Arterial Stiffness and Cardiorespiratory Fitness Impairment in the Community.

Background During exercise, a healthy arterial system facilitates increased blood flow and distributes it effectively to essential organs. Accordingly, we sought to understand how arterial stiffening might impair cardiorespiratory fitness in community-dwelling individuals. Methods and Results Arterial tonometry and maximum effort cardiopulmonary exercise testing were performed on Framingham Heart Study participants (N=2898, age 54±9 years, 53% women, body mass index 28.1±5.3 kg/m2). We related 5 arterial stiffness measures (carotid-femoral pulse wave velocity [CFPWV]: a measure of aortic wall stiffness; central pulse pressure, forward wave amplitude, characteristic impedance: measures of pressure pulsatility; and augmentation index: a measure of relative wave reflection) to multidimensional exercise responses using linear models adjusted for age, sex, resting heart rate, habitual physical activity, and clinical risk factors. Greater CFPWV, augmentation index, and characteristic impedance were associated with lower peak oxygen uptake (VO2; all P<0.0001). We observed consistency of associations of CFPWV with peak oxygen uptake across age, sex, and cardiovascular risk profile (interaction P>0.05). However, the CFPWV-peak oxygen uptake relation was attenuated in individuals with obesity (P=0.002 for obesity*CFPWV interaction). Higher CPFWV, augmentation index, and characteristic impedance were also related to cardiopulmonary exercise testing measures reflecting adverse O2 kinetics and lower stroke volume and peripheral O2 extraction but not to ventilatory efficiency, a prognostic measure of right ventricular-pulmonary vascular performance. Conclusions Our findings delineate relations of arterial stiffness and cardiorespiratory fitness in community-dwelling individuals. Future studies are warranted to evaluate whether the physiological measures implicated here may represent potential targets for improving cardiorespiratory fitness in the general population.

Blood-Based Fingerprint of Cardiorespiratory Fitness and Long-Term Health Outcomes in Young Adulthood.

Background Cardiorespiratory fitness is a powerful predictor of health outcomes that is currently underused in primary prevention, especially in young adults. We sought to develop a blood-based biomarker of cardiorespiratory fitness that is easily translatable across populations. Methods and Results Maximal effort cardiopulmonary exercise testing for quantification of cardiorespiratory fitness (by peak oxygen uptake) and profiling of >200 metabolites at rest were performed in the FHS (Framingham Heart Study; 2016-2019). A metabolomic fitness score was derived/validated in the FHS and was associated with long-term outcomes in the younger CARDIA (Coronary Artery Risk Development in Young Adults) study. In the FHS (derivation, N=451; validation, N=914; age 54±8 years, 53% women, body mass index 27.7±5.3 kg/m2), we used LASSO (least absolute shrinkage and selection operator) regression to develop a multimetabolite score to predict peak oxygen uptake (correlation with peak oxygen uptake r=0.77 in derivation, 0.61 in validation; both P<0.0001). In a linear model including clinical risk factors, a ≈1-SD higher metabolomic fitness score had equivalent magnitude of association with peak oxygen uptake as a 9.2-year age increment. In the CARDIA study (N=2300, median follow-up 26.9 years, age 32±4 years, 44% women, 44% Black individuals), a 1-SD higher metabolomic fitness score was associated with a 44% lower risk for mortality (hazard ratio [HR], 0.56 [95% CI, 0.47-0.68]; P<0.0001) and 32% lower risk for cardiovascular disease (HR, 0.68 [95% CI, 0.55-0.84]; P=0.0003) in models adjusted for age, sex, and race, which remained robust with adjustment for clinical risk factors. Conclusions A blood-based biomarker of cardiorespiratory fitness largely independent of traditional risk factors is associated with long-term risk of cardiovascular disease and mortality in young adults.

Animal Models of Exercise From Rodents to Pythons.

Acute and chronic animal models of exercise are commonly used in research. Acute exercise testing is used, often in combination with genetic, pharmacological, or other manipulations, to study the impact of these manipulations on the cardiovascular response to exercise and to detect impairments or improvements in cardiovascular function that may not be evident at rest. Chronic exercise conditioning models are used to study the cardiac phenotypic response to regular exercise training and as a platform for discovery of novel pathways mediating cardiovascular benefits conferred by exercise conditioning that could be exploited therapeutically. The cardiovascular benefits of exercise are well established, and, frequently, molecular manipulations that mimic the pathway changes induced by exercise recapitulate at least some of its benefits. This review discusses approaches for assessing cardiovascular function during an acute exercise challenge in rodents, as well as practical and conceptual considerations in the use of common rodent exercise conditioning models. The case for studying feeding in the Burmese python as a model for exercise-like physiological adaptation is also explored.

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

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.

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

Cardiorespiratory fitness (CRF) is intricately related to health status. The optimal approach for CRF quantification is through assessment of peak oxygen uptake (VO2), but such measurements have been largely confined to small referral populations. Here we describe protocols and methodological considerations for peak VO2 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/m2, 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 VO2, VO2 at the ventilatory threshold/peak VO2, 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 VO2 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 VO2 values.

