publications

2023

1. Protein-metabolite association studies identify novel proteomic determinants of metabolite levels in human plasma

   Mark D Benson*, Aaron S Eisman*, Usman A Tahir, and 38 more authors

   Cell Metabolism Sep 2023

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   Although many novel gene-metabolite and gene-protein associations have been identified using high-throughput biochemical profiling, systematic studies that leverage human genetics to illuminate causal relationships between circulating proteins and metabolites are lacking. Here, we performed protein-metabolite association studies in 3,626 plasma samples from three human cohorts. We detected 171,800 significant protein-metabolite pairwise correlations between 1,265 proteins and 365 metabolites, including established relationships in metabolic and signaling pathways such as the protein thyroxine-binding globulin and the metabolite thyroxine, as well as thousands of new findings. In Mendelian randomization (MR) analyses, we identified putative causal protein-to-metabolite associations. We experimentally validated top MR associations in proof-of-concept plasma metabolomics studies in three murine knockout strains of key protein regulators. These analyses identified previously unrecognized associations between bioactive proteins and metabolites in human plasma. We provide publicly available data to be leveraged for studies in human metabolism and disease.

2022

1. Whole Genome Association Study of the Plasma Metabolome Identifies Metabolites Linked to Cardiometabolic Disease in Black Individuals

   Usman A Tahir, Daniel H Katz, Julian Avila-Pachecho, and 37 more authors

   Nature communications Aug 2022

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   Integrating genetic information with metabolomics has provided new insights into genes affecting human metabolism. However, gene-metabolite integration has been primarily studied in individuals of European Ancestry, limiting the opportunity to leverage genomic diversity for discovery. In addition, these analyses have principally involved known metabolites, with the majority of the profiled peaks left unannotated. Here, we perform a whole genome association study of 2,291 metabolite peaks (known and unknown features) in 2,466 Black individuals from the Jackson Heart Study. We identify 519 locus-metabolite associations for 427 metabolite peaks and validate our findings in two multi-ethnic cohorts. A significant proportion of these associations are in ancestry specific alleles including findings in APOE, TTR and CD36. We leverage tandem mass spectrometry to annotate unknown metabolites, providing new insight into hereditary diseases including transthyretin amyloidosis and sickle cell disease. Our integrative omics approach leverages genomic diversity to provide novel insights into diverse cardiometabolic diseases.

2021

1. Clinical Note Section Detection Using a Hidden Markov Model of Unified Medical Language System Semantic Types

   Aaron S Eisman, Katherine A Brown, Elizabeth S Chen, and 1 more author

   AMIA Annual Symposium Proceedings Aug 2021

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   Clinical notes are a rich source of biomedical data for natural language processing (NLP). The identification of note sections represents a first step in creating portable NLP tools. Here, a system that used a heterogeneous hidden Markov model (HMM) was designed to identify seven note sections: (1) Medical History, (2) Medications, (3) Family and Social History, (4) Physical Exam, (5) Labs and Imaging, (6) Assessment and Plan, and (7) Review of Systems. Unified Medical Language System (UMLS) concepts were identified using MetaMap, and UMLS semantic type distributions for each section type were empirically determined. The UMLS semantic type distributions were used to train the HMM for identifying clinical note sections. The system was evaluated relative to a template boundary model using manually annotated notes from the Medical Information Mart for Intensive Care III. The results show promise for an approach to segment clinical notes into sections for subsequent NLP tasks.

