Natriuretic Protein Research Articles

Resveratrol alleviates hyperglycemia-induced cardiomyocyte hypertrophy by maintaining mitochondrial homeostasis via enhancing SIRT1 expression

To investigate whether resveratrol alleviates hyperglycemia-induced cardiomyocyte hypertrophy by enhancing the expression of silent information regulation 2 homolog 1 (SIRT1) to maintain mitochondrial homeostasis. Rat cardiomyocytes H9c2 cells with or without lentivirus-mediated mRNA interference of SIRT1 were cultured in high glucose (HG) and treated with resveratrol for 72 h. The changes in superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, reactive oxygen species (ROS) level, and relative surface of the cells were examined, and the mRNA expressions of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) and protein expressions of SIRT1, mitochondrial fusion related proteins optic atrophy protein 1 (OPA1) and mitofusin 2, mitochondrial division related proteins dynamin-related protein 1 (DRP1) and fission protein 1 (FIS1), and mitophagy-related proteins BNIP3L and LC3 were detected using RT-qPCR and Western blotting. HG exposure significantly decreased SOD activity, increased MDA content, ROS production, relative cell surface, and the mRNA expressions of ANF and BNP in the cardiomyocytes; the protein expressions of SIRT1, OPA1, mitofusin 2 and BNIP3L and LC3-Ⅱ/LC3-Ⅰ ratio were all decreased and the protein expressions of DRP1 and FIS1 increased in HG-exposed cells (P<0.01). All these changes in HG-exposed cardiomyocytes were significantly alleviated by treatment with resveratrol (P<0.05). The protective effects of resveratrol against HG exposure in the cardiomyocytes were obviously attenuated by transfection of the cells with si-SIRT1 (P<0.05). Resveratrol inhibits hyperglycemia-induced cardiomyocyte hypertrophy by reducing oxidative stress, the mechanisms of which involve enhancement of SIRT1 protein expression, regulation of mitochondrial fusion and division balance, and promoting BNIP3L-mediated mitophagy to maintain mitochondrial homeostasis in the cells.

Lymphocyte to C-reactive protein ratio is associated with in-hospital cardiac death in elderly patients with non-ST-segment elevation myocardial infarction.

Although percutaneous coronary intervention (PCI) is recommended by guidelines, data from the real world suggest that elderly non-ST-segment elevation myocardial infarction (NSTEMI) patients have a low rate of PCI and a high death rate. Lymphocyte to C-reactive protein ratio (LCR), a novel inflammatory marker, has been shown to be associated with prognosis in a variety of diseases. However, the relationship between LCR and in-hospital cardiac death in elderly NSTEMI patients is unclear. The aim of this study was to investigate the effect of LCR on in-hospital cardiac death in elderly NSTEMI patients without PCI therapy. This was a single-center retrospective observational study, consecutively enrolled elderly (≥75 years) patients diagnosed with NSTEMI and without PCI from February 2019 to February 2024. LCR was defined as lymphocyte count to C-reactive protein ratio. The endpoint of observation was in-hospital cardiac death. The predictive efficacy of the old and new models was evaluated by the net reclassification index (NRI) and the integrated discriminant improvement index (IDI). A total of 506 patients were enrolled in this study, and in-hospital cardiac death occurred in 54 patients (10.7%). Univariate logistic regression analysis showed that left ventricular ejection fraction, LCR, Killip ≥2, and N-terminal B-type natriuretic peptide proteins (NT-proBNP) were associated with the occurrence of in-hospital cardiac death. After adjusting for potential confounders, the results showed that NT-proBNP (OR = 1.695, 95% CI: 1.238-2.322) and LCR (OR = 0.262, 95% CI: 0.072-0.959) were independent risk factors for in-hospital cardiac death. After the addition of LCR to NT-proBNP, the predictive ability of the new model for in-hospital cardiac death was significantly improved (NRI = 0.278, P = 0.030; IDI = 0.017, P < 0.001). Lower LCR is an independent risk factor for in-hospital cardiac death in elderly NSTEMI patients without PCI, and integrating LCR improves the prediction of in-hospital cardiac death occurrence.

Serum-based biomarkers associated with lung cancer risk and cause-specific mortality in the German randomized Lung Cancer Screening Intervention (LUSI) trial.

