Diabetic Pregnancy and Maternal High-Fat Diet Impair Mitochondrial Dynamism in the Developing Fetal Rat Heart by Sex-Specific Mechanisms.

Infants born to diabetic or obese mothers are at greater risk of heart disease at birth and throughout life, but prevention is hindered because underlying mechanisms remain poorly understood. Using a rat model, we showed that prenatal exposure to maternal diabetes and a high-fat diet caused diastolic and systolic dysfunction, myocardial lipid accumulation, decreased respiratory capacity, and oxidative stress in newborn offspring hearts. This study aimed to determine whether mitochondrial dynamism played a role. Using confocal live-cell imaging, we examined mitochondrial dynamics in neonatal rat cardiomyocytes (NRCM) from four prenatally exposed groups: controls, diabetes, high-fat diet, and combination exposed. Cardiac expression of dynamism-related genes and proteins were compared, and gender-specific differences were evaluated. Findings show that normal NRCM have highly dynamic mitochondria with a well-balanced number of fusion and fission events. Prenatal exposure to diabetes or a high-fat diet impaired dynamism resulting in shorter, wider mitochondria. Mechanisms of impaired dynamism were gender-specific and protein regulated. Females had higher expression of fusion proteins which may confer a cardioprotective effect. Prenatally exposed male hearts had post-translational modifications known to impair dynamism and influence mitophagy-mediated cell death. This study identifies mitochondrial fusion and fission proteins as targetable, pathogenic regulators of heart health in offspring exposed to excess circulating maternal fuels.

Magnetic resonance imaging (MRI) assessment of ventricular remodeling after myocardial infarction in rabbits.

To understand the structure-function relationship in the postinfarcted myocardium in rabbits, we induced cardiac ischemia by ligating the left circumflex coronary artery. Sham controls underwent thoracotomy only. At 7 and 30 d after ligation, cardiac MRI was conducted by using pulse-oxymetry-gated cine acquisition to provide complete phases of the heartbeat. The rabbits were anesthetized under 1.5% isoflurane ventilation, and ultrafast techniques made breath-hold 3D coverage in different cardiac axes feasible. Viability imaging was performed after intravenous injection of 0.15 mmol/kg gadolinium to assess the extent of infarction. Data (n ≥ 6) are presented as mean ± SEM and analyzed by ANOVA and ANCOVA. In postligation rabbits, end-systolic (mean ± SEM, 2.3 ± 0.3 mL) and end-diastolic (4.2 ± 0.4 mL) volumes were increased compared with preligation values (end-systolic, 1.1 ± 0.1 mL; end-diastolic, 2.98 ± 0.2 mL). Ejection fraction was influenced adversely by the presence of scar tissue at both 7 and 30 d after ligation and apparently nonlinear with the heart rate. Cardiac force was increased in the basal region in both end-systole and end-diastole in postligation hearts but progressively decreased toward the apex. Late gadolinium enhancement delineated 15.2 ± 5.8% myocardial infarction at 7 d after ligation and 14.5 ± 5.8% at 30 d, with limited wall motion and wall thinness. Compensatory wall thickening was present in the basal region when compared with that in preligation hearts. MRI offers detailed spatial resolution and tissue characterization after myocardial infarction.

Ligation of the left circumflex coronary artery with subsequent MRI and histopathology in rabbits.

Provided is the surgical procedure for ligating the left circumflex coronary artery to simulate heart ischemia by using a rabbit model. Heart rate monitored by electrocardiogram was increased at 5 min after ligation (mean ± SEM, 205 ± 13 bpm) when compared with that before ligation (170 ± 12 bpm), but returned to baseline at 25 min after ligation (183 ± 11 bpm). A marked elevation in the ST segment and reduction of the QRS wave of the electrocardiogram indicated the evolving myocardial infarct. The ejection fraction derived from MRI was decreased by 20% in the infarcted heart. The extent of necrosis and fibrosis in the myocardium due to ischemia led to decreased compliance and efficiency of the left ventricle. Masson trichrome staining showed blue-stained fibrils with the appearance of loose, threadlike scar tissue dispersed transmurally in the left ventricle and extending toward the apex. This study demonstrates the feasibility of MRI analysis of myocardial infarction in a rabbit model. The myocardial architecture, including the geometry of the myofibers which determines the contractile function of the heart, is clearly demonstrated by using cardiac MRI. Understanding the 3-dimensional arrangement of the myocardial microstructure and how remodeling of the infarcted myocardium affects cardiac function in an animal model has important implications for the study of heart disease in humans.