Publications by authors named "Matthew Nayor"

39 Publications

Framingham Heart Study: JACC Focus Seminar, 1/8.

J Am Coll Cardiol 2021 Jun;77(21):2680-2692

National Heart, Lung, and Blood Institute and Boston University's Framingham Heart Study, Framingham, Massachusetts, USA; Section of Preventive Medicine and Epidemiology and Cardiovascular Medicine, Departments of Medicine and Epidemiology, Boston University Schools of Medicine and Public Health, Boston, Massachusetts, USA. Electronic address:

The Framingham Heart Study is the longest-running cardiovascular epidemiological study, starting in 1948. This paper gives an overview of the various cohorts, collected data, and most important research findings to date. In brief, the Framingham Heart Study, funded by the National Institutes of Health and managed by Boston University, spans 3 generations of well phenotyped White persons and 2 cohorts comprised of racial and ethnic minority groups. These cohorts are densely phenotyped, with extensive longitudinal follow-up, and they continue to provide us with important information on human cardiovascular and noncardiovascular physiology over the lifespan, as well as to identify major risk factors for cardiovascular disease. This paper also summarizes some of the more recent progress in molecular epidemiology and discusses the future of the study.
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http://dx.doi.org/10.1016/j.jacc.2021.01.059DOI Listing
June 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 Jun 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.
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http://dx.doi.org/10.1161/CIRCGEN.120.003191DOI Listing
June 2021

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

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

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

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

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

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

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

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

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

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

The Molecular Basis of Predicting Atherosclerotic Cardiovascular Disease Risk.

Circ Res 2021 Jan 21;128(2):287-303. Epub 2021 Jan 21.

Sections of Preventive Medicine & Epidemiology, and Cardiology, Department of Medicine, Boston University School of Medicine, MA (R.S.V.).

Atherosclerotic cardiovascular disease (ASCVD) proceeds through a series of stages: initiation, progression (or regression), and complications. By integrating known biology regarding molecular signatures of each stage with recent advances in high-dimensional molecular data acquisition platforms (to assay the genome, epigenome, transcriptome, proteome, metabolome, and gut microbiome), snapshots of each phase of atherosclerotic cardiovascular disease development can be captured. In this review, we will summarize emerging approaches for assessment of atherosclerotic cardiovascular disease risk in humans using peripheral blood molecular signatures and molecular imaging approaches. We will then discuss the potential (and challenges) for these snapshots to be integrated into a personalized movie providing dynamic readouts of an individual's atherosclerotic cardiovascular disease risk status throughout the life course.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.315890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839236PMC
January 2021

Expected vs Actual Outcomes of Elective Initiation of Inotropic Therapy During Heart Failure Hospitalization.

Mayo Clin Proc Innov Qual Outcomes 2020 Oct 19;4(5):529-536. Epub 2020 Aug 19.

Dartmouth-Hitchcock Medical Center, Heart and Vascular Center, Lebanon, NH.

Objective: To describe the intent and early outcomes of elective inotrope use during heart failure hospitalization.

Patients And Methods: A prospective multisite design was used to collect data for hemodynamically stable patients started electively on inotrope therapy between January 1 and August 31, 2018. We prospectively recorded data when intravenous inotropic therapy was initiated, including survey of the attending cardiologists regarding expectations for the clinical course. Patients were followed up for events through hospital discharge and an additional survey was administered at the end of hospitalization.

Results: For the 92 patients enrolled, average age was 60 years and ejection fraction was 24%±12%. At the time of inotrope initiation, attending heart failure cardiologists predicted that 50% (n=46) of the patients had a "high or very high" likelihood of becoming dependent on intravenous inotropic therapy and 58% (n=53) had a "high" likelihood of death, transplant, or durable ventricular assist device placement within the next 6 months. Provider predictions regarding death/hospice or need for continued home infusions were accurate only 51% (47 of 92) of the time. Only half the patients (n=47) had goals-of-care conversations before inotrope treatment initiation.

Conclusion: More than half the patients (51 of 92) electively started on inotrope treatment without present or imminent cardiogenic shock ultimately required home inotrope therapy, died during admission, or were discharged with hospice. Heart failure clinicians could not reliably identify those patients at the time of inotrope therapy initiation and goals-of-care discussions were not frequently performed.
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http://dx.doi.org/10.1016/j.mayocpiqo.2020.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557209PMC
October 2020

Comprehensive Metabolic Phenotyping Refines Cardiovascular Risk in Young Adults.

