Plasma NT-proBNP Levels Research Articles

Incident HFpEF and time-dependent changes in markers of LVDD severity in women and men with pre-clinical LVDD

Abstract Background Over time, left ventricular diastolic dysfunction (LVDD) can progress towards heart failure with preserved ejection fraction (HFpEF). Yet, the identification of those at high risk of progression is challenging, and guidance on follow-up or preventive treatment is lacking. Purpose To study the incidence of HFpEF and changes over time in markers of LVDD severity in women and men with pre-clinical LVDD. In addition, we evaluate whether blood pressure and kidney function affect progression of LVDD. Methods We reinvited 146 participants from the HELPFul study (58% women and 42% men) with pre-clinical LVDD after a median follow-up of 4.3 [IQR: 3.9-4.7] years (Figure 1). The follow-up measurements were similar to baseline and encompassed a structured interview, physical examination, blood draw, electrocardiogram and (exercise) echocardiography. We determined HFpEF incidence and report changes over time in cardiovascular risk factors as well as echocardiographic characteristics and biomarkers of LVDD. Additionally, we studied whether changes in blood pressure and kidney function affected LVDD progression using generalized mixed models. LVDD progression was defined as an increase in plasma NT-proBNP levels and HFA-PEFF major functional and morphological abnormalities. All analyses were performed for women and men combined as well as stratified by sex. Results Fifteen (10%) of the 146 participants developed HF of whom 13 had HFpEF (9 women and 4 men) during follow-up. Over time, systolic and diastolic blood pressure levels remained stable while mean kidney function (eGFR) declined from 89±14 to 81±17 mL/min/1.73m2. Median NT-proBNP plasma levels increased from 71 [IQR: 44, 120] to 100 [IQR: 51, 157] pg/mL. The prevalence of major functional abnormalities according to the HFA-PEFF score increased from 84 to 91%, while the prevalence of morphological abnormalities increased from 25% to 39% (Figure 2). A higher systolic blood pressure in women and a higher diastolic blood pressure in men was associated with an increase in NT-proBNP plasma levels over time. Additionally, lower eGFR levels were related to increased NT-proBNP plasma levels over time in both men and women. There was a significant rise in the prevalence of major functional and morphological abnormalities with time, but blood pressure and kidney function did not affect this change over time. Conclusions A small proportion of women and men with preclinical LVDD developed incident HF over a 5-year follow-up period. High blood pressure and reduced kidney function were associated with increased levels of NT-proBNP over time. This highlights the need to further explore cardiorenal protection as a method to prevent HFpEF.Study design and HF outcomesLongitudinal changes in LVDD markers

MiR-6089 may prevent the inflammatory events leading to cardiovascular disorders in RA patients

BackgroundCardiovascular disease (CVD) is the most important comorbid condition in rheumatoid arthritis (RA) patients. Dysregulated expression of non-coding RNA families has a critical role in RA-associated inflammatory events, including cardiovascular manifestations. The long non-coding RNA (lncRNA)- HIX003209 has a role in RA associated inflammation. In the current study, we investigated the association of HIX003209 and its downstream microRNA, miR-6089, with various cardiovascular and inflammatory biomarkers in RA patients. Material and methods60 RA patients, including 30 newly diagnosed and 30 on-treatment patients were recruited in this study, and 30 healthy people were selected as a control group. The gene expression of HIX003209, miR-6089, and CXCR3 were measured using Real-time PCR. The CVD risk was measured using Systematic Coronary Risk Evaluation (SCORE) and Framingham Risk Score (FRS). ResultsThe gene expression of LncRNA-HIX003209 was elevated significantly in newly-diagnosed compared to under-treatment and control groups (p < 0.05). The miR-6089 gene expression was elevated significantly in under-treatment RA patients group compared to control group (p < 0.001). There was a significant positive correlation between LncRNA-HIX003209 with CXCR3 gene expression (p < 0.01, r = 0.341). There was a significantly negative correlation between the gene expression of miR-6089 with DAS-28 (p < 0.05, r = −0.309), NT-proBNP plasma level (p = 0.039, r = −0.268), and CXCL9 plasma level (p < 0.001, r = −0.421). ConclusionRegarding its anti-inflammatory effects, miR-6089 may play an important role in preventing the pathological events of cardiovascular disorders in RA patients, through its inhibitory effects on inflammatory chemokines, such as CXCL9, and NT-ProBNP. Higher expression of LncRNA-HIX003209 may disrupt the anti-inflammatory effect of miR-6089 in RA patients.

Interleukin-6 positively correlates with cardiovascular disease predictor algorithms and biomarker in rheumatoid arthritis patients.

