Effects of maternal high fat diet and pharmacological intervention on the developmental origins of metabolic & cardiovascular disease

A high fat (HF) diet leads to hypercholesterolemia and predisposes the individual to developing cardiovascular disease (CVD). We hypothesised that mother‘s HF diet before and during pregnancy and lactation can also influence predisposition to CVD in offspring fed a similar diet. The thesis sets out to investigate whether (1) the effects of long-term consumption of a HF diet by the mother predisposes her offspring to developing a CVD/ metabolic syndrome in adult life and (2) pharmacological intervention using statin alleviates the detrimental effects of maternal HF diet on the health of the dams and their offspring. Female C57BL/6 mice were fed either a HF diet (45% kcal fat) or standard chow (C; 21% kcal fat) from weaning through pregnancy and lactation. Pregnant C57/BL6 mice on HF diet were further given pravastatin in the drinking water (5 mg/kg of body weight per day) either short-term (2nd half of pregnancy and during lactation) or long-term (from weaning through to pregnancy and lactation) to lower cholesterol and improve post-weaning maternal blood pressure. Weaned female offspring from each group were then fed either a HF or C diets to adulthood. Body weight, blood pressure, plasma cholesterol, C-reactive protein (CRP) and bone marrow derived endothelial progenitor cells (EPC) were measured at 24, 28 and 36 weeks post-weaning in different experiments. Histology of the liver and kidneys were performed. Offspring from hypercholesterolemic mothers on HF diet were significantly obese (bodyweight in grams; 17.2+4.2 vs. 13.8+4.7; P&lt;0.05), hypertensive (SBP mmHg; 134+4.2 vs. 117+3.4; P&lt;0.001), less active (distance in cm; 312 + 31 vs. 563 + 45; P&lt;0.001), demonstrated increased lipid laden vacuoles in liver and kidneys; and showed reduced expression of EPC (P&lt;0.05) than offspring from C dams independent of their postnatal nutrition respectively. Pravastatin therapy in HF mothers resulted in abrogation of these variables in offspring independent of post weaning nutrition (P&lt;0.05). The effects were more permanent when the dams were given long-term statin treatment. The study demonstrates that long-term maternal HF feeding from weaning through pregnancy and lactation predisposes offspring to hypertension, raised plasma lipids, fatty liver, kidney disorders, raised CRP and inhibition of EPC numbers and expression in offspring. Pravastatin treatment of these dams inhibits these effects on the offspring and may reduce their risk of later cardiovascular pathophysiology. The findings may have implications for understanding the effects of the ?nutritional transition‘ to higher dietary intake of fat which could lead to increased cardiovascular disease in many societies.<br/

Oxidative stress as a mediator of cardiovascular disease

During physiological processes molecules undergo chemical changes involving reducing and oxidizing reactions. A molecule with an unpaired electron can combine with a molecule capable of donating an electron. The donation of an electron is termed as oxidation whereas the gaining of an electron is called reduction. Reduction and oxidation can render the reduced molecule unstable and make it free to react with other molecules to cause damage to cellular and sub-cellular components such as membranes, proteins and DNA. In this paper, we have discussed the formation of reactive oxidant species originating from a variety of sources such as nitric oxide (NO) synthase (NOS), xanthine oxidases (XO), the cyclooxygenases, nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase isoforms and metal-catalyzed reactions. In addition, we present a treatise on the physiological defences such as specialized enzymes and antioxidants that maintain reduction-oxidation (redox) balance. We have also given an account of how enzymes and antioxidants can be exhausted by the excessive production of reactive oxidant species (ROS) resulting in oxidative stress/nitrosative stress, a process that is an important mediator of cell damage. Important aspects of redox imbalance that triggers the activity of a number of signaling pathways including transcription factors activity, a process that is ubiquitous in cardiovascular disease related to ischemia/reperfusion injury have also been presented

In situ oxidative stress and atrial cell deaths in patients with valve disease.

Left ventricular hypertrophy and myocardial remodelling occur with aortic valve disease and may lead to heart failure. Although increased oxidative stress and inflammatory factors have been implicated in heart failure, their role in the progression of valve disease remains unclear.We investigated the role of oxidative stress and inflammatory factors in valve disease whether this relates to cell death.Blood samples were taken from 24 patients with valve disease before surgery and the results were compared with those from blood samples from 30 control healthy subjects. Myocardial biopsies from patients with valve disease were also collected before cannulation of the right atrial appendage. NF-&alpha;B activities in atrial and mononuclear cells nuclear extracts were determined by electrophoretic mobility shift assay.Nuclear factor kappaB activities were significantly greater in mononuclear cells from AVD patients compared with healthy controls and the antigens were detectable in atrial tissues valve disease patients. Plasma C-reactive protein, B-natriuretic peptides, plasma tumor necrosis factor alpha and soluble tumor necrosis factor receptor 1 and 3-nitrotyrosine levels were significantly higher in valve disease patients. Inducible nitric oxide and 3-nitrotyrosine antigens and cells expressing CD45 antigens were detected within atrial tissues obtained from valve disease patients suggesting oxidative stress originated from in situ leukocytes.The findings suggests that oxidative stress originating from in situ leukocytes within the atrial myocardium may be the potential trigger for excessive transcriptional activities and apoptotic cell death within the atrial myocardium of valve disease patients. This represents a potential therapeutic target

