Amyloid imaging plays an important role in the research and diagnosis of dementing disorders. Sub... more Amyloid imaging plays an important role in the research and diagnosis of dementing disorders. Substantial variation in quantitative methods to measure brain amyloid burden exists in the field. The aim of this work is to investigate the impact of methodological variations to the quantification of amyloid burden using data from the Dominantly Inherited Alzheimer's Network (DIAN), an autosomal dominant Alzheimer's disease population. Cross-sectional and longitudinal [11C]-Pittsburgh Compound B (PiB) PET imaging data from the DIAN study were analyzed. Four candidate reference regions were investigated for estimation of brain amyloid burden. A regional spread function based technique was also investigated for the correction of partial volume effects. Cerebellar cortex, brain-stem, and white matter regions all had stable tracer retention during the course of disease. Partial volume correction consistently improves sensitivity to group differences and longitudinal changes over time...
The aim of this study is to investigate the genetic influence on the cerebral cortex, based on th... more The aim of this study is to investigate the genetic influence on the cerebral cortex, based on the analyses of heritability and genetic correlation between grey matter (GM) thickness, derived from structural MR images (sMRI), and associated white matter (WM) connections obtained from diffusion MRI (dMRI). We measured on sMRI the cortical thickness (CT) from a large twin imaging cohort using a surface-based approach (N = 308, average age 22.8 ± 2.3 SD). An ACE model was employed to compute the heritability of CT. WM connections were estimated based on probabilistic tractography using fiber orientation distributions (FOD) from dMRI. We then fitted the ACE model to estimate the heritability of CT and FOD peak measures along WM fiber tracts. The WM fiber tracts where genetic influence was detected were mapped onto the cortical surface. Bivariate genetic modeling was performed to estimate the cross-trait genetic correlation between the CT and the FOD-based connectivity of the tracts asso...
Background. The p-curve is a plot of the distribution of p-values reported in a set of scientific... more Background. The p-curve is a plot of the distribution of p-values reported in a set of scientific studies. Comparisons between ranges of p-values have been used to evaluate fields of research in terms of the extent to which studies have genuine evidential value, and the extent to which they suffer from bias in the selection of variables and analyses for publication, p-hacking. Methods. p-hacking can take various forms. Here we used R code to simulate the use of ghost variables, where an experimenter gathers data on several dependent variables but reports only those with statistically significant effects. We also examined a text-mined dataset used by Head et al. (2015) and assessed its suitability for investigating p-hacking. Results. We show that when there is ghost p-hacking, the shape of the p-curve depends on whether dependent variables are intercorrelated. For uncorrelated variables, simulated p-hacked data do not give the "p-hacking bump" just below .05 that is regard...
Glucocorticoid receptor (NR3C1) polymorphisms associate with obesity, muscle strength, and cortis... more Glucocorticoid receptor (NR3C1) polymorphisms associate with obesity, muscle strength, and cortisol sensitivity. We examined associations among four NR3C1 polymorphisms and the muscle response to resistance training (RT). European-American adults (n = 602, 23.8±0.4yr) completed a 12 week unilateral arm RT program. Maximum voluntary contraction (MVC) assessed isometric strength (kg) and MRI assessed biceps size (cm2) pre- and post-resistance training. Subjects were genotyped for NR3C1 -2722G>A, -1887G>A, -1017T>C, and +363A>G. Men carrying the -2722G allele gained less relative MVC (17.3±1.2vs33.5±6.1%) (p = 0.010) than AA homozygotes; men with -1887GG gained greater relative MVC than A allele carriers (19.6±1.4vs13.2±2.3%) (p = 0.016). Women carrying the -1017T allele gained greater relative size (18.7±0.5vs16.1±0.9%) (p = 0.016) than CC homozygotes. We found sex-specific NR3C1 associations with the muscle strength and size response to RT. Future studies should investiga...
Reduction in hippocampal and amygdala volume measured via structural magnetic resonance imaging i... more Reduction in hippocampal and amygdala volume measured via structural magnetic resonance imaging is an early marker of Alzheimer's disease (AD). Whether genetic risk factors for AD exert an effect on these subcortical structures independent of clinical status has not been fully investigated. We examine whether increased genetic risk for AD influences hippocampal and amygdala volumes in case-control and population cohorts at different ages, in 1674 older (aged >53 years; 17% AD, 39% mild cognitive impairment [MCI]) and 467 young (16-30 years) adults. An AD polygenic risk score combining common risk variants excluding apolipoprotein E (APOE), and a single nucleotide polymorphism in TREM2, were both associated with reduced hippocampal volume in healthy older adults and those with MCI. APOE ε4 was associated with hippocampal and amygdala volume in those with AD and MCI but was not associated in healthy older adults. No associations were found in young adults. Genetic risk for AD affects the hippocampus before the clinical symptoms of AD, reflecting a neurodegenerative effect before clinical manifestations in older adults.
