The Usefulness of the C2HEST Score in Predicting the Clinical Outcomes of COVID-19 in COPD and Non-COPD Cohorts.

Patients with chronic obstructive pulmonary disease (COPD) infected with SARS-CoV-2 indicate a higher risk of severe COVID-19 course, which is defined as the need for hospitalization in the intensive care unit, mechanical ventilation, or death. However, simple tools to stratify the risk in patients with COPD suffering from COVID-19 are lacking. The current study aimed to evaluate the predictive value of the C2HEST score in patients with COPD. A retrospective analysis of medical records from 2184 patients hospitalized with COVID-19 at the University Hospital in Wroclaw from February 2020 to June 2021, which was previously used in earlier studies, assessed outcomes such as mortality during hospitalization, all-cause mortality at 3 and 6 months, non-fatal discharge, as well as adverse clinical incidents. This re-analysis specifically examines the outcomes using a COPD split. In the COPD group, 42 deaths were recorded, including 18 in-hospital deaths. In-hospital mortality rates at 3 and 6 months did not significantly differ among C2HEST strata, nor did their impact on subsequent treatment. However, a notable association between the C2HEST score and prognosis was observed in the non-COPD cohort comprising 2109 patients. The C2HEST score's predictive ability is notably lower in COPD patients compared to non-COPD subjects, with COPD itself indicating a high mortality risk. However, C2HEST effectively identifies patients at high risk of cardiac complications during COVID-19, especially in non-COPD cases.

The Usefulness of the C2HEST Risk Score in Predicting Clinical Outcomes among Hospitalized Subjects with COVID-19 and Coronary Artery Disease.

BACKGROUND: Even though coronary artery disease (CAD) is considered an independent risk factor of an unfavorable outcome of SARS-CoV-2-infection, the clinical course of COVID-19 in subjects with CAD is heterogeneous, ranging from clinically asymptomatic to fatal cases. Since the individual C2HEST components are similar to the COVID-19 risk factors, we evaluated its predictive value in CAD subjects. MATERIALS AND METHODS: In total, 2183 patients hospitalized due to confirmed COVID-19 were enrolled onto this study consecutively. Based on past medical history, subjects were assigned to one of two of the study arms (CAD vs. non-CAD) and allocated to different risk strata, based on the C2HEST score. RESULTS: The CAD cohort included 228 subjects, while the non-CAD cohort consisted of 1956 patients. In-hospital, 3-month and 6-month mortality was highest in the high-risk C2HEST stratum in the CAD cohort, reaching 43.06%, 56.25% and 65.89%, respectively, whereas in the non-CAD cohort in the high-risk stratum, it reached: 26.92%, 50.77% and 64.55%. Significant differences in mortality between the C2HEST stratum in the CAD arm were observed in post hoc analysis only for medium- vs. high-risk strata. The C2HEST score in the CAD cohort could predict hypovolemic shock, pneumonia and acute heart failure during hospitalization, whereas in the non-CAD cohort, it could predict cardiovascular events (myocardial injury, acute heart failure, myocardial infract, carcinogenic shock), pneumonia, acute liver dysfunction and renal injury as well as bleedings. CONCLUSIONS: The C2HEST score is a simple, easy-to-apply tool which might be useful in risk stratification, preferably in non-CAD subjects admitted to hospital due to COVID-19.

Liver Function Tests in COVID-19: Assessment of the Actual Prognostic Value.

Deviations in laboratory tests assessing liver function in patients with COVID-19 are frequently observed. Their importance and pathogenesis are still debated. In our retrospective study, we analyzed liver-related parameters: aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), total bilirubin (TBIL), albumin, comorbidities and other selected potential risk factors in patients admitted with SARS-CoV-2 infection to assess their prognostic value for intensive care unit admission, mechanical ventilation necessity and mortality. We compared the prognostic effectiveness of these parameters separately and in pairs to the neutrophil-to-lymphocyte ratio (NLR) as an independent risk factor of in-hospital mortality, using the Akaike Information Criterion (AIC). Data were collected from 2109 included patients. We created models using a sample with complete laboratory tests n = 401 and then applied them to the whole studied group excluding patients with missing singular variables. We estimated that albumin may be a better predictor of the COVID-19-severity course compared to NLR, irrespective of comorbidities (p < 0.001). Additionally, we determined that hypoalbuminemia in combination with AST (OR 1.003, p = 0.008) or TBIL (OR 1.657, p = 0.001) creates excellent prediction models for in-hospital mortality. In conclusion, the early evaluation of albumin levels and liver-related parameters may be indispensable tools for the early assessment of the clinical course of patients with COVID-19.

