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1.  Early Expression of Mitral Valve Prolapse in the Framingham Offspring: Phenotypic Spectrum 
Mitral valve prolapse (MVP) is a common disorder associated with mitral regurgitation (MR), endocarditis, heart failure and sudden death. In the familial context, prior studies have described non-diagnostic mitral valve morphologies (‘prodromal forms’ and ‘minimal superior displacement’ [MSD]) that may represent early expression of MVP in those genetically predisposed. Our objective was to explore the spectrum of MVP abnormalities in the community and compare their clinical and echocardiographic features.
Phenotypic heterogeneity of MVP was assessed by measuring annular diameter (D), leaflet displacement (Dis), thickness (T), anterior/posterior leaflet projections (A, P) onto the annulus, coaptation height (C or P/D), and MR jet height (JH) in a sample of 296 individuals of the Framingham Offspring Study who were identified as having MVP (n=77) or its prodromal form (N=11) or MSD (N=57), with 151 controls with no feature of MVP or its non-diagnostic forms.
The prodromal form did not meet diagnostic criteria but resembled fully diagnostic MVP with regards to D, T and JH (all p > 0.05); they were similar to individuals with posterior MVP with regard to leaflet asymmetry and coaptation height (p = 0.91). Compared to MSDs and controls, prodromals had greater C, T, D and JH (all p < 0.05). MSDs shared the posterior leaflet asymmetry with classic MVP, but their coaptation point was more posterior (C = 31% versus 42%, p<0.0001).
Non-diagnostic morphologies of MVP are observed in the community and share the common feature of posterior leaflet asymmetry with fully affected individuals. Prodromal morphology and MSD may represent early expressions of MVP and additional studies are warranted to elucidate the natural history of these phenotypes.
PMCID: PMC4239996  PMID: 24206636
mitral valve prolapse; echocardiography
2.  Navigated DENSE strain imaging for post-radiofrequency ablation lesion assessment in the swine left atria 
Europace  2013;16(1):133-141.
Prior work has demonstrated that magnetic resonance imaging (MRI) strain can separate necrotic/stunned myocardium from healthy myocardium in the left ventricle (LV). We surmised that high-resolution MRI strain, using navigator-echo-triggered DENSE, could differentiate radiofrequency ablated tissue around the pulmonary vein (PV) from tissue that had not been damaged by radiofrequency energy, similarly to navigated 3D myocardial delayed enhancement (3D-MDE).
Methods and results
A respiratory-navigated 2D-DENSE sequence was developed, providing strain encoding in two spatial directions with 1.2 × 1.0 × 4 mm3 resolution. It was tested in the LV of infarcted sheep. In four swine, incomplete circumferential lesions were created around the right superior pulmonary vein (RSPV) using ablation catheters, recorded with electro-anatomic mapping, and imaged 1 h later using atrial-diastolic DENSE and 3D-MDE at the left atrium/RSPV junction. DENSE detected ablation gaps (regions with >12% strain) in similar positions to 3D-MDE (2D cross-correlation 0.89 ± 0.05). Low-strain (<8%) areas were, on average, 33% larger than equivalent MDE regions, so they include both injured and necrotic regions. Optimal DENSE orientation was perpendicular to the PV trunk, with high shear strain in adjacent viable tissue appearing as a sensitive marker of ablation lesions.
Magnetic resonance imaging strain may be a non-contrast alternative to 3D-MDE in intra-procedural monitoring of atrial ablation lesions.
PMCID: PMC3924042  PMID: 24014803
Magnetic resonance imaging ablation; Atrial fibrillation; Porcine model
3.  Mitral Stenosis Reversed by Medical Treatment for Heart Failure 
The Annals of thoracic surgery  2013;96(5):e115-e117.
It is reported that functional mitral stenosis frequently develops after ring annuloplasty for ischemic mitral regurgitation. The mechanism is a combination of annular size reduction by surgery and diastolic mitral valve tethering, restricting the anterior leaflet opening due to posteriorly displaced papillary muscles with left ventricular dilatation. We report the case of a 57-year-old man who had a history of successful mitral valve plasty for degenerative mitral regurgitation. Four years later he developed heart failure, severe hypertension, mild mitral regurgitation, and significant mitral stenosis, which were reversed by aggressive medical treatment for heart failure.
PMCID: PMC4281521  PMID: 24182508
4.  Late Repair of Ischemic Mitral Regurgitation does not Prevent Left Ventricular Remodeling: Importance of Timing for Beneficial Repair 
Circulation  2013;128(11 0 1):S248-S252.
Ischemic mitral regurgitation (MR) is a frequent complication of myocardial infarction (MI) associated with left ventricular (LV) dilatation and dysfunction that doubles mortality. At the molecular level, moderate ischemic MR is characterized by a biphasic response with initial compensatory rise in pro-hypertrophic and anti-apoptotic signals followed by their exhaustion. We have shown that early MR repair 30 days after MI is associated with LV reverse remodeling. It is not known if MR repair performed after the exhaustion of compensatory mechanisms is also beneficial. We hypothesised that late repair will not result in LV reverse remodeling.