Chronic inflammation is believed as the main culprit of the link between cardiovascular disease (CVD) and rheumatoid arthritis (RA). Interleukin-6 (IL-6) is a pro-inflammatory cytokine with a key role in RA pathophysiology and also correlates with joint destruction and disease activity. This study evaluates the association between IL-6 plasma level and cardiac biomarker NT-proBNP, HS-CRP, CVD predictor algorithms, Framingham Risk Score (FRS) and Systematic Coronary Risk Evaluation (SCORE), as well as with CXCL9 and its receptor, CXCR3 in RA patients compared to the controls. Sixty RA patients (30 early and 30 late) and 30 healthy persons were included in this study. IL-6 and NT-proBNP plasma levels were measured by the ELISA. Also, HS-CRP plasma levels were quantified using the immunoturbidimetric assay. The CVD risk was assessed by the FRS and SCORE. IL-6 plasma levels were significantly higher in the early and late RA patients compared to the controls (p < 0.001). There was a positive correlation between IL-6 with DAS-28 (p = 0.007, r = 0.346), BPS (p = 0.002, r = 0.396), BPD (p = 0.046, r = 0.259), SCORE (p < 0.001, r = 0.472), and FRS (p < 0.001, r = 0.553), and a negative association with HDL (p = 0.037, r = -0.270), in the patients. Also, IL-6 plasma level positively correlated with HS-CRP (p = 0.021, r = 0.297) and NT-proBNP (p = 0.045, r = 0.260) in the patients. Furthermore, a positive association was found between IL-6 plasma levels and CXCL9 (p = 0.002, r = 0.386), and CXCR3 (p = 0.018, r = 0.304) in the patients. Given the interesting association between IL-6 with various variables of CVD, IL-6 may be considered a biomarker for assessing the risk for future cardiovascular events in RA patients.

Targeted Quantitative Plasma Metabolomics Identifies Metabolite Signatures that Distinguish Heart Failure with Reduced and Preserved Ejection Fraction.

Two general phenotypes of heart failure (HF) are recognized: HF with reduced ejection fraction (HFrEF) and with preserved EF (HFpEF). To develop HF disease phenotype-specific approaches to define and guide treatment, distinguishing biomarkers are needed. The goal of this study was to utilize quantitative metabolomics on a large, diverse population to replicate and extend existing knowledge of the plasma metabolic signatures in human HF. Quantitative, targeted LC/MS plasma metabolomics was conducted on 787 samples collected by the Penn Medicine BioBank from subjects with HFrEF (n=219), HFpEF (n=357), and matched non-failing Controls (n=211). A total of 90 metabolites were analyzed, comprising 28 amino acids, 8 organic acids, and 54 acylcarnitines. 733 of these samples were also processed via an OLINK protein panel for proteomic profiling. Consistent with previous studies, unsaturated forms of medium/long chain acylcarnitines were elevated in the HFrEF group to a greater extent than the HFpEF group compared to Controls. A number of amino acid derivatives, including 1- and 3-methylhistidine, homocitrulline, and symmetric (SDMA) and asymmetric (ADMA) dimethylarginine were elevated in HF, with ADMA elevated uniquely in HFpEF. Plasma branched-chain amino acids (BCAA) were not different across the groups; however, short-chain acylcarnitine species indicative of BCAA catabolism were significantly elevated in both HF groups. The ketone body 3-hydroxybutyrate (3-HBA) and its metabolite C4-OH carnitine were uniquely elevated in the HFrEF group. Linear regression models demonstrated a significant correlation between plasma 3-HBA and NT-proBNP in both forms of HF, stronger in HFrEF. These results identify plasma signatures that are shared as well as potentially distinguish between HFrEF and HFpEF. Metabolite markers for ketogenic metabolic reprogramming in extra-cardiac tissues were identified as unique signatures in the HFrEF group, possibly related to the lipolytic action of increased levels of BNP. Future studies will be necessary to further validate these metabolites as HF biosignatures that may guide phenotype-specific therapeutics and provide insight into the systemic metabolic responses to HFpEF and HFrEF.

Cardioprotective effect of the anti-ageing protein Klotho on ischemic heart disease

