Previous genome-wide linkage analysis has suggested that chromosomal region 17p13.3 may harbour genes influencing left ventricular mass (LVM) in man. To date, the genetic factors accounting for LVM variability remain largely unknown but a non-coding RNA gene within this region, micro-RNA 22 (miR-22), has been implicated in cardiac hypertrophy and heart failure in animal models. We thus investigated the relationship between common genetic polymorphisms surrounding miR-22 and left ventricular mass in a family-based association study.
Methods and Results
We studied a cohort of 255 families comprising 1,425 individuals ascertained via a hypertensive proband. Ten single nucleotide polymorphisms which together tagged common genetic variation surrounding the miR-22 gene were genotyped. There was evidence of association between the rs7223247 polymorphism, which lies within the 3′UTR of a gene of unknown function, TLCD2, immediately downstream from miR-22, and left ventricular mass determined by Sokolow-Lyon voltage (Bonferroni corrected p-value = 0.038). The T allele at rs7223247 was associated with an 0.272 standard deviation higher Sokolow-Lyon voltage. Genotype was responsible for ∼1% of the population variability in LVM.
Genotype at the rs7223247 polymorphism affects left ventricular mass determined by Sokolow-Lyon voltage. The neighbouring genes miR-22 and TLCD2 are strong candidates to account for this observation.
Background To date little has been published about epidemiology and public health capacity (training, research, funding, human resources) in WHO/AFRO to help guide future planning by various stakeholders.
Methods A bibliometric analysis was performed to identify published epidemiological research. Information about epidemiology and public health training, current research and challenges was collected from key informants using a standardized questionnaire.
Results From 1991 to 2010, epidemiology and public health research output in the WHO/AFRO region increased from 172 to 1086 peer-reviewed articles per annum [annual percentage change (APC) = 10.1%, P for trend < 0.001]. The most common topics were HIV/AIDS (11.3%), malaria (8.6%) and tuberculosis (7.1%). Similarly, numbers of first authors (APC = 7.3%, P for trend < 0.001), corresponding authors (APC = 8.4%, P for trend < 0.001) and last authors (APC = 8.5%, P for trend < 0.001) from Africa increased during the same period. However, an overwhelming majority of respondents (>90%) reported that this increase is only rarely linked to regional post-graduate training programmes in epidemiology. South Africa leads in publications (1978/8835, 22.4%), followed by Kenya (851/8835, 9.6%), Nigeria (758/8835, 8.6%), Tanzania (549/8835, 6.2%) and Uganda (428/8835, 4.8%) (P < 0.001, each vs South Africa). Independent predictors of relevant research productivity were ‘in-country numbers of epidemiology or public health programmes’ [incidence rate ratio (IRR) = 3.41; 95% confidence interval (CI) 1.90–6.11; P = 0.03] and ‘number of HIV/AIDS patients’ (IRR = 1.30; 95% CI 1.02–1.66; P < 0.001).
Conclusions Since 1991, there has been increasing epidemiological research productivity in WHO/AFRO that is associated with the number of epidemiology programmes and burden of HIV/AIDS cases. More capacity building and training initiatives in epidemiology are required to promote research and address the public health challenges facing the continent.
Epidemiology; public health; training; Africa; capacity building; retention; research; WHO/AFRO
The purpose of this study was to quantify the heterogeneous distribution of echodensities in the pericardial fluid of patients with tuberculous pericarditis using echocardiography and fractal analysis, and to determine whether there were differences in the fractal dimensions of effusive-constrictive and effusive non-constrictive disease.
We used fractal geometry to quantify the echocardiographic densities in patients who were enrolled in the Investigation of the Management of Pericarditis in Africa (IMPI Africa) Registry. Sub-costal and four chamber images were included in the analysis if a minimum of two clearly identified fibrin strands were present and the quality of the images were of a standard which allowed for accurate measurement of the fractal dimension. The fractal dimension was calculated as follows: Df = limlog N(s)/[log (l/s)], where Df is the box counting fractal dimension of the fibrin strand, s is the side length of the box and N(s) is the smallest number of boxes of side length s to cover the outline of the object being measured. We compared the fractal dimension of echocardiographic findings in patients with effusive constrictive pericarditis to effusive non-constrictive pericardial effusion using the non-parametric Mann–Whitney test.
