Measuring the global burden of disease and epidemiological transitions: 2002-2030

Any planning process for health development ought to be based on a thorough understanding of the health needs of the population. This should be sufficiently comprehensive to include the causes of premature death and of disability, as well as the major risk factors that underlie disease and injury. To be truly useful to inform health-policy debates, such an assessment is needed across a large number of diseases, injuries and risk factors, in order to guide prioritization. The results of the original Global Burden of Disease Study and, particularly, those of its 2000-2002 update provide a conceptual and methodological framework to quantify and compare the health of populations using a summary measure of both mortality and disability: the disability-adjusted life-year (DALY). Globally, it appears that about 5 6 million deaths occur each year, 10. 5 million (almost all in poor countries) in children. Of the child deaths, about one-fifth result from perinatal causes such as birth asphyxia and birth trauma, and only slightly less from lower respiratory infections. Annually, diarrhoeal diseases kill over 1.5 million children, and malaria, measles and HIV/AIDS each claim between 500,000 and 800,000 children. HIV/AIDS is the fourth leading cause of death world-wide (2.9 million deaths) and the leading cause in Africa. The top three causes of death globally are ischaemic heart disease (7.2 million deaths), stroke (5.5 million) and lower respiratory diseases (3.9 million). Chronic obstructive lung diseases (COPD) cause almost as many deaths as HIV/AIDS (2.7 million). The leading causes of DALY, on the other hand, include causes that are common at young ages [perinatal conditions (7. 1 % of global DALY), lower respiratory infections (6.7%), and diarrhoeal diseases (4.7%)] as well as depression (4.1%). Ischaemic heart disease and stroke rank sixth and seventh, retrospectively, as causes of global disease burden, followed by road traffic accidents, malaria and tuberculosis. Projections to 2030 indicate that, although these major vascular diseases will remain leading causes of global disease burden, with HIV/AIDS the leading cause, diarrhoeal diseases and lower respiratory infections will be outranked by COPD, in part reflecting the projected increases in death and disability from tobacco use.

Relationship between myocardial perfusion and dysfunction in diabetic cardiomyopathy: A study of quantitative contrast echocardiography and strain rate imaging

Objective: To use quantitative myocardial contrast echocardiography (MCE) and strain rate imaging (SRI) to assess the role of microvascular disease in subclinical diabetic cardiomyopathy. Methods: Stress MCE and SRI were performed in 48 patients (22 with type II diabetes mellitus (DM) and 26 controls), all with normal left ventricular systolic function and no obstructive coronary disease by quantitative coronary angiography. Real-time MCE was acquired in three apical views at rest and after combined dipyridamole-exercise stress. Myocardial blood flow (MBF) was quantified in the 10 mid- and apical cardiac segments at rest and after stress. Resting peak systolic strain rate (SR) and peak systolic strain (epsilon) were calculated in the same 10 myocardial segments. Results: The DM and control groups were matched for age, sex and other risk factors, including hypertension. The DM group had higher body mass index and left ventricular mass index. Quantitative SRI analysis was possible in all patients and quantitative MCE in 46 (96%). The mean e, SR and MBF reserve were all significantly lower in the DM group than in controls, with diabetes the only independent predictor of each parameter. No correlation was seen between MBF and SR (r = -0.01, p = 0.54) or between MBF and epsilon ( r = -0.20, p = 0.20). Conclusions: Quantitative MCE shows that patients with diabetes but no evidence of obstructive coronary artery disease have impaired MBF reserve, but abnormal transmural flow and subclinical longitudinal myocardial dysfunction are not related.

Transglutaminase inhibition reduces fibrosis and preserves function in experimental chronic kidney disease

Progressive tissue fibrosis is involved in debilitating diseases that affect organs including the lungs, liver, heart, skin, and kidneys. Recent evidence suggests that tissue transglutaminase, an enzyme that crosslinks proteins, may be involved in tissue fibrosis by crosslinking and stabilizing the extracellular matrix or by recruiting and activating the large latent transforming growth factor (TGF)-β1 complex. We treated rats that had undergone 5/6-nephrectomy with two different irreversible inhibitors of transglutaminase and found that both prevented a decline in kidney function and reduced the development of glomerulosclerosis and tubulointerstitial fibrosis by up to 77% and 92%, respectively. Treatment reduced the accumulation of collagen I and collagen III, with the primary mechanism of action being direct interference with the crosslinking of extracellular matrix rather than altered regulation of TGFβ1. We conclude that inhibition of transglutaminase offers a potential therapeutic option for chronic kidney disease and other conditions that result from tissue fibrosis. Copyright © 2007 by the American Society of Nephrology.