Methods and Results
Twelve sheep underwent distal left anterior descending coronary artery ligation to create apical MI, and implantation of a LV-to-left atrium shunt to create standardized moderate volume overload. At 90 days, animals were randomized to shunt closure (late repair) vs sham (no repair). LV remodeling was assessed by 3D echocardiography, dP/dt, preload recruitable stroke work (PRSW) and myocardial biopsies. At 90 days, animals had moderate volume overload, LV dilatation and reduced ejection fraction (all p<0.01 vs baseline, p=NS between groups). Shunt closure at 90 days corrected the volume overload (regurgitant fraction 6±5% vs 27±16% for late repair vs sham, p<0.01), but was not associated with changes in LV volumes (end-diastolic volume 106±15 vs 110±22 ml; end-systolic volume 35±6 vs 36±6 ml), or increases in PRSW (41±7 vs 39±13 ml·mmHg) or dP/dt (803±210 vs 732±194 mmHg/sec) at 135 days (all p=NS). Activated Akt, central in the hypertrophic process, and STAT3, critical node in the hypertrophic stimulus by cytokines, were equally depressed in both groups.
Late correction of moderate volume overload after MI did not improve LV volume or contractility. Up-regulation of pro-hypertrophic intra-cellular pathways was not observed. This contrasts with previously reported study in which early repair (30 days) reversed LV remodeling. This suggests a “window of opportunity” to repair ischemic MR, after which no beneficial effect on LV is observed despite successful repair.
PMCID: PMC4281522  PMID: 24030415
Mitral regurgitation; ischemic heart disease; remodeling
5.  Mammography Utilization among Black and White Medicare Beneficiaries in High Breast Cancer Mortality US Counties 
Cancer causes & control : CCC  2013;24(12):2187-2196.
Disparities in US breast cancer mortality between older Black and White women have increased in the last twenty years. Regular mammography use is important for early detection and treatment: its utilization among older Blacks especially in counties with high Black mortality is of interest, but its extent and determinants are unknown.
We used Medicare claims for Black and White women 65–74 years old in 203 counties with the highest Black breast cancer mortality. Outcomes over six years were: screening, i.e., ≥1 screening mammogram, and regular screening, i.e., ≥3 mammograms. With logistic regressions, we examined the independent effect of race on screening controlling for individual and county-level factors.
Of 406,602 beneficiaries, 17% were Black. Screening and regular screening was significantly lower among Blacks (51.6% vs. 56.9%; 32.9% vs 43.1%, respectively). Controlling for covariates, including use of cervical cancer screening, flu shots, or lipids tests, Black women were more likely to have screening (OR 1.23, CI: 1.20–1.25), but not regular screening (OR 0.95, CI: 0.93 – 0.97) than White women. County-level managed care penetration was negatively associated with screening and regular screening.
In Medicare enrollees from these counties, breast cancer screening was low. Black women had same or better odds of screening than White women. Some health care factors, e.g., managed care, were negatively associated with screening. Further studies on the determinants of mammography utilization in older women from these counties are warranted.
PMCID: PMC3955601  PMID: 24077760
Cancer; disparities; mammography; screening; Black women
6.  Exploration of Preterm Birth Rates Using the Public Health Exposome Database and Computational Analysis Methods 
Recent advances in informatics technology has made it possible to integrate, manipulate, and analyze variables from a wide range of scientific disciplines allowing for the examination of complex social problems such as health disparities. This study used 589 county-level variables to identify and compare geographical variation of high and low preterm birth rates. Data were collected from a number of publically available sources, bringing together natality outcomes with attributes of the natural, built, social, and policy environments. Singleton early premature county birth rate, in counties with population size over 100,000 persons provided the dependent variable. Graph theoretical techniques were used to identify a wide range of predictor variables from various domains, including black proportion, obesity and diabetes, sexually transmitted infection rates, mother’s age, income, marriage rates, pollution and temperature among others. Dense subgraphs (paracliques) representing groups of highly correlated variables were resolved into latent factors, which were then used to build a regression model explaining prematurity (R-squared = 76.7%). Two lists of counties with large positive and large negative residuals, indicating unusual prematurity rates given their circumstances, may serve as a starting point for ways to intervene and reduce health disparities for preterm births.
PMCID: PMC4276617  PMID: 25464130
exposome; county rates; data reduction; health disparities; geographical variation; premature birth rates; preterm birth
7.  The Public Health Exposome: A Population-Based, Exposure Science Approach to Health Disparities Research 
The lack of progress in reducing health disparities suggests that new approaches are needed if we are to achieve meaningful, equitable, and lasting reductions. Current scientific paradigms do not adequately capture the complexity of the relationships between environment, personal health and population level disparities. The public health exposome is presented as a universal exposure tracking framework for integrating complex relationships between exogenous and endogenous exposures across the lifespan from conception to death. It uses a social-ecological framework that builds on the exposome paradigm for conceptualizing how exogenous exposures “get under the skin”. The public health exposome approach has led our team to develop a taxonomy and bioinformatics infrastructure to integrate health outcomes data with thousands of sources of exogenous exposure, organized in four broad domains: natural, built, social, and policy environments. With the input of a transdisciplinary team, we have borrowed and applied the methods, tools and terms from various disciplines to measure the effects of environmental exposures on personal and population health outcomes and disparities, many of which may not manifest until many years later. As is customary with a paradigm shift, this approach has far reaching implications for research methods and design, analytics, community engagement strategies, and research training.
