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Publication Record


25-Year Physical Activity Trajectories and Development of Subclinical Coronary Artery Disease as Measured by Coronary Artery Calcium: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.
Laddu DR, Rana JS, Murillo R, Sorel ME, Quesenberry CP, Allen NB, Gabriel KP, Carnethon MR, Liu K, Reis JP, Lloyd-Jones D, Carr JJ, Sidney S
(2017) Mayo Clin Proc 92: 1660-1670
MeSH Terms: Adolescent, Adult, Calcium, Coronary Angiography, Coronary Artery Disease, Coronary Vessels, Disease Progression, Exercise, Exercise Test, Female, Follow-Up Studies, Forecasting, Humans, Incidence, Male, Middle Aged, Prevalence, Risk Assessment, Risk Factors, Tomography, X-Ray Computed, United States, Vascular Calcification, Young Adult
Show Abstract · Added January 10, 2020
OBJECTIVE - To evaluate 25-year physical activity (PA) trajectories from young to middle age and assess associations with the prevalence of coronary artery calcification (CAC).
PATIENTS AND METHODS - This study includes 3175 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study who self-reported PA by questionnaire at 8 follow-up examinations over 25 years (from March 1985-June 1986 through June 2010-May 2011). The presence of CAC (CAC>0) at year 25 was measured using computed tomography. Group-based trajectory modeling was used to identify PA trajectories with increasing age.
RESULTS - We identified 3 distinct PA trajectories: trajectory 1, below PA guidelines (n=1813; 57.1%); trajectory 2, meeting PA guidelines (n=1094; 34.5%); and trajectory 3, 3 times PA guidelines (n=268; 8.4%). Trajectory 3 participants had higher adjusted odds of CAC>0 (adjusted odds ratio [OR], 1.27; 95% CI, 0.95-1.70) vs those in trajectory 1. Stratification by race showed that white participants who engaged in PA 3 times the guidelines had higher odds of developing CAC>0 (OR, 1.80; 95% CI, 1.21-2.67). Further stratification by sex showed higher odds for white males (OR, 1.86; 95% CI, 1.16-2.98), and similar but nonsignificant trends were noted for white females (OR, 1.71; 95% CI, 0.79-3.71). However, no such higher odds of CAC>0 for trajectory 3 were observed for black participants.
CONCLUSION - White individuals who participated in 3 times the recommended PA guidelines over 25 years had higher odds of developing coronary subclinical atherosclerosis by middle age. These findings warrant further exploration, especially by race, into possible biological mechanisms for CAC risk at very high levels of PA.
Copyright © 2017 Mayo Foundation for Medical Education and Research. All rights reserved.
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Submaximal Blood Pressure Responses to Exercise in Young Adulthood and Long-Term Cardiovascular Health.
Shah R, Murthy VL, Colangelo LA, Reis JP, Carr JJ, Sidney S, Siddique J, Lewis CE, Lima JAC, Lewis GD, CARDIA Investigators
(2017) J Am Coll Cardiol 70: 1941-1943
MeSH Terms: Adult, Blood Pressure, Blood Pressure Determination, Cardiovascular Diseases, Exercise, Exercise Test, Female, Humans, Male, Risk Factors, Vascular Calcification, Young Adult
Added January 10, 2020
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Efficacy of Flecainide in the Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia: A Randomized Clinical Trial.
