Non-technical summary MicroRNA (miRNA) molecules are essential intracellular mediators of numerous biological processes including angiogenesis, inflammation, and mitochondrial metabolism. Recently, it has been shown that miRNAs are secreted into the bloodstream and that circulating miRNAs (c-miRNAs) may serve important endocrine functions. This study examined plasma profiles of specific c-miRNAs in healthy competitive athletes at rest and during exhaustive exercise testing, before and after a 90 day period of exercise training. In this setting, we observed four distinct patterns of c-miRNA response to exercise: (1) c-miRNAs up-regulated by acute exhaustive exercise before and after sustained exercise training, (2) c-miRNAs responsive to acute exhaustive exercise before but not after sustained exercise training, (3) c-miRNAs responsive only to sustained exercise training, and (4) non-responsive c-miRNAs. These findings set the stage for further work aimed at defining the role of c-miRNAs as fitness biomarkers and physiological mediators of exercise-induced cardiovascular adaptation.Abstract MicroRNAs (miRNAs) are intracellular mediators of essential biological functions. Recently, plasma-based 'circulating' miRNAs (c-miRNAs) have been shown to control cellular processes, but the c-miRNA response to human exercise remains unknown. We sought to determine whether c-miRNAs are dynamically regulated in response to acute exhaustive cycling exercise and sustained rowing exercise training using a longitudinal, repeated measures study design. Specifically, c-miRNAs involved in angiogenesis (miR-20a, miR-210, miR-221, miR-222, miR-328), inflammation (miR-21, miR-146a), skeletal and cardiac muscle contractility (miR-21, miR-133a), and hypoxia/ischaemia adaptation (miR-21, miR-146a, and miR-210) were measured at rest and immediately following acute exhaustive cycling exercise in competitive male rowers (n = 10, age = 19.1 ± 0.6 years) before and after a 90 day period of rowing training. Distinct patterns of c-miRNA response to exercise were observed and adhered to four major profiles: (1) c-miRNA up-regulated by acute exercise before and after sustained training (miR-146a and miR-222), (2) c-miRNA responsive to acute exercise before but not after sustained training (miR-21 and miR-221), (3) c-miRNA responsive only to sustained training (miR-20a), and (4) non-responsive c-miRNA (miR-133a, miR-210, miR-328). Linear correlations were observed between peak exercise levels of miR-146a andV O 2 max (r = 0.63, P = 0.003) and between changes in resting miR-20a and changes inV O 2 max (pre-training vs. post-training, r = 0.73; P = 0.02). Although future work is required, these results suggest the potential value of c-miRNAs as exercise biomarkers and their possible roles as physiological mediators of exercise-induced cardiovascular adaptation.

