0.76 vs. 0.73, p=0.19). Overall, the optimal threshold for predicting good outcome was mTICI 2B-3 (sensitivity 68%, specificity 75% vs. sensitivity 45%, specificity 86% for oTICI 2B-3). Similarly, mTICI 2B-3 was the optimal threshold for predicting decreased mortality and decreased sICH. Inter-rater agreement for discriminating 50-66% vs. 67-99% reperfusion was excellent (kappa=0.84). Conclusions: Greater degrees of reperfusion are associated with a higher likelihood of good outcomes. The most effective threshold, however, for predicting both good clinical outcome and improved safety is mTICI 2B rather than oTICI 2B.

Purpose: Randomized control trials (RCT) are the gold standard of clinical research, yet most RCTs do not finish on time or on budget of the original proposal. The literature lacks research relevant to enhancing investigator recruitment strategies. Therefore, we sought to explore the role of these strategies in the ongoing NIH-funded, Interventional Management of Stroke (IMS) Phase III Trial. Method: We limited this analysis to November 1, 2007 - July 31, 2011 to exclude the start-up period for the trial. We compiled the dates of all potential recruitment enhancing strategies used in the trial, including investigator meetings, contests to reward recruitment, amendments to broaden eligibility criteria, and the addition of more sites in the US and internationally. We compared mean enrollment in the two months immediately before and after the month of intervention, and prespecified that an enrollment change of ≥ 25% would be considered a potentially effective recruitment strategy. Given the limited variability, only descriptive analyses were performed. Results: From November 2007 through July 2011, the mean monthly recruitment in the IMS III Trial was 9.77, ( SD = 3.2) subjects and the range was 4-20. There was no significant change in recruitment rates over time ( p = 0.56). We identified a change of ≥ 25% after each investigators’ meeting at the International Stroke Conference in 2008, 2009, 2010, and 2011. Other interventions that exceeded the 25% change were the submission of Amendment 3 (Jan 2009), conduct of an investigators’ conference call (Aug 2010), and initiation of screening at European sites (Mar 2011). See Table 1. Discussion: Investigators’ meetings and/or the International Stroke Conference appeared to increase enrollment significantly in the IMS III Trial. We speculate that these investigators’ meetings convey the commitment of the PI and administrative staff and increase the enthusiasm of investigators to complete the study. Additional efforts may have been beneficial, but our analysis was limited by multiple confounding factors, including the imprecision of the timing for implementation of some strategies as with IRB-approval of new amendments at each institution, and individual site factors such as the probation of underachieving sites. Review of the literature identified online education pertaining to consent methodology as a new avenue for the IMS III Trial to explore to maintain recruitment. Further evidence-based study of methods to improve investigator-initiated recruitment is needed. Table 1: Recruitment Efforts and Corresponding Monthly Enrollment Rates

Hereditary tyrosinaemia type 1 (HT1) is caused by an enzymatic defect in tyrosine metabolism. It is an autosomal recessive disorder and affects both sexes equally. In young infants HT1 can present as severe liver involvement and in older infants as liver failure and renal tubular dysfunction together with growth failure and rickets. The authors report the case of a 5-month-old, previously healthy, male infant who presented with Escherichia coli sepsis and severe coagulopathy due to liver dysfunction. Despite the early diagnosis of HT1 and treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC), the patient died from severe coagulopathy and multi-organ failure.