Blood RNA signatures outperform CRP triage of tuberculosis lymphadenitis and pericarditis.

Background: Limited data are available on the diagnostic accuracy of blood RNA biomarker signatures for extrapulmonary TB (EPTB). We addressed this question among people investigated for TB lymphadenitis and TB pericarditis, in Cape Town, South Africa. Methods: We enrolled 440 consecutive adults referred to a hospital for invasive sampling for presumptive TB lymphadenitis (n=300) or presumptive TB pericarditis (n=140). Samples from the site of disease underwent culture and/or molecular testing for Mycobacterium tuberculosis complex (Mtb). Discrimination of patients with and without TB defined by microbiology or cytology reference standards was evaluated using seven previously reported blood RNA signatures by area under the receiver-operating characteristic curve (AUROC) and sensitivity/specificity at predefined thresholds, benchmarked against blood C-reactive protein (CRP) and the World Health Organization (WHO) target product profile (TPP) for a TB triage test. Decision curve analysis (DCA) was used to evaluate the clinical utility of the best performing blood RNA signature and CRP. Results: Data from 374 patients for whom results were available from at least one microbiological test from the site of disease, and blood CRP and RNA measurements, were included. Using microbiological results as the reference standard in the primary analysis (N=204 with TB), performance was similar across lymphadenitis and pericarditis patients. In the pooled analysis of both cohorts, all RNA signatures had comparable discrimination with AUROC point estimates ranging 0.77-0.82, superior to that of CRP (0.61, 95% confidence interval 0.56-0.67). The best performing signature (Roe3) achieved an AUROC of 0.82 (0.77-0.86). At a predefined threshold of 2 standard deviations (Z2) above the mean of a healthy reference control group, this signature achieved 78% (72-83%) sensitivity and 69% (62-75%) specificity. In this setting, DCA revealed that Roe3 offered greater net benefit than other approaches for services aiming to reduce the number needed to investigate with confirmatory testing to <4 to identify each case of TB. Interpretation: RNA biomarkers show better accuracy and clinical utility than CRP to trigger confirmatory TB testing in patients with TB lymphadenitis and TB pericarditis, but still fall short of the WHO TPP for TB triage tests. Funding: South African MRC, EDCTP2, NIH/NIAID, Wellcome Trust, NIHR, Royal College of Physicians London. Research in context: Evidence before this study: Blood RNA biomarker signatures and CRP measurements have emerged as potential triage tests for TB, but evidence is mostly limited to their performance in pulmonary TB. Microbiological diagnosis of extrapulmonary TB (EPTB) is made challenging by the need for invasive sampling to obtain tissue from the site of disease. This is compounded by lower sensitivity of confirmatory molecular tests for EPTB compared to their performance in pulmonary disease. We performed a systematic review of diagnostic accuracy studies of blood RNA biomarkers or CRP measurements for EPTB, which could mitigate the need for site-of-disease sampling for the diagnosis of TB. We searched PubMed up to 1 st August 2023, using the following criteria: "extrapulmonary [title/abstract] AND tuberculosis [title/abstract] AND biomarker [title/abstract]". Although extrapulmonary TB was included in several studies, none focused specifically on EPTB or included an adequate number of EPTB cases to provide precise estimates of test accuracy. Added value of this study: To the best of our knowledge, we report the first diagnostic accuracy study of blood RNA biomarkers and CRP for TB among people with EPTB syndromes. We examined the performance of seven previously identified blood RNA biomarkers as triage tests for TB lymphadenitis and TB pericarditis compared to a microbiology reference standard among people referred to hospital for invasive sampling in a high TB and HIV prevalence setting. Multiple blood RNA biomarkers showed comparable diagnostic accuracy to that previously reported for pulmonary TB in both EPTB disease cohorts, irrespective of HIV status. All seven blood RNA biomarkers showed superior diagnostic accuracy to CRP for both lymphadenitis and pericarditis, but failed to meet the combined >90% sensitivity and >70% specificity recommended for a blood-based diagnostic triage test by WHO. Nonetheless, in decision curve analysis, an approach of using the best performing blood RNA biomarker to trigger confirmatory microbiological testing showed superior clinical utility in clinical services seeking to reduce the number needed to test (using invasive confirmatory testing) to less than 4 for each EPTB case detected. If acceptable to undertake invasive testing in more than 4 people for each true case detected, then a test-all approach will provide greater net benefit in this TB/HIV hyperendemic setting.Implications of all the available evidence: Blood RNA biomarkers show some potential as diagnostic triage tests for TB lymphadenitis and TB pericarditis, but do not provide the level of accuracy for blood-based triage tests recommended by WHO for community-based tests. CRP has inferior diagnostic accuracy to blood RNA biomarkers and cannot be recommended for diagnostic triage among people with EPTB syndromes referred for invasive sampling.

Bad company? The pericardium microbiome in people investigated for tuberculosis pericarditis in an HIV-prevalent setting.

