Nina B. Radford

Mice without myoglobin

Myoglobin, an intracellular haemoprotein expressed in the heart and oxidative skeletal myofibres of vertebrates, binds molecular oxygen and may facilitate oxygen transport from erythrocytes to mitochondria, thereby maintaining cellular respiration during periods of high physiological demand. Here we show, however, that mice without myoglobin, generated by gene-knockout technology, are fertile and exhibit normal exercise capacity and a normal ventilatory response to low oxygen levels (hypoxia). Heart and soleus muscles from these animals are depigmented, but function normally in standard assays of muscle performance invitro across a range of work conditions and oxygen availability. These data show that myoglobin is not required to meet the metabolic requirements of pregnancy or exercise in a terrestrial mammal, and raise new questions about oxygen transport and metabolic regulation in working muscles.

Gene targeting in embryonic stem cells: the new physiology and metabolism

Abstract The development of transgenic technology, whereby genes (or mutations) can be stably introduced into the germline of experimental mammals, now allows investigators to create mice of virtually any genotype and to assess the consequences of these mutations in the context of a developing and intact mammal. In contrast to traditional ”gain-of-function” mutations, typically created by microinjection of the gene of interest into the one-celled zygote, gene targeting via homologous recombination in pluripotential embryonic stem cells allows one to modify precisely the gene of interest. The purpose of this review is to introduce the reader to the history of development of embryonic stem cell technology, the current methods employed to create ”knock-out” mice, and the application of these methods to solve problems in biology. While the technology promises to provide enormous insight into mammalian development genetics, our desire is that this review will stimulate the application of gene targeting in embryonic stem cells to begin to unravel problems in complex regulatory pathways, specifically intermediary metabolism and physiology.

Cardiorespiratory Fitness and Long‐Term Survival in “Low‐Risk” Adults

Background We sought to establish whether cardiorespiratory fitness had important implications for long-term cardiovascular risk among individuals classified as low risk by the Framingham Risk Score (10-year coronary heart disease risk <10%). Prognostic factors of long-term cardiovascular risk are needed for low-risk subjects who make up the largest percentage of the US population. Methods and Results The study population was composed of men and women, 30 to 50 years of age, who had a baseline medical exam at the Cooper Clinic, Dallas, TX, between 1970 and 1983. Eligible individuals were defined as at low risk for coronary heart disease by Framingham Risk Score at the time of study entry and had no history of diabetes (n=11 190). Cardiorespiratory fitness was determined by maximum graded exercise treadmill tests. Over an average 27±2-year period, 15% of low-fit (quintile 1) compared to 6% of high-fit (quintile 5) individuals died (P<0.001). A 1–metabolic equivalent level increase in baseline fitness was associated with an 11% reduction in all-cause deaths and an 18% reduction in deaths due to cardiovascular disease (CVD) after adjustment for age, sex, body mass index, systolic blood pressure, total cholesterol, blood glucose levels, smoking, and early family history of coronary disease. There was an incremental decrease in CVD risk with increasing fitness quintile, such that the high fit had the lowest adjusted 30-year CVD mortality rate (hazard ratio 0.29, 95% CI: 0.16–0.51) compared to the low fit. Conclusions Cardiorespiratory fitness is associated with a significant reduction in long-term CVD among individuals identified as low risk by Framingham Risk Score. These data suggest that preventive lifestyle interventions geared to optimize cardiorespiratory fitness, even among a “low-risk” subset, should be considered to improve CVD-free survival. (J Am Heart Assoc. 2012;1:e001354 doi: 10.1161/JAHA.112.001354.)

Midlife Cardiorespiratory Fitness, Incident Cancer, and Survival After Cancer in Men: The Cooper Center Longitudinal Study