Of the 14 echocardiographs from 14 participants that were selected for the study, 42.8% (6/14) of images were subcostal views while 57.1% (8/14) were 4-chamber views. Eight of the patients had tuberculous effusive constrictive pericarditis while 6 had tuberculous effusive non-constrictive pericarditis. The mean fractal dimension Df was 1.325 with a standard deviation (SD) of 0.146. The measured fibrin strand dimension exceeded the topological dimension in all the images over the entire range of grid scales with a correlation coefficient (r2) greater than 0.8 in the majority. The fractal dimension of echodensities was 1.359 ± 0.199 in effusive constrictive pericarditis compared to 1.330 ± 0.166 in effusive non-constrictive pericarditis (p = 0.595).
The echocardiographic densities in tuberculous pericardial effusion have a fractal geometrical dimension which is similar in pure effusive and effusive constrictive disease.
Pericardial effusion; Tuberculosis; Fractal dimension; Effusive constrictive pericarditis; Effusive non-constrictive pericarditis
Maternal mortality in South Africa is rising, and heart conditions currently account for 41 per cent of indirect causes of deaths. Little is known about the burden of heart disease in pregnant South Africans.
We systematically reviewed the contemporary epidemiology and peripartum outcomes of heart disease in South African women attending antenatal care. Searches were performed in PubMed, ISI Web of Science, the EBSCO Africa-Wide database, the South African Union Catalogue, and the Current and Completed Research database (South Africa). References of included articles were also hand-searched. Studies reporting epidemiologic data on antenatal heart disease in South Africa were included. Data on morbidity and mortality were also collected.
Seven studies were included in the systematic review. The prevalence of heart disease ranged from 123 to 943 per 100,000 deliveries, with a median prevalence of 616 per 100,000. Rheumatic valvular lesions were the commonest abnormalities, although cardiomyopathies were disproportionately high in comparison with other developing countries. Peripartum case-fatality rates were as high as 9.5 per cent in areas with limited access to care. The most frequent complications were pulmonary oedema, thromboembolism, and major bleeding with warfarin use. Perinatal mortality ranged from 8.9 to 23.8 per cent, whilst mitral lesions were associated with low birth weight. Meta-analysis could not be performed due to clinical and statistical heterogeneity of the included studies.
Approximately 0.6 per cent of pregnant South Africans have pre-existing cardiac abnormalities, with rheumatic lesions being the commonest. Maternal and perinatal morbidity and mortality continue to be very high. We conclude this review by summarising limitations of the current literature and recommending standard reporting criteria for future reports.
The inflammatory response to Mycobacterium tuberculosis (M.tb) at the site of disease is Th1 driven. Whether the Th17 cytokines, IL-17 and IL-22, contribute to this response in humans is unknown. We hypothesized that IL-17 and IL-22 contribute to the inflammatory response in pleural and pericardial disease sites of human tuberculosis (TB).
We studied pleural and pericardial effusions, established TB disease sites, from HIV-uninfected TB patients. Levels of soluble cytokines were measured by ELISA and MMP-9 by luminex. Bronchoalveolar lavage or pericardial mycobacteria-specific T cell cytokine expression was analyzed by intracellular cytokine staining.
IL-17 was not abundant in pleural or pericardial fluid. IL-17 expression by mycobacteria-specific disease site T cells was not detected in healthy, M.tb-infected persons, or patients with TB pericarditis. These data do not support a major role for IL-17 at established TB disease sites in humans.
IL-22 was readily detected in fluid from both disease sites. These IL-22 levels exceeded matching peripheral blood levels. Further, IL-22 levels in pericardial fluid correlated positively with MMP-9, an enzyme known to degrade the pulmonary extracellular matrix. We propose that our findings support a role for IL-22 in TB-induced pathology or the resulting repair process.
Pleural tuberculosis; Pericardial tuberculosis; IL-17; IL-22; Inflammation
Acute rheumatic fever is considered to be a heritable condition, but the magnitude of the genetic effect is unknown. The objective of this study was to conduct a systematic review and meta-analysis of twin studies of concordance of acute rheumatic fever in order to derive quantitative estimates of the size of the genetic effect.
We searched PubMed/MEDLINE, ISI Web of Science, EMBASE, and Google Scholar from their inception to 31 January 2011, and bibliographies of retrieved articles, for twin studies of the concordance for acute rheumatic fever or rheumatic heart disease in monozygotic versus dizygotic twins that used accepted diagnostic criteria for acute rheumatic fever and zygosity without age, gender or language restrictions. Twin similarity was measured by probandwise concordance rate and odds ratio (OR), and aggregate probandwise concordance risk was calculated by combining raw data from each study. ORs from separate studies were combined by random-effects meta-analysis to evaluate association between zygosity status and concordance. Heritability was estimated by fitting a variance components model to the data.
