The genetic basis for adult-onset idiopathic dilated cardiomyopathy in people of African descent.

Cardiomyopathies are a heterogeneous group of cardiac muscle disorders that result in dilated, hypertrophic, or restrictive pathophysiological entities. Dilated cardiomyopathy (DCM) is the most common form in sub-Saharan Africa (SSA). However, population-specific research studies reporting the actual burden of DCM in this region are still lacking. Also, little is known about the genetic basis of DCM in this population, and genetic testing is still not readily accessible. This review describes the common pathogenic genes implicated in DCM globally and discusses the evidence-based management of patients with DCM. We also present a summary of studies describing genes implicated or associated with DCM in patients residing in SSA.

Effects of Serelaxin in Patients with Acute Heart Failure.

BACKGROUND: Serelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure. METHODS: In this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 µg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days. RESULTS: A total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P = 0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P = 0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups. CONCLUSIONS: In this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778.).

Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients.

BACKGROUND: Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. METHODS: In two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow-up was 10 months. RESULTS: At 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of -56.0% in the bococizumab group and +2.9% in the placebo group, for a between-group difference of -59.0 percentage points (P<0.001) and a median reduction from baseline of 64.2% (P<0.001). In the lower-risk, shorter-duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [1.8 mmol per liter] and the median follow-up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P=0.94). In the higher-risk, longer-duration trial (in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [2.6 mmol per liter] and the median follow-up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P=0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P=0.08). Injection-site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P<0.001). CONCLUSIONS: In two randomized trials comparing the PCSK9 inhibitor bococizumab with placebo, bococizumab had no benefit with respect to major adverse cardiovascular events in the trial involving lower-risk patients but did have a significant benefit in the trial involving higher-risk patients. (Funded by Pfizer; SPIRE-1 and SPIRE-2 ClinicalTrials.gov numbers, NCT01975376 and NCT01975389 .).

Interleukin-6 gene polymorhisms and interleukin-6 levels are associated with atherosclerosis in CKD patients.

Inflammation is a major risk factor for atherosclerosis. Genetic polymorphisms in the inflammatory cytokine genes have been associated with atherosclerosis. Because levels of inflammatory cytokines are markedly elevated in patients with chronic kidney disease (CKD), we hypothesized that genotypic variations in the interleukin-6 (IL-6) gene are a cause of systemic inflammatory states and atherosclerosis in South African CKD patients. 120 CKD patients and 40 healthy controls were included. Serum IL-6 and high-sensitivity C-reactive protein (hs-CRP) levels were measured. Functional polymorphisms in the IL-6 genes were genotyped using polymerase chain reaction-sequence specific primer (PCR-SSP) methods. Carotid intima-media thickness (CIMT) and the presence of plaque were assessed by B-mode ultrasonography. Serum IL-6 and hs-CRP levels were increased in patients with CKD compared with healthy controls (p < 0.001). In CKD patients, serum IL-6 above the median value was associated with carotid plaque (OR: 2.11; 95% CI: 1.74 - 2.57, p = 0.004), with excess risk confined to the group with high IL-6 levels. Significant associations were found between the IL-6 gene and atherosclerosis in the CKD group (for G/G genotype: OR = 1.21, 95% CI = 1.05 - 1.39, p = 0.012; for GG+GC vs. CC: OR = 1.14, 95% CI = 1.02 - 1.28, p = 0.035). Patients with GG+GC genotype of the IL-6 gene polymorphism had higher levels of IL-6 than those with CC genotype (p = 0.029). In South African CKD patients, the IL-6 gene promoter polymorphism is associated with high serum IL-6 levels and atherosclerosis. The relationship between atherosclerosis and -174G/C polymorphism in the IL-6 gene suggests that IL-6 may be a potential pro-inflammatory mediator of atherosclerosis in CKD patients.

Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis.

