Publications by authors named "Jennifer E Ho"

121 Publications

Cardiovascular Biomarkers of Obesity and Overlap With Cardiometabolic Dysfunction.

J Am Heart Assoc 2021 Jul 3;10(14):e020215. Epub 2021 Jul 3.

Cardiology Division Department of Medicine Massachusetts General Hospital Boston MA.

Background Obesity may be associated with a range of cardiometabolic manifestations. We hypothesized that proteomic profiling may provide insights into the biological pathways that contribute to various obesity-associated cardiometabolic traits. We sought to identify proteomic signatures of obesity and examine overlap with related cardiometabolic traits, including abdominal adiposity, insulin resistance, and adipose depots. Methods and Results We measured 71 circulating cardiovascular disease protein biomarkers in 6981 participants (54% women; mean age, 49 years). We examined the associations of obesity, computed tomography measures of adiposity, cardiometabolic traits, and incident metabolic syndrome with biomarkers using multivariable regression models. Of the 71 biomarkers examined, 45 were significantly associated with obesity, of which 32 were positively associated and 13 were negatively associated with obesity (false discovery rate <0.05 for all). There was significant overlap of biomarker profiles of obesity and cardiometabolic traits, but 23 biomarkers, including melanoma cell adhesion molecule (MCAM), growth differentiation factor-15 (GDF15), and lipoprotein(a) (LPA) were unique to metabolic traits only. Using hierarchical clustering, we found that the protein biomarkers clustered along 3 main trait axes: adipose, metabolic, and lipid traits. In longitudinal analyses, 6 biomarkers were significantly associated with incident metabolic syndrome: apolipoprotein B (apoB), insulin-like growth factor-binding protein 2 (IGFBP2), plasma kallikrein (KLKB1), complement C2 (C2), fibrinogen (FBN), and N-terminal pro-B-type natriuretic peptide (NT-proBNP); false discovery rate <0.05 for all. Conclusions We found that the proteomic architecture of obesity overlaps considerably with associated cardiometabolic traits, implying shared pathways. Despite overlap, hierarchical clustering of proteomic profiles identified 3 distinct clusters of cardiometabolic traits: adipose, metabolic, and lipid. Further exploration of these novel protein targets and associated pathways may provide insight into the mechanisms responsible for the progression from obesity to cardiometabolic disease.
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http://dx.doi.org/10.1161/JAHA.120.020215DOI Listing
July 2021

Associations of Alcohol Consumption with Cardiovascular Disease-Related Proteomic Biomarkers: The Framingham Heart Study.

J Nutr 2021 Jun 22. Epub 2021 Jun 22.

Department of Biostatistics, School of Public Health, Boston University, Boston, MA, USA.

Background: Alcohol consumption and cardiovascular disease (CVD) have a complex relation.

Objectives: We examined the associations between alcohol consumption, fasting plasma proteins, and CVD risk.

Methods: We performed cross-sectional association analyses of alcohol consumption with 71 CVD-related plasma proteins, and also performed prospective association analyses of alcohol consumption and protein concentrations with 3 CVD risk factors (obesity, hypertension, and diabetes) in 6745 Framingham Heart Study (FHS) participants (mean age 49 y; 53% women).

Results: A unit increase in log10 transformed alcohol consumption (g/d) was associated with an increased risk of hypertension (HR = 1.14; 95% CI: 1.04, 1.26; P = 0.007), and decreased risks of obesity (HR = 0.80; 95% CI: 0.71, 0.91; P = 4.6 × 10-4) and diabetes (HR: 0.68; 95% CI: 0.58, 0.80; P = 5.1 × 10-6) in a median of 13-y (interquartile = 7, 14) of follow-up. We identified 43 alcohol-associated proteins in a discovery sample (n = 4348, false discovery rate <0.05) and 20 of them were significant (P <0.05/43) in an independent validation sample (n = 2397). Eighteen of the 20 proteins were inversely associated with alcohol consumption. Four of the 20 proteins demonstrated 3-way associations, as expected, with alcohol consumption and CVD risk factors. For example, a greater concentration of APOA1 was associated with higher alcohol consumption (P = 1.2 × 10-65), and it was also associated with a lower risk of diabetes (P = 8.5 × 10-6). However, several others showed unexpected 3-way associations.