Background: The microbiome likely plays a role in tuberculosis (TB) pathogenesis. We evaluated the site-of-disease microbiome and predicted metagenome in people with presumptive tuberculous pericarditis, a major cause of mortality, and explored for the first time, the interaction between its association with C-reactive protein (CRP), a potential diagnostic biomarker and the site-of-disease microbiome in extrapulmonary TB. Methods: People with effusions requiring diagnostic pericardiocentesis (n=139) provided background sampling controls and pericardial fluid (PF) for 16S rRNA gene sequencing analysed using QIIME2 and PICRUSt2. Blood was collected to measure CRP. Results: PF from people with definite (dTB, n=91), probable (pTB, n=25), and non- (nTB, n=23) tuberculous pericarditis differed in ß-diversity. dTBs were, vs. nTBs, Mycobacterium-, Lacticigenium-, and Kocuria- enriched. Within dTBs, HIV-positives were Mycobacterium-, Bifidobacterium- , Methylobacterium- , and Leptothrix -enriched vs. HIV-negatives and HIV-positive dTBs on ART were Mycobacterium - and Bifidobacterium -depleted vs. those not on ART. Compared to nTBs, dTBs exhibited short-chain fatty acid (SCFA) and mycobacterial metabolism microbial pathway enrichment. People with additional non-pericardial involvement had differentially PF taxa (e.g., Mycobacterium -enrichment and Streptococcus -depletion associated with pulmonary infiltrates). Mycobacterium reads were in 34% (31/91), 8% (2/25) and 17% (4/23) of dTBs, pTBs, and nTBs, respectively. ß-diversity differed between patients with CRP above vs. below the median value ( Pseudomonas -depleted). There was no correlation between enriched taxa in dTBs and CRP. Conclusions: PF is compositionally distinct based on TB status, HIV (and ART) status and dTBs are enriched in SCFA-associated taxa. The clinical significance of these findings, including mycobacterial reads in nTBs and pTBs, requires evaluation.

Subclinical cardiovascular remodelling in HIV-infection: A multimodal case study of 2 serodiscordant, monozygotic twins.

Cardiovascular abnormalities are increasingly recognised among people newly diagnosed with HIV, but subclinical pathology may be challenging to diagnose. We present a case study of subtle cardiovascular changes in identical twins, one without HIV-infection and the other recently diagnosed with HIV (serodiscordant). We hypothesise that cardiovascular parameters would be similar between the twins, unless non-genetic (environmental) factors are at play. These differences likely represent occult pathology secondary to the effects of early HIV-infection. A 25-year-old female incidentally diagnosed with HIV, and her HIV-uninfected identical twin, living with her since birth, underwent comprehensive cardiovascular assessments. The HIV-positive twin exhibited a globular left ventricle (LV), larger LV volumes, decreased LV strain, peak atrial longitudinal strain (PALS) and higher native T1 and T2 mapping values compared to her sister. Cardiac biomarkers high sensitivity cardiac troponin T and N-terminal proBNP, as well as the novel markers of fibrosis and remodelling, galectin-3 and soluble-ST2, were higher in the HIV-infected twin. Given the twins' shared environment and genetic makeup, these differences likely stem from HIV-infection. Our study supports previous findings and suggests potential screening markers for HIV-associated cardiovascular disease, including PALS. Further research is warranted to explore PALS' utility in this context.

Antiretroviral therapy and HIV-associated cardiovascular disease: a prospective cardiac biomarker and CMR tissue characterization study.

AIMS: Biochemical markers are fundamental in cardiac evaluation, and various novel assays have recently been discovered. We prospectively evaluated the hearts of newly diagnosed people living with human immunodeficiency virus (PLWH) using cardiac biomarkers, compared them with human immunodeficiency virus (HIV)-uninfected controls, and correlated our prospective findings with cardiovascular magnetic resonance imaging (CMR). METHODS AND RESULTS: Newly diagnosed, antiretroviral therapy (ART)-naïve PLWH were recruited along with HIV-uninfected, age-matched, and sex-matched controls. All participants underwent measurement of high-sensitivity cardiac troponin T (hs-cTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), soluble ST2 (sST2), and galectin-3, as well as a CMR study with multiparametric mapping. The HIV group started ART and was re-evaluated 9 months later. The cardiac biomarkers and their correlation with CMR parameters were evaluated in and between groups. Compared with controls (n = 22), hs-cTnT (4.0 vs. 5.1 ng/L; P = 0.004), NT-proBNP (23.2 vs. 40.8 ng/L; P = 0.02), and galectin-3 (6.8 vs. 9.0 ng/mL; P = 0.002) were all significantly higher in the ART-naïve group (n = 73). After 9 months of ART, hs-cTnT (5.1 vs. 4.3 ng/L; P = 0.02) and NT-proBNP (40.8 vs. 28.5 ng/L; P = 0.03) both decreased significantly and a trend of decrease was seen in sST2 (16.5 vs. 14.8 ng/L; P = 0.08). Galectin-3 did not demonstrate decrease over time (9.0 vs. 8.8 ng/mL; P = 0.6). The cardiac biomarkers that showed the best correlation with CMR measurements native T1, T2, and extracellular volume were NT-proBNP (rs ≥ 0.4, P < 0.001) and galectin-3 (rs ≥ 0.3, P < 0.01). CONCLUSIONS: Our cardiac biomarker data support the presence of subclinical myocardial injury, remodelling, and fibrosis at HIV diagnosis, and ART had a positive influence on these blood markers. It remains unclear if the underlying pathological processes were fully addressed by ART. The ability of cardiac biomarkers to detect and track tissue abnormalities diagnosed with CMR showed promise. With additional research, this could lead to improvements in screening and monitoring myocardial abnormalities, even in CMR-limited settings.

