The prevalence of myocarditis and cardiotropic viral infection in human immunodeficiency virus (HIV)-associated cardiomyopathy is unknown in Africa.
Between April 2002 and December 2007, we compared the prevalence of myocarditis and cardiotropic viral genomes in HIV-associated cardiomyopathy cases with HIV-negative idiopathic dilated cardiomyopathy patients (i.e. negative controls for immunodeficiency) and heart transplant recipients (i.e. positive controls for immunodeficiency) who were seen at Groote Schuur Hospital, Cape Town, South Africa. Myocarditis was sought on endomyocardial biopsy using the imunohistological criteria of the World Heart Federation in 33 patients, 14 of whom had HIV-associated cardiomyopathy, eight with idiopathic dilated cardiomyopathy and 11 heart transplant recipients.
Myocarditis was present in 44% of HIV-associated cardiomyopathy cases, 36% of heart transplant recipients, and 25% of participants with idiopathic dilated cardiomyopathy. While myocarditis was acute in 50% of HIV- and heart transplant-associated myocarditis, it was chronic in all those with idiopathic dilated cardiomyopathy. Cardiotropic viral infection was present in all HIV-associated cardiomyopathy and idiopathic dilated cardiomyopathy cases, and in 90% of heart transplant recipients. Multiple viruses were identified in the majority of cases, with HIV-associated cardiomyopathy, heart transplant recipients and idiopathic dilated cardiomyopathy patients having an average of 2.5, 2.2 and 1.1 viruses per individual, respectively.
Acute myocarditis was present in 21% of cases of HIV-associated cardiomyopathy, compared to none of those with idiopathic dilated cardiomyopathy. Infection with multiple cardiotropic viruses may be ubiquitous in Africans, with a greater burden of infection in acquired immunodeficiency states.
HIV-associated cardiomyopathy; myocarditis; dilated cardiomyopathy; cardiotropic virus
The biennial Congress of the Pan-African Society of Cardiology (PASCAR) was held in Dakar from 16 to 19 May 2013 under the patronage of his Excellency, Macky Sall, president of the Republic of Senegal. This meeting was remarkable in the diversity of its 700 participants from English-, French- and Portuguese-speaking Africa. Important aspects of cardiovascular disease in Africa were presented in 195 abstracts and numerous talks; the topics were hypertension, obesity, diabetes, heart failure, cardiomyopathies, coronary heart disease, stroke and rheumatic heart disease. The general assembly meeting was marked by the review and adoption of a new constitution and elections of a new PASCAR governing council that will be in office for the next four years. The new leadership of PASCAR has committed itself to strengthening the administrative infrastructure of the organisation, developing programmes to address education and training needs of African cardiovascular practitioners, developing a pan-African multi-national research platform, and ensuring that ministries of health implement national programmes for the prevention and control of cardiovascular and other non-communicable diseases.
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
The value of the 12-lead electrocardiogram (ECG) to provide prognostic information in the deadly and disabling syndrome peripartum cardiomyopathy (PPCM) is unknown.
To determine the prevalence of major and minor ECG abnormalities in PPCM patients at the time of diagnosis, and to establish whether there are ECG correlates of persistent left ventricular dysfunction and/or clinical stability at six months of follow up, where available.
Twelve-lead ECGs were performed at the point of diagnosis on 78 consecutive women presenting with PPCM to two tertiary centres in South Africa and 44 cases (56%) at the six-month follow up. Blinded Minnesota coding identified major ECG abnormalities and minor ECG changes.
The cohort mainly comprised young women of black African ancestry (90%) [mean age 29 ± 7 years and median body mass index 24.3 (IQR: 22.7–27.5) kg/m2]. The majority of cases (n = 70; 90%) presented in sinus rhythm (mean heart rate 100 ± 21 beats/min). At baseline, at least one ECG abnormality/variant was detected in 96% of cases. Major ECG abnormalities and minor changes were detected in 49% (95% CI: 37–60%) and 62% (95% CI: 51–74%) of cases, respectively; the most common being T-wave changes (59%), p-wave abnormality (29%) and QRS-axis deviation (25%).