Dietary enrichment by almond supplementation: effects on risk factors for cardiovascular disease

Cardiovascular disease (CVD) is the leading cause of death in Europe responsible for more than 4.3 million deaths annually. The World Health Organisation funded the Monica project (1980s-1990s) which monitored ten million subjects aged 22-6Syrs, and demonstrated that coronary heart disease (CHD) mortality declined over 10 years, was due in two thirds of cases to reduced incidence of CHD (reduced risk behaviours e.g. poor diet and smoking) and one third by improved treatments. Epidemiological evidence suggests diets rich in antioxidants decrease incidence of CVD. Regular consumption of nuts, rich in vitamin E and polyphenols reduces atherosclerosis, an important risk for heart disease. Intervention studies to date using alpha tocopherol (an active component of vitamin E) have not consistently proved beneficial. This thesis aims to investigate the effect of almond supplementation on vascular risk factors in healthy young males (18-3Syrs); mature males and female(>SOyrs); and males considered at increased risk of CVD (18-3Syrs) in a cohort of 67 subjects. The effects of almond intake were assessed after 2Sg/d for four weeks followed by SOg/d for four weeks and compared to a control group which did not consume almonds or change their diet. Cardiovascular risk was assessed by plasma lipid profiles, apolipoprotein A1, plasma nitrates/nitrates, vascular flow, BMl, blood pressure, sVCAM-1 and protein oxidation. Systolic and diastolic blood pressures were reduced in almond supplemented volunteers but not in controls. Dietary monounsaturated fatty acids, polyunsaturated fatty acid content and total dietary fats were increased by almond supplementation. Neither sVCAM-1, venous occlusion plethysmography nor plasma nitrite levels were affected by almond intake in any independent group. No significant changes in plasma lipids, and apolipoprotein A1 were observed. In conclusion almonds supplementation caused a reduction in blood pressure that may be due to increased sensitivity of the baroreceptors after increased monounsaturated fatty acid intake.

Association between miscarriage and cardiovascular disease in a Scottish cohort

Funding This work was supported by a grant from the ‘Merel Foundation’, the Netherlands. The AMND receives support from the University of Aberdeen.

Association between miscarriage and cardiovascular disease in a Scottish cohort

Funding This work was supported by a grant from the ‘Merel Foundation’, the Netherlands. The AMND receives support from the University of Aberdeen.

Maternal gestational weight gain and offspring's risk of cardiovascular disease and mortality

Funding: This research was supported by Chest Heart and Stroke Scotland (R10/A128)

Maternal gestational weight gain and offspring's risk of cardiovascular disease and mortality

Funding: This research was supported by Chest Heart and Stroke Scotland (R10/A128)

Age, job characteristics and coronary health

Background: Workplace demographics are changing in many European countries with a higher proportion of older workers in employment. Research has shown that there is an association between job strain and cardiovascular disease, but this relationship is unclear for the older worker. Aims: To investigate the association between job strain and a coronary event comparing younger and older male workers. Methods: Cases with a first-time coronary event were recruited from four coronary/intensive care units (1999-2001). Matched controls were recruited from the case's general practitioner surgery. Physical measurements were taken and self-administered questionnaires completed with questions on job characteristics, job demands and control. Unconditional logistic regression was carried out adjusting for classical cardiovascular risk factors. Results: There were 227 cases and 277 matched controls. Age stratified analyses showed a clear difference between younger (= 50 years) workers with regard to the exposure of job strain (job demands and control) and the association between these factors and cardiovascular disease. Older workers who had a coronary event were four times as likely to have high job strain [OR = 4.09 (1.29-13.02)] and more likely to report low job control [ OR = 0.83 (0.72-0.95)]. Conclusions: Job control emerged as a potential protective factor for heart disease and this evidence was stronger in the older male worker. Nevertheless, they were significantly more likely to have job strain. These results suggest that older workers may be more susceptible to job strain.