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): ISCIII, Ministerio de Universidades, Education and Research Council of Madrid, Biomedicine Network Comunidad de Madrid Background Cardiovascular diseases are the leading cause of death and disability worldwide. Among them, ischemic heart disease, due to myocardial infarction (MI) remains the first cause of cardiovascular death. The anti-ageing protein Klotho is mainly expressed in membrane at renal level. However, Klotho also has a soluble form with different pleiotropic functions that are still undetermined, including a possible cardioprotective role that is currently the target of several studies. Purpose Firstly, we evaluated circulating Klotho levels related to cardiac damage in a cohort of 146 patients after ST-elevation myocardial infarction (STEMI) and in an experimental post-myocardial infarction (PMI) model. Secondly, we investigated soluble Klotho supplementation as a potential novel therapeutic strategy for the prevention of cardiac dysfunction, deleterious remodeling, cardiomyocyte calcium (Ca2+) mishandling and arrhythmias in PMI mice. Methods Study with human samples: we analysed Klotho and NT-proBNP plasma levels in STEMIpatients with preserved renal function. Experimental study: C57BL6 mice subjected to PMI by ligation of the left anterior descending coronary artery were treated with vehicle solution or recombinant Klotho (10 mg/Kg/day) for 15 days after MI. Cardiac function was studied through non-invasive methods including electrocardiogram (ECG) and cardiac magnetic resonance imaging (CMRI). Intracellular Ca2+ handling was analysed using confocal microscopy in isolated ventricular cardiomyocytes. Cardiac remodeling was studied through histological and biomolecular analysis of several markers of cardiac damage and target proteins involved in Ca2+ handling. Results Plasma Klotho levels decrease rapidly after MI in both STEMI patients and PMI mice. Additionally, MI patients in the lowest Klotho tertile showed significantly elevated NT-proBNP levels. Klotho treatment decreased the infarct area in PMI mice accompanied by a decrease in both cardiac hypertrophy and fibrosis. Moreover, reduction in ejection fraction and MI-related ECG alterations were reduced in PMI mice treated with Klotho, including increased QRS, JT, QTc intervals and occurrence of premature ventricular contractions. Klotho also prevented systolic Ca2+ release and cell shortening disturbances in cardiomyocytes from PMI mice without Klotho. Increased diastolic Ca2+ leak was prevented in mice treated with Klotho via CaMKII-dependent pathway by avoiding its phosphorylation and the RyR2 phosphorylation at CaMKII site. Conclusions Klotho supplementation protect against MI by avoiding deleterious cardiac remodeling and ameliorating one of the main complications of MI such as arrhythmias. Thus, recombinant Klotho prevents the intracardiomyocyte Ca2+ mishandling after MI. Our translational findings support the importance of Klotho as a novel biomarker of ventricular damage just after MI and as a novel therapeutic strategy for prevention cardiac events associated to ischemic heart disease.

Dynamics of the left ventricular ejection fraction after revascularization in patients with heart failure with preserved ejection fraction, association with the TRAIL protein

Aim. To study the association of dynamics of the ejection fraction (EF) of the left ventricle (LV) with the development of adverse cardiovascular events within 12 months after revascularization in patients with chronic heart failure with preserved LV EF (HFpEF), and to determine the value of TNF-related apoptosis-inducing ligand (TRAIL) in predicting changes of LVEF. Materials and methods. 52 patients with HFpEF hospitalized for coronary artery bypass grafting (CABG) were included in the prospective study. The levels of plasma NTproBNP (before CABG) and TRAIL protein (before CABG and 10 days after CABG) were determined. Echocardiography was performed for these patients at the time of enrollment in the study and after 12 months of follow-up. The patients were divided into 2 groups: group 1 (n=23) included patients with increased LVEF, group 2 (n=29) – with unchanged or reduced LVEF. The development of a combined endpoint (cardiovascular death, decompensated of HF, repeat unplanned revascularization) was studied. Results. LVEF before CABG was comparable in the studied groups. The frequency of the combined endpoint was 0 in the first group and 17.2% in the second group (p=0.02). There was an inverse correlation between change of LVEF one year after revascularization and the dynamics of the TRAIL protein in the perioperative period (r=-0.45, p=0.049). The area under the ROC for perioperative TRAIL changes and changes in LVEF during a follow-up was 0.79 (95% confidence interval 0.6–0.985; p=0.018). Conclusion. The increase of LVEF 12 months after CABG in patients with HFpEF is associated with a rarer development of cardiovascular events. The changes of LVEF after CABG can be predicted based on the analysis of the perioperative changes of the TRAIL protein.

Association of Sacubitril/Valsartan vs Valsartan With Blood Pressure Changes and Symptomatic Hypotension: the PARAGLIDE-HF Trial

