Publications by authors named "Emily S Lau"

33 Publications

Hypertensive Heartbreak.

N Engl J Med 2021 06;384(22):2145-2152

From Brigham and Women's Hospital, Boston.

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http://dx.doi.org/10.1056/NEJMcps2018493DOI Listing
June 2021

Association of obesity-related inflammatory pathways with lung function and exercise capacity.

Respir Med 2021 Jul 30;183:106434. Epub 2021 Apr 30.

From the Cardiovascular Research Center, Division of Massachusetts General Hospital, Boston, MA, USA; Cardiology Division of Massachusetts General Hospital, Boston, MA, USA. Electronic address:

Background: Obesity has multifactorial effects on lung function and exercise capacity. The contributions of obesity-related inflammatory pathways to alterations in lung function remain unclear.

Research Question: To examine the association of obesity-related inflammatory pathways with pulmonary function, exercise capacity, and pulmonary-specific contributors to exercise intolerance.

Method: We examined 695 patients who underwent cardiopulmonary exercise testing (CPET) with invasive hemodynamic monitoring at Massachusetts General Hospital between December 2006-June 2017. We investigated the association of adiponectin, leptin, resistin, IL-6, CRP, and insulin resistance (HOMA-IR) with pulmonary function and exercise parameters using multivariable linear regression.

Results: Obesity-related inflammatory pathways were associated with worse lung function. Specifically, higher CRP, IL-6, and HOMA-IR were associated with lower percent predicted FEV and FVC with a preserved FEV/FVC ratio suggesting a restrictive physiology pattern (P ≤ 0.001 for all). For example, a 1-SD higher natural-logged CRP level was associated with a nearly 5% lower percent predicted FEV and FVC (beta -4.8, s.e. 0.9 for FEV1; beta -4.9, s.e. 0.8 for FVC; P < 0.0001 for both). Obesity-related inflammatory pathways were associated with worse pulmonary vascular distensibility (adiponectin, IL-6, and CRP, P < 0.05 for all), as well as lower pulmonary artery compliance (IL-6 and CRP, P ≤ 0.01 for both).

Interpretation: Our findings highlight the importance of obesity-related inflammatory pathways including inflammation and insulin resistance on pulmonary spirometry and pulmonary vascular function. Specifically, systemic inflammation as ascertained by CRP, IL-6 and insulin resistance are associated with restrictive pulmonary physiology independent of BMI. In addition, inflammatory markers were associated with lower exercise capacity and pulmonary vascular dysfunction.
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http://dx.doi.org/10.1016/j.rmed.2021.106434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144063PMC
July 2021

Sex differences in inflammatory markers in patients hospitalized with COVID-19 infection: Insights from the MGH COVID-19 patient registry.

PLoS One 2021 28;16(4):e0250774. Epub 2021 Apr 28.

From the Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, United States of America.

Background: Men are at higher risk for serious complications related to COVID-19 infection than women. More robust immune activation in women has been proposed to contribute to decreased disease severity, although systemic inflammation has been associated with worse outcomes in COVID-19 infection. Whether systemic inflammation contributes to sex differences in COVID-19 infection is not known.

Study Design And Methods: We examined sex differences in inflammatory markers among 453 men (mean age 61) and 328 women (mean age 62) hospitalized with COVID-19 infection at the Massachusetts General Hospital from March 8 to April 27, 2020. Multivariable linear regression models were used to examine the association of sex with initial and peak inflammatory markers. Exploratory analyses examined the association of sex and inflammatory markers with 28-day clinical outcomes using multivariable logistic regression.

Results: Initial and peak CRP were higher in men compared with women after adjustment for baseline differences (initial CRP: ß 0.29, SE 0.07, p = 0.0001; peak CRP: ß 0.31, SE 0.07, p<0.0001) with similar findings for IL-6, PCT, and ferritin (p<0.05 for all). Men had greater than 1.5-greater odds of dying compared with women (OR 1.71, 95% CI 1.04-2.80, p = 0.03). Sex modified the association of peak CRP with both death and ICU admission, with stronger associations observed in men compared with women (death: OR 9.19, 95% CI 4.29-19.7, p <0.0001 in men vs OR 2.81, 95% CI 1.52-5.18, p = 0.009 in women, Pinteraction = 0.02).

Conclusions: In a sample of 781 men and women hospitalized with COVID-19 infection, men exhibited more robust inflammatory activation as evidenced by higher initial and peak inflammatory markers, as well as worse clinical outcomes. Better understanding of sex differences in immune responses to COVID-19 infection may shed light on the pathophysiology of COVID-19 infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250774PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081177PMC
May 2021

Cardiovascular Risk Factors are Associated with Future Cancer.

JACC CardioOncol 2021 Mar 16;3(1):48-58. Epub 2021 Mar 16.

Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.

Background: The extent to which co-occurrence of cardiovascular disease (CVD) and cancer is due to shared risk factors or other mechanisms is unknown.

