Publications by authors named "Martin G Larson"

450 Publications

The association of lung function and pulmonary vasculature volume with cardiorespiratory fitness in the community.

Eur Respir J 2022 Jan 7. Epub 2022 Jan 7.

Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Introduction: Cardiorespiratory fitness is not limited by pulmonary mechanical reasons in the majority of adults. However, the degree to which lung function contributes to exercise response patterns among ostensibly healthy individuals remains unclear.

Methods: We examined 2314 Framingham Heart Study participants who underwent cardiopulmonary exercise testing (CPET) and pulmonary function testing. We investigated the association of FEV, FVC, FEV/FVC and DLCO with the primary outcome of peak VO, along with other CPET parameters using multivariable linear regression. Finally, we investigated the association of total and peripheral pulmonary blood vessel volume with peak VO.

Results: We found lower FEV, FVC and DLCO were associated with lower peak VO. For example, a one-liter lower FEV and FVC were associated with 7.1% (95% CI: 5.1%, 9.1%) and 6.0% (95% CI: 4.3%, 7.7%) lower peak VO, respectively By contrast, FEV/FVC ratio was not associated with peak VO. Lower lung function was associated with lower oxygen uptake efficiency slope oxygen pulse slope, VO at AT, V at AT and breathing reserve. In addition, lower total and peripheral pulmonary blood vessel volume were associated with a lower peak VO.

Conclusion: In a large, community-based cohort of adults, we found lower FEV, FVC and DLCO were associated with lower exercise capacity, as well as oxygen uptake efficiency slope and ventilatory efficiency. In addition, lower total and peripheral pulmonary blood vessel volume were associated with lower peak VO. These findings underscore the importance of lung function and blood vessel volume as contributors to overall exercise capacity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.01821-2021DOI Listing
January 2022

A comparison of statistical methods to predict the residual lifetime risk.

Eur J Epidemiol 2022 Jan 3. Epub 2022 Jan 3.

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

Lifetime risk measures the cumulative risk for developing a disease over one's lifespan. Modeling the lifetime risk must account for left truncation, the competing risk of death, and inference at a fixed age. In addition, statistical methods to predict the lifetime risk should account for covariate-outcome associations that change with age. In this paper, we review and compare statistical methods to predict the lifetime risk. We first consider a generalized linear model for the lifetime risk using pseudo-observations of the Aalen-Johansen estimator at a fixed age, allowing for left truncation. We also consider modeling the subdistribution hazard with Fine-Gray and Royston-Parmar flexible parametric models in left truncated data with time-covariate interactions, and using these models to predict lifetime risk. In simulation studies, we found the pseudo-observation approach had the least bias, particularly in settings with crossing or converging cumulative incidence curves. We illustrate our method by modeling the lifetime risk of atrial fibrillation in the Framingham Heart Study. We provide technical guidance to replicate all analyses in R.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10654-021-00815-8DOI Listing
January 2022

Device-measured physical activity, adiposity and mortality: a harmonised meta-analysis of eight prospective cohort studies.

Br J Sports Med 2021 Dec 7. Epub 2021 Dec 7.

Department of Sports Medicine, Norwegian School of Sports Sciences, Oslo, Norway.

Background: The joint associations of total and intensity-specific physical activity with obesity in relation to all-cause mortality risk are unclear.

Methods: We included 34 492 adults (72% women, median age 62.1 years, 2034 deaths during follow-up) in a harmonised meta-analysis of eight population-based prospective cohort studies with mean follow-up ranging from 6.0 to 14.5 years. Standard body mass index categories were cross-classified with sample tertiles of device-measured total, light-to-vigorous and moderate-to-vigorous physical activity and sedentary time. In five cohorts with waist circumference available, high and low waist circumference was combined with tertiles of moderate-to-vigorous physical activity.

Results: There was an inverse dose-response relationship between higher levels of total and intensity-specific physical activity and mortality risk in those who were normal weight and overweight. In individuals with obesity, the inverse dose-response relationship was only observed for total physical activity. Similarly, lower levels of sedentary time were associated with lower mortality risk in normal weight and overweight individuals but there was no association between sedentary time and risk of mortality in those who were obese. Compared with the obese-low total physical activity reference, the HRs were 0.59 (95% CI 0.44 to 0.79) for normal weight-high total activity and 0.67 (95% CI 0.48 to 0.94) for obese-high total activity. In contrast, normal weight-low total physical activity was associated with a higher risk of mortality compared with the obese-low total physical activity reference (1.28; 95% CI 0.99 to 1.67).