Conclusions: We identified 20 alcohol-associated proteins in 6745 FHS samples. These alcohol-associated proteins demonstrated complex relations with the 3 CVD risk factors. Future studies with integration of more proteomic markers and larger sample size are warranted to unravel the complex relation between alcohol consumption and CVD risk.
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http://dx.doi.org/10.1093/jn/nxab186DOI Listing
June 2021

Deep Learning to Predict Cardiac Magnetic Resonance-Derived Left Ventricular Mass and Hypertrophy From 12-Lead ECGs.

Circ Cardiovasc Imaging 2021 Jun 15;14(6):e012281. Epub 2021 Jun 15.

Cardiovascular Disease Initiative (S.K., J.P.P., C.D.A., P.T.E., J.E.H., S.A.L.), Broad Institute of Harvard and the Massachusetts Institute of Technology, Cambridge.

Background: Classical methods for detecting left ventricular (LV) hypertrophy (LVH) using 12-lead ECGs are insensitive. Deep learning models using ECG to infer cardiac magnetic resonance (CMR)-derived LV mass may improve LVH detection.

Methods: Within 32 239 individuals of the UK Biobank prospective cohort who underwent CMR and 12-lead ECG, we trained a convolutional neural network to predict CMR-derived LV mass using 12-lead ECGs (left ventricular mass-artificial intelligence [LVM-AI]). In independent test sets (UK Biobank [n=4903] and Mass General Brigham [MGB, n=1371]), we assessed correlation between LVM-AI predicted and CMR-derived LV mass and compared LVH discrimination using LVM-AI versus traditional ECG-based rules (ie, Sokolow-Lyon, Cornell, lead aVL rule, or any ECG rule). In the UK Biobank and an ambulatory MGB cohort (MGB outcomes, n=28 612), we assessed associations between LVM-AI predicted LVH and incident cardiovascular outcomes using age- and sex-adjusted Cox regression.

Results: LVM-AI predicted LV mass correlated with CMR-derived LV mass in both test sets, although correlation was greater in the UK Biobank (r=0.79) versus MGB (r=0.60, P<0.001 for both). When compared with any ECG rule, LVM-AI demonstrated similar LVH discrimination in the UK Biobank (LVM-AI c-statistic 0.653 [95% CI, 0.608 -0.698] versus any ECG rule c-statistic 0.618 [95% CI, 0.574 -0.663], P=0.11) and superior discrimination in MGB (0.621; 95% CI, 0.592 -0.649 versus 0.588; 95% CI, 0.564 -0.611, P=0.02). LVM-AI-predicted LVH was associated with incident atrial fibrillation, myocardial infarction, heart failure, and ventricular arrhythmias.

Conclusions: Deep learning-inferred LV mass estimates from 12-lead ECGs correlate with CMR-derived LV mass, associate with incident cardiovascular disease, and may improve LVH discrimination compared to traditional ECG rules.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.012281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217289PMC
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

Heart failure with preserved ejection fraction according to the HFA-PEFF score in COVID-19 patients: clinical correlates and echocardiographic findings.

Eur J Heart Fail 2021 May 1. Epub 2021 May 1.

Department of Cardiology (CBF), Charité Universitätsmedizin Berlin, Berlin, Germany.

Aims: Viral-induced cardiac inflammation can induce heart failure with preserved ejection fraction (HFpEF)-like syndromes. COVID-19 can lead to myocardial damage and vascular injury. We hypothesised that COVID-19 patients frequently develop a HFpEF-like syndrome, and designed this study to explore this.