Usefulness of C2HEST Score in Predicting Clinical Outcomes of COVID-19 in Heart Failure and Non-Heart-Failure Cohorts.

Background: Patients with heart failure represent a vulnerable population for COVID-19 and are prone to having worse prognoses and higher fatality rates. Still, the clinical course of the infection is dynamic, and complication occurrence in particular in patients with heart failure is fairly unpredictable. Considering that individual components of the C2HEST (C2: Coronary Artery Diseases (CAD)/Chronic obstructive pulmonary disease (COPD); H: Hypertension; E: Elderly (Age ≥ 75); S: Systolic HF; T: Thyroid disease) are parallel to COVID-19 mortality risk factors, we evaluate the predictive value of C2HEST score in patients with heart failure (HF) Material and Methods: The retrospective medical data analysis of 2184 COVID-19 patients hospitalized in the University Hospital in Wroclaw between February 2020 and June 2021 was the basis of the study. The measured outcomes included: in-hospital mortality, 3-month and 6-month all-cause-mortality, non-fatal end of hospitalization, and adverse in-hospital clinical events. Results: The heart failure cohort consists of 255 patients, while 1929 patients were assigned to the non-HF cohort. The in-hospital, 3-month, and 6-month mortality rates were highest in the HF cohort high-risk C2HEST stratum, reaching 38.61%, 53.96%, and 65.36%, respectively. In the non-HF cohort, in-hospital, 3-month, and 6-month mortalities were also highest in the high-risk C2HEST stratum and came to 26.39%, 52.78%, and 65.0%, respectively. An additional point in the C2HEST score increased the total death intensity in 10% of HF subjects (HR 1.100, 95% CI 0.968−1.250 p = 0.143) while in the non-HF cohort, the same value increased by 62.3% (HR 1.623, 95% CI 1.518−1.734 p < 0.0001). Conclusions: The C2HEST score risk in the HF cohort failed to show discriminatory performance in terms of mortality and other clinical adverse outcomes during hospitalization. C2HEST score in the non-HF cohort showed significantly better performance in terms of predicting in-hospital and 6-month mortality and other non-fatal clinical outcomes such as cardiovascular events (myocardial injury, acute heart failure, myocardial infarction, cardiogenic shock), pneumonia, sepsis, and acute renal injury.

Role of Erythrocytes in Nitric Oxide Metabolism and Paracrine Regulation of Endothelial Function.

Emerging studies provide new data shedding some light on the complex and pivotal role of red blood cells (RBCs) in nitric oxide (NO) metabolism and paracrine regulation of endothelial function. NO is involved in the regulation of vasodilatation, platelet aggregation, inflammation, hypoxic adaptation, and oxidative stress. Even though tremendous knowledge about NO metabolism has been collected, the exact RBCs' status still requires evaluation. This paper summarizes the actual knowledge regarding the role of erythrocytes as a mobile depot of amino acids necessary for NO biotransformation. Moreover, the complex regulation of RBCs' translocases is presented with a particular focus on cationic amino acid transporters (CATs) responsible for the NO substrates and derivatives transport. The main part demonstrates the intraerythrocytic metabolism of L-arginine with its regulation by reactive oxygen species and arginase activity. Additionally, the process of nitrite and nitrate turnover was demonstrated to be another stable source of NO, with its reduction by xanthine oxidoreductase or hemoglobin. Additional function of hemoglobin in NO synthesis and its subsequent stabilization in steady intermediates is also discussed. Furthermore, RBCs regulate the vascular tone by releasing ATP, inducing smooth muscle cell relaxation, and decreasing platelet aggregation. Erythrocytes and intraerythrocytic NO metabolism are also responsible for the maintenance of normotension. Hence, RBCs became a promising new therapeutic target in restoring NO homeostasis in cardiovascular disorders.