Kannankeril PJ, Moore JP, Cerrone M, Priori SG, Kertesz NJ, Ro PS, Batra AS, Kaufman ES, Fairbrother DL, Saarel EV, Etheridge SP, Kanter RJ, Carboni MP, Dzurik MV, Fountain D, Chen H, Ely EW, Roden DM, Knollmann BC
(2017) JAMA Cardiol 2: 759-766
MeSH Terms: Adolescent, Adrenergic beta-Antagonists, Anti-Arrhythmia Agents, Cross-Over Studies, Death, Sudden, Cardiac, Defibrillators, Implantable, Drug Therapy, Combination, Exercise, Exercise Test, Female, Flecainide, Humans, Male, Maximum Tolerated Dose, Single-Blind Method, Tachycardia, Ventricular, Young Adult
Show Abstract · Added March 24, 2020
Importance - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal genetic arrhythmia syndrome characterized by polymorphic ventricular tachycardia with physical or emotional stress, for which current therapy with β-blockers is incompletely effective. Flecainide acetate directly suppresses sarcoplasmic reticulum calcium release-the cellular mechanism responsible for triggering ventricular arrhythmias in CPVT-but has never been assessed prospectively.
Objective - To determine whether flecainide dosed to therapeutic levels and added to β-blocker therapy is superior to β-blocker therapy alone for the prevention of exercise-induced arrhythmias in CPVT.
Design, Setting, and Participants - This investigator-initiated, multicenter, single-blind, placebo-controlled crossover clinical trial was conducted from December 19, 2011, through December 29, 2015, with a midtrial protocol change at 10 US sites. Patients with a clinical diagnosis of CPVT and an implantable cardioverter-defibrillator underwent a baseline exercise test while receiving maximally tolerated β-blocker therapy that was continued throughout the trial. Patients were then randomized to treatment A (flecainide or placebo) for 3 months, followed by exercise testing. After a 1-week washout period, patients crossed over to treatment B (placebo or flecainide) for 3 months, followed by exercise testing.
Interventions - Patients received oral flecainide or placebo twice daily, with the dosage guided by trough serum levels.
Main Outcomes and Measures - The primary end point of ventricular arrhythmias during exercise was compared between the flecainide and placebo arms. Exercise tests were scored on an ordinal scale of worst ventricular arrhythmia observed (0 indicates no ectopy; 1, isolated premature ventricular beats; 2, bigeminy; 3, couplets; and 4, nonsustained ventricular tachycardia).
Results - Of 14 patients (7 males and 7 females; median age, 16 years [interquartile range, 15.0-22.5 years]) randomized, 13 completed the study. The median baseline exercise test score was 3.0 (range, 0-4), with no difference noted between the baseline and placebo (median, 2.5; range, 0-4) exercise scores. The median ventricular arrhythmia score during exercise was significantly reduced by flecainide (0 [range, 0-2] vs 2.5 [range, 0-4] for placebo; P < .01), with complete suppression observed in 11 of 13 patients (85%). Overall and serious adverse events did not differ between the flecainide and placebo arms.
Conclusions and Relevance - In this randomized clinical trial of patients with CPVT, flecainide plus β-blocker significantly reduced ventricular ectopy during exercise compared with placebo plus β-blocker and β-blocker alone.
Trial Registration - clinicaltrials.gov Identifier: NCT01117454.
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Novel CPVT-Associated Calmodulin Mutation in CALM3 (CALM3-A103V) Activates Arrhythmogenic Ca Waves and Sparks.
Gomez-Hurtado N, Boczek NJ, Kryshtal DO, Johnson CN, Sun J, Nitu FR, Cornea RL, Chazin WJ, Calvert ML, Tester DJ, Ackerman MJ, Knollmann BC
(2016) Circ Arrhythm Electrophysiol 9:
MeSH Terms: Action Potentials, Adult, Animals, Calmodulin, DNA Mutational Analysis, Electrocardiography, Exercise Test, Female, Genotype, Humans, Long QT Syndrome, Male, Mice, Phenotype, Ryanodine, Tachycardia, Ventricular
Show Abstract · Added April 18, 2017
BACKGROUND - Calmodulin (CaM) mutations are associated with severe forms of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT). CaM mutations are found in 13% of genotype-negative long QT syndrome patients, but the prevalence of CaM mutations in genotype-negative CPVT patients is unknown. Here, we identify and characterize CaM mutations in 12 patients with genotype-negative but clinically diagnosed CPVT.