Lung cancer (LC) screening can be optimized using individuals' estimated risks of having a detectable lung tumor, as well as of mortality risk by competing causes, to guide decisions on screening eligibility, ideal screening intervals and stopping ages. Besides age, sex and smoking history, blood-based biomarkers may be used to improve the assessment of LC risk and risk of mortality by competing causes. In the German randomized Lung Screening Intervention Trial (LUSI), we measured growth/differentiation factor-15 (GDF-15), interleukin-6 (IL-6), C-reactive protein (CRP) and N-terminal pro-brain natriuretic protein (NT-proBNP), in blood serum samples collected at start of the trial. Participants in the computed tomography (CT)-screening arm also had a pulmonary function test. Regression models were used to examine these markers as predictors for impaired lung function, LC risk and mortality due to LC or other causes, independently of age, sex and smoking history. Our models showed increases in LC risk among participants with elevated serum levels of GDF-15 [odds ratio (OR)Q4-Q1 =2.47, 95% confidence interval (CI): 1.49-4.26], IL-6 [ORQ4-Q1 =2.36 (1.43-4.00)] and CRP [ORQ4-Q1 =1.81 (1.08-2.75)]. Likewise, proportional hazards models showed increased risks for LC-related mortality, hazard ratio (HR)Q4-Q1 of 4.63 (95% CI: 2.13-10.07) for GDF-15, 3.56 (1.72-7.37) for IL-6 and 2.34 (1.24-4.39) for CRP. All four markers were associated with increased risk of mortality by causes other than LC, with strongest associations for GDF-15 [HRQ4-Q1 =3.04 (2.09-4.43)] and IL-6 [HRQ4-Q1 =2.98 (2.08-4.28)]. Significant associations were also observed between IL-6, CRP, GDF-15 and impaired pulmonary function [chronic obstructive pulmonary disease (COPD), preserved ratio impaired spirometry (PRISm)]. Multi-marker models identified GDF-15 and IL-6 as joint risk predictors for risk of LC diagnosis, without further discrimination by CRP or NT-proBNP. A model based on age, sex, smoking-related variables, GFD-15 and IL-6 provided moderately strong discrimination for prediction of LC diagnoses within 9 years after blood sampling [area under the curve (AUC) =74.3% (57.3-90.2%)], compared to 67.0% (49.3-84.8%) for a model without biomarkers. For mortality by competing causes, a model including biomarkers resulted in an AUC of 76.2% (66.6-85.3%)], compared to 70.0% (60.9-77.9%) a model including age, sex and smoking variables. Serum GDF-15 and IL-6 may be useful indicators for estimating risks for LC and competing mortality among long-term smokers participating in LC screening, to optimize LC screening strategies.

Abstract 15053: Distinct Effects of Sacubitril/Valsartan on Left Atrial Function Between Heart Failure With Preserved and Reduced Ejection Fraction

Background: Although Sacubitril/Valsartan(S/V) could ameliorate left ventricular (LV) function, it was recently reported that S/V worsened the left atrial (LA) remodeling in pre-heart failure with preserved ejection fraction (pre-HFpEF). However, the effects of S/V on LA function remains controversial in heart failure. Accordingly, this study investigated the effects of S/V on LA function and remodeling in both HFpEF and HFrEF. Methods: This was a single-center retrospective study of patients with HF hospitalized at our hospital. Patients with HF underwent clinical evaluation and echocardiography at baseline and after administration with S/V. LA volume index (LAVI) , LA emptying fraction (LAEF), transmitral peak E wave velocity (E), pulsed-wave TDI e’ velocity (e’), and E/e` were measured by echocardiography. Results: A total of 71 consecutive patients (71 ± 13 years, 70% male) were enrolled in this study. Among them, 29 were patients with HFpEF (LVEF 55 ± 7%), and 42 were HFrEF (LVEF 28 ± 7%). S/V administration significantly reduced the serum brain natriuretic protein level in HFpEF and HFrEF (279 ± 343 to 155 ± 214 pg/ml, 638 ± 642 to. 218 ± 288 pg/ml, p&lt;0.05, respectively). LAVI was also significantly decreased after S/V administration in HFpEF and HFrEF (41 ± 11 to 38 ± 12 ml/m 2 , 50 ± 19 to. 41 ± 21 ml/m 2 , p&lt;0.05, respectively), implicating its effects on LA reverse remodeling. Furthermore, the significant decrease in the velocity of E wave and E/e’ were observed in HFpEF and HFrEF. However, LAEF were significantly improved in HFrEF, but not in HFpEF, while e’ were improved in HFpEF, but not in HFrEF. These results indicated that the effects of S/V might be attributable to LV relaxation in HFpEF and to LA reservoir function in HFrEF. Conclusions: This study demonstrated that treatment with Sacubitril/Valsartan could lead to LA reverse remodeling in both HFpEF and HFrEF, possibly due to the distinct mechanisms of Sacubitril/Valsartan for improving the LA function. Further studies should be needed to be clarified.

Human engineered cardiac tissue model of hypertrophic cardiomyopathy recapitulates key hallmarks of the disease and the effect of chronic mavacamten treatment.

Introduction: The development of patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offers an opportunity to study genotype-phenotype correlation of hypertrophic cardiomyopathy (HCM), one of the most common inherited cardiac diseases. However, immaturity of the iPSC-CMs and the lack of a multicellular composition pose concerns over its faithfulness in disease modeling and its utility in developing mechanism-specific treatment. Methods: The Biowire platform was used to generate 3D engineered cardiac tissues (ECTs) using HCM patient-derived iPSC-CMs carrying a β-myosin mutation (MYH7-R403Q) and its isogenic control (WT), withal ECTs contained healthy human cardiac fibroblasts. ECTs were subjected to electro-mechanical maturation for 6weeks before being used in HCM phenotype studies. Results: Both WT and R403Q ECTs exhibited mature cardiac phenotypes, including a lack of automaticity and a ventricular-like action potential (AP) with a resting membrane potential < -75mV. Compared to WT, R403Q ECTs demonstrated many HCM-associated pathological changes including increased tissue size and cell volume, shortened sarcomere length and disorganized sarcomere structure. In functional assays, R403Q ECTs showed increased twitch amplitude, slower contractile kinetics, a less pronounced force-frequency relationship, a smaller post-rest potentiation, prolonged AP durations, and slower Ca2+ transient decay time. Finally, we observed downregulation of calcium handling genes and upregulation of NPPB in R403Q vs. WT ECTs. In an HCM phenotype prevention experiment, ECTs were treated for 5-weeks with 250nM mavacamten or a vehicle control. We found that chronic mavacamten treatment of R403Q ECTs: (i) shortened relaxation time, (ii) reduced APD90 prolongation, (iii) upregulated ADRB2, ATP2A2, RYR2, and CACNA1C, (iv) decreased B-type natriuretic peptide (BNP) mRNA and protein expression levels, and (v) increased sarcomere length and reduced sarcomere disarray. Discussion: Taken together, we demonstrated R403Q ECTs generated in the Biowire platform recapitulated many cardiac hypertrophy phenotypes and that chronic mavacamten treatment prevented much of the pathology. This demonstrates that the Biowire ECTs are well-suited to phenotypic-based drug discovery in a human-relevant disease model.

