Marguerite Irvin

Several large epidemiologic studies and clinical trials have included echocardiography, but images were stored in analog format and these studies predated tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE). We hypothesized that digitization of analog echocardiograms, with subsequent quantification of cardiac mechanics using STE, is feasible, reproducible, accurate, and produces clinically valid results. In the NHLBI HyperGEN study (N = 2234), archived analog echocardiograms were digitized and subsequently analyzed using STE to obtain tissue velocities/strain. Echocardiograms were assigned quality scores and inter-/intra-observer agreement was calculated. Accuracy was evaluated in: (1) a separate second study (N = 50) comparing prospective digital strain versus post hoc analog-to-digital strain, and (2) in a third study (N = 95) comparing prospectively obtained TDI e' velocities with post hoc STE e' velocities. Finally, we replicated previously known associations between tissue velocities/strain, conventional echocardiographic measurements, and clinical data. Of the 2234 HyperGEN echocardiograms, 2150 (96.2%) underwent successful digitization and STE analysis. Inter/intra-observer agreement was high for all STE parameters, especially longitudinal strain (LS). In accuracy studies, LS performed best when comparing post hoc STE to prospective digital STE for strain analysis. STE-derived e' velocities correlated with, but systematically underestimated, TDI e' velocity. Several known associations between clinical variables and cardiac mechanics were replicated in HyperGEN. We also found a novel independent inverse association between fasting glucose and LS (adjusted β = -2.4 [95% CI -3.6, -1.2]% per 1-SD increase in fasting glucose; P < 0.001). Archeological echocardiography, the digitization and speckle tracking analysis of archival echocardiograms, is feasible and generates indices of cardiac mechanics similar to contemporary studies.

Two independent coding variants in the apolipoprotein L1 gene (APOL1), G1 and G2, strongly associate with nephropathy in African Americans; associations with cardiovascular disease are more controversial. Although APOL1 binds plasma high-density lipoproteins (HDLs), data on APOL1 risk variant associations with HDL subfractions are sparse. Two APOL1 G1 single nucleotide polymorphisms and the G2 insertion/deletion polymorphism were genotyped in 2010 Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study participants with nuclear magnetic resonance spectroscopy-based lipoprotein subfraction measurements. Linear regression was used to model associations between numbers of APOL1 G1/G2 risk variants and HDL subfractions, adjusting for demographic, clinical and ancestral covariates. Female sex and higher percentage of African ancestry were positively associated with the number of APOL1 G1/G2 risk alleles. In the unadjusted analysis, mean (standard error) small HDL concentrations (μmol/L) for participants with zero, one and two G1/G2 risk alleles were 19.0 (0.2), 19.7 (0.2) and 19.9 (0.4), respectively (P = 0.02). Adjustment for age, sex, diabetes and African ancestry did not change the results but strengthened the statistical significance (P = 0.004). No significant differences in large or medium HDL, very low-density lipoprotein or low-density lipoprotein particle concentrations were observed by APOL1 genotype. Greater numbers of APOL1 G1/G2 risk alleles were associated with higher small HDL particle concentrations in African Americans. These results may suggest novel areas of investigation to uncover reasons for the association between APOL1 risk variants with adverse outcomes in African Americans.

and Purpose. Blood pressure control is a paramount goal in secondary stroke prevention; however, high prevalence of uncontrolled blood pressure and use of multiple antihypertensive medication classes in stroke patients suggest this goal is not being met. We determined the prevalence and factors associated with apparent treatment-resistant hypertension in persons with/without stroke or transient ischemic attack.. Data came from REGARDS, a national, population-based cohort of 30,239 black and white adults > 45 years, enrolled 2003-2007, restricted to 11,719 participants with treated hypertension. Apparent treatment-resistant hypertension was defined as: 1) uncontrolled blood pressure (systolic ≥ 140 mmHg or diastolic ≥ 90 mmHg) with ≥ 3 antihypertensive medication classes, or 2) use of ≥ 4 antihypertensive medication classes, regardless of blood pressure level. Poisson regression was used to calculate characteristics associated with apparent treatment-resistant hypertension. Among ...

Circulating trans fatty acids (TFAs), which cannot be synthesized by humans, are linked to adverse health outcomes. Although TFAs are obtained from diet, little is known about subsequent influences (e.g., relating to incorporation, metabolism, or intercompetition with other fatty acids) that could alter circulating concentrations and possibly modulate or mediate impacts on health. The objective was to elucidate novel biologic pathways that may influence circulating TFAs by evaluating associations between common genetic variation and TFA biomarkers. We performed meta-analyses using 7 cohorts of European-ancestry participants (n = 8013) having measured genome-wide variation in single-nucleotide polymorphisms (SNPs) and circulating TFA biomarkers (erythrocyte or plasma phospholipids), including trans-16:1n-7, total trans-18:1, trans/cis-18:2, cis/trans-18:2, and trans/trans-18:2. We further evaluated SNPs with genome-wide significant associations among African Americans (n = 1082), Chi...