2020

1. E-Consult Protocoling to Improve the Quality of Cardiac Stress Tests

   Nishant R Shah, Aaron S Eisman, David E Winchester, and 4 more authors

   JACC. Cardiovascular imaging Sep 2020

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2. Extracting Angina Symptoms from Clinical Notes Using Pre-Trained Transformer Architectures

   Aaron S Eisman, Nishant R Shah, Carsten Eickhoff, and 4 more authors

   AMIA Annual Symposium Proceedings Sep 2020

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   Anginal symptoms can connote increased cardiac risk and a need for change in cardiovascular management. In this study, a pre-trained transformer architecture was used to automatically detect and characterize anginal symptoms from within the history of present illness sections of 459 primary care physician notes. Consecutive patients referred for cardiac testing were included. Notes were annotated for positive and negative mentions of chest pain and shortness of breath characterization. The results demonstrate high sensitivity and specificity for the detection of chest pain or discomfort, substernal chest pain, shortness of breath, and dyspnea on exertion. Model performance extracting factors related to provocation and palliation of chest pain were limited by small sample size. Overall, this study shows that pre-trained transformer architectures have promise in automating the extraction of anginal symptoms from clinical texts.

3. Exercise Pulmonary Hypertension Predicts Clinical Outcomes in Patients With Dyspnea on Effort

   Jennifer E Ho, Emily K Zern, Emily S Lau, and 14 more authors

   Journal of the American College of Cardiology Jan 2020

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   BACKGROUND: Abnormal pulmonary arterial pressure (PAP) responses to exercise have been described in select individuals; however, clinical and prognostic implications of exercise pulmonary hypertension (exPH) among broader samples remains unclear. OBJECTIVES: This study sought to investigate the association of exPH with clinical determinants and outcomes. METHODS: The authors studied individuals with chronic exertional dyspnea and preserved ejection fraction who underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring. Exercise pulmonary hypertension was ascertained using minute-by-minute PAP and cardiac output (CO) measurements to calculate a PAP/CO slope, and exPH defined as a PAP/CO slope >3 mm Hg/l/min. The primary outcome was cardiovascular (CV) hospitalization or all-cause mortality. RESULTS: Among 714 individuals (age 57 years, 59% women), 296 (41%) had abnormal PAP/CO slopes. Over a mean follow-up of 3.7 \pm 2.9 years, there were 208 CV or death events. Individuals with abnormal PAP/CO slope had a 2-fold increased hazard of future CV or death event (multivariable-adjusted hazard ratio: 2.03; 95% confidence interval: 1.48 to 2.78; p < 0.001). The association of abnormal PAP/CO slope with outcomes remained significant after excluding rest PH (n = 146, hazard ratio: 1.75; 95% confidence interval: 1.21 to 2.54; p = 0.003). Both pre- and post-capillary contributions to exPH independently predicted adverse events (p < 0.001 for both). CONCLUSIONS: Exercise pulmonary hypertension is independently associated with CV event-free survival among individuals undergoing evaluation of chronic dyspnea. These findings suggest incremental value of exercise hemodynamic assessment to resting measurements alone in characterizing the burden of PH in individuals with dyspnea. Whether PH and PH subtypes unmasked by exercise can be used to guide targeted therapeutic interventions requires further investigation.

