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Biomedical subjects

Gary F Mitchell

Publications and source records attributed to Gary F Mitchell.

At least 19 recordsLinked to original sources
PubMed2007

Aging and arterial structure-function relations.

Aging and hypertension interact and are associated with long-term changes in arterial structure and function. Systolic BP is not constant along the arterial tree due to different proportional contributions of forward and reflected pressure waves. Brachial cuff BP values are inadequate to detect these changes. Increased PP is the result of an imbalance between arterial flow and arterial impedance, which can be due to increased effective arterial wall stiffness or to a smaller proportional arterial diameter. After middle age, there is both dilation and stiffening of large arteries, along with increased effective stiffness caused by the corresponding changes in content of collagen, elastin, and VSM in the vascular wall. Intermediate conduit arteries also dilate with age but their functional characteristics remain relatively preserved. In the microcirculation, vasoconstriction, VSM hypertrophy and rarefaction accompany and may contribute to changes in organ function.

Aging↗
PubMed2006

Cross-sectional relations of multiple biomarkers from distinct biological pathways to brachial artery endothelial function.

BACKGROUND: Endothelial dysfunction is a critical intermediate phenotype in the pathogenesis of cardiovascular disease. We evaluated the relative contributions of distinct biological pathways to interindividual variation in endothelial function by relating prototype biomarkers (representing these pathways) to brachial artery vasodilator function. METHODS AND RESULTS: We investigated the cross-sectional relations of a panel of 7 biomarkers measured at a routine examination to brachial artery vasodilator function (flow-mediated dilation [FMD] and reactive hyperemia) assessed at a subsequent examination (mean interval, 2.9 years) in 2113 Framingham Heart Study participants (mean age, 61 years; 54% women). We selected biomarkers from 4 biological domains: neurohormonal (N-terminal pro-atrial natriuretic peptide [N-ANP], B-type natriuretic peptide [BNP], renin, aldosterone), hemostatic factors (plasminogen activator inhibitor-1 [PAI-1]), inflammation (C-reactive protein [CRP]), and target organ damage (urine albumin-creatinine ratio). In age- and sex-adjusted models, several biomarkers were related to baseline brachial artery diameter (PAI-1, CRP, urine albumin-creatinine ratio), baseline mean flow (N-ANP, BNP, PAI-1, CRP, aldosterone), FMD (N-ANP, PAI-1, CRP, renin), and reactive hyperemia (BNP, PAI-1, CRP, renin, urine albumin-creatinine ratio). In multivariable analyses relating the 7 biomarkers conjointly to each vascular function measure (adjusting for known risk factors), N-ANP and renin were positively related to FMD (P=0.001 and P=0.04, respectively), and N-ANP was inversely related to baseline mean flow velocity (P=0.01). None of the other biomarkers was significantly related to the vascular function measures studied. CONCLUSIONS: In our large community-based sample, a conservative strategy relating several biomarkers to vascular endothelial function identified plasma N-ANP as a key correlate of mean flow under basal conditions and of FMD in response to forearm cuff occlusion.

Aged↗
PubMed2006

Changes in central arterial pressure waveforms during the normal menstrual cycle.

BACKGROUND: Changes in estradiol and progesterone during the human menstrual cycle may impact vascular and cardiac function. Renin-angiotensin-aldosterone system (RAAS) hormones increase during the luteal phase of the menstrual cycle and may antagonize the vascular effects of estradiol. This study was designed to investigate central arterial changes, cardiac function, and RAAS activity in response to gonadal steroid variations during the menstrual cycle. METHODS: We studied 15 women during the follicular and midluteal phases with determination of estradiol, progesterone, hormones of the RAAS, and spot urine sodium and creatinine levels. Central pulsatile hemodynamics was evaluated using calibrated carotid tonometry and central aortic Doppler flow. Systolic ejection period (SEP) and systolic pressure time integral (SPTI) were computed from carotid pressure waveforms. RESULTS: Levels of estradiol, progesterone, and RAAS hormones were higher in the luteal phase. SEP and SPTI were lower during the luteal phase, whereas central and peripheral blood pressures and measures of arterial stiffness were unchanged between the two phases. The urine sodium-to-creatinine ratio was similar at both phases. CONCLUSION: Central arterial stiffness does not differ between the follicular and midluteal phases of the menstrual cycle in healthy women, despite significant changes in estradiol and progesterone levels. Systole was shortened during the midluteal phase. RAAS activation during the luteal phase may be responsible for a lack of the expected estradiol-mediated reduction in arterial stiffness between the two phases of the menstrual cycle. Because load was unchanged, the decrease in SEP and SPTI may represent a direct effect of estrogen, progesterone, or RAAS activation on ventricular function.