METHODS AND RESULTS - We performed mutational analysis of CALM1, CALM2, and CALM3 gene-coding regions, in vitro measurement of CaM-Ca(2+) (Ca)-binding affinity, ryanodine receptor 2-CaM binding, Ca handling, L-type Ca current, and action potential duration. We identified a novel CaM mutation-A103V-in CALM3 in 1 of 12 patients (8%), a female who experienced episodes of exertion-induced syncope since age 10, had normal QT interval, and displayed ventricular ectopy during stress testing consistent with CPVT. A103V modestly lowered CaM Ca-binding affinity (3-fold reduction versus WT-CaM), but did not alter CaM binding to ryanodine receptor 2. In permeabilized cardiomyocytes, A103V-CaM (100 nmol/L) promoted spontaneous Ca wave and spark activity, a cellular phenotype of ryanodine receptor 2 activation. Even a 1:3 mixture of A103V-CaM:WT-CaM activated Ca waves, demonstrating functional dominance. Compared with long QT syndrome D96V-CaM, A103V-CaM had significantly less effects on L-type Ca current inactivation, did not alter action potential duration, and caused delayed afterdepolarizations and triggered beats in intact cardiomyocytes.
CONCLUSIONS - We discovered a novel CPVT mutation in the CALM3 gene that shares functional characteristics with established CPVT-associated mutations in CALM1. A small proportion of A103V-CaM is sufficient to evoke arrhythmogenic Ca disturbances via ryanodine receptor 2 dysregulation, which explains the autosomal dominant inheritance.
© 2016 American Heart Association, Inc.
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16 MeSH Terms
Association of Fitness in Young Adulthood With Survival and Cardiovascular Risk: The Coronary Artery Risk Development in Young Adults (CARDIA) Study.
Shah RV, Murthy VL, Colangelo LA, Reis J, Venkatesh BA, Sharma R, Abbasi SA, Goff DC, Carr JJ, Rana JS, Terry JG, Bouchard C, Sarzynski MA, Eisman A, Neilan T, Das S, Jerosch-Herold M, Lewis CE, Carnethon M, Lewis GD, Lima JA
(2016) JAMA Intern Med 176: 87-95
MeSH Terms: Adolescent, Adult, Asymptomatic Diseases, Cardiovascular Diseases, Coronary Artery Disease, Exercise Test, Female, Heart Ventricles, Humans, Hypertrophy, Left Ventricular, Longitudinal Studies, Male, Middle Aged, Mortality, Obesity, Physical Fitness, Proportional Hazards Models, Prospective Studies, Tomography, X-Ray Computed, Ultrasonography, United States, Vascular Calcification, Young Adult
Show Abstract · Added September 29, 2016
IMPORTANCE - Although cardiorespiratory fitness (CRF) is prognostic in older adults, the effect of CRF during early adulthood on long-term cardiovascular structure, function, and prognosis is less clear.
OBJECTIVE - To examine whether CRF in young adults is associated with long-term clinical outcome and subclinical cardiovascular disease (CVD).
DESIGN, SETTING, AND PARTICIPANTS - Prospective study of 4872 US adults aged 18 to 30 years who underwent treadmill exercise testing at a baseline study visit from March 25, 1985, to June 7, 1986, and 2472 individuals who underwent a second treadmill test 7 years later. Median follow-up was 26.9 years, with assessment of obesity, left ventricular mass and strain, coronary artery calcification (CAC), and vital status and incident CVD. Follow-up was complete on August 31, 2011, and data were analyzed from recruitment through the end of follow-up.
MAIN OUTCOMES AND MEASURES - The presence of CAC was assessed by computed tomography at years 15 (2000-2001), 20 (2005-2006), and 25 (2010-2011), and left ventricular mass was assessed at years 5 (1990-1991) and 25 (with global longitudinal strain). Incident CVD and all-cause mortality were adjudicated.