Broad indications for the use of statin medications are resulting in more patients using these th... more Broad indications for the use of statin medications are resulting in more patients using these therapies. Simultaneously, healthcare professionals are strongly advocating recommendations to increase exercise training (ET) as a means of decreasing cardiovascular disease (CVD) risk and improving other parameters of fitness. We review the literature to explore mechanisms that may increase the risk of statin/ET interactions, examine the benefits and risks of combining ET and statin use, and offer strategies to minimize the hazards of this combination therapy. The combined use of statins and ET can result in health gains and decreased CVD risk; however, multiple factors may increase the risk of adverse events. Some of the events that have been reported with the combination of statins and ET include decreased athletic performance, muscle injury, myalgia, joint problems, decreased muscle strength, and fatigue. The type of statin, the dose, drug interactions, genetic variants, coenzyme Q10 ...
Physically active adults may be especially vulnerable to the adverse muscular side effects of sta... more Physically active adults may be especially vulnerable to the adverse muscular side effects of statins. We determined if short-term cessation of statin therapy would improve aerobic exercise performance in middle-aged adults engaged in regular aerobic exercise training. Physically active middle-aged adults on statin therapy ≥6 mo (n = 16; 58 ± 10 y) or not taking lipid-lowering medications (controls) (n = 19; 51 ± 9 y) completed a peak oxygen consumption (VO2peak) and time to exhaustion test on a cycle ergometer 2-7 d apart. Tests were repeated following 1 mo of statin cessation or a 1 mo period for controls. Questionnaires were administered to assess exercise history and muscle complaints. Statin users reported little or no muscle complaints and participation in aerobic exercise was similar between groups (p≥0.13). The lower VO2peak (37.3 ± 9.0 vs. 43.1 ± 4.9 ml/kg/min; p = 0.02) and time to exhaustion (21.9 ± 4.4 vs. 26.0 ± 6.3 min; p = 0.04) in statin users versus controls did not...
Hypertension research : official journal of the Japanese Society of Hypertension, Jan 26, 2015
Cardiovascular disease mortality is reduced following smoking cessation but the reversibility of ... more Cardiovascular disease mortality is reduced following smoking cessation but the reversibility of specific atherogenic risk factors such as endothelial dysfunction is less established. We assessed brachial artery flow-mediated dilation (FMD) in 57 chronic smokers and 15 healthy controls, alone and after oral tetrahydrobiopterin (BH4) administration, to assess the extent to which reduced bioactivity of BH4, a cofactor for the endothelial nitric oxide synthase enzyme (eNOS), contributes to smoking-associated reductions in FMD. Thirty-four smokers then ceased cigarette and nicotine use for 1 week, after which FMD (±BH4 administration) was repeated. Brachial artery FMD was calculated as the peak dilatory response observed relative to baseline (%FMD). Endothelium-independent dilation was assessed by measuring the dilatory response to sublingual nitroglycerin (%NTG). Chronic smokers exhibited reduced %FMD relative to controls: (5.6±3.0% vs. 8.1±3.7%; P<0.01) and %NTG was not different b...
Multiple epidemiological studies document that habitual physical activity reduces the risk of ath... more Multiple epidemiological studies document that habitual physical activity reduces the risk of atherosclerotic cardiovascular disease (ASCVD), and most demonstrate progressively lower rates of ASCVD with progressively more physical activity. Few studies have included individuals performing high-intensity, lifelong endurance exercise, however, and recent reports suggest that prodigious amounts of exercise may increase markers for, and even the incidence of, cardiovascular disease. This review examines the evidence that extremes of endurance exercise may increase cardiovascular disease risk by reviewing the causes and incidence of exercise-related cardiac events, and the acute effects of exercise on cardiovascular function, the effect of exercise on cardiac biomarkers, including "myocardial" creatine kinase, cardiac troponins, and cardiac natriuretic peptides. This review also examines the effect of exercise on coronary atherosclerosis and calcification, the frequency of atri...