Circulation 2020 Dec 19;142(22):2110-2127. Epub 2020 Oct 19.

Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston (R.K., G.D.L., M.N., R.V.S.).

Background: Whereas cardiovascular disease (CVD) metrics define risk in individuals >40 years of age, the earliest lesions of CVD appear well before this age. Despite the role of metabolism in CVD antecedents, studies in younger, biracial populations to define precise metabolic risk phenotypes are lacking.

Methods: We studied 2330 White and Black young adults (mean age, 32 years; 45% Black) in the CARDIA study (Coronary Artery Risk Development in Young Adults) to identify metabolite profiles associated with an adverse CVD phenome (myocardial structure/function, fitness, vascular calcification), mechanisms, and outcomes over 2 decades. Statistical learning methods (elastic nets/principal components analysis) and Cox regression generated parsimonious, metabolite-based risk scores validated in >1800 individuals in the Framingham Heart Study.

Results: In the CARDIA study, metabolite profiles quantified in early adulthood were associated with subclinical CVD development over 20 years, specifying known and novel pathways of CVD (eg, transcriptional regulation, brain-derived neurotrophic factor, nitric oxide, renin-angiotensin). We found 2 multiparametric, metabolite-based scores linked independently to vascular and myocardial health, with metabolites included in each score specifying microbial metabolism, hepatic steatosis, oxidative stress, nitric oxide modulation, and collagen metabolism. The metabolite-based vascular scores were lower in men, and myocardial scores were lower in Black participants. Over a nearly 25-year median follow-up in CARDIA, the metabolite-based vascular score (hazard ratio, 0.68 per SD [95% CI, 0.50-0.92]; =0.01) and myocardial score (hazard ratio, 0.60 per SD [95% CI, 0.45-0.80]; =0.0005) in the third and fourth decades of life were associated with clinical CVD with a synergistic association with outcome (=0.009). We replicated these findings in 1898 individuals in the Framingham Heart Study over 2 decades, with a similar association with outcome (including interaction), reclassification, and discrimination. In the Framingham Heart Study, the metabolite scores exhibited an age interaction (=0.0004 for a combined myocardial-vascular score with incident CVD), such that young adults with poorer metabolite-based health scores had highest hazard of future CVD.

Conclusions: Metabolic signatures of myocardial and vascular health in young adulthood specify known/novel pathways of metabolic dysfunction relevant to CVD, associated with outcome in 2 independent cohorts. Efforts to include precision measures of metabolic health in risk stratification to interrupt CVD at its earliest stage are warranted.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880553PMC
December 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

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

Aptamer-Based Proteomic Platform Identifies Novel Protein Predictors of Incident Heart Failure and Echocardiographic Traits.

Circ Heart Fail 2020 05 15;13(5):e006749. Epub 2020 May 15.

Framingham Heart Study, Framingham, MA (M.N., M.G.L, R.S.V).

Background: We used a large-scale, high-throughput DNA aptamer-based discovery proteomic platform to identify circulating biomarkers of cardiac remodeling and incident heart failure (HF) in community-dwelling individuals.

Methods: We evaluated 1895 FHS (Framingham Heart Study) participants (age 55±10 years, 54% women) who underwent proteomic profiling and echocardiography. Plasma levels of 1305 proteins were related to echocardiographic traits and to incident HF using multivariable regression. Statistically significant protein-HF associations were replicated in the HUNT (Nord-Trøndelag Health) study (n=2497, age 63±10 years, 43% women), and results were meta-analyzed. Genetic variants associated with circulating protein levels (pQTLs) were related to echocardiographic traits in the EchoGen (n=30 201) and to incident HF in the CHARGE (n=20 926) consortia.

Results: Seventeen proteins associated with echocardiographic traits in cross-sectional analyses (false discovery rate <0.10), and 8 of these proteins had pQTLs associated with echocardiographic traits in EchoGen (<0.0007). In Cox models adjusted for clinical risk factors, 29 proteins demonstrated associations with incident HF in FHS (174 HF events, mean follow-up 19 [limits, 0.2-23.7] years). In meta-analyses of FHS and HUNT, 6 of these proteins were associated with incident HF (<3.8×10; 3 with higher risk: NT-proBNP [N-terminal proB-type natriuretic peptide], TSP2 [thrombospondin-2], MBL [mannose-binding lectin]; and 3 with lower risk: ErbB1 [epidermal growth factor receptor], GDF-11/8 [growth differentiation factor-11/8], and RGMC [hemojuvelin]). For 5 of the 6 proteins, pQTLs were associated with echocardiographic traits (<0.0006) in EchoGen, and for RGMC, a protein quantitative trait loci was associated with incident HF (=0.001).