Objectives: We investigated the association of standard CVD risk factors, CVD biomarkers, preexisting CVD, and ideal CV health metrics with the development of future cancer.

Methods: We prospectively followed Framingham Heart Study and PREVEND participants free of cancer at baseline, and ascertained histology-proven cancer. We studied the association of baseline CV risk factors, 10-year atherosclerotic CVD risk score, established CVD biomarkers, prevalent CVD, and AHA Life's Simple 7 CV health score with incident cancer using multivariable Cox models. Analyses of interim CVD events with incident cancer used time-dependent covariates.

Results: Among 20,305 participants (mean age 50 ± 14 years, 54% women), 2,548 incident cancer cases occurred over a median follow-up of 15.0 (13.3-15.0) surveillance years. Traditional CVD risk factors including age, sex, and smoking status were independently associated with cancer (P <0.001 for all). Estimated 10-year atherosclerotic CVD risk was also associated with future cancer (HR 1.16 per 5% increase in risk, 95% CI 1.14-1.17, P<0.001). We found that natriuretic peptides (NP) (tertile 3 vs 1: HR 1.40, 95% CI 1.03-1.91, p=0.035) was associated with incident cancer, but not high sensitivity troponin (hs-cTn) (p=0.47). Prevalent CVD and the development of interim CV events were not associated with higher risk of subsequent cancer. However, ideal CV health was associated with lower future cancer risk (HR 0.95 per 1-point increase in AHA health score, 95% CI 0.92-0.99, p=0.009).

Conclusions: CVD risk as captured by traditional CVD risk factors, 10-year atherosclerotic CVD risk score, and NP concentrations are associated with increased risk of future cancer. Conversely, a heart healthy lifestyle is associated with a reduced risk of future cancer. Our data suggest that the association between CVD and future cancer is attributable to shared risk factors.
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http://dx.doi.org/10.1016/j.jaccao.2020.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045786PMC
March 2021

Age dependent associations of risk factors with heart failure: pooled population based cohort study.

BMJ 2021 03 23;372:n461. Epub 2021 Mar 23.

Cardiovascular Research Center, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

Objective: To assess age differences in risk factors for incident heart failure in the general population.

Design: Pooled population based cohort study.

Setting: Framingham Heart Study, Prevention of Renal and Vascular End-stage Disease Study, and Multi-Ethnic Study of Atherosclerosis.

Participants: 24 675 participants without a history of heart failure stratified by age into young (<55 years; n=11 599), middle aged (55-64 years; n=5587), old (65-74 years; n=5190), and elderly (≥75 years; n=2299) individuals.

Main Outcome Measure: Incident heart failure.

Results: Over a median follow-up of 12.7 years, 138/11 599 (1%), 293/5587 (5%), 538/5190 (10%), and 412/2299 (18%) of young, middle aged, old, and elderly participants, respectively, developed heart failure. In young participants, 32% (n=44) of heart failure cases were classified as heart failure with preserved ejection fraction compared with 43% (n=179) in elderly participants. Risk factors including hypertension, diabetes, current smoking history, and previous myocardial infarction conferred greater relative risk in younger compared with older participants (P for interaction <0.05 for all). For example, hypertension was associated with a threefold increase in risk of future heart failure in young participants (hazard ratio 3.02, 95% confidence interval 2.10 to 4.34; P<0.001) compared with a 1.4-fold risk in elderly participants (1.43, 1.13 to 1.81; P=0.003). The absolute risk for developing heart failure was lower in younger than in older participants with and without risk factors. Importantly, known risk factors explained a greater proportion of overall population attributable risk for heart failure in young participants (75% 53% in elderly participants), with better model performance (C index 0.79 0.64). Similarly, the population attributable risks of obesity (21% 13%), hypertension (35% 23%), diabetes (14% 7%), and current smoking (32% 1%) were higher in young compared with elderly participants.

Conclusions: Despite a lower incidence and absolute risk of heart failure among younger compared with older people, the stronger association and greater attributable risk of modifiable risk factors among young participants highlight the importance of preventive efforts across the adult life course.
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http://dx.doi.org/10.1136/bmj.n461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986583PMC
March 2021

A Treacherous Course.

N Engl J Med 2021 Mar;384(9):860-865

From the Department of Medicine, Brigham and Women's Hospital (N.J., E.S.L., M.A.B., B.D.L., J.L.), the Department of Medicine, Massachusetts General Hospital (N.J.), and the Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute (M.A.B.) - all in Boston.

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http://dx.doi.org/10.1056/NEJMcps2020668DOI Listing
March 2021

Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Arterial Stiffness and Aabnormal Left Ventricular Hemodynamic Responses During Exercise.

J Card Fail 2021 Jun 26;27(6):625-634. Epub 2021 Feb 26.