Adult↗
PubMed2005

Cross-sectional relations of peripheral microvascular function, cardiovascular disease risk factors, and aortic stiffness: the Framingham Heart Study.

BACKGROUND: Aortic stiffness and small-artery structure and function share various risk factors; however, relations between these 2 measures of vascular function are complex and incompletely understood. METHODS AND RESULTS: We examined hyperemic forearm blood flow, an indicator of microvascular structure and function, and aortic stiffness in 2045 participants (1107 women, mean age 61+/-9 years) in the Framingham Heart Study offspring cohort. Using arterial tonometry, we evaluated 3 measures of aortic stiffness: brachial pulse pressure; carotid-femoral pulse wave velocity (CFPWV), which is related directly to aortic wall stiffness; and forward pressure wave amplitude (Pf), which is related directly to aortic wall stiffness and inversely to aortic diameter. Using high-resolution ultrasound and Doppler, we evaluated brachial artery diameter, blood flow, and forearm vascular resistance (FVR) at baseline and during reactive hyperemia after 5 minutes of forearm ischemia. In multivariable models that adjusted for cardiovascular disease risk factors, local brachial pulse pressure, CFPWV, and Pf, considered separately, were associated with increased baseline and hyperemic FVR (P<0.001). In models that further adjusted for mean arterial pressure, each measure of aortic stiffness was associated with reduced hyperemic flow (P<0.001). In risk factor-adjusted models that simultaneously considered CFPWV and Pf, both were associated with increased FVR at baseline (P<0.01) and during hyperemia (P<0.001). CONCLUSIONS: Our findings indicate that abnormal aortic stiffness and increased pressure pulsatility are associated with blunted microvascular reactivity to ischemic stress that is in excess of changes attributable to conventional cardiovascular disease risk factors alone, including mean arterial pressure.

Adult↗
PubMed2005

Changes in aortic stiffness and augmentation index after acute converting enzyme or vasopeptidase inhibition.

Augmentation index (AI), a measure of enhanced wave reflection, has been proposed as a bedside measure of aortic stiffness. However, because AI is potentially sensitive to various factors other than vessel wall stiffness, the utility of AI as a stiffness indicator may be limited. To assess relations between AI and vascular properties, we used arterial tonometry and aortic Doppler flow to evaluate trough (24 hours) and peak (4 hours) pulsatile hemodynamics and pulse wave velocity in 159 individuals with systolic hypertension at the completion of a 12-week period of monotherapy with the vasopeptidase inhibitor omapatrilat (80 mg; n=75) or the converting enzyme inhibitor enalapril (40 mg; n=84). Characteristic impedance (Zc) was calculated from the ratio of change in carotid pressure and aortic flow in early systole. Systolic ejection period (SEP), timing of wave reflection, and AI were assessed from the carotid waveform. Comparable acute reductions in mean pressure were associated with greater reductions in peripheral resistance with enalapril, whereas neither drug had an acute effect on Zc. Both drugs reduced AI, but neither drug altered the timing of wave reflection. Both drugs increased heart rate and shortened SEP. Multiple regression analysis demonstrated that the acute reduction in AI was most affected by reductions in SEP and peripheral resistance. Change in AI was inversely related to change in Zc and pulse wave velocity did not enter the model. Our findings indicate that AI is a complex surrogate marker that is inversely related to changes in proximal aortic stiffness in systolic hypertension.