IMPORTANCE Cardiorespiratory fitness (CRF) as assessed by formalized incremental exercise testing is an independent predictor of numerous chronic diseases, but its association with incident cancer or survival following a diagnosis of cancer has received little attention. OBJECTIVE To assess the association between midlife CRF and incident cancer and survival following a cancer diagnosis. DESIGN, SETTING, AND PARTICIPANTS This was a prospective, observational cohort study conducted at a preventive medicine clinic. The study included 13 949 community-dwelling men who had a baseline fitness examination. All men completed a comprehensive medical examination, a cardiovascular risk factor assessment, and incremental treadmill exercise test to evaluate CRF. We used age- and sex-specific distribution of treadmill duration from the overall Cooper Center Longitudinal Study population to define fitness groups as those with low (lowest 20%), moderate (middle 40%), and high (upper 40%) CRF groups. The adjusted multivariable model included age, examination year, body mass index, smoking, total cholesterol level, systolic blood pressure, diabetes mellitus, and fasting glucose level. Cardiorespiratory fitness levels were assessed between 1971 and 2009, and incident lung, prostate, and colorectal cancer using Medicare Parts A and B claims data from 1999 to 2009; the analysis was conducted in 2014. MAIN OUTCOMES AND MEASURES The main outcomes were (1) incident prostate, lung, and colorectal cancer and (2) all-cause mortality and cause-specific mortality among men who developed cancer at Medicare age (≥65 years). RESULTS Compared with men with low CRF, the adjusted hazard ratios (HRs) for incident lung, colorectal, and prostate cancers among men with high CRF were 0.45 (95% CI, 0.29-0.68), 0.56 (95% CI, 0.36-0.87), and 1.22 (95% CI, 1.02-1.46), respectively. Among those diagnosed as having cancer at Medicare age, high CRF in midlife was associated with an adjusted 32% (HR, 0.68; 95% CI, 0.47-0.98) risk reduction in all cancer-related deaths and a 68% reduction in cardiovascular disease mortality following a cancer diagnosis (HR, 0.32; 95% CI, 0.16-0.64) compared with men with low CRF in midlife. CONCLUSIONS AND RELEVANCE There is an inverse association between midlife CRF and incident lung and colorectal cancer but not prostate cancer. High midlife CRF is associated with lower risk of cause-specific mortality in those diagnosed as having cancer at Medicare age.

Association of a Favorable Cardiovascular Health Profile With the Presence of Coronary Artery Calcification

Background—To examine the association between the American Heart Association’s 7 metrics of ideal cardiovascular health (ICH) and the presence of subclinical coronary atherosclerosis as assessed by coronary artery calcification (CAC) using electron-beam computed tomography. Methods and Results—This study is a cross-sectional analysis of data obtained on 3121 male and female patients evaluated at the Cooper Clinic in Dallas, Texas, between 1997 and 2007. We included men aged ≥45 and women aged ≥55 without known cardiovascular disease and for whom information on all ICH metrics and a CAC score were available. Patients were grouped into 3 categories according to their number of ICH metrics: favorable (4–7 ICH metrics), intermediate (3 metrics), and unfavorable (0–2 metrics). Patients with favorable ICH profiles had a lower prevalence and severity of subclinical atherosclerosis than those with unfavorable or intermediate ICH profiles as estimated by CAC. This inverse association of CAC with ICH metrics was evident whether the presence of coronary calcium was defined as CAC score >0, CAC score >100, or CAC score >400. Patients with favorable ICH profiles had odds of coronary calcium (CAC>0) less than half of those for patients with unfavorable profiles (odds ratio 0.41; 95% confidence interval, 0.34–0.50) and patients with intermediate ICH profiles had odds of detectable CAC 32% lower (odds ratio 0.68; 95% confidence interval, 0.57–0.82). Conclusions—A statistically significant association was found between a favorable level of ICH metrics and less or absent subclinical atherosclerosis as measured by CAC underscoring the importance of primordial prevention.

Cardiorespiratory Fitness, Body Mass Index, and Heart Failure Mortality in Men: Cooper Center Longitudinal Study

Background—We evaluated the individual and joint associations among cardiorespiratory fitness (CRF), body mass index, and heart failure (HF) mortality, as well as the additive effect of an increasing number of cardiovascular risk factors on HF mortality in fit versus unfit men. Methods and Results—A total of 44 674 men without a history of cardiovascular disease underwent a baseline examination between 1971 and 2010. Measures included body mass index and CRF quantified as duration of maximal treadmill exercise testing. Participants were divided into age-specific low, moderate, and high CRF categories. Hazard ratios were computed with Cox regression analysis. During a mean follow-up of 19.8±10.4 years, 153 HF deaths occurred. Adjusted hazard ratios across high, moderate, and low CRF categories were 1.0, 1.63, and 3.97, respectively, whereas those of normal, overweight, and obese body mass index categories were 1.0, 1.56, and 3.71, respectively (P for trend <0.0001 for each). When grouped into categories of fit and unfit (upper 80% and lower 20% of CRF distribution, respectively), hazard ratios were significantly lower in fit compared with unfit men in normal and overweight body mass index strata (P<0.002) but not in obese men. Within men matched for the same number of HF risk factors, fit men had significantly lower HF mortality than unfit men (P⩽0.02). Conclusions—Higher baseline CRF is associated with lower HF mortality risk in men, regardless of the number of HF risk factors present. Men should be counseled on physical activity with the goal of achieving at least a moderate level of CRF, thereby presumably decreasing their risk of HF mortality.