Corrigan Minehan Heart Center, Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Background: Arterial stiffness is thought to contribute to the pathophysiology of heart failure with preserved ejection fraction (HFpEF). We sought to examine arterial stiffness in HFpEF and hypertension and investigate associations of arterial and left ventricular hemodynamic responses to exercise.

Methods And Results: A total of 385 symptomatic individuals with an EF of ≥50% underwent upright cardiopulmonary exercise testing with invasive hemodynamic assessment of arterial stiffness and load (aortic augmentation pressure, augmentation index, systemic vascular resistance index, total arterial compliance index, effective arterial elastance index, and pulse pressure amplification) at rest and during incremental exercise. An abnormal hemodynamic response to exercise was defined as a steep increase in pulmonary capillary wedge pressure relative to cardiac output (∆PCWP/∆CO > 2 mm Hg/L/min). We compared rest and exercise measures between HFpEF and hypertension in multivariable analyses. Among 188 participants with HFpEF (mean age 61 ± 13 years, 56% women), resting arterial stiffness parameters were worse compared with 94 hypertensive participants (mean age 55 ± 15 years, 52% women); these differences were accentuated during exercise in HFpEF (all P ≤ .0001). Among all participants, exercise measures of arterial stiffness correlated with worse ∆PCWP/∆CO. Specifically, a 1 standard deviation higher exercise augmentation pressure was associated with 2.15-fold greater odds of abnormal LV hemodynamic response (95% confidence interval 1.52-3.05; P < .001). Further, exercise measures of systemic vascular resistance index, elastance index, and pulse pressure amplification correlated with a lower peak oxygen consumption.

Conclusions: Exercise accentuates the increased arterial stiffness found in HFpEF, which in turn correlates with left ventricular hemodynamic responses. Unfavorable ventricular-vascular interactions during exercise in HFpEF may contribute to exertional intolerance and inform future therapeutic interventions.
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http://dx.doi.org/10.1016/j.cardfail.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8180488PMC
June 2021

Does Patient-Physician Gender Concordance Influence Patient Perceptions or Outcomes?

J Am Coll Cardiol 2021 Mar;77(8):1135-1138

Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jacc.2020.12.031DOI Listing
March 2021

Sex, Permanent Drug Discontinuation, and Study Retention in Clinical Trials: Insights From the TIMI trials.

Circulation 2021 Feb 15;143(7):685-695. Epub 2021 Feb 15.

TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (E.B., D.A.M., R.P.G., E.M.A., B.M.S., E.A.B., S.D.W., K.I., J.G., M.S.S., M.O.D.).

Background: Women are underrepresented across cardiovascular clinical trials. Whether women are more likely than men to prematurely discontinue study drug or withdraw consent once enrolled in a clinical trial is unknown.

Methods: Eleven phase 3/4 TIMI (Thrombolysis in Myocardial Infarction) trials were included (135 879 men and 51 812 women [28%]). The association between sex and premature study drug discontinuation and withdrawal of consent were examined by multivariable logistic regression after adjusting for potential confounders in each individual trial and combining the individual point estimates in random effects models.

Results: After adjusting for baseline differences, women had 22% higher odds of premature drug discontinuation (adjusted odds ratio [OR], 1.22 [95% CI, 1.16-1.28]; <0.001) compared with men. Qualitatively consistent results were observed for women versus men in the placebo arms (OR, 1.20 [95% CI, 1.13-1.27]) and active therapy arms (OR, 1.23 [95% CI, 1.17-1.30)]; there was some evidence for regional heterogeneity ( interaction <0.001). Of those who stopped study drug prematurely, a similar proportion of men and women in the active arm stopped because of an adverse event (36% for both; =0.60). Women were also more likely to withdraw consent compared with men (OR, 1.26 [95% CI, 1.17-1.36]; <0.001).

Conclusions: Women were more likely than men to prematurely discontinue study drug and withdraw consent across cardiovascular outcome trials. Premature study drug discontinuation was not explained by baseline differences by sex or a higher proportion of adverse events. Future trials should better capture reasons for drug discontinuation and withdrawal of consent to understand barriers to continued study drug use and clinical trial participation, particularly among women.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.052339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894618PMC
February 2021

Diet Diversity in Carnivorous Terebrid Snails Is Tied to the Presence and Absence of a Venom Gland.

Toxins (Basel) 2021 02 2;13(2). Epub 2021 Feb 2.

Department of Chemistry, Hunter College Belfer Research Center, City University of New York, New York, NY 10021, USA.

