Unravelling the impact of intrauterine growth restriction on heart development: insights into mitochondria and sexual dimorphism from a non-hominoid primate.

Fetal exposure to an unfavorable intrauterine environment programs an individual to have a greater susceptibility later in life to non-communicable diseases, such as coronary heart disease, but the molecular processes are poorly understood. An article in Clinical Science recently reported novel details on the effects of maternal nutrient reduction (MNR) on fetal heart development using a primate model that is about 94% genetically similar to humans and is also mostly monotocous. MNR adversely impacted fetal left ventricular (LV) mitochondria in a sex-dependent fashion with a greater effect on male fetuses, although mitochondrial transcripts increased more so in females. Increased expression for several respiratory chain and adenosine triphosphate (ATP) synthase proteins were observed. However, fetal LV mitochondrial complex I and complex II/III activities were significantly decreased, likely contributing to a 73% decreased LV ATP content and increased LV lipid peroxidation. Moreover, MNR fetal LV mitochondria showed sparse and disarranged cristae. This study indicates that mitochondria are targets of the remodeling and imprinting processes in a sex-dependent manner. Mitochondrial ROS production and inadequate energy production add another layer of complexity. Altogether these observations raise the possibility that dysfunctional mitochondria in the fetus may contribute in turn to epigenetic memory of in utero stress in the adult. The role of mitoepigenetics and involvement of mitochondrial and genomic non-coding RNAs in mitochondrial functions and nuclei-mitochondria crosstalk with in utero stress awaits further investigation.

The Angiotensin II Type 1(AT1) Receptor and Cardiac Hypertrophy: Did We Have It Wrong All Along?

ABSTRACT: An ongoing issue in cardiac pharmacology is whether angiotensin II has direct growth promoting effects on the heart via the angiotensin II type 1 (AT1) receptor. This question has relevance for whether angiotensin-converting enzyme inhibitors and AT1 receptor blockers offer additional benefit in preventing adverse cardiac remodeling in hypertension. In a recent study, 2 strains of mice were infused with angiotensin II. In both, AT1 receptors were deleted in the heart and conduit vessels, but in one, AT1 receptors were also deleted in resistance vessels. Angiotensin II caused hypertrophy and hypertension in the strain lacking AT1 receptors in the heart and conduit vessels, but not in the strain without AT1 receptors in resistance vessels. This finding supports the conclusion that blood pressure is more important in determining cardiac hypertrophy than direct AT1 activation by angiotensin II, when the two are rapidly and simultaneously introduced. Surprisingly, mice with no cardiac AT1 receptor expression developed ventricular dilation and eccentric hypertrophy with pressure overload, in contrast to wild type mice that exhibited concentric hypertrophy, suggesting that cardiac AT1 receptors protect against high blood pressure. This interpretation revives issues related to ß-arrestin-biased signaling and mechanosensitivity of AT1 receptors. Synthetic nanobodies, which are based on the variable regions of camelid-derived heavy chain-only antibodies, could be applied to explore the therapeutic potential of exploiting different activation states of AT1 under stress conditions, such as hypertension and heart failure. At the very least, this experimental approach is likely to reveal new facets of AT1 receptor signaling in the heart.

Risk of thromboembolic events in non-hospitalized COVID-19 patients: A systematic review.

The risk of thromboembolism in non-hospitalized COVID-19 patients remains uncertain and was assessed in this review to better weigh benefits vs. risks of prophylactic anticoagulation in this population. A search was performed through three databases: Medline, Embase, and Cochrane Library until 2022. Self-controlled case series, case-control and cohort studies were included, and findings summarized narratively. Meta-analyses for risk of thromboembolism including deep vein thrombosis (DVT), pulmonary embolism (PE), and myocardial infarction (MI) between COVID-19 and non-COVID-19 non-hospitalized patients were conducted. Frequency, incidence rate ratio (IRR), and risk ratio (RR) of stroke were used to assess risk in non-hospitalized COVID-19 patients considering the lack of studies to conduct a meta-analysis. Ten studies met inclusion criteria characterized by adult non-hospitalized COVID-19 patients. Risk of bias was relatively low. Risk of DVT (RR: 1.98 with 95% CI: 1.03-3.83) and PE (OR: 6.72 with 95% CI: 4.81-9.39 and RR: 4.44 with 95% CI: 1.98-9.99) increased in non-hospitalized COVID-19 patients compared to controls. Risk of MI (OR: 1.91 with 95% CI: 0.89-4.09) is possibly increased in non-hospitalized COVID-19 patients with moderate certainty when compared to controls. A trend in favor of stroke was documented in the first week following infection. Our meta-analyses support the increase in risk of DVT and PE, and likely increase of MI, in non-hospitalized COVID-19 patients. The risk of stroke appears significant in the first week following infection but drops to insignificance two weeks later. More studies are needed to establish evidence-based recommendations for prophylactic anticoagulation therapy in non-hospitalized COVID-19 patients.