PMCID: PMC4276651  PMID: 25514145
exposome; public health; health disparities; trans-disciplinary; exposure science; social-ecological; combinatorial analysis; CBPR; geographical information systems; PPGIS
8.  Social Determinants and the Classification of Disease: Descriptive Epidemiology of Selected Socially Mediated Disease Constellations 
PLoS ONE  2014;9(11):e110271.
Most major diseases have important social determinants. In this context, classification of disease based on etiologic or anatomic criteria may be neither mutually exclusive nor optimal.
Methods and Findings
Units of analysis comprised large metropolitan central and fringe metropolitan counties with reliable mortality rates – (n = 416). Participants included infants and adults ages 25 to 64 years with selected causes of death (1999 to 2006). Exposures included that residential segregation and race-specific social deprivation variables. Main outcome measures were obtained via principal components analyses with an orthogonal rotation to identify a common factor. To discern whether the common factor was socially mediated, negative binomial multiple regression models were developed for which the dependent variable was the common factor. Results showed that infant deaths, mortality from assault, and malignant neoplasm of the trachea, bronchus and lung formed a common factor for race-gender groups (black/white and men/women). Regression analyses showed statistically significant, positive associations between low socio-economic status for all race-gender groups and this common factor.
Between 1999 and 2006, deaths classified as “assault” and “lung cancer”, as well as “infant mortality” formed a socially mediated factor detectable in population but not individual data. Despite limitations related to death certificate data, the results contribute important information to the formulation of several hypotheses: (a) disease classifications based on anatomic or etiologic criteria fail to account for social determinants; (b) social forces produce demographically and possibly geographically distinct population-based disease constellations; and (c) the individual components of population-based disease constellations (e.g., lung cancer) are phenotypically comparable from one population to another but genotypically different, in part, because of socially mediated epigenetic variations. Additional research may produce new taxonomies that unify social determinants with anatomic and/or etiologic determinants. This may lead to improved medical management of individuals and populations.
PMCID: PMC4220931  PMID: 25372286
9.  Impact of Net Atrioventricular Compliance on Clinical Outcome in Mitral Stenosis 
Circulation. Cardiovascular imaging  2013;6(6):1001-1008.
Net atrioventricular compliance (Cn) has been reported to be an important determinant of pulmonary hypertension in mitral stenosis (MS). We hypothesized that, as Cn reflects hemodynamic consequences of MS, it may be useful in assessing prognosis. To date, limited data with an assumed Cn cutoff have indicated the need for larger prospective studies. This prospective study was designed to determine the impact of Cn on clinical outcome and its contribution to pulmonary pressure in MS. In addition, we aimed to identify a cutoff value of Cn for outcome prediction in this setting.
Methods and Results
A total of 128 patients with rheumatic MS without other significant valve disease were prospectively enrolled. Comprehensive echocardiography was performed and Doppler-derived Cn estimated using a previously validated equation. The endpoint was either mitral valve intervention or death. Cn was an important predictor of pulmonary pressure, regardless of classic measures of MS severity. During a median follow-up of 22 months, the endpoint was reached in 45 patients (35%). Baseline Cn predicted outcome, adding prognostic information beyond that provided by mitral valve area and functional status. Cn ≤ 4 mL/mmHg best predicted unfavorable outcome in derivation and validation sets. A subgroup analysis including only initially asymptomatic patients with moderate to severe MS without initial indication for intervention (40.6 % of total) demonstrated that baseline Cn predicted subsequent adverse outcome even after adjusting for classic measures of hemodynamic MS severity (hazard ratio [HR] 0.33, 95% confidence interval [CI] 0.14–0.79, p = 0.013).
Cn contributes to pulmonary hypertension beyond of stenosis severity itself. In a wide spectrum of MS severity, Cn is a powerful predictor of adverse outcome, adding prognostic value to clinical data and mitral valve area. Importantly, baseline Cn predicts a progressive course with subsequent need for intervention in initially asymptomatic patients. Cn assessment therefore has potential value for clinical risk stratification and monitoring in MS patients.