Development and testing of a transcatheter heart valve with reduced calcification potential.

Introduction: Patients from developing countries who require heart valve surgery are younger and have less access to open heart surgery than those from developed countries. Transcatheter heart valves (THVs) may be an alternative but are currently unsuitable for young patients because of their inadequate durability. We developed and tested a THV utilizing two new types of decellularized bovine pericardial leaflets in an ovine model. Methods: The two decellularized tissues [one with a very low dose (0.05%) of monomeric glutaraldehyde (GA) fixation and detoxification (DF) and the other without glutaraldehyde (DE)] were compared to an industry standard [Glycar-fixed with the standard dose (0.625%) of glutaraldehyde]. THVs were manufactured with the three tissue types and implanted in the pulmonary position of nine juvenile sheep for 180 days. Baseline and post-explantation evaluations were performed to determine the hemodynamic performance of the valves and their dynamic strength, structure, biological interaction, and calcification. Results: Heart failure occurred in one animal due to incompetence of its Glycar valve, and the animal was euthanized at 158 days. The gradients over the Glycar valves were higher at the explant than at the implant, but the DE and DF valves maintained normal hemodynamic performance throughout the study. The DF and DE tissues performed well during the mechanical testing of explanted leaflets. Glycar tissue developed thick pannus and calcification. Compared to Glycar, the DF tissue exhibited reduced pannus overgrowth and calcification and the DE tissue exhibited no pannus formation and calcification. All tissues were endothelialized adequately. There was a striking absence of host ingrowth in the DE tissue leaflets, yet these leaflets maintained integrity and mechanical function. Conclusion: In the juvenile sheep THV model, Glycar tissue developed significant pannus, calcification, and hemodynamic deterioration. Using a very low dose of monomeric GA to fix the decellularized bovine pericardium yielded less pannus formation, less calcification, and better hemodynamic function. We postulate that the limited pannus formation in the DF group results from GA. Bovine pericardium decellularized with our proprietary method resulted in inert tissue, which is a unique finding. These results justify further development and evaluation of the two decellularized tissue types in THVs for use in younger patients.

Clinical Profile of Patients with Hypertensive Emergency Referred to a Tertiary Hospital in the Western Cape Province of South Africa.

BACKGROUND: Despite advances in managing hypertension, hypertensive emergencies remain a common indication for emergency room visits. Our study aimed to determine the clinical profile of patients referred with hypertensive emergencies. METHODS: We conducted an observational study involving patients aged ≥18 years referred with hypertensive crisis. A diagnosis of hypertensive emergencies was based on a systolic blood pressure (BP) ≥180 mmHg and/or a diastolic BP ≥110 mmHg, with acute hypertension-mediated organ damage (aHMOD). Patients without evidence of aHMOD were considered hypertensive urgencies. Hypertensive disorders of pregnancy and unconscious patients were excluded from the study. RESULTS: Eighty-two patients were included, comprising 66 (80.5%) with hypertensive emergencies and 16 (19.5%) with hypertensive urgencies. The mean age of patients with hypertensive emergencies was 47.9 (13.2) years, and 66.7% were males. Age, systolic BP, and duration of hypertension were similar in the hypertensive crisis cohort. Most patients with hypertensive emergencies reported nonadherence to medication (78%) or presented de novo without a prior diagnosis of hypertension (36%). Cardiac aHMOD (acute pulmonary edema and myocardial infarction) occurred in 66%, while neurological emergencies (intracranial hemorrhage, ischemic stroke, and hypertensive encephalopathy) occurred in 33.3%. Lactate dehydrogenase (LDH) (P < 0.001), NT-proBNP (P=0.024), and cardiac troponin (P<0.001) were higher in hypertensive emergencies compared to urgencies. LDH did not differ in the subtypes of hypertensive emergencies. CONCLUSION: Cardiovascular and neurological emergencies are the most common hypertensive emergencies. Most patients reported nonadherence to medication or presented de novo without a prior diagnosis of hypertension.

A retrospective audit of young adults who received permanent pacemakers at a teaching hospital in the Western Cape, South Africa.