Statins are the accepted standard for lowering low-density lipoprotein cholesterol (LDL-C). Howev... more Statins are the accepted standard for lowering low-density lipoprotein cholesterol (LDL-C). However, 5% to 10% of statin-treated patients report intolerance, mostly due to muscle-related adverse effects. Challenges exist to objective identification of statin-intolerant patients. Evolocumab is a monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in marked LDL-C reduction. We report the design of Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3 (GAUSS-3), a phase 3, multicenter, randomized, double-blind, ezetimibe-controlled study to compare effectiveness of 24 weeks of evolocumab 420 mg monthly vs ezetimibe 10 mg daily in hypercholesterolemic patients unable to tolerate an effective statin dose. The study incorporates a novel atorvastatin-controlled, double-blind, crossover phase to objectively identify statin intolerance. Eligible patients had LDL-C above the National Cholesterol Education Project Ad...
The results of mitral valve repair operations conducted at community hospitals in rural states ar... more The results of mitral valve repair operations conducted at community hospitals in rural states are not well studied or reported in the literature. We retrospectively assessed consecutive patients who underwent isolated mitral valve repair operations performed by a single experienced cardiothoracic surgeon at a large community hospital from May 1, 2006 - April 30, 2010. Patients were monitored for up to three years (average 2.2 years) following surgery for a variety of surgical variables, including morbidity, mortality, and serial two-dimensional transthoracic echocardiographic findings. Comparisons were made with the Society of Thoracic Surgeons Adult Cardiac Surgery Database (ACSD). Sixty-three consecutive patients underwent isolated complex mitral repair operations. Echocardiographic and morbidity data demonstrated successful outcomes, with no operative mortality and a single cardiac-related death within three years postoperatively. Other variables, especially those that relate to post-repair outcomes, showed no significant differences between our patients and comparison data from the ASCD. Our study demonstrates equivalent risks and outcomes for complex mitral valve repair performed in a community hospital setting as those found in a national database. The appropriate institutional setting for performing highly complex procedures has substantial implications for health policy, especially regarding access and quality issues.
The goal was to examine lipoprotein subclass responses to regular exercise as measured in 10 exer... more The goal was to examine lipoprotein subclass responses to regular exercise as measured in 10 exercise interventions derived from six cohorts. Nuclear magnetic resonance spectroscopy was used to quantify average particle size, total and subclass concentrations of very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein particles (VLDL-P, LDL-P, and HDL-P, respectively) before and after an exercise intervention in 1555 adults from six studies, encompassing 10 distinct exercise programs: APOE (N = 106), DREW (N = 385), GERS (N = 79), HERITAGE (N = 715), STRRIDE I (N = 168) and II (N = 102). Random-effects meta-analyses were performed to evaluate the overall estimate of mean change across the unadjusted and adjusted mean change values from each exercise group. Meta-analysis of unadjusted data showed that regular exercise induced significant decreases in the concentration of large VLDL-P, small LDL-P, and medium HDL-P and mean VLDL-P size, with significant incr...
Meta-analysis of genome-wide association studies identified obesity-related genetic variants. Due... more Meta-analysis of genome-wide association studies identified obesity-related genetic variants. Due to the pleiotropic effects of related phenotypes, we tested six of these obesity-related genetic variants for their association with physical activity: fat mass and obesity-associated (FTO)(rs9939609)T>A, potassium channel tetramerization domain containing (KCTD15) (rs11084753)G>A, melanocortin receptor4 (MC4R)(rs17782313)T>C, neuronal growth regulator 1 (NEGR1)(rs2815752)A>G, SH2B adapter protein 1 (SH2B1)(rs7498665)A>G, and transmembrane protein18 (TMEM18)(rs6548238)C>T. European-American women (n = 263) and men (n = 229) (23.5 ± 0.3 years, 24.6 ± 0.2 kg/m(2)) were genotyped and completed the Paffenbarger physical activity Questionnaire. Physical activity volume in metabolic energy equivalents [MET]-hour/week was derived from the summed time spent (hour/week) times the given MET value for vigorous, moderate, and light intensity physical activity, and sitting and slee...