BACKGROUND: Tuberculous pericarditis is associated with high morbidity and mortality even if antituberculosis therapy is administered. We evaluated the effects of adjunctive glucocorticoid therapy and Mycobacterium indicus pranii immunotherapy in patients with tuberculous pericarditis. METHODS: Using a 2-by-2 factorial design, we randomly assigned 1400 adults with definite or probable tuberculous pericarditis to either prednisolone or placebo for 6 weeks and to either M. indicus pranii or placebo, administered in five injections over the course of 3 months. Two thirds of the participants had concomitant human immunodeficiency virus (HIV) infection. The primary efficacy outcome was a composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis. RESULTS: There was no significant difference in the primary outcome between patients who received prednisolone and those who received placebo (23.8% and 24.5%, respectively; hazard ratio, 0.95; 95% confidence interval [CI], 0.77 to 1.18; P=0.66) or between those who received M. indicus pranii immunotherapy and those who received placebo (25.0% and 24.3%, respectively; hazard ratio, 1.03; 95% CI, 0.82 to 1.29; P=0.81). Prednisolone therapy, as compared with placebo, was associated with significant reductions in the incidence of constrictive pericarditis (4.4% vs. 7.8%; hazard ratio, 0.56; 95% CI, 0.36 to 0.87; P=0.009) and hospitalization (20.7% vs. 25.2%; hazard ratio, 0.79; 95% CI, 0.63 to 0.99; P=0.04). Both prednisolone and M. indicus pranii, each as compared with placebo, were associated with a significant increase in the incidence of cancer (1.8% vs. 0.6%; hazard ratio, 3.27; 95% CI, 1.07 to 10.03; P=0.03, and 1.8% vs. 0.5%; hazard ratio, 3.69; 95% CI, 1.03 to 13.24; P=0.03, respectively), owing mainly to an increase in HIV-associated cancer. CONCLUSIONS: In patients with tuberculous pericarditis, neither prednisolone nor M. indicus pranii had a significant effect on the composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis. (Funded by the Canadian Institutes of Health Research and others; IMPI ClinicalTrials.gov number, NCT00810849.).

Correlation between volume overload, chronic inflammation, and left ventricular dysfunction in chronic kidney disease patients.

BACKGROUND: Fluid overload is common in chronic kidney disease (CKD) patients, potentially driving chronic inflammation and left ventricular dysfunction. We investigated the association between volume overload, chronic inflammation, and left ventricular dysfunction across subgroups of CKD patients. METHODS: The study included 160 participants, comprising peritoneal dialysis (PD), hemodialysis (HD), stage-3 CKD patients, and age- and sex-matched controls (40 in each group). Fluid status was assessed using a body composition monitor (BCM); serum endotoxin, lipopolysaccharide binding protein (LBP), C-reactive protein (CRP). and interleukin-6 (IL-6) levels were measured as markers of inflammation. Echocardiography was done to assess left ventricular dimension and function. RESULTS: Endotoxemia and volume overload were common across the spectrum of CKD patients and were aggravated by worsening kidney function. Among HD cohorts, postdialysis endotoxemia was increased among patients with dialysis-induced hemodynamic instability and was also closely related to ultrafiltration volume. Endotoxin, IL-6, CRP, and LBP levels were elevated in patients with volume overload compared to euvolemic patients (p < 0.05). Patients with elevated circulating endotoxemia had higher left ventricular mass index (LVMI) compared to patients with lower endotoxin levels. Fluid overload correlated with endotoxin levels, IL-6, and LVMI; while LVMI correlated weakly with LBP and CRP. CONCLUSION: CKD patients typically presented with significant endotoxemia and overt volume overload, which may contribute significantly to chronic low-grade inflammation and left ventricular dysfunction. An additive contribution from hemodialysis treatment may strongly enhance the severity of endotoxemia in HD patients.

Volume overload and its risk factors in South African chronic kidney disease patients: an appraisal of bioimpedance spectroscopy and inferior vena cava measurements.