Introduction: While most pacemaker implantations occur in older individuals, younger patients also receive pacemakers. In these, degenerative conduction system disease is less likely to be the cause of atrioventricular block (AVB), with other diseases being more common. There is, however, a paucity of data on this group as well as on younger pacemaker recipients that have undergone pacemaker implantation for reasons other than AVB. The aim of this study was to perform an audit of young adult permanent pacemaker recipients. Method: This was a retrospective record review, conducted in the Division of Cardiology at Tygerberg Hospital, Cape Town, South Africa. We included 169 adult patients between the ages of 18 and 60, who received permanent pacemakers between 2010 and 2020. A subgroup analysis of patients 55 years and younger was also performed. Results: Third degree AVB was the most common indication for pacemaker implantation (n = 115; 68%), followed by high degree AVB (n = 23; 13.6%) and sick sinus syndrome (SSS; n = 14; 8.3%). A specific underlying cause for conduction system abnormalities was found in only 25.4% of patients (n = 43), with most of them being 55 years or younger (n = 32; 30.8% of patients ≤ 55 years). Specific causes that were identified included prosthetic valve implantation and/or valve repair (n = 14; 8.3%), myocardial infarction (n = 6; 3.6%), cardiac sarcoidosis (n = 5; 3.0%), coronary artery bypass grafting (n = 3; 1.8%), cardiomyopathy (n = 2; 1.2%), muscular dystrophy (n = 2; 1.2%), congenital heart disease (ventricular septal defect; atrioventricular septal defect; Tetralogy of Fallot; bicuspid aortic valve; n = 6; 3.6%), acute myocarditis (n = 1; 0.6%), atrial myxoma removal (n = 1; 0.6%), planned AV node ablation (n = 2; 1.2%), and following a previous stab in the chest (n = 1; 0.6%). Conclusion: Given that the mean age of our study population was high, the low number of identified underlying causes in the whole cohort (≤60 years) may reflect some AVB due to age related degeneration of the conductions system in the patients 56 to 60 years age, but also raises the possibility that these patients may be less likely to be extensively investigated for an underlying cause than those ≤55 years, where diseases such as sarcoidosis were more readily confirmed. As access to advanced diagnostic tools improves, the percentage of young pacemaker recipients with an underlying cause identified may increase.

Myocardial Tissue Characterization in Patients with Hypertensive Crisis, Positive Troponin, and Unobstructed Coronary Arteries: A Cardiovascular Magnetic Resonance-Based Study.

Hypertensive crisis can present with cardiac troponin elevation and unobstructed coronary arteries. We used cardiac magnetic resonance (CMR) imaging to characterize the myocardial tissue in patients with hypertensive crisis, elevated cardiac troponin, and unobstructed coronary arteries. Patients with hypertensive crisis and elevated cardiac troponin with coronary artery stenosis <50% were enrolled. Patients with troponin-negative hypertensive crisis served as controls. All participants underwent CMR imaging at 1.5 Tesla. Imaging biomarkers and tissue characteristics were compared between the groups. There were 19 patients (63% male) with elevated troponin and 24 (33% male) troponin-negative controls. The troponin-positive group was older (57 ± 11 years vs. 47 ± 14 years, p = 0.015). The groups had similar T2-weighted signal intensity ratios and native T1 times. T2 relaxation times were longer in the troponin-positive group, and the difference remained significant after excluding infarct-pattern late gadolinium enhancement (LGE) from the analysis. Extracellular volume (ECV) was higher in the troponin-positive group (25 ± 4 ms vs. 22 ± 3 ms, p = 0.008) and correlated strongly with T2 relaxation time (rs = 0.701, p = 0.022). Late gadolinium enhancement was 32% more prevalent in the troponin-positive group (82% vs. 50%, p = 0.050), with 29% having infarct-pattern LGE. T2 relaxation time was independently associated with troponin positivity (OR 2.1, p = 0.043), and both T2 relaxation time and ECV predicted troponin positivity (C-statistics: 0.71, p = 0.009; and 0.77, p = 0.006). Left ventricular end-diastolic and left atrial volumes were the strongest predictors of troponin positivity (C-statistics: 0.80, p = 0.001; and 0.82, p < 0.001). The increased T2 relaxation time and ECV and their significant correlation in the troponin-positive group suggest myocardial injury with oedema, while the non-ischaemic LGE could be due to myocardial fibrosis or acute necrosis. These CMR imaging biomarkers provide important clinical indices for risk stratification and prognostication in patients with hypertensive crisis.

Cardiac Morphology, Function, and Left Ventricular Geometric Pattern in Patients with Hypertensive Crisis: A Cardiovascular Magnetic Resonance-Based Study.

(1) Background: Altered cardiac morphology and function are associated with increased risks of adverse cardiac events in hypertension. Our study aimed to assess left ventricular (LV) morphology, geometry, and function using cardiovascular magnetic resonance (CMR) imaging in patients with hypertensive crisis. (2) Methods: Patients with hypertensive crisis underwent CMR imaging at 1.5 Tesla to assess cardiac volume, mass, function, and contrasted study. Left ventricular (LV) function and geometry were defined according to the guideline recommendations. Late gadolinium enhancement (LGE) was qualitatively assessed and classified into ischemic and nonischemic patterns. Predictors of LGE was determined using regression analysis. (3) Results: Eighty-two patients with hypertensive crisis (aged 48.5 ± 13.4 years, and 57% males) underwent CMR imaging. Of these patients, seventy-eight percent were hypertensive emergency and twenty-two percent were urgency. Diastolic blood pressure was higher under hypertensive emergency (p = 0.032). Seventy-nine percent (92% of emergency vs. 59% of urgency, respectively; p = 0.003) had left ventricular hypertrophy (LVH). The most prevalent LV geometry was concentric hypertrophy (52%). Asymmetric LVH occurred in 13 (22%) of the participants after excluding ischemic LGE. Impaired systolic function occurred in 46% of patients, and predominantly involved hypertensive emergency. Nonischemic LGE occurred in 75% of contrasted studies (67.2% in emergency versus 44.4% in urgency, respectively; p < 0.001). Creatinine and LV mass were independently associated with nonischemic LGE. (5) Conclusion: LVH, altered geometry, asymmetric LVH, impaired LV systolic function, and LGE are common under hypertensive crisis. LVH and LGE more commonly occurred under hypertensive emergency. Longitudinal studies are required to determine the prognostic implications of asymmetric LVH and LGE in hypertensive crisis.