435 twin pairs from six independent studies met the inclusion criteria. The pooled probandwise concordance risk for acute rheumatic fever was 44% in monozygotic twins and 12% in dizygotic twins, and the association between zygosity and concordance was strong (OR 6.39; 95% confidence interval, 3.39 to 12.06; P<0.001), with no significant study heterogeneity (P = 0.768). The estimated heritability across all the studies was 60%.
Acute rheumatic fever is an autoimmune disorder with a high heritability. The discovery of all genetic susceptibility loci through whole genome scanning may provide a clinically useful genetic risk prediction tool for acute rheumatic fever and its sequel, rheumatic heart disease.
The combined thickness of the intima and media of the carotid artery (carotid intima-medial thickness, CIMT) is associated with cardiovascular disease and stroke. Previous studies indicate that carotid intima-medial thickness is a significantly heritable phenotype, but the responsible genes are largely unknown. Hexose-6 phosphate dehydrogenase (H6PDH) is a microsomal enzyme whose activity regulates corticosteroid metabolism in the liver and adipose tissue; variability in measures of corticosteroid metabolism within the normal range have been associated with risk factors for cardiovascular disease. We performed a genetic association study in 854 members of 224 families to assess the relationship between polymorphisms in the gene coding for hexose-6 phosphate dehydrogenase (H6PD) and carotid intima-medial thickness.
Families were ascertained via a hypertensive proband. CIMT was measured using B-mode ultrasound. Single nucleotide polymorphisms (SNPs) tagging common variation in the H6PD gene were genotyped. Association was assessed following adjustment for significant covariates including “classical” cardiovascular risk factors. Functional studies to determine the effect of particular SNPs on H6PDH were performed.
There was evidence of association between the single nucleotide polymorphism rs17368528 in exon five of the H6PD gene, which encodes an amino-acid change from proline to leucine in the H6PDH protein, and mean carotid intima-medial thickness (p = 0.00065). Genotype was associated with a 5% (or 0.04 mm) higher mean carotid intima-medial thickness measurement per allele, and determined 2% of the population variability in the phenotype.
Our results suggest a novel role for the H6PD gene in atherosclerosis susceptibility.
We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st century. This proposed holistic strategy involves comprehensive patient-centered integrated care and multi-scale, multi-modal and multi-level systems approaches to tackle NCDs as a common group of diseases. Rather than studying each disease individually, it will take into account their intertwined gene-environment, socio-economic interactions and co-morbidities that lead to individual-specific complex phenotypes. It will implement a road map for predictive, preventive, personalized and participatory (P4) medicine based on a robust and extensive knowledge management infrastructure that contains individual patient information. It will be supported by strategic partnerships involving all stakeholders, including general practitioners associated with patient-centered care. This systems medicine strategy, which will take a holistic approach to disease, is designed to allow the results to be used globally, taking into account the needs and specificities of local economies and health systems.
cardiovascular disease; global burden; epidemiology
Heart failure in sub‐Saharan Africans is mainly due to non‐ischaemic causes, such as hypertension, rheumatic heart disease, cardiomyopathy and pericarditis. The two endemic diseases that are major contributors to the clinical syndrome of heart failure in Africa are cardiomyopathy and pericarditis. The major forms of endemic cardiomyopathy are idiopathic dilated cardiomyopathy, peripartum cardiomyopathy and endomyocardial fibrosis. Endomyocardial fibrosis, which affects children, has the worst prognosis. Other cardiomyopathies have similar epidemiological characteristics to those of other populations in the world. HIV infection is associated with occurrence of HIV‐associated cardiomyopathy in patients with advanced immunosuppression, and the rise in the incidence of tuberculous pericarditis. HIV‐associated tuberculous pericarditis is characterised by larger pericardial effusion, a greater frequency of myopericarditis, and a higher mortality than in people without AIDS. Population‐based studies on the epidemiology of heart failure, cardiomyopathy and pericarditis in Africans, and studies of new interventions to reduce mortality, particularly in endomyocardial fibrosis and tuberculous pericarditis, are needed.