Sex-Dependent Differences in Predictive Value of the C2HEST Score in Subjects with COVID-19-A Secondary Analysis of the COLOS Study.

Background: Since the outbreak of the COVID-19 pandemic, a growing number of evidence suggests that COVID-19 presents sex-dependent differences in clinical course and outcomes. Nevertheless, there is still an unmet need to stratify the risk for poor outcome at the beginning of hospitalization. Since individual C2HEST components are similar COVID-19 mortality risk factors, we evaluated sex-related predictive value of the score. Material and Methods: A total of 2183 medical records of consecutive patients hospitalized due to confirmed SARS-CoV-2 infections were analyzed. Subjects were assigned to one of two of the study arms (male vs. female) and afterward allocated to different stratum based on the C2HEST score result. The measured outcomes included: in-hospital-mortality, three-month- and six-month-all-cause-mortality and in-hospital non-fatal adverse clinical events. Results: The C2HEST score predicted the mortality with better sensitivity in female population regarding the short- and mid-term. Among secondary outcomes, C2HEST-score revealed predictive value in both genders for pneumonia, myocardial injury, myocardial infarction, acute heart failure, cardiogenic shock, and acute kidney injury. Additionally in the male cohort, the C2HEST value predicted acute liver dysfunction and all-cause bleeding, whereas in the female arm-stroke/TIA and SIRS. Conclusion: In the present study, we demonstrated the better C2HEST-score predictive value for mortality in women and illustrated sex-dependent differences predicting non-fatal secondary outcomes.

Mortality Predictive Value of the C2HEST Score in Elderly Subjects with COVID-19-A Subanalysis of the COLOS Study.

Senility has been identified among the strongest risk predictors for unfavorable COVID-19-outcome. However, even in the elderly population, the clinical course of infection in individual patients remains unpredictable. Hence, there is an urgent need for developing a simple tool predicting adverse COVID-19-outcomes. We assumed that the C2HEST-score could predict unfavorable clinical outcomes in the elderly subjects with COVID-19-subjects. METHODS: We retrospectively analyzed 1047 medical records of patients at age > 65 years, hospitalized at the medical university center due to COVID-19. Subsequently, patients were divided into three categories depending on their C2HEST-score result. RESULTS: We noticed significant differences in the in-hospital and 3-month and 6-month mortality-which was the highest in high-risk-C2HEST-stratum reaching 35.7%, 54.4%, and 65.9%, respectively. The medium-risk-stratum mortalities reached 24.1% 43.4%, and 57.6% and for low-risk-stratum 14.4%, 25.8%, and 39.2% respectively. In the C2HEST-score model, a change from the low to the medium category increased the probability of death intensity approximately two-times. Subsequently, transfer from the low-risk to the high-risk-stratum raised all-cause-death-intensity 2.7-times. Analysis of the secondary outcomes revealed that the C2HEST-score has predictive value for acute kidney injury, acute heart failure, and cardiogenic shock. CONCLUSIONS: C2HEST-score analysis on admission to the hospital may predict the mortality, acute kidney injury, and acute heart failure in elderly subjects with COVID-19.

Usefulness of the C2HEST Score in Predicting the Clinical Outcomes of COVID-19 in Diabetic and Non-Diabetic Cohorts.