Conclusions: A large-scale proteomics approach identified new predictors of cardiac remodeling and incident HF. Future studies are warranted to elucidate how biological pathways represented by these proteins may mediate cardiac remodeling and HF risk and to assess if these proteins can improve HF risk prediction.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236427PMC
May 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

For Non-HDL Cholesterol, "Lower Is Better" but "Lower for Longer" May Be Best.

Circ Res 2020 03 26;126(7):836-838. Epub 2020 Mar 26.

From the Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (M.N., R.V.S.).

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http://dx.doi.org/10.1161/CIRCRESAHA.120.316697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147968PMC
March 2020

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

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

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

Background: Abnormal pulmonary arterial pressure (PAP) responses to exercise have been described in select individuals; however, clinical and prognostic implications of exercise pulmonary hypertension (exPH) among broader samples remains unclear.

Objectives: This study sought to investigate the association of exPH with clinical determinants and outcomes.

Methods: The authors studied individuals with chronic exertional dyspnea and preserved ejection fraction who underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring. Exercise pulmonary hypertension was ascertained using minute-by-minute PAP and cardiac output (CO) measurements to calculate a PAP/CO slope, and exPH defined as a PAP/CO slope >3 mm Hg/l/min. The primary outcome was cardiovascular (CV) hospitalization or all-cause mortality.

Results: Among 714 individuals (age 57 years, 59% women), 296 (41%) had abnormal PAP/CO slopes. Over a mean follow-up of 3.7 ± 2.9 years, there were 208 CV or death events. Individuals with abnormal PAP/CO slope had a 2-fold increased hazard of future CV or death event (multivariable-adjusted hazard ratio: 2.03; 95% confidence interval: 1.48 to 2.78; p < 0.001). The association of abnormal PAP/CO slope with outcomes remained significant after excluding rest PH (n = 146, hazard ratio: 1.75; 95% confidence interval: 1.21 to 2.54; p = 0.003). Both pre- and post-capillary contributions to exPH independently predicted adverse events (p < 0.001 for both).

Conclusions: Exercise pulmonary hypertension is independently associated with CV event-free survival among individuals undergoing evaluation of chronic dyspnea. These findings suggest incremental value of exercise hemodynamic assessment to resting measurements alone in characterizing the burden of PH in individuals with dyspnea. Whether PH and PH subtypes unmasked by exercise can be used to guide targeted therapeutic interventions requires further investigation.
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http://dx.doi.org/10.1016/j.jacc.2019.10.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043927PMC
January 2020

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

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

Division of Cardiology, Massachusetts General Hospital, Boston.

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

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

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

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

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

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

Pre-emptive pangenotypic direct acting antiviral therapy in donor HCV-positive to recipient HCV-negative heart transplantation: an open-label study.

Lancet Gastroenterol Hepatol 2019 10 26;4(10):771-780. Epub 2019 Jul 26.

Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital Transplant Center, Massachusetts General Hospital, Boston, MA, USA; Cardiothoracic Surgery Division, Massachusetts General Hospital, Boston, MA, USA; Transplant Surgery Division, Massachusetts General Hospital, Boston, MA, USA.

Background: Low donor heart availability underscores the need to identify all potentially transplantable organs. We sought to determine whether pre-emptive administration of pangenotypic direct-acting antiviral therapy can safely prevent the development of chronic hepatitis C virus (HCV) infection in uninfected recipients of HCV-infected donor hearts.

Methods: Patients were recruited for this an open-label, single-centre, proof-of-concept study from Nov 1, 2017, to Nov 30, 2018. Following enrolment, the recipient's status on the heart transplantation waiting list was updated to reflect a willingness to accept either an HCV-positive or HCV-negative heart donor. Patients who underwent transplantation with a viraemic donor heart, as determined by nucleic acid testing (NAT), received pre-emptive oral glecaprevir-pibrentasvir before transport to the operating room followed by an 8-week course of glecaprevir-pibrentasvir after transplantation. Patients receiving HCV antibody-positive donor hearts without detectable circulating HCV RNA were followed using a reactive approach and started glecaprevir-pibrentasvir only if they developed viraemia. The primary outcome was achievement of sustained virological response 12 weeks after completion of glecaprevir-pibrentasvir therapy (SVR12). Patients were followed from study enrolment to 1 year after transplantation. This is an interim analysis, initiated after all enrolled patients reached the primary outcome. Results reflect data from Nov 1, 2017, to May 30, 2019. This trial is registered with ClinicalTrials.gov, number NCT03208244.

