Background: Aging myocardium undergoes progressive cardiac hypertrophy and interstitial fibrosis with diastolic and systolic dysfunction. Recent metabolomics studies shed light on amino acids in aging. The present study aimed to dissect how aging leads to elevated plasma levels of the essential amino acid phenylalanine (Phe) and how it may promote age-related cardiac dysfunction. Methods: We studied cardiac structure and function, together with Phe catabolism in wild-type (WT) and p21 -/- mice (male; 2 to 24 months), the latter known to be protected from cellular senescence. To explore Phe's effects on cellular senescence and ectopic Phe catabolism we treated cardiomyocytes (primary adult rat or human AC-16) with Phe. To establish a role for Phe in driving cardiac aging, WT male mice were treated twice a day with Phe (200 mg/kg) for a month. We also treated aged WT mice with tetrahydrobiopterin (BH4; 10 mg/kg), the essential cofactor for the Phe-degrading enzyme phenylalanine hydroxylase (PAH), or restricted dietary Phe intake. The impact of senescence on hepatic Phe catabolism was explored in vitro in AML12 hepatocytes treated with Nutlin3a (a p53 activator), with or without p21-targeting siRNA or BH4, with quantification of PAH and tyrosine levels. Results: Natural aging is associated with a progressive increase in plasma Phe levels concomitant with cardiac dysfunction, whilst p21 deletion delayed these changes. Phe treatment induced premature cardiac deterioration in young WT mice, strikingly akin to that occurring with aging, whilst triggering cellular senescence, redox and epigenetic changes. Pharmacological restoration of Phe catabolism with BH4 administration or dietary Phe restriction abrogated the rise in plasma Phe and reversed cardiac senescent alterations in aged WT mice. Observations from aged mice and human samples implicated age-related decline in hepatic Phe catabolism as a key driver of elevated plasma Phe levels and showed increased myocardial PAH-mediated Phe catabolism, a novel signature of cardiac aging. Conclusions: Our findings establish a pathogenic role for increased Phe levels in cardiac aging, linking plasma Phe levels to cardiac senescence via dysregulated Phe catabolism along a hepatic-cardiac axis. They highlight Phe/PAH modulation as a potential therapeutic strategy for age-associated cardiac impairment.

Hypoxemia is the main feature of COVID-19-related acute respiratory distress syndrome (C-ARDS), but its underlying mechanisms are debated, especially in patients with low respiratory system elastance (Ers). We assessed 60 critically ill patients hospitalized in our intensive care unit for CARDS. We used contrast transthoracic echocardiography to assess patent foramen ovale (PFO) shunt and transpulmonary bubble transit (TPBT). The median Ers was 32 cmH 2 O/L. PFO shunt was detected in six (10%) patients and TPBT in 12 (20%) patients. PFO shunt and TPBT were similar in patients with higher or lower Ers. In conclusion, PFO and TPBT do not seem to be the main drivers of hypoxemia in CARDS , especially in patients with lower Ers.