Hypoxia-induced epigenetic modifications are associated with cardiac tissue fibrosis and the development of a myofibroblast-like phenotype

Ischemia caused by coronary artery disease and myocardial infarction leads to aberrant ventricular remodeling and cardiac fibrosis. This occurs partly through accumulation of gene expression changes in resident fibroblasts, resulting in an overactive fibrotic phenotype. Long-term adaptation to a hypoxic insult is likely to require significant modification of chromatin structure in order to maintain the fibrotic phenotype. Epigenetic changes may play an important role in modulating hypoxia-induced fibrosis within the heart. Therefore, the aim of the study was to investigate the potential pro-fibrotic impact of hypoxia on cardiac fibroblasts and determine whether alterations in DNA methylation could play a role in this process. This study found that within human cardiac tissue, the degree of hypoxia was associated with increased expression of collagen 1 and alpha-smooth muscle actin (ASMA). In addition, human cardiac fibroblast cells exposed to prolonged 1% hypoxia resulted in a pro-fibrotic state. These hypoxia-induced pro-fibrotic changes were associated with global DNA hypermethylation and increased expression of the DNA methyltransferase (DNMT) enzymes DNMT1 and DNMT3B. Expression of these methylating enzymes was shown to be regulated by hypoxia-inducible factor (HIF)-1α. Using siRNA to block DNMT3B expression significantly reduced collagen 1 and ASMA expression. In addition, application of the DNMT inhibitor 5-aza-2'-deoxycytidine suppressed the pro-fibrotic effects of TGFβ. Epigenetic modifications and changes in the epigenetic machinery identified in cardiac fibroblasts during prolonged hypoxia may contribute to the pro-fibrotic nature of the ischemic milieu. Targeting up-regulated expression of DNMTs in ischemic heart disease may prove to be a valuable therapeutic approach.

Double Coronary Artery Fistulae: Clinical and Imaging Concerns, and a Review of the Literature

Coronary artery fistulae (CAF) are a rare entity describing abnormal communication between a coronary artery and cardiac chamber or a large intrathoracic vessel and are seldom described in the literature[1]. These fistulae can be either congenital or acquired. Often incidental in finding, CAFs can have serious clinical sequelae, and should be duly reported and discussed with the cardiac team. More than 50% of patients with CAFs may be asymptomatic; 34% may report chest pain; 13% may have symptoms of heart failure, and a minority of 2% may suffer from endocarditis and arrhythmias[2]. The largest series to our knowledge was reported by the Cleveland Clinic, which found 225 patients with incidental CAF out of 126,595 coronary catheterizations (incidence of 0.18%), performed during a span of 28 years [3]. Multiple CAFs are an even rarer entity and only a handful of cases have been reported in the literature to date. Few cases of double CAFs have been reported that describe two different feeder coronary arteries giving rise to separate drainage sites[3]. In our report, however, we describe a new entity: a single-feeder coronary vessel communicated with two drainage sites. Our case is curiously unique, in which we report a single artery, originating from the right coronary artery (RCA) with double drainage sites – one to the left pulmonary artery and the second to the left bronchial artery.

HPLC-DAD-ESI/MS analysis of phenolic compounds in four tomato varieties and evaluation of the antioxidant capacity

Tomato (Lycopersicon esculentum L.) is the second most important vegetable crop worldwide and a key component in the so-called “Mediterranean diet”. In the Northeastern region of Portugal, local populations still prefer to consume traditional tomato varieties which they find very tasty and healthy, as they are grown using extensive farming techniques. A previous study of our research team described the nutritional value of the round (batateiro), long (comprido), heart (coração) and yellow (amarelo) tomato varieties [1], but the phenolic profile was unknown until now. Thus, the objective of this study was to characterize the phenolic profiles of these four tomato farmers’ varieties by using HPLC-DAD-ESI/MS and evaluate its antioxidant capacity through four in vitro assays based on different reaction mechanisms. A cis p-coumaric acid derivative was the most abundant compound in yellow and round tomato varieties, while 4-O-caffeolyquinic acid was the most abundant in long and heart varieties. The most abundant flavonoid was quercetin pentosylrutinoside in the four tomato varieties. Yellow tomato presented the highest levels of phenolic compounds, including phenolic acids and flavonoids, but the lowest antioxidant activity. In turn, the round tomato gave the best results in all the antioxidant activity assays. This study demonstrated that these tomato farmers’ varieties are a source of phenolic compounds, mainly phenolic acid derivatives [2], and possess high antioxidant capacity [1]; being thus key elements in the diet to prevent chronic degenerative diseases associated to oxidative stress, such as cancer and coronary artery disease.