BACKGROUND: Diabetes mellitus is among the most frequent comorbidities worsening COVID-19 outcome. Nevertheless, there are no data regarding the optimal risk stratification of patients with diabetes and COVID-19. Since individual C2HEST components reflect the comorbidities, we assumed that the score could predict COVID-19 outcomes. MATERIAL AND METHODS: A total of 2184 medical records of patients hospitalized for COVID-19 at the medical university center were analyzed, including 473 diabetic patients and 1666 patients without any glucose or metabolic abnormalities. The variables of patients' baseline characteristics were retrieved to calculate the C2HEST score and subsequently the diabetic and non-diabetic subjects were assigned to the following categories: low-, medium- or high-risk. The measured outcomes included: in-hospital mortality; 3-month and 6-month all-cause mortality; non-fatal end of hospitalization (discharged home/sudden-deterioration/rehabilitation) and adverse in-hospital clinical events. RESULTS: A total of 194 deaths (41%) were reported in the diabetic cohort, including 115 in-hospital deaths (24.3%). The 3-month and 6-month in-hospital mortality was highest in the high-risk C2HEST stratum. The C2HEST score revealed to be more sensitive in non-diabetic-group. The estimated six-month survival probability for high-risk subjects reached 0.4 in both cohorts whereas for the low-risk group, the six-month survival probability was 0.7 in the diabetic vs. 0.85 in the non-diabetic group-levels which were maintained during whole observation period. In both cohorts, receiver operating characteristics revealed that C2HEST predicts the following: cardiogenic shock; acute heart failure; myocardial injury; and in-hospital acute kidney injury. CONCLUSIONS: We demonstrated the usefulness and performance of the C2HEST score in predicting the adverse COVID-19 outcomes in hospitalized diabetic subjects.

Anticoagulation Prior to COVID-19 Infection Has No Impact on 6 Months Mortality: A Propensity Score-Matched Cohort Study.

The coronavirus disease 2019 (COVID-19) shows high incidence of thromboembolic events in humans. In the present study, we aimed to evaluate if anticoagulation prior to COVID-19 infection may impact clinical profile, as well as mortality rate among patients hospitalized with COVID-19. The study was based on retrospective analysis of medical records of patients with laboratory confirmed SARS-CoV-2 infection. After propensity score matching (PSM), a group of 236 patients receiving any anticoagulant treatment prior to COVID-19 infection (AT group) was compared to 236 patients without previous anticoagulation (no AT group). In 180 days, the observation we noted comparable mortality rate in AT and no AT groups (38.5% vs. 41.1%, p = 0.51). Similarly, we did not observe any statistically significant differences in admission in the intensive care unit (14.1% vs. 9.6%, p = 0.20), intubation and mechanical ventilation (15.0% vs. 11.6%, p = 0.38), catecholamines usage (14.3% vs. 13.8%, p = 0.86), and bleeding rate (6.3% vs. 8.9%, p = 0.37) in both groups. Our results suggest that antithrombotic treatment prior to COVID-19 infection is unlikely to be protective for morbidity and mortality in patients hospitalized with COVID-19.

A Cross-Talk between the Erythrocyte L-Arginine/ADMA/Nitric Oxide Metabolic Pathway and the Endothelial Function in Subjects with Type 2 Diabetes Mellitus.

(1) Background: Type-2-diabetes-mellitus (DM) is one the most important cardiovascular-risk-factors. Among many molecules regulating vascular tone, nitric oxide appears to be the most pivotal. Although micro- and macrovascular-abnormalities are extensively studied, the alterations in the nitric-oxide-metabolic-pathway require further investigations. Additionally, the role of erythrocytes in the vascular tone regulation has not been extensively explored. The aim of this study was to evaluate the endothelial-function and the nitric-oxide-metabolic-pathway in erythrocytes and plasma of diabetic individuals. (2) Methods: A total of 80 subjects were enrolled in this cross-sectional study, including 35 patients with DM and 45 healthy individuals. The endothelial-function was evaluated in response to different stimuli. (3) Results: In the DM group, decreased Arginine and citrulline concentrations in the plasma compartment with reduced Arginine/ADMA and ADMA/DMA-ratios were observed. Preserved nitric-oxide-metabolism in erythrocytes with reduced citrulline level and significantly higher NO-bioavailability were noted. Significant endothelial dysfunction in DM individuals was proved in response to the heat-stimulus. (4) Conclusions: DM patients at an early stage of disease show significant differences in the nitric-oxide-metabolic-pathway, which are more pronounced in the plasma compartment. Erythrocytes constitute a buffer with a higher nitric-oxide-bioavailability, less affected by the DM-related deviations. Patients at an early-stage of DM reveal endothelial-dysfunction, which could be diagnosed earlier using the laser-Doppler-flowmetry.

