Prognostic value of biochemical parameters among severe COVID-19 patients admitted to an intensive care unit of a tertiary hospital in South Africa.

Background: Data on biochemical markers and their association with mortality rates in patients with severe coronavirus disease 2019 (COVID-19) admitted to intensive care units (ICUs) in sub-Saharan Africa are scarce. An evaluation of baseline routine biochemical parameters was performed in COVID-19 patients admitted to the ICU, in order to identify prognostic biomarkers. Methods: Demographic, clinical, and laboratory data were collected prospectively from patients with PCR-confirmed COVID-19 admitted to the adult ICU of a tertiary hospital in Cape Town, South Africa, between October 2020 and February 2021. Robust Poisson regression methods and the receiver operating characteristic (ROC) curve were used to explore the association of biochemical parameters with severity and mortality. Results: A total of 82 patients (median age 53.8 years, interquartile range 46.4-59.7 years) were enrolled, of whom 55 (67%) were female and 27 (33%) were male. The median duration of ICU stay was 10 days (interquartile range 5-14 days); 54/82 patients died (66% case fatality rate). Baseline lactate dehydrogenase (LDH) (adjusted relative risk 1.002, 95% confidence interval 1.0004-1.004; P = 0.016) and N-terminal pro B-type natriuretic peptide (NT-proBNP) (adjusted relative risk 1.0004, 95% confidence interval 1.0001-1.0007; P = 0.014) were both found to be independent risk factors of a poor prognosis, with optimal cut-off values of 449.5 U/l (sensitivity 100%, specificity 43%) and 551 pg/ml (sensitivity 49%, specificity 86%), respectively. Conclusions: LDH and NT-proBNP appear to be promising predictors of a poor prognosis in COVID-19 patients in the ICU. Studies with a larger sample size are required to confirm the validity of this combination of biomarkers.

Clec4e-Receptor Signaling in Myocardial Repair After Ischemia-Reperfusion Injury.

The bacterial C-type lectin domain family 4 member E (CLEC4E) has an important role in sterile inflammation, but its role in myocardial repair is unknown. Using complementary approaches in porcine, murine, and human samples, we show that CLEC4E expression levels in the myocardium and in blood correlate with the extent of myocardial injury and left ventricular (LV) functional impairment. CLEC4E expression is markedly increased in the vasculature, cardiac myocytes, and infiltrating leukocytes in the ischemic heart. Loss of Clec4e signaling is associated with reduced acute cardiac injury, neutrophil infiltration, and infarct size. Reduced myocardial injury in Clec4e -/- translates into significantly improved LV structural and functional remodeling at 4 weeks' follow-up. The early transcriptome of LV tissue from Clec4e -/- mice versus wild-type mice reveals significant upregulation of transcripts involved in myocardial metabolism, radical scavenging, angiogenesis, and extracellular matrix organization. Therefore, targeting CLEC4E in the early phase of ischemia-reperfusion injury is a promising therapeutic strategy to modulate myocardial inflammation and enhance repair after ischemia-reperfusion injury.

Reversible Myocardial Injury Associated With SARS-CoV-2 in an Infant.

Coronavirus disease-2019 is caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and has been associated with myocardial dysfunction and heart failure in adult patients. We report a case of reversible myocardial injury and heart failure in an infant with SARS-CoV-2 infection. (Level of Difficulty: Intermediate.).

Coronavirus disease 2019 and cardiovascular system: A narrative review.

At the end of 2019, a viral pneumonia disease called coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV2), emerged in Wuhan, China. This novel disease rapidly spread at an alarming rate that as a result, it has now been declared pandemic by the World Health Organization. Although this infective disease is mostly characterized by respiratory tract symptoms, increasing numbers of evidence had shown considerable amounts of patients with cardiovascular involvements and these were associated with higher mortality among COVID-19 patients. Cardiac involvement as a possible late phenomenon of the viral respiratory infection is an issue that should be anticipated in patients with COVID-19. Cardiovascular manifestation in COVID-19 patients include myocardial injury (MI), arrhythmias, cardiac arrests, heart failure and coagulation abnormality, ranging from 7.2% up to 33%. The mechanism of cardiac involvement in COVID-19 patients involves direct injury to myocardial cells mediated by angiotensin-converting enzyme 2 (ACE2) receptors as suggested by some studies, while the other studies suggest that systemic inflammation causing indirect myocyte injury may also play a role. Combination of proper triage, close monitoring, and avoidance of some drugs that have cardiovascular toxicity are important in the management of cardiovascular system involvement in COVID-19 patients. The involvement of the cardiovascular system in COVID-19 patients is prevalent, variable, and debilitating. Therefore, it requires our attention and comprehensive management.

An IL-6-IL-8 score derived from principal component analysis is predictive of adverse outcome in acute myocardial infarction.

