PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-22 (22)
 

Clipboard (0)
None

Select a Filter Below

Year of Publication
Document Types
1.  Effects of Phosphate Binder Therapy on Vascular Stiffness in Early Stage Chronic Kidney Disease 
American journal of nephrology  2013;38(2):10.1159/000353569.
Background/Aims
Cardiovascular disease (CVD) is increased in chronic kidney disease (CKD), and contributed to by the CKD-mineral bone disorder (CKD-MBD). The CKD-MBD begins in early CKD and its vascular manifestations begin with vascular stiffness proceeding to increased carotid artery intima-media thickness (cIMT) and vascular calcification (VC). Phosphorus is associated with this progression and is considered a CVD risk factor in CKD. We hypothesized that modifying phosphorus balance with lanthanum carbonate (LaCO3) in early CKD would not produce hypophosphatemia and may affect vascular manifestations of the CKD-MBD.
Methods
We randomized 38 subjects with normophosphatemic stage 3 CKD to a fixed dose of LaCO3 or matching placebo without adjusting dietary phosphorus in a 12-month randomized, double-blind, pilot and feasibility study. The primary outcome was the change in serum phosphorus. Secondary outcomes were changes in measures of phosphate homeostasis and vascular stiffness assessed by carotid-femoral pulse wave velocity (PWV), cIMT and VC over 12 months.
Results
There were no statistically significant differences between LaCO3 and placebo with respect to the change in serum phosphorus, urinary phosphorus, tubular reabsorption of phosphorus, PWV, cIMT, or VC. Biomarkers of the early CKD-MBD such as plasma fibroblast growth factor-23 (FGF23), Dickkopf-related protein 1 (DKK1), and sclerostin were increased 2–3-fold at baseline but were not affected by LaCO3.
Conclusion
12 months of LaCO3 had no effect on serum phosphorus and did not alter phosphate homeostasis, PWV, cIMT, VC, or biomarkers of the CKD-MBD.
doi:10.1159/000353569
PMCID: PMC3874122  PMID: 23941761
Cardiovascular disease; chronic kidney disease; phosphate binders; vascular calcification; randomized controlled trials
2.  Relationships Among HIV Infection, Metabolic Risk Factors, and Left Ventricular Structure and Function 
AIDS Research and Human Retroviruses  2013;29(8):1151-1160.
Abstract
Our objective was to determine if the presence of metabolic complications (MC) conveyed an additional risk for left ventricular (LV) dysfunction in people with HIV. HIV+ and HIV− men and women were categorized into four groups: (1) HIV+ with MC (43±7 years, n=64), (2) HIV+ without MC (42±7 years, n=59), (3) HIV− with MC (44±8 years, n=37), or (4) HIV− controls without MC (42±8 years, n=41). All participants underwent two-dimensional (2-D), Doppler, and tissue Doppler echocardiography. Overall, the prevalence of systolic dysfunction (15 vs. 4%, p=0.02) and LV hypertrophy (9 vs. 1%, p=0.03) was greater in HIV+ than in HIV− participants. Participants with MC had a greater prevalence of LV hypertrophy (10% vs. 1%). Early mitral annular velocity during diastole was significantly (p<0.005) lower in groups with MC (HIV+/MC+: 11.6±2.3, HIV−/MC+: 12.0±2.3 vs. HIV+/MC−: 12.4±2.3, HIV−/MC−: 13.1±2.4 cm/s) and tended to be lower in groups with HIV (p=0.10). However, there was no interaction effect of HIV and MC for any systolic or diastolic variable. Regardless of HIV status, participants with MC had reduced LV diastolic function. Although both the presence of MC and HIV infection were associated with lower diastolic function, there was no additive negative effect of HIV on diastolic function beyond the effect of MC. Also, HIV was independently associated with lower systolic function. Clinical monitoring of LV function in individuals with metabolic risk factors, regardless of HIV status, is warranted.
doi:10.1089/aid.2012.0254
PMCID: PMC3715767  PMID: 23574474
3.  An Overview of the Genomics of Metabolic Syndrome 
Purpose
This article provides a brief overview of the diagnostic criteria and genomic risk factors for the components of metabolic syndrome (MetS).
Organizing Constructs
Contributions of cardiovascular, obesity, and diabetes genomic risk factors to the development of MetS as reported in the literature have been reviewed.
Findings
The genomic risk factors for the development of MetS are strongly linked to the genomic risk factors that make up the components of the disease. Many of the cardiovascular and renal genomic risk factors for MetS development are similar to those found in the development of hypertension and dyslipidemia. Obesity may act as a master trigger to turn on the gene expression changes necessary for the other components of the disease. Studies in the genomics of type 2 diabetes show a number of overlapping genes and polymorphisms that influence both the development of diabetes and MetS.