Protecting the heart of the American Athlete: Proceedings of the American college of cardiology sports and exercise cardiology think tank October 18, 2012, Washington, DC

Yvette L. Rooks, MD, CAQ, FAAFP[1][1] G. Paul Matherne, MD, FACC[2][2] Jim Whitehead[3][3] Dan Henkel[3][3] Irfan M. Asif, MD[4][4] James C. Dreese, MD[5][5] Rory B. Weiner, MD[6][6] Barbara A. Hutchinson, MD, PhD, FACC[7][7] Linda Tavares, MS, RN, AACC[8][8] Steven Krueger, MD, FACC[9][9

Cardiorespiratory fitness and coronary artery calcification in women.

INTRODUCTION Cardiorespiratory fitness (fitness) has been shown to be inversely associated with coronary heart disease morbidity and mortality. The cardioprotective mechanisms of fitness are not well defined. The goal of this study was to assess the relationship between coronary artery calcification as a measure of atherosclerotic burden and fitness in a large population of generally healthy women. METHODS 5341 women ages 40-90 years seen between 1997 and 2007 underwent maximal treadmill exercise testing and coronary artery calcium (CAC) scanning. Fitness was reported in METs estimated from maximal treadmill time, grade, and speed. CAC was characterized dichotomously as CAC=0 versus CAC>0, and CAC<100 versus CAC≥100. Multiple logistic regression models were used to calculate the adjusted odds ratio of any CAC (CAC>0) and CAC≥100. Fitness was added to these models continuously and categorically based on standard and sample-specific cut-points. RESULTS With a mean age of 52.0 years, the overall prevalence of detectable CAC was 19.9% and CAC≥100 was 6.8%. Univariable analysis showed a modest inverse relationship between fitness and CAC>0 (24% in low fit versus 19% in high fit, p-trend=0.006), with a similar trend observed for CAC≥100. In multivariable models, age adjustment diminished this association and the relationship was no longer statistically significant after adjustment for traditional risk factors. CONCLUSIONS The cardioprotective benefit of fitness does not appear to be mediated by an effect independent of traditional risk factors on the development of calcified coronary atherosclerosis as measured by electron beam tomography.

Cardiovascular Risk Factors and Coronary Atherosclerosis in Retired National Football League Players

A high prevalence of obesity exists in National Football League (NFL) players as determined by body mass index (BMI). It is not established whether increased BMI is associated with a greater prevalence of cardiovascular (CV) risk factors or coronary atherosclerosis in former NFL players than in nonathletes. This study compared CV risk factors and coronary atherosclerosis in retired NFL players to 2 groups of community controls, the population-based Dallas Heart Study and the preventive medicine cohort, the Aerobics Center Longitudinal Study. Retired NFL players (n = 201) were matched for ethnicity, age, and BMI (Aerobics Center Longitudinal Study, age only). CV risk factors were assessed by survey and screening visit. Coronary atherosclerosis was measured by computed tomography as coronary artery calcium (CAC). Compared to population-based controls, retired NFL players had a significantly lower prevalence of diabetes, hypertension, sedentary lifestyle, and metabolic syndrome, yet a higher prevalence of impaired fasting glucose and hyperlipidemia. However, there was no significant difference in the prevalence of detectable CAC (46% vs 48.3%, p = 0.69) or distribution of CAC (0 to 10, 10 to 100, 100 to 400, > or =400, p = 0.11). Comparing retired NFL players to the physically active preventive medicine controls, there was no difference in the amount of CAC. In retired NFL players, age and hyperlipidemia, not body size, were the most significant predictors of CAC. In conclusion, despite their large body size, retired NFL players do not have a greater prevalence of CV risk factors or amount of CAC than community controls.

Disagreement Between Different Definitions of Coronary Artery Calcium Progression.

Progression of coronary artery calcium (CAC) as measured by computed tomography independently predicts coronary heart disease (CHD) events [(1)][1]. Several methods have been proposed to define and quantify CAC progression yet very few studies have compared different CAC progression definitions [(2,