Of the 44 cases (56%) reviewed at six months, normalisation of the 12-lead ECG occurred in 25%; the most labile ECG features being heart rate (mean reduction of 27 beats/min; p < 0.001) and abnormal QRS axis (36 vs 14%; p = 0.014). On an adjusted basis, major T-wave abnormalities on the baseline 12-lead ECG were associated with lower left ventricular ejection fraction (LVEF) at baseline (average of –9%, 95% CI: –1 to –16; p = 0.03) and at six months (–12%; 95% CI: –4 to –24; p = 0.006). Similarly, baseline ST-segment elevation was also associated with lower LVEF at six months (–25%; 95% CI: –0.7 to –50; p = 0.04).
In this unique study, we found that almost all women suffering from PPCM had an ‘abnormal’ 12-lead ECG. Pending more definitive studies, the ECG appears to be a useful adjunctive tool in both screening and prognostication in resource-poor settings.
peripartum cardiomyopathy; ECG; baseline; follow up; comparative study; South Africa
There is sparse information on the epidemiology of effusive constrictive pericarditis (ECP). The objective of this article was to review and summarise the literature on the prevalence and outcome of ECP, and identify gaps for further research. The prevalence of ECP ranged from 2.4 to 14.8%, with a weighted average of 4.5% [95% confidence interval (CI) 2.2–7.5%]. Sixty-five per cent (95% CI: 43–82%) of patients required pericardiectomy regardless of the aetiology. The combined death rate across the studies was 22% (95% CI: 4–50%). The prevalence of ECP is low in non-tuberculous pericarditis, while pericardiectomy rates are high and mortality is variable. In this review, of 10 patients identified with tuberculous ECP, only one presumed case had a definite diagnosis of ECP. Appropriate studies are needed to determine the epidemiology of ECP in tuberculous pericarditis, which is one of the leading causes of pericardial disease in the world.
effusive constrictive pericarditis; prevalence; pericardiectomy and death
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.
Cardiovascular diseases (CVDs) are becoming increasingly significant in sub-Saharan Africa (SSA). Reliable measures of the contribution of major determinants are essential for informing health services and policy solutions.
To perform a systematic review of all longitudinal studies of CVDs and related risk factors that have been conducted in SSA.
We searched electronic databases from 1966 to October 2009. Published studies were retrieved from PubMed and Africa EBSCO. Reference lists of identified articles were scanned for additional publications.
Any longitudinal study with data collection at baseline on major cardiovascular risk factors or CVD, including 30 or more participants, and with at least six months of follow up were included.
Data were extracted on the country of study, year of inception, baseline evaluation, primary focus of the study, outcomes, and number of participants at baseline and final evaluation.
Eighty-one publications relating to 41 studies from 11 SSA countries with a wide range of participants were included. Twenty-two were historical/prospective hospital-based studies. These studies focused on risk factors, particularly diabetes mellitus and hypertension, or CVD including stroke, heart failure and rheumatic heart disease. The rate of participants followed through the whole duration of studies was 72% (64–80%), with a significant heterogeneity between studies (for heterogeneity, p < 0.001). Outcomes monitored during follow up included trajectories of risk markers and mortality.
Well-designed prospective cohort studies are needed to inform and update our knowledge regarding the epidemiology CVDs and their interactions with known risk factors in the context of common infectious diseases in this region.
cohort studies; cardiovascular diseases; risk factors; outcomes; sub-Saharan Africa
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.
The year 2011 marks the 30th anniversary of the founding of the Pan-African Society of Cardiology (PASCAR). Throughout its brief history, PASCAR has been integral to improving the cardiovascular health of the people of Africa. During the past three decades, many African countries have been vulnerable to political and social turmoil, and PASCAR itself has been repeatedly challenged to press on with its mission, in spite of innumerable practical obstacles. This article celebrates the hard work and dedication of PASCAR’s founders and subsequent leaders, and challenges the present and future generations to carry on the charge of furthering the health of Africans.
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.