BACKGROUND: Fluid retention occurs early in chronic kidney disease (CKD) resulting in increased cardiovascular morbidity and mortality. This study aimed to assess volume and nutritional status among South African CKD participants and determine the relationship between malnutrition, inflammation, atherosclerosis, and volume overload using a body composition monitor (BCM). We also evaluated the usefulness of BCM measurement in assessing volume overload. METHODS: 160 participants comprising hemodialysis, peritoneal dialysis, stage 3 CKD patients, and healthy controls (40 in each group) were studied. A BCM was used to assess fluid and nutritional status. Cardiac dimension measurements, and inferior vena cava diameter (IVCD) and carotid intima media thickness were assessed by echocardiography and ultrasonography, respectively. Serum interleukin-6 (IL-6) and C-reactive protein (CRP) levels were measured as markers of inflammation. RESULTS: Fluid overload and malnutrition were present in 68% and 63% of studied patients, respectively. Using physical examination findings as the reference measurements for volume overload, the area under the concentration curves for BCM and IVCD measurements were 0.866 (sensitivity 82%, specificity 74%, p < 0.001) and 0.727 (sensitivity 57%, specificity 70%, p < 0.001), respectively. Lean tissue index, inflammation, and atherosclerosis were associated with volume overload. CONCLUSIONS: Volume overload and malnutrition were common across the spectrum of South African CKD cohorts; volume overload was associated with malnutrition, inflammation, and atherosclerosis. Bioimpedance spectroscopy (BIS) is a useful and sensitive tool for the assessment of fluid status in clinically euvolumic nondialytic CKD patients.

Rationale and design of the Investigation of the Management of Pericarditis (IMPI) trial: a 2 × 2 factorial randomized double-blind multicenter trial of adjunctive prednisolone and Mycobacterium w immunotherapy in tuberculous pericarditis.

BACKGROUND: In spite of antituberculosis chemotherapy, tuberculous (TB) pericarditis causes death or disability in nearly half of those affected. Attenuation of the inflammatory response in TB pericarditis may improve outcome by reducing cardiac tamponade and pericardial constriction, but there is uncertainty as to whether adjunctive immunomodulation with corticosteroids and Mycobacterium w (M. w) can safely reduce mortality and morbidity. OBJECTIVES: The primary objective of the IMPI Trial is to assess the effectiveness and safety of prednisolone and M. w immunotherapy in reducing the composite outcome of death, constriction, or cardiac tamponade requiring pericardial drainage in 1,400 patients with TB pericardial effusion. DESIGN: The IMPI trial is a multicenter international randomized double-blind placebo-controlled 2 × 2 factorial study. Eligible patients are randomly assigned to receive oral prednisolone or placebo for 6 weeks and M. w injection or placebo for 3 months. Patients are followed up at weeks 2, 4, and 6 and months 3 and 6 during the intervention period and 6-monthly thereafter for up to 4 years. The primary outcome is the first occurrence of death, pericardial constriction, or cardiac tamponade requiring pericardiocentesis. The secondary outcome is safety of immunomodulatory treatment measured by effect on opportunistic infections (eg, herpes zoster) and malignancy (eg, Kaposi sarcoma) and impact on measures of immunosuppression and the incidence of immune reconstitution disease. CONCLUSIONS: IMPI is the largest trial yet conducted comparing adjunctive immunotherapy in pericarditis. Its results will define the role of adjunctive corticosteroids and M. w immunotherapy in patients with TB pericardial effusion.

Cardiovascular Magnetic Resonance Imaging Findings in Africans with Idiopathic Dilated Cardiomyopathy.