The aim of this study was to investigate whether there is a genotype-by-treatment interaction in patients experiencing stroke and treated with one of three antihypertensive drugs, that is chlorthalidone, amlodipine, or lisinopril. A population of 436 African Americans and 539 whites who had experienced stroke in the GenHAT study were genotyped for 768 single nucleotide polymorphisms (SNPs) in 280 candidate genes. To detect a genotype-by-treatment interaction, we used the Pearson's χ-test to assess whether the genotype frequencies differed at the single SNP level for the three drug treatment groups. From these single SNP analyses, we derived a summary statistic for the degree of association at the gene and gene complex levels. This was done by grouping SNPs using information on gene locations and defining gene complexes on the basis of protein-protein interactions. To assess the statistical significance of the observed test statistic, we derived an empirical P-value by simulating data under the null hypothesis. We found that, in patients who have experienced stroke, there is a significant genetic difference between hypertension drug treatment groups. In African Americans, SNP rs12143842 showed a significant association (P<0.001) with drug treatment. At the gene level, HNRNPA1P4 and NOS1AP in African Americans and PRICKLE1 and NINJ2 in non-Hispanic whites were significantly associated (P<0.01) with drug treatment, whereas none of the gene complexes tested showed significance. On the basis of the genetic differences between drug treatment groups, we conclude that there may be an interaction between certain genotypes and antihypertensive treatment in stroke patients. This needs to be replicated in other studies.

Carotid intima-media thickness (cIMT) is a subclinical measure of atherosclerosis with mounting evidence that higher cIMT confers an increased risk of cardiovascular disease. The ryanodine receptor 3 gene (RYR3) has previously been linked to increased cIMT; however, the causal variants have not yet been localized. Therefore, we sequenced 339 480 bp encompassing 104 exons and 2 kb flanking region of the RYR3 gene in 96 HIV-positive white men from the extremes of the distribution of common cIMT from the Fat Redistribution and Metabolic Changes in HIV infection study (FRAM). We identified 2710 confirmed variants (2414 single-nucleotide polymorphisms (SNPs) and 296 insertion/deletions (indels)), with a mean count of 736 SNPs (ranging from 528 to 1032) and 170 indels (ranging from 128 to 214) distributed in each individual. There were 39 variants in the exons and 15 of these were non-synonymous, of which with only 4 were common variants and the remaining 11 were rare variants, one was a novel SNP. We confirmed that the common variant rs2229116 was significantly associated with cIMT in this design (P<7.9 × 10(-9)), and observed seven other significantly associated SNPs (P<10(-8)). These variants including the private non-synonymous SNPs need to be followed up in a larger sample size and also tested with clinical atherosclerotic outcomes.

Diastolic wall strain (DWS), defined using posterior wall thickness (PWT) measurements from standard echocardiographic images (DWS = [PWT(systole)-PWT(diastole)]/PWT(systole)), has been proposed as a marker of left ventricular (LV) diastolic stiffness. However, the equation for DWS is closely related to systolic radial strain, and whether DWS is associated with abnormal cardiac mechanics (reduced systolic strains and diastolic tissue velocities) is unknown. We sought to determine the relationship between DWS and systolic and diastolic cardiac mechanics. We calculated DWS and performed speckle-tracking analysis in a large population- and family-based study (Hypertension Genetic Epidemiology Network [HyperGEN]; N=1907 after excluding patients with ejection fraction [EF] <50% or posterior wall motion abnormalities). We measured global longitudinal, circumferential, and radial strain (GLS, GCS, and GRS, respectively) and early diastolic (e') tissue velocities, and we determined t...