Findings: 55 patients were assessed for eligibility and 52 consented to enrolment. 25 patients underwent heart transplantation with HCV-positive donor hearts (20 NAT-positive, five NAT-negative), three of whom underwent simultaneous heart-kidney transplantation. All 20 recipients of NAT-positive hearts tolerated glecaprevir-pibrentasvir and showed rapid viral suppression (median time to clearance 3·5 days, IQR 0·0-8·3), with the subsequent achievement of SVR12 by all 20. The five recipients of NAT-negative grafts did not become viraemic. Median pre-transplant waiting time for patients following enrolment in the HCV protocol was 20 days (IQR 8-57). Patient and allograft survival were 100% at a median follow-up of 10·7 months (range 6·5-18·0).

Interpretation: Pre-emptive administration of glecaprevir-pibrentasvir therapy results in expedited organ transplantation, rapid HCV suppression, prevention of chronic HCV infection, and excellent early allograft function in patients receiving HCV-infected donor hearts. Long-term outcomes are not yet known.

Funding: American Association for the Study of Liver Diseases, National Institutes of Health, and the Massachusetts General Hospital.
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http://dx.doi.org/10.1016/S2468-1253(19)30240-7DOI Listing
October 2019

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

Circulation 2019 07 28;140(5):353-365. Epub 2019 May 28.

Cardiology Division, Department of Medicine (J.E.H., L.W., C.S.B., T.C., A.S.E., K.M.H., P.P.P., R.M., M.N., G.D.L.), Massachusetts General Hospital, Boston.

Background: Heart failure with preserved ejection fraction (HFpEF) is common, yet there is currently no consensus on how to define HFpEF according to various society and clinical trial criteria. How clinical and hemodynamic profiles of patients vary across definitions is unclear. We sought to determine clinical characteristics, as well as physiologic and prognostic implications of applying various criteria to define HFpEF.

Methods: We examined consecutive patients with chronic exertional dyspnea (New York Heart Association class II to IV) and ejection fraction ≥50% referred for comprehensive cardiopulmonary exercise testing with invasive hemodynamic monitoring. We applied societal and clinical trial HFpEF definitions and compared clinical profiles, exercise responses, and cardiovascular outcomes.

Results: Of 461 patients (age 58±15 years, 62% women), 416 met American College of Cardiology/American Heart Association (ACC/AHA), 205 met European Society of Cardiology (ESC), and 55 met Heart Failure Society of America (HFSA) criteria for HFpEF. Clinical profiles and exercise capacity varied across definitions, with peak oxygen uptake of 16.2±5.2 (ACC/AHA), 14.1±4.2 (ESC), and 12.7±3.1 mL·kg·min (HFSA). A total of 243 patients had hemodynamic evidence of HFpEF (abnormal rest or exercise filling pressures), of whom 222 met ACC/AHA, 161 met ESC, and 41 met HFSA criteria. Over a mean follow-up of 3.8 years, the incidence of cardiovascular outcomes ranged from 75 (ACC/AHA) to 298 events per 1000 person-years (HFSA). Application of clinical trial definitions of HFpEF similarly resulted in distinct patient classification and prognostication.

Conclusions: Use of different HFpEF classifications variably enriches for future cardiovascular events, but at the expense of not including up to 85% of individuals with physiologic evidence of HFpEF. Comprehensive phenotyping of patients with suspected heart failure highlights the limitations and heterogeneity of current HFpEF definitions and may help to refine HFpEF subgrouping to test therapeutic interventions.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.039136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684250PMC
July 2019

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

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

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

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

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

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

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

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

High-Sensitivity Troponin and Heart Failure With Preserved Ejection Fraction-Balancing P Values With Prior Knowledge and Common Sense-Reply.

JAMA Cardiol 2018 09;3(9):892-893

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

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http://dx.doi.org/10.1001/jamacardio.2018.1623DOI Listing
September 2018

Left Ventricular Diastolic Dysfunction in the Community: Impact of Diagnostic Criteria on the Burden, Correlates, and Prognosis.

J Am Heart Assoc 2018 06 1;7(11). Epub 2018 Jun 1.

Framingham Heart Study, Framingham, MA.

Background: Left ventricular diastolic dysfunction (DD) is common, particularly in women and older individuals, and it is associated with adverse cardiovascular outcomes. We evaluated the impact of age- and sex-specific diagnostic criteria on the assessment of DD in the community-based Framingham Heart Study.