Methods And Results: Cardiac function was assessed in 64 consecutive, hospitalized, and clinically stable COVID-19 patients from April-November 2020 with left ventricular ejection fraction (LVEF) ≥50% (age 56 ± 19 years, females: 31%, severe COVID-19 disease: 69%). To investigate likelihood of HFpEF presence, we used the HFA-PEFF score. A low (0-1 points), intermediate (2-4 points), and high (5-6 points) HFA-PEFF score was observed in 42%, 33%, and 25% of patients, respectively. In comparison, 64 subjects of similar age, sex, and comorbidity status without COVID-19 showed these scores in 30%, 66%, and 4%, respectively (between groups: P = 0.0002). High HFA-PEFF scores were more frequent in COVID-19 patients than controls (25% vs. 4%, P = 0.001). In COVID-19 patients, the HFA-PEFF score significantly correlated with age, estimated glomerular filtration rate, high-sensitivity troponin T (hsTnT), haemoglobin, QTc interval, LVEF, mitral E/A ratio, and H FPEF score (all P < 0.05). In multivariate, ordinal regression analyses, higher age and hsTnT were significant predictors of increased HFA-PEFF scores. Patients with myocardial injury (hsTnT ≥14 ng/L: 31%) vs. patients without myocardial injury, showed higher HFA-PEFF scores [median 5 (interquartile range 3-6) vs. 1 (0-3), P < 0.001] and more often showed left ventricular diastolic dysfunction (75% vs. 27%, P < 0.001).

Conclusion: Hospitalized COVID-19 patients frequently show high likelihood of presence of HFpEF that is associated with cardiac structural and functional alterations, and myocardial injury. Detailed cardiac assessments including echocardiographic determination of left ventricular diastolic function and biomarkers should become routine in the care of hospitalized COVID-19 patients.
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http://dx.doi.org/10.1002/ejhf.2210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239668PMC
May 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

Metabolic Cost of Exercise Initiation in Patients With Heart Failure With Preserved Ejection Fraction vs Community-Dwelling Adults.

JAMA Cardiol 2021 Jun;6(6):653-660

Simches Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston.

Importance: Heart failure with preserved ejection fraction (HFpEF) is a joint metabolic and cardiovascular disorder with significant noncardiac contributions.

Objective: To define and quantify the metabolic cost of initiating exercise in individuals with and without HFpEF and its functional consequences.

Design, Setting, And Participants: This prospective cohort study included individuals with hemodynamically confirmed HFpEF from the Massachusetts General Hospital Exercise Study (MGH-ExS) and community-dwelling participants from the Framingham Heart Study (FHS). Analysis began April 2016 and ended November 2020.

Exposures: Internal work (IW), a measure of work equivalents required to initiate movement.

Main Outcomes And Measures: Using breath-by-breath oxygen uptake (V̇o2) measurements and V̇o2-work rate associations, cost of initiating exercise (IW) in patients with HFpEF (MGH-ExS) and in community-dwelling individuals (FHS) was quantified. Linear regression was used to estimate associations between IW and clinical/hemodynamic measures.

Results: Of 3231 patients, 184 (5.7%) had HFpEF and were from MGH-ExS, and 3047 (94.3%) were community-dwelling individuals from FHS. In the MGH-ExS cohort, 86 (47%) were women, the median (interquartile range) age was 63 (53-72) years, and the median (interquartile range) peak V̇o2 level was 13.33 (11.77-15.62) mL/kg/min. In the FHS cohort, 1620 (53%) were women, the median (interquartile range) age was 54 (48-60) years, and the median (interquartile range) peak V̇o2 level was 22.2 (17.85-27.35) mL/kg/min. IW was higher in patients with HFpEF and accounted for 27% (interquartile range, 21%-39%) of the total work (IW + measured external workload on the cycle), compared with 15% (interquartile range, 12%-20%) of that in FHS participants. Body mass index accounted for greatest explained variance in patients with HFpEF from MGH-ExS and FHS participants (22% and 18%, respectively), while resting cardiac output and biventricular filling pressures were not significantly associated with variance in IW in patients with HFpEF. A higher IW in patients with HFpEF was associated with a greater increase in left- and right-sided cardiac filing pressure during unloaded exercise, despite similar resting hemodynamic measures across IW.