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

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%; P=1.5×10-55; dimethylguanidino valeric acid [DMGV], -18%; P=5.8×10-18) and increases in metabolites associated with lipolysis (1-methylnicotinamide, +33%; P=6.1×10-67), nitric oxide bioavailability (arginine/ornithine + citrulline, +29%; P=2.8×10-169), and adipose browning (12,13-dihydroxy-9Z-octadecenoic acid +26%; P=7.4×10-38), 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 Vo2). 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 (P≤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.

An expanded repertoire of intensity-dependent exercise-responsive plasma proteins tied to loci of human disease risk.

Routine endurance exercise confers numerous health benefits, and high intensity exercise may accelerate and magnify many of these benefits. To date, explanatory molecular mechanisms and the influence of exercise intensity remain poorly understood. Circulating factors are hypothesized to transduce some of the systemic effects of exercise. We sought to examine the role of exercise and exercise intensity on the human plasma proteome. We employed an aptamer-based method to examine 1,305 plasma proteins in 12 participants before and after exercise at two physiologically defined intensities (moderate and high) to determine the proteomic response. We demonstrate that the human plasma proteome is responsive to acute exercise in an intensity-dependent manner with enrichment analysis suggesting functional biological differences between the moderate and high intensity doses. Through integration of available genetic data, we estimate the effects of acute exercise on exercise-associated traits and find proteomic responses that may contribute to observed clinical effects on coronary artery disease and blood pressure regulation. In sum, we provide supportive evidence that moderate and high intensity exercise elicit different signaling responses, that exercise may act in part non-cell autonomously through circulating plasma proteins, and that plasma protein dynamics can simulate some the beneficial and adverse effects of acute exercise.

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

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.

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

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/VCO2pre-VATslope, VE/VCO2post-VATslope), the slope throughout exercise (VE/VCO2overall-slope), and as the lowest 30-second value (VE/VCO2nadir). RESULTS: In the MGH-ExS (N=493, age 56±15 years, 61% women, left ventricular ejection fraction 64±8%), higher VE/VCO2nadir was associated with lower peak exercise cardiac output and steeper increases in exercise pulmonary capillary wedge pressure (both P<0.0001). VE/VCO2nadir (hazard ratio, 1.34 per 1-SD unit [95% CI, 1.10-1.62] P=0.003) was associated with future cardiovascular hospitalization/death and outperformed classical VE/VCO2 measures used in heart failure with reduced ejection fraction (VE/VCO2overall-slope). In FHS (N=1936, age 54±9 years, 53% women), VE/VCO2 measures taken in low-to-moderate intensity exercise (including VE/VCO2pre-VATslope, VE/VCO2nadir) were directly associated with cardiovascular risk factor burden (smoking, Framingham cardiovascular disease risk score, and lower fitness; all P<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.

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

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.

Cardiac macrophages promote diastolic dysfunction.

Macrophages populate the healthy myocardium and, depending on their phenotype, may contribute to tissue homeostasis or disease. Their origin and role in diastolic dysfunction, a hallmark of cardiac aging and heart failure with preserved ejection fraction, remain unclear. Here we show that cardiac macrophages expand in humans and mice with diastolic dysfunction, which in mice was induced by either hypertension or advanced age. A higher murine myocardial macrophage density results from monocyte recruitment and increased hematopoiesis in bone marrow and spleen. In humans, we observed a parallel constellation of hematopoietic activation: circulating myeloid cells are more frequent, and splenic 18F-FDG PET/CT imaging signal correlates with echocardiographic indices of diastolic dysfunction. While diastolic dysfunction develops, cardiac macrophages produce IL-10, activate fibroblasts, and stimulate collagen deposition, leading to impaired myocardial relaxation and increased myocardial stiffness. Deletion of IL-10 in macrophages improves diastolic function. These data imply expansion and phenotypic changes of cardiac macrophages as therapeutic targets for cardiac fibrosis leading to diastolic dysfunction.

Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Diagnosing and Ranking Its Causes Using Personalized O2 Pathway Analysis.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with a pressing shortage of therapies. Exercise intolerance is a cardinal symptom of HFpEF, yet its pathophysiology remains uncertain. METHODS: We investigated the mechanism of exercise intolerance in 134 patients referred for cardiopulmonary exercise testing: 79 with HFpEF and 55 controls. We performed cardiopulmonary exercise testing with invasive monitoring to measure hemodynamics, blood gases, and gas exchange during exercise. We used these measurements to quantify 6 steps of oxygen transport and utilization (the O2 pathway) in each patient with HFpEF, identifying the defective steps that impair each one's exercise capacity (peak Vo2). We then quantified the functional significance of each O2 pathway defect by calculating the improvement in exercise capacity a patient could expect from correcting the defect. RESULTS: Peak Vo2 was reduced by 34±2% (mean±SEM, P<0.001) in HFpEF compared with controls of similar age, sex, and body mass index. The vast majority (97%) of patients with HFpEF harbored defects at multiple steps of the O2 pathway, the identity and magnitude of which varied widely. Two of these steps, cardiac output and skeletal muscle O2 diffusion, were impaired relative to controls by an average of 27±3% and 36±2%, respectively (P<0.001 for both). Due to interactions between a given patient's defects, the predicted benefit of correcting any single one was often minor; on average, correcting a patient's cardiac output led to a 7±0.5% predicted improvement in exercise intolerance, whereas correcting a patient's muscle diffusion capacity led to a 27±1% improvement. At the individual level, the impact of any given O2 pathway defect on a patient's exercise capacity was strongly influenced by comorbid defects. CONCLUSIONS: Systematic analysis of the O2 pathway in HFpEF showed that exercise capacity was undermined by multiple defects, including reductions in cardiac output and skeletal muscle diffusion capacity. An important source of disease heterogeneity stemmed from variation in each patient's personal profile of defects. Personalized O2 pathway analysis could identify patients most likely to benefit from treating a specific defect; however, the system properties of O2 transport favor treating multiple defects at once, as with exercise training.

