Heather L. Blackmore

Writing a narrative biomedical review: Considerations for authors, peer reviewers, and editors

Review articles comprehensively covering a specific topic are crucial for successful research and academic projects. Most editors consider review articles for special and regular issues of journals. Writing a review requires deep knowledge and understanding of a field. The aim of this review is to analyze the main steps in writing a narrative biomedical review and to consider points that may increase the chances of success. We performed a comprehensive search through MEDLINE, EMBASE, Scopus, and Web of Science using the following keywords: review of the literature, narrative review, title, abstract, authorship, ethics, peer review, research methods, medical writing, scientific writing, and writing standards. Opinions expressed in the review are also based on personal experience as authors, peer reviewers, and editors.

The Programming of Cardiac Hypertrophy in the Offspring by Maternal Obesity Is Associated with Hyperinsulinemia, AKT, ERK, and mTOR Activation

Human and animal studies suggest that suboptimal early nutrition during critical developmental periods impacts long-term health. For example, maternal overnutrition during pregnancy and lactation in mice programs insulin resistance, obesity, and endothelial dysfunction in the offspring. Here we investigated the effects of diet-induced maternal obesity on the offspring cardiac phenotype and explored potential underlying molecular mechanisms. Dams fed the obesogenic diet were heavier (P < 0.01) and fatter (P < 0.0001) than controls throughout pregnancy and lactation. There was no effect of maternal obesity on offspring body weight or body composition up to 8 wk of age. However, maternal obesity resulted in increased offspring cardiac mass (P < 0.05), increased heart-body weight (P < 0.01), heart weight-tibia length (P < 0.05), increased left ventricular free wall thickness and area (P < 0.01 and P < 0.05, respectively), and increased myocyte width (P < 0.001). Consistent with these structural changes, the expression of molecular markers of cardiac hypertrophy were also increased [Nppb(BNP), Myh7-Myh6(βMHC-αMHC) (both P < 0.05) and mir-133a (P < 0.01)]. Offspring were hyperinsulinemic and displayed increased insulin action through AKT (P < 0.01), ERK (P < 0.05), and mammalian target of rapamycin (P < 0.05). p38MAPK phosphorylation was also increased (P < 0.05), suggesting pathological remodeling. Increased Ncf2(p67phox) expression (P < 0.05) and impaired manganese superoxide dismutase levels (P < 0.01) suggested oxidative stress, which was consistent with an increase in levels of 4-hydroxy-2-trans-nonenal (a measure of lipid peroxidation). We propose that maternal diet-induced obesity leads to offspring cardiac hypertrophy, which is independent of offspring obesity but is associated with hyperinsulinemia-induced activation of AKT, mammalian target of rapamycin, ERK, and oxidative stress.

Maternal Diet-induced Obesity Programs Cardiovascular Dysfunction in Adult Male Mouse Offspring Independent of Current Body Weight

Obese pregnancies are not only associated with adverse consequences for the mother but also the long-term health of her child. Human studies have shown that individuals from obese mothers are at increased risk of premature death from cardiovascular disease (CVD), but are unable to define causality. This study aimed to determine causality using a mouse model of maternal diet–induced obesity. Obesity was induced in female C57BL/6 mice by feeding a diet rich in simple sugars and saturated fat 6 weeks prior to pregnancy and throughout pregnancy and lactation. Control females were fed laboratory chow. Male offspring from both groups were weaned onto chow and studied at 3, 5, 8, and 12 weeks of age for gross cardiac morphometry using stereology, cardiomyocyte cell area by histology, and cardiac fetal gene expression using qRT-PCR. Cardiac function was assessed by isolated Langendorff technology at 12 weeks of age and hearts were analyzed at the protein level for the expression of the β1 adrenergic receptor, muscarinic type-2 acetylcholine receptor, and proteins involved in cardiac contraction. Offspring from obese mothers develop pathologic cardiac hypertrophy associated with re-expression of cardiac fetal genes. By young adulthood these offspring developed severe systolic and diastolic dysfunction and cardiac sympathetic dominance. Importantly, cardiac dysfunction occurred in the absence of any change in corresponding body weight and despite the offspring eating a healthy low-fat diet. These findings provide a causal link to explain human observations relating maternal obesity with premature death from CVD in her offspring.