epidemiology; management; cardiomyopathy; pericarditis; sub‐Saharan Africa
Single nucleotide polymorphisms (SNPs) on chromosome 9p21 are associated with coronary artery disease, diabetes, and multiple cancers. Risk SNPs are mainly non-coding, suggesting that they influence expression and may act in cis. We examined the association between 56 SNPs in this region and peripheral blood expression of the three nearest genes CDKN2A, CDKN2B, and ANRIL using total and allelic expression in two populations of healthy volunteers: 177 British Caucasians and 310 mixed-ancestry South Africans. Total expression of the three genes was correlated (P<0.05), suggesting that they are co-regulated. SNP associations mapped by allelic and total expression were similar (r = 0.97, P = 4.8×10−99), but the power to detect effects was greater for allelic expression. The proportion of expression variance attributable to cis-acting effects was 8% for CDKN2A, 5% for CDKN2B, and 20% for ANRIL. SNP associations were similar in the two populations (r = 0.94, P = 10−72). Multiple SNPs were independently associated with expression of each gene (P<0.05 after correction for multiple testing), suggesting that several sites may modulate disease susceptibility. Individual SNPs correlated with changes in expression up to 1.4-fold for CDKN2A, 1.3-fold for CDKN2B, and 2-fold for ANRIL. Risk SNPs for coronary disease, stroke, diabetes, melanoma, and glioma were all associated with allelic expression of ANRIL (all P<0.05 after correction for multiple testing), while association with the other two genes was only detectable for some risk SNPs. SNPs had an inverse effect on ANRIL and CDKN2B expression, supporting a role of antisense transcription in CDKN2B regulation. Our study suggests that modulation of ANRIL expression mediates susceptibility to several important human diseases.
Genetic variants on chromosome 9p21 have been associated with several important diseases including coronary artery disease, diabetes, and multiple cancers. Most of the risk variants in this region do not alter any protein sequence and are therefore likely to act by influencing the expression of nearby genes. We investigated whether chromosome 9p21 variants are correlated with expression of the three nearest genes (CDKN2A, CDKN2B, and ANRIL) which might mediate the association with disease. Using two different techniques to study effects on expression in blood from two separate populations of healthy volunteers, we show that variants associated with disease are all correlated with ANRIL expression, but associations with the other two genes are weaker and less consistent. Multiple genetic variants are independently associated with expression of all three genes. Although total expression levels of CDKN2A, CDKN2B, and ANRIL are positively correlated, individual genetic variants influence ANRIL and CDKN2B expression in opposite directions, suggesting a possible role of ANRIL in CDKN2B regulation. Our study suggests that modulation of ANRIL expression mediates susceptibility to several important human diseases.
Chronic kidney disease (CKD) is a significant public health problem that leads to end-stage renal disease (ESRD) with as many as 2 million people predicted to need therapy worldwide by 2010. Obesity is a risk factor for CKD and leptin, the obesity hormone, correlates with body fat mass and markers of renal function. A number of clinical and experimental studies have suggested a link between serum leptin and kidney disease. We hypothesised that variants in the leptin gene (LEP) may be associated with markers of CKD in indigenous black Africans.
Black South Africans of Xhosa (distinct cultural Bantu-speaking population) descent were recruited for the study and four common polymorphisms of the LEP (rs7799039, rs791620, rs2167270 and STS-U43653 [ENSSNP5824596]) were analysed for genotype and haplotype association with urine albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), Serum creatinine (Scr) and serum leptin level. In one of the four single nucleotide polymorphisms (SNPs) we examined, an association with the renal phenotypes was observed. Hypertensive subjects with the T allele (CT genotype) of the ENSSNP5824596 SNP had a significantly higher eGFR (p = 0.0141), and significantly lower Scr (p = 0.0137). This was confirmed by haplotype analysis. Also, the haplotype GAAC had a modest effect on urine albumin-to-creatinine ratio in normotensive subjects (p = 0.0482).
These results suggest that genetic variations of the LEP may be associated with phenotypes that are markers of CKD in black Africans.
Defining myocardial contours is often the most time consuming portion of dynamic cardiac MRI image analysis. Displacement encoding with stimulated echoes (DENSE) is a quantitative MRI technique that encodes tissue displacement into the phase of the complex MRI images. Cine DENSE provides a time series of these images, thus facilitating the non-invasive study of myocardial kinematics. Epicardial and endocardial contours need to be defined at each frame on cine DENSE images for the quantification of regional displacement and strain as a function of time. This work presents a reliable and effective two dimensional semi-automated segmentation technique that uses the encoded motion to project a manually defined region of interest through time. Contours can then easily be extracted for each cardiac phase. This method boasts several advantages, including, 1. parameters are based on practical physiological limits, 2. contours are calculated for the first few cardiac phases, where it is difficult to visually distinguish blood from myocardium, and 3. the method is independent of the shape of the tissue delineated and can be applied to short- or long-axis views, and on arbitrary regions of interest. Motion-guided contours were compared to manual contours for six conventional and six slice-followed mid-ventricular short-axis cine DENSE datasets. Using an area measure of segmentation error, the accuracy of the segmentation algorithm was shown to be similar to inter-observer variability. In addition, a radial segmentation error metric was introduced for short-axis data. The average radial epicardial segmentation error was 0.36±0.08 and 0.40±0.10 pixels for slice followed and conventional cine DENSE, respectively, and the average radial endocardial segmentation error was 0.46±0.12 and 0.46±0.16 pixels for slice following and conventional cine DENSE, respectively. Motion-guided segmentation employs the displacement-encoded phase shifts intrinsic to DENSE MRI to accurately propagate a single set of pre-defined contours throughout the remaining cardiac phases.