Mechanisms of exercise intolerance in heart failure with preserved ejection fraction: the role of abnormal peripheral oxygen extraction.

BACKGROUND: Exercise capacity as measured by peak oxygen uptake (Vo2) is similarly impaired in patients with heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). However, characterization of how each component of Vo2 changes in response to incremental exercise in HFpEF versus HFrEF has not been previously defined. We hypothesized that abnormally low peripheral o2 extraction (arterio-mixed venous o2 content difference, [C(a-v)o2]) during exercise significantly contributes to impaired exercise capacity in HFpEF. METHODS AND RESULTS: We performed maximum incremental cardiopulmonary exercise testing with invasive hemodynamic monitoring on 104 patients with symptomatic NYHA II to IV heart failure (HFpEF, n=48, peak Vo2=13.9±0.5 mL kg(-1) min(-1), mean±SEM, and HFrEF, n=56, peak Vo2=12.1±0.5 mL kg(-1) min(-1)) and 24 control subjects (peak Vo2 27.0±1.7 mL kg(-1) min(-1)). Peak exercise C(a-v)o2 was lower in HFpEF compared with HFrEF (11.5±0.27 versus 13.5±0.34 mL/dL, respectively, P<0.0001), despite no differences in age, hemoglobin level, peak respiratory exchange ratio, Cao2, or cardiac filling pressures. Peak C(a-v)o2 and peak heart rate emerged as the leading predictors of peak Vo2 in HFpEF. Impaired peripheral o2 extraction was the predominant limiting factor to exercise capacity in 40% of patients with HFpEF and was closely related to elevated systemic blood pressure during exercise (r=0.49, P=0.0005). CONCLUSIONS: In the first study to directly measure C(a-v)o2 throughout exercise in HFpEF, HFrEF, and normals, we found that peak C(a-v)o2 was a major determinant of exercise capacity in HFpEF. The important functional limitation imposed by impaired o2 extraction may reflect intrinsic abnormalities in skeletal muscle or peripheral microvascular function, and represents a potential target for therapeutic intervention.

Causes of exercise intolerance in heart failure with preserved ejection fraction: searching for consensus.

Exercise intolerance is one of the cardinal symptoms of heart failure with preserved ejection fraction (HFpEF). We review its mechanistic basis using evidence from exercise studies. One barrier to a consensus understanding of the pathophysiology is heterogeneity of the patient population. Therefore, we pay special attention to varying study definitions of the disease and their possible impact on the causal factors that are implicated. We then discuss the role of exercise testing and its potential to subtype HFpEF in to more homogeneous mechanism-based subclasses.

The adipokine lipocalin 2 is regulated by obesity and promotes insulin resistance.

OBJECTIVE: We identified lipocalin 2 (Lcn2) as a gene induced by dexamethasone and tumor necrosis factor-alpha in cultured adipocytes. The purpose of this study was to determine how expression of Lcn2 is regulated in fat cells and to ascertain whether Lcn2 could be involved in metabolic dysregulation associated with obesity. RESEARCH DESIGN AND METHODS: We examined Lcn2 expression in murine tissues and in 3T3-L1 adipocytes in the presence and absence of various stimuli. We used quantitative Western blotting to observe Lcn2 serum levels in lean and obese mouse models. To assess effects on insulin action, we used retroviral delivery of short hairpin RNA to reduce Lcn2 levels in 3T3-L1 adipocytes. RESULTS: Lcn2 is highly expressed by fat cells in vivo and in vitro. Expression of Lcn2 is elevated by agents that promote insulin resistance and is reduced by thiazolidinediones. The expression of Lcn2 is induced during 3T3-L1 adipogenesis in a CCAAT/enhancer-binding protein-dependent manner. Lcn2 serum levels are elevated in multiple rodent models of obesity, and forced reduction of Lcn2 in 3T3-L1 adipocytes improves insulin action. Exogenous Lcn2 promotes insulin resistance in cultured hepatocytes. CONCLUSIONS: Lcn2 is an adipokine with potential importance in insulin resistance associated with obesity.