Publications by authors named "Hannah A Valantine"

69 Publications

Higher levels of allograft injury in black patients early after heart transplantation.

J Heart Lung Transplant 2021 Dec 23. Epub 2021 Dec 23.

Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland; Laborarory of Applied Precision Omics (APO), Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland; Department of Medicine, Stanford University School of Medicine, Palo Alto, California. Electronic address:

Black patients suffer higher rates of antibody-mediated rejection and have worse long-term graft survival after heart transplantation. Donor-derived cell free DNA (ddcfDNA) is released into the blood following allograft injury. This study analyzed %ddcfDNA in 63 heart transplant recipients categorized by Black and non-Black race, during the first 200 days after transplant. Immediately after transplant, %ddcfDNA was higher for Black patients (mean [SE]: 8.3% [1.3%] vs 3.2% [1.2%], p = 0.001). In the first week post-transplant, the rate of decay in %ddcfDNA was similar (0.7% [0.68] vs 0.7% [0.11], p = 0.78), and values declined in both groups to a comparable plateau at 7 days post-transplant (0.46% [0.03] vs 0.45% [0.04], p = 0.78). The proportion of Black patients experiencing AMR was higher than non-Black patients (21% vs 9% [hazard ratio of 2.61 [95% confidence interval: 0.651-10.43], p = 0.18). Black patients were more likely to receive a race mismatched organ than non-Black patients (69% vs 35%, p = 0.01), which may explain the higher levels of early allograft injury.
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http://dx.doi.org/10.1016/j.healun.2021.12.006DOI Listing
December 2021

Can We Predict Rejection Early After Heart Transplantation?

Circulation 2021 11 1;144(18):1473-1475. Epub 2021 Nov 1.

Division of Cardiovascular Medicine and Cardiovascular Institute, Stanford University, CA (W.F.F., H.A.V.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.056808DOI Listing
November 2021

Ending Sexual Harassment in Science: Designing and Administering a Survey That Can Lead to an Improved Organizational Climate.

Acad Med 2021 Oct 26. Epub 2021 Oct 26.

H.A. Valantine is professor of cardiovascular medicine, Stanford University Medical Center, Stanford, California. C.E. Le Fauve is senior advisor to the chief officer for scientific workforce diversity, Scientific Workforce Diversity Office, National Institutes of Health, Bethesda, Maryland. K.A. Morris is a health science policy analyst, Office of Behavioral and Social Sciences Research, National Institutes of Health, Bethesda, Maryland. W.T. Riley is associate director for behavioral and social sciences research, and director, Office of Behavioral and Social Sciences Research, National Institutes of Health, Bethesda, Maryland.

Workplace harassment, particularly sexual harassment, has substantial negative implications for individuals and organizations and for scientific advancement. The National Institutes of Health (NIH) is uniquely positioned to lead the effort to prevent sexual harassment in the scientific community and mitigate its detrimental effects. Recognizing the need for benchmark data, NIH developed and validated the 2019 NIH Workplace Climate and Harassment Survey. The goal was to use best practices in survey design methods to create an instrument for rigorous assessment of harassment incidence and organizational climate predictors of sexual harassment in scientific research environments. This article summarizes the processes used to design and administer the NIH survey and provides brief descriptions of 3 products of the process developed to guide scientific institutions wishing to embark on a data-driven approach to assess and prevent harassment: a document detailing survey development and methods; a survey implementation guide; and the key findings obtained from the survey, including recommendations for interventions targeting organizational climate at NIH and limitations of the survey. The survey identified that 1 in 5 respondents had experienced sexual harassment in the 12 months preceding their participation in the survey and that women, sexual and gender minorities, younger respondents, trainees/students, and individuals with a disability were more likely to have experienced sexual harassment. Those who had experienced sexual harassment during that period were also more likely to have experienced incivility, bullying, and intimidating behaviors in the workplace. NIH intends to use the survey findings as a quality assurance and quality improvement guide to inform future activities to prevent and address harassment across NIH.
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http://dx.doi.org/10.1097/ACM.0000000000004491DOI Listing
October 2021

Response by Shah et al to Letter Regarding Article, "Cell-Free DNA to Detect Heart Allograft Acute Rejection".

Circulation 2021 09 7;144(10):e198-e199. Epub 2021 Sep 7.

Genomic Research Alliance for Transplantation (GRAfT), Bethesda, MD (P.S., S.A-E., I.T., S.H., E.F., K.S., M.E.R., S.S.N., H.K., U.F., A.B., A.M., K.B., Y.Y., M.K.J., C.Marboe, G.J.B., H.A.V.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.055697DOI Listing
September 2021

Cell-Free DNA to Detect Heart Allograft Acute Rejection.

Circulation 2021 03 13;143(12):1184-1197. Epub 2021 Jan 13.

Genomic Research Alliance for Transplantation, Bethesda, MD (S.A.-E., P.S., I.T., S.H., E.F., K.S., M.E.R., S.S.N., H.K., U.F., A.B., A.M., K.B., Y.Y., M.K.J., C.M., G.J.B., H.A.V.).

Background: After heart transplantation, endomyocardial biopsy (EMBx) is used to monitor for acute rejection (AR). Unfortunately, EMBx is invasive, and its conventional histological interpretation has limitations. This is a validation study to assess the performance of a sensitive blood biomarker-percent donor-derived cell-free DNA (%ddcfDNA)-for detection of AR in cardiac transplant recipients.