Cardiac MRI; DENSE; myocardial tagging; segmentation; tissue tracking
The long-term cumulative cytotoxicity of antiretrovirals (ARVs) is among the major causes of treatment failure in patients infected with human immunodeficiency virus (HIV) and patients with AIDS. This calls for the development of novel ARVs with less or no cytotoxicity. In the present study, we compared the cytotoxic effects of a cross-clade HIV type 1-neutralizing aptamer called B40 with those of a panel of nonnucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs), and the entry inhibitor (EI) T20 in human cardiomyocytes and peripheral blood mononuclear cells. An initial screen in which cell death was used as the end-point measurement revealed that the B40 aptamer and T20 were the only test molecules that had insignificant (0.61 < P < 0.92) effects on the viability of both cell types at the maximum concentration used. PIs were the most toxic class (0.001 < P < 0.00001), followed by NNRTIs and NRTIs (0.1 < P < 0.00001). Further studies revealed that B40 and T20 did not interfere with the cellular activity of the cytochrome P450 3A4 enzyme (0.78 < P < 0.24) or monoamine oxidases A and B (0.83 < P < 0.56) when the activities of the enzymes were compared to those in untreated controls of both cell types. Mitochondrion-initiated cellular toxicity is closely associated with the use of ARVs. Therefore, we used real-time PCR to quantify the relative ratio of mitochondrial DNA to nuclear DNA as a marker of toxicity. The levels of mitochondrial DNA remained unchanged in cells exposed to the B40 aptamer compared to the levels in untreated control cells (0.5 > P > 0.06). These data support the development of B40 and related EI aptamers as new ARVs with no cytotoxicity at the estimated potential therapeutic dose.
Blood pressure (BP) has significant heritability, but the genes responsible remain largely unknown. Single nucleotide polymorphisms (SNPs) at the STK39 locus were recently associated with hypertension by genome-wide association in an Amish population; in vitro data from transient transfection experiments using reporter constructs suggested that altered STK39 expression might mediate the effect. However, other large studies have not implicated STK39 in hypertension. We determined whether reported SNPs influenced STK39 expression in vivo, or were associated with BP in a large British Caucasian cohort.
1372 members of 247 Caucasian families ascertained through a hypertensive proband were genotyped for reported risk variants in STK39 (rs6749447, rs3754777, rs35929607) using Sequenom technology. MERLIN software was used for family-based association testing. Cis-acting influences on expression were assessed in vivo using allelic expression ratios in cDNA from peripheral blood cells in 35 South African individuals heterozygous for a transcribed SNP in STK39 (rs1061471) and quantified by mass spectrometry (Sequenom).
No significant association was seen between the SNPs tested and systolic or diastolic BP in clinic or ambulatory measurements (all p > 0.05). The tested SNPs were all associated with allelic expression differences in peripheral blood cells (p < 0.05), with the most significant association for the intronic SNP rs6749447 (P = 9.9 × 10-4). In individuals who were heterozygous for this SNP, on average the G allele showed 13% overexpression compared to the T allele.
STK39 expression is modified by polymorphisms acting in cis and the typed SNPs are associated with allelic expression of this gene, but there is no evidence for an association with BP in a British Caucasian cohort.
Objectives To develop a new methodology to systematically compare evidence across diverse risk markers for coronary heart disease and to compare this evidence with guideline recommendations.
Design “Horizontal” systematic review incorporating different sources of evidence.
Data sources Electronic search of Medline and hand search of guidelines.
Study selection Two reviewers independently determined eligibility of studies across three sources of evidence (observational studies, genetic association studies, and randomised controlled trials) related to four risk markers: depression, exercise, C reactive protein, and type 2 diabetes.
Data extraction For each risk marker, the largest meta-analyses of observational studies and genetic association studies, and meta-analyses or individual randomised controlled trials were analysed.