Transcatheter heart valve interventions for patients with rheumatic heart disease.

Rheumatic heart disease [RHD] is the most prevalent cause of valvular heart disease in the world, outstripping degenerative aortic stenosis numbers fourfold. Despite this, global resources are firmly aimed at improving the management of degenerative disease. Reasons remain complex and include lack of resources, expertise, and overall access to valve interventions in developing nations, where RHD is most prevalent. Is it time to consider less invasive alternatives to conventional valve surgery? Several anatomical and pathological differences exist between degenerative and rheumatic valves, including percutaneous valve landing zones. These are poorly documented and may require dedicated solutions when considering percutaneous intervention. Percutaneous balloon mitral valvuloplasty (PBMV) is the treatment of choice for severe mitral stenosis (MS) but is reserved for patients with suitable valve anatomy without significant mitral regurgitation (MR), the commonest lesion in RHD. Valvuloplasty also rarely offers a durable solution for patients with rheumatic aortic stenosis (AS) or aortic regurgitation (AR). MR and AR pose unique challenges to successful transcatheter valve implantation as landing zone calcification, so central in docking transcatheter aortic valves in degenerative AS, is often lacking. Surgery in young RHD patients requires mechanical prostheses for durability but morbidity and mortality from both thrombotic complications and bleeding on Warfarin remains excessively high. Also, redo surgery rates are high for progression of aortic valve disease in patients with prior mitral valve replacement (MVR). Transcatheter treatments may offer a solution to anticoagulation problems and address reoperation in patients with prior MVR or failing ventricles, but would have to be tailored to the rheumatic environment. The high prevalence of MR and AR, lack of calcification and other unique anatomical challenges remain. Improvements in tissue durability, the development of novel synthetic valve leaflet materials, dedicated delivery systems and docking stations or anchoring systems to securely land the transcatheter devices, would all require attention. We review the epidemiology of RHD and discuss anatomical differences between rheumatic valves and other pathologies with a view to transcatheter solutions. The shortcomings of current RHD management, including current transcatheter treatments, will be discussed and finally we look at future developments in the field.

Exploring the mechanisms responsible for reduced systolic function in high-gradient aortic stenosis.

OBJECTIVE: To characterise the mechanics responsible for the reduced ejection fraction (rEF) in high-gradient severe aortic stenosis (AS). METHODS: 21 patients with high-gradient severe AS (aortic valve area (AVA) <1.0 cm2 and mean gradient (MG) >40 mm Hg) were included. They included 9 patients with rEF (EF <50%) and 12 with preserved ejection fraction (pEF) (EF >50%). Valve area and MG were assessed echocardiographically, and myocardial fibrosis was quantified using MRI. Load-independent measures of intrinsic contractility was assessed with pressure-volume haemodynamics. RESULTS: 80% of the cohort was female, with a mean age of 64 years. Patients were matched for age, sex and body surface area. Load-independent contractile function was similar between the rEF and pEF groups: preload recruitable stroke work slope (101 vs 112 mm Hg; p=0.65), end-systolic pressure-volume relationship slope (1.91 vs 1.28 mmHg/mL; p=0.07) and Starling Contractile Index slope (3.47 vs 7.96 mm Hg/mL/s; p=0.31). End-systolic wall stress and valvuloarterial impedance were higher in cases with rEF (150 vs 83.5 N/cm2; p<0.01 and 4.8 vs 3.4 mm Hg/mL; p=0.05), driven by higher degrees of valvular stenosis (valve area 0.46 vs 0.78 cm2; p<0.01). The rEF group was more symptomatic (New York Heart Association 3.3 vs 2.3; p=0.02), with higher pulmonary pressures (50 vs 30 mm Hg; p=0.04) and more fibrosis (24% vs 13% of left ventricular mass; p=0.03). CONCLUSION: The pathophysiological problem in patients with high-gradient AS with rEF relates to an excessively increased afterload due to more severe valvular stenosis, with preserved intrinsic contractile function. Myocardial fibrosis in the rEF group did not translate into worse muscle function.

In-silico modelling of the impact of hypertension on the mean transvalvular gradients in aortic stenosis.