Conclusions: Higher levels of physical activity were associated with lower risk of mortality irrespective of weight status. Compared with obesity-low physical activity, there was no survival benefit of being normal weight if physical activity levels were low.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bjsports-2021-104827DOI Listing
December 2021

Matrix Gla Protein Levels Are Associated With Arterial Stiffness and Incident Heart Failure With Preserved Ejection Fraction.

Arterioscler Thromb Vasc Biol 2022 Feb 23;42(2):e61-e73. Epub 2021 Nov 23.

Framingham Heart Study, MA (S.J.H., C.Y., E.J.B., M.G.L., S.C., D.L.).

Objective: Arterial stiffness is a risk factor for cardiovascular disease, including heart failure with preserved ejection fraction (HFpEF). MGP (matrix Gla protein) is implicated in vascular calcification in animal models, and circulating levels of the uncarboxylated, inactive form of MGP (ucMGP) are associated with cardiovascular disease-related and all-cause mortality in human studies. However, the role of MGP in arterial stiffness is uncertain. Approach and Results: We examined the association of ucMGP levels with vascular calcification, arterial stiffness including carotid-femoral pulse wave velocity (PWV), and incident heart failure in community-dwelling adults from the Framingham Heart Study. To further investigate the link between MGP and arterial stiffness, we compared aortic PWV in age- and sex-matched young (4-month-old) and aged (10-month-old) wild-type and Mgp mice. Among 7066 adults, we observed significant associations between higher levels of ucMGP and measures of arterial stiffness, including higher PWV and pulse pressure. Longitudinal analyses demonstrated an association between higher ucMGP levels and future increases in systolic blood pressure and incident HFpEF. Aortic PWV was increased in older, but not young, female Mgp mice compared with wild-type mice, and this augmentation in PWV was associated with increased aortic elastin fiber fragmentation and collagen accumulation.

Conclusions: This translational study demonstrates an association between ucMGP levels and arterial stiffness and future HFpEF in a large observational study, findings that are substantiated by experimental studies showing that mice with Mgp heterozygosity develop arterial stiffness. Taken together, these complementary study designs suggest a potential role of therapeutically targeting MGP in HFpEF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.121.316664DOI Listing
February 2022

Arteriosclerosis, Atherosclerosis, and Cardiovascular Health: Joint Relations to the Incidence of Cardiovascular Disease.

Hypertension 2021 11 4;78(5):1232-1240. Epub 2021 Oct 4.

Section of Preventive Medicine and Epidemiology, Boston University School of Medicine, MA (R.S.V., V.X.).

[Figure: see text].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/HYPERTENSIONAHA.121.18075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516717PMC
November 2021

Cardiovascular disease related circulating biomarkers and cancer incidence and mortality: is there an association?

Cardiovasc Res 2021 Sep 1. Epub 2021 Sep 1.

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA.

Aims: Recent studies suggest an association between cardiovascular disease (CVD) and cancer incidence/mortality, but the pathophysiological mechanisms underlying these associations are unclear. We aimed to examine biomarkers previously associated with CVD and study their association with incident cancer and cancer-related death in a prospective cohort study.

Methods And Results: We used a proteomic platform to measure 71 cardiovascular biomarkers among 5,032 participants in the Framingham Heart Study who were free of cancer at baseline. We used multivariable-adjusted Cox models to examine the association of circulating protein biomarkers with risk of cancer incidence and mortality. To account for multiple testing, we set a 2-sided false discovery rate (FDR Q-value) <0.05.Growth differentiation factor-15 (GDF15; also known as macrophage inhibitory cytokine-1 [MIC1])) was associated with increased risk of incident cancer (hazards ratio [HR] per 1 standard deviation increment 1.31, 95% CI 1.17-1.47), incident gastrointestinal cancer (HR 1.85, 95% CI 1.37-2.50), incident colorectal cancer (HR 1.94, 95% CI 1.29-2.91) and cancer-related death (HR 2.15, 95% CI 1.72-2.70). Stromal cell-derived factor-1 (SFD1) showed an inverse association with cancer-related death (HR 0.75, 95% CI 0.65-0.86). Fibroblast growth factor-23 (FGF23) showed an association with colorectal cancer (HR 1.55, 95% CI 1.20-2.00), and granulin (GRN) was associated with hematologic cancer (HR 1.61, 95% CI 1.30-1.99). Other circulating biomarkers of inflammation, immune activation, metabolism, and fibrosis showed suggestive associations with future cancer diagnosis.