2019

1. Differential Clinical Profiles, Exercise Responses, and Outcomes Associated With Existing HFpEF Definitions

   Jennifer E Ho, Emily K Zern, Luke Wooster, and 10 more authors

   Circulation Jul 2019

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   BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is common, yet there is currently no consensus on how to define HFpEF according to various society and clinical trial criteria. How clinical and hemodynamic profiles of patients vary across definitions is unclear. We sought to determine clinical characteristics, as well as physiologic and prognostic implications of applying various criteria to define HFpEF. METHODS: We examined consecutive patients with chronic exertional dyspnea (New York Heart Association class II to IV) and ejection fraction \geq50% referred for comprehensive cardiopulmonary exercise testing with invasive hemodynamic monitoring. We applied societal and clinical trial HFpEF definitions and compared clinical profiles, exercise responses, and cardiovascular outcomes. RESULTS: Of 461 patients (age 58\pm15 years, 62% women), 416 met American College of Cardiology/American Heart Association (ACC/AHA), 205 met European Society of Cardiology (ESC), and 55 met Heart Failure Society of America (HFSA) criteria for HFpEF. Clinical profiles and exercise capacity varied across definitions, with peak oxygen uptake of 16.2\pm5.2 (ACC/AHA), 14.1\pm4.2 (ESC), and 12.7\pm3.1 mL·kg-1·min-1 (HFSA). A total of 243 patients had hemodynamic evidence of HFpEF (abnormal rest or exercise filling pressures), of whom 222 met ACC/AHA, 161 met ESC, and 41 met HFSA criteria. Over a mean follow-up of 3.8 years, the incidence of cardiovascular outcomes ranged from 75 (ACC/AHA) to 298 events per 1000 person-years (HFSA). Application of clinical trial definitions of HFpEF similarly resulted in distinct patient classification and prognostication. CONCLUSIONS: Use of different HFpEF classifications variably enriches for future cardiovascular events, but at the expense of not including up to 85% of individuals with physiologic evidence of HFpEF. Comprehensive phenotyping of patients with suspected heart failure highlights the limitations and heterogeneity of current HFpEF definitions and may help to refine HFpEF subgrouping to test therapeutic interventions.

2018

1. Impaired right ventricular reserve predicts adverse cardiac outcomes in adults with congenital right heart disease

   Doreen DeFaria Yeh, Ada C Stefanescu Schmidt, Aaron S Eisman, and 9 more authors

   Heart Jul 2018

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   OBJECTIVE: The prevalence of heart failure (HF) among adult patients with congenital heart disease (ACHD) is rising. Right ventricle (RV) exercise reserve and its relationship to outcomes have not been characterised. We aim to evaluate the prognostic impact of impaired RV reserve in an ACHD population referred for cardiopulmonary exercise testing (CPET). METHODS: This retrospective study evaluates patients with ACHD who underwent CPET (n=147) with first-pass radionuclide ventriculography at a single tertiary care centre. RV reserve was categorised as normal, mild to moderately or severely impaired. The primary composite clinical outcome included clinical right HF, arrhythmia, transplantation or death. RESULTS: Patients were median age 41\pm13 years, 50% were female and median follow-up was 1.1 (IQR: 0.7-2.0) years. Exercise RV reserve was impaired in 103 patients (70%), of whom 32% were asymptomatic. Resting RV systolic function poorly predicted RV reserve, with 52% of patients with severe impairment having a qualitatively normal echocardiographic assessment. The severely impaired reserve group had lower peak oxygen consumption (VO2)(17.2 vs 22.5 mL/kg/min, p<0.0001) compared with the normal reserve group, and was more likely to develop the composite outcome (48% vs 9%, log-rank p<0.001). Severely impaired RV reserve predicted event-free survival after adjusting for peak VO2, age, sex, RV pathology, QRS duration, New York Heart Association class, resting RV ejection fraction and RV dilation by echocardiography or MRI (HR 3.7, 95% CI 1.1 to 13.0, p=0.039). CONCLUSION: Impaired RV reserve, occurred in asymptomatic patients, was not well predicted by resting systolic function assessment, and strongly predicted adverse cardiovascular outcomes.