Conclusions
Although health practitioners now have some insights into the genomics of risk factors associated with MetS, the overall understanding of MetS remains inadequate. Clinical applications based on some of the discussed genomic risk factors are being developed but are not yet available for the diagnosis and treatment of MetS.
Clinical Relevance
A broad knowledge of the genomic contributions to disease processes will enable the clinician to better utilize genomics to assess and tailor management of patients.
doi:10.1111/j.1547-5069.2012.01484.x
PMCID: PMC3594572  PMID: 23368731
Genomics; metabolic syndrome; cardiovascular; diabetes; obesity
4.  The role of SNP-loop diuretic interactions in hypertension across ethnic groups in HyperGEN 
Frontiers in Genetics  2013;4:304.
Blood pressure (BP) is significantly influenced by genetic factors; however, less than 3% of the BP variance has been accounted for by variants identified from genome-wide association studies (GWAS) of primarily European-descent cohorts. Other genetic influences, including gene-environment (GxE) interactions, may explain more of the unexplained variance in BP. African Americans (AA) have a higher prevalence and earlier age of onset of hypertension (HTN) as compared with European Americans (EA); responses to anti-hypertensive drugs vary across race groups. To examine potential interactions between the use of loop diuretics and HTN traits, we analyzed systolic (SBP) and diastolic (DBP) blood BP from 1222 AA and 1231 EA participants in the Hypertension Genetic Epidemiology Network (HyperGEN). Population-specific score tests were used to test associations of SBP and DBP, using a panel of genotyped and imputed single nucleotide polymorphisms (SNPs) for AA (2.9 million SNPs) and EA (2.3 million SNPs). Several promising loci were identified through gene-loop diuretic interactions, although no SNP reached genome-wide significance after adjustment for genomic inflation. In AA, SNPs in or near the genes NUDT12, CHL1, GRIA1, CACNB2, and PYHIN1 were identified for SBP, and SNPs near ID3 were identified for DBP. For EA, promising SNPs for SBP were identified in ESR1 and for DBP in SPATS2L and EYA2. Among these SNPs, none were common across phenotypes or population groups. Biologic plausibility exists for many of the identified genes, suggesting that these are candidate genes for regulation of BP and/or anti-hypertensive drug response. The lack of genome-wide significance is understandable in this small study employing gene-drug interactions. These findings provide a set of prioritized SNPs/candidate genes for future studies in HTN. Studies in more diversified population samples may help identify previously missed variants.
doi:10.3389/fgene.2013.00304
PMCID: PMC3872290  PMID: 24400021
blood pressure; hypertension; loop diuretic; gene-drug interaction; genome-wide association; african americans; european americans
5.  Pathway-based genome-wide association analysis of coronary heart disease identifies biologically important gene sets 
European Journal of Human Genetics  2012;20(11):1168-1173.
Genome-wide association (GWA) studies of complex diseases including coronary heart disease (CHD) challenge investigators attempting to identify relevant genetic variants among hundreds of thousands of markers being tested. A selection strategy based purely on statistical significance will result in many false negative findings after adjustment for multiple testing. Thus, an integrated analysis using information from the learned genetic pathways, molecular functions, and biological processes is desirable. In this study, we applied a customized method, variable set enrichment analysis (VSEA), to the Framingham Heart Study data (404 467 variants, n=6421) to evaluate enrichment of genetic association in 1395 gene sets for their contribution to CHD. We identified 25 gene sets with nominal P<0.01; at least four sets are previously known for their roles in CHD: vascular genesis (GO:0001570), fatty-acid biosynthetic process (GO:0006633), fatty-acid metabolic process (GO:0006631), and glycerolipid metabolic process (GO:0046486). Although the four gene sets include 170 genes, only three of the genes contain a variant ranked among the top 100 in single-variant association tests of the 404 467 variants tested. Significant enrichment for novel gene sets less known for their importance to CHD were also identified: Rac 1 cell-motility signaling pathway (h_rac1 Pathway, P<0.001) and sulfur amino-acid metabolic process (GO:0000096, P<0.001). In summary, we showed that the pathway-based VSEA can help prioritize association signals in GWA studies by identifying biologically plausible targets for downstream searches of genetic variants associated with CHD.