PMCID: PMC3896378  PMID: 24097419
mitral stenosis; net atrioventricular compliance; pulmonary hypertension; outcome
10.  Scalable Combinatorial Tools for Health Disparities Research 
Despite staggering investments made in unraveling the human genome, current estimates suggest that as much as 90% of the variance in cancer and chronic diseases can be attributed to factors outside an individual’s genetic endowment, particularly to environmental exposures experienced across his or her life course. New analytical approaches are clearly required as investigators turn to complicated systems theory and ecological, place-based and life-history perspectives in order to understand more clearly the relationships between social determinants, environmental exposures and health disparities. While traditional data analysis techniques remain foundational to health disparities research, they are easily overwhelmed by the ever-increasing size and heterogeneity of available data needed to illuminate latent gene x environment interactions. This has prompted the adaptation and application of scalable combinatorial methods, many from genome science research, to the study of population health. Most of these powerful tools are algorithmically sophisticated, highly automated and mathematically abstract. Their utility motivates the main theme of this paper, which is to describe real applications of innovative transdisciplinary models and analyses in an effort to help move the research community closer toward identifying the causal mechanisms and associated environmental contexts underlying health disparities. The public health exposome is used as a contemporary focus for addressing the complex nature of this subject.
PMCID: PMC4210988  PMID: 25310540
combinatorial algorithms; data science; graph theoretical techniques; health disparities research; heterogeneous data analysis; high performance computing; public health exposome; relevance networks; scalable computation
11.  Calcific extension towards the mitral valve causes non-rheumatic mitral stenosis in degenerative aortic stenosis: real-time 3D transoesophageal echocardiography study 
Open Heart  2014;1(1):e000136.
Mitral annular/leaflet calcification (MALC) is frequently observed in patients with degenerative aortic stenosis (AS). However, the impact of MALC on mitral valve function has not been established. We aimed to investigate whether MALC reduces mitral annular area and restricts leaflet opening, resulting in non-rheumatic mitral stenosis.
Real-time three-dimensional transoesophageal images of the mitral valve were acquired in 101 patients with degenerative AS and 26 control participants. The outer and inner borders of the mitral annular area (MAA) and the maximal leaflet opening angle were measured at early diastole. The mitral valve area (MVA) was calculated as the left ventricular stroke volume divided by the velocity time integral of the transmitral flow velocity.
Although the outer MAA was significantly larger in patients with AS compared to control participants (8.2±1.3 vs 7.3±0.9 cm2, p<0.001), the inner MAA was significantly smaller (4.5±1.1 vs 5.9±0.9 cm2, p<0.001), resulting in an average decrease of 45% in the effective MAA. The maximal anterior and posterior leaflet opening angle was also significantly smaller in patients with AS (64±10 vs 72±8°, p<0.001, 71±12 vs 87±7°, p<0.001). Thus, MVA was significantly smaller in patients with AS (2.5±1.0 vs 3.8±0.8 cm2, p<0.001). Twenty-four (24%) patients with AS showed MVA <1.5 cm2. Multivariate regression analysis including parameters for mitral valve geometry revealed that a decrease in effective MAA and a reduced posterior leaflet opening angle were independent predictors for MVA.
Calcific extension to the mitral valve in patients with AS reduced effective MAA and the leaflet opening, resulting in a significant non-rheumatic mitral stenosis in one-fourth of the patients.
PMCID: PMC4189318  PMID: 25332828
12.  Assessment of Mitral Valve Adaptation with Gated Cardiac Computed Tomography: Validation with Three-Dimensional Echocardiography and Mechanistic Insight to Functional Mitral Regurgitation 
Circulation. Cardiovascular imaging  2013;6(5):10.1161/CIRCIMAGING.113.000561.
Mitral valve (MV) enlargement is a compensatory mechanism capable of preventing functional mitral regurgitation (FMR) in dilated ventricles. Total leaflet area and its relation with closure area measured by 3D-echocardiography have been related to FMR. Whether these parameters can be assessed with other imaging modalities is not known. Our objectives are to compare cardiac CT-based measurements of MV leaflets with 3D-echocardiography and determine the relationship of these metrics to the presence of FMR.
Methods and Results
We used two cohorts of patients who had cardiac CT to measure MV total leaflet, closure and annulus areas. In cohort 1 (26 patients), we validated these CT metrics to 3D-echocardiography. In cohort 2 (66 patients), we assessed the relation of MV size with the presence of FMR in three populations: heart failure with FMR, heart failure without FMR, and normal controls. Cardiac CT and 3D-echocardiography produced similar results for total leaflet (R2=0.97), closure (R2=0.89) and annulus areas (R2=0.84). MV size was largest in heart failure without FMR compared with controls and FMR patients (9.1±1.7 vs 7.5±1.0 vs 8.1±0.9 cm2/m2, p<0.01). FMR patients had reduced ratios of total leaflet:closure areas and total leaflet:annulus areas when compared to patients without FMR (p<0.01).
MV size measured by CT is comparable to 3D-echocardiography. MV enlargement in cardiomyopathy suggests leaflet adaptation. Patients with FMR have inadequate adaptation as reflected by decreased ratios of leaflet area and areas determined by ventricle size (annulus and closure areas). These measurements provide additional insight into the mechanism of FMR.