Coenzyme Q10 prevents accelerated cardiac aging in a rat model of poor maternal nutrition and accelerated postnatal growth

Studies in human and animals have demonstrated that nutritionally induced low birth-weight followed by rapid postnatal growth increases the risk of metabolic syndrome and cardiovascular disease. Although the mechanisms underlying such nutritional programming are not clearly defined, increased oxidative-stress leading to accelerated cellular aging has been proposed to play an important role. Using an established rodent model of low birth-weight and catch-up growth, we show here that post-weaning dietary supplementation with coenzyme Q10, a key component of the electron transport chain and a potent antioxidant rescued many of the detrimental effects of nutritional programming on cardiac aging. This included a reduction in nitrosative and oxidative-stress, telomere shortening, DNA damage, cellular senescence and apoptosis. These findings demonstrate the potential for postnatal antioxidant intervention to reverse deleterious phenotypes of developmental programming and therefore provide insight into a potential translatable therapy to prevent cardiovascular disease in at risk humans.

Maternal diet-induced obesity and offspring cardiovascular health.

It is widely recognized that environmental insults during adulthood including smoking, lack of exercise and a poor diet increases an individuals risk of cardiovascular disease (CVD). However, research initiated over the last two decades has highlighted that our risk of CVD can be programmed following adverse exposures during early development. Such adverse exposures may include, undernutrition, placental insufficiency, hypoxia, overnutrition and obesity. This review aims to address the current Western obesity crisis by addressing the long-term impact of maternal overnutrition and obesity on the offsprings future risk of CVD. Although current human studies have observed the presence of adverse CVD markers in children born to obese mothers, animal models have proved vital in understanding the underlying mechanisms involved. Mechanisms suggested to be involved in the programming of CVD in the offspring include increased oxidative stress, inflammation, lipotoxicity and epigenetics. CVD remains the greatest cause of death worldwide, therefore further understanding of the mechanisms mediating these effects is important in the development of intervention strategies.

Programming of cardiovascular disease across the life-course

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality, affecting both developed and developing countries. Whilst it is well recognized that our risk of CVD can be determined by the interaction between our genetics and lifestyle, this only partly explains the variability at the population level. Based on these well-known risk factors, for many years, intervention and primary prevention strategies have focused on modifying lifestyle factors in adulthood. However, research shows that our risk of CVD can be pre-determined by our early life environment and this area of research is known as the Developmental Origins of Health and Disease. The aim of this review is to evaluate our current understanding of mechanisms underlying the programming of CVD. This article is part of a special issue entitled CV Aging.

Apolipoprotein E Gene Polymorphisms Are Strong Predictors of Inflammation and Dyslipidemia in Rheumatoid Arthritis

Objective. Rheumatoid arthritis (RA), a condition with a strong genetic etiology, is associated with excess cardiovascular disease (CVD). Dyslipidemia in RA may be driven by inflammation and genetic factors. Apolipoprotein E (ApoE) is important for the regulation of lipid levels and CVD risk and immune function in the general population. We compared the frequency of 2 ApoE single-nucleotide polymorphisms (SNP) in patients with RA and controls, and studied the relationship of ApoE genotypes with lipids and inflammation in RA. Methods. A total of 387 patients with well-characterized RA and 420 non-RA controls were studied. Two ApoE SNP, rs7412 (ApoE2) and rs429358 (ApoE4), were identified. Results. Genotypic (p = 0.908) and allelic (p = 0.894) frequencies did not differ between RA and controls. Within RA, the E2 allele was associated with the lowest and E4 allele with the highest levels of total cholesterol (p = 0.007), low-density lipoproteins (p = 0.004), and apolipoprotein B (p = 0.009). The E4 allele was also associated with lower C-reactive protein (p = 0.007), erythrocyte sedimentation rate (p = 0.001), and Disease Activity Score (p = 0.015) compared to the E3 allele. E2 or E4 alleles were not associated with CVD in RA, although a trend was observed (p = 0.074). Conclusion. The frequency of ApoE polymorphisms did not differ between patients with RA and controls. ApoE genotypes are strongly linked to inflammation and lipid levels in RA, raising interest in the prognostic implications of ApoE genotypes.

Poor maternal nutrition programmes a pro-atherosclerotic phenotype in ApoE-/- mice.