In PARAGLIDE-HF, among patients with ejection fraction (EF) >40%, stabilized after worsening heart failure (WHF), sacubitril/valsartan led to greater reduction in plasma NT-proBNP levels and was associated with clinical benefit compared to valsartan alone, despite more symptomatic hypotension (SH). Concern over SH may be limiting use of sacubitril/valsartan in appropriate patients. We characterized patients by the occurrence of SH (investigator-reported) after randomization to either sacubitril/valsartan or valsartan. A key trial inclusion criterion was systolic blood pressure (SBP) ≥100 mmHg for the preceding 6 hours and no SH. We also compared outcomes based on baseline SBP stratified by the median blood pressure. The primary endpoint was time-averaged proportional change in NT-proBNP from baseline through Weeks 4 and 8. A secondary hierarchical outcome (win ratio) consisted of: a) cardiovascular death, b) HF hospitalizations, c) urgent HF visits, and d) change in NT-proBNP. Among 466 randomized patients, 92 (19.7%) experienced SH (sacubitril/valsartan, N=56 [24.0%]; valsartan, N=36 [15.5%], p=0.020). The median time to the first SH event was similar between treatment arms (18 days vs. 15 days, respectively, p=0.42) as was the proportion of first SH events classified as "serious" by investigators. Patients who experienced SH with sacubitril/valsartan were more likely to be White (OR 1.87 [95%CI: 0.31, 11.15]), to have a lower baseline SBP (per 10mmHg increase OR 0.68 [95%CI: 0.55, 0.85]), or to have a left ventricular ejection fraction (LVEF) of >60% (OR 2.21 [95%CI: 1.05, 4.65]). Time-averaged change in NT-proBNP did not differ between patients with baseline SBP ≥128 mmHg vs. SBP<128mmHg (interaction p=0.43). The composite hierarchical outcome for sacubitril/valsartan in patients with baseline SBP≥128mmHg had a win ratio of 1.34 ([95%CI: 0.91, 1.99], p=0.096) vs SBP<128mmHg with a win ratio of 1.09 ([95%CI: 0.73, 1.66], p=0.62; interaction p value=0.42). Among patients with LVEF>40% stabilized after WHF, incident SH was more common with sacubitril/valsartan compared with valsartan. SH was associated with lower baseline SBP, White race, and higher LVEF. Treatment benefits with sacubitril/valsartan may be more pronounced in patients with higher baseline SBP and lower LVEF (≤ 60%). (Funded by Novartis Pharmaceutical Corporation; ClinicalTrials.gov number, NCT03988634.) ABBREVIATIONS: : HFpEF, heart failure with preserved ejection fraction; HFmrEF, heart failure with mildly reduced ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; NT-proBNP, amino terminal-pro b-type natriuretic peptide; SBP, systolic blood pressure; WHF, worsening heart failure.

Excessive fat expenditure in MCT-induced heart failure rats is associated with BMAL1/REV-ERBα circadian rhythmic loop disruption

Fat loss predicts adverse outcomes in advanced heart failure (HF). Disrupted circadian clocks are a primary cause of lipid metabolic issues, but it's unclear if this disruption affects fat expenditure in HF. To address this issue, we investigated the effects of disruption of the BMAL1/REV-ERBα circadian rhythmic loop on adipose tissue metabolism in HF.50 Wistar rats were initially divided into control (n = 10) and model (n = 40) groups. The model rats were induced with HF via monocrotaline (MCT) injections, while the control group received equivalent solvent injections. After establishing the HF model, the model group was further subdivided into four groups: normal rhythm (LD), inverted rhythm (DL), lentivirus vector carrying Bmal1 short hairpin RNA (LV-Bmal1 shRNA), and empty lentivirus vector control (LV-Control shRNA) groups, each with 10 rats. The DL subgroup was exposed to a reversed light–dark cycle of 8 h: 16 h (dark: light), while the rest adhered to normal light–dark conditions (light: dark 12 h: 12 h). Histological analyses were conducted using H&E, Oil Red O, and Picrosirius red stains to examine adipose and liver tissues. Immunohistochemical staining, RT-qPCR, and Western blotting were performed to detect markers of lipolysis, lipogenesis, and beiging of white adipose tissue (WAT), while thermogenesis indicators were detected in brown adipose tissue (BAT). The LD group rats exhibited decreased levels of BMAL1 protein, increased levels of REV-ERBα protein, and disrupted circadian circuits in adipose tissue compared to controls. Additionally, HF rats showed reduced adipose mass and increased ectopic lipid deposition, along with smaller adipocytes containing lower lipid content and fibrotic adipose tissue. In the LD group WAT, expression of ATGL, HSL, PKA, and p-PKA proteins increased, alongside elevated mRNA levels of lipase genes (Hsl, Atgl, Peripilin) and FFA β-oxidation genes (Cpt1, acyl-CoA). Conversely, lipogenic gene expression (Scd1, Fas, Mgat, Dgat2) decreased, while beige adipocyte markers (Cd137, Tbx-1, Ucp-1, Zic-1) and UCP-1 protein expression increased. In BAT, HF rats exhibited elevated levels of PKA, p-PKA, and UCP-1 proteins, along with increased expression of thermogenic genes (Ucp-1, Pparγ, Pgc-1α) and lipid transportation genes (Cd36, Fatp-1, Cpt-1). Plasma NT-proBNP levels were higher in LD rats, accompanied by elevated NE and IL-6 levels in adipose tissue. Remarkably, morphologically, the adipocytes in the DL and LV-Bmal1 shRNA groups showed reduced size and lower lipid content, while lipid deposition in the liver was more pronounced in these groups compared to the LD group. At the gene/protein level, the BMAL1/REV-ERBα circadian loop exhibited severe disruption in LV-Bmal1 shRNA rats compared to LD rats. Additionally, there was increased expression of lipase genes, FFA β oxidation genes, and beige adipocyte markers in WAT, as well as higher expression of thermogenic genes and lipid transportation genes in BAT. Furthermore, plasma NT-proBNP levels and adipose tissue levels of NE and IL-6 were elevated in LV-Bmal1 shRNA rats compared with LD rats. The present study demonstrates that disruption of the BMAL1/REV-ERBα circadian rhythmic loop is associated with fat expenditure in HF. This result suggests that restoring circadian rhythms in adipose tissue may help counteract disorders of adipose metabolism and reduce fat loss in HF.