Conclusion: We observed several significant associations between circulating CVD biomarkers and cancer, supporting the idea that shared biological pathways underlie both diseases. Further investigations of specific mechanisms that lead to both CVD and cancer are warranted.

Translational Perspective: In our prospective cohort study, baseline levels of biomarkers previously associated with CVD were found to be associated with future development of cancer. In particular, GDF15 was associated with increased risk of cancer incidence and mortality, including gastrointestinal and colorectal cancers; SDF1 was inversely associated with cancer-related death, and FGF23 and GRN were associated with increased risk of colorectal and hematologic cancers, respectively. Other biomarkers of inflammation, immune activation, metabolism, and fibrosis showed suggestive associations. These results suggest potential shared biological pathways that underlie both development of cancer and CVD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cvr/cvab282DOI Listing
September 2021

Physical activity and fitness in the community: the Framingham Heart Study.

Eur Heart J 2021 11;42(44):4565-4575

Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Aims: While greater physical activity (PA) is associated with improved health outcomes, the direct links between distinct components of PA, their changes over time, and cardiorespiratory fitness are incompletely understood.

Methods And Results: Maximum effort cardiopulmonary exercise testing (CPET) and objective PA measures [sedentary time (SED), steps/day, and moderate-vigorous PA (MVPA)] via accelerometers worn for 1 week concurrent with CPET and 7.8 years prior were obtained in 2070 Framingham Heart Study participants [age 54 ± 9 years, 51% women, SED 810 ± 83 min/day, steps/day 7737 ± 3520, MVPA 22.3 ± 20.3 min/day, peak oxygen uptake (VO2) 23.6 ± 6.9 mL/kg/min]. Adjusted for clinical risk factors, increases in steps/day and MVPA and reduced SED between the two assessments were associated with distinct aspects of cardiorespiratory fitness (measured by VO2) during initiation, early-moderate level, peak exercise, and recovery, with the highest effect estimates for MVPA (false discovery rate <5% for all). Findings were largely consistent across categories of age, sex, obesity, and cardiovascular risk. Increases of 17 min of MVPA/day [95% confidence interval (CI) 14-21] or 4312 steps/day (95% CI 3439-5781; ≈54 min at 80 steps/min), or reductions of 249 min of SED per day (95% CI 149-777) between the two exam cycles corresponded to a 5% (1.2 mL/kg/min) higher peak VO2. Individuals with high (above-mean) steps or MVPA demonstrated above average peak VO2 values regardless of whether they had high or low SED.

Conclusions: Our findings provide a detailed assessment of relations of different types of PA with multidimensional cardiorespiratory fitness measures and suggest favourable longitudinal changes in PA (and MVPA in particular) are associated with greater objective fitness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eurheartj/ehab580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633734PMC
November 2021

Feasibility, Methodology, and Interpretation of Broad-Scale Assessment of Cardiorespiratory Fitness in a Large Community-Based Sample.

Am J Cardiol 2021 10 12;157:56-63. Epub 2021 Aug 12.

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

Cardiorespiratory fitness (CRF) is intricately related to health status. The optimal approach for CRF quantification is through assessment of peak oxygen uptake (VO), but such measurements have been largely confined to small referral populations. Here we describe protocols and methodological considerations for peak VO assessment and determination of volitional effort in a large community-based sample. Maximum incremental ramp cycle ergometry cardiopulmonary exercise testing (CPET) was performed by Framingham Heart Study participants at a routine study visit (2016 to 2019). Of 3,486 individuals presenting for a multicomponent study visit, 3,116 (89%) completed CPET. The sample was middle-aged (54 ± 9 years), with 53% women, body mass index 28.3 ± 5.6 kg/m, 48% with hypertension, 6% smokers, and 8% with diabetes. Exercise duration was 12.0 ± 2.1 minutes (limits 3.7to20.5). No major cardiovascular events occurred. A total of 98%, 96%, 90%, 76%, and 57% of the sample reached peak respiratory exchange ratio (RER) values of ≥1.0, ≥1.05, ≥1.10, ≥1.15, and ≥1.20, respectively (mean peak RER = 1.21 ± 0.10). With rising peak RER values up to ≈1.10, steep changes were observed for percent predicted peak VO, VO at the ventilatory threshold/peak VO, heart rate response, and Borg (subjective dyspnea) scores. More shallow changes for effort dependent CPET variables were observed with higher achieved RER values. In conclusion, measurement of peak VO is feasible and safe in a large sample of middle-aged, community-dwelling individuals with heterogeneous cardiovascular risk profiles. Peak RER ≥1.10 was achievable by the majority of middle-aged adults and RER values beyond this threshold did not necessarily correspond to higher peak VO values.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.amjcard.2021.07.020DOI Listing
October 2021