Results Meta-analyses of observational studies reported adjusted relative risks of coronary heart disease for depression of 1.9 (95% confidence interval 1.5 to 2.4), for top compared with bottom fourths of exercise 0.7 (0.5 to 1.0), for top compared with bottom thirds of C reactive protein 1.6 (1.5 to 1.7), and for diabetes in women 3.0 (2.4 to 3.7) and in men 2.0 (1.8 to 2.3). Prespecified study limitations were more common for depression and exercise. Meta-analyses of studies that allowed formal Mendelian randomisation were identified for C reactive protein (and did not support a causal effect), and were lacking for exercise, diabetes, and depression. Randomised controlled trials were not available for depression, exercise, or C reactive protein in relation to incidence of coronary heart disease, but trials in patients with diabetes showed some preventive effect of glucose control on risk of coronary heart disease. None of the four randomised controlled trials of treating depression in patients with coronary heart disease reduced the risk of further coronary events. Comparisons of this horizontal evidence review with two guidelines published in 2007 showed inconsistencies, with depression prioritised more in the guidelines than in our review.
Conclusions This horizontal systematic review pinpoints deficiencies and strengths in the evidence for depression, exercise, C reactive protein, and diabetes as unconfounded and unbiased causes of coronary heart disease. This new method could be used to develop a field synopsis and prioritise future development of guidelines and research.
Abnormal blood pressure response to exercise is reported to occur in up to a third of hypertrophic cardiomyopathy (HCM) cases and is associated with an increased risk of death, particularly in the young, but it is not known whether the HCM-causing mutation influences blood pressure response to exercise. The purpose of this article is to ascertain whether the blood pressure response to exercise differs among carriers of the R92W mutation in the cardiac troponin T gene (TNNT2), which has been associated with an increased risk of sudden cardiac death in young males; carriers of mutations in the cardiac β-myosin heavy chain gene (MYH7); and their noncarrier relatives. Thirty R92WTNNT2 carriers, 51 MYH7 mutation carriers, and 68 of their noncarrier relatives were subjected to bicycle ergonometric exercise testing to assess blood pressure response to, as well as heart rate recovery after, exercise. Additional echocardiographic and demographic details were documented for all participants. R92WTNNT2 carriers demonstrated significantly more abnormal blood pressure responses to exercise (P = .021; odds ratio 3.03; confidence interval 1.13–8.12) and smaller increases in systolic blood pressure than MYH7 mutation carriers or related noncarrier control individuals. Although abnormal blood pressure response occurred at similar frequencies in males in all groups (23%–26%), the percentage of R92WTNNT2 females with abnormal blood pressure response was 64%, compared with 25% for MYH7 and 22% for noncarriers. Therefore, these results show that blood pressure response to exercise is influenced by genotype and gender in patients with HCM.
Hypertrophic cardiomyopathy; Abnormal blood pressure response; Survival; Troponin T; Beta-myosin; Genetic mutation; Ca2+, calcium; CR, chronotropic response; DBP, diastolic blood pressure; ECG, electrocardiogram; HCM, hypertrophic cardiomyopathy; HR, heart rate; LV, left ventricle; LVM, left ventricular mass; maxLVWT, maximum left ventricular wall thickness; METs, metabolic equivalents; MYH7, beta cardiac myosin heavy chain gene; SBP, systolic blood pressure; SCD, sudden cardiac death; TNNT2, cardiac troponin T gene
The mitochondrial DNA (mtDNA) T16189C polymorphism, with a homopolymeric C-tract of 10–12 cytosines, is a putative genetic risk factor for idiopathic dilated cardiomyopathy in the African and British populations. We hypothesized that this variant may predispose to dilated cardiomyopathy in people who are infected with the human immunodeficiency virus (HIV).
A case-control study of 30 HIV-positive cases with dilated cardiomyopathy and 37 HIV-positive controls without dilated cardiomyopathy was conducted. The study was confined to persons of black African ancestry to minimize confounding of results by population admixture. HIV-positive patients with an echocardiographically confirmed diagnosis of dilated cardiomyopathy and HIV-positive controls with echocardiographically normal hearts were studied. Patients with secondary causes of cardiomyopathy (such as hypertension, diabetes, pregnancy, alcoholism, valvular heart disease, and opportunistic infection) were excluded from the study. DNA samples were sequenced for the mtDNA T16189C polymorphism with a homopolymeric C-tract in the forward and reverse directions on an ABI3100 sequencer.
The cases and controls were well matched for age (median 35 years versus 34 years, P = 0.93), gender (males 60% vs 53%, P = 0.54), and stage of HIV disease (mean CD4 T cell count 260.7/μL vs. 176/μL, P = 0.21). The mtDNA T16189C variant with a homopolymeric C-tract was detected at a frequency of 26.7% (8/30) in the HIV-associated cardiomyopathy cases and 13.5% (5/37) in the HIV-positive controls. There was no significant difference between cases and controls (Odds Ratio 2.33, 95% Confidence Interval 0.67–8.06, p = 0.11).