N-terminal pro-B-type natriuretic peptide as a predictive marker of the outcomes of fibrinolytic therapy in acute ST-elevation myocardial infarction

Abstract Background: Risk assessment is vital in delivering appropriate treatment and enhancing patient outcomes during acute ST-elevation myocardial infarction (STEMI). This study sought to ascertain the significance of NT-proBNP in predicting the outcome of thrombolysis in acute STEMI. Materials and Methods: In this prospective study, we enrolled individuals with acute STEMI who underwent fibrinolytic therapy. Plasma N-terminal-proBNP (NT-proBNP) levels were assessed upon admission. Patients were categorized as thrombolysis success or failure groups based on electrocardiogram (ECG) criteria. The outcomes were measured in terms of in-hospital mortality and adverse cardiovascular events. Results: Thrombolysis achieved success in 59.13% of acute STEMI cases. Patients experiencing failed thrombolysis had a significantly longer mean time to reperfusion than those with successful thrombolysis (4.74 ± 2.42 vs. 5.97 ± 2.35 h, P = 0.0078). The median baseline NT-proBNP concentration was 983 pg/mL (interquartile range 777–2987 pg/mL). The plasma NT-proBNP levels on admission were notably higher in the thrombolysis failure group (P &lt; 0.001). NT-proBNP, time to reperfusion, heart rate, blood urea, and serum uric acid exhibited negative correlations with thrombolysis outcomes. The most prevalent adverse event was cardiac failure. Receiver operating characteristic (ROC) curve analysis indicated a robust association between NT-proBNP and in-hospital mortality. High NT-proBNP (&gt;983 pg/mL) and prolonged time to reperfusion (&gt;6 h) emerged as independent predictors of thrombolysis failure on multivariate logistic regression analysis (P = 0.017 and 0.035, respectively). Conclusion: Elevated plasma NT-proBNP upon admission during acute STEMI serves as a robust predictor for both fibrinolytic therapy failure and in-hospital mortality.

Does Telotristat Have a Role in Preventing Carcinoid Heart Disease?

Carcinoid heart disease (CHD) is a frequent and life-threatening complication in patients with carcinoid tumors. Its clinical management is challenging is some cases since serotonin-induced valve fibrosis leads to heart failure. Telotristat is an inhibitor of tryptophan-hydroxylase (TPH), a key enzyme in serotonin production. Telotristat use in patients with carcinoid syndrome and uncontrollable diarrhea under somatostatin analogs is approved, but its specific role in patients with CHD is still not clear. IN this context, we aimed to explore the effect of telotristat in heart fibrosis using a mouse model of serotonin-secreting metastasized neuroendocrine neoplasm (NEN). To this aim, four treatment groups (n = 10/group) were evaluated: control, monthly octreotide, telotristat alone, and telotristat combined with octreotide. Plasma serotonin and NT-proBNP levels were determined. Heart fibrosis was histologically evaluated after 6 weeks of treatment or when an individual mouse's condition was close to being terminal. Heart fibrosis was observed in all groups. Non-significant reductions in primary tumor growth were observed in all of the treated groups. Feces volume was increased in all groups. A non-significant decrease in feces volume was observed in the octreotide or telotristat-treated groups, while it was significantly reduced with the combined treatment at the end of the study compared with octreotide (52 g reduction; p < 0.01) and the control (44.5 g reduction; p = 0.05). Additionally, plasma NT-proBNP decreased in a non-significant, but clinically relevant, manner in the octreotide (28.2% reduction), telotristat (45.9% reduction), and the octreotide + telotristat (54.1% reduction) treatment groups. No significant changes were observed in plasma serotonin levels. A similar non-significant decrease in heart valve fibrosis was observed in the three treated groups. In conclusion, Telotristat alone and especially in combination with octreotide decreases NT-proBNP levels in a mouse model of serotonin-secreting metastasized NEN, when compared with the control and octreotide, but its effect on heart valve fibrosis (alone and in combination) was not superior to octreotide in monotherapy.

The Importance of Nitric Oxide and Oxidative Stress in Atrial High-Rate Episodes in Patients with Cardiac Devices.