Apparent treatment-resistant hypertension is defined as systolic/diastolic BP ≥ 140/90 mmHg with concurrent use of three or more antihypertensive medication classes or use of four or more antihypertensive medication classes regardless of BP level. The prevalence of apparent treatment-resistant hypertension among Reasons for Geographic and Racial Differences in Stroke study participants treated for hypertension (n=10,700) was determined by level of estimated GFR and albumin-to-creatinine ratio, and correlates of apparent treatment-resistant hypertension among those participants with CKD were evaluated. CKD was defined as an albumin-to-creatinine ratio ≥ 30 mg/g or estimated GFR<60 ml/min per 1.73 m(2). The prevalence of apparent treatment-resistant hypertension was 15.8%, 24.9%, and 33.4% for those participants with estimated GFR ≥ 60, 45-59, and <45 ml/min per 1.73 m(2), respectively, and 12.1%, 20.8%, 27.7%, and 48.3% for albumin-to-creatinine ratio<10, 10-29, 30-299, and ≥ 300 mg/g, respectively. The multivariable-adjusted prevalence ratios (95% confidence intervals) for apparent treatment-resistant hypertension were 1.25 (1.11 to 1.41) and 1.20 (1.04 to 1.37) for estimated GFR levels of 45-59 and <45 ml/min per 1.73 m(2), respectively, versus ≥ 60 ml/min per 1.73 m(2) and 1.54 (1.39 to 1.71), 1.76 (1.57 to 1.97), and 2.44 (2.12 to 2.81) for albumin-to-creatinine ratio levels of 10-29, 30-299, and ≥ 300 mg/g, respectively, versus albumin-to-creatinine ratio<10 mg/g. After multivariable adjustment, men, black race, larger waist circumference, diabetes, history of myocardial infarction or stroke, statin use, and lower estimated GFR and higher albumin-to-creatinine ratio levels were associated with apparent treatment-resistant hypertension among individuals with CKD. This study highlights the high prevalence of apparent treatment-resistant hypertension among individuals with CKD.

Studies suggest that treatment-resistant hypertension is common and increasing in prevalence among US adults. Although hypertension is a risk factor for end-stage renal disease (ESRD), few data are available for the association between treatment-resistant hypertension and ESRD risk. Prospective cohort study. We analyzed data from 9,974 REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study participants treated for hypertension without ESRD at baseline. Treatment-resistant hypertension was defined as uncontrolled blood pressure (BP) with concurrent use of 3 antihypertensive medication classes including a diuretic or use of 4 or more antihypertensive medication classes including a diuretic regardless of BP. Incident ESRD was identified by linkage of REGARDS Study participants with the US Renal Data System. During a baseline in-home study visit, BP was measured twice and classes of antihypertensive medication being taken were determined by pill bottle inspection. During a median follow-up of 6.4 years, there were 152 incident cases of ESRD (110 ESRD cases among 2,147 with treatment-resistant hypertension and 42 ESRD cases among 7,827 without treatment-resistant hypertension). The incidence of ESRD per 1,000 person-years for hypertensive participants with and without treatment-resistant hypertension was 8.86 (95% CI, 7.35-10.68) and 0.88 (95% CI, 0.65-1.19), respectively. After multivariable adjustment, the HR for ESRD comparing hypertensive participants with versus without treatment-resistant hypertension was 6.32 (95% CI, 4.30-9.30). Of participants who developed incident ESRD during follow-up, 72% had treatment-resistant hypertension at baseline. BP, estimated glomerular filtration rate, and albuminuria assessed at a single time. Individuals with treatment-resistant hypertension are at increased risk for ESRD. Appropriate clinical management strategies are needed to treat treatment-resistant hypertension in order to preserve kidney function in this high-risk group.

Genome-wide association studies (GWASs) primarily performed in European-ancestry (EA) populations have identified numerous loci associated with body mass index (BMI). However, it is still unclear whether these GWAS loci can be generalized to other ethnic groups, such as African Americans (AAs). Furthermore, the putative functional variant or variants in these loci mostly remain under investigation. The overall lower linkage disequilibrium in AA compared to EA populations provides the opportunity to narrow in or fine-map these BMI-related loci. Therefore, we used the Metabochip to densely genotype and evaluate 21 BMI GWAS loci identified in EA studies in 29,151 AAs from the Population Architecture using Genomics and Epidemiology (PAGE) study. Eight of the 21 loci (SEC16B, TMEM18, ETV5, GNPDA2, TFAP2B, BDNF, FTO, and MC4R) were found to be associated with BMI in AAs at 5.8 × 10(-5). Within seven out of these eight loci, we found that, on average, a substantially smaller number of variants was correlated (r(2) > 0.5) with the most significant SNP in AA than in EA populations (16 versus 55). Conditional analyses revealed GNPDA2 harboring a potential additional independent signal. Moreover, Metabochip-wide discovery analyses revealed two BMI-related loci, BRE (rs116612809, p = 3.6 × 10(-8)) and DHX34 (rs4802349, p = 1.2 × 10(-7)), which were significant when adjustment was made for the total number of SNPs tested across the chip. These results demonstrate that fine mapping in AAs is a powerful approach for both narrowing in on the underlying causal variants in known loci and discovering BMI-related loci.