Methods: This multicenter, prospective cohort study recruited heart transplant subjects and collected plasma samples contemporaneously with EMBx for %ddcfDNA measurement by shotgun sequencing. Histopathology data were collected to define AR, its 2 phenotypes (acute cellular rejection [ACR] and antibody-mediated rejection [AMR]), and controls without rejection. The primary analysis was to compare %ddcfDNA levels (median and interquartile range [IQR]) for AR, AMR, and ACR with controls and to determine %ddcfDNA test characteristics using receiver-operator characteristics analysis.

Results: The study included 171 subjects with median posttransplant follow-up of 17.7 months (IQR, 12.1-23.6), with 1392 EMBx, and 1834 %ddcfDNA measures available for analysis. Median %ddcfDNA levels decayed after surgery to 0.13% (IQR, 0.03%-0.21%) by 28 days. Also, %ddcfDNA increased again with AR compared with control values (0.38% [IQR, 0.31-0.83%], versus 0.03% [IQR, 0.01-0.14%]; <0.001). The rise was detected 0.5 and 3.2 months before histopathologic diagnosis of ACR and AMR. The area under the receiver operator characteristic curve for AR was 0.92. A 0.25%ddcfDNA threshold had a negative predictive value for AR of 99% and would have safely eliminated 81% of EMBx. In addition, %ddcfDNA showed distinctive characteristics comparing AMR with ACR, including 5-fold higher levels (AMR ≥2, 1.68% [IQR, 0.49-2.79%] versus ACR grade ≥2R, 0.34% [IQR, 0.28-0.72%]), higher area under the receiver operator characteristic curve (0.95 versus 0.85), higher guanosine-cytosine content, and higher percentage of short ddcfDNA fragments.

Conclusions: We found that %ddcfDNA detected AR with a high area under the receiver operator characteristic curve and negative predictive value. Monitoring with ddcfDNA demonstrated excellent performance characteristics for both ACR and AMR and led to earlier detection than the EMBx-based monitoring. This study supports the use of %ddcfDNA to monitor for AR in patients with heart transplant and paves the way for a clinical utility study. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02423070.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221834PMC
March 2021

NIH's scientific approach to inclusive excellence.

FASEB J 2020 10;34(10):13085-13090

Scientific Workforce Diversity, National Institutes of Health, Bethesda, MD, USA.

The representation of women and scientists from underrepresented groups (URGs), including Black/African Americans, Hispanic/Latinx, Pacific Islanders, and American Indians, diminishes as individuals advance in their careers from training to senior leadership positions. Correcting this imbalance requires integrated strategies to achieve inclusive excellence within the scientific workforce reflected by creating and sustaining environments, in which diverse talent thrives. The National Institutes of Health (NIH) Scientific Workforce Diversity office has led the charge to develop and implement evidence-informed interventions toward achieving this goal that undergirds NIH's mission to improve the nation's health. Past and current efforts aiming to enhance workforce diversity but targeted to individuals are necessary but insufficient for lasting change. Thus, NIH-funded institutions should develop and prioritize integrated, systems-targeted efforts as foundational components of a well-supported, productive workforce. At the heart of these endeavors is institutional accountability that ties progress toward inclusive excellence to institutional values and reward systems.
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http://dx.doi.org/10.1096/fj.202001937DOI Listing
October 2020

Transcriptomics in transplantation: More than just biomarkers of allograft rejection.

Am J Transplant 2021 06 21;21(6):2000-2001. Epub 2020 Dec 21.

Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.

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http://dx.doi.org/10.1111/ajt.16429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178244PMC
June 2021

Where Are We in Bridging the Gender Leadership Gap in Academic Medicine?

Acad Med 2020 10;95(10):1475-1476

H.A. Valantine is chief officer, scientific workforce diversity, National Institutes of Health, Bethesda, Maryland.

In nearly all walks of life, leadership sets the tone for what gets done, who does it, and how it is achieved. In 2020, the top ranks of academic medicine have not yet attained gender parity-an aspirational goal set 7 years ago in this journal as "50:50 by 2020," and a vital aim for the United States' productivity and innovation as a leader in biomedical research. Parity in academic leadership for women and other groups underrepresented in science and medicine will seed the culture change necessary for inclusive excellence: environments in which individuals from all backgrounds thrive in their pursuit of new knowledge to benefit human health.In this Invited Commentary, the author describes the National Institutes of Health's (NIH's) current system-wide framework and tools for creating cultures of inclusive excellence through a set of guiding principles and integrated strategies. Successful efforts will recognize that individually focused solutions are necessary but not sufficient for institutional culture change. In keeping with a systems approach are implementing accountability and transparency; establishing clear metrics of inclusion, diversity, and equity; tracking and evaluating such metrics; as well as tying these metrics to institutional reward systems. These essential steps to institutional culture transformation require strong partnerships between NIH and the academic community. The author argues that with committed vision, focus, and energy, success is attainable, and soon.
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http://dx.doi.org/10.1097/ACM.0000000000003574DOI Listing
October 2020

NIH progress toward inclusive excellence.

Science 2020 Mar;367(6483):1204

Director, National Institutes of Health, Bethesda, MD 20814, USA.

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http://dx.doi.org/10.1126/science.abb4619DOI Listing
March 2020

Topic choice contributes to the lower rate of NIH awards to African-American/black scientists.

Sci Adv 2019 10 9;5(10):eaaw7238. Epub 2019 Oct 9.

Office of Portfolio Analysis, National Institutes of Health, Bethesda, MD, USA.