Methods And Results: We estimated age- and sex-specific reference limits for echocardiographic measures of DD in a healthy reference subsample (N=2355, mean age 44 years, 66% women). The prevalence, correlates, and association with future cardiovascular disease were compared for DD using age- and sex-specific versus single cut point reference limits in a broad sample (N=6102, mean age 50 years, 56% women). Using age- and sex-specific criteria, DD was present in ≈25% to 30% of individuals across age groups, and it was directly associated with a number of modifiable risk factors. In contrast, with single cut point criteria, age was the primary determinant of DD. During follow-up (mean 7.9±2.2 years), incident cardiovascular disease occurred in 213 of 5770 individuals. Using age- and sex-specific criteria, mild and moderate-severe DD were associated with 50% (95% confidence interval, 1.09-2.05) and 65% (95% confidence interval, 1.14-2.38) higher incidences of cardiovascular disease, respectively, in age- and sex-adjusted analyses. With single cut point criteria, moderate-severe DD (hazard ratio, 1.66; 95% confidence interval, 1.05-2.61), but not mild DD (hazard ratio, 0.94; 95% confidence interval, 0.63-1.40), was associated with incident cardiovascular disease.

Conclusions: Age- and sex-specific reference limits may result in DD assessments that are less dependent on age, more robustly related to modifiable risk factors, and are more closely associated with incident cardiovascular disease.
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http://dx.doi.org/10.1161/JAHA.117.008291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015390PMC
June 2018

Comorbidities and Cardiometabolic Disease: Relationship With Longitudinal Changes in Diastolic Function.

JACC Heart Fail 2018 04 7;6(4):317-325. Epub 2018 Mar 7.

Framingham Heart Study, Framingham, Massachusetts; Section of Preventive Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; Cardiology Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts.

Objectives: This study sought to evaluate the course, correlates, and prognosis of longitudinal changes in left ventricular (LV) diastolic dysfunction (DD) in the community-based Framingham Heart Study.

Background: Relationships of clinical risk factors to longitudinal progression of DD are incompletely understood.

Methods: Diastolic function was assessed by echocardiography performed at consecutive examinations (visits 1 and 2, mean interval 5.6 years) in 1,740 participants (64 ± 8 years of age at visit 1, 59% women) with normal LV systolic function and no atrial fibrillation.

Results: Of 1,615 individuals with normal-to-mild DD at visit 1, 198 (12%) progressed to ≥ moderate DD at visit 2. Progression was more likely in women and with advancing age (p < 0.0001). Of 125 individuals with ≥ moderate DD at visit 1, 25 (20%) regressed to normal-to-mild DD by visit 2. Regression of DD was associated with younger age (p < 0.03). In stepwise regression models, age, female sex, baseline and changes in systolic blood pressure, diastolic blood pressure, body mass index, serum triglycerides, and diabetes were positively associated with worsening diastolic function (all p < 0.05). Noncardiac comorbidity tracked with progressive DD. Cardiovascular disease (CVD) or death events occurred in 44 of 1,509 participants free of CVD at visit 2, during 2.7 ± 0.6 years of post-visit 2 follow-up. Presence of ≥ moderate DD was associated with higher risk (age- and sex-adjusted hazard ratio for CVD or death: 2.14; 95% confidence interval: 1.06 to 4.32; p = 0.03).

Conclusions: In a community-based cohort of middle-aged to older adults, cardiometabolic risk factors and noncardiac comorbidities were associated with DD progression. Moderate or worse DD was associated with higher risk of CVD or death.
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http://dx.doi.org/10.1016/j.jchf.2017.12.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5878123PMC
April 2018

Incidental Statin Use and the Risk of Stroke or Transient Ischemic Attack after Radiotherapy for Head and Neck Cancer.

J Stroke 2018 Jan 31;20(1):71-79. Epub 2018 Jan 31.

Cardiac MR PET CT Program, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background And Purpose: Interventions to reduce the risk for cerebrovascular events (CVE; stroke and transient ischemic attack [TIA]) after radiotherapy (RT) for head and neck cancer (HNCA) are needed. Among broad populations, statins reduce CVEs; however, whether statins reduce CVEs after RT for HNCA is unclear. Therefore, we aimed to test whether incidental statin use at the time of RT is associated with a lower rate of CVEs after RT for HNCA.