Biomarkers and Coronary Microvascular Dysfunction in Women With Angina and No Obstructive Coronary Artery Disease

BackgroundCoronary microvascular dysfunction (CMD) is a major cause of ischemia with no obstructed coronary arteries. ObjectivesThe authors sought to assess protein biomarker signature for CMD. MethodsWe quantified 184 unique cardiovascular proteins with proximity extension assay in 1,471 women with angina and no obstructive coronary artery disease characterized for CMD by coronary flow velocity reserve (CFVR) by transthoracic echo Doppler. We performed Pearson’s correlations of CFVR and each of the 184 biomarkers, and principal component analyses and weighted correlation network analysis to identify clusters linked to CMD. For prediction of CMD (CFVR < 2.25), we applied logistic regression and machine learning algorithms (least absolute shrinkage and selection operator, random forest, extreme gradient boosting, and adaptive boosting) in discovery and validation cohorts. ResultsSixty-one biomarkers were correlated with CFVR with strongest correlations for renin (REN), growth differentiation factor 15, brain natriuretic protein (BNP), N-terminal-proBNP (NT-proBNP), and adrenomedullin (ADM) (all P < 1e-06). Two principal components with highest loading on BNP/NTproBNP and interleukin 6, respectively, were strongly associated with low CFVR. Weighted correlation network analysis identified 2 clusters associated with low CFVR reflecting involvement of hypertension/vascular function and immune modulation. The best prediction model for CFVR <2.25 using clinical data had area under the receiver operating characteristic curve (ROC-AUC) of 0.61 (95% CI: 0.56-0.66). ROC-AUC was 0.66 (95% CI: 0.62-0.71) with addition of biomarkers (P for model improvement = 0.01). Stringent two-layer cross-validated machine learning models had ROC-AUC ranging from 0.58 to 0.66; the most predictive biomarkers were REN, BNP, NT-proBNP, growth differentiation factor 15, and ADM. ConclusionsCMD was associated with pathways particularly involving inflammation (interleukin 6), blood pressure (REN, ADM), and ventricular remodeling (BNP/NT-proBNP) independently of clinical risk factors. Model prediction improved with biomarkers, but prediction remained moderate.