In sub-Saharan Africa, idiopathic dilated cardiomyopathy (IDCM) is a common yet poorly investigated cause of heart failure. Cardiovascular magnetic resonance (CMR) imaging is the gold standard for tissue characterisation and volumetric quantification. In this paper, we present CMR findings obtained from a cohort of patients with IDCM in Southern Africa suspected of having a genetic cause of cardiomyopathy. A total of 78 IDCM study participants were referred for CMR imaging. The participants had a median left ventricular ejection fraction of 24% [interquartile range, (IQR): 18-34]. Late gadolinium enhancement (LGE) was visualised in 43 (55.1%) participants and localised in the midwall in 28 (65.0%) participants. At the time of enrolment into the study, non-survivors had a higher median left ventricular end diastolic wall mass index of 89.4 g/m2 (IQR: 74.5-100.6) vs. 73.6 g/m2 (IQR: 51.9-84.7), p = 0.025 and a higher median right ventricular end-systolic volume index of 86 mL/m2 (IQR:74-105) vs. 41 mL/m2 (IQR: 30-71), p < 0.001. After one year, 14 participants (17.9%) died. The hazard ratio for the risk of death in patients with evidence of LGE from CMR imaging was 0.435 (95% CI: 0.259-0.731; p = 0.002). Midwall enhancement was the most common pattern, visualised in 65% of participants. Prospective, adequately powered, and multi-centre studies across sub-Saharan Africa are required to determine the prognostic significance of CMR imaging parameters such as late gadolinium enhancement, extracellular volume fraction, and strain patterns in an African IDCM cohort.

Clinical characteristics and one-year all-cause mortality outcomes in Africans with dilated cardiomyopathy.

AIMS: Dilated cardiomyopathy (DCM) is a common cause of heart failure in sub-Saharan Africa (SSA). The affected individuals present with new-onset heart failure with reduced ejection fraction and no identifiable primary or secondary aetiology. We aim to describe the clinical characteristics of participants with heart failure of unknown origin. METHODS: We screened 161 participants with heart failure of unknown origin and prospectively excluded primary and secondary causes of DCM. All study participants were subjected to laboratory biochemical testing, echocardiography, cardiovascular magnetic resonance (CMR) imaging and invasive coronary angiography. RESULTS: The study comprised 93 participants with a mean age of 47.5 SD 13.1 years. Forty-six (56.1%) participants had evidence of late gadolinium enhancement (LGE) on imaging, and LGE was visualised in the mid wall in 28 (61.0%) of these participants. After a median duration of 13.4 months [interquartile range (IQR): 8.8-28.9 months], 18 (19%) participants died. Non-survivors had a higher median left atrial volume index (44.9 mL/m2 (IQR: 34.4-58.7) compared to survivors [32.9 mL/m2 (IQR: 24.5-47.0), p = 0.017)]. The rate of all-cause rehospitalisation was 29.3%, of which 17 of the 22 re-hospitalisations were heart failure related. CONCLUSION: Dilated cardiomyopathy in Africans primarily affects young males. In our cohort, this disease was associated with an all-cause mortality of 19% in one year. In SSA, large multicenter studies are required to investigate this disease's pathogenesis and outcomes.

Emerging Role of Platelet-Endothelium Interactions in the Pathogenesis of Severe SARS-CoV-2 Infection-Associated Myocardial Injury.

Cardiovascular dysfunction and disease are common and frequently fatal complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Indeed, from early on during the SARS-CoV-2 virus pandemic it was recognized that cardiac complications may occur, even in patients with no underlying cardiac disorders, as part of the acute infection, and that these were associated with more severe disease and increased morbidity and mortality. The most common cardiac complication is acute cardiac injury, defined by significant elevation of cardiac troponins. The potential mechanisms of cardiovascular complications include direct viral myocardial injury, systemic inflammation induced by the virus, sepsis, arrhythmia, myocardial oxygen supply-demand mismatch, electrolyte abnormalities, and hypercoagulability. This review is focused on the prevalence, risk factors and clinical course of COVID-19-related myocardial injury, as well as on current data with regard to disease pathogenesis, specifically the interaction of platelets with the vascular endothelium. The latter section includes consideration of the role of SARS-CoV-2 proteins in triggering development of a generalized endotheliitis that, in turn, drives intense activation of platelets. Most prominently, SARS-CoV-2-induced endotheliitis involves interaction of the viral spike protein with endothelial angiotensin-converting enzyme 2 (ACE2) together with alternative mechanisms that involve the nucleocapsid and viroporin. In addition, the mechanisms by which activated platelets intensify endothelial activation and dysfunction, seemingly driven by release of the platelet-derived calcium-binding proteins, SA100A8 and SA100A9, are described. These events create a SARS-CoV-2-driven cycle of intravascular inflammation and coagulation, which contributes significantly to a poor clinical outcome in patients with severe disease.