RESULTS - Of the 4872 individuals, 273 (5.6%) died and 193 (4.0%) experienced CVD events during follow-up. After comprehensive adjustment, each additional minute of baseline exercise test duration was associated with a 15% lower hazard of death (hazard ratio [HR], 0.85; 95% CI, 0.80-0.91; P < .001) and a 12% lower hazard of CVD (HR, 0.88; 95% CI, 0.81-0.96; P = .002). Higher levels of baseline CRF were associated with significantly lower left ventricular mass index (β = -0.24; 95% CI, -0.45 to -0.03; P = .02) and significantly better lobal longitudinal strain (β = -0.09; 95% CI, -0.14 to -0.05; P < .001) at year 25. Fitness was not associated with CAC. A 1-minute reduction in fitness by year 7 was associated with 21% and 20% increased hazards of death (HR, 1.21; 95% CI, 1.07-1.37; P = .002) and CVD (HR, 1.20; 95% CI, 1.06-1.37; P = .006), respectively, along with a more impaired strain (β = 0.15; 95% CI, 0.08-0.23; P < .001). No association between change in fitness and CAC was found.
CONCLUSIONS AND RELEVANCE - Higher levels of fitness at baseline and improvement in fitness early in adulthood are favorably associated with lower risks for CVD and mortality. Fitness and changes in fitness are associated with myocardial hypertrophy and dysfunction but not CAC. Regular efforts to ascertain and improve CRF in young adulthood may play a critical role in promoting cardiovascular health and interrupting early CVD pathogenesis.
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23 MeSH Terms
The effect of social integration on outcomes after major lower extremity amputation.
Hawkins AT, Pallangyo AJ, Herman AM, Schaumeier MJ, Smith AD, Hevelone ND, Crandell DM, Nguyen LL
(2016) J Vasc Surg 63: 154-62
MeSH Terms: Adult, Aged, Aged, 80 and over, Amputation, Amputees, Boston, Chi-Square Distribution, Cross-Sectional Studies, Exercise Test, Female, Humans, Linear Models, Lower Extremity, Male, Middle Aged, Mobility Limitation, Multivariate Analysis, Quality of Life, Recovery of Function, Risk Factors, Social Behavior, Social Support, Surveys and Questionnaires, Tanzania, Treatment Outcome, Walking, Young Adult
Show Abstract · Added September 27, 2016
OBJECTIVE - Major lower extremity (MLE) amputation is a common procedure that results in a profound change in a patient's life. We sought to determine the association between social support and outcomes after amputation. We hypothesized that patients with greater social support will have better post amputation outcomes.
METHODS - From November 2011 to May 2013, we conducted a cross-sectional, observational, multicenter study. Social integration was measured by the social integration subset of the Short Form Craig Handicap Assessment and Reporting Technique. Systemic social support was assessed by comparing a United States and Tanzanian population. Walking function was measured using the 6-minute walk test and quality of life (QoL) was measured using the EuroQol-5D.
RESULTS - We recruited 102 MLE amputees. Sixty-three patients were enrolled in the United States with a mean age of 58.0. Forty-two (67%) were male. Patients with low social integration were more likely to be unable to ambulate (no walk 39% vs slow walk 23% vs fast walk 10%; P = .01) and those with high social integration were more likely to be fast walkers (no walk 10% vs slow walk 59% vs fast walk 74%; P = .01). This relationship persisted in a multivariable analysis. Increasing social integration scores were also positively associated with increasing QoL scores in a multivariable analysis (β, .002; standard error, 0.0008; P = .02). In comparing the United States population with the Tanzanian cohort (39 subjects), there were no differences between functional or QoL outcomes in the systemic social support analysis.
CONCLUSIONS - In the United States population, increased social integration is associated with both improved function and QoL outcomes among MLE amputees. Systemic social support, as measured by comparing the United States population with a Tanzanian population, was not associated with improved function or QoL outcomes. In the United States, steps should be taken to identify and aid amputees with poor social integration.
Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.
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27 MeSH Terms
The effect of age and microstructural white matter integrity on lap time variation and fast-paced walking speed.
Tian Q, Ferrucci L, Resnick SM, Simonsick EM, Shardell MD, Landman BA, Venkatraman VK, Gonzalez CE, Studenski SA
(2016) Brain Imaging Behav 10: 697-706
MeSH Terms: Aged, Aging, Baltimore, Brain, Diffusion Tensor Imaging, Exercise Test, Female, Humans, Linear Models, Male, Middle Aged, Walking Speed, White Matter
Show Abstract · Added February 15, 2016
Macrostructural white matter damage (WMD) is associated with less uniform and slower walking in older adults. The effect of age and subclinical microstructural WM degeneration (a potentially earlier phase of WM ischemic damage) on walking patterns and speed is less clear. This study examines the effect of age on the associations of regional microstructural WM integrity with walking variability and speed, independent of macrostructural WMD. This study involved 493 participants (n = 51 young; n = 209 young-old; n = 233 old-old) from the Baltimore Longitudinal Study of Aging. All completed a 400-meter walk test and underwent a concurrent brain MRI with diffusion tensor imaging. Microstructural WM integrity was measured as fractional anisotropy (FA). Walking variability was measured as trend-adjusted variation in time over ten 40-meter laps (lap time variation, LTV). Fast-paced walking speed was assessed as mean lap time (MLT). Multiple linear regression models of FA predicting LTV and MLT were adjusted for age, sex, height, weight, and WM hyperintensities. Independent of WM hyperintensities, lower FA in the body of the corpus callosum was associated with higher LTV and longer MLT only in the young-old. Lower FA in superior longitudinal, inferior fronto-occipital, and uncinate fasciculi, the anterior limb of the internal capsule, and the anterior corona radiate was associated with longer MLT only in the young-old. While macrostructural WMD is known to predict more variable and slower walking in older adults, microstructural WM disruption is independently associated with more variable and slower fast-paced walking only in the young-old. Disrupted regional WM integrity may be a subclinical contributor to abnormal walking at an earlier phase of aging.
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The Exercise Ankle-Brachial Index: A Leap Forward in Noninvasive Diagnosis and Prognosis.
Drachman DE, Beckman JA
(2015) JACC Cardiovasc Interv 8: 1245-1247
MeSH Terms: Ankle Brachial Index, Endovascular Procedures, Exercise Test, Female, Humans, Lower Extremity, Male, Peripheral Arterial Disease, Vascular Surgical Procedures
Added January 15, 2016
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9 MeSH Terms
Abnormal exercise response in long-term survivors of hodgkin lymphoma treated with thoracic irradiation: evidence of cardiac autonomic dysfunction and impact on outcomes.
Groarke JD, Tanguturi VK, Hainer J, Klein J, Moslehi JJ, Ng A, Forman DE, Di Carli MF, Nohria A
(2015) J Am Coll Cardiol 65: 573-83
MeSH Terms: Adult, Autonomic Nervous System, Exercise Test, Exercise Tolerance, Female, Follow-Up Studies, Hodgkin Disease, Humans, Male, Massachusetts, Middle Aged, Prognosis, Retrospective Studies, Risk Factors, Survival Rate, Time Factors
Show Abstract · Added March 4, 2015
BACKGROUND - Hodgkin lymphoma (HL) survivors treated with thoracic radiation therapy (RT) have impaired exercise tolerance and increased cardiovascular mortality.
OBJECTIVES - The purpose of this study was to evaluate the prevalence of autonomic dysfunction and its implications on exercise capacity and mortality in long-term survivors of HL.