Adult↗
PubMed2005

Pulsatile hemodynamic effects of candesartan in patients with chronic heart failure: the CHARM Program.

BACKGROUND: Abnormal large artery function and increased pulsatile load are exacerbated by excess angiotensin-II acting through the AT1 receptor and contribute to the pathogenesis and progression of chronic heart failure (CHF). AIMS: To evaluate effects of the AT1 receptor blocker candesartan (N = 30) or placebo (N = 34) on pulsatile hemodynamics in participants with CHF in the CHARM program. METHODS AND RESULTS: Noninvasive hemodynamics were assessed following 6 and 14 months of treatment and averaged. Using calibrated tonometry and aortic outflow Doppler, characteristic impedance was calculated as the ratio of the change in carotid pressure and aortic flow in early systole. Total arterial compliance was calculated by the diastolic area method. Brachial blood pressure, cardiac output and peripheral resistance did not differ between groups. Lower central pulse pressure in the candesartan group (57+/-20 vs. 67+/-17 mmHg, P = 0.043) was accompanied by lower characteristic impedance (200+/-78 vs. 240+/-74 dyne s/cm5, P = 0.039) and higher total arterial compliance (1.87+/-0.70 vs. 1.47+/-0.48 ml/mmHg, P = 0.008). Similar favorable differences were seen when analyses were stratified for ejection fraction (< or = 0.40 vs. >0.40) and baseline angiotensin converting enzyme inhibitor use. CONCLUSIONS: Candesartan has a favorable effect on large artery function in patients with chronic heart failure.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

Common genetic variation at the endothelial nitric oxide synthase locus and relations to brachial artery vasodilator function in the community.

BACKGROUND: Sequence variants at the endothelial nitric oxide synthase (NOS3) locus have been associated with endothelial function measures, but replication has been limited. METHODS AND RESULTS: In reference pedigrees, we characterized linkage disequilibrium structure at the NOS3 locus using 33 common single nucleotide polymorphisms (SNPs). Eighteen SNPs that capture underlying common variation were genotyped in unrelated Framingham Heart Study participants (49.5% women; mean age, 62 years) with measured brachial artery flow-mediated dilation (n=1446) or hyperemic flow velocity (n=1043). Within 3 defined blocks of strong linkage disequilibrium that spanned NOS3, 11 SNPs captured >80% of common haplotypic variation. Among men, there were nominally significant associations between 8 NOS3 SNPs (minimum P=0.002) and between haplotypes (minimum P=0.002) and either flow-mediated dilation or hyperemic flow velocity. In women, we did not observe significant associations between NOS3 SNPs or haplotypes and endothelial function measures. To correct for multiple testing, we constructed 1000 bootstrapped null data sets and found that empirical probability values exceeded 0.05 for both phenotypes. CONCLUSIONS: A parsimonious set of SNPs captures common genetic variation at the NOS3 locus. A conservative interpretation of our results is that, accounting for multiple testing, we did not observe statistically significant relations between NOS3 sequence variants and endothelial function measures in either sex. The nominal associations of select NOS3 variants with endothelial function in men (unadjusted for multiple testing) should be viewed as hypothesis-generating observations and may merit testing in other cohorts and experimental designs.

Aged↗
PubMed2005

Heritability and a genome-wide linkage scan for arterial stiffness, wave reflection, and mean arterial pressure: the Framingham Heart Study.