doi:10.1038/ejhg.2012.66
PMCID: PMC3477866  PMID: 22510845
gene set enrichment; pathway-based analysis; SNP; genome-wide association
6.  Role of Serotoninergic Pathways in Drug-induced Valvular Heart Disease and Diagnostic Features by Echocardiography 
Serotonin plays a significant role in the development of carcinoid heart disease, which primarily leads to fibrosis and contraction of right-sided heart valves. Recently, strong evidence has emerged that the use of specific drug classes such as ergot alkaloids (for migraine headaches), 5-hydroxytryptamine (5-HT or serotonin) uptake regulators/inhibitors (for weight reduction), and ergot-derived dopamine agonists (for Parkinson’s disease) can result in left-sided heart valve damage that resembles carcinoid heart disease. Recent studies suggest that both right- and left-sided drug-induced heart valve disease involves increased serotoninergic activity and in particular activation of the 5-HT receptors, including the 5-HT2B receptor subtype, which mediate many of the central and peripheral functions of serotonin. G-proteins that inhibit adenylate cyclase activity mediate the activity of the 5-HT2B receptor subunit which is widely expressed in a variety of tissues including liver, lung, heart, and coronary and pulmonary arteries; and it has also been reported in embryonic mouse heart, particularly on mouse heart valve leaflets. In this review we discuss the salient features of serotoninergic manifestations of both carcinoid heart disease and drug-induced cardiac valvulopathy with an emphasis on echocardiographic diagnosis.
doi:10.1016/j.echo.2009.05.002
PMCID: PMC3808845  PMID: 19553085
Carcinoid heart disease; Serotonin; Echocardiography
7.  The St. Louis African American health-heart study: methodology for the study of cardiovascular disease and depression in young-old African Americans 
Background
Coronary artery disease (CAD) is a major cause of death and disability worldwide. Depression has complex bidirectional adverse associations with CAD, although the mechanisms mediating these relationships remain unclear. Compared to European Americans, African Americans (AAs) have higher rates of morbidity and mortality from CAD. Although depression is common in AAs, its role in the development and features of CAD in this group has not been well examined. This project hypothesizes that the relationships between depression and CAD can be explained by common physiological pathways and gene-environment interactions. Thus, the primary aims of this ongoing project are to: a) determine the prevalence of CAD and depression phenotypes in a population-based sample of community-dwelling older AAs; b) examine the relationships between CAD and depression phenotypes in this population; and c) evaluate genetic variants from serotoninP and inflammatory pathways to discover potential gene-depression interactions that contribute significantly to the presence of CAD in AAs.
Methods/design
The St. Louis African American Health (AAH) cohort is a population-based panel study of community-dwelling AAs born in 1936–1950 (inclusive) who have been followed from 2000/2001 through 2010. The AAH-Heart study group is a subset of AAH participants recruited in 2009–11 to examine the inter-relationships between depression and CAD in this population. State-of-the-art CAD phenotyping is based on cardiovascular characterizations (coronary artery calcium, carotid intima-media thickness, cardiac structure and function, and autonomic function). Depression phenotyping is based on standardized questionnaires and detailed interviews. Single nucleotide polymorphisms of selected genes in inflammatory and serotonin-signaling pathways are being examined to provide information for investigating potential gene-depression interactions as modifiers of CAD traits. Information from the parent AAH study is being used to provide population-based prevalence estimates. Inflammatory and other biomarkers provide information about potential pathways.
Discussion
This population-based investigation will provide valuable information on the prevalence of both depression and CAD phenotypes in this population. The study will examine interactions between depression and genetic variants as modulators of CAD, with the intent of detecting mechanistic pathways linking these diseases to identify potential therapeutic targets. Analytic results will be reported as they become available.