Atrial High Rate Episodes (AHRE) are subclinical atrial tachyarrhythmias detectable by cardiac implantable electronic devices (CIEDs). AHREs have been associated with an increased risk of developing atrial fibrillation (AF), thromboembolism, cardiovascular and cerebrovascular events, and mortality. Although recent studies have assessed the value of oxidative stress markers in patients with AF, the relationships between AHRE and oxidative stress markers, including nitric oxide, has not yet been elucidated. This study aims to investigate the relationship between these markers and AHRE. This prospective, cross-sectional study comprised 180 patients with CIEDs. The study population was divided into two groups based on the presence (n = 78) and absense (n = 102) of AHRE to analyze its association with biomarkers. The AHRE (+) group was significantly older, had a higher prevalence of hypertension, higher NT-proBNP (508.8 ± 249 pg/mL vs. 415.3 ± 292.1; P = 0.037), MDA levels (20.9 ± 4.1 μmol/L vs. 19.1 ± 3.1 μmol/L; P = 0.006), and iNOS activity (1,935.9 ± 326.1 pg/mL vs. 1,677.4 ± 363.2 pg/mL; P < 0.001). Logistic regression analysis identified age, hypertension, MDA (odds ratio [OR]: 1.131, 95%CI: 1.009 - 1.268, P = 0.035), inducible nitric oxide synthase (iNOS) activity (OR = 1.002, 95% CI = 1.001 - 1.003, P < 0.001), and endothelial nitric oxide synthase (eNOS) activity (OR = 0.990, 95% CI = 0.986 - 0.984, P < 0.001) as independent predictors of AHRE. The study findings indicated that plasma levels of NT-proBNP, MDA, nitric oxide, and the expression of iNOS and eNOS were significantly associated with AHRE. Moreover, elevated plasma MDA concentrations, increased iNOS activity, and decreased eNOS activity were identified as independent predictors of AHRE.

Significance of Galectin-3 and N-terminal pro b-type natriuretic peptide in the prediction of atrial fibrillation after cardiac surgery.

Post-operative atrial fibrillation (POAF) is a frequent complication after cardiac surgery. It is associated with prolonged hospital stay, increased morbidity, mortality rate and economic costs. The aim of the study was to determine the association between the values of Galectin3 and N-terminal pro-B-type natriuretic peptide (NTproBNP) with POAF after cardiac surgery. A prospective study enrolled patients aged 18-85 years old admitted due to elective coronary artery bypass graft surgery (CABG) or CABG + aortic valve replacement. The plasma Galectin-3 and NT-proBNP levels were measured one day before surgery postoperative days 1 and 7. The study included a total of 103 patients. POAF was registered in 45 patients. The mean age of patients in whom POAF occurred was 68.8 years, while other patients' mean age was 65.5 years (p=0.028). Patients with POAF did not differ from the group without POAF in the values of Galectin-3 and NT-proBNP preoperatively as well as on the first and seventh postoperative days. Changes in Galectin-3 levels on the first postoperative day had statistically significant value for predicting POAF (AUC=0.627 0.509-0.745 , p<0.05). Decrease in Galectin-3 level con centration on the first postoperative day over 17% increases the risk of developing AF. Preoperative values of Galectin-3 and NTproBNP are not associated with POAF development after cardiac surgery.

Correlation Between B line in Lung Ultrasound and Plasma NT-proBNP Level in Patients with Acute Heart Failure

Background: Acute heart failure (AHF) is a major cause of morbidity and mortality worldwide. Although this is a common cause of dyspnoea, its diagnosis still represents a challenge. Lung ultrasound (LUS) is an emerging point-of-care diagnostic tool. Objective: The aim of the study was to assess the Correlation between B line in lung ultrasound and plasma NT-proBNP level in patients with acute heart failure &amp; thus to assess the predictive value of B line in patients with suspected acute heart failure. Materials and Method: Crosssectional observational study conducted in cardiology department of BSMMU from October 2020 to September 2021. Study procedure: 36 patients presenting with of shortness of breath or heart failure diagnosis were enrolled meeting inclusion and exclusion criteria. The number of B-lines by Lung Ultrasound was measured. Correlation between number of B-lines on lung ultrasonography and NT-proBNP level were analyzed. Results: There is a positive correlation between the number of B-lines and the NT-proBNP levels (r=0.55, p&lt; 0.01) in acute heart failure patients. Conclusion: Patients presenting with acute shortness of breath with raised NTproBNP level, B line detection &amp;quantification by lung ultrasound can be used as a tool for a faster diagnosis and decision-making on lung congestion in acute heart failure. University Heart Journal 2023; 19(1): 15-19

Vascular endothelial growth factor-D plasma levels in fluid overload and cardiac function evaluation of elderly patients with cardiovascular disease.