In this Issue

HomeCirculation ResearchVol. 132, No. 4In this Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIn this Issue Originally published16 Feb 2023https://doi.org/10.1161/RES.0000000000000595Circulation Research. 2023;132:397is related toADAR1 Non-Editing Function in Macrophage Activation and Abdominal Aortic AneurysmCirculating Extracellular Vesicle-Propagated microRNA Signature as a Vascular Calcification Factor in Chronic Kidney DiseaseCNP Promotes Antiarrhythmic Effects via Phosphodiesterase 2CNP Promotes Anti-Arrhythmic Effects via Phosphodiesterase 2 (p 400)Download figureDownload PowerPointCachorro et al suggest new targets for treating arrhythmia in heart failure.If a person survives a myocardial infarction they remain at risk of eventual death from heart failure, with arrhythmia and sudden cardiac death being major causes. β-blockers are often used to mitigate arrhythmia in heart failure but have side effects such as hypotension, dizziness and brachycardia due to the heart’s reduced contractile force. In the search for novel targets and treatments, it was discovered that overexpression of the enzyme phosphodiesterase 2 (PDE2), involved in cardiomyocyte contractility among other things, protected mice from arrhythmia and death after infarction. Furthermore, in rats with acute myocardial ischemia, treatment with the vasoactive molecule c-type natriuretic protein (CNP) also reduced arrhythmia. Cachorro and colleagues now show that these two separate findings are in fact linked. Indeed, CNP treatment of mice induced PDE2 to reduce arrhythmia, they found. And, pharmaceutical or genetic inhibition of PDE2 activity, prevented CNP’s antiarrhythmic effects. Similar results were found in cultured cells, where CNP suppressed arrhythmogenic activity in mouse and human cardiomyocytes but not if PDE2 was inhibited. Together the results point to the CNP-PDE2 pathway as a possible target for new heart failure medications, say the team.ADAR1 Non-Editing Function in Macrophage Activation and Abdominal Aortic Aneurysm (p e78)Download figureDownload PowerPointMacrophage ADAR1 is a key driver of abdominal aortic aneurysm, report Cai et al.Abdominal aortic aneurysm (AAA) is a life-threatening chronic inflammatory disorder in which the wall of the vessel becomes progressively weakened leading to its localized bulging and potential rupture. It causes around 10,000 deaths annually in the US alone and with the exception of surgery there are no targeted treatments. An RNA processing protein called ADAR1, with RNA-editing and non-editing functions, has been linked to the disease, being found at raised levels in mouse and patient AAA lesions. Deletion of ADAR1 from smooth muscle cells (SMCs)—key cells of blood vessel walls—has also been shown to reduce AAA formation in mice. Now Cai and colleagues show that SMCs are not the only cells in which ADAR1 plays a role in AAA. Mice whose macrophages lacked ADAR1, were more resistant to AAA induction than were their wildtype counterparts. And the ADAR1-lacking macrophages were less inflammatory. Mechanistically, the team showed that ADAR1 normally enhances inflammation not by its RNA editing activity but by degrading another RNA protein called Drosha, which triggers a molecular cascade to inflammatory signaling. Finally, the team showed this ADAR1-Drosha interaction also exists in human AAA tissue, thus confirming the clinical relevance of their discoveries.Circulating Extracellular Vesicle-Propagated microRNA Signature a A Vascular Calcification Factor in Chronic Kidney Disease (p 415)Download figureDownload PowerPointExtracellular vesicles drive vascular calcification in chronic kidney disease, say Koide et al.Declining renal function in chronic kidney disease (CKD) is associated with the risk of cardiovascular issues such as vascular calcification. This link to calcification is partly due to the body’s altered handling of minerals. But, as Koide and colleagues show, extracellular vesicles (EVs), also play a role. EVs are membrane-bound packets released from cells that act as an inter-cellular and inter-organ communication system. Previously, the serum of CKD patients, but not healthy subjects, was shown to promote calcification of cultured vascular smooth muscle cells (VSMCs), but the agent responsible was unknown. Now the team show, serum from rats with CKD also promotes VSMC calcification, but not if EVs are depleted. Furthermore, injection of an EV inhibitor into CKD-model mice prevented vascular calcification. Analyses of EVs from CKD rodents revealed four microRNAs that were less abundant than in control EVs. And these miRNAs were found to target and suppress the pro-calcification activity of growth factor VEGFA. The same four miRNAs were reduced in human CKD patient EVs where levels of the RNAs correlated with kidney function. The authors thus conclude, these EV RNAs have the potential to be biomarkers of disease severity as well as targets for new therapies. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesADAR1 Non-Editing Function in Macrophage Activation and Abdominal Aortic AneurysmDunpeng Cai, et al. Circulation Research. 2023;132:e78-e93Circulating Extracellular Vesicle-Propagated microRNA Signature as a Vascular Calcification Factor in Chronic Kidney DiseaseTakaaki Koide, et al. Circulation Research. 2023;132:415-431CNP Promotes Antiarrhythmic Effects via Phosphodiesterase 2Eleder Cachorro, et al. Circulation Research. 2023;132:400-414 February 17, 2023Vol 132, Issue 4 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000595 Originally publishedFebruary 16, 2023 PDF download Advertisement

New Approach to Hyponatremia: High Prevalence of Cerebral/Renal Salt Wasting, Identification of Natriuretic Protein That Causes Salt Wasting.

Our understanding of hyponatremic conditions has undergone major alterations. There is a tendency to treat all patients with hyponatremia because of common subtle symptoms that include unsteady gait that lead to increased falls and bone fractures and can progress to mental confusion, irritability, seizures, coma and even death. We describe a new approach that is superior to the ineffectual volume approach. Determination of fractional excretion (FE) of urate has simplified the diagnosis of a reset osmostat, Addison's disease, edematous causes such as congestive heart failure, cirrhosis and nephrosis, volume depletion from extrarenal salt losses with normal renal tubular function and the difficult task of differentiating the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) from cerebral/renal salt wasting (C/RSW). SIADH and C/RSW have identical clinical and laboratory parameters but have diametrically opposite therapeutic goals of water-restricting water-loaded patients with SIADH or administering salt water to dehydrated patients with C/RSW. In a study of nonedematous patients with hyponatremia, we utilized FEurate and response to isotonic saline infusions to differentiate SIADH from C/RSW. Twenty-four (38%) of 62 hyponatremic patients had C/RSW with 21 having no clinical evidence of cerebral disease to support our important proposal to change cerebral to renal salt wasting (RSW). Seventeen (27%) had SIADH and 19 (31%) had a reset osmostat. One each from hydrochlorothiazide and Addison's disease. We demonstrated natriuretic activity in the plasma of patients with neurosurgical and Alzheimer diseases (AD) in rat clearance studies and have now identified the natriuretic protein to be haptoglobin related protein without signal peptide (HPRWSP). We introduce a new syndrome of RSW in AD that needs further confirmation. Future studies intend to develop HPRWSP as a biomarker to simplify the diagnosis of RSW in hyponatremic and normonatremic patients and explore other clinical applications that can improve clinical outcomes.