Numerous animal studies have consistently shown that early life exposure to LP (low-protein) diet programmes risk factors for CVD (cardiovascular disease) such as dyslipidaemia, high BP (blood pressure) and cardiac dysfunction in the offspring. However, studies on the effect of maternal under-nutrition on offspring development of atherosclerosis are scarce. Applying our LP model to the ApoE−/− atherosclerosis-prone mouse model, we investigated the development of atherosclerotic lesions in the aortic root of 6-month-old offspring. In addition, markers of plaque progression including SMA (smooth muscle actin) and Mac3 (macrophage marker 3) were studied. Pregnant dams were fed on a control (20% protein) or on an isocaloric LP diet (8% protein) throughout pregnancy and lactation. After weaning, male offspring were maintained on 20% normal laboratory chow. At 6 months of age, LP offspring showed a significantly greater plaque area (P<0.05) with increased cholesterol clefts and significantly higher indices of DNA damage compared with controls (P<0.05). The expression of HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA reductase) (P<0.05) and LDL (low-density lipoprotein) receptor in the liver of LP offspring were increased. Furthermore, LP offspring had higher LDL-cholesterol levels (P<0.05) and a trend towards elevated insulin. There were no differences in other lipid measurements and fasting glucose between groups. These observations suggest that early exposure to an LP diet accelerates the development and increases the progression of atherosclerotic lesions in young adult offspring. Future studies are needed to elucidate the specific mechanisms linking in utero exposure to a diet low in protein to the development of atherosclerosis.

Maternal diet-induced obesity programmes cardiac dysfunction in male mice independently of post-weaning diet

Abstract Aims Obesity during pregnancy increases risk of cardiovascular disease (CVD) in the offspring and individuals exposed to over-nutrition during fetal life are likely to be exposed to a calorie-rich environment postnatally. Here, we established the consequences of combined exposure to a maternal and post-weaning obesogenic diet on offspring cardiac structure and function using an established mouse model of maternal diet-induced obesity. Methods and results The impact of the maternal and postnatal environment on the offspring metabolic profile, arterial blood pressure, cardiac structure, and function was assessed in 8-week-old C57BL/6 male mice. Measurement of cardiomyocyte cell area, the transcriptional re-activation of cardiac fetal genes as well as genes involved in the regulation of contractile function and matrix remodelling in the adult heart were determined as potential mediators of effects on cardiac function. In the adult offspring: a post-weaning obesogenic diet coupled with exposure to maternal obesity increased serum insulin (P < 0.0001) and leptin levels (P < 0.0001); maternal obesity (P = 0.001) and a post-weaning obesogenic diet (P = 0.002) increased absolute heart weight; maternal obesity (P = 0.01) and offspring obesity (P = 0.01) caused cardiac dysfunction but effects were not additive; cardiac dysfunction resulting from maternal obesity was associated with re-expression of cardiac fetal genes (Myh7: Myh6 ratio; P = 0.0004), however, these genes were not affected by offspring diet; maternal obesity (P = 0.02); and offspring obesity (P = 0.05) caused hypertension and effects were additive. Conclusions Maternal diet-induced obesity and offspring obesity independently promote cardiac dysfunction and hypertension in adult male progeny. Exposure to maternal obesity alone programmed cardiac dysfunction, associated with hallmarks of pathological left ventricular hypertrophy, including increased cardiomyocyte area, upregulation of fetal genes, and remodelling of cardiac structure. These data highlight that the perinatal period is just as important as adult-onset obesity in predicting CVD risk. Therefore, early developmental periods are key intervention windows to reduce the prevalence of CVD.

Maternal exercise intervention in obese pregnancy improves the cardiovascular health of the adult male offspring

Objective Obesity during pregnancy is associated with an elevated risk of cardiovascular disease in the offspring. With increased numbers of women entering pregnancy overweight or obese, there is a requirement for targeted interventions to reduce disease risk in future generations. Using an established murine model of maternal obesity during pregnancy, we investigated if a treadmill exercise intervention in the mother could improve offspring cardiac health and explored potential underlying mechanisms. Methods A 20-minute treadmill exercise intervention protocol was performed 5 days a week in diet-induced obese female C57BL/6 mice 1 week prior to, and up to E17 of pregnancy. All male offspring were weaned onto a control diet and studied at 8 weeks of age when their cardiovascular physiology was assessed by in vivo echocardiography and non-invasive tail cuff plethysmography. Cardiomyocyte cell area, re-expression of fetal genes and the expression of calcium handling and sympathetic activation proteins were determined. Results At 8 weeks, there was no difference in bodyweight or fat mass between groups. Offspring of obese dams developed pathologic cardiac hypertrophy, hypertension and cardiac dysfunction characterized by reduced ejection fraction (p < 0.001). Maternal exercise prevented cardiac hypertrophy and dysfunction but failed to prevent hypertension. These offspring of exercised dams also had enhanced (p < 0.001) levels of calcium handling proteins and a sympathetic-activated inotropic response. Conclusions Exercise in obese pregnancy was beneficial to offspring cardiac function and structure but did not influence hypertension suggesting they are programmed by separate mechanistic pathways. These data suggest combination interventions in obese pregnancies will be required to improve all aspects of the cardiovascular health of the next generation.