2. Pulmonary Capillary Wedge Pressure Patterns During Exercise Predict Exercise Capacity and Incident Heart Failure

   Aaron S Eisman, Ravi V Shah, Bishnu P Dhakal, and 9 more authors

   Circulation. Heart failure May 2018

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   BACKGROUND: Single measurements of left ventricular filling pressure at rest lack sensitivity for identifying heart failure with preserved ejection fraction (HFpEF) in patients with dyspnea on exertion. We hypothesized that exercise hemodynamic measurements (ie, changes in pulmonary capillary wedge pressure [PCWP] indexed to cardiac output [CO]) may more sensitively differentiate HFpEF and non-HFpEF disease states, reflect aerobic capacity, and forecast heart failure outcomes in individuals with normal PCWP at rest. METHODS AND RESULTS: We studied 175 patients referred for cardiopulmonary exercise testing with hemodynamic monitoring: controls (n=33), HFpEF with resting PCWP\geq15 mm Hg (n=32), and patients with dyspnea on exertion with normal resting PCWP and left ventricular ejection fraction (DOE-nlrW; n=110). Across 1835 paired PCWP-CO measurements throughout exercise, we used regression techniques to define normative bounds of “PCWP/CO slope” in controls and tested the association of PCWP/CO slope with exercise capacity and composite cardiac outcomes (defined as cardiac death, incident resting PCWP elevation, or heart failure hospitalization) in the DOE-nlrW group. Relative to controls (PCWP/CO slope, 1.2\pm0.4 mm Hg/L/min), patients with HFpEF had a PCWP/CO slope of 3.4\pm1.9 mm Hg/L/min. We used a threshold (2 SD above the mean in controls) of 2 mm Hg/L/min to define abnormal. PCWP/CO slope >2 in DOE-nlrW patients was common (n=45/110) and was associated with reduced peak Vo2 (P2 mm Hg/L/min) is common in DOE-nlrW and predicts exercise capacity and heart failure outcomes. These findings suggest that current definitions of HFpEF based on single measures during rest are insufficient and that assessment of exercise PCWP/CO slope may refine early HFpEF diagnosis.

2017

1. An Automated System for Categorizing Transthoracic Echocardiography Indications According to the Echocardiography Appropriate Use Criteria

   Aaron S Eisman, Rory B Weiner, Elizabeth S Chen, and 4 more authors

   AMIA Annual Symposium Proceedings May 2017

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   The Echocardiography Appropriate Use Criteria (EAUC) are a set of indications for transthoracic echocardiography (TTE) developed to guide physician decision making around ordering of TTE. In this study, an automated rule-based method for processing “indications” listed within TTE reports and classification into one of the major EAUC categories was developed and validated against a clinician-annotated reference standard. The system performed at a comparable level to trained physicians allowing for the automated classification of more than 30,000 TTE indications from a public database in less than ten minutes. The most common indication for TTE was Valvular assessment closely followed by General. Hypertension/Heart Failure/Cardiomyopathy, Acute, and Cardiac Structure assessment each contributed more than ten percent within this patient population. These results suggest potential for automated approaches for tracking appropriate use of TTE, as well as guide the development of systems for prospectively identifying when TTE use is recommended.

2. Exercise Intolerance in HFpEF: Diagnosing and Ranking its Causes Using Personalized O2 Pathway Analysis

   Nicholas E Houstis, Aaron S Eisman, Paul P Pappagianopoulos, and 4 more authors

   Circulation Oct 2017

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   Background -Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with a pressing shortage of therapies. Exercise intolerance is a cardinal symptom of HFpEF, yet its pathophysiology remains uncertain. Methods -We investigated the mechanism of exercise intolerance in each of 134 patients referred for cardiopulmonary exercise testing (CPET): 79 with HFpEF and 55 controls. We performed CPET with invasive monitoring to measure hemodynamics, blood gases, and gas exchange during exercise. We used these measurements to quantify 6 steps of oxygen transport and utilization (the “O2 pathway”) in each HFpEF patient, identifying the defective steps that impair each one’s exercise capacity (peak VO2). We then quantified the functional significance of each O2 pathway defect by calculating the improvement in exercise capacity a patient could expect from correcting the defect. Results -Peak VO2)was reduced by 34%\pm2% (mean\pmSEM, P<0.001) in HFpEF compared with controls of comparable age, gender, and body mass index. The vast majority (97%) of HFpEF patients harbored defects at multiple steps of the O2 pathway, the identity and magnitude of which varied widely. Two of these steps, cardiac output and skeletal muscle O2 diffusion, were impaired relative to controls by an average of 27\pm3% and 36\pm2%, respectively (P<0.001 for both). Due to interactions between a given patient’s defects, the predicted benefit of correcting any single one was often minor; on average, correcting a patient’s cardiac output led to a 7\pm0.5% predicted improvement in exercise intolerance, while correcting a patient’s muscle diffusion capacity led to a 27\pm1% improvement. At the individual level, the impact of any given O2 pathway defect on a patient’s exercise capacity was strongly influenced by comorbid defects. Conclusions -Systematic analysis of the O2 pathway in HFpEF showed that exercise capacity was undermined by multiple defects, including reductions in cardiac output and skeletal muscle diffusion capacity. An important source of disease heterogeneity stemmed from variation in each patient’s personal profile of defects. Personalized O2 pathway analysis could identify patients most likely to benefit from treating a specific defect; however, the system properties of O2 transport favor treating multiple defects at once, as with exercise training.