Statins exacerbate exercise-induced skeletal muscle injury. Muscle-specific microRNAs (myomiRs) i... more Statins exacerbate exercise-induced skeletal muscle injury. Muscle-specific microRNAs (myomiRs) increase in plasma after prolonged exercise, but the patterns of myomiRs release after statin-associated muscle injury have not been examined. We examined the relationships between statin exposure, in vitro and in vivo muscle contraction, and expression of candidate circulating myomiRs. We measured plasma levels of myomiRs, circulating microRNA-1 (c-miR-1), c-miR-133a, c-miR-206 and c-miR-499-5p, from 28 statin-using and 28 non-statin using runners before (PRE), immediately after (FINISH), and 24 hours after they ran a 42 km footrace (the 2011 Boston marathon) (POST-24). To examine the cellular regulation myomiRs, we used contracting mouse C2C12 myotubes in culture with and without statin exposure to compare intracellular and extracellular expression of these molecules. In marathoners, c-miR-1, c-miR-133a, and c-miR-206 increased at FINISH, returned to baseline at POST-24, and were unaffected by statin use. In contrast, c-miR-499-5p was unchanged at FINISH but increased at POST-24 among statin users compared to PRE and to runners not taking statins. In cultured C2C12 myotubes, extracellular miR-1, 133a, and 206 were increased significantly by muscle contraction regardless of statin use. In contrast, extracellular miR-499-5p was unaffected by either isolated statin exposure or isolated carbachol exposure but increased when muscle contraction was combined with statin exposure. In sum, we found that statin-potentiated muscle injury during exercise is accompanied by augmented extracellular release of miR-499-5p. Thus, c-miR-499-5p may serve as a biomarker of statin-potentiated muscle damage.
The Journal of steroid biochemistry and molecular biology, Jan 8, 2016
Age, apolipoprotein E ε4 (APOE) and chromosomal sex are well-established risk factors for late-on... more Age, apolipoprotein E ε4 (APOE) and chromosomal sex are well-established risk factors for late-onset Alzheimer's disease (LOAD; AD). Over 60% of persons with AD harbor at least one APOE-ε4 allele. The sex-based prevalence of AD is well documented with over 60% of persons with AD being female. Evidence indicates that the APOE-ε4 risk for AD is greater in women than men, which is particularly evident in heterozygous women carrying one APOE-ε4 allele. Paradoxically, men homozygous for APOE-ε4 are reported to be at greater risk for mild cognitive impairment and AD. Herein, we discuss the complex interplay between the three greatest risk factors for Alzheimer's disease, age, APOE-ε4 genotype and female sex. We propose that the convergence of these three risk factors, and specifically the bioenergetic aging perimenopause to menopause transition unique to the female, creates a risk profile for AD unique to the female. Further, we discuss the unique risk of the APOE4 positive male w...
To determine whether decreases in exercise 1) were greater in individuals who were diagnosed as h... more To determine whether decreases in exercise 1) were greater in individuals who were diagnosed as having hypercholesterolemia than in those without the diagnosis during follow-up and 2) were greater in incident hypercholesterolemic participants starting statins than in those not treated with cholesterol-lowering medications. Regression analyses of changes since baseline (Δ) in exercise vs diagnosis of hypercholesterolemia and its treatment in 66,377 runners and 12,031 walkers not using cholesterol medications at baseline who were resurveyed during the National Runners' and Walkers' Health Study follow-up (January 1, 1991, through December 31, 2006). A total of 3510 runners began statin treatment, 1779 began other or unspecified cholesterol-lowering drug treatment, and 2583 had untreated hypercholesterolemia; 58,505 runners remained nonhypercholesterolemic controls during the mean 7.2-year follow-up. Usual distance run decreased significantly more in hypercholesterolemic runner...