doi:10.1186/1471-2261-13-66
PMCID: PMC3847628  PMID: 24011389
Coronary artery disease; Depression; Genetic analyses; African Americans; Inflammatory biomarkers; Inflammatory pathway; Serotonin-signaling pathway; Heart rate variability; Built environment; Bayesian analysis
8.  Obesity–insulin targeted genes in the 3p26-25 region in human studies and LG/J and SM/J mice 
Identifying metabolic syndrome (MetS) genes is important for novel drug development and health care. This study extends the findings on human chromosome 3p26-25 for an identified obesity–insulin factor QTL, with an LOD score above 3. A focused association analysis comprising up to 9578 African American and Caucasian subjects from the HyperGEN Network (908 African Americans and 1025 whites), the Family Heart Study (3035 whites in time 1 and 1943 in time 2), and the Framingham Heart Study (1317 in Offspring and 1320 in Generation 3) was performed. The homologous mouse region was explored in an F16 generation of an advanced intercross between the LG/J and SM/J inbred strains, in an experiment where 1002 animals were fed low-fat (247 males; 254 females) or high-fat (253 males; 248 females) diets. Association results in humans indicate pleiotropic effects for SNPs within or surrounding CNTN4 on obesity, lipids and blood pressure traits and for SNPs near IL5RA, TRNT1, CRBN, and LRRN1 on central obesity and blood pressure. Linkage analyses of this region in LG/J × SM/J mice identify a highly significant pleiotropic QTL peak for insulin and glucose levels, as well as response to glucose challenge. The mouse results show that insulin and glucose levels interact with high and low fat diets and differential gene expression was identified for Crbn and Arl8b. In humans, ARL8B resides ~137 kbps away from BHLHE40, expression of which shows up-regulation in response to insulin treatment. This focused human genetic analysis, incorporating mouse research evidenced that 3p26-25 has important genetic contributions to MetS components. Several of the candidate genes have functions in the brain. Their interaction with MetS and the brain warrants further investigation.
doi:10.1016/j.metabol.2012.01.008
PMCID: PMC3586585  PMID: 22386932
9.  Abnormalities in Cardiac Structure and Function in Adults with Sickle Cell Disease are not Associated with Pulmonary Hypertension 
Background
In sickle cell disease (SCD), pulmonary hypertension (assessed by tricuspid regurgitant jet [TRJ] velocity ≥ 2.5 m/s) is associated with increased mortality. The relationships between TRJ velocity, left ventricular (LV) and right ventricular (RV) systolic and diastolic function (i.e., relaxation and compliance) have not been well characterized in SCD.
Design and Methods
Prospective study of 53 ambulatory SCD adults (age, mean: 34 years; range 21-65 years) and 33 African American controls to define the relationship between LV and RV function and TRJ velocity by use of echocardiography.
Results
SCD subjects had larger left and right atrial volumes and increased LV mass compared to controls. When SCD cases were compared to controls, LV and RV relaxation (i.e., E’) were similar. Among SCD subjects, pulmonary hypertension (TRJ ≥ 2.5 m/s) was present in 40% of cases. Higher TRJ velocity was correlated with larger LA volumes and areas in SCD cases. Additionally, some measures of LV (peak A, lateral and septal annulus E/E’) and RV compliance (TV E/E’) were correlated with TRJ velocity. No other measures of LV/RV systolic function or LV diastolic function (i.e., relaxation and compliance) were associated with TRJ velocity.
Conclusions
Ambulatory adults with SCD exhibited structural (i.e., LV and RV chamber enlargement) and functional (i.e., higher surrogate measures of LV and RV filling pressure) abnormalities compared to the control group. In SCD subjects, few abnormalities of LV and RV structure/function were associated with TRJ velocity.
doi:10.1016/j.echo.2011.07.009
PMCID: PMC3200507  PMID: 21873028
Pulmonary hypertension; diastolic dysfunction; sickle cell disease
10.  Variable set enrichment analysis in genome-wide association studies 
Complex diseases such as hypertension are inherently multifactorial and involve many factors of mild-to-minute effect sizes. A genome-wide association study (GWAS) typically tests hundreds of thousands of single-nucleotide polymorphisms (SNPs), and offers opportunity to evaluate aggregated effects of many genetic variants with effects that are too small to detect individually. The gene-set-enrichment analysis (GSEA) is a pathway-based approach that tests for such aggregated effects of genes that are linked by biological functions. A key step in GSEA is the summary statistic (gene score) used to measure the overall relevance of a gene based on all SNPs tested in the gene. Existing GSEA methods use maximum statistics sensitive to gene size and linkage equilibrium. We propose the approach of variable set enrichment analysis (VSEA) and study new gene score methods that are less dependent on gene size. The new method treats groups of variables (SNPs or other variants) as base units for summarizing gene scores and relies less on gene definition itself. The power of VSEA is analyzed by simulation studies modeling various scenarios of complex multiloci interactions. Results show that the new gene scores generally performed better, some substantially so, than existing GSEA extension to GWAS. The new methods are implemented in an R package and when applied to a real GWAS data set demonstrated its practical utility in a GWAS setting.
doi:10.1038/ejhg.2011.46
PMCID: PMC3172928  PMID: 21427759
gene set enrichment; pathway-based analysis; SNP; genome-wide association
11.  Effects of Sodium Thiosulfate on Vascular Calcification in End-Stage Renal Disease: A Pilot Study of Feasibility, Safety and Efficacy 
American Journal of Nephrology  2011;33(2):131-138.