Coronary revascularization in patients with HIV.

With combined antiretroviral therapy, people living with HIV (PLWH) survive longer and are now more likely to die from cardiovascular diseases. PLWH presenting with a ST-segment elevation myocardial infarction are likely to have a high thrombus burden and are at high risk for in-hospital and long-term adverse events. An increasing number of PLWH are presenting with stable coronary artery disease related to atherosclerosis. Revascularization in these patients is associated with higher in-hospital and long-term major adverse cardiovascular events, including stent thrombosis and in-stent restenosis. However, data in this expanding population concerning optimal revascularization strategy are still lacking. In particular, data comparing percutaneous versus surgical revascularization in PLWH are needed. In this review we highlight the currently available data related to coronary revascularization in PLWH.

A comprehensive overview of pneumococcal vaccination recommendations for adults in South Africa, 2022.

Pneumococcal infections remain a common global cause of significant morbidity and mortality. The first recommendations for adult pneumococcal vaccination, published in South Africa in 1999, contained information only on the 23-valent polysaccharide vaccine (PPV23). With the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) for use in adults and the perceived uncertainty that most clinicians had regarding use of these vaccines in adults, these vaccine recommendations were updated in 2022. A Working Group, which consisted of individuals in various fields of medical practice in South Africa, who were from different areas of the country, and included clinicians from both the public and private sectors, was assembled to revise the recommendations. The expertise of the participants varied widely, dependent on their training and specialty, and encompassed different organ systems, disease conditions, and/or practice types. Each participant was allocated a different section, based on their expertise, for which they were required to do an extensive review of the current literature and write their section. The entire working group then reviewed the complete document several times, following additional comments and recommendations. This update contains recommendations for the use of both PPV23 and PCV13, either alone, or in sequence, both in vaccine naïve and in previously vaccinated individuals. It includes both age and risk categories, and encompasses the elderly (≥65 years), as well as younger adults (<65 years) with comorbid conditions or with high-risk conditions and/or immunocompromise. It is hoped that this review and its associated vaccine recommendations will clarify for clinicians, from all spheres of practice in South Africa, how, where, and when pneumococcal vaccines should be used in adults, with the ultimate goal of significantly increasing the appropriate use of these vaccines, in order to decrease the substantial morbidity and mortality associated with pneumococcal infections in adults in South Africa. Furthermore, it is hoped that this review of local epidemiological data and the manner in which this information was interpreted in the development of these local vaccine recommendations, could be used as an example for other regions of the world, to tailor their recommendations to locally available epidemiological data.

The prevalence of depression, stress and anxiety symptoms in patients with chronic heart failure.

BACKGROUND: Mental health illnesses are associated with frequent hospitalisation and an increased risk of all-cause mortality. Despite the high prevalence of depression in patients with chronic heart failure (CHF), there is a paucity of data on this subject from low and middle-income countries (LMIC). The aim of this study was to determine the prevalence of depression, anxiety, and stress symptoms in patients attending a dedicated CHF clinic. METHODS: A prospective study was conducted at an outpatient heart failure clinic in a tertiary academic centre. The study participants completed a Depression, Anxiety and Stress (DASS-21) questionnaire to screen for the presence and severity of depression, anxiety and stress symptoms. Furthermore, the Minnesota Living with Heart Failure Questionnaire (MLHFQ) was completed and used to evaluate the impact of CHF on health-related quality of life (QoL). Descriptive statistics were used to describe patients' characteristics and logistic regression analysis to identify predictors of symptoms of depression. RESULTS: The study population comprised of 103 patients, predominantly female (62.1%) with a median age of 53 (interquartile range 38-61) years. Symptoms of depression were reported by 52.4%, with 11.6% reporting symptoms suggestive of extremely severe depression. Anxiety was diagnosed in 53.4% of patients and extremely severe anxiety was reported by 18.4% of patients. Fifty patients were classified as stressed, and only 7.7% had extremely severe stress. More than half of the patients (54.4%) were in New York Heart Association functional class I. The mean left ventricular ejection fraction in the entire cohort was 30% (SD = ± 11.1%). In the multivariable logistic regression model, the MLHFQ score [odds ratio (OR) 1.04, 95% CI:1.02-1.06, p = 0.001] and the six-minute walk test [OR 0.99, 95% CI: 0.98-0.99, p = 0.014] were identified as independent predictors of depression. CONCLUSION: Depression and anxiety symptoms were found in over half of patients attending the CHF clinic. We recommend that mental health screening should be routinely performed in patients with CHF. Prospective, adequately powered, multicentre studies from LMIC investigating the impact of depression, anxiety and stress on CHF outcomes such as health-related QoL, hospitalisation and mortality are required.