INTRODUCTION: The influence of hypertension on the diagnostic assessment of aortic stenosis (AS) severity is unclear, yet clinically relevant. To clarify the effect of hypertension on transvalvular gradients, requires a better understanding of the impact that blood pressure change has on mean flow rate. Also, the effect of various degrees of AS severity, the valve geometry and intrinsic left ventricular contractile function (elastance) on this interaction, needs to be clarified. The current work aims to assess this interaction and the magnitude of these effects. METHODS: A validated, zero-dimensional electro-hydraulic analogue computer model of the human cardiovascular circulatory system was generated. It was used to assess the impact of blood pressure changes on left ventricular pressure and transvalvular gradients at various flow rates, left ventricular elastances, a range of aortic valve areas and for different aortic valve morphologies. RESULTS AND DISCUSSION: The magnitude of the impact of hypertension induced changes on the mean gradient (MG) is influenced by the mean flow rate, the AS severity, the hydraulic effective valve orifice area and the left ventricular elastance. Generally, for a given change in systemic arterial pressure, the impact on MG will be the most marked for lower flow rate states such as is expected in more severe degrees of AS, for worse intrinsic left ventricular (LV) contractility, shorter ejection times and lower end diastolic LV volumes. Given the above conditions, the magnitude of the effect will be more for a larger aortic sinus diameter, and also for a typical degenerative valve morphology compared to a typical rheumatic valve morphology. CONCLUSION: The interaction between hypertension and mean gradients in AS is complex. The current work places previous recommendations in perspective by quantifying the magnitude of the effect that the changes in blood pressure has on mean gradient in various pathophysiological states. The work creates a framework for the parameters that should be considered in future clinical research on the topic.

The Role of Cardiac Biomarkers in the Diagnosis of Hypertensive Emergency.

There is a growing interest in the role of biomarkers in differentiating hypertensive emergency from hypertensive urgency. This study aimed to determine the diagnostic utility of lactate dehydrogenase (LDH), high-sensitivity cardiac troponin T (hscTnT), and N-terminal prohormone of brain-type natriuretic peptide (NT-proBNP) for identifying hypertensive emergency. A diagnosis of hypertensive emergency was made based on a systolic blood pressure of ≥180 mmHg and/or a diastolic blood pressure of ≥110 mmHg with acute hypertension-mediated organ damage. The predictive value of LDH, hscTnT, NT-proBNP, and models of these biomarkers for hypertensive emergency was determined using the area under the receiver operator characteristic curve (AUC). There were 66 patients (66.7% male) with a hypertensive emergency and 16 (31.3% male) with hypertensive urgency. LDH, NT-proBNP, and hscTnT were significantly higher in hypertensive emergency. Serum LDH > 190 U/L and high creatinine were associated with hypertensive emergency. LDH had an AUC ranging from 0.87 to 0.92 for the spectrum of hypertensive emergencies, while hscTnT had an AUC of 0.82 to 0.92, except for neurological emergencies, in which the AUC was 0.72. NT-proBNP was only useful in predicting acute pulmonary edema (AUC of 0.89). A model incorporating LDH with hscTnT had an AUC of 0.92 to 0.97 for the spectrum of hypertensive emergencies. LDH in isolation or combined with hscTnT correctly identified hypertensive emergency in patients presenting with hypertensive crisis. The routine assessment of these biomarkers has the potential to facilitate the timely identification of hypertensive emergencies, especially in patients with subtle and subclinical target organ injury.

Morpho-mechanistic screening criteria for the echocardiographic detection of rheumatic heart disease.

INTRODUCTION: Screening echocardiography, guided by the current World Heart Federation (WHF) criteria, has important limitations that impede the establishment of large-scale rheumatic heart disease (RHD) control programmes in endemic regions. The criteria misclassify a significant number of normal cases as borderline RHD. Prior attempts to simplify them are limited by incorporation bias due to the lack of an externally validated, accurate diagnostic test for RHD. We set out to assess novel screening criteria designed to avoid incorporation bias and to compare this against the performance of the current WHF criteria. METHODS: The performance of the WHF and the morpho-mechanistic (MM) RHD screening criteria (a novel set of screening criteria that evaluate leaflet morphology, motion and mechanism of regurgitation) as well as a simplified RHD MM 'rule-out' test (based on identifying a predefined sign of anterior mitral valve leaflet restriction for the mitral valve and any aortic regurgitation for the aortic valve) were assessed in two contrasting cohorts: first, a low-risk RHD cohort consisting of children with a very low-risk RHD profile. and second, a composite reference standard (CRS) RHD-positive cohort that was created using a composite of two criteria to ensure a cohort with the highest possible likelihood of RHD. Subjects included in this group required (1) proven, prior acute rheumatic fever and (2) current evidence of predefined valvular regurgitation on echocardiography. RESULTS: In the low-risk RHD cohort (n=364), the screening specificities for detecting RHD of the MM and WHF criteria were 99.7% and 95.9%, respectively (p=0.0002). The MM rule-out test excluded 359/364 cases (98.6%). In the CRS RHD-positive cohort (n=65), the screening sensitivities for the detection of definite RHD by MM and WHF criteria were 92.4% and 89.2%, respectively (p=0.2231). The MM RHD rule-out test did not exclude any cases from the CRS RHD-positive cohort. CONCLUSION: Our proposed MM approach showed an equal sensitivity to the WHF criteria but with significantly improved specificity. The MM RHD rule-out test excluded RHD-negative cases while identifying all cases within the CRS RHD-positive cohort. This holds promise for the development of a two-step RHD screening algorithm to enable task shifting in RHD endemic regions.

Altered cardiac structure and function in newly diagnosed people living with HIV: a prospective cardiovascular magnetic resonance study after the initiation of antiretroviral treatment.