Cardiovascular Biomarkers of Obesity and Overlap With Cardiometabolic Dysfunction.

J Am Heart Assoc 2021 07 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.120.020215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483498PMC
July 2021

Digital Peripheral Arterial Tonometry and Cardiovascular Disease Events: The Framingham Heart Study.

Stroke 2021 08 1;52(9):2866-2873. Epub 2021 Jul 1.

Whitaker Cardiovascular Institute (E.J.B., R.S.V., N.M.H.), Boston University School of Medicine, MA.

Background And Purpose: Novel noninvasive measures of vascular function are emerging as subclinical markers for cardiovascular disease (CVD) and may be useful to predict CVD events. The purpose of our prospective study was to assess associations between digital peripheral arterial tonometry (PAT) measures and first-onset major CVD events in a sample of FHS (Framingham Heart Study) participants.

Methods: Using a fingertip PAT device, we assessed pulse amplitude in Framingham Offspring and Third Generation participants (n=3865; mean age, 55±14 years; 52% women) at baseline and in 30-second intervals for 4 minutes during reactive hyperemia. The PAT ratio (relative hyperemia index) was calculated as the post-to-pre occlusion pulse signal ratio in the occluded arm, relative to the same ratio in the control (nonoccluded) arm, and corrected for baseline vascular tone. Baseline pulse amplitude and PAT ratio during hyperemia are measures of pressure pulsatility and microvascular function in the finger, respectively. We used Cox proportional hazards regression to relate PAT measures in the fingertip to incident CVD events.

Results: During follow-up (median, 9.2 years; range, 0.04–10.0 years), 270 participants (7%) experienced new-onset CVD events (n=270). In multivariable models adjusted for cardiovascular risk factors, baseline pulse amplitude (hazard ratio [HR] per 1 SD, 1.04 [95% CI, 0.90–1.21]; P=0.57) and PAT ratio (HR, 0.95 [95% CI, 0.84–1.08]; P=0.43) were not significantly related to incident composite CVD events, including myocardial infarction or heart failure. However, higher PAT ratio (HR, 0.76 [95% CI, 0.61–0.94]; P=0.013), but not baseline pulse amplitude (HR, 1.15 [95% CI, 0.89–1.49]; P=0.29), was related to lower risk for incident stroke. In a sensitivity analysis by stroke subtype, higher PAT ratio was related to lower risk of incident ischemic stroke events (HR, 0.68 [95% CI, 0.53–0.86]; P=0.001).

Conclusions: Novel digital PAT measures may represent a marker of stroke risk in the community.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/STROKEAHA.120.031102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378441PMC
August 2021

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

J Nutr 2021 Sep;151(9):2574-2582

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jn/nxab186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417922PMC
September 2021

Multiomic Profiling in Black and White Populations Reveals Novel Candidate Pathways in Left Ventricular Hypertrophy and Incident Heart Failure Specific to Black Adults.

Circ Genom Precis Med 2021 06 21;14(3):e003191. Epub 2021 May 21.

Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA (D.H.K., U.A.T., D.N., M.D.B., X.S., M.J.K., D.S., M.H., J.M.R., Z.-Z.C., D.E.C., B.P., J.G.W., R.E.G.).

Background: Increased left ventricular (LV) mass is associated with adverse cardiovascular events including heart failure (HF). Both increased LV mass and HF disproportionately affect Black individuals. To understand the underlying mechanisms, we undertook a proteomic screen in a Black cohort and compared the findings to results from a White cohort.