Predator-prey interactions are thought to play a driving role in animal evolution, especially for groups that have developed venom as their predatory strategy. However, how the diet of venomous animals influences the composition of venom arsenals remains uncertain. Two prevailing hypotheses to explain the relationship between diet and venom composition focus on prey preference and the types of compounds in venom, and a positive correlation between dietary breadth and the number of compounds in venom. Here, we examined venom complexity, phylogenetic relationship, collection depth, and biogeography of the Terebridae (auger snails) to determine if repeated innovations in terebrid foregut anatomy and venom composition correspond to diet variation. We performed the first molecular study of the diet of terebrid marine snails by metabarcoding the gut content of 71 terebrid specimens from 17 species. Our results suggest that the presence or absence of a venom gland is strongly correlated with dietary breadth. Specifically, terebrid species without a venom gland displayed greater diversity in their diet. Additionally, we propose a revision of the definition of venom complexity in conoidean snails to more accurately capture the breadth of ecological influences. These findings suggest that prey diet is an important factor in terebrid venom evolution and diversification and further investigations of other understudied organisms, like terebrids, are needed to develop robust hypotheses in this area.
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http://dx.doi.org/10.3390/toxins13020108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912948PMC
February 2021

Galectin-3 Inhibition With Modified Citrus Pectin in Hypertension.

JACC Basic Transl Sci 2021 Jan 6;6(1):12-21. Epub 2021 Jan 6.

Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.

We investigated the effect of galectin-3 (Gal-3) inhibition with modified citrus pectin on markers of collagen metabolism in a proof-of-concept randomized placebo-controlled trial of participants with elevated Gal-3 levels and hypertension. Although higher Gal-3 levels were associated with female sex, diabetes, and reduced glomerular filtration rate in cross-sectional analyses, treatment with modified citrus pectin did not change collagen markers. The effect of Gal-3 inhibition among individuals with heart failure warrants further investigation.
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http://dx.doi.org/10.1016/j.jacbts.2020.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838053PMC
January 2021

The role of obesity in inflammatory markers in COVID-19 patients.

Obes Res Clin Pract 2021 Jan-Feb;15(1):96-99. Epub 2020 Dec 23.

The Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, United States; Division of Cardiology, Massachusetts General Hospital, Boston, MA, United States. Electronic address:

Obesity has emerged as a significant risk factor for severe COVID-19 worldwide. Given both COVID-19 infection and obesity have been associated with increased systemic inflammation, we evaluated inflammatory markers in obese and non-obese individuals hospitalized for COVID-19 at Massachusetts General Hospital. We hypothesized that obese patients would have a more exuberant inflammatory response as evidenced by higher initial and peak inflammatory markers along with worse clinical outcomes. Of the 781 patients, 349 were obese (45%). Obese individuals had higher initial and peak levels of CRP and ESR as well as higher peak d-dimer (P < 0.01 for all) in comparison to non-obese individuals, while. IL-6 and ferritin were similar. In addition, obese individuals had a higher odds of requiring vasopressor use (OR 1.54, 95% CI 1.00-2.38, P = 0.05), developing hypoxemic respiratory failure (OR 1.58, 95% CI 1.04-2.40, P = 0.03) and death (OR 2.20, 95% CI 1.31-3.70, P = 0.003) within 28 days of presentation to care. Finally, higher baseline levels of CRP and D-dimer were associated with worse clinical outcomes even after adjustment for BMI. Our findings suggest greater disease severity in obese individuals is characterized by more exuberant inflammation.
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http://dx.doi.org/10.1016/j.orcp.2020.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833898PMC
February 2021

Multi-level convergence of complex traits and the evolution of bioluminescence.

Biol Rev Camb Philos Soc 2021 Apr 11;96(2):673-691. Epub 2020 Dec 11.

Ecology, Evolution, and Marine Biology, University of California, Santa Barbara, Santa Barbara, CA, 93106, U.S.A.

Evolutionary convergence provides natural opportunities to investigate how, when, and why novel traits evolve. Many convergent traits are complex, highlighting the importance of explicitly considering convergence at different levels of biological organization, or 'multi-level convergent evolution'. To investigate multi-level convergent evolution, we propose a holistic and hierarchical framework that emphasizes breaking down traits into several functional modules. We begin by identifying long-standing questions on the origins of complexity and the diverse evolutionary processes underlying phenotypic convergence to discuss how they can be addressed by examining convergent systems. We argue that bioluminescence, a complex trait that evolved dozens of times through either novel mechanisms or conserved toolkits, is particularly well suited for these studies. We present an updated estimate of at least 94 independent origins of bioluminescence across the tree of life, which we calculated by reviewing and summarizing all estimates of independent origins. Then, we use our framework to review the biology, chemistry, and evolution of bioluminescence, and for each biological level identify questions that arise from our systematic review. We focus on luminous organisms that use the shared luciferin substrates coelenterazine or vargulin to produce light because these organisms convergently evolved bioluminescent proteins that use the same luciferins to produce bioluminescence. Evolutionary convergence does not necessarily extend across biological levels, as exemplified by cases of conservation and disparity in biological functions, organs, cells, and molecules associated with bioluminescence systems. Investigating differences across bioluminescent organisms will address fundamental questions on predictability and contingency in convergent evolution. Lastly, we highlight unexplored areas of bioluminescence research and advances in sequencing and chemical techniques useful for developing bioluminescence as a model system for studying multi-level convergent evolution.
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http://dx.doi.org/10.1111/brv.12672DOI Listing
April 2021

Sex-Specific Associations of Cardiovascular Risk Factors and Biomarkers With Incident Heart Failure.