PMCID: PMC3833459  PMID: 23873402
mitral regurgitation; cardiac computed tomography; 3-dimensional echocardiography
13.  Mitral Apparatus Assessment by Delayed Enhancement CMR – Relative Impact of Infarct Distribution on Mitral Regurgitation 
JACC. Cardiovascular imaging  2013;6(2):220-234.
To assess patterns and functional consequences of mitral apparatus infarction after acute MI (AMI).
The mitral apparatus contains two myocardial components – papillary muscles and the adjacent LV wall. Delayed-enhancement CMR (DE-CMR) enables in-vivo study of inter-relationships and potential contributions of LV wall and papillary muscle infarction (PMI) to mitral regurgitation (MR).
Multimodality imaging was performed: CMR was used to assess mitral geometry and infarct pattern, including 3D DE-CMR for PMI. Echocardiography (echo) was used to measure MR. Imaging occurred 27±8 days post-AMI (CMR, echo within 1 day).
153 patients with first AMI were studied. PMI was present in 30% (n=46; 72% posteromedial, 39% anterolateral). When stratified by angiographic culprit vessel, PMI occurred in 65% of patients with left circumflex, 48% with right coronary, and only 14% of patients with left anterior descending infarctions (p<0.001). Patients with PMI had more advanced remodeling as measured by LV size and mitral annular diameter (p<0.05). Increased extent of PMI was accompanied by a stepwise increase in mean infarct transmurality within regional LV segments underlying each papillary muscle (p<0.001). Prevalence of lateral wall infarction was 3.0 fold higher among patients with, compared to those without, PMI (65% vs. 22%, p<0.001). Infarct distribution also impacted MR, with greater MR among patients with lateral wall infarction (p=0.002). Conversely, MR severity did not differ based on presence (p=0.19) or extent (p=0.12) of PMI, or by angiographic culprit vessel. In multivariable analysis, lateral wall infarct size (OR=1.20[CI=1.05–1.39], p=0.01) was independently associated with substantial (≥moderate) MR even after controlling for mitral annular (OR=1.22[1.04–1.43], p=0.01) and LV end-diastolic diameter (OR=1.11 [0.99–1.23], p=0.056).
PMI is common post-AMI, affecting nearly one-third of patients. PMI extent parallels adjacent LV wall injury, with lateral infarction – rather than PMI - associated with increased severity of post-AMI MR.
PMCID: PMC4048744  PMID: 23489536
14.  Anatomy of the Mitral Valve Apparatus – Role of 2D and 3D Echocardiography 
Cardiology clinics  2013;31(2):10.1016/j.ccl.2013.03.001.
The mitral valve apparatus is a complex three–dimensional functional unit that is critical to unidirectional heart pump function. This review details the normal anatomy, histology and function of the main mitral valve apparatus components 1) mitral annulus, 2) mitral valve leaflets, 3) chordae tendineae and 4) papillary muscles. 2 and 3 dimensional Echocardiography is ideally suited to examine the mitral valve apparatus and has provided insights into the mechanism of mitral valve disease. An overview of standardized image acquisition and interpretation is provided. Understanding normal mitral valve apparatus function is essential to comprehend alterations in mitral valve disease and the rationale for repair strategies.
PMCID: PMC3856635  PMID: 23743068
mitral valve apparatus; mitral valve; mitral annulus; papillary muscles; chordae tendineae; mitral regurgitation; echocardiography
15.  Racial/ethnic Differences in Clinical and Biochemical Type 2 Diabetes Mellitus Risk Factors in Children 
Obesity (Silver Spring, Md.)  2013;21(10):2081-2090.
To examine whether peri-adolescent children demonstrate the significant racial/ethnic differences in body fatness relative to BMI and in the prevalence and relationship of body composition to risk factors for type 2 diabetes (T2DM) as in adults.
Design and Methods
We examined family history of obesity and T2DM, anthropometry, insulin sensitivity and secretory capacity, lipids, and cytokines (IL-6, CRP, TNF-α, and adiponectin) in a cohort of 994 middle school students (47% male, 53%, female; 12% African American, 14% East Asian, 13% South Asian, 9% Caucasian, 44% Hispanic, and 8% other).
Fractional body fat content was significantly greater at any BMI among South Asians. There were racial/ethnic specific differences in lipid profiles, insulin secretory capacity, insulin sensitivity, and inflammatory markers corrected for body fatness that are similar to those seen in adults. Family history of T2DM was associated with lower insulin secretory capacity while family history of obesity was more associated with insulin resistance.
Children show some of the same racial/ethnic differences in risk factors for adiposity-related co-morbidities as adults. BMI and waist circumference cutoffs to identify children at-risk for adiposity-related co-morbidities should be adjusted by racial/ethnic group as well as other variables such as birthweight and family history.
PMCID: PMC3766484  PMID: 23596082
Obesity; pediatrics; diabetes; inflammation; lipid
16.  Short-Term Trends in Heart Failure-Related Hospitalizations in a High-Risk State 
Southern medical journal  2013;106(2):147-154.
We sought to determine whether there are signs of improvement in the rates of heart failure (HF) hospitalizations given the recent reports of improvement in national trends.