Conclusions And Relevance: This study found that internal work, a new body mass index-related measure reflecting the metabolic cost of initiating movement, is higher in individuals with HFpEF compared with middle-aged adults in the community and is associated with steep, early increases in cardiac filling pressures. These findings highlight the importance of quantifying heterogeneous responses to exercise initiation when evaluating functional intolerance in individuals at risk for or with HFpEF.
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http://dx.doi.org/10.1001/jamacardio.2021.0292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970388PMC
June 2021

Association of premature menopause with incident pulmonary hypertension: A cohort study.

PLoS One 2021 10;16(3):e0247398. Epub 2021 Mar 10.

Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.

Background: Several forms of pulmonary hypertension (PH) disproportionately affect women. Animal and human studies suggest that estradiol exerts mixed effects on the pulmonary vasculature. Whether premature menopause represents a risk factor for PH is unknown.

Methods And Findings: In this cohort study, women in the UK Biobank aged 40-69 years who were postmenopausal and had complete data available on reproductive history were included. Premature menopause, defined as menopause occurring before age 40 years. Postmenopausal women without premature menopause served as the reference group. The primary outcome was incident PH, ascertained by appearance of a qualifying ICD code in the participant's UK Biobank study record. Of 136,715 postmenopausal women included, 5,201 (3.8%) had premature menopause. Participants were followed up for a median of 11.1 (interquartile range 10.5-11.8) years. The primary outcome occurred in 38 women (0.73%) with premature menopause and 409 (0.31%) without. After adjustment for age, race, ever-smoking, body-mass index, systolic blood pressure, antihypertensive medication use, non-high-density lipoprotein cholesterol, cholesterol-lowering medication use, C-reactive protein, prevalent type 2 diabetes, obstructive sleep apnea, heart failure, mitral regurgitation, aortic stenosis, venous thromboembolism, forced vital capacity (FVC), the forced expiratory volume in 1 second-to-FVC ratio, use of menopausal hormone therapy, and hysterectomy status, premature menopause was independently associated with PH (hazard ratio 2.13, 95% CI 1.31-3.23, P<0.001). In analyses of alternate menopausal age thresholds, risk of PH appeared to increase progressively with younger age at menopause (Ptrend <0.001), with 4.8-fold risk in women with menopause before age 30 years (95% CI 1.82-12.74, P = 0.002). Use of menopausal hormone therapy did not modify the association of premature menopause with PH.

Conclusions: Premature menopause may represent an independent risk factor for PH in women. Further investigation of the role of sex hormones in PH is needed in animal and human studies to elucidate pathobiology and identify novel therapeutic targets.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247398PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946190PMC
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

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

Deliberating the Diagnostic Dilemma of Heart Failure With Preserved Ejection Fraction.

Circulation 2020 Nov 2;142(18):1770-1780. Epub 2020 Nov 2.

National Heart Centre Singapore (C.S.P.L.).

There is a lack of consensus on how we define heart failure with preserved ejection fraction (HFpEF), with wide variation in diagnostic criteria across society guidelines. This lack of uniformity in disease definition stems in part from an incomplete understanding of disease pathobiology, phenotypic heterogeneity, and natural history. We review current knowledge gaps and existing diagnostic tools and algorithms. We present a simple approach to implement these tools within the constraints of the current knowledge base, addressing separately (1) hospitalized individuals with rest congestion, where diagnosis is more straightforward; and (2) individuals with exercise intolerance, where diagnosis is more complex. Here, a potential role for advanced or provocative testing, including evaluation of hemodynamic responses to exercise is considered. More importantly, we propose focus areas for future studies to develop accurate and feasible diagnostic tools for HFpEF, including animal models that recapitulate human HFpEF, and human studies that both address a fundamental understanding of HFpEF pathobiology, and new diagnostic approaches and tools, as well. In sum, there is an urgent need to more accurately define the syndrome of HFpEF to inform diagnosis, patient selection for clinical trials, and, ultimately, future therapeutic approaches.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.041818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805557PMC
November 2020

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

Metabolic Architecture of Acute Exercise Response in Middle-Aged Adults in the Community.

Circulation 2020 Nov 15;142(20):1905-1924. Epub 2020 Sep 15.