Background and Objectives
Vascular calcification is a major contributor to morbidity and mortality in hemodialysis. The objective of this pilot study was to determine the feasibility, safety and efficacy of sodium thiosulfate (STS) in the progression of vascular calcification in hemodialysis patients.
Methods
Chronic hemodialysis patients underwent a battery of cardiovascular tests. Those with coronary artery calcium (Agatston scores >50) received intravenous STS after each dialysis for 5 months (n = 22) and the tests were repeated. Changes in MDCT-determined calcification were assessed as the mean annualized rate of change in 3 vascular beds (coronary, thoracic and carotid arteries) and in L1-L2 vertebral bone density.
Results
Although individual analyses showed coronary artery calcification progression in 14/22 subjects, there was no progression in the mean annualized rate of change of vascular calcification in the entire group. The L1-L2 vertebral bone density showed no changes. There were no correlations between rates of progression of vascular calcification and phosphorus, fetuin or C-reactive protein levels. Changes in coronary artery calcification scores correlated with those of the thoracic aorta.
Conclusion
STS treatment is feasible, appears safe and may decrease the rate of progression of vascular calcification in hemodialysis patients. A large, randomized, controlled trial is warranted.
doi:10.1159/000323550
PMCID: PMC3064860  PMID: 21242673
Hemodialysis; Sodium thiosulfate; Vascular calcification
12.  Are Normative Values for LV Geometry and Mass Based on Fundamental Imaging Valid With Use of Harmonic Imaging? 
Background
Multiple studies have reported echocardiographically determined normal reference values for left ventricular mass (LVM) derived using fundamental imaging (FI). Modern ultrasound systems now use harmonic imaging (HI) due to the improved LV endomyocardial definition. However, the 2005 American Society of Echocardiography (ASE) Recommendations noted that the applicability of the reference values to HI-derived measurements has not been established.
Methods
LV end-diastolic volume, diameter, wall thickness, and mass were determined using HI in healthy subjects (n=251) including a normal weight (NW, body mass index [BMI] < 25 kg/m2, n=149, 68% women) and an otherwise-healthy overweight (OW, BMI ≥25 and <30 kg/m2, n=102, 41% women) groups. Measurements were compared to ASE-endorsed reference values. The agreement between FI and HI was determined in a prospective cohort of 51 subjects.
Results
2D-derived LV volumes were similar between NW and OW subjects; although M-mode (MM)-derived LV diameters were slightly greater in OW. 2D- and MM-derived LVM was greater in OW compared to NW subjects, including after adjustment by height or height2.7; however, indexing to body surface area eliminated these differences. The partition values for abnormal 2D- and MM-derived LVM were generally greater in NW and OW subjects of both sexes compared with the ASE endorsed values (except MM-derived in NW men). However, there were no significant differences in LVM determined by HI compared to FI in a prospectively studied cohort.
Conclusions
Reference values for LVM derived from NW and OW cohorts are generally higher than the ASE-endorsed referenced values. The difference between NW and ASE-endorsed values is unlikely to result from the use of HI rather than FI since there is excellent agreement between these two imaging modalities. This study emphasizes the need to update normal reference values to reflect modern imaging methods.
doi:10.1016/j.echo.2010.08.014
PMCID: PMC2993783  PMID: 20863657
echocardiography; fundamental imaging; harmonic imaging; left ventricular mass; body mass index
13.  Insulin resistance predicts endothelial dysfunction and cardiovascular risk in HIV-infected persons on long-term highly active antiretroviral therapy 
AIDS (London, England)  2008;22(7):849-856.
Objective
Cardiovascular disease risk among persons with HIV is likely multifactorial, thus testing a variety of available noninvasive vascular ultrasound and other surrogate tests may yield differing results. To address this issue, we assessed multiple metabolic and clinical predictors of endothelial function and carotid intima–media thickness in HIV-infected subjects and compared results with HIV-negative controls.
Design
Prospective, cross-sectional study of 50 HIV-infected, healthy adults on stable highly active antiretroviral therapy matched to 50 HIV-negative controls by age, sex, race, and body mass index.
Methods
Flow-mediated vasodilation of the brachial artery, carotid intima–media thickness, dual energy X-ray absorptiometry (HIV-infected subjects), and fasting insulin, lipids, and oral glucose tolerance tests were performed. Results were compared between HIV-infected and control groups.