HF admissions data from the Tennessee Hospital Discharge Data System were analyzed.
Hospitalization for primary diagnosis of HF (HFPD) in adults (aged 20 years old or older) decreased from 4.5% in 2006 to 4.2% in 2008. Similarly, age-adjusted HF hospitalization (per 10,000 population) declined by 19.1% (from 45.5 in 2006 to 36.8 in 2008). The age-adjusted rates remain higher among blacks than whites and higher among men than women. Notably, the rate ratio of black-to-white men ages 20 to 34 years admitted with HFPD increased from 8.5 in 2006 to 11.1 in 2008; similarly, the adjusted odds ratios for HFPD were 4.75 (95% confidence interval 3.29–6.86) and 5.61 (95% confidence interval 3.70–8.49), respectively. There was, however, a significant improvement in odds ratio for HF rates among young black women, as evidenced by a decrease from 4.60 to 3.97 (aged 20–34 years) and 4.21 to 3.12 (aged 35–44 years) between 2006 and 2008, respectively. Among patients aged 20 to 34 and 35 to 44 years, hypertension was the strongest independent predictor for HF. Diabetes and myocardial infarction emerged as predictors for HF among patients aged 35 years and older.
The overall rate of HF hospitalization declined during the period surveyed, but the persistent disproportionate involvement of blacks with evidence of worsening among younger black men, requires close attention.
PMCID: PMC3565177  PMID: 23380751
heart failure; prevention; blacks; disparities; risk factors
17.  United States counties with low black male mortality rates 
The American journal of medicine  2013;126(1):10.1016/j.amjmed.2012.06.019.
In the United States, young and middle-aged black men have significantly higher total mortality than any other racial or ethnic group. We describe the characteristics of US counties with low non–Hispanic Black or African American male mortality (ages 25-64 years, 1999-2007).
Information was accessed through public data, the US Census, the US Compressed Mortality File, and the Native American Graves Repatriation Act military database.
Of 1307 counties with black mortality rates classified as reliable by the National Center for Health Statistics (at least 20 deaths), 66 recorded lower mortality among black men than corresponding US whites. Most notable, 97% of the 66 counties were home to or adjacent a military installation versus 37% of comparable US counties (P .001). Blacks in these counties had less poverty, higher percentages of elderly civilian veterans, and higher per capita income. Within these counties, national black:white disparities in mortality were eliminated for ischemic heart disease, accidents, diseases of the liver, chronic lower respiratory diseases, and mental disorder from psychoactive substance use. Application of age-, race-, ethnicity-, gender-, and urbanization-specific mortality rates from counties with relatively low mortality would reduce the black:white mortality rate ratio for black men aged 25 to 64 years from 1.67 to 1.20 nationally and to 1.00 in areas outside large central metropolitan areas.
These descriptive data demonstrate a small number of communities with low mortality rates among young and middle-aged black/African American men. Their characteristics may provide clinical and public health insights to reduce these higher mortality rates in the US population. Analytic epidemiologic studies are necessary to test these hypotheses.
PMCID: PMC3856918  PMID: 23260504
low mortality; black men; clinical characteristics
18.  Comprehensive Annular and Subvalvular Repair of Chronic Ischemic Mitral Regurgitation Improves Long-Term Results With the Least Ventricular Remodeling 
Circulation  2012;126(23):2720-2727.
Undersized ring annuloplasty for ischemic mitral regurgitation (MR) is associated with variable results and >30% MR recurrence. We tested whether subvalvular repair by severing second-order mitral chordae can improve annuloplasty by reducing papillary muscle tethering.
Methods and Results
Posterolateral myocardial infarction known to produce chronic remodeling and MR was created in 28 sheep. At 3 months, sheep were randomized to sham surgery versus isolated undersized annuloplasty versus isolated bileaflet chordal cutting versus the combined therapy (n=7 each). At baseline, chronic myocardial infarction (3 months), and euthanasia (6.6 months), we measured left ventricular (LV) volumes and ejection fraction, wall motion score index, MR regurgitation fraction and vena contracta, mitral annulus area, and posterior leaflet restriction angle (posterior leaflet to mitral annulus area) by 2-dimensional and 3-dimensional echocardiography. All groups were comparable at baseline and chronic myocardial infarction, with mild to moderate MR (MR vena contracta, 4.6±0.1 mm; MR regurgitation fraction, 24.2±2.9%) and mitral annulus dilatation (P<0.01). At euthanasia, MR progressed to moderate to severe in controls but decreased to trace with ring plus chordal cutting versus trace to mild with chordal cutting alone versus mild to moderate with ring alone (MR vena contracta, 5.9±1.1 mm in controls, 0.5±0.08 with both, 1.0±0.9 with chordal cutting alone, 2.0±0.7 with ring alone; P<0.01). In addition, LV end-systolic volume increased by 108% in controls versus 28% with ring plus chordal cutting, less than with each intervention alone (P<0.01). In multivariate analysis, LV end-systolic volume and mitral annulus area most strongly predicted MR (r2=0.82, P<0.01).