Cardiology Division and the Simches Cardiovascular Research Center, Department of Medicine, Harvard Medical School (M.N., R.V.S., J.B.B., M.T., R.M., N.E.H., J.E.H., A.L.B., G.D.L.), Massachusetts General Hospital, Boston.

Background: Whereas regular exercise is associated with lower risk of cardiovascular disease and mortality, mechanisms of exercise-mediated health benefits remain less clear. We used metabolite profiling before and after acute exercise to delineate the metabolic architecture of exercise response patterns in humans.

Methods: Cardiopulmonary exercise testing and metabolite profiling was performed on Framingham Heart Study participants (age 53±8 years, 63% women) with blood drawn at rest (n=471) and at peak exercise (n=411).

Results: We observed changes in circulating levels for 502 of 588 measured metabolites from rest to peak exercise (exercise duration 11.9±2.1 minutes) at a 5% false discovery rate. Changes included reductions in metabolites implicated in insulin resistance (glutamate, -29%; =1.5×10; dimethylguanidino valeric acid [DMGV], -18%; =5.8×10) and increases in metabolites associated with lipolysis (1-methylnicotinamide, +33%; =6.1×10), nitric oxide bioavailability (arginine/ornithine + citrulline, +29%; =2.8×10), and adipose browning (12,13-dihydroxy-9Z-octadecenoic acid +26%; =7.4×10), among other pathways relevant to cardiometabolic risk. We assayed 177 metabolites in a separate Framingham Heart Study replication sample (n=783, age 54±8 years, 51% women) and observed concordant changes in 164 metabolites (92.6%) at 5% false discovery rate. Exercise-induced metabolite changes were variably related to the amount of exercise performed (peak workload), sex, and body mass index. There was attenuation of favorable excursions in some metabolites in individuals with higher body mass index and greater excursions in select cardioprotective metabolites in women despite less exercise performed. Distinct preexercise metabolite levels were associated with different physiologic dimensions of fitness (eg, ventilatory efficiency, exercise blood pressure, peak Vo). We identified 4 metabolite signatures of exercise response patterns that were then analyzed in a separate cohort (Framingham Offspring Study; n=2045, age 55±10 years, 51% women), 2 of which were associated with overall mortality over median follow-up of 23.1 years (≤0.003 for both).

Conclusions: In a large sample of community-dwelling individuals, acute exercise elicits widespread changes in the circulating metabolome. Metabolic changes identify pathways central to cardiometabolic health, cardiovascular disease, and long-term outcome. These findings provide a detailed map of the metabolic response to acute exercise in humans and identify potential mechanisms responsible for the beneficial cardiometabolic effects of exercise for future study.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049528PMC
November 2020

Aldosterone Antagonism in Atrial Fibrillation: Implications for AF-Predominant HFpEF.

Authors:
Jennifer E Ho

J Am Heart Assoc 2020 09 10;9(18):e018396. Epub 2020 Sep 10.

Division of Cardiology Cardiovascular Research Center Department of Medicine Massachusetts General Hospital, and Harvard Medical School Boston MA.

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http://dx.doi.org/10.1161/JAHA.120.018396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727010PMC
September 2020

Impaired Exercise Tolerance in Heart Failure With Preserved Ejection Fraction: Quantification of Multiorgan System Reserve Capacity.

JACC Heart Fail 2020 08 10;8(8):605-617. Epub 2020 Jun 10.

Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Pulmonary Critical Care Unit, Massachusetts General Hospital, Boston, Massachusetts; Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Exercise intolerance is a principal feature of heart failure with preserved ejection fraction (HFpEF), whether or not there is evidence of congestion at rest. The degree of functional limitation observed in HFpEF is comparable to patients with advanced heart failure and reduced ejection fraction. Exercise intolerance in HFpEF is characterized by impairments in the physiological reserve capacity of multiple organ systems, but the relative cardiac and extracardiac deficits vary among individuals. Detailed measurements made during exercise are necessary to identify and rank-order the multiorgan system limitations in reserve capacity that culminate in exertional intolerance in a given person. We use a case-based approach to comprehensively review mechanisms of exercise intolerance and optimal approaches to evaluate exercise capacity in HFpEF. We also summarize recent and ongoing trials of novel devices, drugs, and behavioral interventions that aim to improve specific exercise measures such as peak oxygen uptake, 6-min walk distance, heart rate, and hemodynamic profiles in HFpEF. Evaluation during the clinically relevant physiological perturbation of exercise holds promise to improve the precision with which HFpEF is defined and therapeutically targeted.
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http://dx.doi.org/10.1016/j.jchf.2020.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395858PMC
August 2020