Introduction. Vitamin D deficiency is associated with the onset and progression of hypertension a... more Introduction. Vitamin D deficiency is associated with the onset and progression of hypertension and cardiovascular disease (CVD). However, mechanisms underlying vitamin D deficiency-mediated increased risk of CVD remain unknown. We sought to examine the differential effect of high-dose versus low-dose vitamin D supplementation on markers of arterial stiffness among ~40 vitamin D deficient adults with prehypertension. Methods. Participants were randomized to high-dose (4000 IU/d) versus low-dose (400 IU/d) oral vitamin D3 for 6 months. 24 hr ambulatory blood pressure (BP), carotid-femoral pulse wave velocity, and pulse wave analyses were obtained at baseline and after 6 months of vitamin D supplementation. Results. There were no changes in resting BP or pulse wave velocity over 6 mo regardless of vitamin D dose (all p…
Amyloid imaging plays an important role in the research and diagnosis of dementing disorders. Sub... more Amyloid imaging plays an important role in the research and diagnosis of dementing disorders. Substantial variation in quantitative methods to measure brain amyloid burden exists in the field. The aim of this work is to investigate the impact of methodological variations to the quantification of amyloid burden using data from the Dominantly Inherited Alzheimer's Network (DIAN), an autosomal dominant Alzheimer's disease population. Cross-sectional and longitudinal [11C]-Pittsburgh Compound B (PiB) PET imaging data from the DIAN study were analyzed. Four candidate reference regions were investigated for estimation of brain amyloid burden. A regional spread function based technique was also investigated for the correction of partial volume effects. Cerebellar cortex, brain-stem, and white matter regions all had stable tracer retention during the course of disease. Partial volume correction consistently improves sensitivity to group differences and longitudinal changes over time...
The aim of this study is to investigate the genetic influence on the cerebral cortex, based on th... more The aim of this study is to investigate the genetic influence on the cerebral cortex, based on the analyses of heritability and genetic correlation between grey matter (GM) thickness, derived from structural MR images (sMRI), and associated white matter (WM) connections obtained from diffusion MRI (dMRI). We measured on sMRI the cortical thickness (CT) from a large twin imaging cohort using a surface-based approach (N = 308, average age 22.8 ± 2.3 SD). An ACE model was employed to compute the heritability of CT. WM connections were estimated based on probabilistic tractography using fiber orientation distributions (FOD) from dMRI. We then fitted the ACE model to estimate the heritability of CT and FOD peak measures along WM fiber tracts. The WM fiber tracts where genetic influence was detected were mapped onto the cortical surface. Bivariate genetic modeling was performed to estimate the cross-trait genetic correlation between the CT and the FOD-based connectivity of the tracts asso...
Background. The p-curve is a plot of the distribution of p-values reported in a set of scientific... more Background. The p-curve is a plot of the distribution of p-values reported in a set of scientific studies. Comparisons between ranges of p-values have been used to evaluate fields of research in terms of the extent to which studies have genuine evidential value, and the extent to which they suffer from bias in the selection of variables and analyses for publication, p-hacking. Methods. p-hacking can take various forms. Here we used R code to simulate the use of ghost variables, where an experimenter gathers data on several dependent variables but reports only those with statistically significant effects. We also examined a text-mined dataset used by Head et al. (2015) and assessed its suitability for investigating p-hacking. Results. We show that when there is ghost p-hacking, the shape of the p-curve depends on whether dependent variables are intercorrelated. For uncorrelated variables, simulated p-hacked data do not give the "p-hacking bump" just below .05 that is regard...
Glucocorticoid receptor (NR3C1) polymorphisms associate with obesity, muscle strength, and cortis... more Glucocorticoid receptor (NR3C1) polymorphisms associate with obesity, muscle strength, and cortisol sensitivity. We examined associations among four NR3C1 polymorphisms and the muscle response to resistance training (RT). European-American adults (n = 602, 23.8±0.4yr) completed a 12 week unilateral arm RT program. Maximum voluntary contraction (MVC) assessed isometric strength (kg) and MRI assessed biceps size (cm2) pre- and post-resistance training. Subjects were genotyped for NR3C1 -2722G>A, -1887G>A, -1017T>C, and +363A>G. Men carrying the -2722G allele gained less relative MVC (17.3±1.2vs33.5±6.1%) (p = 0.010) than AA homozygotes; men with -1887GG gained greater relative MVC than A allele carriers (19.6±1.4vs13.2±2.3%) (p = 0.016). Women carrying the -1017T allele gained greater relative size (18.7±0.5vs16.1±0.9%) (p = 0.016) than CC homozygotes. We found sex-specific NR3C1 associations with the muscle strength and size response to RT. Future studies should investiga...
Reduction in hippocampal and amygdala volume measured via structural magnetic resonance imaging i... more Reduction in hippocampal and amygdala volume measured via structural magnetic resonance imaging is an early marker of Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD). Whether genetic risk factors for AD exert an effect on these subcortical structures independent of clinical status has not been fully investigated. We examine whether increased genetic risk for AD influences hippocampal and amygdala volumes in case-control and population cohorts at different ages, in 1674 older (aged &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;53 years; 17% AD, 39% mild cognitive impairment [MCI]) and 467 young (16-30 years) adults. An AD polygenic risk score combining common risk variants excluding apolipoprotein E (APOE), and a single nucleotide polymorphism in TREM2, were both associated with reduced hippocampal volume in healthy older adults and those with MCI. APOE ε4 was associated with hippocampal and amygdala volume in those with AD and MCI but was not associated in healthy older adults. No associations were found in young adults. Genetic risk for AD affects the hippocampus before the clinical symptoms of AD, reflecting a neurodegenerative effect before clinical manifestations in older adults.