Comprehensive annular and subvalvular repair improves long-term reduction of both chronic ischemic MR and LV remodeling without decreasing global or segmental LV function at follow-up.
PMCID: PMC3515706  PMID: 23139296
echocardiography; mitral valve regurgitation; myocardial infarction; regurgitation; remodeling
19.  Brainstem Auditory Evoked Potentials Suggest a Role for the Ventral Cochlear Nucleus in Tinnitus 
Numerous studies have demonstrated elevated spontaneous and sound-evoked brainstem activity in animal models of tinnitus, but data on brainstem function in people with this common clinical condition are sparse. Here, auditory nerve and brainstem function in response to sound was assessed via auditory brainstem responses (ABR) in humans with tinnitus and without. Tinnitus subjects showed reduced wave I amplitude (indicating reduced auditory nerve activity) but enhanced wave V (reflecting elevated input to the inferior colliculi) compared with non-tinnitus subjects matched in age, sex, and pure-tone threshold. The transformation from reduced peripheral activity to central hyperactivity in the tinnitus group was especially apparent in the V/I and III/I amplitude ratios. Compared with a third cohort of younger, non-tinnitus subjects, both tinnitus, and matched, non-tinnitus groups showed elevated thresholds above 4 kHz and reduced wave I amplitude, indicating that the differences between tinnitus and matched non-tinnitus subjects occurred against a backdrop of shared peripheral dysfunction that, while not tinnitus specific, cannot be discounted as a factor in tinnitus development. Animal lesion and human neuroanatomical data combine to indicate that waves III and V in humans reflect activity in a pathway originating in the ventral cochlear nucleus (VCN) and with spherical bushy cells (SBC) in particular. We conclude that the elevated III/I and V/I amplitude ratios in tinnitus subjects reflect disproportionately high activity in the SBC pathway for a given amount of peripheral input. The results imply a role for the VCN in tinnitus and suggest the SBC pathway as a target for tinnitus treatment.
PMCID: PMC3505586  PMID: 22869301
auditory brainstem response (ABR); brainstem auditory evoked potential (BAEP); auditory nerve; ventral cochlear nucleus; spherical bushy cells; inferior colliculus; dorsal cochlear nucleus
20.  Using Animated Computer-generated Text and Graphics to Depict the Risks and Benefits of Medical Treatment 
The American journal of medicine  2012;125(11):1103-1110.
Conventional print materials for presenting risks and benefits of treatment are often difficult to understand. This study was undertaken to evaluate and compare subjects’ understanding and perceptions of risks and benefits presented using animated computerized text and graphics.
Adult subjects were randomized to receive identical risk/benefit information regarding taking statins that was presented on an iPad (Apple Corp, Cupertino, Calif) in 1 of 4 different animated formats: text/numbers, pie chart, bar graph, and pictograph. Subjects completed a questionnaire regarding their preferences and perceptions of the message delivery together with their understanding of the information. Health literacy, numeracy, and need for cognition were measured using validated instruments.
There were no differences in subject understanding based on the different formats. However, significantly more subjects preferred graphs (82.5%) compared with text (17.5%, P < .001). Specifically, subjects preferred pictographs (32.0%) and bar graphs (31.0%) over pie charts (19.5%) and text (17.5%). Subjects whose preference for message delivery matched their randomly assigned format (preference match) had significantly greater understanding and satisfaction compared with those assigned to something other than their preference.
Results showed that computer-animated depictions of risks and benefits offer an effective means to describe medical risk/benefit statistics. That understanding and satisfaction were significantly better when the format matched the individual’s preference for message delivery is important and reinforces the value of “tailoring” information to the individual’s needs and preferences.
PMCID: PMC3639495  PMID: 22939094
Computer animation; Patient comprehension; Patient preferences; Risk/benefit statistics
21.  Tuskegee redux: Evolution of legal mandates for human experimentation 
Human health experiments systematically expose people to conditions beyond the boundaries of medical evidence. Such experiments have included legal-medical collaboration, exemplified in the US by the PHS Syphilis Study (Tuskegee). That medical experiment was legal, conforming to segregationist protocols and specific legislative authorization which excluded a selected group of African Americans from any medical protection from syphilis. Subsequent corrective action outlawed unethical medical experiments but did not address other forms of collaboration, including PHS submission to laws which may have placed African American women at increased risk from AIDS and breast cancer. Today, anti-lobbying law makes it a felony for PHS workers to openly question legally anointed suspension of medical evidence. African Americans and other vulnerable populations may thereby face excess risks -- not only from cancer, but also from motor vehicle crashes, firearm assault, end stage renal disease and other problems -- with PHS workers as silent partners.
PMCID: PMC3731206  PMID: 23124504
Bioethics; public health; disparity, healthcare; communicable disease contact tracing; breast cancer; Medicare;
22.  Improving Fatty Acid Availability for Bio-Hydrocarbon Production in Escherichia coli by Metabolic Engineering 
PLoS ONE  2013;8(10):e78595.