Results
Fifty percent of subjects were African–American with 34% women. Among HIV-infected, mean CD4 cell count was 547 cells/ µl; 90% had HIV RNA less than 50 copies/ml. There were no significant differences between HIV-infected and control subjects with regard to brachial artery flow-mediated vasodilation or carotid intima–media thickness. In multivariate analyses of the HIV cohort, independent predictors of endothelial dysfunction (lower flow-mediated vasodilation) were increasing insulin resistance, greater alcohol consumption, and higher baseline brachial artery diameter (P < 0.05); predictors of increased carotid intima–media thickness were hypertension, higher trunk/limb fat ratio, and insulin resistance (P < 0.05).
Conclusion
In this HIV cohort on modern highly active antiretroviral therapy with well controlled HIV, there were no significant differences with regard to preclinical markers of cardiovascular disease. Insulin resistance was a strong predictor of impaired brachial artery flow-mediated vasodilation and increased carotid intima–media thickness, and may be an important cardiovascular disease risk factor in the HIV population.
doi:10.1097/QAD.0b013e3282f70694
PMCID: PMC3166228  PMID: 18427203
endothelial dysfunction; HIV; insulin resistance
14.  Molecular Determinants of the Cardiometabolic Phenotype 
The metabolic syndrome represents a clustering of risk factors that has been shown to predict adverse cardiovascular outcomes. Although the precise mechanisms contributing to the cardiometabolic syndrome (CMS) remain poorly defined, accumulating evidence identifies two intersecting candidate pathways responsible for inflammation and energy homeostasis in the pathophysiology that underlie cardiometabolic traits. Although currently no pharmacologic interventions specifically target CMS, future drug development efforts should attempt to capitalize on molecular nodes at the intersections of these pathways in the CMS.
PMCID: PMC2887744  PMID: 20384572
Metabolic syndrome; cardiometabolic syndrome; substrate metabolism; inflammation; obesity; insulin resistance; hypertension; dyslipidemia
15.  Central Aortic Pressure is Independently Associated With Diastolic Function 
American heart journal  2010;159(6):1081-1088.
Background
Studies investigating the association between central aortic pressures and diastolic function have been limited.
Methods
Consecutive ambulatory patients (n=281, mean age 49±13 yrs, 49% male) with normal LV systolic function were included. LV filling pressure (E/Em) was estimated by Doppler-derived ratio of mitral inflow velocity [E] to septal [Em] by tissue Doppler, LV relaxation by Em, central aortic pressures by radial tonometry. Central aortic systolic (cSBP), diastolic (cDBP), mean (cMAP), and pulse pressure (cPP) were entered individually into stepwise linear regression models to determine their association with E/Em or Em.
Results
In univariate analysis, cPP correlated most strongly with E/Em (Spearman’s rho=0.45, p<0.001), while cSBP correlated most strongly with Em (Spearman’s rho=−0.51, p<0.001). Multivariate analysis demonstrated that the pulsatile component of afterload, cPP, contributed most to E/Em (partial r2=23%); meanwhile the nonpulsatile components (cDBP and cMAP), were significant but small contributors (partial r2 of 6% and 5% respectively) of LV relaxation (Em).
Conclusion
The nonpulsatile components of aortic afterload (central mean aortic pressure (cMAP) and central aortic diastolic blood pressure cDBP), exhibited a weak but significant association with LV relaxation, while the pulsatile component of afterload, central aortic pulse pressure (cPP), exhibited strong association with LV filling pressure.
doi:10.1016/j.ahj.2010.02.024
PMCID: PMC2913412  PMID: 20569723
diastolic function; pulse pressure; aortic blood pressures
16.  Effect of moderate diet-induced weight loss and weight regain on cardiovascular structure and function 
Objectives
The objective of this prospective, single-site, two-year dietary intervention study was to evaluate the effects of moderate weight reduction and subsequent partial weight regain on cardiovascular structure and function.
Background
Obesity is associated with adverse cardiac and vascular structural and functional alterations.
Methods
Sixty obese subjects (age: 46±10 years, body mass index: 37±3 kg/m2) were evaluated during their participation in a weight loss study. Cardiac and vascular ultrasound studies were performed at baseline and at 3, 6, 12, and 24 months after start of intervention.
Results
Forty-seven subjects (78%) completed the entire two-year follow-up. Average weight loss was 7.3±4.0, 9.2±5.6, 7.8±6.6 and 3.8±7.9% at 3, 6, 12, and 24 months, respectively. Age- and sex- adjusted mixed linear models revealed that the follow-up time was significantly associated with decreases in weight (p<0.0001), left ventricular (LV) mass (p=0.001), and carotid intima-media thickness (p<0.0001); there was also significant improvement in LV diastolic (E’, p≤0.0001) and systolic (S’, p=.001) function. Partial weight regain diminished the maximal observed beneficial effects of weight loss, however cardiovascular parameters measured at two years still showed a net benefit compared with baseline.