J Am Coll Cardiol 2020 09;76(12):1455-1465

Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address:

Background: Whether cardiovascular (CV) disease risk factors and biomarkers associate differentially with heart failure (HF) risk in men and women is unclear.

Objectives: The purpose of this study was to evaluate sex-specific associations of CV risk factors and biomarkers with incident HF.

Methods: The analysis was performed using data from 4 community-based cohorts with 12.5 years of follow-up. Participants (recruited between 1989 and 2002) were free of HF at baseline. Biomarker measurements included natriuretic peptides, cardiac troponins, plasminogen activator inhibitor-1, D-dimer, fibrinogen, C-reactive protein, sST2, galectin-3, cystatin-C, and urinary albumin-to-creatinine ratio.

Results: Among 22,756 participants (mean age 60 ± 13 years, 53% women), HF occurred in 2,095 participants (47% women). Age, smoking, type 2 diabetes mellitus, hypertension, body mass index, atrial fibrillation, myocardial infarction, left ventricular hypertrophy, and left bundle branch block were strongly associated with HF in both sexes (p < 0.001), and the combined clinical model had good discrimination in men (C-statistic = 0.80) and in women (C-statistic = 0.83). The majority of biomarkers were strongly and similarly associated with HF in both sexes. The clinical model improved modestly after adding natriuretic peptides in men (ΔC-statistic = 0.006; likelihood ratio chi-square = 146; p < 0.001), and after adding cardiac troponins in women (ΔC-statistic = 0.003; likelihood ratio chi-square = 73; p < 0.001).

Conclusions: CV risk factors are strongly and similarly associated with incident HF in both sexes, highlighting the similar importance of risk factor control in reducing HF risk in the community. There are subtle sex-related differences in the predictive value of individual biomarkers, but the overall improvement in HF risk estimation when included in a clinical HF risk prediction model is limited in both sexes.
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http://dx.doi.org/10.1016/j.jacc.2020.07.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493711PMC
September 2020

Sex Differences in Exercise Capacity and Quality of Life in Heart Failure With Preserved Ejection Fraction: A Secondary Analysis of the RELAX and NEAT-HFpEF Trials.

J Card Fail 2020 Mar 13;26(3):276-280. Epub 2020 Jan 13.

Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: Few studies have compared clinical characteristics, echocardiographic parameters, exercise capacity, and quality of life between women and men with heart failure with preserved ejection fraction (HFpEF).

Methods And Results: Subjects in the NIH-sponsored RELAX (N = 216) and NEAT (N = 107) trials completed baseline echocardiography, the Minnesota Living with Heart Failure Questionnaire (MLHFQ), and 6-minute walk test (6MWT). In an exploratory analysis, multivariable linear regression models were used to associate clinical and imaging characteristics with baseline 6MWT distance and MLHFQ score in women and men. Our cohort included 158 (49%) men and 165 (51%) women. Men had higher prevalence of atrial arrhythmias, ischemic heart disease, diabetes, anemia, and left ventricular (LV) hypertrophy. 6MWT and MLHFQ score did not differ between sexes. In multivariable analysis, ischemic heart disease, diastolic dysfunction, and exercise capacity predicted MLHFQ score for men, whereas only age and body mass index predicted MLHFQ score for women.

Conclusions: Men with HFpEF had more comorbidities and LV hypertrophy than women with HFpEF. In men, quality of life was associated with diastolic dysfunction, ischemic heart disease, and exercise capacity. Further research is needed to identify determinants of quality of life in women with HFpEF.
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http://dx.doi.org/10.1016/j.cardfail.2020.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078056PMC
March 2020

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

J Am Coll Cardiol 2020 01;75(1):17-26

Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

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 ± 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.
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http://dx.doi.org/10.1016/j.jacc.2019.10.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043927PMC
January 2020

Sex Differences in Cardiometabolic Traits and Determinants of Exercise Capacity in Heart Failure With Preserved Ejection Fraction.

JAMA Cardiol 2020 01;5(1):30-37

Division of Cardiology, Massachusetts General Hospital, Boston.

Importance: Sex differences in heart failure with preserved ejection fraction (HFpEF) have been established, but insights into the mechanistic drivers of these differences are limited.

Objective: To examine sex differences in cardiometabolic profiles and exercise hemodynamic profiles among individuals with HFpEF.

Design, Setting, And Participants: This cross-sectional study was conducted at a single-center tertiary care referral hospital from December 2006 to June 2017 and included 295 participants who met hemodynamic criteria for HFpEF based on invasive cardiopulmonary exercise testing results. We examined sex differences in distinct components of oxygen transport and utilization during exercise using linear and logistic regression models. The data were analyzed from June 2018 to May 2019.

Main Outcomes And Measures: Resting and exercise gas exchange and hemodynamic parameters obtained during cardiopulmonary exercise testing.