Evaluation of Neurodevelopment and Factors Affecting it in Children With Acyanotic Congenital Cardiac Disease

Background: The rate of congenital heart disease is 0.8% in all live births. The majority of this, however, is acyanotic congenital heart disease. The survival rate of children with cardiac disease has increased with the developments provided in recent years and their lifetime is extended. Objectives: This study aims to evaluate neurodevelopment of children with uncomplicated acyanotic congenital heart disease in preschool period and determine the factors affecting their neurodevelopmental process. Patients and Methods: 132 children with acyanotic congenital heart disease aged 6 - 72 months were involved in the study. Mental development and intelligence levels of patients under 2 years old were assessed by using Bayley Development Scale-III, and Stanford Binet Intelligence test was employed for patients over 2 years old. Denver Developmental Screening Test II was applied to all patients for their personal-social, fine motor, gross motor and language development. Results: The average age of patients (67 girls, 65 boys) included in the study was 35.2 ± 19.6 months. It was determined that there were subnormal mental level in 13 (10%) patients and at least one specific developmental disorder in 33 (25%) patients. Bayley Mental Development Scale score of patients who had received incubator care in perinatal period was found significantly low (88 ± 4.2) compared to those with no incubator care (93.17 ± 8.5) (P = 0.028). Low educational level of father was established to be linked with low mental development scores at the age of 2 and following that age (P < 0.05). Iron deficiency anemia was discovered to be related to low psychometric test scores at every age (P < 0.05). Conclusions: Neurodevelopmental problems in children with acyanotic congenital heart disease were found higher compared to those in society. Mental development and intelligence levels of patients were determined to be closely associated with receiving incubator care, father’s educational level and iron deficiency anemia.

Investigating Angiotensin II in cardiac remodelling and the counter-regulatory actions of Angiotensin-(1-9)