Despite efforts to promote diversity in the biomedical workforce, there remains a lower rate of funding of National Institutes of Health R01 applications submitted by African-American/black (AA/B) scientists relative to white scientists. To identify underlying causes of this funding gap, we analyzed six stages of the application process from 2011 to 2015 and found that disparate outcomes arise at three of the six: decision to discuss, impact score assignment, and a previously unstudied stage, topic choice. Notably, AA/B applicants tend to propose research on topics with lower award rates. These topics include research at the community and population level, as opposed to more fundamental and mechanistic investigations; the latter tend to have higher award rates. Topic choice alone accounts for over 20% of the funding gap after controlling for multiple variables, including the applicant's prior achievements. Our findings can be used to inform interventions designed to close the funding gap.
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http://dx.doi.org/10.1126/sciadv.aaw7238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785250PMC
October 2019

Early invasive assessment of the coronary microcirculation predicts subsequent acute rejection after heart transplantation.

Int J Cardiol 2019 09 8;290:27-32. Epub 2019 Apr 8.

Division of Cardiovascular Medicine, Stanford Cardiovascular Institute, Stanford University School of Medicine, USA. Electronic address:

Background: Acute allograft rejection (AAR) plays an important role in patient and graft survival; therefore, more emphasis should be placed on its prediction. This study aimed to investigate baseline clinical and diagnostic variables associated with subsequent AAR during the first year post-transplant, especially focusing on early physiologic and anatomic measures.

Methods: This study enrolled 88 heart transplant patients who underwent fractional flow reserve (FFR), coronary flow reserve (CFR), the index of microcirculatory resistance (IMR) and intravascular ultrasound (IVUS) in the left anterior descending artery at baseline (within 8 weeks post-transplant). Cardiac index (CI), pulmonary capillary wedge pressure (PCWP), mean pulmonary artery pressure (mPAP), right atrial pressure and left ventricular ejection fraction were also evaluated. AAR was defined as acute cellular rejection of grade ≥2R and/or pathological antibody-mediated rejection of grade ≥pAMR2.

Results: During the first year post-transplant, 25.0% of patients experienced AAR. Patients with AAR during the first year showed higher rates of recipient obesity, lower rates of recipient-donor sex mismatch and rATG and tacrolimus uses, higher PCWP, mPAP and IMR, and lower CFR at baseline, compared with those without. In the multivariate analysis, only baseline IMR ≥ 16.0 was independently associated with AAR during the first year, demonstrating high negative predictive value (96.7%).

Conclusions: Invasively assessing microvascular resistance (baseline IMR ≥ 16.0) in the early post-transplant period was an independent determinant of subsequent acute allograft rejection during the first year post-transplant, suggesting that early assessment of IMR may enhance patient risk stratification and target medical therapies to improve patient outcome.
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http://dx.doi.org/10.1016/j.ijcard.2019.04.018DOI Listing
September 2019

Donor-derived cell-free DNA predicts allograft failure and mortality after lung transplantation.

EBioMedicine 2019 Feb 26;40:541-553. Epub 2019 Jan 26.

Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, MD 20982, United States; Division of Intramural Research, National Heart, Lung and Blood Institute, 10 Center Drive, 7S261, Bethesda, MD 20982, United States. Electronic address:

Background: Allograft failure is common in lung-transplant recipients and leads to poor outcomes including early death. No reliable clinical tools exist to identify patients at high risk for allograft failure. This study tested the use of donor-derived cell-free DNA (%ddcfDNA) as a sensitive marker of early graft injury to predict impending allograft failure.

Methods: This multicenter, prospective cohort study enrolled 106 subjects who underwent lung transplantation and monitored them after transplantation for the development of allograft failure (defined as severe chronic lung allograft dysfunction [CLAD], retransplantation, and/or death from respiratory failure). Plasma samples were collected serially in the first three months following transplantation and assayed for %ddcfDNA by shotgun sequencing. We computed the average levels of ddcfDNA over three months for each patient (avddDNA) and determined its relationship to allograft failure using Cox-regression analysis.

Findings: avddDNA was highly variable among subjects: median values were 3·6%, 1·6% and 0·7% for the upper, middle, and low tertiles, respectively (range 0·1%-9·9%). Compared to subjects in the low and middle tertiles, those with avddDNA in the upper tertile had a 6·6-fold higher risk of developing allograft failure (95% confidence interval 1·6-19·9, p = 0·007), lower peak FEV1 values, and more frequent %ddcfDNA elevations that were not clinically detectable.

Interpretation: Lung transplant patients with early unresolving allograft injury measured via %ddcfDNA are at risk of subsequent allograft injury, which is often clinically silent, and progresses to allograft failure. FUND: National Institutes of Health.
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http://dx.doi.org/10.1016/j.ebiom.2018.12.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412014PMC
February 2019

Long-term prognostic value of invasive and non-invasive measures early after heart transplantation.

Int J Cardiol 2018 06;260:31-35

Stanford University Medical Center, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford, CA, USA. Electronic address:

Background: Invasively assessed coronary microvascular resistance early after heart transplantation predicts worse long-term outcome; however, little is known about the relationship between microvascular resistance, left ventricular function and outcomes in this setting.

Methods: A total of 100 cardiac transplant recipients had fractional flow reserve (FFR) and the index of microcirculatory resistance (IMR) measured in the left anterior descending artery and echocardiographic assessment of left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) at 1 year after heart transplantation. The primary endpoint was the composite of death and retransplantation occurring beyond the first post-operative year.

