Person:

Lewis, Gregory

Background: Beyond their resting values, exercise responses in blood pressure (BP) and heart rate (HR) may add prognostic information for cardiovascular disease (CVD). In cross‐sectional studies, exercise BP and HR responses correlate with CVD risk factors; however, it is unclear which factors influence longitudinal changes in exercise responses over time, which is important for our understanding of the development of CVD. Methods and Results: We assessed BP and HR responses to low‐level exercise tests (6‐minute Bruce protocol) in 1231 Framingham Offspring participants (55% women) who underwent a routine treadmill test in 1979–1983 (baseline; mean age 39±8 years) that was repeated in 1998–2001 (follow‐up; mean age 58±8 years). Adjusting for baseline exercise responses, we related the follow‐up exercise responses to baseline CVD risk factors and to their changes between examinations. Compared with men, women had greater rise in exercise systolic (S)BP and HR at 20‐year follow‐up (both P<0.005). Baseline blood lipid levels, resting SBP and HR, and smoking status were associated with greater exercise SBP at follow‐up (all P<0.05). Weight gain across examinations was associated with higher exercise SBP and HR at follow‐up (both P<0.0001). Smoking cessation was associated with a 53% reduced risk of attaining the highest quartile of exercise SBP (≥180 mm Hg) at follow‐up (P<0.05). Conclusion: An adverse CVD risk factor profile in young adults and its worsening over time were associated with higher SBP and HR responses to low‐level exercise in midlife. Maintaining or adopting a healthy risk factor profile may favorably impact the exercise responses over time.

Abstract The functional and prognostic significance of pulmonary hypertension (PH) is well established, yet our understanding of circulating peptides and metabolites that might mark or contribute to various forms of PH remains limited. Metabolites are the end result of all the regulatory complexity present in a cell, tissue, or organism and therefore serve as the most proximal reporters of the body’s response to a disease process or drug therapy. This review presents the rationale, methodology, and preliminary findings from studies that apply comprehensive metabolite profiling to gain knowledge of new circulating markers of PH.

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) regulates metabolic genes in skeletal muscle and contributes to the response of muscle to exercise. Muscle PGC-1α transgenic expression and exercise both increase the expression of thermogenic genes within white adipose. How the PGC-1α-mediated response to exercise in muscle conveys signals to other tissues remains incompletely defined. We employed a metabolomic approach to examine metabolites secreted from myocytes with forced expression of PGC-1α, and identified β-aminoisobutyric acid (BAIBA) as a small molecule myokine. BAIBA increases the expression of brown adipocyte-specific genes in white adipocytes and β-oxidation in hepatocytes both in vitro and in vivo through a PPARα-mediated mechanism, induces a brown adipose-like phenotype in human pluripotent stem cells, and improves glucose homeostasis in mice. In humans, plasma BAIBA concentrations are increased with exercise and inversely associated with metabolic risk factors. BAIBA may thus contribute to exercise-induced protection from metabolic diseases.

Human disease is heterogeneous, with similar disease phenotypes resulting from distinct combinations of genetic and environmental factors. Small-molecule profiling can address disease heterogeneity by evaluating the underlying biologic state of individuals through non-invasive interrogation of plasma metabolite levels. We analyzed metabolite profiles from an oral glucose tolerance test (OGTT) in 50 individuals, 25 with normal (NGT) and 25 with impaired glucose tolerance (IGT). Our focus was to elucidate underlying biologic processes. Although we initially found little overlap between changed metabolites and preconceived definitions of metabolic pathways, the use of unbiased network approaches identified significant concerted changes. Specifically, we derived a metabolic network with edges drawn between reactant and product nodes in individual reactions and between all substrates of individual enzymes and transporters. We searched for “active modules”—regions of the metabolic network enriched for changes in metabolite levels. Active modules identified relationships among changed metabolites and highlighted the importance of specific solute carriers in metabolite profiles. Furthermore, hierarchical clustering and principal component analysis demonstrated that changed metabolites in OGTT naturally grouped according to the activities of the System A and L amino acid transporters, the osmolyte carrier SLC6A12, and the mitochondrial aspartate-glutamate transporter SLC25A13. Comparison between NGT and IGT groups supported blunted glucose- and/or insulin-stimulated activities in the IGT group. Using unbiased pathway models, we offer evidence supporting the important role of solute carriers in the physiologic response to glucose challenge and conclude that carrier activities are reflected in individual metabolite profiles of perturbation experiments. Given the involvement of transporters in human disease, metabolite profiling may contribute to improved disease classification via the interrogation of specific transporter activities.

Background: Obesity is associated with cardiometabolic disease, including insulin resistance (IR) and diabetes. Cyclic guanosine monophosphate (cGMP) signaling affects energy balance, IR, and glucose metabolism in experimental models. We sought to examine effects of phosphodiesterase‐5 inhibition with tadalafil on IR in a pilot study of obese nondiabetic individuals. Methods and Results: We conducted a randomized, double‐blinded, placebo‐controlled trial of adults age 18 to 50 years with obesity and elevated fasting insulin levels (≥10 μU/mL). Participants were randomized to tadalafil 20 mg daily or placebo for 3 months. Oral glucose tolerance tests were performed, and the effect of tadalafil on IR was examined. A total of 53 participants (mean age, 33 years; body mass index [BMI], 38 kg/m2) were analyzed, 25 randomized to tadalafil and 28 to placebo. In the overall sample, measures of IR did not differ between tadalafil and placebo groups at 3 months. However, in individuals with severe obesity (BMI ≥36.2 kg/m2), tadalafil use was associated with improved IR (homeostatic model assessment for IR), compared to placebo (P=0.02, respectively). Furthermore, one measure of β‐cell compensation for IR (oral disposition index) improved with tadalafil in the overall sample (P=0.009) and in the subgroup with severe obesity (P=0.01). Conclusion: Results of this pilot study did not show improvements in IR with tadalafil, compared to placebo. However, tadalafil may have favorable effects on β‐cell compensation, particularly in individuals with severe obesity. Future studies evaluating the potential metabolic benefits of cGMP modulation in obesity are warranted. Clinical Trial Registration URL: ClinicalTrials.gov. Unique Identifier: NCT01444651.