1336. Six-Year Clinical Experience of Pediatric Murine Typhus in Houston, TX

Abstract Background Murine typhus is a flea-borne rickettsial disease endemic to gulf states. It shares clinical features of Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C). We sought to explore the six-year experience with murine typhus among children living in Houston, TX. Methods We conducted a retrospective chart review to identify clinical and laboratory features of children with murine typhus from January 2015 to July 2021. Cases were identified by positive Rickettsia typhi serology with single IgG &amp;gt;=1:256, single IgM &amp;gt;=1:128, or increase in IgG from 1:64 to 1:28 in convalescent sera. Results 162 cases of pediatric murine typhus were identified. Most cases (85, 52.5%) occurred in the summer. There was a bimodal distribution of age, with peaks at 4 and 17 years (Figure 1). Most children (96, 59.3%) required hospitalization; 11 were admitted to intensive care, and 3 required intubation. All children had fever; the mean duration of fever at presentation was 8.9 days (+/-2.9). Only 67 (41.4%) had a combination of fever, headache, and rash (Table 1). 64 (39.5%) had documented flea or opossum exposure. The most common laboratory abnormalities were elevated serum liver transaminases, hypoalbuminemia, thrombocytopenia, and hyponatremia (Table 1). Cardiac abnormalities were not uncommon: 20/59 (33.9%) had an abnormal electrocardiogram, 5/50 (10.0%) had troponin &amp;gt;0.04 ng/mL, and 4/50 (8.0%) had b-type natriuretic protein &amp;gt;100 pg/mL (Table 1). Most children (149, 92.0%) were diagnosed based on positive initial serological testing. Nine (5.6%) received intravenous immunoglobulin for a diagnosis of KD before typhus was diagnosed. The median duration of hospitalization was 3 days (IQR 2,5), and most children were treated with doxycycline (146, 90.1%). Figure 1.Histogram of age at time of murine typhus diagnosis.Table 1.Clinical and Laboratory Features of Children Diagnosed with Murine Typhus. Conclusion Murine typhus is a common cause of prolonged unexplained fever in children living in endemic areas and shares clinical features of KD and MIS-C. Cardiac abnormalities are not uncommon, and severity of illness can range from outpatient to intensive care. Lack of flea or opossum exposure or lack of headache or rash does not rule out infection. Therefore, a high index of suspicion is warranted, and initial serology testing may accelerate diagnosis in children with prolonged fever. Disclosures All Authors: No reported disclosures.

72 Distinguishing features of MIS-C to other paediatric febrile diseases in the acute setting

BackgroundMultisystem inflammatory syndrome in children (MIS-C) presents with fever, shock, rash, abdominal pain and raised inflammatory markers, as well as common features of inflammatory childhood illnesses. In the acute setting, especially in countries where infectious diseases are common differential diagnoses, it is challenging to diagnose MIS-C. Therefore, data differentiating MIS-C from other inflammatory and/or febrile diseases at presentation is needed.MethodsProspective data was collected from children admitted to the Red Cross War Memorial Children’s Hospital in Cape Town, South Africa from May 2020 to end November 2021 where MIS-C was part of their differential diagnoses. Clinical features on the day of admission were compared between children with confirmed MIS-C (MIS-C+) and those with alternate diagnoses (MIS-C-).ResultsIn this time period, 60 children were MIS-C+ and 34 were MIS-C-. There was no significant difference in age (p = 0.321), sex (p = 0.525), ethnicity (p = 0.279), or in the frequency of comorbidities (p = 0.151) between the two groups. The presence of conjunctivitis (OR = 8.12), rash (OR = 8.67), tachycardia (OR = 2.8) and oral mucositis (OR = 3.75) was associated with MIS-C+ while abdominal pain and hypotension were not. MIS-C+ had statistically higher median C-reactive protein (CRP), pro-brain natriuretic protein (pro-BNP) and ferritin, and lower median lymphocyte count, platelet count and sodium levels than MIS-C-. Ferritin discriminated MIS-C+ well (AUC = 0.86) with a 94% sensitivity and 60% specificity at a cut off of > 195ng/l. Sodium had an AUC of 0.72, with a 70% sensitivity and 71% specificity at a cut off of < 132.5 mmol/l. CRP did not distinguish MIS-C well (AUC = 0.52) and although they had good AUC, platelet count and pro-BNP had cut off values in the normal range decreasing clinical utility.ConclusionWe provide evidence for the use of accessible clinical and laboratory variables for the diagnosis of MIS-C in diverse settings.ImplicationsThese data will aid clinicians to do a rapid diagnosis (and ultimately treat earlier) of patients with MIS-C in the acute setting, especially those in under-resourced settings. 72 Table 4ROC analysis of laboratory tests which were different between MIS-C- and MIS-C+Test AUC (95%CI) p Potential cut-off value Sensitivity Specificity Youden ratio Ferritin 0.86 (0.70, 1) 0.017 *>19594%60% 54% 7-84 ng/L ** >31672%80% 52% Pro-BNP 0.80 (0.62, 0.98) 0.044 *>23983%40%23%<450 ng/L ** >37878%80% 57% Platelet count 0.75 (0.59, 0.90) 0.006 *<285 81% 71% 52% 180-440 x109/LSodium 0.726 (0.56, 0.88) 0.014 *<134.587%35.7%22%136-145 mmol/L ** <132.570%71%41%CRP0.54 (0.62, 0.98) 0.766 *>77100%40%40%<10 mg/L ** >161.550%60%10%2 potentials cut off values are given.*the value which gives the best specificity with a sensitivity >80% and.**the value that achieves the best sensitivity with a specificity of at least 60%.