Conclusions
Diet-induced moderate weight loss in obese subjects is associated with beneficial changes in cardiovascular structure and function. Subsequent weight regain is associated with partial loss of these beneficial effects.
doi:10.1016/j.jacc.2009.07.054
PMCID: PMC2818984  PMID: 20082927
obesity; echocardiography; hypertrophy; carotid arteries; diastolic function
17.  Interatrial Conduction Time and Left Atrial Function in Patients with Left Ventricular Systolic Dysfunction: Effects of Cardiac Resynchronization Therapy 
Background
Prolonged inter-atrial conduction time (IACT) can be associated with abnormal left atrial (LA) function but has not been characterized in patients with left ventricular systolic dysfunction (LVSD) and a QRS interval >130 ms.
Methods
2D-Doppler echocardiography and tissue Doppler imaging (TDI) was performed in 41 patients with LVSD (LV ejection fraction 26±5%) and 41 similarly-age normal controls (NC). 2D measurements included LV volumes, ejection fraction and LA volumes for determination of LA emptying fraction and LA ejection fraction. IACT was defined as onset of P-wave to onset of the TDI-derived late diastolic (A') velocity at the lateral mitral annulus. 2D-Doppler measurements were re-assessed in LVSD patients 4 ± 2 months after cardiac resynchronization therapy (CRT).
Results
IACT was longer in LVSD patients compared to NC (105±25 vs. 74±12 ms, p <.001);none of the NC had IACT> 100ms.In LVSD patients, IACT correlated modestly with measurements of LA volumes (r =.41-.48, all p <.009) but not with measurements of LA function. LVSD patients with IACT > 100 ms (n=20) prior to CRT had larger LA volumes and lower indices of LA function after CRT compared to the ≤ 100ms group. Significant reductions in LV end-systolic volume and increases in LV ejection fraction occurred in both groups after CRT.
Conclusion
TDI-derived IACT can be prolonged in patients with severe LVSD and a wide QRS interval. An IACT > 100 ms. can affect LA remodeling and function at early follow-up after CRT but does not influence the response in LV end-systolic volume or ejection fraction.
doi:10.1016/j.echo.2009.02.020
PMCID: PMC2684572  PMID: 19345063
interatrial conduction time; left ventricular systolic dysfunction; left atrial function; cardiac resynchronization therapy
18.  Association and interaction of PPAR-complex gene variants with latent traits of left ventricular diastolic function 
BMC Medical Genetics  2010;11:65.
Background
Abnormalities in myocardial metabolism and/or regulatory genes have been implicated in left ventricular systolic dysfunction. However, the extent to which these modulate left ventricular diastolic function (LVDF) is uncertain.
Methods
Independent component analysis was applied to extract latent LVDF traits from 14 measured echocardiography-derived endophenotypes of LVDF in 403 Caucasians. Genetic association was assessed between measured and latent LVDF traits and 64 single nucleotide polymorphisms (SNPs) in three peroxisome proliferator-activated receptor (PPAR)-complex genes involved in the transcriptional regulation of fatty acid metabolism.
Results
By linear regression analysis, 7 SNPs (4 in PPARA, 2 in PPARGC1A, 1 in PPARG) were significantly associated with the latent LVDF trait, whereas a range of 0-4 SNPs were associated with each of the 14 measured echocardiography-derived endophenotypes. Frequency distribution of P values showed a greater proportion of significant associations with the latent LVDF trait than for the measured endophenotypes, suggesting that analyses of the latent trait improved detection of the genetic underpinnings of LVDF. Ridge regression was applied to investigate within-gene and gene-gene interactions. In the within-gene analysis, there were five significant pair-wise interactions in PPARGC1A and none in PPARA or PPARG. In the gene-gene analysis, significant interactions were found between rs4253655 in PPARA and rs1873532 (p = 0.02) and rs7672915 (p = 0.02), both in PPARGC1A, and between rs1151996 in PPARG and rs4697046 in PPARGC1A (p = 0.01).
