Purpose: Metabolomics identifies molecular products produced in response to numerous stimuli, including both adaptive (includes exercise training) and disease processes. We analyzed a longitudinal cohort of American-style football (ASF) athletes, who reliably acquire maladaptive cardiovascular (CV) phenotypes during competitive training, with high-resolution metabolomics to determine whether metabolomics can discriminate exercise-induced CV adaptations from early CV pathology. Methods: Matched discovery (N=42) and validation (N=40) multi-center cohorts of collegiate freshman ASF athletes were studied with longitudinal echocardiography, applanation tonometry, and high-resolution metabolomics. Liquid-chromatography mass spectrometry identified metabolites that changed (P<0.05,FDR<0.2) over the season. Metabolites demonstrating similar changes in both cohorts were further analyzed in linear and mixed-effects models to identify those associated with left ventricular (LV) mass, tissue-Doppler myocardial E′ velocity (diastolic function), and arterial function (pulse wave velocity, PWV). Results: In both cohorts, 20 common metabolites changed similarly across the season. Metabolites reflective of favorable CV health included an increase in arginine and decreases in hypoxanthine and saturated fatty acids (heptadecanoate, arachidic acid, stearate, and hydroxydecanoate). In contrast, metabolic perturbations of increased lysine and pipecolate, reflective of adverse CV health, were also observed. Adjusting for player position, race, height, and changes in systolic blood pressure, weight, and PWV, increased lysine (β=0.018,P=0.02) and pipecolate (β=0.018,P=0.02) were associated with increased LV mass-index. In addition, increased lysine (β=−0.049,P=0.01) and pipecolate (β=−0.052,P=0.008) were also associated with lower Eʹ (reduced diastolic function). Conclusions: ASF athletes appear to develop metabolomic changes reflective of both favorable CV health and early CV maladaptive phenotypes. Whether metabolomics can discriminate early pathologic CV transformations among athletes is a warranted future research direction.

Bone marrow-derived progenitor cells are mobilized into the peripheral blood after acute myocardial injury and in chronic ischemic heart disease. However, the mechanisms responsible for this mobilization are poorly understood. We examined the relationship between plasma levels of bioactive lipids and number of circulating progenitor cells (CPCs) in patients (N = 437) undergoing elective or emergent cardiac catheterization. Plasma levels of sphingosine-1 phosphate (S1P) and ceramide-1 phosphate (C1P) were quantified using mass spectrometry. CPCs were assessed using flow cytometry. S1P levels correlated with the numbers of CD341, CD341/CD1331, and CD341/CXCR41CPCs even after adjustment for potential confounding factors. However, no significant correlation was observed between C1P levels and CPC count. Plasma levels of S1P correlated with the number of CPCs in patients with coronary artery disease, suggesting an important mechanistic role for S1P in stem cell mobilization. The therapeutic effects of adjunctive S1P therapy to mobilize endogenous stem cells need to be investigated.

The COVID-19 pandemic brought the global world of sports to a staggering halt. In unprecedented fashion and with few exceptions, professional leagues, mass participation endurance events, and youth sport around the globe went silent. In the face of a rapidly evolving health crisis, the decision to cancel or postpone sporting events was a logical and necessary step. COVID-19 is a highly contagious, potentially fatal virus that is transmitted primarily through contact with aerosolised or surface-dwelling respiratory secretions, a process that requires close human contact.1 Competitive sport as we know it, from athletes ‘elbowing’ one another for position on the pitch to arenas packed with fans, may be the quintessential antithesis of social distancing. There is concern that the Champions League match between Atalanta and Valencia in Milan may have influenced the trajectory of COVID-19 cases in Europe.2 In the absence of a vaccination or curative intervention, physical distancing emerged as the key step to slow or stop the spread of COVID-19. Thus, the decision to turn off the lights and to silence competitive athletics represented a logical, essential and highly visible component in the global fight against COVID-19.

This study sought to determine the cardiovascular physiologic correlates of sleep-disordered breathing (SDB) in American-style football (ASF) participants using echocardiography, vascular applanation tonometry, and peripheral arterial tonometry. Forty collegiate ASF participants were analyzed at pre- and postseason time points with echocardiography and vascular applanation tonometry. WatchPAT (inclusive of peripheral arterial tonometry) used to assess for SDB was then performed at the postseason time point. Twenty-two of 40 (55%) ASF participants demonstrated SDB with an apnea-hypopnea index (pAHI) ≥5. ASF participants with SDB were larger (109 ± 20 vs 92 ± 14 kg, p = 0.004) and more likely linemen position players (83% vs 50%, p = 0.03). Compared with those without SDB, ASF participants with SDB demonstrated relative impairments in left ventricular diastolic and vascular function as reflected by lower lateral e′ (14 ± 3 vs 17 ± 3 cm/s, p = 0.007) and septal e′ (11 ± 2 vs 13 ± 2 cm/s, p = 0.009) tissue velocities and higher pulse wave velocity (5.4 ± 0.9 vs 4.8 ± 0.5 m/s, p = 0.02). In the total cohort, there were significant positive correlations between pAHI and pulse wave velocity (r = 0.42, p = 0.008) and inverse correlations between pAHI and the averaged e′ tissue velocities (r = −0.42, p = 0.01). In conclusion, SDB is highly prevalent in youthful collegiate ASF participants and associated with relative impairments in cardiac and vascular function. Targeted efforts to identify youthful populations with SDB, including ASF participants, and implement SDB treatment algorithms, represent important future clinical directives.