INTRODUCTION: Many studies have shown that elevated biomarkers of inflammation following acute myocardial infarction (AMI) are associated with major adverse cardiovascular events (MACE). However, the optimal way of measuring the complex inflammatory response following AMI has not been determined. In this study we explore the use of principal component analysis (PCA) utilising multiple inflammatory cytokines to generate a combined cytokine score that may be predictive of MACE post-AMI. METHODS: Thirteen inflammatory cytokines were measured in plasma of 317 AMI patients, drawn 48-72 h following symptom onset. Patients were followed-up for one year to determine the incidence of MACE. PCA was used to generate a combined score using six cytokines that were detectable in the majority of patients (IL-1ß, -6, -8, and -10; MCP-1; and RANTES), and using a subset of cytokines that were associated with MACE on univariate analysis. Multivariate models using baseline characteristics, elevated individual cytokines and PCA-derived scores determined independent predictors of MACE. RESULTS: IL-6 and IL-8 were significantly associated with MACE on univariate analysis and were combined using PCA into an IL-6-IL-8 score. The combined cytokine score and IL-6-IL-8 PCA-derived score were both significantly associated with MACE on univariate analysis. In multivariate models IL-6-IL-8 scores (OR = 2.77, p = 0.007) and IL-6 levels (OR = 2.18, p = 0.035) were found to be independent predictors of MACE. CONCLUSION: An IL-6-IL-8 score derived from PCA was found to independently predict MACE at one year and was a stronger predictor than any individual cytokine, which suggests this may be an appropriate strategy to quantify inflammation post-AMI. Further investigation is required to determine the optimal set of cytokines to measure in this context.

Matrix Signaling Subsequent to a Myocardial Infarction: A Proteomic Profile of Tissue Factor Microparticles.

This study investigated the release and proteomic profile of tissue factor microparticles (TFMPs) prospectively (up to 6 months) following a myocardial infarction (MI) in a chronic porcine model to establish their utility in tracking cellular level activities that predict physiologic outcomes. Our animal groups (n = 6 to 8 each) consisted of control, noninfarcted (negative control); infarcted only (positive control); and infarcted animals treated with cardiac resynchronization therapy (CRT) and a ß-blocker (BB) (metoprolol succinate). The authors found different protein profiles in TFMPs between the control, infarcted only group, and the CRT + BB treated group with predictive impact on the outward phenotype of pathological remodeling after an MI within and between groups. This novel approach of monitoring cellular level activities by profiling the content of TFMPs has the potential of addressing a shortfall of the current crop of cardiac biomarkers, which is the inability to capture composite molecular changes associated with chronic maladaptive signaling in a spatial and temporal manner.

Distinct conformational and functional effects of two adjacent pathogenic mutations in cardiac troponin I at the interface with troponin T.

The α-helix in troponin I (TnI) at the interface with troponin T (TnT) is a highly conserved structure. A point mutation in this region, A116G, was found in human cardiac TnI in a case of cardiomyopathy. An adjacent dominantly negative mutation found in turkey cardiac TnI (R111C, equivalent to K117C in human and K118C in mouse) decreased diastolic function and blunted beta-adrenergic response in transgenic mice. To investigate the functional importance of the TnI-TnT interface and pathological impact of the cardiac TnI mutations, we engineered K118C and A117G mutations in mouse cardiac TnI for functional studies. Despite their adjacent locations, A117G substitution results in faster mobility of cardiac TnI in SDS-PAGE whereas K118C decreases gel mobility, indicating significant and distinct changes in overall protein conformation. Consistently, monoclonal antibody epitope analysis demonstrated distinct local and remote conformational alterations in the two mutant proteins. Protein binding assays showed that K118C, but not A117G, decreased the relative binding affinity of cardiac TnI for TnT. K118C mutation decreased binding affinity for troponin C in a Ca(2+)-dependent manner, whereas A117G had a similar but less profound effect. Protein kinase A phosphorylation or truncation to remove the cardiac specific N-terminal extension of cardiac TnI resulted in similar conformational changes in the region interfacing with TnT and minimized the functional impacts of the mutations. The data demonstrate potent conformational and functional impacts of the TnT-interfacing helix in TnI and suggest a role of the N-terminal extension of cardiac TnI in modulating TnI-TnT interface functions.

Up-regulation of alpha-smooth muscle actin in cardiomyocytes from non-hypertrophic and non-failing transgenic mouse hearts expressing N-terminal truncated cardiac troponin I.

We previously reported that a restrictive N-terminal truncation of cardiac troponin I (cTnI-ND) is up-regulated in the heart in adaptation to hemodynamic stresses. Over-expression of cTnI-ND in the hearts of transgenic mice revealed functional benefits such as increased relaxation and myocardial compliance. In the present study, we investigated the subsequent effect on myocardial remodeling. The alpha-smooth muscle actin (α-SMA) isoform is normally expressed in differentiating cardiomyocytes and is a marker for myocardial hypertrophy in adult hearts. Our results show that in cTnI-ND transgenic mice of between 2 and 3 months of age (young adults), a significant level of α-SMA is expressed in the heart as compared with wild-type animals. Although blood vessel density was increased in the cTnI-ND heart, the mass of smooth muscle tissue did not correlate with the increased level of α-SMA. Instead, immunocytochemical staining and Western blotting of protein extracts from isolated cardiomyocytes identified cardiomyocytes as the source of increased α-SMA in cTnI-ND hearts. We further found that while a portion of the up-regulated α-SMA protein was incorporated into the sarcomeric thin filaments, the majority of SMA protein was found outside of myofibrils. This distribution pattern suggests dual functions for the up-regulated α-SMA as both a contractile component to affect contractility and as possible effector of early remodeling in non-hypertrophic, non-failing cTnI-ND hearts.