The mtDNA T16189C variant with a homopolymeric C-tract is not associated with dilated cardiomyopathy in black African people infected with HIV.
Cardiac MRI; wall motion; constrictive pericarditis
Pericardial constriction is a serious complication of tuberculous pericardial effusion that occurs in up to a quarter of patients despite anti-tuberculosis chemotherapy. The impact of human immunodeficiency virus (HIV) infection on the incidence of constrictive pericarditis following tuberculous pericardial effusion is unknown.
Methods and Results
We conducted a prospective observational study to determine the association between HIV infection and the incidence of constrictive pericarditis among 185 patients (median age 33 years) with suspected tuberculous pericardial effusion. These patients were recruited consecutively between March and October 2004 on commencement of anti-tuberculosis treatment, from 15 hospitals in Cameroon, Nigeria and South Africa. Surviving patients (N = 119) were assessed for clinical evidence of constrictive pericarditis at 3 and 6 months of follow-up. Clinical features of HIV infection were present in 42 (35.2%) of the 119 patients at enrolment into the study. 66 of the 119 (56.9%) patients consented to HIV testing at enrolment. During the 6 months of follow-up, a clinical diagnosis of constrictive pericarditis was made in 13 of the 119 patients (10.9 %, 95% confidence interval [CI] 5.9–18%). Patients with clinical features of HIV infection appear less likely to develop constriction than those without (4.8% versus 14.3%; P = 0.08). None of the 33 HIV seropositive patients developed constriction, but 8 (24.2%, 95%CI 11.1–42.3%) of the 33 HIV seronegative patients did (P = 0.005). In a multivariate logistic regression model adjusting simultaneously for several baseline characteristics, only clinical signs of HIV infection were significantly associated with a lower risk of constriction (odd ratio 0.14, 95% CI 0.02–0.87, P = 0.035).
These data suggest that HIV infection is associated with a lower incidence of pericardial constriction in patients with presumed tuberculous pericarditis.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable disorder characterized by progressive degeneration of right ventricular myocardium, arrhythmias and an increased risk of sudden death at a young age. By linkage analysis, ARVC type 6 was previously mapped to a 10.6 cM region on chromosome 10p12-p14 in a large North American kindred. To date, the genetic defect that causes ARVC6 has not been identified.
We identified a South African family of 13 members with ARVC segregating as an autosomal dominant disorder. The diagnosis of ARVC was based on international diagnostic criteria. All available family members were genotyped with microsatellite markers at six known ARVC loci, and positional candidate gene screening was performed.
Genetic linkage and haplotype analysis provided lod scores that are highly suggestive of linkage to the ARVC6 locus on chromosome 10p12-p14, and the narrowing of the critical region to ~2.9 Mb. Two positional candidate genes (ITG8 and FRMD4A) were screened in which defects could possibly disrupt cell-cell adhesion. A non-positional candidate gene with apoptosis inducing properties, LAMR1P6 (laminin receptor 1 pseudogene 6) was also screened. Direct sequencing of DNA from affected individuals failed to detect disease-causing mutations in the exonic sequences of the three genes investigated.
The narrowing of the ARVC6 critical region may facilitate progress towards the identification of the gene that is involved in ARVC. Identification of the causative genes for ARVC will contribute to the understanding of the pathogenesis and management of this poorly understood condition.
The incidence of tuberculous pericarditis has increased in Africa as a result of the human immunodeficiency virus (HIV) epidemic. However, the effect of HIV co-infection on clinical features and prognosis in tuberculous pericarditis is not well characterised. We have used baseline data of the Investigation of the Management of Pericarditis in Africa (IMPI Africa) registry to assess the impact of HIV co-infection on clinical presentation, diagnostic evaluation, and treatment of patients with suspected tuberculous pericarditis in sub-Saharan Africa.
Consecutive adult patients in 15 hospitals in three countries in sub-Saharan Africa were recruited on commencement of treatment for tuberculous pericarditis, following informed consent. We recorded demographic, clinical, diagnostic and therapeutic information at baseline, and have used the chi-square test and analysis of variance to assess probabilities of significant differences (in these variables) between groups defined by HIV status.