Current Concepts Underlying Benefits of Exercise Training in Congestive Heart Failure Patients

The pathophysiology of several conditions including heart failure is partly attributable to a failure of the cell energy metabolism. Studies have shown that exercise training (ET) improves quality of life (QOL) and is beneficial in terms of reduction of symptoms, mortality and duration of hospitalization. Increasingly, ET is now achieving acceptance as complimentary therapy in addition to routine clinical practice in patients with chronic heart failure (CHF). However, the mechanisms underlying the beneficial effects of ET are far less understood and need further evaluation. Evidence suggests that while CHF induces generalized metabolic energy depletion, ET largely enhances the overall function of the heart muscle. Hence, research efforts are now aiming to uncover why ET is beneficial as a complimentary treatment of CHF in the context of improving endothelial function and coronary perfusion, decreasing peripheral resistance, induction of cardiac and skeletal muscle cells remodeling, increasing oxygen uptake, substrate oxidation, and resistance to fatigue. Here we discuss the current evidence that suggest that there are beneficial effects of ET on cardiac and skeletal muscle cells oxidative metabolism and intracellular energy transfer in patients with CHF

Prognosis of Colorectal Cancer Patients with Elevated Endothelin-1 Concentrations

Prognostic indicators from clinical, laboratory and pathological data of patients with colorectal cancer are essential to identify high-risk groups in whom adjuvant therapy could be beneficial. Endothelin-1 (ET-1), a growth factor, has been associated with the development and spread of solid tumours. This prospective study was performed to determine whether preoperative plasma big ET-1 concentrations might be useful as a prognostic indicator in patients with colorectal carcinoma. Methods: Overall, 65 consecutive patients with colorectal cancer confirmed by biopsy were included prospectively in this study from 1998 to 2001. Plasma samples from a peripheral vein were obtained prior to surgery. Univariate analysis of survival used age (less than or more than 70 years), gender, Dukes' stage (A/B vs C), tumour size (less than or more than 50 mm), vascular invasion, and plasma big ET-1 concentrations, and significant factors were then analysed using a Cox regression model. Results: Three variables, age, Dukes' tumour stage and plasma big ET-1 concentration, had prognostic significance (p < 0.05). Factors associated with a poorer prognosis were age more than 70 years (p = 0.02), Dukes' C (p = 0.04) and plasma big ET-1 concentration more than 4.2 pg/mL (p = 0.02). The Cox regression model identified the same three variables as having independent prognostic value for overall survival. Conclusion: Preoperative plasma big ET-1 concentrations may be useful in predicting overall survival in patients with colorectal cancer. Plasma big ET-1 concentrations may be useful in the selection of high-risk, lymph node-negative patients with colorectal cancer for adjuvant therapy

Spontaneous Pneumomediastinum Associated with Sex

We present a case of spontaneous pneumomediastinum (SPM) associated with sex. A 22-year-old lesbian with a history of asthma, cigarette and illicit drug smoking was diagnosed with a SPM after developing chest pain and dyspnoea in the context of performing oral sex. The main finding was subcutaneous emphysema involving the neck. SPM is an important differential diagnosis for chest pain in young people. It is a benign condition and diagnosis mainly limited to chest X-ray with increased incidence in asthmatics, smokers and drug addicts

Ethnic differences in the management of coronary heart disease patients : lessons to be learned in Indo-Asians

Objectives: To examine the impact of ethnicity on the outcome of coronary artery bypass grafting (CABG) for myocardial revascularization. Subjects and Methods: We evaluated retrospectively 7,226 Caucasian (CC) and 650 Indo-Asian (IA) patients who underwent isolated first-time CABG surgery over 5 years. The relationship between ethnicity (IA vs. CC) and 30-day mortality, 6-month mortality and complications were analysed. Results: After adjustment for baseline characteristics, IA and CC patients had similar 30-day [IA/CC odds ratio (OR) 1.07; 95% confidence interval (CI) 0.84–1.35; p = 0.59] and 6-month mortality risk (IA/CC OR 1.10; 95% CI 0.91–1.34; p = 0.31). However, IA patients were more likely to experience complications following surgery (OR 1.28; 95% CI 1.14–1.45; p < 0.01). Conclusion: Ethnicity does not appear to be a strong risk factor for adverse outcomes following CABG surgery in the IA patients. However, future studies are needed to elucidate the specific reasons for higher complication rates in IA patients and to devise strategies to reduce complications following the operation for these patients