Methods: We measured 1305 plasma proteins using the SomaScan platform in 1772 Black participants (mean age, 56 years; 62% women) in JHS (Jackson Heart Study) with LV mass assessed by 2-dimensional echocardiography. Incident HF was assessed in 1600 participants. We then compared protein associations in JHS to those observed in White participants from FHS (Framingham Heart Study; mean age, 54 years; 56% women).

Results: In JHS, there were 110 proteins associated with LV mass and 13 proteins associated with incident HF hospitalization with false discovery rate <5% after multivariable adjustment. Several proteins showed expected associations with both LV mass and HF, including NT-proBNP (N-terminal pro-B-type natriuretic peptide; β=0.04; =2×10; hazard ratio, 1.48; =0.0001). The strongest association with LV mass was novel: LKHA4 (leukotriene-A4 hydrolase; β=0.05; =5×10). This association was confirmed on an alternate proteomics platform and further supported by related metabolomic data. Fractalkine/CX3CL1 (C-X3-C Motif Chemokine Ligand 1) showed a novel association with incident HF (hazard ratio, 1.32; =0.0002). While established biomarkers such as cystatin C and NT-proBNP showed consistent associations in Black and White individuals, LKHA4 and fractalkine were significantly different between the two groups.

Conclusions: We identified several novel biological pathways specific to Black adults hypothesized to contribute to the pathophysiologic cascade of LV hypertrophy and incident HF including LKHA4 and fractalkine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.120.003191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497179PMC
June 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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 06;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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamacardio.2021.0292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970388PMC
June 2021

Proteomic profiling reveals biomarkers and pathways in type 2 diabetes risk.

JCI Insight 2021 03 8;6(5). Epub 2021 Mar 8.

Cardiovascular Institute.

Recent advances in proteomic technologies have made high-throughput profiling of low-abundance proteins in large epidemiological cohorts increasingly feasible. We investigated whether aptamer-based proteomic profiling could identify biomarkers associated with future development of type 2 diabetes (T2DM) beyond known risk factors. We identified dozens of markers with highly significant associations with future T2DM across 2 large longitudinal cohorts (n = 2839) followed for up to 16 years. We leveraged proteomic, metabolomic, genetic, and clinical data from humans to nominate 1 specific candidate to test for potential causal relationships in model systems. Our studies identified functional effects of aminoacylase 1 (ACY1), a top protein association with future T2DM risk, on amino acid metabolism and insulin homeostasis in vitro and in vivo. Furthermore, a loss-of-function variant associated with circulating levels of the biomarker WAP, Kazal, immunoglobulin, Kunitz, and NTR domain-containing protein 2 (WFIKKN2) was, in turn, associated with fasting glucose, hemoglobin A1c, and HOMA-IR measurements in humans. In addition to identifying potentially novel disease markers and pathways in T2DM, we provide publicly available data to be leveraged for insights about gene function and disease pathogenesis in the context of human metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.144392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021115PMC
March 2021

Intrinsic Frequencies of Carotid Pressure Waveforms Predict Heart Failure Events: The Framingham Heart Study.

Hypertension 2021 02 4;77(2):338-346. Epub 2021 Jan 4.

Cardiovascular Engineering, Inc, Norwood, MA (G.F.M.).

Intrinsic frequencies (IFs) derived from arterial waveforms are associated with cardiovascular performance, aging, and prevalent cardiovascular disease (CVD). However, prognostic value of these novel measures is unknown. We hypothesized that IFs are associated with incident CVD risk. Our sample was drawn from the Framingham Heart Study Original, Offspring, and Third Generation Cohorts and included participants free of CVD at baseline (N=4700; mean age 52 years, 55% women). We extracted 2 dominant frequencies directly from a series of carotid pressure waves: the IF of the coupled heart and vascular system during systole (ω) and the IF of the decoupled vasculature during diastole (ω). Total frequency variation (Δω) was defined as the difference between ω and ω. We used Cox proportional hazards regression models to relate IFs to incident CVD events during a mean follow-up of 10.6 years. In multivariable models adjusted for CVD risk factors, higher ω (hazard ratio [HR], 1.14 [95% CI], 1.03-1.26]; =0.01) and Δω (HR, 1.16 [95% CI, 1.03-1.30]; =0.02) but lower ω (HR, 0.87 [95% CI, 0.77-0.99]; =0.03) were associated with higher risk for incident composite CVD events. In similarly adjusted models, higher ω (HR, 1.23 [95% CI, 1.07-1.42]; =0.004) and Δω (HR, 1.26 [95% CI, 1.05-1.50]; =0.01) but lower ω (HR, 0.81 [95% CI, 0.66-0.99]; =0.04) were associated with higher risk for incident heart failure. IFs were not significantly associated with incident myocardial infarction or stroke. Novel IFs may represent valuable markers of heart failure risk in the community.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803452PMC
February 2021

