Prospective evaluation of cardiac effects of first-time marathon training, running, and recovery in middle-aged men: cohort study rationale and design.

BACKGROUND: Several phenomena may point to potentially detrimental cardiac effects of endurance exercise, such as elevated circulating cardiac troponin levels and reductions in systolic and diastolic function directly after marathon completion. Furthermore, while myocardial abnormalities have been reported in patients who recovered from COVID-19, the cardiac impact of extensive endurance exercise in individuals who recovered from COVID-19 remains unknown. We therefore aim to investigate (potentially detrimental) cardiac effects of first-time marathon training and participation, including a subset of participants who recovered from COVID-19, in apparently healthy middle-aged men. STUDY DESIGN: This exploratory prospective cohort study investigates cardiac effects of first-time marathon running in 24 middle-aged (35-50 years) healthy men. Primary outcomes are cardiac morphological changes from pre-training up to 1 month after marathon completion, measured with magnetic resonance imaging (MRI) at 4 time points: 1) baseline (4 months before the marathon), 2) pre-marathon (2 weeks before the marathon), 3) post-marathon (< 24 h post-marathon), and 4) recovery (4 weeks after the marathon). Secondary parameters include other cardiac or non-cardiac changes: 1) quantitative MRI myocardial mapping, including mean diffusivity and extracellular volume fraction, 2) echocardiographic morphology and function changes, 3) VO2max, 4) electrocardiogram changes, and 5) levels of cardiac biomarkers. DISCUSSION: This study will contribute to our understanding of cardiac adaptations and maladaptations to first-time marathon running in middle-aged men, and the interaction between extreme endurance exercise and potential detrimental cardiac effects, also in the context of COVID-19. Results will inform on future research directions while providing new clinical insights for health professionals involved in athlete care.

TrimetaziDine as a Performance-enhancING drug in heart failure with preserved ejection fraction (DoPING-HFpEF): rationale and design of a placebo-controlled cross-over intervention study.

BACKGROUND: Currently, no specific treatment exists for heart failure with preserved ejection fraction (HFpEF). Left ventricular (LV) relaxation during diastole is a highly energy-demanding process, while energy homeostasis is known to be compromised in HFpEF. We hypothesise that trimetazidine - a fatty acid ß­oxidation inhibitor - improves LV diastolic function in HFpEF, by altering myocardial substrate use and improving the myocardial energy status. OBJECTIVES: To assess whether trimetazidine improves LV diastolic function by improving myocardial energy metabolism in HFpEF. METHODS: The DoPING-HFpEF trial is a randomised, double-blind, placebo-controlled cross-over intervention trial comparing the efficacy of trimetazidine and placebo in 25 patients with stable HFpEF. The main inclusion criteria are: New York Heart Association functional class II to IV, LV ejection fraction ≥50%, and evidence of LV diastolic dysfunction. Patients are treated with one 20-mg trimetazidine tablet or placebo thrice daily (twice daily in the case of moderate renal dysfunction) for two periods of 3 months separated by a 2-week washout period. The primary endpoint is the change in pulmonary capillary wedge pressure during different intensities of exercise measured by right heart catheterisation. Our key secondary endpoint is the myocardial phosphocreatine (PCr)/ATP ratio measured by phosphorus-31 magnetic resonance spectroscopy and its relation to the primary endpoint. Exploratory endpoints are 6­min walk distance, N-terminal pro-brain natriuretic peptide levels, and quality of life. CONCLUSION: The DoPING-HFpEF is a phase-II trial that evaluates the effect of trimetazidine, a metabolic modulator, on diastolic function and myocardial energy status in HFpEF. [EU Clinical Trial Register: 2018-002170-52; NTR registration: NL7830].

Cerebral dopamine deficiency, plasma monoamine alterations and neurocognitive deficits in adults with phenylketonuria.

BACKGROUND: Phenylketonuria (PKU), a genetic metabolic disorder that is characterized by the inability to convert phenylalanine to tyrosine, leads to severe intellectual disability and other cerebral complications if left untreated. Dietary treatment, initiated soon after birth, prevents most brain-related complications. A leading hypothesis postulates that a shortage of brain monoamines may be associated with neurocognitive deficits that are observable even in early-treated PKU. However, there is a paucity of evidence as yet for this hypothesis. METHODS: We therefore assessed in vivo striatal dopamine D2/3 receptor (D2/3R) availability and plasma monoamine metabolite levels together with measures of impulsivity and executive functioning in 18 adults with PKU and average intellect (31.2 ± 7.4 years, nine females), most of whom were early and continuously treated. Comparison data from 12 healthy controls that did not differ in gender and age were available. RESULTS: Mean D2/3R availability was significantly higher (13%; p = 0.032) in the PKU group (n = 15) than in the controls, which may reflect reduced synaptic brain dopamine levels in PKU. The PKU group had lower plasma levels of homovanillic acid (p < 0.001) and 3-methoxy-4-hydroxy-phenylglycol (p < 0.0001), the predominant metabolites of dopamine and norepinephrine, respectively. Self-reported impulsivity levels were significantly higher in the PKU group compared with healthy controls (p = 0.033). Within the PKU group, D2/3R availability showed a positive correlation with both impulsivity (r = 0.72, p = 0.003) and the error rate during a cognitive flexibility task (r = 0.59, p = 0.020). CONCLUSIONS: These findings provide further support for the hypothesis that executive functioning deficits in treated adult PKU may be associated with cerebral dopamine deficiency.