Results: Of 295 participants, 121 (41.0%) were men (mean [SD] age, 64 [12] years) and 174 (59.0%) were women (mean [SD] age, 61 [13] years). Compared with men, women with HFpEF in this tertiary referral cohort had fewer comorbidities, including diabetes, insulin resistance, and hypertension, and a more favorable adipokine profile. Exercise capacity was similar in men and women (percent predicted peak oxygen [O2] consumption: 66% in women vs 68% in men; P = .38), but women had distinct deficits in components of the O2 pathway, including worse biventricular systolic reserve (multivariable-adjusted analyses: ΔLVEF β = -1.70; SE, 0.86; P < .05; ΔRVEF β = -2.39, SE=0.80; P = .003), diastolic reserve (PCWP/CO: β = 0.63; SE, 0.31; P = .04), and peripheral O2 extraction (C(a-v)O2 β=-0.90, SE=0.22; P < .001)).

Conclusions And Relevance: Despite a lower burden of cardiometabolic disease and a similar percent predicted exercise capacity, women with HFpEF demonstrated greater cardiac and extracardiac deficits, including systolic reserve, diastolic reserve, and peripheral O2 extraction. These sex differences in cardiac and skeletal muscle responses to exercise may illuminate the pathophysiology underlying the development of HFpEF and should be investigated further.
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http://dx.doi.org/10.1001/jamacardio.2019.4150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822160PMC
January 2020

Sex Differences in Circulating Biomarkers of Cardiovascular Disease.

J Am Coll Cardiol 2019 09;74(12):1543-1553

Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Background: Differences in proteomic profiles between men and women may provide insights into the biological pathways that contribute to known sex differences in cardiovascular disease (CVD).

Objectives: This study sought to investigate sex differences in circulating biomarkers representative of biological pathways implicated in the development of CVD among Framingham Heart Study participants.

Methods: The authors measured 71 circulating CVD protein biomarkers in 7,184 participants (54% women, mean age 49 years). Multivariable models were used to evaluate the associations of sex, menopause, and hormone status with biomarkers. Cox models were used to examine whether sex modified the association of biomarkers with incident CVD.

Results: Of 71 biomarkers examined, 61 (86%) differed significantly between men and women, of which 37 were higher in women (including adipokines and inflammatory markers such as leptin and C-reactive protein), and 24 were higher in men (including fibrosis and platelet markers such as MMP-8 (matrix metalloproteinase-8) and TIMP-1 (tissue inhibitor of metalloproteinases 1); false discovery rate q < 0.05 for all). Sex differences in biomarker profiles were most pronounced between pre-menopausal women versus men, with attenuated sex differences among post-menopausal women not taking hormone replacement therapy. Sex modified the association of specific biomarkers with incident CVD, including CD14 and apolipoprotein B (p <0.05 for all).

Conclusions: In a predominantly Caucasian population, the authors identified widespread sex differences in circulating biomarkers that reflect distinct pathways implicated in CVD, including inflammation, adiposity, fibrosis, and platelet homeostasis. Menopause and hormone status accounted for some, but not all, of the observed sex differences. Further investigation into factors underlying sex-based differences may provide mechanistic insight into CVD development.
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http://dx.doi.org/10.1016/j.jacc.2019.06.077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756178PMC
September 2019

Where are the women in academic cardiology?

Lancet 2018 11;392(10160):2152-2153

Division of Cardiology, Massachusetts General Hospital, Boston MA, USA.

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http://dx.doi.org/10.1016/S0140-6736(18)32618-7DOI Listing
November 2018

The Association of Obesity and Cardiometabolic Traits With Incident HFpEF and HFrEF.

JACC Heart Fail 2018 08 11;6(8):701-709. Epub 2018 Jul 11.

Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Objectives: This study evaluated the associations of obesity and cardiometabolic traits with incident heart failure with preserved versus reduced ejection fraction (HFpEF vs. HFrEF). Given known sex differences in HF subtype, we examined men and women separately.

Background: Recent studies suggest that obesity confers greater risk of HFpEF versus HFrEF. Contributions of associated metabolic traits to HFpEF are less clear.

Methods: We studied 22,681 participants from 4 community-based cohorts followed for incident HFpEF versus HFrEF (ejection fraction ≥50% vs. <50%). We evaluated the association of body mass index (BMI) and cardiometabolic traits with incident HF subtype using Cox models.

Results: The mean age was 60 ± 13 years, and 53% were women. Over a median follow-up of 12 years, 628 developed incident HFpEF and 835 HFrEF. Greater BMI portended higher risk of HFpEF compared with HFrEF (hazard ratio [HR]: 1.34 per 1-SD increase in BMI; 95% confidence interval [CI]: 1.24 to 1.45 vs. HR: 1.18; 95% CI: 1.10 to 1.27). Similarly, insulin resistance (homeostatic model assessment of insulin resistance) was associated with HFpEF (HR: 1.20 per 1-SD; 95% CI: 1.05 to 1.37), but not HFrEF (HR: 0.99; 95% CI: 0.88 to 1.11; p < 0.05 for difference HFpEF vs. HFrEF). We found that the differential association of BMI with HFpEF versus HFrEF was more pronounced among women (p for difference HFpEF vs. HFrEF = 0.01) when compared with men (p = 0.34).