Exercise provides numerous salutary effects, but our understanding of how these occur is limited. To gain a clearer picture of exercise-induced metabolic responses, we have developed comprehensive plasma metabolite signatures by using mass spectrometry to measure over 200 metabolites before and after exercise. We identified plasma indicators of glycogenolysis (glucose-6-phosphate), tricarboxylic acid (TCA) cycle span 2 expansion (succinate, malate, and * To whom correspondence should be addressed Corresponding authors Robert E. Gerszten, MD Cardiology Division and Center for Immunology & Inflammatory Diseases Massachusetts General Hospital, Room 8307 149 13th Street Charlestown, MA 02129 rgerszten@partners.org Gregory D. Lewis, MD Cardiology Division Massachusetts General Hospital, GRB 800 55 Fruit Street, Boston, MA 02114 glewis@partners.org. Authors contributions: G.D.L conceived the study, designed the experiments, performed primary data analysis and wrote the manuscript. M.J.W. led the effort to recruit and phenotype marathon subjects, L.F. and M.M. recruited subjects, processed samples, and assisted with experimental design. Z.A. and G.C.R. designed and performed the gene expression profiling experiments, A.S., E.Y., X.S., A.A., S.A.C. and C.B.C. developed the metabolic profiling platform, performed mass spectrometry experiments, and analyzed the data, S.C., E.L.M, T.W., and R.S.V. designed experiments and analyzed data from the Framingham Heart Study cohort, R.D. and F.P.R. assisted with statistical analysis and constructed the metabolite interrelatedness dendrogram, E.P.R. contributed to mass spectrometry data analysis and helped to write the manuscript, D.M.S. and M.J.S. contributed to the cardiopulmonary exercise testing metabolic profiling experiment, M.S.S. helped to conceive and design the exercise treadmill testing studies and assisted in data interpretation and in writing the manuscript, R.E.G. conceived of the study, designed experiments, analyzed data, and wrote the manuscript. Competing interests:The authors declare that they have no competing interests. NIH Public Access Author ManuscriptSci Transl Med. Author manuscript; available in PMC 2010 December 27. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript fumarate), and lipolysis (glycerol), as well as modulators of insulin sensitivity (niacinamide) and fatty acid oxidation (pantothenic acid). Metabolites that were highly correlated with fitness parameters were found in subjects undergoing acute exercise testing, marathon running, and in 302 subjects from a longitudinal cohort study. Exercise-induced increases in glycerol were strongly related to fitness levels in normal individuals and were attenuated in subjects with myocardial ischemia. A combination of metabolites that increased in plasma in response to exercise (glycerol, niacinamide, glucose-6-phosphate, pantothenate, and succinate) upregulated the expression of nur77, a transcriptional regulator of glucose utilization and lipid metabolism genes in skeleta...

Background-The clinical relevance of exercise-induced pulmonary arterial hypertension (PAH) is uncertain, and its existence has never been well studied by direct measurements of central hemodynamics. Using invasive cardiopulmonary exercise testing, we hypothesized that exercise-induced PAH represents a symptomatic stage of PAH, physiologically intermediate between resting pulmonary arterial hypertension and normal. Methods and Results-A total of 406 consecutive clinically indicated cardiopulmonary exercise tests with radial and pulmonary arterial catheters and radionuclide ventriculographic scanning were analyzed. The invasive hemodynamic phenotype of exercise-induced PAH (nϭ78) was compared with resting PAH (nϭ15) and normals (nϭ16). Log-log plots of mean pulmonary artery pressure versus oxygen uptake (V O 2 ) were obtained, and a "join-point" for a least residual sum of squares for 2 straight-line segments (slopes m1, m2) was determined; m2Ͻm1ϭ"plateau," and m2Ͼm1ϭ"takeoff" pattern.

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Background-Heart failure (HF) is frequently associated with dysregulation of nitric oxide-mediated pulmonary vascular tone. Sildenafil, a type 5 phosphodiesterase inhibitor, lowers pulmonary vascular resistance in pulmonary hypertension by augmenting intracellular levels of the nitric oxide second messenger, cyclic GMP. We tested the hypothesis that a single oral dose of sildenafil (50 mg) would improve exercise capacity and exercise hemodynamics in patients with chronic systolic HF through pulmonary vasodilation. Methods and Results-Thirteen patients with New York Heart Association class III HF underwent assessment of right heart hemodynamics, gas exchange, and first-pass radionuclide ventriculography at rest and with cycle ergometry before and 60 minutes after administration of 50 mg of oral sildenafil. Sildenafil reduced resting pulmonary arterial pressure, systemic vascular resistance, and pulmonary vascular resistance, and increased resting and exercise cardiac index (PϽ0.05 for all) without altering mean arterial pressure, heart rate, or pulmonary capillary wedge pressure. Sildenafil reduced exercise pulmonary arterial pressure, pulmonary vascular resistance, and pulmonary vascular resistance/ systemic vascular resistance ratio, which indicates a selective pulmonary vasodilator effect with exercise. Peak V O 2 increased (15Ϯ9%) and ventilatory response to CO 2 output (V E/V CO 2 slope) decreased (16Ϯ5%) after sildenafil treatment. Improvements in right heart hemodynamics and exercise capacity were confined to patients with secondary pulmonary hypertension (rest pulmonary arterial pressure Ͼ25 mm Hg). Conclusions-The present study shows that in patients with systolic HF, type 5 phosphodiesterase inhibition with sildenafil improves peak V O 2 , reduces V E/V CO 2 slope, and acts as a selective pulmonary vasodilator during rest and exercise in patients with HF and pulmonary hypertension.