Cardiovascular Disorders Triggered by Obstructive Sleep Apnea-A Focus on Endothelium and Blood Components.

Obstructive sleep apnea (OSA) is known to be an independent cardiovascular risk factor. Among arousal from sleep, increased thoracic pressure and enhanced sympathetic activation, intermittent hypoxia is now considered as one of the most important pathophysiological mechanisms contributing to the development of endothelial dysfunction. Nevertheless, not much is known about blood components, which justifies the current review. This review focuses on molecular mechanisms triggered by sleep apnea. The recurrent periods of hypoxemia followed by reoxygenation promote reactive oxygen species (ROS) overproduction and increase inflammatory response. In this review paper we also intend to summarize the effect of treatment with continuous positive airway pressure (CPAP) on changes in the profile of the endothelial function and its subsequent potential clinical advantage in lowering cardiovascular risk in other comorbidities such as diabetes, atherosclerosis, hypertension, atrial fibrillation. Moreover, this paper is aimed at explaining how the presence of OSA may affect platelet function and exert effects on rheological activity of erythrocytes, which could also be the key to explaining an increased risk of stroke.

Increased Intraplatelet ADMA Level May Promote Platelet Activation in Diabetes Mellitus.

BACKGROUND: Antiplatelet therapy has become a standard therapeutic approach in the secondary prevention of cardiovascular system disorders of thrombotic origin. Patients with concomitant diabetes mellitus (DM) obtain fewer benefits from this treatment. Hence, the pathophysiology of altered platelet function in response to glucose metabolism impairment should be of particular interest. OBJECTIVES: The aim of our study was to verify if the platelet expression of the asymmetric dimethylarginine (ADMA) in diabetic patients differs in comparison to the nondiabetic ones. The correlation of platelet-ADMA with platelet activation and aggregation as well as with other risk factors was also investigated. Material and Methods. A total of 61 subjects were enrolled in this study, including thirty-one type 2 diabetic subjects without diabetes-related organ damage. Physical examination was followed by blood collection with an assessment of platelet aggregation, traditional biochemical cardiovascular risk factors, and evaluation of nitric oxide bioavailability parameters in plasma and thrombocytes. Subsequently, the assessment of endothelial function using Peripheral Arterial Tonometry and Laser Doppler Flowmetry (LDF) was performed. RESULTS: In the DM group, elevated concentration of intraplatelet ADMA and higher ADMA/SDMA ratio compared to the control group was observed. It was accompanied by higher ADP-mediated platelet aggregation and lower microvascular response to a local thermal stimulus measured by LDF in the diabetes group. CONCLUSIONS: Type 2 diabetes is related to higher intraplatelet concentration of asymmetric dimethylarginine (ADMA), which may result in impaired platelet-derived nitric oxide synthesis and subsequent increased platelet activity, as assessed by the ADP-induced aggregation. Laser Doppler Flowmetry, compared to EndoPAT 2000, appears to be a more sensitive indicator of the impaired microvasculature vasodilation in diabetics without the presence of clinically significant target organ damage.

Role of the Platelets and Nitric Oxide Biotransformation in Ischemic Stroke: A Translative Review from Bench to Bedside.