2016

1. Association of Fitness in Young Adulthood With Survival and Cardiovascular Risk: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

   R V Shah, V L Murthy, L A Colangelo, and 18 more authors

   JAMA internal medicine Oct 2016

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   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 (beta = -0.24; 95% CI, -0.45 to -0.03; P = .02) and significantly better lobal longitudinal strain (beta = -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 (beta = 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.

2. Native Myocardial T1 as a Biomarker of Cardiac Structure in Non-Ischemic Cardiomyopathy

   R V Shah, S Kato, S Roujol, and 8 more authors

   The American journal of cardiology Oct 2016

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   Diffuse myocardial fibrosis is involved in the pathology of nonischemic cardiomyopathy (NIC). Recently, the application of native (noncontrast) myocardial T1 measurement has been proposed as a method for characterizing diffuse interstitial fibrosis. To determine the association of native T1 with myocardial structure and function, we prospectively studied 39 patients with NIC (defined as left ventricular ejection fraction (LVEF) </= 50% without cardiac magnetic resonance (CMR) evidence of previous infarction) and 27 subjects with normal LVEF without known overt cardiovascular disease. T1, T2, and extracellular volume fraction (ECV) were determined over 16 segments across the base, mid, and apical left ventricular (LV). NIC participants (57 +/- 15 years) were predominantly men (74%), with a mean LVEF 34 +/- 10%. Subjects with NIC had a greater native T1 (1,131 +/- 51 vs 1,069 +/- 29 ms; p <0.0001), a greater ECV (0.28 +/- 0.04 vs 0.25 +/- 0.02, p = 0.002), and a longer myocardial T2 (52 +/- 8 vs 47 +/- 5 ms; p = 0.02). After multivariate adjustment, a lower global native T1 time in NIC was associated with a greater LVEF (beta = -0.59, p = 0.0003), greater right ventricular ejection fraction (beta = -0.47, p = 0.006), and smaller left atrial volume index (beta = 0.51, p = 0.001). The regional distribution of native myocardial T1 was similar in patients with and without NIC. In NIC, native myocardial T1 is elevated in all myocardial segments, suggesting a global (not regional) abnormality of myocardial tissue composition. In conclusion, native T1 may represent a rapid, noncontrast alternative to ECV for delineating myocardial tissue remodeling in NIC.