This study aimed to investigate the clinical significance of vascular endothelial growth factor (VEGF) subtypes and growth differentiation factor-15 (GDF-15) plasma levels in evaluating the fluid overload and cardiac function of elderly patients with cardiovascular disease. The plasma levels of VEGF-C, VEGF-D, and GDF-15 were measured using ELISA. Their correlations with N-terminal pro B-type natriuretic peptide (NT-Pro BNP) and echocardiography data were analyzed. 1. Higher plasma levels of VEGF-D and GDF-15 were observed in elderly patients with cardiovascular disease and heart failure(P < .01). VEGF-D plasma levels were higher in patients with chronic heart failure than those with acute myocardial infarction (P < .01). VEGF-D plasma levels were positively correlated with amino-terminal pro-B type natriuretic peptide (NT-pro BNP) (P < .001). VEGF-D plasma levels were positively correlated with echocardiographic parameters, including left atrial diameter, left ventricular end-diastolic diameter and left ventricular ejection fraction, in patients with cardiovascular disease (P < .01). 2. VEGF-C plasma levels were higher in acute myocardial infarction group (P < .05). The plasma levels of VEGF-C were not correlated with either VEGF-D or NT-pro BNP plasma levels. VEGF-C plasma levels had no correlation with echocardiographic parameters. 3. GDF-15 plasma levels were positively correlated with sera biomarkers of cardiac injury (creatine kinase isoenzyme MB and cardiac troponin I). GDF-15 plasma levels were positively correlated with urinary biomarkers of tubular injury (N-acetyl-β-galactosidase and α1-microglobulin). Both GDF-15 and NT-pro BNP plasma levels were correlated with age, estimated glomerular filtration rate (eGFR), and nutritional biomarkers (albumin and hemoglobin plasma levels). VEGF-D plasma levels is a potential biomarker of fluid overload and cardiac function in elderly patients with cardiovascular disease. Age, nutrition, and kidney injury are factors influencing both GDF-15 and NT-pro BNP plasma levels in estimating cardiac function and fluid overload.

Elevated NT-proBNP predicts worse clinical outcome in patients after acute ischemic stroke

Abstract Background/introduction Elevated levels of NT-proBNP in ischemic stroke patients may indicate increased cardiac stress, which can be associated with poor outcome. However, clinical utility and cut offs are not completely known. Purpose We aimed to describe relation between NT-proBNP elevation with stroke severity and poor clinical outcome in patients after acute ischemic stroke (AIS). Methods Patients after AIS were enrolled in our study. Blood samples were obtained from patients at the time of admission, 24 and 48 hours later to determine the plasma levels of NT-proBNP. Twelve-lead ECGs were obtained at the time of admission, 24 and 48 h later. Standard echocardiographic examination was performed within the first 7 days of hospitalization if patients were eligible. Demographic characteristics, clinical data, functional outcome, and all-cause mortality were compared between groups according to NT-proBNP levels (NT-proBNP ≤ 125 pg/ml; &amp;gt;125 and ≤450 pg/ml; &amp;gt;450 pg/ml). National Institutes of Health Stroke Scale (NIHSS) at the time of admission and the modified Rankin Scale (mRS) 90 days following the patient’s discharge from the hospital were used to assess stroke severity and clinical outcome. All analyses were performed with SPSS 29.0 (SPSS Inc). Results Between August 2020 and August 2022, 177 patients after AIS were enrolled. Elevated NT-proBNP &amp;gt;125pg/ml was observed in 82 patients (46,3%), 34 patients (19,2%) presented with NT-proBNP &amp;gt;450pg/ml. Most common comorbidities included arterial hypertension, dyslipidemia, type 2 DM and atrial fibrillation. In analysis, we observed a connection between elevated NT-proBNP with unfavorable outcome evaluated by mRS at 90 days (p&amp;lt;0.001) and with all-cause death at 30 days (P=0.001) and 90 days (P&amp;lt;0.001). Kaplan-Meier survival curve showed that all-cause mortality was significantly higher in patients with elevated NT-proBNP (P&amp;lt;0.001), however with no difference between elevation &amp;gt;125pg/ml and &amp;gt;450pg/ml (p=0.14). In survival analysis, there was close to significant association between patients who presented with elevated NT-proBNP&amp;gt;125pg/ml and &amp;gt;20% change in value comparing to those with elevated NT-proBNP without subsequent change &amp;gt;20%. Moreover, we observed a connection with stroke severity evaluated by NIHSS (p=0.005). In ECG analysis, we showed higher occurrence of T wave inversion (P&amp;lt;0.001), ST segment depression (P&amp;lt; 0.001) and QTc prolongation (P=0.003) in patients with elevated NT-proBNP. In multivariate regression analysis elevated NT-proBNP was associated with atrial fibrillation, high-sensitive troponin I elevation and age≥75 years. Conclusion The results show that elevated NT-proBNP is associated with stroke severity, unfavorable functional outcome, and short-term mortality in patients after acute ischemic stroke. Moreover, we described connection between NT-proBNP elevation and ECG changes.Kaplan Meier survival analysisAssociation worse outcome and severity