Proteomics to identify biological pathways and develop prediction models of coronary microvascular dysfunction in women with angina and no obstructive coronary artery disease

Abstract Aims Coronary microvascular dysfunction (CMD) is a major cause of angina and impaired outcome. Protein biomarkers could simplify patient selection for assessment and help uncover pathophysiologic pathways. Methods and results We quantified 184 protein biomarkers in 1471 women with angina and no obstructive coronary artery disease on angiography characterized for CMD by coronary flow velocity reserve (CFVR) by Doppler Echocardiography. Sixty-one biomarkers were significantly associated with CFVR (Figure 1). The strongest correlations were seen for renin, growth differentiation factor 15 (GDF15), brain natriuretic protein (BNP), NT-proBNP and adrenomedullin (ADM) (all p&amp;lt;1e-06). To identify pathophysiological patterns, we applied principal components (PC) analyses and weighted protein co-abundance network analyses. Two PCs with the highest loading on BNP/ NTproBNP and interleukin 6 (IL-6), respectively, were strongly associated with low CFVR. The weighted protein co-abundance network analyses identified two clusters associated with low CFVR reflecting involvement of hypertension/vascular function and immune modulation. For prediction of CMD (CFVR &amp;lt;2.25, n=646), data was split into model and validation cohorts. The best model using only clinical data had area under the receiver operating characteristic curve (ROC-AUC) of 0.61 (95% CI 0.56–0.66). ROC-AUC improved to 0.66 (95% CI: 0.62–0.71) with addition of biomarkers. Stringent two-layer cross-validated machine learning models had ROC-AUC ranging from 0.58 to 0.66 (Figure 2); the most predictive biomarkers were renin, BNP, NT-proBNP, GDF15 and ADM. Conclusion CMD was associated with biological pathways, particularly involving inflammation (IL-6), blood pressure (renin, ADM) and ventricular remodelling (BNP/NTproBNP). The identified biomarker pathways may prove potential treatment targets for CMD. Diagnostic models improved significantly when adding protein biomarkers to clinical information. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Danish Heart Foundation

Four decades of experience with carcinoid heart disease: An analysis of 84 patients.

Carcinoid heart disease (CHD) is a serious cardiac condition which is caused by elevated serotonin in the systemic circulation, secreted by neuroendocrine tumours (NET). It mostly affects the right-sided heart valves, where it causes fibrotic disturbances and is associated with worse survival. In this study, we describe a large cohort of patients with CHD and provide an insight into their survival over the past decades. All consecutive patients with a serotonin producing NET and CHD referred to the Netherlands Cancer Institute that presented with CHD or developed CHD during their follow up time were included from 1984 until 2021. Patients were divided into three time periods: 1984-2000, 2000-2010 and 2010-2018. Median N-terminal pro B-type natriuretic protein (NT-proBNP) and serum serotonin levels were stratified according to tricuspid regurgitation severity. Kaplan-Meier curves and log rank test were used for visualisation of survival. Cox regression was used for identification of the characteristics associated with disease specific mortality (DSM). A total of 84 patients with CHD were included of whom 49 (58.3%) were male. Median age at NET diagnosis was 62.3 (range 23.9-81.7) years, and median time to development of CHD was 1.1 (range 0-24.2) years. NT-proBNP was significantly higher when more severe tricuspid regurgitation (TR) was present (p= .027). Median survival from CHD diagnosis for 1984-2000, 2000-2010 and 2010-2018 were 1.3 (confidence interval [CI]: 0.9-1.6), 1.9 (CI: 1.2-2.6) and 3.9 (CI: 1.7-6.2) years (p= .025). Valve replacement surgery (VSR) occurred more frequent in later time periods. VSR (hazard ratio [HR] 0.33, p= .005) and NT-proBNP (HR 1.003, 1.00-1.005, p= .036) were significantly associated with DSM. The prognosis of patients with CHD has improved over the past decades, possibly caused by more VSR. NT-proBNP is a valuable biomarker in patients with CHD. Clinical practice should be aimed at timely diagnosis and intervention of CHD.

Ranolazine Versus Allopurinol for Eligible Symptomatic Patients With a History of Angioplasty: Comparative Efficacy Study.

Recurrent angina, which is defined as a return of chest pain or chest discomfort, occurs in many patients undergoing coronary interventions. This study aims to compare the antianginal efficacy of ranolazine versus allopurinol for eligible symptomatic patients with a history of angioplasty. A total of 62 eligible symptomatic patients with a history of angioplasty were randomly allocated into two groups. For group A, 300 mg of allopurinol was administered twice daily, while for group B, 1000 mg of ranolazine daily was prescribed for a duration of 4 weeks. An initial screening visit was done for all participants where patients' medical history was recorded and a physical examination was given; electrocardiography, blood pressure, and heart rate measurements were done as well. The patients were also given a blood and exercise test. At the end of the medication period, participants were revisited, and the tests were done again. All the required data were collected via a researcher-made form, and data analysis was conducted using SPSS. The study was approved by a formal ethics committee. The mean age of participants in the two groups (A and B) was 57.36 (SD 8.36) and 60.27 (SD 9.17) years, respectively. Among the 62 patients, 34 (59%) were men, while 28 (41%) were women. Creatinine, fasting blood sugar, C-reactive protein, N-terminal prohormone of brain natriuretic protein, uric acid, white blood cell, and hemoglobin levels of participants were not significantly different between groups (P>.05). Both allopurinol and ranolazine increased the total exercise time and decreased the ST depression of the patients. Additionally, they both improved the chest pain severity and Duke Treadmill Score of patients. At the same time, ranolazine had a statistically greater effect on ST depression reduction (mean 2.64, SD 0.74 vs mean 1.57, SD 0.49), while allopurinol showed better efficacy in reducing chest pain severity (mean 1.86, SD 0.37 vs mean 0.59, SD 0.21) and the Duke Treadmill Score (mean -14.77, SD 3.65 vs mean -6.88, SD 1.93). Based on the results, the antianginal efficacy of allopurinol and ranolazine was approved but with different effects on ST depression, chest pain severity, and the Duke Treadmill Score. Therefore, the precise differences in their effects need to be explored further.