Conclusions: Obesity and related cardiometabolic traits including insulin resistance are more strongly associated with risk of future HFpEF versus HFrEF. The differential risk of HFpEF with obesity seems particularly pronounced among women and may underlie sex differences in HF subtypes.
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http://dx.doi.org/10.1016/j.jchf.2018.05.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076337PMC
August 2018

Valvular Heart Disease and Pregnancy.

Curr Treat Options Cardiovasc Med 2018 Apr 26;20(6):46. Epub 2018 Apr 26.

Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA.

With improving reproductive assistive technologies, advancing maternal age, and improved survival of patients with congenital heart disease, valvular heart disease has become an important cause of morbidity and mortality in pregnant women. In general, stenotic lesions, even those in the moderate range, are poorly tolerated in the face of hemodynamic changes of pregnancy. Regurgitant lesions, however, fare better due to the physiologic afterload reduction that occurs. Intervention on regurgitant valve preconception follows the same principles as a non-pregnant population. Prosthetic valves in pregnancy are increasingly commonplace, presenting new management challenges including valve deterioration and valve thrombosis. In particular, anticoagulation during pregnancy is challenging. Pregnancy is a hypercoagulable state and the risks of maternal bleeding and fetal anticoagulant risks need to be balanced. Maternal mortality and complications are lowest with warfarin use throughout pregnancy; however, fetal outcomes are best with low molecular weight heparin use. ACC/AHA guidelines recommend warfarin use, even in the first trimester, if doses are less than 5 mg/day; however, adverse fetal events are not zero at this dose. In addition, it is unclear if better monitoring of low molecular weight heparin with peak and trough anti-Xa levels would lower maternal risks as this has been inconsistently monitored in reported studies. Fortunately, with the emergence of newer data, our understanding of anticoagulant strategies in pregnancy is improving over time which should translate to better pregnancy outcomes in this higher risk population.
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http://dx.doi.org/10.1007/s11936-018-0643-xDOI Listing
April 2018

Sex Differences in Subclinical Coronary Atherosclerotic Plaque Among Individuals With HIV on Antiretroviral Therapy.

J Acquir Immune Defic Syndr 2018 08;78(4):421-428

Endocrine Division, Program in Nutritional Metabolism, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Background: In high-resource settings, the HIV-attributable risk of myocardial infarction (MI) is higher among women than among men. The extent to which unique mechanisms contribute to MI risk among women vs. men with HIV remains unclear.

Methods: Subclinical coronary atherosclerotic plaque characteristics-including high-risk morphology plaque features-were compared among 48 HIV-infected women [48 (41, 54) years] and 97 HIV-infected men [48 (42, 52) years] on stable antiretroviral therapy (ART) without known cardiovascular disease. These individuals had previously completed coronary computed tomography angiography and metabolic/immune phenotyping as part of a prospective study.

Results: Extending previous analyses, now focusing exclusively on ART-treated participants, we found that HIV-infected women had a lower prevalence of any subclinical coronary atherosclerotic plaque (35% vs. 62%, P = 0.003) and a lower number of segments with plaque (P = 0.01), compared with HIV-infected men. We also report for the first time that ART-treated HIV-infected women had a lower prevalence of high-risk positively remodeled plaque (25% vs. 51%, P = 0.003) and a lower number of positively remodeled plaque segments (P = 0.002). In models adjusting for cardiovascular risk factors, we further showed that male sex remained associated with any coronary plaque [odds ratio 3.8, 95% confidence interval: (1.4 to 11.4)] and with positively remodeled plaque [odds ratio 3.7, 95% confidence interval: (1.4, 10.9)].

Conclusions: ART-treated HIV-infected women (vs. HIV-infected men) had a lower prevalence and burden of subclinical coronary plaque and high-risk morphology plaque. Thus, unique sex-specific mechanisms beyond subclinical plaque may drive the higher HIV-attributable risk of MI among women vs. men.
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http://dx.doi.org/10.1097/QAI.0000000000001686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019171PMC
August 2018

Right atrial structure and function in patients with hypertension and with chronic heart failure.

Echocardiography 2018 07 30;35(7):905-914. Epub 2018 Mar 30.

Department of Emergency Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Background: Prior studies have shown that both heart failure (HF) and atrial fibrillation (AF) are factors that impact left atrial function and structure. However, right atrial (RA) function measured as RA emptying fraction (RAEF) on echocardiography has not been analyzed systematically in a chronic HF population. The aim of this study was to assess RA volume index (RAVI) and RAEF in patients with chronic HF and patients with hypertension (HTN) and to relate these findings to other cardiopulmonary ultrasound parameters and 12-month outcomes.