Ischemic stroke remains the fifth cause of death, as reported worldwide annually. Endothelial dysfunction (ED) manifesting with lower nitric oxide (NO) bioavailability leads to increased vascular tone, inflammation, and platelet activation and remains among the major contributors to cardiovascular diseases (CVD). Moreover, temporal fluctuations in the NO bioavailability during ischemic stroke point to its key role in the cerebral blood flow (CBF) regulation, and some data suggest that they may be responsible for the maintenance of CBF within the ischemic penumbra in order to reduce infarct size. Several years ago, the inhibitory role of the platelet NO production on a thrombus formation has been discovered, which initiated the era of extensive studies on the platelet-derived nitric oxide (PDNO) as a platelet negative feedback regulator. Very recently, Radziwon-Balicka et al. discovered two subpopulations of human platelets, based on the expression of the endothelial nitric oxide synthase (eNOS-positive or eNOS-negative platelets, respectively). The e-NOS-negative ones fail to produce NO, which attenuates their cyclic guanosine monophosphate (cGMP) signaling pathway and-as result-promotes adhesion and aggregation while the e-NOS-positive ones limit thrombus formation. Asymmetric dimethylarginine (ADMA), a competitive NOS inhibitor, is an independent cardiovascular risk factor, and its expression alongside with the enzymes responsible for its synthesis and degradation was recently shown also in platelets. Overproduction of ADMA in this compartment may increase platelet activation and cause endothelial damage, additionally to that induced by its plasma pool. All the recent discoveries of diverse eNOS expression in platelets and its role in regulation of thrombus formation together with studies on the NOS inhibitors have opened a new chapter in translational medicine investigating the onset of acute cardiovascular events of ischemic origin. This translative review briefly summarizes the role of platelets and NO biotransformation in the pathogenesis and clinical course of ischemic stroke.

Novel Molecular Mechanisms of Pulmonary Hypertension: A Search for Biomarkers and Novel Drug Targets-From Bench to Bed Site.

Pulmonary hypertension (PH) is defined as increased mean pulmonary artery pressure (mPAP) above 25 mmHg, measured at rest by right heart catheterization. The exact global prevalence of PH is difficult to estimate, mainly due to the complex aetiology, and its spread may be underestimated. To date, numerous studies on the aetiology and pathophysiology of PH at molecular level were conducted. Simultaneously, some clinical studies have shown potential usefulness of well-known and widely recognized cardiovascular biomarkers, but their potential clinical usefulness in diagnosis and management of PH is poor due to their low specificity accompanied with numerous other cardiovascular comorbidities of PH subjects. On the other hand, a large body of basic research-based studies provides us with novel molecular pathomechanisms, biomarkers, and drug targets, according to the evidence-based medicine principles. Unfortunately, the simple implementation of these results to clinical practice is impossible due to a large heterogeneity of the PH pathophysiology, where the clinical symptoms constitute only a common denominator and a final result of numerous crosstalking metabolic pathways. Therefore, future studies, based mostly on translational medicine, are needed in order to both organize better the pathophysiological classification of various forms of PH and define precisely the optimal diagnostic markers and therapeutic targets in particular forms of PH. This review paper summarizes the current state of the art regarding the molecular background of PH with respect to its current classification. Novel therapeutic strategies and potential biomarkers are discussed with respect to their limitations in use in common clinical practice.

Intraplatelet L-Arginine-Nitric Oxide Metabolic Pathway: From Discovery to Clinical Implications in Prevention and Treatment of Cardiovascular Disorders.

Despite the development of new drugs and other therapeutic strategies, cardiovascular disease (CVD) remains still the major cause of morbidity and mortality in the world population. A lot of research, performed mostly in the last three decades, revealed an important correlation between "classical" demographic and biochemical risk factors for CVD, (i.e., hypercholesterolemia, hyperhomocysteinemia, smoking, renal failure, aging, diabetes, and hypertension) with endothelial dysfunction associated directly with the nitric oxide deficiency. The discovery of nitric oxide and its recognition as an endothelial-derived relaxing factor was a breakthrough in understanding the pathophysiology and development of cardiovascular system disorders. The nitric oxide synthesis pathway and its regulation and association with cardiovascular risk factors were a common subject for research during the last decades. As nitric oxide synthase, especially its endothelial isoform, which plays a crucial role in the regulation of NO bioavailability, inhibiting its function results in the increase in the cardiovascular risk pattern. Among agents altering the production of nitric oxide, asymmetric dimethylarginine-the competitive inhibitor of NOS-appears to be the most important. In this review paper, we summarize the role of L-arginine-nitric oxide pathway in cardiovascular disorders with the focus on intraplatelet metabolism.