Methods: From an institutional database we identified all consecutive subjects treated with neck RT from 2002 to 2012 for HNCA. Data collection and event adjudication was performed by blinded teams. The primary outcome was a composite of ischemic stroke and TIA. The secondary outcome was ischemic stroke. The association between statin use and events was determined using Cox proportional hazard models after adjustment for traditional and RT-specific risk factors.

Results: The final cohort consisted of 1,011 patients (59±13 years, 30% female, 44% hypertension) with 288 (28%) on statins. Over a median follow-up of 3.4 years (interquartile range, 0.1 to 14) there were 102 CVEs (89 ischemic strokes and 13 TIAs) with 17 in statin users versus 85 in nonstatins users. In a multivariable model containing known predictors of CVE, statins were associated with a reduction in the combination of stroke and TIA (hazard ratio [HR], 0.4; 95% confidence interval [CI], 0.2 to 0.8; =0.01) and ischemic stroke alone (HR, 0.4; 95% CI, 0.2 to 0.8; =0.01).

Conclusions: Incidental statin use at the time of RT for HNCA is associated with a lower risk of stroke or TIA.
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http://dx.doi.org/10.5853/jos.2017.01802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836583PMC
January 2018

Association of Cardiovascular Biomarkers With Incident Heart Failure With Preserved and Reduced Ejection Fraction.

JAMA Cardiol 2018 03;3(3):215-224

Center for Population Studies, National Heart, Lung, and Blood Institute, Bethesda, Maryland.

Importance: Nearly half of all patients with heart failure have preserved ejection fraction (HFpEF) as opposed to reduced ejection fraction (HFrEF), yet associations of biomarkers with future heart failure subtype are incompletely understood.

Objective: To evaluate the associations of 12 cardiovascular biomarkers with incident HFpEF vs HFrEF among adults from the general population.

Design, Setting, And Participants: This study included 4 longitudinal community-based cohorts: the Cardiovascular Health Study (1989-1990; 1992-1993 for supplemental African-American cohort), the Framingham Heart Study (1995-1998), the Multi-Ethnic Study of Atherosclerosis (2000-2002), and the Prevention of Renal and Vascular End-stage Disease study (1997-1998). Each cohort had prospective ascertainment of incident HFpEF and HFrEF. Data analysis was performed from June 25, 2015, to November 9, 2017.

Exposures: The following biomarkers were examined: N-terminal pro B-type natriuretic peptide or brain natriuretic peptide, high-sensitivity troponin T or I, C-reactive protein (CRP), urinary albumin to creatinine ratio (UACR), renin to aldosterone ratio, D-dimer, fibrinogen, soluble suppressor of tumorigenicity, galectin-3, cystatin C, plasminogen activator inhibitor 1, and interleukin 6.

Main Outcomes And Measures: Development of incident HFpEF and incident HFrEF.

Results: Among the 22 756 participants in these 4 cohorts (12 087 women and 10 669 men; mean [SD] age, 60 [13] years) in the study, during a median follow-up of 12 years, 633 participants developed incident HFpEF, and 841 developed HFrEF. In models adjusted for clinical risk factors of heart failure, 2 biomarkers were significantly associated with incident HFpEF: UACR (hazard ratio [HR], 1.33; 95% CI, 1.20-1.48; P < .001) and natriuretic peptides (HR, 1.27; 95% CI, 1.16-1.40; P < .001), with suggestive associations for high-sensitivity troponin (HR, 1.11; 95% CI, 1.03-1.19; P = .008), plasminogen activator inhibitor 1 (HR, 1.22; 95% CI, 1.03-1.45; P = .02), and fibrinogen (HR, 1.12; 95% CI, 1.03-1.22; P = .01). By contrast, 6 biomarkers were associated with incident HFrEF: natriuretic peptides (HR, 1.54; 95% CI, 1.41-1.68; P < .001), UACR (HR, 1.21; 95% CI, 1.11-1.32; P < .001), high-sensitivity troponin (HR, 1.37; 95% CI, 1.29-1.46; P < .001), cystatin C (HR, 1.19; 95% CI, 1.11-1.27; P < .001), D-dimer (HR, 1.22; 95% CI, 1.11-1.35; P < .001), and CRP (HR, 1.19; 95% CI, 1.11-1.28; P < .001). When directly compared, natriuretic peptides, high-sensitivity troponin, and CRP were more strongly associated with HFrEF compared with HFpEF.