Endothelial dysfunction in HIV-positive patients with acute coronary syndromes.

AIM: This study investigated endothelial function in HIV-positive patients with acute coronary syndrome (ACS). Flow-mediated dilatation, pulse-wave velocity, carotid intima-media thickness and endothelial biomarkers were used to non-invasively investigate endothelial dysfunction. METHODS: Twenty HIV-positive patients with ACS (HIV+/ACS) were compared to 20 HIV-negative patients with ACS (HIV-/ACS) and 20 HIV-positive patients without ACS (HIV+/no ACS). RESULTS: Endothelial function measured by flow-mediated dilatation (FMD) was similar in both the HIV+/ACS (5.2; IQR 1.4-13.4%) and HIV-/ACS groups (3.7; IQR 2.3-4.4%) (p = 0.78). Arterial stiffness, measured by pulse-wave velocity (PWV) was low in all three cohorts. Carotid intima-media thickness (CIMT) was also low in all three cohorts. The vascular cellular adhesion molecule-1 (VCAM-1) levels in HIV-positive patients with and without ACS were significantly higher than in the HIV-/ACS cohort (p = 0.033 and 0.024, respectively). CONCLUSIONS: Non-invasive investigations such as FMD, CIMT and PWV did not identify patients with HIV who were at high risk of ACS. Endothelial biomarkers may be more useful markers to identify HIV-positive patients who have endothelial dysfunction and increased risk of ACS.

Biomarkers for Diagnosis and Prediction of Outcomes in Contrast-Induced Nephropathy.

BACKGROUND: Serum creatinine is suboptimal as a biomarker in the early diagnosis of contrast-induced nephropathy (CIN). In this study, we investigated a panel of novel biomarkers in the early diagnosis of CIN and in assessing patient outcomes. METHODS: This single-centre, nested, prospective case-controlled study included 30 patients with CIN and 60 matched controls. Serum and urine samples were collected before contrast administration and at 24 hours, 48 hours, and ≥5 days after contrast administration. Concentrations of NGAL, cystatin C, ß 2M, IL18, IL10, KIM1, and TNFα were determined using Luminex and ELISA assays. Outcomes were biomarker diagnostic discrimination performance for CIN and mortality after generation of area under receiver operating characteristic curves (AUROCs). RESULTS: Median serum levels for 24 h cystatin C (p < 0.01) and 48 h ß 2M levels (p < 0.001) and baseline urine NGAL (p=0.02) were higher in CIN patients compared to controls with AUROCs of 0.75, 0.78, and 0.74, respectively, for the early diagnosis of CIN. Serum ß 2M levels were higher in CIN patients at all time points. Elevated baseline serum concentrations of IL18 (p < 0.001), ß 2M (p=0.04), TNFα (p < 0.001), and baseline urine KIM (p=0.01) and 24 h urine NGAL (p=0.02) were significantly associated with mortality. Baseline serum concentrations of IL18, ß 2M, and TNFα showed the best discrimination performance for mortality with AUROCs, all >0.80. Baseline NGAL was superior for excluding patients at risk for CIN, with positive and negative predictive ranges of 0.50-0.55 and 0.81-0.88, respectively. Cystatin C (p=0.003) and ß 2M (p=0.03) at 24 h independently predicted CIN risk. ß 2M predicted increased mortality of 40% at baseline and 50% at 24 hours. CONCLUSION: Serum cystatin C at 24 h was the best biomarker for CIN diagnosis, while baseline levels of serum IL18, ß 2M, and TNFα were best for predicting prognosis.