Compared with traditional exercise tests, cardiopulmonary exercise testing (CPET) provides a thorough assessment of exercise integrative physiology involving the pulmonary, cardiovascular, muscular, and cellular oxidative systems. Due to the prognostic ability of key variables, CPET applications in cardiology have grown impressively to include all forms of exercise intolerance, with a predominant focus on heart failure with reduced or with preserved ejection fraction. As impaired cardiac output and peripheral oxygen diffusion are the main determinants of the abnormal functional response in cardiac patients, invasive CPET has gained new popularity, especially for diagnosing early heart failure with preserved ejection fraction and exercise-induced pulmonary hypertension. The most impactful advance has recently come from the introduction of CPET combined with echocardiography or CPET imaging, which provides basic information regarding cardiac and valve morphology and function. This review highlights modern CPET use as a single or combined test that allows the pathophysiological bases of exercise limitation to be translated, quite easily, into clinical practice.

Background-Patients with systolic heart failure (HF) who develop secondary pulmonary hypertension (PH) have reduced exercise capacity and increased mortality compared with HF patients without PH. We tested the hypothesis that sildenafil, an effective therapy for pulmonary arterial hypertension, would lower pulmonary vascular resistance and improve exercise capacity in patients with HF complicated by PH. Methods and Results-Thirty-four patients with symptomatic HF and PH were randomized to 12 weeks of treatment with sildenafil (25 to 75 mg orally 3 times daily) or placebo. Patients underwent cardiopulmonary exercise testing before and after treatment. The change in peak V O 2 from baseline, the primary end point, was greater in the sildenafil group (1.8Ϯ0.7 mL · kg Ϫ1 · min

Background Elevated resting pulmonary arterial pressure (PAP) in patients with left ventricular systolic dysfunction (LVSD) purports a poor prognosis. However, PAP response patterns to exercise in LVSD and their relationship to functional capacity and outcomes have not been characterized. Methods and Results Sixty consecutive patients with LVSD (age 60±12 years, LV ejection fraction 0.31±0.07, mean±SD) and 19 controls underwent maximum incremental cardiopulmonary exercise testing with simultaneous hemodynamic monitoring. During low-level exercise (30 Watts), LVSD subjects compared to controls, had greater augmentation in mean PAPs (15±1 vs. 5±1 mmHg), transpulmonary gradients (5±1 vs. 1±1 mmHg), and effective PA elastance (0.05±0.02 vs. −0.03±0.01 mmHg/ml, p<0.0001 for all). A linear increment in PAP relative to work (0.28±0.12 mmHg/watt) was observed in 65% of LVSD patients, which exceeded that observed in controls (0.07±0.02 mmHg/watt, P<0.0001). Exercise capacity and survival was worse in patients with a PAP/watt slope above the median than in patients with a lower slope. In the remaining 35% of LVSD patients, exercise induced a steep initial increment in PAP (0.41±0.16 mmHg/watt) followed by a plateau. The plateau pattern, compared to a linear pattern, was associated with reduced peak VO2 (10.6±2.6 vs. 13.1±4.0 ml/kg/min, P=0.005), lower right ventricular stroke work index augmentation with exercise (5.7±3.8 vs. 9.7±5.0 g/m2, P=0.002), and increased mortality (HR 8.1, 95% CI 2.7-23.8, P<0.001). Conclusions A steep increment in PAP during exercise and failure to augment PAP throughout exercise are associated with decreased exercise capacity and survival in patients with LVSD, and may therefore represent therapeutic targets. Clinical Trial Information URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00309790)