Broad indications for the use of statin medications are resulting in more patients using these th... more Broad indications for the use of statin medications are resulting in more patients using these therapies. Simultaneously, healthcare professionals are strongly advocating recommendations to increase exercise training (ET) as a means of decreasing cardiovascular disease (CVD) risk and improving other parameters of fitness. We review the literature to explore mechanisms that may increase the risk of statin/ET interactions, examine the benefits and risks of combining ET and statin use, and offer strategies to minimize the hazards of this combination therapy. The combined use of statins and ET can result in health gains and decreased CVD risk; however, multiple factors may increase the risk of adverse events. Some of the events that have been reported with the combination of statins and ET include decreased athletic performance, muscle injury, myalgia, joint problems, decreased muscle strength, and fatigue. The type of statin, the dose, drug interactions, genetic variants, coenzyme Q10 ...
Physically active adults may be especially vulnerable to the adverse muscular side effects of sta... more Physically active adults may be especially vulnerable to the adverse muscular side effects of statins. We determined if short-term cessation of statin therapy would improve aerobic exercise performance in middle-aged adults engaged in regular aerobic exercise training. Physically active middle-aged adults on statin therapy ≥6 mo (n = 16; 58 ± 10 y) or not taking lipid-lowering medications (controls) (n = 19; 51 ± 9 y) completed a peak oxygen consumption (VO2peak) and time to exhaustion test on a cycle ergometer 2-7 d apart. Tests were repeated following 1 mo of statin cessation or a 1 mo period for controls. Questionnaires were administered to assess exercise history and muscle complaints. Statin users reported little or no muscle complaints and participation in aerobic exercise was similar between groups (p≥0.13). The lower VO2peak (37.3 ± 9.0 vs. 43.1 ± 4.9 ml/kg/min; p = 0.02) and time to exhaustion (21.9 ± 4.4 vs. 26.0 ± 6.3 min; p = 0.04) in statin users versus controls did not...
Hypertension research : official journal of the Japanese Society of Hypertension, Jan 26, 2015
Cardiovascular disease mortality is reduced following smoking cessation but the reversibility of ... more Cardiovascular disease mortality is reduced following smoking cessation but the reversibility of specific atherogenic risk factors such as endothelial dysfunction is less established. We assessed brachial artery flow-mediated dilation (FMD) in 57 chronic smokers and 15 healthy controls, alone and after oral tetrahydrobiopterin (BH4) administration, to assess the extent to which reduced bioactivity of BH4, a cofactor for the endothelial nitric oxide synthase enzyme (eNOS), contributes to smoking-associated reductions in FMD. Thirty-four smokers then ceased cigarette and nicotine use for 1 week, after which FMD (±BH4 administration) was repeated. Brachial artery FMD was calculated as the peak dilatory response observed relative to baseline (%FMD). Endothelium-independent dilation was assessed by measuring the dilatory response to sublingual nitroglycerin (%NTG). Chronic smokers exhibited reduced %FMD relative to controls: (5.6±3.0% vs. 8.1±3.7%; P<0.01) and %NTG was not different b...
Multiple epidemiological studies document that habitual physical activity reduces the risk of ath... more Multiple epidemiological studies document that habitual physical activity reduces the risk of atherosclerotic cardiovascular disease (ASCVD), and most demonstrate progressively lower rates of ASCVD with progressively more physical activity. Few studies have included individuals performing high-intensity, lifelong endurance exercise, however, and recent reports suggest that prodigious amounts of exercise may increase markers for, and even the incidence of, cardiovascular disease. This review examines the evidence that extremes of endurance exercise may increase cardiovascular disease risk by reviewing the causes and incidence of exercise-related cardiac events, and the acute effects of exercise on cardiovascular function, the effect of exercise on cardiac biomarkers, including "myocardial" creatine kinase, cardiac troponins, and cardiac natriuretic peptides. This review also examines the effect of exercise on coronary atherosclerosis and calcification, the frequency of atri...