3. Abdominal fat radiodensity, quantity and cardiometabolic risk: The Multi-Ethnic Study of Atherosclerosis

   R V Shah, M A Allison, J A Lima, and 6 more authors

   Nutrition, metabolism, and cardiovascular diseases: NMCD Oct 2016

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   BACKGROUND AND AIMS: Fat radiodensity, as measured by fat attenuation on computed tomography (CT), has emerged as a potential biomarker of “fat quality.” We sought to characterize the relationship between fat radiodensity and quantity in subcutaneous, visceral, and intermuscular fat depots, and its role in inflammation, insulin resistance, and metabolic syndrome (MetS). METHODS AND RESULTS: We studied 1511 individuals from the Multi-Ethnic Study of Atherosclerosis who underwent CT for measurement of regional fat distribution and radiodensity, along with biomarker assessments and adjudication of incident metabolic syndrome (MetS). Linear, logistic and Cox regression analyses were used to measure association between fat radiodensity and (1) fat quantity, (2) biomarkers of cardiometabolic dysfunction, and (3) both prevalent and incident MetS. In each fat depot, radiodensity was strongly and inversely associated with quantity (e.g., visceral fat radiodensity vs. quantity: rho = -0.82, P < 0.01). After adjustment for age, sex and race, lower visceral fat radiodensity was associated with greater C-reactive protein, leptin and insulin, but lower adiponectin (P < 0.01 for all). After full adjustment for cardiovascular disease risk factors, visceral (but not subcutaneous or intermuscular) fat radiodensity was associated with prevalent MetS (OR = 0.96, 95% CI = 0.93-0.99, P = 0.01). Moreover, lower visceral fat radiodensity was associated with incident MetS after the same adjustment (HR = 0.95, 95% CI 0.93-0.98, P < 0.01). However, this association became non-significant after further adjustment for visceral fat quantity. CONCLUSION: Fat radiodensity is strongly correlated with fat quantity and relevant inflammatory biomarkers. Fat radiodensity (especially for visceral fat) may be a complementary, easily assessed marker of cardiometabolic risk.

4. Pulmonary Vascular Distensibility Predicts Pulmonary Hypertension Severity, Exercise Capacity, and Survival in Heart Failure

   R Malhotra, B P Dhakal, A S Eisman, and 6 more authors

   Circulation. Heart failure Oct 2016

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   BACKGROUND: Pulmonary vascular (PV) distensibility, defined as the percent increase in pulmonary vessel diameter per mm Hg increase in pressure, permits the pulmonary vessels to increase in size to accommodate increased blood flow. We hypothesized that PV distensibility is abnormally low in patients with heart failure (HF) and serves as an important determinant of right ventricular performance and exercise capacity. METHODS AND RESULTS: Patients with HF with preserved ejection fraction (n=48), HF with reduced ejection fraction (n=55), pulmonary arterial hypertension without left heart failure (n=18), and control subjects (n=30) underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring and first-pass radionuclide ventriculography. PV distensibility was derived from 1257 matched measurements (mean+/-SD, 8.3+/-2.8 per subject) of pulmonary arterial pressure, pulmonary arterial wedge pressure and cardiac output. PV distensibility was lowest in the pulmonary arterial hypertension group (0.40+/-0.24% per mm Hg) and intermediate in the HF with preserved ejection fraction and HF with reduced ejection fraction groups (0.92+/-0.39 and 0.84+/-0.33% per mm Hg, respectively) compared to the control group (1.39+/-0.32% per mm Hg, P<0.0001 for all three). PV distensibility was associated with change in right ventricular ejection fraction (RVEF, rho=0.39, P<0.0001) with exercise and was an independent predictor of peak VO2. PV distensibility also predicted cardiovascular mortality independent of peak VO2 in HF patients (n=103; Cox hazard ratio, 0.30; 95% confidence interval, 0.10-0.93; P=0.036). In a subset of patients with HF with reduced ejection fraction (n=26), 12 weeks of treatment with the pulmonary vasodilator sildenafil or placebo led to a 24.6% increase in PV distensibility (P=0.015) in the sildenafil group only. CONCLUSIONS: PV distensibility is reduced in patients with HF and pulmonary arterial hypertension and is closely related to RV systolic function during exercise, maximal exercise capacity, and survival. Furthermore, PV distensibility is modifiable with selective pulmonary vasodilator therapy and may represent an important target for therapy in selected HF patients with pulmonary hypertension. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00309790.