Purpose: American-style football (ASF) participation rates in the United States are highest among high school (HS) athletes. This study sought to compare the cardiovascular response to HS versus collegiate ASF participation. Methods: The ASF participants (HS, n = 61; collegiate, n = 87) were studied at preseason and postseason time points with echocardiography and applanation tonometry. Primary outcome variables included: left ventricular (LV) mass index, LV diastolic function (early relaxation velocity [E′]), and arterial stiffness (pulse wave velocity [PWV]). Results: High school (17.1 ± 0.4 yr) and collegiate ASF participants (18 ± 0.4 yr) experienced similar LV hypertrophy (ΔLV mass HS = 10.5 ± 10 vs collegiate = 11.2 ± 13.6 g·m-2, P = 0.97). Among HS participants, increases in LV mass were associated with stable diastolic tissue velocities (ΔE′ = -0.3 ± 2.9 cm·s-1, P = 0.40) and vascular function (ΔPWV = -0.1 ± 0.6 m·s-1, P = 0.13). In contrast, collegiate participants demonstrated a higher burden of concentric LV hypertrophy (21/87, 24% vs 7/61, 11%, P = 0.026) with concomitant reductions in diastolic tissue velocities (ΔE′: -2.0 ± 2.7 cm·s-1, P < 0.001) and increased arterial stiffness (ΔPWV: Δ0.2 ± 0.6 m·s-1, P = 0.003), changes that were influenced by linemen who had the highest post-season weight (124 ± 10 kg) and systolic blood pressure ([SBP], 138.8 ± 11 mm Hg). In multivariable analyses adjusting for age and ethnicity, body mass was an independent predictor of post-season PWV (β estimate = 0.01, P = 0.04) and E′ (β estimate = -0.04, P = 0.05), whereas SBP was an independent predictor of postseason LV mass index (β estimate = 0.18, P = 0.01) and PWV (β estimate = 0.01, P = 0.007). Conclusions: The transition from HS to college represents an important physiologic temporal data point after which differential ASF cardiovascular phenotypes manifest. Future work aimed to clarify underlying mechanisms, and the long-term clinical implications of these findings is warranted.

Background: Low diastolic blood pressure (DBP) is associated with increased risk of cardiovascular events. In patients with coronary artery disease (CAD), limitations in coronary blood flow and immune activity are implicated mechanisms, but evidence is lacking. We investigated the association between DBP, biomarkers of myocardial injury, inflammation, immune activation and incident events in patients with CAD. Methods: We studied 2448 adults (mean age 65 ± 12 years, 68% male, median follow-up 4.5 years) with CAD. DBP was categorized into 10 mm Hg increments. Biomarkers of myocardial injury (high sensitivity cardiac troponin-I [hs-cTnI]) and immune activity/inflammation (soluble urokinase plasminogen activator receptor [suPAR]) were dichotomized at their median values. DBP 70–79 mm Hg was used as the referent group, and individuals were followed prospectively for adverse outcomes. Results: After adjusting for demographic and clinical covariates, individuals with DBP < 60 mm Hg had increased odds of elevated levels of hs-cTnI (OR = 1.68; 95% CI = 1.07, 2.65) and suPAR (OR = 1.71; 95% CI = 1.10, 2.65) compared to the referent group. Additionally, DBP < 60 mm Hg was associated with increased adjusted risk of cardiovascular death or MI (HR = 2.04; 95% CI = 1.32, 3.16) and all-cause mortality (HR = 2.41; 95% CI = 1.69, 3.45). Conclusion: In patients with CAD, DBP < 60 mm Hg is associated with subclinical myocardial injury, immune/inflammatory dysregulation and incident events. Aggressive BP control may be harmful in these patients, and further investigation is warranted to determine appropriate BP targets in patients with CAD.