Statins are the accepted standard for lowering low-density lipoprotein cholesterol (LDL-C). Howev... more Statins are the accepted standard for lowering low-density lipoprotein cholesterol (LDL-C). However, 5% to 10% of statin-treated patients report intolerance, mostly due to muscle-related adverse effects. Challenges exist to objective identification of statin-intolerant patients. Evolocumab is a monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in marked LDL-C reduction. We report the design of Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3 (GAUSS-3), a phase 3, multicenter, randomized, double-blind, ezetimibe-controlled study to compare effectiveness of 24 weeks of evolocumab 420 mg monthly vs ezetimibe 10 mg daily in hypercholesterolemic patients unable to tolerate an effective statin dose. The study incorporates a novel atorvastatin-controlled, double-blind, crossover phase to objectively identify statin intolerance. Eligible patients had LDL-C above the National Cholesterol Education Project Ad...
The results of mitral valve repair operations conducted at community hospitals in rural states ar... more The results of mitral valve repair operations conducted at community hospitals in rural states are not well studied or reported in the literature. We retrospectively assessed consecutive patients who underwent isolated mitral valve repair operations performed by a single experienced cardiothoracic surgeon at a large community hospital from May 1, 2006 - April 30, 2010. Patients were monitored for up to three years (average 2.2 years) following surgery for a variety of surgical variables, including morbidity, mortality, and serial two-dimensional transthoracic echocardiographic findings. Comparisons were made with the Society of Thoracic Surgeons Adult Cardiac Surgery Database (ACSD). Sixty-three consecutive patients underwent isolated complex mitral repair operations. Echocardiographic and morbidity data demonstrated successful outcomes, with no operative mortality and a single cardiac-related death within three years postoperatively. Other variables, especially those that relate to post-repair outcomes, showed no significant differences between our patients and comparison data from the ASCD. Our study demonstrates equivalent risks and outcomes for complex mitral valve repair performed in a community hospital setting as those found in a national database. The appropriate institutional setting for performing highly complex procedures has substantial implications for health policy, especially regarding access and quality issues.
The goal was to examine lipoprotein subclass responses to regular exercise as measured in 10 exer... more The goal was to examine lipoprotein subclass responses to regular exercise as measured in 10 exercise interventions derived from six cohorts. Nuclear magnetic resonance spectroscopy was used to quantify average particle size, total and subclass concentrations of very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein particles (VLDL-P, LDL-P, and HDL-P, respectively) before and after an exercise intervention in 1555 adults from six studies, encompassing 10 distinct exercise programs: APOE (N = 106), DREW (N = 385), GERS (N = 79), HERITAGE (N = 715), STRRIDE I (N = 168) and II (N = 102). Random-effects meta-analyses were performed to evaluate the overall estimate of mean change across the unadjusted and adjusted mean change values from each exercise group. Meta-analysis of unadjusted data showed that regular exercise induced significant decreases in the concentration of large VLDL-P, small LDL-P, and medium HDL-P and mean VLDL-P size, with significant incr...
Meta-analysis of genome-wide association studies identified obesity-related genetic variants. Due... more Meta-analysis of genome-wide association studies identified obesity-related genetic variants. Due to the pleiotropic effects of related phenotypes, we tested six of these obesity-related genetic variants for their association with physical activity: fat mass and obesity-associated (FTO)(rs9939609)T>A, potassium channel tetramerization domain containing (KCTD15) (rs11084753)G>A, melanocortin receptor4 (MC4R)(rs17782313)T>C, neuronal growth regulator 1 (NEGR1)(rs2815752)A>G, SH2B adapter protein 1 (SH2B1)(rs7498665)A>G, and transmembrane protein18 (TMEM18)(rs6548238)C>T. European-American women (n = 263) and men (n = 229) (23.5 ± 0.3 years, 24.6 ± 0.2 kg/m(2)) were genotyped and completed the Paffenbarger physical activity Questionnaire. Physical activity volume in metabolic energy equivalents [MET]-hour/week was derived from the summed time spent (hour/week) times the given MET value for vigorous, moderate, and light intensity physical activity, and sitting and slee...
