Transmission of Mitochondrial DNA Diseases and Ways to Prevent Them

Recent reports of strong selection of mitochondrial DNA (mtDNA) during transmission in animal models of mtDNA disease, and of nuclear transfer in both animal models and humans, have important scientific implications. These are directly applicable to the genetic management of mtDNA disease. The risk that a mitochondrial disorder will be transmitted is difficult to estimate due to heteroplasmy—the existence of normal and mutant mtDNA in the same individual, tissue, or cell. In addition, the mtDNA bottleneck during oogenesis frequently results in dramatic and unpredictable inter-generational fluctuations in the proportions of mutant and wild-type mtDNA. Pre-implantation genetic diagnosis (PGD) for mtDNA disease enables embryos produced by in vitro fertilization (IVF) to be screened for mtDNA mutations. Embryos determined to be at low risk (i.e., those having low mutant mtDNA load) can be preferentially transferred to the uterus with the aim of initiating unaffected pregnancies. New evidence that some types of deleterious mtDNA mutations are eliminated within a few generations suggests that women undergoing PGD have a reasonable chance of generating embryos with a lower mutant load than their own. While nuclear transfer may become an alternative approach in future, there might be more difficulties, ethical as well as technical. This Review outlines the implications of recent advances for genetic management of these potentially devastating disorders

Physiology and Cardioprotection of the Epicardial Adipose Tissue

Epicardial adipose tissue (EAT) is a peculiar visceral fat depot with both protective and detrimental properties. The physiological role of EAT within the heart is complex and not completely understood. EAT functions can be distinguished in (1) nutritional, (2) metabolic, (3) thermogenic, (4) regulatory, and (5) mechanical. Under normal physiological EAT serves as a buffer, absorbing fatty acids and protecting the heart against high fatty acids levels and as pad protecting abnormal curvature of the coronary arteries. EAT is enriched in genes coding for cardioprotective adipokines such as adiponectin and adrenomedullin, both with potential anti-inflammatory and anti-atherogenic properties. EAT could also function as local energy source at times of high demand, channeling fatty acids to the myocardium and as brown fat to defend the myocardium against hypothermia. EAT expresses genes and secretes cytokines actively involved in the thermogenesis and regulation of lipid and glucose metabolism of the adjacent myocardium. EAT may adapt itself to different metabolic circumstances and function as brown-like or beige fat depot as needed

Pathology and Cardiotoxicity of the Epicardial Adipose Tissue

Intra-organ fatty infiltration is associated with end-organ damages and increased cardiovascular risk. Ectopic fat deposition occurs also within the heart and may cause a metabolic cardiomyopathy. Epicardial fat (EAT) can be considered ectopic fat accumulation of the heart. Epicardial fat and intra-myocardial triglycerides content are related. Excessive EAT can produce lipotoxic effects throughout an abnormal lipid deposition and fatty infiltration in the myocardium. As cardiomyocytes fat storage capacity is very limited, high levels of plasma lipids cause cardiac steatosis, hypertrophy, dysfunction, and ultimately failure, as observed in morbid obesity and uncontrolled diabetes. Due to its anatomical and functional vicinity to the myocardium, EAT can affect the morphology and function of all of the heart chambers. Increased epicardial fat has been largely associated with increased left ventricular mass, abnormal geometry, enlarged atria, and diastolic dysfunction. Multifactorial physical and biomolecular mechanisms can explain the effects of excessive EAT on the heart