Background Endogenous regenerative capacity, assessed as circulating progenitor cell (PC) numbers, is an independent predictor of adverse outcomes in patients with cardiovascular disease. However, their predictive role in heart failure (HF) remains controversial. We assessed the relationship between the number of circulating PCs and the pathogenesis and severity of HF and their impact on incident HF events. Methods and Results We recruited 2049 adults of which 651 had HF diagnosis. PCs were enumerated by flow cytometry as CD45med+blood mononuclear cells expressing CD34, CD133, vascular endothelial growth factor receptor-2, and chemokine (C-X-C motif) receptor 4 epitopes. PC subsets were lower in number in HF and after adjustment for clinical characteristics in multivariable analyses, a low CD34+and CD34+/CXCR+cell count remained independently associated with a diagnosis of HF (P<0.01). PC levels were not significantly different in reduced versus preserved ejection fraction patients. In 514 subjects with HF, there were 98 (19.1%) all-cause deaths during a 2.2±1.5-year follow-up. In a Cox regression model adjusting for clinical variables, hematopoietic-enriched PCs (CD34+, CD34+/CD133+, and CD34+/CXCR4+) were independent predictors of all-cause death (hazard ratio 2.0, 1.6, 1.6-fold higher mortality, respectively; P<0.03) among HF patients. Endothelial-enriched PCs (CD34+/VEGF+) were independent predictors of mortality in patients with HF with preserved ejection fraction only (hazard ratio, 5.0; P=0.001). Conclusions PC levels are lower in patients with HF, and lower PC counts are strongly and independently predictive of mortality. Strategies to increase PCs and exogenous stem cell therapies designed to improve regenerative capacity in HF, especially, in HF with preserved ejection fraction, need to be further explored.

BACKGROUND: Clinical practice recommendations for participation in sports and exercise among young competitive athletes with cardiovascular conditions at risk for sudden death are based largely on expert consensus with a paucity of prospective outcomes data. Recent guidelines have taken a more permissive approach, using a shared decision-making model. However, the impact and outcomes of this strategy remain unknown. METHODS: The ORCCA (Outcomes Registry for Cardiac Conditions in Athletes) study is a prospective, multicenter, longitudinal, observational cohort study designed to monitor clinical outcomes in athletes with potentially life-threatening cardiovascular conditions. The study will assess sports eligibility decision-making, exercise habits, psychosocial well-being, and long-term cardiovascular outcomes among young competitive athletes with cardiovascular conditions. Competitive athletes aged 18 to <35 years diagnosed with a confirmed cardiovascular condition or borderline finding with potential increased risk of major adverse cardiovascular events are eligible. Outcomes will be monitored for an initial 5-year follow-up period or until age 35, and metrics of psychosocial well-being and composite adverse cardiovascular events including arrhythmias, sudden cardiac arrest/sudden cardiac death, and evidence of disease progression will be compared among athletes who continue versus discontinue competitive sports participation. CONCLUSIONS: The ORCCA study aims to assess the process and results of return to sport decision-making and to monitor major adverse cardiovascular events, exercise habits, and the psychosocial well-being among young competitive athletes diagnosed with confirmed cardiovascular conditions or borderline findings with potential increased risk of major adverse cardiovascular events. The results of this work will generate an evidence base to inform future guidelines.

BACKGROUND: Clinically relevant aortic dilatation (>40 mm) and increased cardiovascular risk are common among retired professional American-style football athletes. Among younger athletes, the effect of American-style football participation on aortic size is incompletely understood. We sought to determine changes in aortic root (AR) size and associated cardiovascular phenotypes across the collegiate career. METHODS AND RESULTS: This was a multicenter, longitudinal repeated-measures observational cohort study of athletes across 3 years of elite collegiate American-style football participation. A total of 247 athletes (119 [48%] Black, 126 [51%] White, 2 [1%] Latino; 91 [37%] linemen, 156 [63%] non-linemen) were enrolled as freshmen and studied at pre-and postseason year 1, postseason year 2 (N=140 athletes), and postseason year 3 (N=82 athletes). AR size was measured with transthoracic echo-cardiography. AR diameter increased over the study period from 31.7 (95% CI, 31.4–32.0) to 33.5 mm (95% CI, 33.1–33.8; P<0.001). No athlete developed an AR ≥40 mm. Athletes also demonstrated increased weight (cumulative mean Δ, 5.0 [95% CI, 4.1–6.0] kg, P<0.001), systolic blood pressure (cumulative mean Δ, 10.6 [95% CI, 8.0–13.2] mm Hg, P<0.001), pulse wave velocity (cumulative mean Δ, 0.43 [95% CI, 0.31–0.56] m/s, P<0.001), and left ventricular mass index (cumulative mean Δ, 21.2 [95% CI, 19.2–23.3] g/m2, P<0.001), and decreased E′ velocity (cumulative mean Δ, −2.4 [95%CI, −2.9 to −1.9] cm/s, P<0.001). Adjusting for height, player position, systolic blood pressure, and diastolic blood pressure, higher weight (β=0.030, P=0.003), pulse wave velocity (β=0.215, P=0.02), and left ventricular mass index (β=0.032, P<0.001) and lower E′ (β=−0.082, P=0.001) were associated with increased AR diameter. CONCLUSIONS: Over the collegiate American-style football career, athletes demonstrate progressive AR dilatation associated with cardiac and vascular functional impairment. Future studies delineating aortic outcomes are necessary to determine whether AR dilation is indicative of maladaptive vascular remodeling in this population.