2015

1. ECG findings in competitive rowers: normative data and the prevalence of abnormalities using contemporary screening recommendations

   M M Wasfy, J DeLuca, F Wang, and 7 more authors

   British journal of sports medicine Oct 2015

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   BACKGROUND/AIM: The international governing body for competitive rowing recently mandated the inclusion of 12-lead ECG during preparticipation screening. We therefore sought to describe normative ECG characteristics and to examine the prevalence of abnormal ECG findings as defined by contemporary athlete ECG interpretation criteria among competitive rowers. METHODS: Competitive rowers (n=330, 56% male) underwent standard 12-lead ECG at the time of collegiate preparticipation screening. ECGs were analysed quantitatively to develop a sport-specific normative database and then for the presence of abnormalities in accordance with the 2010 European Society of Cardiology (ESC) recommendations and 2013 ’Seattle Criteria.’ RESULTS: 94% of rowers had one or more training-related ECG patterns including sinus bradycardia (51%), sinus arrhythmia (55%), and incomplete right bundle branch block (42%). Males were more likely than females to have isolated voltage criteria for left ventricular hypertrophy (LVH) (51% vs 8%, p<0.001) and early repolarisation pattern (76% vs 23%, p<0.001). Application of the 2010 ESC criteria, compared to the Seattle criteria, resulted in the classification of a significantly greater number of abnormal ECGs (47% vs 4%; p<0.001). The detection of true pathology, accomplished by both interpretation criteria, was confined to a single case of ventricular pre-excitation. CONCLUSIONS: Training-related ECG patterns with several gender-based differences are common among competitive rowers. The diagnostic accuracy and down-stream clinical implications of ECG-inclusive preparticipation screening among rowers will be dictated by the choice and future refinement of ECG interpretation criteria.

2. Mechanisms of exercise intolerance in heart failure with preserved ejection fraction: the role of abnormal peripheral oxygen extraction

   B P Dhakal, R Malhotra, R M Murphy, and 7 more authors

   Circulation. Heart failure Oct 2015

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   BACKGROUND: Exercise capacity as measured by peak oxygen uptake (Vo2) is similarly impaired in patients with heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). However, characterization of how each component of Vo2 changes in response to incremental exercise in HFpEF versus HFrEF has not been previously defined. We hypothesized that abnormally low peripheral o2 extraction (arterio-mixed venous o2 content difference, [C(a-v)o2]) during exercise significantly contributes to impaired exercise capacity in HFpEF. METHODS AND RESULTS: We performed maximum incremental cardiopulmonary exercise testing with invasive hemodynamic monitoring on 104 patients with symptomatic NYHA II to IV heart failure (HFpEF, n=48, peak Vo2=13.9+/-0.5 mL kg(-1) min(-1), mean+/-SEM, and HFrEF, n=56, peak Vo2=12.1+/-0.5 mL kg(-1) min(-1)) and 24 control subjects (peak Vo2 27.0+/-1.7 mL kg(-1) min(-1)). Peak exercise C(a-v)o2 was lower in HFpEF compared with HFrEF (11.5+/-0.27 versus 13.5+/-0.34 mL/dL, respectively, P<0.0001), despite no differences in age, hemoglobin level, peak respiratory exchange ratio, Cao2, or cardiac filling pressures. Peak C(a-v)o2 and peak heart rate emerged as the leading predictors of peak Vo2 in HFpEF. Impaired peripheral o2 extraction was the predominant limiting factor to exercise capacity in 40% of patients with HFpEF and was closely related to elevated systemic blood pressure during exercise (r=0.49, P=0.0005). CONCLUSIONS: In the first study to directly measure C(a-v)o2 throughout exercise in HFpEF, HFrEF, and normals, we found that peak C(a-v)o2 was a major determinant of exercise capacity in HFpEF. The important functional limitation imposed by impaired o2 extraction may reflect intrinsic abnormalities in skeletal muscle or peripheral microvascular function, and represents a potential target for therapeutic intervention.