A total of 185 patients were enrolled from 01 March 2004 to 31 October 2004, 147 (79.5%) of whom had effusive, 28 (15.1%) effusive-constrictive, and 10 (5.4%) constrictive or acute dry pericarditis. Seventy-four (40%) had clinical features of HIV infection. Patients with clinical HIV disease were more likely to present with dyspnoea (odds ratio [OR] 3.2, 95% confidence interval [CI] 1.4 to 7.4, P = 0.005) and electrocardiographic features of myopericarditis (OR 2.8, 95% CI 1.1 to 6.9, P = 0.03). In addition to electrocardiographic features of myopericarditis, a positive HIV serological status was associated with greater cardiomegaly (OR 3.89, 95% CI 1.34 to 11.32, P = 0.01) and haemodynamic instability (OR 9.68, 95% CI 2.09 to 44.80, P = 0.0008). However, stage of pericardial disease at diagnosis and use of diagnostic tests were not related to clinical HIV status. Similar results were obtained for serological HIV status. Most patients were treated on clinical grounds, with microbiological evidence of tuberculosis obtained in only 13 (7.0%) patients. Adjunctive corticosteroids were used in 109 (58.9%) patients, with patients having clinical HIV disease less likely to be put on them (OR 0.37, 95% CI 0.20 to 0.68). Seven patients were on antiretroviral drugs.
Patients with suspected tuberculous pericarditis and HIV infection in Africa have greater evidence of myopericarditis, dyspnoea, and haemodynamic instability. These findings, if confirmed in other studies, may suggest more intensive management of the cardiac disease is warranted in patients with HIV-associated pericardial disease.
Rheumatic fever continues to put a significant burden on the health of low socio-economic populations in low and middle-income countries despite the near disappearance of the disease in the developed world over the past century. Antibiotics have long been thought of as an effective method for preventing the onset of acute rheumatic fever following a Group-A streptococcal (GAS) throat infection; however, their use has not been widely adopted in developing countries for the treatment of sore throats. We have used the tools of systematic review and meta-analysis to quantify the effectiveness of antibiotic treatment for sore throat, with symptoms suggestive of group A streptococcal (GAS) infection, for the primary prevention of acute rheumatic fever.
Trials were identified through a systematic search of titles and abstracts found in the Cochrane Central Register of Controlled Trials (Cochrane Library Issue 4, 2003), MEDLINE (1966–2003), EMBASE (1966–2003), and the reference lists of identified studies. The selection criteria included randomised or quasi-randomised controlled trials comparing the effectiveness of antibiotics versus no antibiotics for the prevention of rheumatic fever in patients presenting with a sore throat, with or without confirmation of GAS infection, and no history of rheumatic fever.
Ten trials (n = 7665) were eligible for inclusion in this review. The methodological quality of the studies, in general, was poor. All of the included trials were conducted during the period of 1950 and 1961 and in 8 of the 10 trials the study population consisted of young adult males living on United States military bases. Fixed effects, meta-analysis revealed an overall protective effect for the use of antibiotics against acute rheumatic fever of 70% (RR = 0.32; 95% CI = 0.21–0.48). The absolute risk reduction was 1.67% with an NNT of 53. When meta-analysis was restricted to include only trials evaluating penicillin, a protective effect of 80% was found (Fixed effect RR = 0.20, 95% CI = 0.11–0.36) with an NNT of 60. The marginal cost of preventing one case of rheumatic fever by a single intramuscular injection of penicillin is approximately US$46 in South Africa.
Antibiotics appear to be effective in reducing the incidence of acute rheumatic fever following an episode of suspected GAS pharyngitis. This effect may be achieved at relatively low cost if a single intramuscular penicillin injection is administered.
HIV-1-infected people have an increased risk of developing extrapulmonary tuberculosis (TB), the immunopathogenesis of which is poorly understood. Here, we conducted a detailed immunological analysis of human pericardial TB, to determine the effect of HIV-1 co-infection on the phenotype of Mycobacterium tuberculosis (MTB)-specific memory T cells and the role of polyfunctional T cells at the disease site, using cells from pericardial fluid and blood of 74 patients with (n=50) and without (n=24) HIV-1 co-infection. The MTB antigen-induced IFN-γ response was elevated at the disease site, irrespective of HIV-1 status or antigenic stimulant. However, the IFN-γ ELISpot showed no clear evidence of increased numbers of antigen-specific cells at the disease site except for ESAT-6 in HIV-1 uninfected individuals (p=0.009). Flow cytometric analysis showed that CD4+ memory T cells in the pericardial fluid of HIV-1-infected patients were of a less differentiated phenotype, with the presence of polyfunctional CD4+ T cells expressing TNF, IL-2 and IFN-γ. These results indicate that HIV-1 infection results in altered phenotype and function of MTB-specific CD4+ T cells at the disease site, which may contribute to the increased risk of developing TB at all stages of HIV-1 infection.
CD4+ T cells; HIV-1; Mycobacterium tuberculosis; Pericarditis