A complex approach to continuous cardiac monitoring of neoadjuvant chemotherapy: Observational study

A complex approach to continuous cardiac monitoring of neoadjuvant chemotherapy: Observational study

Benefits of a Balance Exercise Assist Robot in the Cardiac Rehabilitation of Older Adults with Cardiovascular Disease: A Preliminary Study.

We examined whether adding robot-supported balance exercises to cardiac rehabilitation improves the ability to balance in older adults with cardiovascular disease (CVD). We conducted a prospective study in 52 older adults who had been hospitalized for worsening CVD. Once weekly for four months, for a total of sixteen sessions as outpatients, the subjects used a Balance Exercise Assist Robot (BEAR) to perform balance exercises and an ergometer for aerobic exercises. Participants’ mean age was 76.9 ± 6.8 years (range, 65–95 years), and their mean brain natriuretic protein level was 164.0 ± 190.0 pg/mL. After the intervention, participants showed significant improvements in gait speed (before, 1.06 ± 0.33 m/s; after, 1.23 ± 0.30 m/s; p < 0.001), Short Physical Performance Battery score (before, 10.02 ± 2.25; after, 10.88 ± 1.79; p ˂ 0.001), timed up-and-go (before, 11.11 ± 5.07 s; after, 9.45 ± 3.45 s; p ˂ 0.001), and knee extension (before, 26.97 ± 11.78 kgf; after, 30.13 ± 13.04 kgf; p = 0.001). Cardiac rehabilitation including exercises using BEAR improved physical functioning and the ability to balance in older adults with CVD. Frail and prefrail patients improved, whereas robust ones did not change.

Epigallocatechin-3-gallate exerts cardioprotective effects related to energy metabolism in pressure overload-induced cardiac dysfunction

BackgroundTo investigate the mechanisms of potential cardioprotective effects of epigallocatechin-3-gallate (EGCG) in pressure overload-induced cardiac dysfunction. MethodsA chronic heart failure model was established using abdominal aortic constriction (AAC) surgery, rats were divided into sham, AAC, and AAC + EGCG groups. Echocardiography and tissue section staining were performed to evaluate cardiac function and pathology, respectively. Gene expression level were detected with quantitative real-time polymerase chain reactions. Label-free quantitative proteomics was used to investigate the whole proteomes of heart, and the differentially expressed proteins were analyzed using bioinformatics methods. Western blot was performed to validate the levels and the reliability of the differential proteins. ResultsCompared with the AAC group, systolic dysfunction was improved in AAC + EGCG group after EGCG treatment. EGCG inhibited myocardial fibrosis and cardiac hypertrophy after AAC, along with reducing atrial natriuretic protein, B-type natriuretic peptide, collagen types 1 and 3 alpha 1, and transforming growth factor β-1. Quantitative proteomics identified a total of 162 differentially expressed proteins, among them, 18 were closely related to cardiovascular disorders. Bioinformatics analyses showed that EGCG played a therapeutic role mainly by changing energy metabolism processes, such as oxidative phosphorylation and lipid metabolism. Furthermore, NADH: ubiquinone oxidoreductase subunit S4, an important component of the mitochondrial respiratory chain, was increased after AAC and then reversed by EGCG, which was consistent with the proteomics results. ConclusionsEGCG may correct cardiac systolic dysfunction and prevent cardiac remodeling after heart failure via enhancing the energy metabolism, which provides us with new insights into cardioprotective effects of EGCG related to the energy metabolisms in pressure overload-induced cardiac dysfunction.

Biomarker changes as surrogate endpoints in early-phase trials in heart failure with reduced ejection fraction.

AimsNo biomarker has achieved widespread acceptance as a surrogate endpoint for early‐phase heart failure (HF) trials. We assessed whether changes over time in a panel of plasma biomarkers were associated with subsequent morbidity/mortality in HF with reduced ejection fraction (HFrEF).Methods and resultsIn 1040 patients with HFrEF from the BIOSTAT‐CHF cohort, we investigated the associations between changes in the plasma concentrations of 30 biomarkers, before (baseline) and after (9 months) attempted optimization of guideline‐recommended therapy, on top of the BIOSTAT risk score and the subsequent risk of HF hospitalization/all‐cause mortality using Cox regression models. C‐statistics were calculated to assess discriminatory power of biomarker changes/month‐nine assessment. Changes in N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and WAP four‐disulphide core domain protein HE4 (WAP‐4C) were the only independent predictors of the outcome after adjusting for their baseline plasma concentration, 28 other biomarkers (both baseline and changes), and BIOSTAT risk score at baseline. When adjusting for month‐nine rather than baseline biomarkers concentrations, only changes in NT‐proBNP were independently associated with the outcome. The C‐statistic of the model including the BIOSTAT risk score and NT‐proBNP increased by 4% when changes were considered on top of baseline concentrations and by 1% when changes in NT‐proBNP were considered on top of its month‐nine concentrations and the BIOSTAT risk score.ConclusionsAmong 30 relevant biomarkers, a change over time was significantly and independently associated with HF hospitalization/all‐cause death only for NT‐proBNP. Changes over time were modestly more prognostic than baseline or end‐values alone. Changes in biomarkers should be further explored as potential surrogate endpoints in early phase HF trials.