Conclusions And Relevance: Biomarkers of renal dysfunction, endothelial dysfunction, and inflammation were associated with incident HFrEF. By contrast, only natriuretic peptides and UACR were associated with HFpEF. These findings highlight the need for future studies focused on identifying novel biomarkers of the risk of HFpEF.
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http://dx.doi.org/10.1001/jamacardio.2017.4987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862778PMC
March 2018

Predictors and outcomes of heart failure with mid-range ejection fraction.

Eur J Heart Fail 2018 04 11;20(4):651-659. Epub 2017 Dec 11.

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

Aims: While heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF) are well described, determinants and outcomes of heart failure with mid-range ejection fraction (HFmrEF) remain unclear. We sought to examine clinical and biochemical predictors of incident HFmrEF in the community.

Methods And Results: We pooled data from four community-based longitudinal cohorts, with ascertainment of new heart failure (HF) classified into HFmrEF [ejection fraction (EF) 41-49%], HFpEF (EF ≥50%), and HFrEF (EF ≤40%). Predictors of incident HF subtypes were assessed using multivariable Cox models. Among 28 820 participants free of HF followed for a median of 12 years, there were 200 new HFmrEF cases, compared with 811 HFpEF and 1048 HFrEF. Clinical predictors of HFmrEF included age, male sex, systolic blood pressure, diabetes mellitus, and prior myocardial infarction (multivariable adjusted P ≤ 0.003 for all). Biomarkers that predicted HFmrEF included natriuretic peptides, cystatin-C, and high-sensitivity troponin (P ≤ 0.0004 for all). Natriuretic peptides were stronger predictors of HFrEF [hazard ratio (HR) 2.00 per 1 standard deviation increase, 95% confidence interval (CI) 1.81-2.20] than of HFmrEF (HR 1.51, 95% CI 1.20-1.90, P = 0.01 for difference), and did not differ in their association with incident HFmrEF and HFpEF (HR 1.56, 95% CI 1.41-1.73, P = 0.68 for difference). All-cause mortality following the onset of HFmrEF was worse than that of HFpEF (50 vs. 39 events per 1000 person-years, P = 0.02), but comparable to that of HFrEF (46 events per 1000 person-years, P = 0.78).

Conclusions: We found overlap in predictors of incident HFmrEF with other HF subtypes. In contrast, mortality risk after HFmrEF was worse than HFpEF, and similar to HFrEF.
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http://dx.doi.org/10.1002/ejhf.1091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899688PMC
April 2018

Incidence of cardiovascular disease in individuals affected by recent changes to US blood pressure treatment guidelines.

J Hypertens 2018 02;36(2):436-443

Framingham Heart Study, Framingham.

Objective: We evaluated the incidence of cardiovascular disease (CVD) in individuals whose blood pressure (BP) management strategy would change with adoption of recent US hypertension guidelines in two large, community-based cohorts with different racial and geographic compositions: the Framingham and Jackson Heart Studies (FHS and JHS).

Methods: We assigned 11 237 FHS (mean age 46, 53% women) and 2948 JHS (mean age 55, 69% women) participants free of CVD and chronic kidney disease to one of five categories representing different treatment recommendations between 2014 Evidence-Based Guidelines for the Management of High Blood Pressure in Adults: Report from the Panel Members Appointed to the Eighth Joint National Committee and The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines. Absolute incidence rates (incidence rate; per 1000 person-years) and multivariable-adjusted hazard ratios were calculated for each group; cohort-specific results were combined using fixed effect meta-analysis.

Results: CVD events occurred in 1047 FHS and 230 JHS participants during mean follow-up times of 11 and 8.9 years, respectively. Compared with individuals without hypertension, those with BP 140-149/<90 mmHg had increased risk for CVD regardless of treatment status [hazard ratio for untreated BP 140-149/<90 mmHg 1.96, 95% confidence interval (CI) 1.40-2.75; hazard ratio for treated BP 140-149/<90 mmHg 3.37, 95% CI 2.37-4.78]. The risk for those with treated BP 140-149/<90 mmHg was consistent in those aged at least 60 years (hazard ratio: 2.61, 95% CI 1.75-3.90). Statistical power was limited to evaluate the effect of diabetes.

Conclusion: Individuals with treated BP 140-149/<90 mmHg have increased risk of CVD compared with those without hypertension including in participants at least 60 years. The 2014 Evidence-Based Guidelines for the Management of High Blood Pressure in Adults: Report from the Panel Members Appointed to the Eighth Joint National Committee recommendations to treat BP levels less aggressively may be associated with substantial residual CVD risk.
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http://dx.doi.org/10.1097/HJH.0000000000001570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6062206PMC
February 2018

Chest Pain and Shortness of Breath After a Heart Transplant.