Conclusions
Myocardial metabolism PPAR-complex genes, including within and between genes interactions, may play an important role modulating left ventricular diastolic function.
doi:10.1186/1471-2350-11-65
PMCID: PMC2874543  PMID: 20426853
19.  Relation of Serum Fetuin-A Levels to Coronary Artery Calcium in African-American Patients on Chronic Hemodialysis 
Vascular calcium deposition in end-stage renal disease occurs commonly, however its relationship to cardiovascular risk factors and fetuin-A levels in African-Americans is not known. Compliant African-American HD patients (n=17) agreed to undergo a 64-slice multidetector computed tomography for the assessment of coronary artery calcium score (CACS). The relationship between traditional cardiovascular risk factors (i.e., age, gender, dialysis vintage, history of diabetes, means of the previous 3 years of the weekly pre-dialysis blood pressure and hemoglobin, means of monthly values of calcium, phosphorus, alkaline phosphatase, uric acid and albumin, and means of quarterly measures of parathyroid hormone and lipids), and fetuin-A levels and CACS was explored by univariate analyses. Serum phosphorus levels over the previous 3 years were well controlled. The CACS range was 0-3,877 Agatston units (mean: 996; median :196). Among the tested variables, only fetuin-A was significantly and inversely associated with CACS (standardized β = -0.64 [95% confidence limits [CL]: -18.09, -3.62], p=0.006). There was no association between age and fetuin-A level (standardized β = -0.02 [95%CL: -0.10, 0.23]). In conclusion, African-American patients on long-term HD and with good phosphorus control exhibit a strong inverse correlation between fetuin-A levels and CACS which is independent of age.
doi:10.1016/j.amjcard.2008.08.032
PMCID: PMC2631229  PMID: 19101228
Fetuin-A; Hemodialysis; Coronary artery calcium score; African-American
20.  Genetic association analysis of coronary heart disease by profiling gene-environment interaction based on latent components in longitudinal endophenotypes 
BMC Proceedings  2009;3(Suppl 7):S86.
Studies of complex diseases collect panels of disease-related traits, also known as secondary phenotypes or endophenotypes. They reflect intermediate responses to environment exposures, and as such, are likely to contain hidden information of gene-environment (G × E) interactions. The information can be extracted and used in genetic association studies via latent-components analysis. We present such a method that extracts G × E information in longitudinal data of endophenotypes, and apply the method to repeated measures of multiple phenotypes related to coronary heart disease in Genetic Analysis Workshop 16 Problem 2. The new method identified many genes, including SCNN1B (sodium channel nonvoltage-gated 1 beta) and PKP2 (plakophilin 2), with potential time-dependent G × E interactions; and several others including a novel cardiac-specific kinase gene (TNNI3K), with potential G × E interactions independent of time and marginal effects.
PMCID: PMC2795989  PMID: 20018082
21.  Doppler Echocardiographic Methods for Optimization of the Atrioventricular Delay during Cardiac Resynchronization Therapy 
Echocardiography (Mount Kisco, N.Y.)  2008;25(9):1047-1055.
Cardiac resynchronization therapy (CRT) is beneficial for a majority of patients with medically-refractory heart failure due to severe left ventricular (LV) systolic dysfunction and prolonged interventricular conduction to improve symptoms and LV performance. An optimally programmed atrioventricular delay (AVD) during CRT can be also important to maximize the response in left ventricular function. Several Doppler-echocardiographic methods have been reported to be useful for determination of the optimal AVD. This review will discuss the various Doppler-based approaches to program the AVD in patients that receive CRT.
doi:10.1111/j.1540-8175.2008.00787.x
PMCID: PMC2649785  PMID: 18986435
Doppler Echocardiography; Heart Failure; Cardiac Pacing
22.  Osteopontin Promoter Polymorphism is Associated with Increased Carotid Intima-Media Thickness 
Background
Osteopontin (OPN)-transgenic mice exhibit increased carotid artery intima-media thickness (CIMT), smooth muscle cell proliferation, and atheroma formation.
Methods
An association of the human T-66G promoter variant with CIMT was examined in Caucasian adults grouped according to metabolic syndrome (MetS) criteria: Present (+MetS, n=70) and Absent (−MetS, n=70).
Results
The G allele frequency was 22%. For the entire cohort, the G group (TG and GG) was associated with significantly lower age/gender-adjusted CIMT compared to the TT group (p=0.008); similar analysis by MetS group found a significant difference only in the −MetS group (p=0.018). Stepwise multivariable regression showed that after age and waist circumference, the T-66G variant was predictive of CIMT (p=0.007). These data suggest that in a normoglycemic environment, human vascular OPN gene expression contributes to arterial structure, an effect diminished in dysmetabolic states.
Conclusions
Humans with the OPN −66 TT genotype, particularly those without MetS, exhibit thicker CIMT.
doi:10.1016/j.echo.2008.02.005
PMCID: PMC2536614  PMID: 18406574

Results 1-22 (22)