Cardiovascular diseases (CVDs) including, hypertension, coronary heart disease and heart failure are the leading cause of death worldwide. Hypertension, a chronic increase in blood pressure above 140/90 mmHg, is the single main contributor to deaths due to heart disease and stroke. In the heart, hypertension results in adaptive cardiac remodelling, including LV hypertrophy to normalize wall stress and maintain cardiac contractile function. However, chronic increases in BP results in the development of hypertensive heart disease (HHD). HHD describes the maladaptive changes during cardiac remodelling which result in reduced systolic and diastolic function and eventually heart failure. This includes ventricular dilation due to eccentric hypertrophy, cardiac fibrosis which stiffens the ventricular wall and microvascular rarefaction resulting in a decrease in coronary blood flow albeit an increase in energy demand. Chronic activation of the renin-angiotensin-system (RAS) with its effector peptide angiotensin (Ang)II plays a key role in the development of hypertension and the maladaptive changes in HHD. Ang II acts via the angiotensin type 1 receptor (AT1R) to mediate most of its pathological actions during HHD, including stimulation of cardiomyocyte hypertrophy, activation of cardiac fibroblasts and increased collagen deposition. The counter-regulatory axis of the RAS which is centred on the ACE2/Ang-(1-7)/Mas axis has been demonstrated to counteract the pathological actions of Ang II in the heart and vasculature. Ang-(1-7) via the Mas receptor prevents Ang II-induced cardiac hypertrophy and fibrosis and improves cardiac contractile function in animal models of HHD. In contrast, less is known about Ang-(1-9) although evidence has demonstrated that Ang-(1-9) also antagonises Ang II and is anti-hypertrophic and anti-fibrotic in animal models of acute cardiac remodelling. However, so far it is not well documented whether Ang-(1-9) can reverse established cardiac dysfunction and remodelling and whether it is beneficial when administered chronically. Therefore, the main aim of this thesis was to assess the effects of chronic Ang-(1-9) administration on cardiac structure and function in a model of Ang II-induced cardiac remodelling. Furthermore, this thesis aimed to investigate novel pathways contributing to the pathological remodelling in response to Ang II. First, a mouse model of chronic Ang II infusion was established and characterised by comparing the structural and functional effects of the infusion of a low and high dose of Ang II after 6 weeks. Echocardiographic measurements demonstrated that low dose Ang II infusion resulted in a gradual decline in cardiac function while a high dose of Ang II induced acute cardiac contractile dysfunction. Both doses equally induced the development of cardiac hypertrophy and cardiac fibrosis characterised by an increase in the deposition of collagen I and collagen III. Moreover, increases in gene expression of fibrotic and hypertrophic markers could be detected following high dose Ang II infusion over 6 weeks. Following this characterisation, the high dose infusion model was used to assess the effects of Ang-(1-9) on cardiac structural and functional remodelling in established disease. Initially, it was evaluated whether Ang-(1-9) can reverse Ang II-induced cardiac disease by administering Ang-(1-9) for 2-4 weeks following an initial 2 week infusion of a high dose of Ang II to induce cardiac contractile dysfunction. The infusion of Ang-(1-9) for 2 weeks was associated with a significant improvement of LV fractional shortening compared to Ang II infusion. However, after 4 weeks fractional shortening declined to Ang II levels. Despite the transient improvement in cardiac contractile function, Ang-(1-9) did not modulate blood pressure, LV hypertrophy or cardiac fibrosis. To further investigate the direct cardiac effects of Ang-(1-9), cardiac contractile performance in response to Ang-(1-9) was evaluated in the isolated Langendorff-perfused rat heart. Perfusion of Ang-(1-9) in the paced and spontaneously beating rat heart mediated a positive inotropic effect characterised by an increase in LV developed pressure, cardiac contractility and relaxation. This was in contrast to Ang II and Ang-(1-7). Furthermore, the positive inotropic effect to Ang-(1-9) was blocked by the AT1R antagonist losartan and the protein kinase A inhibitor H89. Next, endothelial-to-mesenchymal transition (EndMT) as a novel pathway that may contribute to Ang II-induced cardiac remodelling was assessed in Ang II-infused mice in vivo and in human coronary artery endothelial cells (HCAEC) in vitro. Infusion of Ang II to mice for 2-6 weeks resulted in a significant decrease in myocardial capillary density and this was associated with the occurrence of dual labelling of endothelial cells for endothelial and mesenchymal markers. In vitro stimulation of HCAEC with TGFβ and Ang II revealed that Ang II exacerbated TGF-induced gene expression of mesenchymal markers. This was not correlated with any changes in SMAD2 or ERK1/2 phosphorylation with co-stimulation of TGFβ and Ang II. However, superoxide production was significantly increased in HCAEC stimulated with Ang II but not TGFβ. Finally, the role of Ang II in microvesicle (MV)-mediated cardiomyocyte hypertrophy was investigated. MVs purified from neonatal rat cardiac fibroblasts were found to contain detectable Ang II and this was increased by stimulation of fibroblasts with Ang II. Treatment of cardiomyocytes with MVs derived from Ang II-stimulated fibroblasts induced cardiomyocyte hypertrophy which could be blocked by the AT1R antagonist losartan and an inhibitor of MV synthesis and release brefeldin A. Furthermore, Ang II was found to be present in MVs isolated from serum and plasma of Ang II-infused mice and SHRSP and WKY rats. Overall, the findings of this thesis demonstrate for the first time that the actions of Ang-(1-9) in cardiac pathology are dependent on its time of administration and that Ang-(1-9) can reverse Ang II-induced cardiac contractile dysfunction by acting as a positive inotrope. Furthermore, this thesis demonstrates evidence for an involvement of EndMT and MV signalling as novel pathways contributing to Ang II-induced cardiac fibrosis and hypertrophy, respectively. These findings provide incentive to further investigate the therapeutic potential of Ang-(1-9) in the treatment of cardiac contractile dysfunction in heart disease, establish the importance of novel pathways in Ang II-mediated cardiac remodelling and evaluate the significance of the presence of Ang II in plasma-derived MVs.