Advancing Research on the Complex Interrelations Between Atrial Fibrillation and Heart Failure: A Report From a US National Heart, Lung, and Blood Institute Virtual Workshop.

Circulation 2020 Jun 8;141(23):1915-1926. Epub 2020 Jun 8.

Division of Research, Kaiser Permanente Northern California, Oakland (A.S.G.).

The interrelationships between atrial fibrillation (AF) and heart failure (HF) are complex and poorly understood, yet the number of patients with AF and HF continues to increase worldwide. Thus, there is a need for initiatives that prioritize research on the intersection between AF and HF. This article summarizes the proceedings of a virtual workshop convened by the US National Heart, Lung, and Blood Institute to identify important research opportunities in AF and HF. Key knowledge gaps were reviewed and research priorities were proposed for characterizing the pathophysiological overlap and deleterious interactions between AF and HF; preventing HF in people with AF; preventing AF in individuals with HF; and addressing symptom burden and health status outcomes in AF and HF. These research priorities will hopefully help inform, encourage, and stimulate innovative, cost-efficient, and transformative studies to enhance the outcomes of patients with AF and HF.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.045204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291844PMC
June 2020

Mechanistic Biomarkers Informative of Both Cancer and Cardiovascular Disease: JACC State-of-the-Art Review.

J Am Coll Cardiol 2020 06;75(21):2726-2737

Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Division of Cardiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Cardiovascular disease (CVD) and cancer are leading causes of morbidity and mortality worldwide. Although conventionally managed as separate disease processes, recent research has lent insight into compelling commonalities between CVD and cancer, including shared mechanisms for disease development and progression. In this review, the authors discuss several pathophysiological processes common to both CVD and cancer, such as inflammation, resistance to cell death, cellular proliferation, neurohormonal stress, angiogenesis, and genomic instability, in an effort to understand common mechanisms of both disease states. In particular, the authors highlight key circulating and genomic biomarkers associated with each of these processes, as well as their associations with risk and prognosis in both cancer and CVD. The purpose of this state-of-the-art review is to further our understanding of the potential mechanisms underlying cancer and CVD by contextualizing pathways and biomarkers common to both diseases.
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http://dx.doi.org/10.1016/j.jacc.2020.03.067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261288PMC
June 2020

Clinical and Hemodynamic Associations and Prognostic Implications of Ventilatory Efficiency in Patients With Preserved Left Ventricular Systolic Function.

Circ Heart Fail 2020 05 4;13(5):e006729. Epub 2020 May 4.

Cardiology Division, Department of Medicine (M.N., M.T., J.B.B., R.V.S., M.S., J.S., R.F., R.M., N.E.H., A.L.B., J.E.H., G.D.L.), Massachusetts General Hospital, Harvard Medical School, Boston.

Background: Ventilatory efficiency (minute ventilation required to eliminate carbon dioxide, VE/VCO2) during exercise potently predicts outcomes in advanced heart failure with reduced ejection fraction, but its prognostic significance for at-risk individuals with preserved left ventricular systolic function is unclear. We aimed to characterize mechanistic determinants and prognostic implications of VE/VCO2 in a single-center dyspneic referral cohort (MGH-ExS [Massachusetts General Hospital Exercise Study]) and in a large sample of community-dwelling participants in the FHS (Framingham Heart Study).

Methods: Maximum incremental cardiopulmonary exercise tests were performed. VE/VCO2 was assessed as the slope pre- and post-ventilatory anaerobic threshold (VE/VCO2, VE/VCO2), the slope throughout exercise (VE/VCO2), and as the lowest 30-second value (VE/VCO2).