Proteomic Signatures of Lifestyle Risk Factors for Cardiovascular Disease: A Cross-Sectional Analysis of the Plasma Proteome in the Framingham Heart Study.

J Am Heart Assoc 2021 01 29;10(1):e018020. Epub 2020 Dec 29.

Boston University Department of Medicine Boston MA.

Background Proteomic biomarkers related to cardiovascular disease risk factors may offer insights into the pathogenesis of cardiovascular disease. We investigated whether modifiable lifestyle risk factors for cardiovascular disease are associated with distinctive proteomic signatures. Methods and Results We analyzed 1305 circulating plasma proteomic biomarkers (assayed using the SomaLogic platform) in 897 FHS (Framingham Heart Study) Generation 3 participants (mean age 46±8 years; 56% women; discovery sample) and 1121 FOS (Framingham Offspring Study) participants (mean age 52 years; 54% women; validation sample). Participants were free of hypertension, diabetes mellitus, and clinical cardiovascular disease. We used linear mixed effects models (adjusting for age, sex, body mass index, and family structure) to relate levels of each inverse-log transformed protein to 3 lifestyle factors (ie, smoking, alcohol consumption, and physical activity). A Bonferroni-adjusted value indicated statistical significance (based on number of proteins and traits tested, <4.2×10 in the discovery sample; <6.85×10 in the validation sample). We observed statistically significant associations of 60 proteins with smoking (37/40 top proteins validated in FOS), 30 proteins with alcohol consumption (23/30 proteins validated), and 5 proteins with physical activity (2/3 proteins associated with the physical activity index validated). We assessed the associations of protein concentrations with previously identified genetic variants (protein quantitative trait loci) linked to lifestyle-related disease traits in the genome-wide-association study catalogue. The protein quantitative trait loci were associated with coronary artery disease, inflammation, and age-related mortality. Conclusions Our cross-sectional study from a community-based sample elucidated distinctive sets of proteins associated with 3 key lifestyle factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.120.018020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955453PMC
January 2021

The Dynamic Platelet Transcriptome in Obesity and Weight Loss.

Arterioscler Thromb Vasc Biol 2021 02 10;41(2):854-864. Epub 2020 Dec 10.

Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester (M.E.M., O.V., K.T., J.E.F.).

Objective: Adiposity is associated with oxidative stress, inflammation, and glucose intolerance. Previous data suggest that platelet gene expression is associated with key cardiometabolic phenotypes, including body mass index but stable in healthy individuals over time. However, modulation of gene expression in platelets in response to metabolic shifts (eg, weight reduction) is unknown and may be important to defining mechanism. Approach and Results: Platelet RNA sequencing and aggregation were performed from 21 individuals with massive weight loss (>45 kg) following bariatric surgery. Based on RNA sequencing data, we measured the expression of 67 genes from isolated platelet RNA using high-throughput quantitative reverse transcription quantitative PCR in 1864 FHS (Framingham Heart Study) participants. Many transcripts not previously studied in platelets were differentially expressed with bariatric surgical weight loss, appeared specific to platelets (eg, not differentially expressed in leukocytes), and were enriched for a nonalcoholic fatty liver disease pathway. Platelet aggregation studies did not detect alteration in platelet function after significant weight loss. Linear regression models demonstrated several platelet genes modestly associated with cross-sectional cardiometabolic phenotypes, including body mass index. There were no associations between studied transcripts and incident diabetes or cardiovascular end points.

Conclusions: In summary, while there is no change in platelet aggregation function after significant weight loss, the human platelet experiences a dramatic transcriptional shift that implicates pathways potentially relevant to improved cardiometabolic risk postweight loss (eg, nonalcoholic fatty liver disease). Further studies are needed to determine the mechanistic importance of these observations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.120.315186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105277PMC
February 2021

Joint associations of accelero-meter measured physical activity and sedentary time with all-cause mortality: a harmonised meta-analysis in more than 44 000 middle-aged and older individuals.