BACKGROUND: Arterial stiffness and mean arterial pressure variably contribute to systolic hypertension and increased cardiovascular risk. However, few prior community-based studies have evaluated the genetics of arterial stiffness and separate mean and pulsatile components of blood pressure. METHODS AND RESULTS: Using arterial tonometry, we evaluated heritability and linkage of forward and reflected wave amplitude, mean arterial pressure, and carotid-femoral pulse wave velocity (CFPWV) in 1480 participants representing 817 pedigrees in the Framingham Study offspring cohort. In 204 families with tonometry data, a genome-wide scan was performed with microsatellite markers that covered the genome at 10-cM intervals. Heritability estimates were moderate for reflected wave amplitude (h2=0.48), forward wave amplitude (h2=0.21), CFPWV (h2=0.40), and mean arterial pressure (h2=0.33). Variance components linkage analysis identified 2 regions of linkage for reflected wave amplitude: chromosome 4 at 181 cM (logarithm of odds [LOD]=4.93, permuted P=0.002) and chromosome 8 at 33 cM (LOD=3.27, permuted P=0.058). There was 1 region of linkage for forward wave amplitude on chromosome 7 at 174 cM (LOD=2.88, permuted P=0.017). There were several regions of suggestive linkage for CFPWV: chromosome 2 at 94 cM (LOD=2.46), chromosome 7 at 29 cM (LOD=2.50), chromosome 13 at 108 cm (LOD=2.10), and chromosome 15 at 108 cM (LOD=2.48). There was 1 region of suggestive linkage for mean arterial pressure on chromosome 1 at 192 cM (LOD=2.18). CONCLUSIONS: Arterial stiffness measures and mean and pulsatile components of blood pressure are heritable and appear to have genetic determinants that may be linked to separate genetic loci in humans.

Aged↗
PubMed2005

Subclinical inflammation and vascular dysfunction in women with previous gestational diabetes mellitus.

CONTEXT: A history of gestational diabetes (GDM) significantly increases the risk of developing type 2 diabetes, an independent risk factor for cardiovascular disease (CVD). It is not known whether nondiabetic women with prior GDM are also at increased risk of CVD. OBJECTIVE: The aim of this study was to compare biochemical and hemodynamic surrogate markers of CVD in nondiabetic women with and without a history of GDM who were at least 1 yr post delivery. DESIGN: This was a single center cross-sectional study. SETTING: The study was performed in an academic referral center. SUBJECTS: Forty-eight premenopausal healthy women with a history of GDM (n = 25) or a history of normal pregnancy (n = 23) were studied in the follicular phase of the menstrual cycle. MAIN OUTCOME MEASURES: The main outcome measures were: 1) inflammatory markers associated with CVD including C-reactive protein, IL-6, and plasminogen activator inhibitor-1; 2) the adipokine adiponectin; and 3) conduit vessel stiffness. RESULTS: When compared to normal controls, women with prior GDM had higher mean levels of C-reactive protein (3.58 +/- 3.86 vs. 0.52 +/- 0.16 mg/liter; P < 0.001), IL-6 (1.81 +/- 1.04 vs. 0.99 +/- 0.52 pg/ml; P = 0.001), plasminogen activator inhibitor-1 (29.6 +/- 17.6 vs. 16.5 +/- 14.0 ng/ml; P = 0.001), and lower levels of adiponectin (8.9 +/- 3.9 vs. 15.9 +/- 7.3 microg/ml; P = 0.001). Women with prior GDM also had significantly (P </= 0.04) increased peripheral vascular resistance (1658 +/- 290 vs. 1462 +/- 340 dyne.sec/cm(5)), decreased stroke volume (65 +/- 13 vs. 75 +/- 14 ml/beat), and decreased cardiac output (70 +/- 12 vs. 74 +/- 13 ml/sec) when compared to controls, after adjusting for body mass index. CONCLUSIONS: Nondiabetic women with prior GDM have evidence of subclinical inflammation, hypoadiponectinemia, and early vascular dysfunction; this population may be at increased risk of developing CVD.

Adiponectin↗
PubMed2004

Brachial artery vasodilator function and systemic inflammation in the Framingham Offspring Study.