Methods And Results: In this prospective observational study, we identified 119 patients with chronic HF (64 patients without a history of AF [HF without AF], 55 with AF [HF with AF]), and 127 patients with HTN but without important cardiac disease who underwent routine outpatient transthoracic echocardiography. We found that RAEF was impaired in patients with HF without AF compared to patients with HTN (35% ±2 vs 50% ±1, P < .001), whereas RAVI did not differ between these two groups. Lower RAEF was associated with larger RAVI and higher estimated RA pressures but not with a higher degree of pulmonary congestion by lung ultrasound. Both lower RAEF and higher RAVI were associated with an increased risk of 12-month HF hospitalizations or all-cause death (age, sex, and AF adjusted HR: 4.07, 95% CI: 1.69-9.79; P = .002, vs 2.74, 95% CI: 1.15-6.54, P = .023).

Conclusions: In an outpatient HF cohort, both lower RAEF and increased RAVI were associated with other markers of impaired cardiac function and 12-month adverse events.
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http://dx.doi.org/10.1111/echo.13876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035770PMC
July 2018

Pulmonary Congestion by Lung Ultrasound in Ambulatory Patients With Heart Failure With Reduced or Preserved Ejection Fraction and Hypertension.

J Card Fail 2018 Apr 1;24(4):219-226. Epub 2018 Mar 1.

Harvard Medical School, Boston, Massachusetts; Department of Emergency Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address:

Background: Although pulmonary congestion can be quantified in heart failure (HF) by means of lung ultrasonography (LUS), little is known about LUS findings (B-lines) in different HF phenotypes. This prospective cohort study investigated the prevalence and clinical and echocardiographic correlates of B-lines in ambulatory HF patients with preserved (HFpEF) or reduced (HFrEF) ejection fraction compared with hypertensive patients. We related LUS findings to 12-month HF hospitalizations and all-cause mortality.

Methods And Results: We used LUS to examine hypertensive (n = 111), HFpEF (n = 46), and HFrEF (n = 73) patients (median age 66 y, 56% male, 79% white, and median EF 55%) undergoing clinically indicated outpatient echocardiography. B-line number was quantified offline, across 8 chest zones, blinded to clinical and echocardiographic characteristics. The proportion of patients with ≥3 B-lines was lower in hypertensive patients (13.5%) compared with both HFrEF (45.2%, P < .001) and HFpEF (34.8%; P = .05). HF patients with ≥3 B-lines had a higher risk of the composite outcome (age- and sex-adjusted hazard ratio 2.62, 95% confidence interval 1.15-5.96; P = .022).

Conclusions: When performed at the time of outpatient echocardiography, LUS findings of pulmonary congestion differ between patients with known HF and those with hypertension, and may be associated with adverse outcomes.
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http://dx.doi.org/10.1016/j.cardfail.2018.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895087PMC
April 2018

How do we attract and retain women in cardiology?

Clin Cardiol 2018 Feb 26;41(2):264-268. Epub 2018 Feb 26.

Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts.

The recruitment and advancement of women in cardiology is an important priority for the cardiology community. Despite improvements in sex disparities over the last 2 decades, women remain a small minority in cardiology. Recent studies have revealed key obstacles facing female cardiologists including radiation exposure, family responsibilities, unequal financial compensations, and lack of career advancement. To attract and retain more women into the field of cardiology, the cardiology community, including professional society leaders, division chiefs, and program directors, must all work to overcome these barriers.
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http://dx.doi.org/10.1002/clc.22921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6490032PMC
February 2018

Utility of Imaging in Risk Stratification of Chest Pain in Women.

Curr Treat Options Cardiovasc Med 2017 Sep;19(9):72

Massachusetts General Hospital, 55 Fruit Street, Boston, MA, USA.

Opinion Statement: Recent decades have seen a growing recognition that the understanding of sex differences in cardiovascular disease (CVD) is vital to optimal diagnosis and management, particularly of women (Mosca et al. Circulation 124:2145-54, 2011). There is simultaneously an increasing appreciation of the multifactorial nature of ischemic heart disease (IHD) in many patients, in whom disease may extend beyond the epicardial coronaries. While obstructive coronary artery disease (CAD) remains underdiagnosed in women and still represents a major burden of disease, women also present with nonobstructive CAD more commonly than men (Patel et al. N Engl J Med 362:886-95, 2010). Indeed, microvascular dysfunction, coronary artery vasospasm, and coronary dissections contribute to a larger proportion of IHD in women than men (Bairey Merz et al. J Am Coll Cardiol 47:S21-9, 2006). Here, we review the symptom presentation of women with IHD and the noninvasive modalities used to risk stratify women with suspected IHD.
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http://dx.doi.org/10.1007/s11936-017-0568-9DOI Listing
September 2017