Br J Sports Med 2020 Dec;54(24):1499-1506

Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Objectives: To examine the joint associations of accelerometer-measured physical activity and sedentary time with all-cause mortality.

Methods: We conducted a harmonised meta-analysis including nine prospective cohort studies from four countries. 44 370 men and women were followed for 4.0 to 14.5 years during which 3451 participants died (7.8% mortality rate). Associations between different combinations of moderate-to-vigorous intensity physical activity (MVPA) and sedentary time were analysed at study level using Cox proportional hazards regression analysis and summarised using random effects meta-analysis.

Results: Across cohorts, the average time spent sedentary ranged from 8.5 hours/day to 10.5 hours/day and 8 min/day to 35 min/day for MVPA. Compared with the referent group (highest physical activity/lowest sedentary time), the risk of death increased with lower levels of MVPA and greater amounts of sedentary time. Among those in the highest third of MVPA, the risk of death was not statistically different from the referent for those in the middle (16%; 95% CI 0.87% to 1.54%) and highest (40%; 95% CI 0.87% to 2.26%) thirds of sedentary time. Those in the lowest third of MVPA had a greater risk of death in all combinations with sedentary time; 65% (95% CI 1.25% to 2.19%), 65% (95% CI 1.24% to 2.21%) and 263% (95% CI 1.93% to 3.57%), respectively.

Conclusion: Higher sedentary time is associated with higher mortality in less active individuals when measured by accelerometry. About 30-40 min of MVPA per day attenuate the association between sedentary time and risk of death, which is lower than previous estimates from self-reported data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bjsports-2020-103270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719907PMC
December 2020

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Genome-Wide Association Study Highlights as a Novel Locus for Lipoprotein(a) Levels-Brief Report.

Arterioscler Thromb Vasc Biol 2021 01 29;41(1):458-464. Epub 2020 Oct 29.

Division of Experimental Medicine (M.H., H.Y.C., G.T., J.C.E.), McGill University, Montreal, Quebec.

Objective: Lp(a) (lipoprotein[a]) is an independent risk factor for cardiovascular diseases and plasma levels are primarily determined by variation at the locus. We performed a genome-wide association study in the UK Biobank to determine whether additional loci influence Lp(a) levels. Approach and Results: We included 293 274 White British individuals in the discovery analysis. Approximately 93 095 623 variants were tested for association with natural log-transformed Lp(a) levels using linear regression models adjusted for age, sex, genotype batch, and 20 principal components of genetic ancestry. After quality control, 131 independent variants were associated at genome-wide significance ≤5×10). In addition to validating previous associations at , , and , we identified a novel variant at the locus, encoding β2GPI (beta2-glycoprotein I). The variant rs8178824 was associated with increased Lp(a) levels (β [95% CI] [ln nmol/L], 0.064 [0.047-0.081]; =2.8×10) and demonstrated a stronger effect after adjustment for variation at the locus (β [95% CI] [ln nmol/L], 0.089 [0.076-0.10]; =3.8×10). This association was replicated in a meta-analysis of 5465 European-ancestry individuals from the Framingham Offspring Study and Multi-Ethnic Study of Atherosclerosis (β [95% CI] [ln mg/dL], 0.16 [0.044-0.28]; =0.0071).

Conclusions: In a large-scale genome-wide association study of Lp(a) levels, we identified as a novel locus for Lp(a) in individuals of European ancestry. Additional studies are needed to determine the precise role of β2GPI in influencing Lp(a) levels as well as its potential as a therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.120.314965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769958PMC
January 2021

An Early-Onset Subgroup of Type 2 Diabetes: A Multigenerational, Prospective Analysis in the Framingham Heart Study.

Diabetes Care 2020 12 8;43(12):3086-3093. Epub 2020 Oct 8.

Institute for Research on Healthy Aging and Department of Cardiology, Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA.

Objective: To assess the relation of type 2 diabetes occurring earlier (age <55 years) versus later in life to the risk of cardiovascular death and to diabetes in offspring.