Assessment for residual disease after pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension.

ObjectivesPulmonary endarterectomy (PEA) is recommended for eligible patients with chronic thromboembolic pulmonary hypertension (CTEPH) and is potentially curative. However, persistent/recurrent CTEPH post-PEA can occur. Here we describe symptom and diagnostic assessment rates for residual disease post-PEA and longitudinal diagnostic patterns before and after riociguat approval for persistent/recurrent CTEPH after PEA.MethodsThis US retrospective cohort study analysed MarketScan data (1 January 2002–30 September 2018) from patients who underwent PEA following a CTEPH/pulmonary hypertension (PH) claim with at least 730 days of continuous enrolment post-PEA. Data on pre-specified PH symptoms and the types and timings of diagnostic assessments were collected.ResultsOf 103 patients (pre-riociguat approval, n=55; post-riociguat approval, n=48), residual PH symptoms >3 months after PEA were reported in 89% of patients. Overall, 89% of patients underwent one or more diagnostic tests (mean 4.6 tests/patient), most commonly echocardiography (84%), with only 5% of patients undergoing right heart catheterisation (RHC). In the post- versus pre-riociguat approval subgroup, assessments were more specific for CTEPH with an approximately two-fold increase in 6-min walk distance and N-terminal prohormone of brain natriuretic protein measurements and ventilation/perfusion scans, and a four-fold increase in RHCs.ConclusionsLow RHC rates suggest that many patients with PH symptoms post-PEA are not being referred for full diagnostic workup. Changes to longitudinal diagnostic patterns may indicate increased recognition of persistent/recurrent CTEPH post-PEA; however, there remains a need for greater awareness around the importance of continued follow-up for patients with residual PH symptoms post-PEA.

A systematic review with meta-analysis of biomarkers for detection of pulmonary arterial hypertension.

RationaleThe blood is a rich source of potential biomarkers for the diagnosis of idiopathic and hereditary pulmonary arterial hypertension (iPAH and hPAH, referred to as “PAH”). While a lot of biomarkers have been identified for PAH, the clinical utility of these biomarkers often remains unclear. Here, we performed an unbiased meta-analysis of published biomarkers to identify biomarkers with the highest performance for detection of PAH.MethodsA literature search (in PubMed, Embase.com, Clarivate Analytics/Web of Science Core Collection and Wiley/Cochrane Library) was performed up to 28 January 2021. Primary end points were blood biomarker levels in PAH versus asymptomatic controls or patients suspected of pulmonary hypertension (PH) with proven normal haemodynamic profiles.Results149 articles were identified by the literature search. Meta-analysis of 26 biomarkers yielded 17 biomarkers that were differentially expressed in PAH and non-PH control subjects. Red cell distribution width, low density lipid-cholesterol, d-dimer, N-terminal prohormone of brain natriuretic protein (NT-proBNP), interleukin-6 (IL-6) and uric acid were biomarkers with the largest observed differences, largest sample sizes and a low risk of publication bias. Receiver operating characteristic curves and sensitivity/specificity analyses demonstrated that NT-proBNP had a high sensitivity, but low specificity for PAH. For the other biomarkers, insufficient data on diagnostic accuracy with receiver operating characteristic curves were available for meta-analysis.ConclusionThis meta-analysis validates NT-proBNP as a biomarker with high sensitivity for PAH, albeit with low specificity. The majority of biomarkers evaluated in this meta-analysis lacked either external validation or data on diagnostic accuracy. Further validation studies are required as well as studies that test combinations of biomarkers to improve specificity.

Cardiovascular Function and Exercise Capacity in Childhood Cancer Survivors.

Introduction: Childhood cancer survivors (CCS) might be at high risk of additional chronic diseases due to cardiotoxic side effects. The aim of this study was to analyze long-term side effects of cancer therapy on vascular structure/function, cardiac biomarkers and on physical activity. Methods: In total, 68 asymptomatic patients aged 16–30 years with childhood cancer (diagnosed 10.6 ± 3.9 years ago) were examined from 2015–2020. (Central) blood pressure and pulse wave velocity were registered via the oscillometric method, while carotid intima-media thickness (cIMT) was measured non-invasively by ultrasound. cIMT values of patients were compared to healthy controls (n = 68; aged 22.3 ± 3.5 years). Patients’ exercise capacity was recorded. The plasma N-terminal pro-brain natriuretic protein (NTproBNP) and troponin levels were measured as cardiac biomarkers. CCS were categorized in groups with low, moderate and high anthracyclines. Results: No differences were found in cIMT between patients and controls as well as between patients with various anthracycline dosage. Patients with high dose anthracyclines showed a significant lower performance versus patients with moderate dose anthracyclines (84.4% of predicted VO2peak; p = 0.017). A total of 11.6% of CCS had abnormal NTproBNP values which correlated with received anthracycline dosage (p = 0.024; r = 0.343). Conclusion: NTproBNP levels and exercise capacity might be early markers for cardiovascular dysfunction in CCS and should be included in a follow-up protocol, while cIMT and troponin seem not to be adequate parameters.