Results: The mean FFR, IMR, LVEF, and GLS values at 1 year were 0.87 ± 0.06, 21.3 ± 17.3, 60.4 ± 5.4%, and 14.2 ± 2.4%, respectively. FFR and IMR had no significant correlation with LVEF and GLS. During a mean follow-up of 6.7 ± 4.2 years, the primary endpoint occurred in 24 patients (24.0%). By ROC curve analysis, IMR = 19.3 and GLS = 13.3% were the best cutoff values for predicting death or retransplantation. Cumulative event-free survival was significantly lower in patients with higher IMR (log-rank p = 0.02) and lower GLS (log-rank p < 0.001). Cumulative event-free survival can be further stratified by the combination of IMR and GLS (long-rank p < 0.001). By multivariable Cox proportional hazards model, higher IMR and lower GLS were independently associated with long-term death or retransplantation (elevated IMR, hazard ratio = 2.50, p = 0.04 and reduced GLS, hazard ratio = 3.79, p = 0.003, respectively).

Conclusion: Invasively assessed IMR does not correlate with GLS at 1 year after heart transplantation. IMR and GLS determined at 1 year may be used as independent predictors of late death or retransplantation.
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http://dx.doi.org/10.1016/j.ijcard.2018.01.070DOI Listing
June 2018

Late manifestation of alloantibody-associated injury and clinical pulmonary antibody-mediated rejection: Evidence from cell-free DNA analysis.

J Heart Lung Transplant 2018 07 31;37(7):925-932. Epub 2018 Jan 31.

Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA. Electronic address:

Background: Antibody-mediated rejection (AMR) often progresses to poor health outcomes in lung transplant recipients (LTRs). This, combined with the relatively insensitive clinical tools used for its diagnosis (spirometry, histopathology) led us to determine whether clinical AMR is diagnosed significantly later than its pathologic onset. In this study, we leveraged the high sensitivity of donor-derived cell-free DNA (ddcfDNA), a novel genomic tool, to detect early graft injury after lung transplantation.

Methods: We adjudicated AMR and acute cellular rejection (ACR) in 157 LTRs using the consensus criteria of the International Society for Heart and Lung Transplantation (ISHLT). We assessed the kinetics of allograft injury in relation to ACR or AMR using both clinical criteria (decline in spirometry from baseline) and molecular criteria (ddcfDNA); percent ddcfDNA was quantitated via shotgun sequencing. We used a mixed-linear model to assess the relationship between and ddcfDNA levels and donor-specific antibodies (DSA) in AMR LTRs.

Results: Compared with ACR, AMR episodes (n = 42) were associated with significantly greater allograft injury when assessed by both spirometric (0.1 liter vs -0.6 liter, p < 0.01) and molecular (ddcfDNA) analysis (1.1% vs 5.4%, p < 0.001). Allograft injury detected by ddcfDNA preceded clinical AMR diagnosis by a median of 2.8 months. Within the same interval, spirometry or histopathology did not reveal findings of allograft injury or dysfunction. Elevated levels of ddcfDNA before clinical diagnosis of AMR were associated with a concurrent rise in DSA levels.

Conclusion: Diagnosis of clinical AMR in LTRs lags behind DSA-associated molecular allograft injury as assessed by ddcfDNA.
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http://dx.doi.org/10.1016/j.healun.2018.01.1305DOI Listing
July 2018

50 Years to Gender Parity: Can STEM Afford to Wait?: A Cardiologist and NIH Chief Officer of Scientific Workforce Diversity Reflects on What It Will Take to Keep Women in Biomedicine.

IEEE Pulse 2017 Nov-Dec;8(6):46-48

The first spark of my desire to become a cardiologist came, believe it or not, in a third-grade art class where I was asked to draw and color the circulation of blood as depicted by 16th-century English physician William Harvey. This task enraptured me-seeing that something so beautiful could work so flawlessly. So, many years later, I remain intrigued by cardiac transplantation, the subspecialty in which I ultimately chose to anchor my career as a physician scientist. Each day I live in awe of the fact that you can remove someone's organ, place it in another, and still have that organ work beautifully, most of the time. But why does it sometimes fail?
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http://dx.doi.org/10.1109/MPUL.2017.2750839DOI Listing
May 2018

Impact of Asymmetric Dimethylarginine on Coronary Physiology Early After Heart Transplantation.

Am J Cardiol 2017 Sep 29;120(6):1020-1025. Epub 2017 Jun 29.

Division of Cardiovascular Medicine, Stanford University, Stanford, California. Electronic address:

Cardiac allograft vasculopathy is a major cause of long-term graft failure following heart transplantation. Asymmetric dimethylarginine (ADMA), a marker of endothelial dysfunction, has been mechanistically implicated in the development of cardiac allograft vasculopathy, but its impact on coronary physiology early after transplantation is unknown. Invasive indices of coronary physiology, namely, fractional flow reserve (FFR), the index of microcirculatory resistance, and coronary flow reserve, were measured with a coronary pressure wire in the left anterior descending artery within 8 weeks (baseline) and 1 year after transplant. Plasma levels of ADMA were concurrently assayed using high-performance liquid chromatography. In 46 heart transplant recipients, there was a statistically significant correlation between elevated ADMA levels and lower FFR values at baseline (r = -0.33; p = 0.024); this modest association persisted 1 year after transplant (r = -0.39; p = 0.0085). Patients with a baseline FFR <0.90 (a prognostically validated cutoff) had significantly higher baseline ADMA levels (0.63 ± 0.16 vs 0.54 ± 0.12 µM; p = 0.034). Baseline ADMA (odds ratio 1.80 per 0.1 µM; 95% confidence interval 1.07 to 3.03; p = 0.027) independently predicted a baseline FFR <0.90 after multivariable adjustment. Even after dichotomizing ADMA (≥0.60 µM, provides greatest diagnostic accuracy by receiver operating characteristic curve), this association remained significant (odds ratio 7.52, 95% confidence interval 1.74 to 32.49; p = 0.006). No significant relationship between ADMA and index of microcirculatory resistance or coronary flow reserve was detected. In conclusion, baseline ADMA was a strong independent predictor of FFR <0.90, suggesting that elevated ADMA levels are associated with abnormal epicardial function soon after heart transplantation.
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http://dx.doi.org/10.1016/j.amjcard.2017.06.036DOI Listing
September 2017

Angiotensin-Converting Enzyme Inhibition Early After Heart Transplantation.