HIV associated cardiomyopathy (HIVAC) is a poorly understood entity that may progress along a continuum. We evaluated a group of persons newly diagnosed with HIV and studied the evolution of cardiac abnormalities after ART initiation. We recruited a group of newly diagnosed, ART naïve persons with HIV and a healthy, HIV uninfected group. Participants underwent comprehensive cardiovascular evaluation, including cardiovascular magnetic resonance imaging. The HIV group was started on ART and re-evaluated 9 months later. The cardiovascular parameters of the study groups were compared at diagnosis and after 9 months. The ART naïve group's (n = 66) left- and right end diastolic volume indexed for height were larger compared with controls (n = 22) (p < 0.03). The left ventricular mass indexed for height was larger in the naïve group compared with controls (p = 0.04). The ART naïve group had decreased left- and right ventricular ejection fraction (p < 0.03) and negative, non-linear associations with high HIV viral load (p = 0.02). The left ventricular size increased after 9 months (p = 0.04), while the systolic function remained unchanged. The HIV group had a high rate of non-resolving pericardial effusions. HIV infected persons demonstrate structurally and functionally altered ventricles at diagnosis. High HIV viral load was associated with left- and right ventricular dysfunction. Cardiac parameters and pericardial effusion prevalence did not show improvement with ART. Conversely, a concerning trend of increase was observed with left ventricular size. These subclinical cardiac abnormalities may represent a stage on the continuum of HIVAC that can progress to symptomatic disease if the causes are not identified and addressed.

The prevalence of pulmonary hypertension after successful tuberculosis treatment in a community sample of adult patients.

There are an estimated 155 million survivors of tuberculosis (TB). Clinical experience suggests that post tuberculosis lung disease (PTLD) is an important cause of Group 3 pulmonary hypertension (PH). However, TB is not listed as a cause of PH in most guidelines. A cross-sectional, community-based study was conducted in nonhealthcare seeking adults who had successfully completed TB treatment. Subjects underwent questionnaires, spirometry, a 6-min walk distance test (6MWD) and transthoracic echocardiography (TTE). Screen probable PH was defined on TTE as an estimated pulmonary artery peak systolic pressure (PASP) of ≥40 mmHg. One hundred adults (71 males) were enrolled, with a mean age of 42 years (SD 13.8 years) and a median of one TB episode (interquartile range: 1-2). Co-morbidities included hypertension (21%), diabetes (16%), human immunodeficiency virus (10%) and asthma/COPD (5%). Only 25% had no residual symptoms after TB. Probable PH was found in 9%, while 7% had borderline raised PASP values (PASP 35-40 mmHg). An association was found between PH and the number of previous TB episodes, with each additional episode of TB increasing the odds of PH-postTB 2.13-fold (confidence interval [CI]: 1.17-3.88; p = 0.013). All of those found to have PH were smokers or ex-smokers yielding an unadjusted odds ratio for PH-postTB of 3.67 (95% CI: 0.77-17.46). There was no statistical difference in spirometry or 6MWD, between those with and without PH. Neither symptoms nor co-morbidities demonstrated significant association with PH. PH after TB was a common finding in this community-based population. Further research is needed to confirm and determine the significance of these findings.

Lupus myocarditis: review of current diagnostic modalities and their application in clinical practice.

Lupus myocarditis (LM) is a potentially fatal manifestation of SLE, occurring in 5-10% of patients. Clinical manifestations may vary from an unexplained tachycardia to fulminant congestive cardiac failure (CCF). With no single clinical or imaging modality being diagnostic, a rational and practical approach to the patient presenting with possible LM is essential. Markers of myocyte injury (including troponin I and creatine kinase) may be unelevated and do not exclude a diagnosis of LM. Findings on ECG are non-specific but remain essential to exclude other causes of CCF such as an acute coronary syndrome or conduction disorders. Echocardiographic modalities including wall motion abnormalities and speckle tracking echocardiography may demonstrate regional and/or global left ventricular dysfunction and is more sensitive than conventional echocardiography, especially early in the course of LM. Cardiac magnetic resonance imaging (CMRI) is regarded as the non-invasive diagnostic modality of choice in myocarditis. While more sensitive and specific than echocardiography, CMRI has certain limitations in the context of SLE, including technical challenges in acutely unwell and uncooperative patients, contraindications to gadolinium use in the context of renal impairment (including lupus nephritis) and limited literature regarding the application of recommended diagnostic CMRI criteria in SLE. Both echocardiography as well as CMRI may detect subclinical myocardial dysfunction and/or injury of which the clinical significance remains uncertain. Considering these challenges, a combined decision-making approach by rheumatologists and cardiologists interpreting diagnostic test results within the clinical context of the patient is essential to ensure an accurate, early diagnosis of LM.