Association of chronic inflammation and accelerated atherosclerosis among an indigenous black population with chronic kidney disease.

INTRODUCTION: Inflammation plays a major role in the development of atherosclerosis and cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. Toll-like receptor-4 (TLR4) is a major receptor for lipopolysaccharides (endotoxin) and other ligands involved in the pathogenesis of inflammation. We determined whether endotoxin levels and the presence of TLR4 polymorphisms are associated with markers of inflammation and atherosclerosis among South African CKD patients. MATERIALS AND METHODS: Endotoxin, lipopolysaccharide binding protein (LBP), serum CD14 (sCD14), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and carotid intima media thickness (CIMT) were measured in 160 participants (120 CKD patients and 40 controls). Associations between endotoxins and CIMT in the presence of sCD14, IL-8 and MCP-1, were assessed using odds ratios. Participants were screened for the presence of Asp299Gly and Thr399Ile TLR4 polymorphisms, and CIMT and inflammatory markers were compared between subjects with and without TLR4 polymorphisms. RESULTS: Endotoxin levels correlated with sCD14 (r = 0.441, p<0.001) and MCP-1 (r = 0.388, p<0.001) levels while increased CIMT was associated with MCP-1 (r = 0.448, p<0.001), sCD14 levels (r = 0.476, p<0.001), LBP (r = 0.340, p<0.001), and IL-8 (r = 0.395, p<0.001). Atherosclerosis was associated with endotoxin levels (odds ratio: 4.95; 95% confidence interval: 2.52-9.73; p<0.001), and was predicted by higher serum levels of inflammatory markers. Analysis of patients with TLR4 polymorphisms showed reduced serum levels of inflammatory markers and CIMT values compared with the patients carrying the wild type TLR4 alleles. CONCLUSION: The study demonstrated associations between circulating endotoxaemia, systemic inflammation and accelerated atherosclerosis among South African CKD patients, and showed that the atherogenic predictive power of endotoxaemia was significantly increased by the presence of elevated levels of inflammatory markers. Additional findings, which must be confirmed, suggest that TLR4 polymorphisms are associated with low levels of inflammatory markers and CIMT values.

APOL1 Genetic Variants Are Associated with Serum-Oxidized Low-Density Lipoprotein Levels and Subclinical Atherosclerosis in South African CKD Patients.

INTRODUCTION: Apolipoprotein L1 (APOL1) plays an important role in cholesterol metabolism and attenuation of low-density lipoprotein (LDL) oxidation. While protecting against Trypanosoma brucei rhodesiense infection, APOL1 risk alleles confer greater risk for CKD and cardiovascular disease among patients of African descent. OBJECTIVES: We investigated whether APOL1 risk variants are associated with atherosclerosis and oxidized LDL (OxLDL) levels among black South African CKD patients. METHODS: A cross-sectional study of 120 adult CKD patients and 40 controls was undertaken. DNA samples of participants were genotyped for APOL1 G1 and G2 variants. High-sensitivity C-reactive protein, serum lipids, and OxLDL levels were measured, and carotid doppler ultrasonography was performed on all participants. RESULTS: APOL1 alleles rs73885319, rs60910145, and rs71785313 had minor allele frequencies of 9.2, 8.8, and 17.5%, respectively, in the patients, and 8.8, 8.8, and 13.8%, respectively, in the controls. Of the 9 patients with 2 APOL1 risk alleles, 77.8% were compound G1/G2 heterozygotes and 22.2% were G2 homozygotes. Carriers of at least 1 APOL1 risk allele had a 3-fold increased risk of subclinical atherosclerosis (odds ratio 3.19; 95% confidence interval: 1.64-6.19; p = 0.01) compared to individuals with no risk alleles. Patients with 1 or 2 APOL1 risk alleles showed a significant increase in OxLDL levels when compared with those without the APOL1 risk allele. CONCLUSION: These findings suggest an increased risk for atherosclerosis in carriers of a single APOL1 risk variant, and the presence of APOL1 risk variants was associated with increased serum OxLDL levels in black South African CKD patients.