Results: In the MGH-ExS (N=493, age 56±15 years, 61% women, left ventricular ejection fraction 64±8%), higher VE/VCO2 was associated with lower peak exercise cardiac output and steeper increases in exercise pulmonary capillary wedge pressure (both <0.0001). VE/VCO2 (hazard ratio, 1.34 per 1-SD unit [95% CI, 1.10-1.62] =0.003) was associated with future cardiovascular hospitalization/death and outperformed classical VE/VCO2 measures used in heart failure with reduced ejection fraction (VE/VCO2). In FHS (N=1936, age 54±9 years, 53% women), VE/VCO2 measures taken in low-to-moderate intensity exercise (including VE/VCO2, VE/VCO2) were directly associated with cardiovascular risk factor burden (smoking, Framingham cardiovascular disease risk score, and lower fitness; all <0.001).

Conclusions: Impaired ventilatory efficiency is associated with cardiovascular risk in the community and with adverse hemodynamic profiles and future hospitalizations/death in a referral population, highlighting the prognostic importance of easily acquired submaximum exercise ventilatory gas exchange measurements in broad populations with preserved left ventricular systolic function.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224335PMC
May 2020

Sex-related differences in contemporary biomarkers for heart failure: a review.

Eur J Heart Fail 2020 05 27;22(5):775-788. Epub 2020 Mar 27.

University of Groningen, University Medical Center Groningen, Department of Cardiology, Groningen, The Netherlands.

The use of circulating biomarkers for heart failure (HF) is engrained in contemporary cardiovascular practice and provides objective information about various pathophysiological pathways associated with HF syndrome. However, biomarker profiles differ considerably among women and men. For instance, in the general population, markers of cardiac stretch (natriuretic peptides) and fibrosis (galectin-3) are higher in women, whereas markers of cardiac injury (cardiac troponins) and inflammation (sST2) are higher in men. Such differences may reflect sex-specific pathogenic processes associated with HF risk, but may also arise as a result of differences in sex hormone profiles and fat distribution. From a clinical perspective, sex-related differences in biomarker levels may affect the objectivity of biomarkers in HF management because what is considered to be 'normal' in one sex may not be so in the other. The objectives of this review are, therefore: (i) to examine the sex-specific dynamics of clinically relevant HF biomarkers in the general population, as well as in HF patients; (ii) to discuss the overlap between sex-related and obesity-related effects, and (iii) to identify knowledge gaps to stimulate research on sex-related differences in HF.
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http://dx.doi.org/10.1002/ejhf.1771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319414PMC
May 2020

Obesity Is Associated With Pulmonary Hypertension and Modifies Outcomes.

J Am Heart Assoc 2020 03 21;9(5):e014195. Epub 2020 Feb 21.

Cardiovascular Research Center Massachusetts General Hospital Boston MA.

Background Experimental studies support a link between obesity and pulmonary hypertension (PH), yet clinical studies have been limited. This study sought to determine the association of obesity and pulmonary hemodynamic measures and mortality in PH. Methods and Results We examined patients undergoing right-sided heart catherization (2005-2016) in a hospital-based cohort. Multivariable regression models tested associations of body mass index and pulmonary vascular hemodynamics, with PH defined as mean pulmonary artery pressure >20 mm Hg, and further subclassified into precapillary, postcapillary, and mixed PH. Multivariable Cox models were used to examine the effect of PH and obesity on mortality. Among 8940 patients (mean age, 62 years; 40% women), 52% of nonobese and 69% of obese individuals had evidence of PH. Higher body mass index was independently associated with greater odds of overall PH (odds ratio, 1.34; 95% CI, 1.29-1.40; <0.001 per 5-unit increase in body mass index) as well as each PH subtype (<0.001 for all). Patients with PH had greater risk of mortality compared with individuals without PH regardless of subgroup (<0.001 for all). We found that obesity was associated with 23% lower hazard of mortality among patients with PH (hazard ratio, 0.77; 95% CI, 0.69-0.85; <0.001). The effect of obesity was greatest among those with precapillary PH (hazard ratio, 0.57; 95% CI, 0.46-0.70; <0.001), where obesity modified the effect of PH on mortality ( for interaction=0.02). Conclusions Obesity is independently associated with PH. PH is associated with greater mortality; this is modified by obesity such that obese patients with precapillary PH have lower mortality compared with nonobese counterparts. Further studies are needed to elucidate mechanisms underlying obesity-related PH.
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http://dx.doi.org/10.1161/JAHA.119.014195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335575PMC
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

Adipsin preserves beta cells in diabetic mice and associates with protection from type 2 diabetes in humans.