JAMA Cardiol 2017 11;2(11):1271-1272

Brigham and Women's Hospital, Center for Advanced Heart Failure/Cardiomyopathy, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jamacardio.2017.2337DOI Listing
November 2017

The association of chronic kidney disease and microalbuminuria with heart failure with preserved vs. reduced ejection fraction.

Eur J Heart Fail 2017 05 20;19(5):615-623. Epub 2017 Feb 20.

National Heart, Lung, and Blood Institute's and Boston University's Framingham Heart Study, Framingham, MA, USA.

Aims: Chronic kidney disease (CKD) and microalbuminuria are associated with incident heart failure (HF), but their relative contributions to HF with preserved vs. reduced EF (HFpEF and HFrEF) are unknown. We sought to evaluate the associations of CKD and microalbuminuria with incident HF subtypes in the community-based Framingham Heart Study (FHS).

Methods And Results: We defined CKD as glomerular filtration rate <60 mL/min/1.73 m , and microalbuminuria as a urine albumin to creatinine ratio (UACR) ≥17 mg/g in men and ≥25 mg/g in women. We observed 754 HF events (324 HFpEF/326 HFrEF/104 unclassified) among 9889 FHS participants with serum creatinine measured (follow-up 13 ± 4 years). In Cox models adjusted for clinical risk factors, CKD (prevalence = 9%) was associated with overall HF [hazard ratio (HR) 1.24, 95% confidence interval (CI) 1.01-1.51], but was not significantly associated with individual HF subtypes. Among 2912 individuals with available UACR (follow-up 15 ± 4 years), 192 HF events (91 HFpEF/93 HFrEF/8 unclassified) occurred. Microalbuminuria (prevalence = 17%) was associated with a higher risk of overall HF (HR 1.71, 95% CI 1.25-2.34) and HFrEF (HR 2.10, 95% CI 1.35-3.26), but not HFpEF (HR 1.26, 95% CI 0.78-2.03). In cross-sectional analyses, microalbuminuria was associated with LV systolic dysfunction (odds ratio 3.19, 95% CI 1.67-6.09).

Conclusions: Microalbuminuria was associated with incident HFrEF prospectively, and with LV systolic dysfunction cross-sectionally in a community-based sample. In contrast, CKD was modestly associated with overall HF but not differentially associated with HFpEF vs. HFrEF. The mechanisms responsible for the relationship of microalbuminuria to future development of HFrEF warrant further investigation.
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http://dx.doi.org/10.1002/ejhf.778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423843PMC
May 2017

Recent Update to the US Cholesterol Treatment Guidelines: A Comparison With International Guidelines.

Circulation 2016 May;133(18):1795-806

From Framingham Heart Study, Framingham, MA (M.N., R.S.V.); Brigham and Women's Hospital, Division of Cardiovascular Medicine, Boston, MA (M.N.); Sections of Preventive Medicine and Cardiology, Boston University School of Medicine, MA (R.S.V.); and Department of Epidemiology, Boston University School of Public Health, MA (R.S.V.).

The 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol guideline advocated several changes from the previous Adult Treatment Panel III guidelines. Assuming full implementation, the 2013 ACC/AHA guideline would identify ≈13 million Americans as newly eligible for consideration of statin therapy. Three features of the 2013 ACC/AHA guideline primarily responsible for these differences are the specific risk assessment tool endorsed, the risk threshold considered sufficient to warrant primary prevention statin therapy, and the decision not to include cholesterol treatment targets. There is no consensus among international guidelines on the optimal approach to these 3 components. The 2013 ACC/AHA guideline recommends assessing absolute risk with the Pooled Cohort equations, which were developed to improve on previous risk assessment models by including stroke as an outcome and by broadening racial and geographic diversity. Each of the leading international guidelines recommends a different equation for absolute risk assessment. The 2013 ACC/AHA guideline advises consideration of statin therapy for an estimated 10-year risk of atherosclerotic vascular disease of ≥7.5%, which is lower than the thresholds recommended by other leading international guidelines. Lastly, the 2013 ACC/AHA guideline does not endorse a treat-to-target strategy but instead specifies the appropriate intensity of statin for each risk category. This approach is shared by the National Institute for Health and Care Excellence guidelines but differs from other international guidelines. In this review, we summarize the 2013 ACC/AHA cholesterol guideline recommendations and compare them with recommendations from Adult Treatment Panel III and other leading international guidelines.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.116.021407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4857879PMC
May 2016