Pregnancy outcomes in women with aortic coarctation.

OBJECTIVE: Pregnancy in women with aortic coarctation (CoA) has an estimated moderately increased risk (mWHO II-III) of adverse cardiovascular, obstetric or fetal events, but prospective data to validate this risk classification are scarce. We examined pregnancy outcomes and identified associations with adverse outcomes. METHODS: Pregnancies in women with CoA were selected from the worldwide prospective Registry of Pregnancy and Cardiac Disease (ROPAC, n=303 out of 5739), part of the European Society of Cardiology EURObservational Research Programme. The frequency of and associations with major adverse cardiac events (MACE) and hypertensive disorders (pregnancy-induced hypertension, (pre-)eclampsia or haemolysis, elevated liver enzymes and low platelets syndrome) were analysed. RESULTS: Of 303 pregnancies (mean age 30 years, pregnancy duration 39 weeks), 9.6% involved unrepaired CoA and 27.1% were in women with pre-existing hypertension. No maternal deaths or aortic dissections occurred. MACE occurred in 13 pregnancies (4.3%), of which 10 cases were of heart failure (3.3%). Univariable associations with MACE included prepregnancy clinical signs of heart failure (OR 31.8, 95% CI 6.8 to 147.7), left ventricular ejection fraction <40% (OR 10.4, 95% CI 1.8 to 59.5), New York Heart Association class >1 (OR 11.4, 95% CI 3.6 to 36.3) and cardiac medication use (OR 4.9, 95% CI 1.3 to 18.3). Hypertensive disorders of pregnancy occurred in 16 (5.3%), cardiac medication use being their only predictor (OR 3.2, 95% CI 1.1 to 9.6). Premature births were 9.1%, caesarean section was performed in 49.7% of pregnancies. Of 4 neonatal deaths, 3 were after spontaneous extreme preterm birth. CONCLUSIONS: The ROPAC data show low MACE and hypertensive disorder rates during pregnancy in women with CoA, suggesting pregnancy to be more safe and better tolerated than previously appreciated.

Atherosclerotic plaque in HIV-positive patients presenting with acute coronary syndromes.

AIM: This study aimed to characterise the atherosclerotic plaque and plaque burden in HIV-positive patients presenting with acute coronary syndromes (ACS), using intravascular ultrasound (IVUS) and virtual histology (VH). METHODS: This was a prospective study of 20 HIV-positive patients who presented with ACS. IVUS and VH were used to assess plaque burden and plaque characteristics in the culprit and non-culprit coronary arteries. RESULTS: HIV-positive patients with ACS had a mean age of 51.1 ± 8.1 years. There were 13 (65%) male patients. ST-segment elevation myocardial infarction was the most common presentation of ACS (75%) with the left anterior descending artery being the most common culprit artery (60%). In 60% of patients, the total plaque burden was of moderate degree (40-70% stenosis) while it was of mild degree (< 40% stenosis) in 35%, and in 5% of patients it was severe (> 70% stenosis). A severe degree of total plaque burden was more commonly found in the culprit vessel (30%) than in the non-culprit vessels (5%). Furthermore, the plaque burden was found to be located predominantly in the proximal portion of the coronary arteries. The predominant plaque morphology consisted of fibrous plaque (55.4%) and fibro-fatty plaque (26.6%), while necrotic core was present in 13.3%. Dense calcium was present in only 4.7% of the cohort. CONCLUSIONS: IVUS and VH demonstrated a high burden of atherosclerosis in the left anterior descending artery and proximal vasculature of HIV-positive patients. The atherosclerotic plaque predominantly comprised non-calcified fibrous and fibro-fatty plaque.