3. Pulmonary vascular response patterns during exercise in interstitial lung disease

   L H Degani-Costa, B Levarge, S R Digumarthy, and 3 more authors

   The European respiratory journal: official journal of the European Society for Clinical Respiratory Physiology Oct 2015

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   When overt pulmonary hypertension arises in interstitial lung disease (ILD), it contributes to exercise intolerance. We sought to determine the functional significance of abnormal pulmonary arterial pressure (PAP) responses to exercise in ILD.27 ILD patients and 11 age-matched controls underwent invasive cardiopulmonary exercise testing (iCPET). Mean PAP (mPAP) was indexed to cardiac output (Q’T) during exercise, with a mPAP-Q’T slope >/=3 mmHg.min.L(-1) defined as an abnormal pulmonary vascular response.All control subjects had mPAP-Q’T slopes /=3 mmHg.min.L(-1) (4.1+/-0.2 mmHg.min.L(-1)) and were labelled as having ILD plus pulmonary vascular dysfunction (PVD). Subjects without pulmonary hypertension and with mPAP-Q T slopes /=3 mmHg.min.L(-1) is associated with lower peak oxygen consumption, increased VD/VT and inefficient ventilation. While noninvasive parameters were unable to predict those with abnormal pulmonary vascular responses to exercise, iCPET-derived mPAP-Q’T slope may aid in identifying physiologically significant, early pulmonary vascular disease in ILD.

2007

1. Inhibition of Rho via Arg and p190RhoGAP in the postnatal mouse hippocampus regulates dendritic spine maturation, synapse and dendrite stability, and behavior

   M K Sfakianos, A Eisman, S L Gourley, and 7 more authors

   The Journal of neuroscience: the official journal of the Society for Neuroscience Oct 2007

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   The RhoA (Rho) GTPase is a master regulator of dendrite morphogenesis. Rho activation in developing neurons slows dendrite branch dynamics, yielding smaller, less branched dendrite arbors. Constitutive activation of Rho in mature neurons causes dendritic spine loss and dendritic regression, indicating that Rho can affect dendritic structure and function even after dendrites have developed. However, it is unclear whether and how endogenous Rho modulates dendrite and synapse morphology after dendrite arbor development has occurred. We demonstrate that a Rho inhibitory pathway involving the Arg tyrosine kinase and p190RhoGAP is essential for synapse and dendrite stability during late postnatal development. Hippocampal CA1 pyramidal dendrites develop normally in arg-/- mice, reaching their mature size by postnatal day 21 (P21). However, dendritic spines do not undergo the normal morphological maturation in these mice, leading to a loss of hippocampal synapses and dendritic branches by P42. Coincident with this synapse and dendrite loss, arg-/- mice exhibit progressive deficits in a hippocampus-dependent object recognition behavioral task. p190RhoGAP localizes to dendritic spines, and its activity is reduced in arg-/- hippocampus, leading to increased Rho activity. Although mutations in p190rhogap enhance dendritic regression resulting from decreased Arg levels, reducing gene dosage of the Rho effector ROCKII can suppress the dendritic regression observed in arg-/- mice. Together, these data indicate that signaling through Arg and p190RhoGAP acts late during synaptic refinement to promote dendritic spine maturation and synapse/dendrite stability by attenuating synaptic Rho activity.

2004

1. Lightcurve of asteroid (21652) 1999 OQ2

   Aaron Eisman, and Monty Robson

   Minor Planet Bulletin Dec 2004

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   594 CCD images were taken of the main-belt asteroid (21652) 1999 OQ2 through a Bessel R-band filter over the course of four nights. Differential photometric reduction and Fourier transformation of the relative magnitudes show a period of 16.207 \pm 0.002h with a mean R magnitude of 14.05 and a lightcurve amplitude of 0.9 magnitudes. Compared on average with similar-sized asteroids, 1999 OQ2 rotates more slowly and has a larger amplitude, suggesting a highly elongated shape.