J Am Coll Cardiol 2017 Jun;69(23):2832-2841

Stanford Cardiovascular Institute and Division of Cardiovascular Medicine, Stanford, California.

Background: Cardiac allograft vasculopathy (CAV) remains a leading cause of mortality after heart transplantation (HT). Angiotensin-converting enzyme inhibitors (ACEIs) may retard the development of CAV but have not been well studied after HT.

Objectives: This study tested the safety and efficacy of the ACEI ramipril on the development of CAV early after HT.

Methods: In this prospective, multicenter, randomized, double-blind, placebo-controlled trial, 96 HT recipients were randomized to undergo ramipril or placebo therapy. They underwent coronary angiography, endothelial function testing; measurements of fractional flow reserve (FFR) and coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR); and intravascular ultrasonography (IVUS) of the left anterior descending coronary artery, within 8 weeks of HT. At 1 year, the invasive assessment was repeated. Circulating endothelial progenitor cells (EPCs) were quantified at baseline and 1 year.

Results: Plaque volumes at 1 year were similar between the ramipril and placebo groups (162.1 ± 70.5 mm vs. 177.3 ± 94.3 mm, respectively; p = 0.73). Patients receiving ramipril had improvement in microvascular function as shown by a significant decrease in IMR (21.4 ± 14.7 to 14.4 ± 6.3; p = 0.001) and increase in CFR (3.8 ± 1.7 to 4.8 ± 1.5; p = 0.017), from baseline to 1 year. This did not occur with IMR (17.4 ± 8.4 to 21.5 ± 20.0; p = 0.72) or CFR (4.1 ± 1.8 to 4.1 ± 2.2; p = 0.60) in the placebo-treated patients. EPCs decreased significantly at 1 year in the placebo group but not in the ramipril group.

Conclusions: Ramipril does not slow development of epicardial plaque volume but does stabilize levels of endothelial progenitor cells and improve microvascular function, which have been associated with improved long-term survival after HT. (Angiotensin Converting Enzyme [ACE] Inhibition and Cardiac Allograft Vasculopathy; NCT01078363).
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http://dx.doi.org/10.1016/j.jacc.2017.03.598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546225PMC
June 2017

The effect of negative remodeling on fractional flow reserve after cardiac transplantation.

Int J Cardiol 2017 Aug 8;241:283-287. Epub 2017 Apr 8.

Division of Cardiovascular Medicine, Stanford University Medical Center, Stanford, CA, United States.

Background: Negative remodeling is a common occurrence early after cardiac transplantation. Its impact on the development of myocardial ischemia is not well documented. The aim of this study is to investigate the impact of negative remodeling on fractional flow reserve after cardiac transplantation.

Methods: Thirty-four cardiac transplant recipients underwent intravascular ultrasound (IVUS) and fractional flow reserve (FFR) assessment soon after transplantation and one year later. Patients were divided into those with and without negative remodeling based on IVUS, and the impact on FFR was assessed. In the 19 patients with negative remodeling, there was no significant change in plaque volume (119.3±82.0 to 131.3±91.2mm, p=0.21), but vessel volume (775.6±212.0 to 621.9±144.1mm, p<0.0001) and lumen volume (656.3±169.1 to 490.7±132.0mm, p<0.0001) decreased significantly and FFR likewise decreased significantly (0.88±0.06 to 0.84±0.07, p=0.04). In the 15 patients without negative remodeling, vessel volume did not change (711.7±217.6 to 745.7±198.5, p=0.28), but there was a significant increase in plaque volume (126.8±88.3 to 194.4±92.7, p<0.001) and a resultant significant decrease in FFR (0.89±0.05 to 0.85±0.05, p=0.01).

Conclusion: Negative remodeling itself, without any change in plaque volume can cause a significant decrease in fractional flow reserve after cardiac transplantation and appears to be another possible mechanism for myocardial ischemia.
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http://dx.doi.org/10.1016/j.ijcard.2017.04.020DOI Listing
August 2017

Science Has a Gender Problem.

Sci Am 2016 Nov;315(6):12

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http://dx.doi.org/10.1038/scientificamerican1216-12DOI Listing
November 2016

From the NIH: A Systems Approach to Increasing the Diversity of the Biomedical Research Workforce.

CBE Life Sci Educ Fall 2016;15(3)

National Institute of General Medical Sciences, National Institutes of Health, Bethesda, MD 20892.

The National Institutes of Health (NIH) is committed to attracting, developing, and supporting the best scientists from all groups as an integral part of excellence in training. Biomedical research workforce diversity, capitalizing on the full spectrum of skills, talents, and viewpoints, is essential for solving complex human health challenges. Over the past few decades, the biomedical research workforce has benefited from NIH programs aimed at enhancing diversity. However, there is considerable room for improvement, particularly at the level of independent scientists and within scientific leadership. We provide a rationale and specific opportunities to develop and sustain a diverse biomedical research workforce through interventions that promote the successful transitions to different stages on the path toward completion of training and entry into the biomedical workforce.
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http://dx.doi.org/10.1187/cbe.16-03-0138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008902PMC
February 2017

Advancing the Progress of Mentoring for Diversity in AIDS Research: Warming the Mentoring Climate.