BACKGROUND: In experimental studies, traditional risk factors and proinflammatory processes alter the regulatory functions of the vascular endothelium to promote atherosclerosis. These alterations include expression of leukocyte adhesion molecules and decreased bioavailability of endothelium-derived nitric oxide, an important regulator of vascular homeostasis and tone. The precise relations among risk factors, inflammation, and nitric oxide bioavailability remain uncertain. METHODS AND RESULTS: To test the hypothesis that inflammation impairs endothelial function in humans, we measured brachial artery flow-mediated dilation, reactive hyperemia, and serum concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), soluble intracellular adhesion molecule-1 (sICAM-1), and monocyte chemotactic protein-1 (MCP-1) in 2701 participants from the Framingham Study (mean age 61 years, 53% women). There were modest unadjusted inverse correlations between flow-mediated dilation and CRP, IL-6, and sICAM-1 (P<0.001 for all) that were rendered nonsignificant after accounting for traditional coronary risk factors. For reactive hyperemia, we observed inverse correlations with markers of inflammation in unadjusted models that were attenuated 57% to 74% after accounting for risk factors. However, partial correlations of CRP, IL-6, and sICAM-1 with reactive hyperemia remained significant. CONCLUSIONS: Our observations are consistent with the hypothesis that risk factors induce a state of inflammation that impairs vascular function. For flow-mediated dilation, we found no evidence that inflammation has additional effects beyond those attributable to traditional risk factors. The incremental contribution of CRP, IL-6, and sICAM-1 to reactive hyperemia above and beyond known risk factors suggests that systemic inflammation may contribute to impaired vasomotor function in forearm microvessels.

Biomarkers↗
PubMed2004

Local shear stress and brachial artery flow-mediated dilation: the Framingham Heart Study.

Endothelium-dependent flow-mediated dilation is a homeostatic response to short-term increases in local shear stress. Flow-mediated dilation of the brachial artery in response to postischemic reactive hyperemia is impaired in patients with cardiovascular disease risk factors and may reflect local endothelial dysfunction in the brachial artery. However, previous studies have largely neglected the effect of risk factors on evoked shear stress, which is the stimulus for dilation. We evaluated brachial artery percent dilation and evoked diastolic shear stress during reactive hyperemia using high-resolution ultrasound and Doppler in 2045 participants (1107 women, mean age 61 years) in the Framingham Offspring Study. In age- and sex-adjusted models, baseline and hyperemic shear stress were related to brachial artery percent dilation. In stepwise multivariable analyses examining clinical correlates of percent dilation (without shear stress in the model), age, sex, mean arterial pressure, pulse pressure, heart rate, body mass index, lipid medication use, and hormone replacement therapy were related to percent dilation (R2=0.189; P<0.001). When hyperemic shear stress was incorporated, the overall R2 improved (R2=0.335; P<0.001), but relationships between risk factors and percent dilation were attenuated (age and mean arterial pressure) or no longer significant (all others). In contrast, risk factors were related to baseline and hyperemic shear stress in multivariable analyses. Evoked hyperemic shear stress is a major correlate of brachial artery flow-mediated dilation. The associations between many risk factors and brachial artery flow-mediated dilation may be attributable to reduced stimulus for dilation rather than impaired local conduit artery response during hyperemia.

Adult↗
PubMed2004

Genome-wide scan for pulse pressure in the National Heart, Lung and Blood Institute's Framingham Heart Study.

The objective of this study was to assess heritability and identify chromosomal regions showing evidence of linkage to pulse pressure (PP), a simple indicator of proximal conduit vessel stiffness. Blood pressure data were analyzed for 8478 members of the National Heart, Lung and Blood Institute's (NHLBI) Framingham Heart Study. Long-term PP was defined using 2-stage analysis. First, the difference between systolic and diastolic blood pressure was averaged over all qualifying clinic examinations. In the second stage, mean PP was adjusted for mean age, time period of examination, and body mass index by regression analysis. PP values were available for 6421 individuals in 1593 families for heritability estimation and for 2492 individuals in 330 families for linkage analysis. Microsatellite markers covering the genome at 10 cM intervals were typed by the NHLBI Mammalian Genotyping Service; genome scan data were available on 1585 individuals with PP data. Heritability estimates of long-term PP accounting for hypertension treatment and for ignoring treatment were 0.52 and 0.51, respectively. Variance component linkage analysis identified several locations with suggestive evidence of linkage: chromosome 15 at 122 cM (logarithm of odds [LOD]=2.94), chromosome 7 at 71 cM (LOD=2.42), chromosome 5 at 53 cM (LOD=2.03), and chromosome 10 at 81 cM (LOD=1.83) for PP accounting for treatment. LOD scores were slightly lower when ignoring treatment, with the exception of a peak on chromosome 10 at 81 cM (LOD=2.58). In conclusion, we have demonstrated a substantial genetic component to PP and have identified 4 chromosomal regions that may harbor genes influencing vascular stiffness.