Research Design And Methods: In the Framingham Heart Study, a community-based prospective cohort study, glycemic status was ascertained at serial examinations over six decades among 5,571 first- and second-generation participants with mortality data and 2,123 second-generation participants who initially did not have diabetes with data on parental diabetes status. We assessed cause of death in a case (cardiovascular death)-control (noncardiovascular death) design and incident diabetes in offspring in relation to parental early-onset diabetes.

Results: Among the participants in two generations ( = 5,571), there were 1,822 cardiovascular deaths (including 961 coronary deaths). The odds of cardiovascular versus noncardiovascular death increased with decreasing age of diabetes onset ( < 0.001 trend). Compared with never developing diabetes, early-onset diabetes conferred a 1.81-fold odds (95% CI 1.10-2.97, = 0.02) of cardiovascular death and 1.75-fold odds (0.96-3.21, = 0.07) of coronary death, whereas later-onset diabetes was not associated with greater risk for either ( = 0.09 for cardiovascular death; = 0.51 for coronary death). In second-generation participants, having a parent with early-onset diabetes increased diabetes risk by 3.24-fold (1.73-6.07), whereas having one or both parents with late-onset diabetes increased diabetes risk by 2.19-fold (1.50-3.19).

Conclusions: Our findings provide evidence for a diabetes subgroup with an early onset, a stronger association with cardiovascular death, and higher transgenerational transmission.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc19-1758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770277PMC
December 2020

Eicosanoid Inflammatory Mediators Are Robustly Associated With Blood Pressure in the General Population.

J Am Heart Assoc 2020 10 25;9(19):e017598. Epub 2020 Sep 25.

Department of Internal Medicine University of Turku Finland.

Background Epidemiological and animal studies have associated systemic inflammation with blood pressure (BP). However, the mechanistic factors linking inflammation and BP remain unknown. Fatty acid-derived eicosanoids serve as mediators of inflammation and have been suggested to regulate renal vascular tone, peripheral resistance, renin-angiotensin system, and endothelial function. We hypothesize that specific proinflammatory and anti-inflammatory eicosanoids are linked with BP. Methods and Results We studied a population sample of 8099 FINRISK 2002 participants randomly drawn from the Finnish population register (53% women; mean age, 48±13 years) and, for external validation, a sample of 2859 FHS (Framingham Heart Study) Offspring study participants (55% women; mean age, 66±9 years). Using nontargeted liquid chromatography-mass spectrometry, we profiled 545 distinct high-quality eicosanoids and related oxylipin mediators in plasma. Adjusting for conventional hypertension risk factors, we observed 187 (34%) metabolites that were significantly associated with systolic BP (
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.120.017598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792391PMC
October 2020

Circulating testican-2 is a podocyte-derived marker of kidney health.

Proc Natl Acad Sci U S A 2020 10 21;117(40):25026-25035. Epub 2020 Sep 21.

Nephrology Division, Massachusetts General Hospital, Boston, MA 02114;

In addition to their fundamental role in clearance, the kidneys release select molecules into the circulation, but whether any of these anabolic functions provides insight on kidney health is unknown. Using aptamer-based proteomics, we characterized arterial (A)-to-renal venous (V) gradients for >1,300 proteins in 22 individuals who underwent invasive sampling. Although most of the proteins that changed significantly decreased from A to V, consistent with renal clearance, several were found to increase, the most significant of which was testican-2. To assess the clinical implications of these physiologic findings, we examined proteomic data in the Jackson Heart Study (JHS), an African-American cohort ( = 1,928), with replication in the Framingham Heart Study (FHS), a White cohort ( = 1,621). In both populations, testican-2 had a strong, positive correlation with estimated glomerular filtration rate (eGFR). In addition, higher baseline testican-2 levels were associated with a lower rate of eGFR decline in models adjusted for age, gender, hypertension, type 2 diabetes, body mass index, baseline eGFR, and albuminuria. Glomerular expression of testican-2 in human kidneys was demonstrated by immunohistochemistry, immunofluorescence, and electron microscopy, while single-cell RNA sequencing of human kidneys showed expression of the cognate gene, , exclusively in podocytes. In vitro, testican-2 increased glomerular endothelial tube formation and motility, raising the possibility that its secretion has a functional role within the glomerulus. Taken together, our findings identify testican-2 as a podocyte-derived biomarker of kidney health and prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2009606117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547280PMC
October 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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 11 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049528PMC
November 2020
-->