AIDS Behav 2016 09;20 Suppl 2:219-21

National Institutes of Health, Building 1 Room 316, 1 Center Drive, Bethesda, MD, 20814, USA.

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http://dx.doi.org/10.1007/s10461-016-1490-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993797PMC
September 2016

Attenuated-Signal Plaque Progression Predicts Long-Term Mortality After Heart Transplantation: IVUS Assessment of Cardiac Allograft Vasculopathy.

J Am Coll Cardiol 2016 07;68(4):382-92

Division of Cardiovascular Medicine, Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California. Electronic address:

Background: Although cardiac allograft vasculopathy (CAV) is typically characterized by diffuse coronary intimal thickening with pathological vessel remodeling, plaque instability may also play an important role in CAV. Previous studies of native coronary atherosclerosis have demonstrated associations between attenuated-signal plaque (ASP), plaque instability, and adverse clinical events.

Objectives: This study's aim was to characterize the association between ASP and long-term mortality post-heart transplantation.

Methods: In 105 heart transplant recipients, serial (baseline and 1-year post-transplant) intravascular ultrasound was performed in the first 50 mm of the left anterior descending artery. The ASP score was calculated by grading the measured angle of attenuation from grades 0 to 4 (specifically, 0°, 1° to 90°, 91° to 180°, 181° to 270°, and >270°) at 1-mm intervals. The primary endpoint was all-cause death or retransplantation.

Results: At 1-year post-transplant, 10.5% of patients demonstrated ASP progression (newly developed or increased ASP). Patients with ASP progression had a higher incidence of acute cellular rejection during the first year (63.6% vs. 22.3%; p = 0.006) and tendency for greater intimal growth (percent intimal volume: 9.2 ± 9.3% vs. 4.4 ± 5.3%; p = 0.07) than those without. Over a median follow-up of 4.6 years, there was a significantly lower event-free survival rate in patients with ASP progression at 1-year post-transplant compared with those without. In contrast, maximum intimal thickness did not predict long-term mortality.

Conclusions: ASP progression appears to reflect chronic inflammation related to acute cellular rejection and is an independent predictor of long-term mortality after heart transplantation. Serial assessments of plaque instability may enhance identification of high-risk patients who may benefit from closer follow-up and targeted medical therapies.
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http://dx.doi.org/10.1016/j.jacc.2016.05.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4959008PMC
July 2016

Single-stranded DNA library preparation uncovers the origin and diversity of ultrashort cell-free DNA in plasma.

Sci Rep 2016 06 14;6:27859. Epub 2016 Jun 14.

Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.

Circulating cell-free DNA (cfDNA) is emerging as a powerful monitoring tool in cancer, pregnancy and organ transplantation. Nucleosomal DNA, the predominant form of plasma cfDNA, can be adapted for sequencing via ligation of double-stranded DNA (dsDNA) adapters. dsDNA library preparations, however, are insensitive to ultrashort, degraded cfDNA. Drawing inspiration from advances in paleogenomics, we have applied a single-stranded DNA (ssDNA) library preparation method to sequencing of cfDNA in the plasma of lung transplant recipients (40 samples, six patients). We found that ssDNA library preparation yields a greater portion of sub-100 bp nuclear genomic cfDNA (p 10(-5), Mann-Whitney U Test), and an increased relative abundance of mitochondrial (10.7x, p 10(-5)) and microbial cfDNA (71.3x, p 10(-5)). The higher yield of microbial sequences from this method increases the sensitivity of cfDNA-based monitoring for infections following transplantation. We detail the fragmentation pattern of mitochondrial, nuclear genomic and microbial cfDNA over a broad fragment length range. We report the observation of donor-specific mitochondrial cfDNA in the circulation of lung transplant recipients. A ssDNA library preparation method provides a more informative window into understudied forms of cfDNA, including mitochondrial and microbial derived cfDNA and short nuclear genomic cfDNA, while retaining information provided by standard dsDNA library preparation methods.
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http://dx.doi.org/10.1038/srep27859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906518PMC
June 2016

Paradoxical Vessel Remodeling of the Proximal Segment of the Left Anterior Descending Artery Predicts Long-Term Mortality After Heart Transplantation.

JACC Heart Fail 2015 Dec 11;3(12):942-52. Epub 2015 Nov 11.

Division of Cardiovascular Medicine, Stanford Cardiovascular Institute, Stanford University Medical Center, Palo Alto, California. Electronic address:

Objectives: This study investigated the association between arterial remodeling and geographic distribution of cardiac allograft vasculopathy (CAV), and outcomes after heart transplantation.

Background: CAV is characterized by a combination of coronary intimal thickening and pathological vessel remodeling, which varies at different locations in coronary arteries.

Methods: In 100 transplant recipients, serial volumetric intravascular ultrasonography (IVUS) was performed at baseline and 1 year post-transplantation in the first 50 mm of the left anterior descending artery (LAD). IVUS indices were evaluated in the entire segment and 3 equally divided LAD segments. Paradoxical vessel remodeling was defined as [Δvessel volume/Δintimal volume <0].