Nat Med 2019 11 7;25(11):1739-1747. Epub 2019 Nov 7.

Weill Center for Metabolic Health and Division of Cardiology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.

Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function. Currently, there are no therapies proven to prevent beta cell loss and some, namely insulin secretagogues, have been linked to accelerated beta cell failure, thereby limiting their use in type 2 diabetes. The adipokine adipsin/complement factor D controls the alternative complement pathway and generation of complement component C3a, which acts to augment beta cell insulin secretion. In contrast to other insulin secretagogues, we show that chronic replenishment of adipsin in diabetic db/db mice ameliorates hyperglycemia and increases insulin levels while preserving beta cells by blocking dedifferentiation and death. Mechanistically, we find that adipsin/C3a decreases the phosphatase Dusp26; forced expression of Dusp26 in beta cells decreases expression of core beta cell identity genes and sensitizes to cell death. In contrast, pharmacological inhibition of DUSP26 improves hyperglycemia in diabetic mice and protects human islet cells from cell death. Pertaining to human health, we show that higher concentrations of circulating adipsin are associated with a significantly lower risk of developing future diabetes among middle-aged adults after adjusting for body mass index (BMI). Collectively, these data suggest that adipsin/C3a and DUSP26-directed therapies may represent a novel approach to achieve beta cell health to treat and prevent type 2 diabetes.
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http://dx.doi.org/10.1038/s41591-019-0610-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256970PMC
November 2019

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

Intramyocardial Triglycerides Among Women With vs Without HIV: Hormonal Correlates and Functional Consequences.

J Clin Endocrinol Metab 2019 12;104(12):6090-6100

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Context: Women with HIV (WHIV) on anti-retroviral therapy (ART) are living longer but facing heightened vulnerability to heart failure.

Objective: We investigated metabolic/hormonal/immune parameters relating to diastolic dysfunction-a precursor to heart failure-among WHIV without known cardiovascular disease (CVD).

Design And Outcome Measures: Nineteen ART-treated WHIV and 11 non-HIV-infected women without known CVD enrolled and successfully completed relevant study procedures [cardiac magnetic resonance spectroscopy (MRS) and cardiac MRI]. Groups were matched on age and body mass index. Primary outcome measures included intramyocardial triglyceride content (cardiac MRS) and diastolic function (cardiac MRI). Relationships between intramyocardial triglyceride content and clinical parameters were also assessed.

Results: Among WHIV (vs non-HIV-infected women), intramyocardial triglyceride content was threefold higher [1.2 (0.4, 3.1) vs 0.4 (0.1, 0.5)%, P = 0.01], and diastolic function was reduced (left atrial passive ejection fraction: 27.2 ± 9.6 vs 35.9 ± 6.4%, P = 0.007). There was a strong inverse relationship between intramyocardial triglyceride content and diastolic function (ρ = -0.62, P = 0.004). Among the whole group, intramyocardial triglyceride content did not relate to chronologic age but did increase across the reproductive aging spectrum (P = 0.02). HIV status and reproductive aging status remained independent predictors of intramyocardial triglyceride content after adjusting for relevant cardiometabolic parameters (overall model R2 = 0.56, P = 0.003; HIV status P = 0.01, reproductive aging status P = 0.02).

Conclusions: For asymptomatic WHIV, increased intramyocardial triglyceride content is associated with diastolic dysfunction. Moreover, relationships between intramyocardial triglyceride accumulation and women's reproductive aging are noted.
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http://dx.doi.org/10.1210/jc.2019-01096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954489PMC
December 2019
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