Statins exacerbate exercise-induced skeletal muscle injury. Muscle-specific microRNAs (myomiRs) i... more Statins exacerbate exercise-induced skeletal muscle injury. Muscle-specific microRNAs (myomiRs) increase in plasma after prolonged exercise, but the patterns of myomiRs release after statin-associated muscle injury have not been examined. We examined the relationships between statin exposure, in vitro and in vivo muscle contraction, and expression of candidate circulating myomiRs. We measured plasma levels of myomiRs, circulating microRNA-1 (c-miR-1), c-miR-133a, c-miR-206 and c-miR-499-5p, from 28 statin-using and 28 non-statin using runners before (PRE), immediately after (FINISH), and 24 hours after they ran a 42 km footrace (the 2011 Boston marathon) (POST-24). To examine the cellular regulation myomiRs, we used contracting mouse C2C12 myotubes in culture with and without statin exposure to compare intracellular and extracellular expression of these molecules. In marathoners, c-miR-1, c-miR-133a, and c-miR-206 increased at FINISH, returned to baseline at POST-24, and were unaffected by statin use. In contrast, c-miR-499-5p was unchanged at FINISH but increased at POST-24 among statin users compared to PRE and to runners not taking statins. In cultured C2C12 myotubes, extracellular miR-1, 133a, and 206 were increased significantly by muscle contraction regardless of statin use. In contrast, extracellular miR-499-5p was unaffected by either isolated statin exposure or isolated carbachol exposure but increased when muscle contraction was combined with statin exposure. In sum, we found that statin-potentiated muscle injury during exercise is accompanied by augmented extracellular release of miR-499-5p. Thus, c-miR-499-5p may serve as a biomarker of statin-potentiated muscle damage.
The Journal of steroid biochemistry and molecular biology, Jan 8, 2016
Age, apolipoprotein E ε4 (APOE) and chromosomal sex are well-established risk factors for late-on... more Age, apolipoprotein E ε4 (APOE) and chromosomal sex are well-established risk factors for late-onset Alzheimer's disease (LOAD; AD). Over 60% of persons with AD harbor at least one APOE-ε4 allele. The sex-based prevalence of AD is well documented with over 60% of persons with AD being female. Evidence indicates that the APOE-ε4 risk for AD is greater in women than men, which is particularly evident in heterozygous women carrying one APOE-ε4 allele. Paradoxically, men homozygous for APOE-ε4 are reported to be at greater risk for mild cognitive impairment and AD. Herein, we discuss the complex interplay between the three greatest risk factors for Alzheimer's disease, age, APOE-ε4 genotype and female sex. We propose that the convergence of these three risk factors, and specifically the bioenergetic aging perimenopause to menopause transition unique to the female, creates a risk profile for AD unique to the female. Further, we discuss the unique risk of the APOE4 positive male w...
To determine whether decreases in exercise 1) were greater in individuals who were diagnosed as h... more To determine whether decreases in exercise 1) were greater in individuals who were diagnosed as having hypercholesterolemia than in those without the diagnosis during follow-up and 2) were greater in incident hypercholesterolemic participants starting statins than in those not treated with cholesterol-lowering medications. Regression analyses of changes since baseline (Δ) in exercise vs diagnosis of hypercholesterolemia and its treatment in 66,377 runners and 12,031 walkers not using cholesterol medications at baseline who were resurveyed during the National Runners' and Walkers' Health Study follow-up (January 1, 1991, through December 31, 2006). A total of 3510 runners began statin treatment, 1779 began other or unspecified cholesterol-lowering drug treatment, and 2583 had untreated hypercholesterolemia; 58,505 runners remained nonhypercholesterolemic controls during the mean 7.2-year follow-up. Usual distance run decreased significantly more in hypercholesterolemic runner...
Introduction. Vitamin D deficiency is associated with the onset and progression of hypertension a... more Introduction. Vitamin D deficiency is associated with the onset and progression of hypertension and cardiovascular disease (CVD). However, mechanisms underlying vitamin D deficiency-mediated increased risk of CVD remain unknown. We sought to examine the differential effect of high-dose versus low-dose vitamin D supplementation on markers of arterial stiffness among ~40 vitamin D deficient adults with prehypertension. Methods. Participants were randomized to high-dose (4000 IU/d) versus low-dose (400 IU/d) oral vitamin D3 for 6 months. 24 hr ambulatory blood pressure (BP), carotid-femoral pulse wave velocity, and pulse wave analyses were obtained at baseline and after 6 months of vitamin D supplementation. Results. There were no changes in resting BP or pulse wave velocity over 6 mo regardless of vitamin D dose (all p…
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