Results: After 1 year, death or re-transplantation occurred in 20 patients over a median follow-up period of 4.7 years. Paradoxical vessel remodeling was observed in 57%, 41%, 50%, and 40% for the entire vessel, proximal, middle, and distal LAD segments, respectively. Kaplan-Meier analysis revealed a significantly lower event-free rate of survival in patients with paradoxical vessel remodeling involving the proximal LAD segment, which was not present when involving the entire LAD or mid and distal LAD segments. In multivariate analysis, paradoxical vessel remodeling of the proximal LAD segment was independently associated with death or re-transplantation (hazard ratio [HR]: 11.18; 95% confidence interval [CI]: 2.39 to 83.23; p = 0.0015).

Conclusions: Despite the diffuse nature of CAV, paradoxical vessel remodeling of the proximal LAD segment at 1 year was the primary determinant of long-term mortality or re-transplantation. Assessment of arterial remodeling combined with coronary intimal thickening may enhance identification of high-risk patients who may benefit from closer follow-up and targeted medical therapies.
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http://dx.doi.org/10.1016/j.jchf.2015.07.013DOI Listing
December 2015

Monitoring pharmacologically induced immunosuppression by immune repertoire sequencing to detect acute allograft rejection in heart transplant patients: a proof-of-concept diagnostic accuracy study.

PLoS Med 2015 Oct 14;12(10):e1001890. Epub 2015 Oct 14.

Department of Bioengineering, Stanford University, Stanford, California, United States of America; Department of Applied Physics, Stanford University, Stanford, California, United States of America; Howard Hughes Medical Institute, Stanford, California, United States of America.

Background: It remains difficult to predict and to measure the efficacy of pharmacological immunosuppression. We hypothesized that measuring the B-cell repertoire would enable assessment of the overall level of immunosuppression after heart transplantation.

Methods And Findings: In this proof-of-concept study, we implemented a molecular-barcode-based immune repertoire sequencing assay that sensitively and accurately measures the isotype and clonal composition of the circulating B cell repertoire. We used this assay to measure the temporal response of the B cell repertoire to immunosuppression after heart transplantation. We selected a subset of 12 participants from a larger prospective cohort study (ClinicalTrials.gov NCT01985412) that is ongoing at Stanford Medical Center and for which enrollment started in March 2010. This subset of 12 participants was selected to represent post-heart-transplant events, with and without acute rejection (six participants with moderate-to-severe rejection and six without). We analyzed 130 samples from these patients, with an average follow-up period of 15 mo. Immune repertoire sequencing enables the measurement of a patient's net state of immunosuppression (correlation with tacrolimus level, r = -0.867, 95% CI -0.968 to -0.523, p = 0.0014), as well as the diagnosis of acute allograft rejection, which is preceded by increased immune activity with a sensitivity of 71.4% (95% CI 30.3% to 94.9%) and a specificity of 82.0% (95% CI 72.1% to 89.1%) (cell-free donor-derived DNA as noninvasive gold standard). To illustrate the potential of immune repertoire sequencing to monitor atypical post-transplant trajectories, we analyzed two more patients, one with chronic infections and one with amyloidosis. A larger, prospective study will be needed to validate the power of immune repertoire sequencing to predict rejection events, as this proof-of-concept study is limited to a small number of patients who were selected based on several criteria including the availability of a large number of samples and the absence or presence of rejection events.

Conclusions: If confirmed in larger, prospective studies, the method described here has potential applications in the tailored management of post-transplant immunosuppression and, more broadly, as a method for assessing the overall activity of the immune system.
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http://dx.doi.org/10.1371/journal.pmed.1001890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605651PMC
October 2015

National Institutes of Health addresses the science of diversity.

Proc Natl Acad Sci U S A 2015 Oct 21;112(40):12240-2. Epub 2015 Sep 21.

Director, US National Institutes of Health, Bethesda, MD 20814.

The US biomedical research workforce does not currently mirror the nation's population demographically, despite numerous attempts to increase diversity. This imbalance is limiting the promise of our biomedical enterprise for building knowledge and improving the nation's health. Beyond ensuring fairness in scientific workforce representation, recruiting and retaining a diverse set of minds and approaches is vital to harnessing the complete intellectual capital of the nation. The complexity inherent in diversifying the research workforce underscores the need for a rigorous scientific approach, consistent with the ways we address the challenges of science discovery and translation to human health. Herein, we identify four cross-cutting diversity challenges ripe for scientific exploration and opportunity: research evidence for diversity's impact on the quality and outputs of science; evidence-based approaches to recruitment and training; individual and institutional barriers to workforce diversity; and a national strategy for eliminating barriers to career transition, with scientifically based approaches for scaling and dissemination. Evidence-based data for each of these challenges should provide an integrated, stepwise approach to programs that enhance diversity rapidly within the biomedical research workforce.
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http://dx.doi.org/10.1073/pnas.1515612112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603507PMC
October 2015

Gene expression profiling to study racial differences after heart transplantation.

J Heart Lung Transplant 2015 Jul 7;34(7):970-7. Epub 2015 Feb 7.

Stanford University School of Medicine, Stanford, California.

Background: The basis for increased mortality after heart transplantation in African Americans and other non-Caucasian racial groups is poorly defined. We hypothesized that increased risk of adverse events is driven by biologic factors. To test this hypothesis in the Invasive Monitoring Attenuation through Gene Expression (IMAGE) study, we determined whether the event rate of the primary outcome of acute rejection, graft dysfunction, death, or retransplantation varied by race as a function of calcineurin inhibitor (CNI) levels and gene expression profile (GEP) scores.