METHODS - Exercise parameters in 263 HL survivors referred for exercise treadmill testing at a median interval of 19 years after RT were compared with 526 age-, sex-, and cardiovascular risk score-matched control subjects. Within the RT cohort, the presence of autonomic dysfunction, defined by an elevated resting heart rate (HR) (≥80 beats/min) and abnormal heart rate recovery (HRR) at 1 min (≤12 beats/min if active cool-down, or ≤18 beats/min if passive recovery), was correlated with exercise capacity and all-cause mortality over a median follow-up of 3 years.
RESULTS - RT was associated with elevated resting HR and abnormal HRR after adjusting for age, sex, cardiovascular risk factors, medications, and indication for exercise treadmill testing: odds ratio: 3.96 (95% confidence interval [CI]: 2.52 to 6.23) and odds ratio: 5.32 (95% CI: 2.94 to 9.65), respectively. Prevalence of autonomic dysfunction increased with radiation dose and time from RT. Both elevated resting HR and abnormal HRR were associated with reduced exercise capacity in RT patients. Abnormal HRR was also associated with increased all-cause mortality (age-adjusted hazard ratio: 4.60 [95% CI: 1.62 to 13.02]).
CONCLUSIONS - Thoracic RT is associated with autonomic dysfunction, as measured by elevated resting HR and abnormal HRR. These abnormalities are associated with impaired exercise tolerance, and abnormal HRR predicts increased all-cause mortality in RT patients.
Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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16 MeSH Terms
Serum endostatin is a genetically determined predictor of survival in pulmonary arterial hypertension.
Damico R, Kolb TM, Valera L, Wang L, Housten T, Tedford RJ, Kass DA, Rafaels N, Gao L, Barnes KC, Benza RL, Rand JL, Hamid R, Loyd JE, Robbins IM, Hemnes AR, Chung WK, Austin ED, Drummond MB, Mathai SC, Hassoun PM
(2015) Am J Respir Crit Care Med 191: 208-18
MeSH Terms: Biomarkers, Collagen Type XVIII, Endostatins, Exercise Test, Female, Follow-Up Studies, Humans, Hypertension, Pulmonary, Kaplan-Meier Estimate, Male, Middle Aged, Polymorphism, Single Nucleotide, Predictive Value of Tests, Prognosis, Proportional Hazards Models, ROC Curve, Severity of Illness Index, Ventricular Dysfunction, Right
Show Abstract · Added February 12, 2015
RATIONALE - Pulmonary arterial hypertension (PAH) is a medically incurable disease resulting in death from right ventricular (RV) failure. Both pulmonary vascular and RV remodeling are linked to dynamic changes in the microvasculature. Therefore, we hypothesized that circulating angiostatic factors could be linked to outcomes and represent novel biomarkers of disease severity in PAH.
OBJECTIVES - We sought to determine the relationship of a potent angiostatic factor, endostatin (ES), with disease severity and mortality in PAH. Furthermore, we assessed genetic predictors of ES expression and/or function and their association with outcomes in PAH.
METHODS - We measured levels of serum ES in two independent cohorts of patients with PAH. Contemporaneous clinical data included New York Heart Association functional class, 6-minute-walk distance, invasive hemodynamics, and laboratory chemistries.
MEASUREMENTS AND MAIN RESULTS - Serum ES correlated with poor functional status, decreased exercise tolerance, and invasive hemodynamics variables. Furthermore, serum ES was a strong predictor of mortality. A loss-of-function, missense variant in the gene encoding ES, Col18a1, was linked to lower circulating protein and was independently associated with reduced mortality.
CONCLUSIONS - Our data link increased expression of ES to disease severity in PAH and demonstrate a significant relationship with adverse outcomes. Circulating ES levels can be genetically influenced, implicating ES as a genetically determined modifier of disease severity impacting on survival. These observations support serum ES as a potential biomarker in PAH with the capacity to predict poor outcomes. More importantly, this study implicates Col18a1/ES as a potential new therapeutic target in PAH.
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18 MeSH Terms