Blood Pressure↗
PubMed2004

Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: the Framingham Heart Study.

With advancing age, arterial stiffness and wave reflections increase and elevate systolic and pulse pressures. An elevated central pulse pressure is generally ascribed to increased wave reflection and portends an unfavorable prognosis. Using arterial tonometry, we evaluated central (carotid-femoral) and peripheral (carotid-brachial) pulse wave velocity, amplitudes of forward and reflected pressure waves, and augmentation index in 188 men and 333 women in the Framingham Heart Study offspring cohort who were free of clinical cardiovascular disease, hypertension, diabetes, smoking within the past 12 months, dyslipidemia, and obesity. In multivariable linear regression models, advancing age was the predominant correlate of higher carotid-femoral pulse wave velocity; other correlates were higher mean arterial pressure, heart rate, and triglycerides and walk test before tonometry (model R2=0.512, P<0.001). A similar model was obtained for carotid-brachial pulse wave velocity (model R2=0.227, P<0.001), although the increase with advancing age was smaller. Owing to different relations of age to central and peripheral stiffness measures, carotid-femoral pulse wave velocity was lower than carotid-brachial pulse wave velocity before age 50 years but exceeded it thereafter, leading to reversal of the normal central-to-peripheral arterial stiffness gradient. In this healthy cohort with a minimal burden of cardiovascular disease risk factors, an age-related increase in aortic stiffness, as compared with peripheral arterial stiffness, was associated with increasing forward wave amplitude and pulse pressure and reversal of the arterial stiffness gradient. This phenomenon may facilitate forward transmission of potentially deleterious pressure pulsations into the periphery.

Adult↗
PubMed2004

Clinical correlates and heritability of flow-mediated dilation in the community: the Framingham Heart Study.

BACKGROUND: Studies in selected samples have linked impaired endothelial function with cardiovascular disease and its risk factors. The clinical correlates and heritability of endothelial function in the community have not been described. METHODS AND RESULTS: We examined a measure of endothelial function, brachial artery flow-mediated dilation (FMD), expressed as both percent (FMD%) and actual dilation by ultrasound with the occlusion cuff below the elbow in 2883 Framingham Study participants (52.9% women; mean age, 61 years). A subset of 1096 participants performed a 6-minute walk test before FMD determination. Mean FMD% was 3.3+/-3.0% in women and 2.4+/-2.4% in men. In stepwise multivariable linear regression models, FMD% was inversely related to age, systolic blood pressure, body mass index (BMI), lipid-lowering medication, and smoking, whereas it was positively related to female gender, heart rate, and prior walk test. The estimated heritability of FMD% was 0.14. FMD actual dilation findings were similar, except that female sex and BMI were not significantly associated. CONCLUSIONS: Increasing age, systolic blood pressure, BMI, and smoking were associated with lower FMD% in our community-based sample, whereas prior exercise and increasing heart rate were associated with higher FMD%. The estimated heritability of FMD was modest. Future research will permit more complete characterization of the genetic and environmental determinants of endothelial function and its prognostic value in the community.

Adult↗
PubMed2004

Arterial stiffness and wave reflection in hypertension: pathophysiologic and therapeutic implications.

Numerous studies performed in the past decade have shown that increased pulse pressure, an indicator of arterial stiffening, is associated with adverse clinical outcomes. Research is now focused on better defining the anatomic and physiologic determinants of increased pulse pressure. Early work considered aortic stiffening to be a passive, irreversible consequence of aging that was accelerated by hypertension. Recent studies suggest that aortic stiffening is dynamic and reversible and that abnormalities in aortic function may play a primary role in the pathogenesis of hypertension. This review summarizes current work on the genesis of increased pulse pressure and abnormal pulsatile load in hypertension, and underscores areas for future research.

Aorta↗