Previous studies have demonstrated the feasibility of producing fatty-acid-derived hydrocarbons in Escherichia coli. However, product titers and yields remain low. In this work, we demonstrate new methods for improving fatty acid production by modifying central carbon metabolism and storing fatty acids in triacylglycerol. Based on suggestions from a computational model, we deleted seven genes involved in aerobic respiration, mixed-acid fermentation, and glyoxylate bypass (in the order of cyoA, nuoA, ndh, adhE, dld, pta, and iclR) to modify the central carbon metabolic/regulatory networks. These gene deletions led to increased total fatty acids, which were the highest in the mutants containing five or six gene knockouts. Additionally, when two key enzymes in the fatty acid biosynthesis pathway were over-expressed, we observed further increase in strain △cyoA△adhE△nuoA△ndh△pta△dld, leading to 202 mg/g dry cell weight of total fatty acids, ~250% of that in the wild-type strain. Meanwhile, we successfully introduced a triacylglycerol biosynthesis pathway into E. coli through heterologous expression of wax ester synthase/acyl-coenzyme:diacylglycerol acyltransferase (WS/DGAT) enzymes. The added pathway improved both the amount and fuel quality of the fatty acids. These new metabolic engineering strategies are providing promising directions for future investigation.
PMCID: PMC3798384  PMID: 24147139
23.  Developmental basis for filamin-A-associated myxomatous mitral valve disease 
Cardiovascular Research  2012;96(1):109-119.
We hypothesized that the structure and function of the mature valves is largely dependent upon how these tissues are built during development, and defects in how the valves are built can lead to the pathological progression of a disease phenotype. Thus, we sought to uncover potential developmental origins and mechanistic underpinnings causal to myxomatous mitral valve disease. We focus on how filamin-A, a cytoskeletal binding protein with strong links to human myxomatous valve disease, can function as a regulatory interface to control proper mitral valve development.
Methods and results
Filamin-A-deficient mice exhibit abnormally enlarged mitral valves during foetal life, which progresses to a myxomatous phenotype by 2 months of age. Through expression studies, in silico modelling, 3D morphometry, biochemical studies, and 3D matrix assays, we demonstrate that the inception of the valve disease occurs during foetal life and can be attributed, in part, to a deficiency of interstitial cells to efficiently organize the extracellular matrix (ECM). This ECM organization during foetal valve gestation is due, in part, to molecular interactions between filamin-A, serotonin, and the cross-linking enzyme, transglutaminase-2 (TG2). Pharmacological and genetic perturbations that inhibit serotonin-TG2-filamin-A interactions lead to impaired ECM remodelling and engender progression to a myxomatous valve phenotype.
These findings illustrate a molecular mechanism by which valve interstitial cells, through a serotonin, TG, and filamin-A pathway, regulate matrix organization during foetal valve development. Additionally, these data indicate that disrupting key regulatory interactions during valve development can set the stage for the generation of postnatal myxomatous valve disease.
PMCID: PMC3444235  PMID: 22843703
Filamin-A; Serotonin; Myxomatous valve disease; Transglutaminase-2; Valve maturation
24.  A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of GS-9450 in Subjects With Nonalcoholic Steatohepatitis 
Hepatology (Baltimore, Md.)  2011;55(2):419-428.
In nonalcoholic steatohepatitis (NASH), the extent of hepatocyte apoptosis correlates with disease severity. Reducing hepatocyte apoptosis with the selective caspase inhibitor GS-9450 has a potential for altering the course of the liver disease. In this phase 2, double-blind study, 124 subjects with biopsy-proven NASH were randomized to once-daily placebo or 1, 5, 10, or 40 mg GS-9450 for 4 weeks. Absolute and percent changes from baseline in ALT levels, AST levels, and caspase-3–cleaved cytokeratin (CK)-18 fragments at week 4 were assessed by an analysis of covariance model with adjustment for baseline values. In the 40-mg group, mean (SD) ALT decreased by 47 (43) U/L from baseline to week 4 (P < 0.0001 versus placebo), and the proportion of subjects with normal ALT increased from 0% to 35% at week 4. In the 40-mg group, mean AST decreased by 13 U/L from baseline (not significant), and the proportion with normal AST increased from 20% at baseline to 48% at week 4. By week 4, mean CK-18 fragment levels had decreased to 393 (723) U/L in the GS-9450 10-mg group and 125 (212) U/L in the 40-mg group, but these reductions were not statistically significant. No serious adverse events were reported during treatment, and the percentage of subjects with at least one treatment-emergent grade 3 or 4 laboratory abnormality ranged from 11.5% to 17% across the GS-9450 treatment groups versus 35% in the placebo group.
GS-9450 treatment induced significant reductions in ALT levels in NASH patients. Reductions in CK-18 fragment levels also occurred, although they were not statistically significant. At appropriate therapeutic indices, selective caspase inhibitors may be a promising treatment option in patients with NASH.
PMCID: PMC3779694  PMID: 22006541

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