Comparing the findings and diagnostic sensitivity of cardiovascular magnetic resonance in biopsy confirmed acute myocarditis with infarct-like vs. heart failure presentation.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is considered the reference imaging modality in providing a non-invasive diagnosis of acute myocarditis (AM), as it allows for the detection of myocardial injury associated with AM. However, the diagnostic sensitivity and pattern of CMR findings appear to differ according to clinical presentation. METHODS: This is a retrospective cross-sectional study. Consecutive adult patients presenting to a single tertiary centre in South Africa between August 2017 and January 2022 with AM confirmed on endomyocardial biopsy (EMB) were enrolled. Patients with infarct-like symptoms, defined as those presenting primarily with chest pain syndrome with associated ST-T wave changes on electrocardiogram, or heart failure (HF) symptoms, defined as clinical signs and symptoms of HF without significant chest discomfort, were compared using contrasted CMR and parametric techniques with EMB confirmation of AM as diagnostic gold standard. RESULTS: Forty-one patients were identified including 23 (56%) with infarct-like symptoms and 18 (44%) with HF symptoms. On CMR, the infarct-like group had significantly higher ejection fractions of both ventricles (LVEF 55.3 ± 15.3% vs. 34.4 ± 13.5%, p < 0.001; RVEF 57.3 ± 10.9% vs. 42.9 ± 18.2%, p = 0.008), without significant differences in end diastolic volumes (LVEDVI 82.7 ± 30.3 ml/m2 vs. 103.4 ± 35.9 ml/m2, p = 0.06; RVEDVI 73.7 ± 22.1 ml/m2 vs. 83.9 ± 29.9 ml/m2, p = 0.25). Myocardial oedema was detected more frequently on T2-weighted imaging (91.3% vs. 61.1%, p = 0.03) and in more myocardial segments [3.0 (IQR 2.0-4.0) vs. 1.0 (IQR 0-1.0), p = 0.003] in the infarct-like group. Despite the absence of a significant statistical difference in the prevalence of late gadolinium enhancement (LGE) between the two groups (95.7% vs. 72.2%, p = 0.07), the infarct-like group had LGE detectable in significantly more ventricular segments [4.5 (IQR 2.3-6.0) vs. 2.0 (IQR 0-3.3), p = 0.02] and in a different distribution. The sensitivity of the original Lake Louise Criteria (LLC) was 91.3% in infarct-like patients and 55.6% in HF patients. When the updated LLC, which included the use of parametric myocardial mapping techniques, were applied, the sensitivity improved to 95.7% and 72.2% respectively. CONCLUSION: The pattern of CMR findings and its diagnostic sensitivity appears to differ in AM patients presenting with infarct-like and HF symptoms. Although the sensitivity of the LLC improved with the addition of parametric mapping in the HF group, it remained lower than that of the infarct-like group, and suggests that EMB should be considered earlier in the course of patients with clinically suspected AM presenting with HF.

Evolution of myocardial oedema and fibrosis in HIV infected persons after the initiation of antiretroviral therapy: a prospective cardiovascular magnetic resonance study.

BACKGROUND: Human immunodeficiency virus (HIV) infected persons on antiretroviral therapy (ART) have been shown to have functionally and structurally altered ventricles and may be related to cardiovascular inflammation. Mounting evidence suggests that the myocardium of HIV infected individuals may be abnormal before ART is initiated and may represent subclinical HIV-associated cardiomyopathy (HIVAC). The influence of ART on subclinical HIVAC is not known. METHODS: Newly diagnosed, ART naïve persons with HIV infection were enrolled along with HIV uninfected, age- and sex-matched controls. All participants underwent comprehensive cardiovascular assessment, including contrasted cardiovascular magnetic resonance (CMR) with multiparametric mapping on a 1.5T CMR system. The HIV group was started on ART (tenofovir/lamivudine/dolutegravir) and prospectively evaluated 9 months later. Cardiac tissue characterisation was compared in, and between groups using the appropriate statistical tests for the cross sectional data and the paired, prospective data respectively. RESULTS: Seventy-three ART naïve HIV infected individuals (32 ± 7 years, 45% female) and 22 healthy non-HIV subjects (33 ± 7 years, 50% female) were enrolled. Compared with non-HIV healthy subjects, the global native T1 (1008 ± 31 ms vs 1032 ± 44 ms, p = 0.02), global T2 (46 ± 2 vs 48 ± 3 ms, p = 0.006), and the prevalence of pericardial effusion (18% vs 67%, p < 0.001) were significantly higher in the HIV infected group at diagnosis. Global native T1 (1032 ± 44 to 1014 ± 34 ms, p < 0.001) and extracellular volume (ECV) (26 ± 4% to 25 ± 3%, p = 0.001) decreased significantly after 9 months on ART and were significantly associated with a decrease in the HIV viral load, decreased high sensitivity C-reactive protein, and improvement in the CD4 count (p < 0.001). Replacement fibrosis was significantly higher in the HIV infected group than controls (49% vs 10%, p = 0.02). The prevalence of late gadolinium enhancement did not change significantly over the 9-month study period (49% vs 55%, p = 0.4). CONCLUSION: Subclinical HIVAC may already be present at the time of HIV diagnosis, as suggested by the combination of subclinical myocardial oedema and fibrosis found to be present before administration of ART. Markers of myocardial oedema on tissue characterization improved on ART in the short term, however, it is unclear if the underlying pathological mechanism is halted, or merely slowed by ART. Mid- to long term prospective studies are needed to evaluate subtle myocardial changes over time and to assess the significance of subclinical myocardial fibrosis.