Methods: We determined the event rate of the primary outcome, comparing racial groups, stratified by time after transplant. Logistic regression was used to compute the relative risk across racial groups, and linear modeling was used to measure the dependence of CNI levels and GEP score on race.

Results: In 580 patients monitored for a median of 19 months, the incidence of the primary end point was 18.3% in African Americans, 22.2% in other non-Caucasians, and 8.5% in Caucasians (p < 0.001). There were small but significant correlations of race and tacrolimus trough levels to the GEP score. Tacrolimus levels were similar among the races. Of patients receiving tacrolimus, other non-Caucasians had higher GEP scores than the other racial groups. African American recipients demonstrated a unique decrease in expression of the FLT3 gene in response to higher tacrolimus levels.

Conclusions: African Americans and other non-Caucasian heart transplant recipients were 2.5-times to 3-times more likely than Caucasians to experience outcome events in the Invasive Monitoring Attenuation through Gene Expression study. The increased risk of adverse outcomes may be partly due to the biology of the alloimmune response, which is less effectively inhibited at similar tacrolimus levels in minority racial groups.
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http://dx.doi.org/10.1016/j.healun.2015.01.987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475410PMC
July 2015

Teaching corporate in college.

Sci Transl Med 2014 Aug;6(251):251fs33

Department of Pharmacology, School of Medicine, University of Colorado, Aurora, CO 80045, USA.

By applying the strengths of corporate models for effective teamwork, academic scientists can drive transdisciplinary research and accelerate biomedical translation.
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http://dx.doi.org/10.1126/scitranslmed.3009450DOI Listing
August 2014

Circulating cell-free DNA enables noninvasive diagnosis of heart transplant rejection.

Sci Transl Med 2014 Jun;6(241):241ra77

Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.

Monitoring allograft health is an important component of posttransplant therapy. Endomyocardial biopsy is the current gold standard for cardiac allograft monitoring but is an expensive and invasive procedure. Proof of principle of a universal, noninvasive diagnostic method based on high-throughput screening of circulating cell-free donor-derived DNA (cfdDNA) was recently demonstrated in a small retrospective cohort. We present the results of a prospective cohort study (65 patients, 565 samples) that tested the utility of cfdDNA in measuring acute rejection after heart transplantation. Circulating cell-free DNA was purified from plasma and sequenced (mean depth, 1.2 giga-base pairs) to quantify the fraction of cfdDNA. Through a comparison with endomyocardial biopsy results, we demonstrate that cfdDNA enables diagnosis of acute rejection after heart transplantation, with an area under the receiver operating characteristic curve of 0.83 and sensitivity and specificity that are comparable to the intrinsic performance of the biopsy itself. This noninvasive genome transplant dynamics approach is a powerful and informative method for routine monitoring of allograft health without incurring the risk, discomfort, and expense of an invasive biopsy.
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http://dx.doi.org/10.1126/scitranslmed.3007803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326260PMC
June 2014

The gender gap in academic medicine: comparing results from a multifaceted intervention for stanford faculty to peer and national cohorts.

Acad Med 2014 Jun;89(6):904-11

Dr. Valantine is professor of medicine and senior associate dean for diversity and leadership, Stanford University School of Medicine, Stanford, California. Dr. Grewal is associate director, Office of Diversity and Leadership, Stanford University School of Medicine, Stanford, California. Dr. Ku is program director and senior research scientist, Office of Diversity and Leadership, Stanford University School of Medicine, Stanford, California. Dr. Moseley is director of organizational effectiveness, Office of Diversity and Leadership, Stanford University School of Medicine, Stanford, California. Dr. Shih is assistant professor of biostatistics, Stanford University School of Medicine, Stanford, California. Dr. Stevenson is vice dean and senior associate dean for academic affairs, Harold K. Faber Professor of Pediatrics, and professor, by courtesy, of obstetrics and gynecology, Stanford University School of Medicine, Stanford, California. Dr. Pizzo is David and Susan Heckerman Professor of Pediatrics and of Microbiology and Immunology and former dean of the School of Medicine, Stanford University, Stanford, California.

Purpose: To assess whether the proportion of women faculty, especially at the full professor rank, increased from 2004 to 2010 at Stanford University School of Medicine after a multifaceted intervention.

Method: The authors surveyed gender composition and faculty satisfaction five to seven years after initiating a multifaceted intervention to expand recruitment and development of women faculty. The authors assessed pre/post relative change and rates of increase in women faculty at each rank, and faculty satisfaction; and differences in pre/post change and estimated rate of increase between Stanford and comparator cohorts (nationally and at peer institutions).

Results: Post intervention, women faculty increased by 74% (234 to 408), with assistant, associate, and full professors increasing by 66% (108 to 179), 87% (74 to 138), and 75% (52 to 91), respectively. Nationally and at peer institutions, women faculty increased by about 30% (30,230 to 39,200 and 4,370 to 5,754, respectively), with lower percentages at each rank compared with Stanford. Estimated difference (95% CI) in annual rate of increase was larger for Stanford versus the national cohort: combined ranks 0.36 (0.17 to 0.56), P = .001; full professor 0.40 (0.18 to 0.62), P = .001; and versus the peer cohort: combined ranks 0.29 (0.07 to 0.51), P = .02; full professor 0.37 (0.14 to 0.60), P = .003. Stanford women faculty satisfaction increased from 48% (2003) to 71% (2008).

Conclusions: Increased satisfaction and proportion of women faculty, especially full professors, suggest that the intervention may ameliorate the gender gap in academic medicine.
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http://dx.doi.org/10.1097/ACM.0000000000000245DOI Listing
June 2014
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