Maternal metabolism during pregnancy impacts the developing fetus, affecting offspring birth weight and adiposity. This has important implications for metabolic health later in life (e.g., offspring of mothers with pre-existing or gestational diabetes mellitus have an increased risk of metabolic disorders in childhood). To identify genetic loci associated with measures of maternal metabolism obtained during an oral glucose tolerance test at ∼28 weeks’ gestation, we performed a genome-wide association study of 4,437 pregnant mothers of European (n = 1,367), Thai (n = 1,178), Afro-Caribbean (n = 1,075), and Hispanic (n = 817) ancestry, along with replication of top signals in three additional European ancestry cohorts. In addition to identifying associations with genes previously implicated with measures of glucose metabolism in nonpregnant populations, we identified two novel genome-wide significant associations: 2-h plasma glucose and HKDC1, and fasting C-peptide and BACE2. These results suggest that the genetic architecture underlying glucose metabolism may differ, in part, in pregnancy.

Background Novel coronavirus-19 disease (COVID-19) is associated with significant cardiovascular morbidity and mortality. To date, there have not been reports of sinus node dysfunction (SND) associated with COVID-19. This case series describes clinical characteristics, potential mechanisms, and short-term outcomes of COVID-19 patients who experience de novo SND. Case summary We present two cases of new-onset SND in patients recently diagnosed with COVID-19. Patient 1 is a 70-year-old female with no major past medical history who was intubated for acute hypoxic respiratory failure secondary to COVID-19 pneumonia and developed new-onset sinus bradycardia without a compensatory increase in heart rate in response to relative hypotension. Patient 2 is an 81-year-old male with a past medical history of an ascending aortic aneurysm, hypertension, and obstructive sleep apnoea who required intubation for COVID-19-induced acute hypoxic respiratory failure and exhibited new-onset sinus bradycardia followed by numerous episodes of haemodynamically significant accelerated idioventricular rhythm. Two weeks following the onset of SND, both patients remain in sinus bradycardia. Discussion COVID-19-associated SND has not previously been described. The potential mechanisms for SND in patients with COVID-19 include myocardial inflammation or direct viral infiltration. Patients diagnosed with COVID-19 should be monitored closely for the development of bradyarrhythmia and haemodynamic instability.

Many common genetic polymorphisms are associated with glycemic traits and type 2 diabetes (T2D), but knowledge about genetic determinants of glycemic traits in pregnancy is limited. We tested genetic variants known to be associated with glycemic traits and T2D in the general population for associations with glycemic traits in pregnancy and gestational diabetes mellitus (GDM). Participants in two cohorts (Genetics of Glucose regulation in Gestation and Growth [Gen3G] and Hyperglycemia and Adverse Pregnancy Outcome [HAPO]) underwent oral glucose tolerance testing at 24–32 weeks’ gestation. We built genetic risk scores (GRSs) for elevated fasting glucose and insulin, reduced insulin secretion and sensitivity, and T2D, using variants discovered in studies of nonpregnant individuals. We tested for associations between these GRSs, glycemic traits in pregnancy, and GDM. In both cohorts, the fasting glucose GRS was strongly associated with fasting glucose. The insulin secretion and sensitivity GRSs were also significantly associated with these traits in Gen3G, where insulin measurements were available. The fasting insulin GRS was weakly associated with fasting insulin (Gen3G) or C-peptide (HAPO). In HAPO (207 GDM case subjects), all five GRSs (T2D, fasting glucose, fasting insulin, insulin secretion, and insulin sensitivity) were significantly associated with GDM. In Gen3G (43 GDM case subjects), both the T2D and insulin secretion GRSs were associated with GDM; effect sizes for the other GRSs were similar to those in HAPO. Thus, despite the profound changes in glycemic physiology during pregnancy, genetic determinants of fasting glucose, fasting insulin, insulin secretion, and insulin sensitivity discovered outside of pregnancy influence GDM risk.

PYK2 is a Ca 2+ -dependent, nonreceptor protein tyrosine kinase that is involved in the induction of left ventricular hypertrophy (LVH) and its transition to heart failure. We and others have previously investigated PYK2's function in vitro using cultured neonatal and adult rat ventricular myocytes as model systems. However, the function of PYK2 in the in vivo adult heart remains unclear. Here we evaluate the effect of PYK2 inhibition following myocardial infarction (MI) using adenoviral (Adv) overexpression of the C-terminal domain of PYK2, known as CRNK. First we demonstrate that CRNK functions as a dominant-negative inhibitor of PYK2-dependent signaling, presumably by displacing PYK2 from focal adhesions and costameres. Then, male Sprague-Dawley rats (~300g) underwent permanent left anterior descending coronary artery ligation. One wk post-MI, either Adv-GFP (n=34) or Adv-CRNK (n=28) was administered (10 10 pfu, 0.1ml) via catheter-based, Optison®-mediated gene transfer. LV structure and function were evaluated by echocardiography 1 and 3wk after gene transfer, and LV tissue was analyzed by real-time RT-PCR and Western blotting. CRNK overexpression was readily detected by Western blotting 1wk following gene transfer. Adv-CRNK improved overall survival (P=0.03; Logrank Test) and LV fractional shortening (23±2% vs. 31±2% for Adv-GFP vs. Adv-CRNK infected animals, respectively; P<0.05). Whereas MI hearts exhibited increased β-, and decreased α-myosin heavy chain (MHC) mRNA expression characteristic of LVH, Adv-CRNK reversed the MHC isoenzyme switch (3.3±1.4 fold increase in αMHC; 0.4±0.1 fold decrease in βMHC; P<0.05 for both). In summary, CRNK gene transfer improves survival, increases LV function, and alters MHC gene expression suggesting an attenuation of LV remodeling post-MI.Proofs and Correspondences to:

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