PAK1 and PP2A are integral components of a macromolecular complex with cardiac Cx43, and increased activation of associated PAK1 can contribute to enhanced Cx43 dephosphorylation and impaired intercellular coupling that may underlie slow conduction in HF.
Background
In the normal heart, phosphodiesterase type 5 (PDE5) hydrolyzes cGMP coupled to nitric oxide (specifically from NOS3) but not natriuretic peptide (NP) stimulated guanylyl cyclase. PDE5 is upregulated in hypertrophied and failing hearts and is thought to contribute to their pathophysiology. Since NO signaling declines whereas NP-derived cGMP rises in such diseases, we hypothesized that PDE5 substrate selectivity is retargeted to blunt NP-derived signaling.
Methods and Results
Mice with cardiac myocyte inducible PDE5 overexpression (P5+) were crossed to those lacking NOS3 (N3−), and each model, the double cross, and controls were subjected to transaortic constriction (TAC). P5+ mice developed worse dysfunction and hypertrophy, and enhanced NP stimulation, whereas N3− mice were protected. However, P5+/N3− mice behaved similarly to P5+ despite the lack of NOS3-coupled cGMP generation, with PKG activity suppressed in both models. PDE5 inhibition did not alter ANP-stimulated cGMP in the resting heart, but augmented it in the TAC heart. This functional retargeting was associated with PDE5 translocation from sarcomeres to a dispersed distribution. P5+ hearts exhibited higher oxidative stress whereas P5+/N3− hearts had low levels (likely due to the absence of NOS3 uncoupling). This highlights the importance of myocyte PKG activity as a protection to pathological remodeling.
Conclusions
These data provide the first evidence for functional retargeting of PDE5 from one compartment to another, revealing a role for NP-derived cGMP hydrolysis by this esterase in diseased heart myocardium. Retargeting likely impacts the pathophysiologic consequence and also therapeutic impact of PDE5 modulation in heart disease.
Background
Between 2016 and 2018, San Diego County experienced a hepatitis A outbreak with a historically high mortality rate (3.4%) that highlighted the need for early recognition of those at risk of developing acute liver failure (ALF).
Methods
A retrospective case series of adult hospitalized patients with acute hepatitis A.
Results
One hundred six patients with hepatitis A were studied, of whom 11 (10.4%) developed ALF, of whom 7 (6.6%) died. A history of alcohol abuse, hyperbilirubinemia, hypoalbuminemia, hyponatremia, and anemia were associated with increased odds of developing ALF. Initial Maddrey’s and Model of End-Stage Liver Disease Sodium (MELD-Na) scores were also associated with the development of ALF. Multivariable analysis showed that a higher initial MELD-Na score (odds ratio [OR], 1.205; 95% confidence interval [CI], 1.018–1.427) and a lower initial serum albumin concentration (OR, 9.35; 95% CI, 1.15–76.9) were associated with increased odds of developing ALF. Combining serum albumin and MELD-Na (SAM; C-statistic, 0.8878; 95% CI, 0.756–0.988) yielded a model that was not better than either serum albumin (C-statistic, 0.852; 95% CI, 0.675–0.976) or MELD-Na (C-statistic, 0.891; 95% CI, 0.784–0.968; P = .841). Finally, positive blood cultures were more common among patients with ALF compared with those without ALF (63.6% vs 4.3%; P < .00001).
Conclusions
Hypoalbuminemia was associated with an increased risk of ALF in patients with acute hepatitis A. Positive blood cultures and septic shock as a cause of death were common among patients with ALF. Providers caring for patients with acute hepatitis A should monitor for early signs of sepsis and consider empiric antibiotics, especially in patients presenting with hypoalbuminemia.
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