Abstract 15257: The “Free Choice” Diet-Induced Obese Nonalcoholic Steatohepatitis Hamster, a Clinically Relevant Model for Evaluating Drugs Targeting Heart Failure With Preserved Ejection Fraction

Intro: Heart failure with preserved ejection fraction (HFpEF) is frequently associated with multiple comorbidities including nonalcoholic steatohepatitis (NASH) and obesity. Drug development for HFpEF is partly hampered by the limitations of preclinical models, such as diet-induced obese mouse and rat. Hypothesis: To overcome these limitations, we recently established a nutritional hamster model developing obesity, with human features for dyslipidemia NASH, and HFpEF. To confirm the relevance of our model, we tested whether the clinical benchmarks empagliflozin (EMPA, a SGLT2 inhibitor), vardenafil (VAR, a PDE5 inhibitor) and semaglutide (SEMA, a GLP-1r agonist) would improve HFpEF. Methods: To induce obesity, NASH and HFpEF, hamsters were fed with a free choice diet, which presents hamsters with a choice between control chow or high fat/cholesterol diet, and normal or 10% fructose water for 20 weeks. Obese hamsters were then randomized based on echocardiography parameters, i.e., E/A ratio and ejection fraction (EF) and were treated QD for 5 weeks with vehicle, EMPA (30mg/kg), VAR (10mg/kg) or SEMA (0.06mg/kg). Chow fed hamsters were used as control. Results: Compared with control, echocardiography in obese hamsters showed cardiac remodeling, preserved systolic function and normal EF. Free choice fed hamsters had impaired diastolic function with higher E/A (2.0±0.1 vs 1.41±0.03 in control, p&lt;0.001), while the inverted E’/A’ (0.8± 0.1 vs 1.3±0.04, p&lt;0.001), a sign of relaxation default, suggested restrictive filling pattern. Increased E/E’ suggested higher filling pressure (18-20 vs 12-14 in control, p&lt;0.01). Plasma NT-proBNP levels were also increased (p&lt;0.05 vs. control). Compared with vehicle, all drug treatments alleviated diastolic dysfunction: E/A returned to control values (E/A=1.4-1.5) with VAR (p&lt;0.001 vs. vehicle), EMPA (p&lt;0.01) and SEMA (p&lt;0.05). As well, E’/A’ was normalized (p&lt;0.01 for all), and E/E’ was also reduced (p&lt;0.05 for all). EMPA and VAR reduced NT-proBNP levels (p&lt;0.05 vs. vehicle). Conclusion: Our data indicate that, VAR, EMPA and SEMA improved diastolic function in the obese NASH hamster. This novel model provides a unique alternative to mice and rats limitations for evaluating drugs targeting HFpEF.

Microvascular endothelial dysfunction in skin is associated with higher risk of heart failure with preserved ejection fraction in women with type 2 diabetes: the Hoorn Diabetes Care System Cohort

BackgroundMicrovascular dysfunction plays a crucial role in complications of type 2 diabetes and might contribute to heart failure with preserved ejection fraction (HFpEF), a disease that disproportionally affects women. We aimed to investigate if presence and degree of microvascular dysfunction (MVD) in skin relates to markers of left ventricular diastolic dysfunction (LVDD) and HFpEF risk in adults with type 2 diabetes, and whether sex modifies this association.MethodsWe recruited 154 participants (50% women) from the Hoorn Diabetes Care System Cohort, a prospective cohort study, for in vivo evaluation of skin MVD, echocardiography and blood sampling. MVD was assessed by laser speckle contrast analysis combined with iontophoresis of insulin, acetylcholine and sodium nitroprusside (SNP). We performed a cross-sectional analysis of the association between perfusion responses and echocardiographic and clinical markers of LVDD and the H2FPEF score by multivariable linear regression analysis adjusted for confounders. Sex was evaluated as a potential effect modifier and the analysis was stratified.ResultsMean age was 67 ± 6y, mean HbA1c 7.6 ± 1.3%. Women were more frequently obese (54.5 vs. 35.1%), had higher NT-proBNP plasma levels (80, IQR:34–165 vs. 46, 27–117 pg/ml) and E/E’(13.3 ± 4.3 vs. 11.4 ± 3.0) than men. Eleven women and three men were diagnosed with HFpEF, and showed lower perfusion response to insulin than those without HFpEF. A lower perfusion response to insulin and acetylcholine was associated with higher HFpEF risk in women, but not men (10% decreased perfusion response was associated with 5.8% [95%CI: 2.3;9.4%] and 5.9% [1.7;10.1%] increase of the H2FPEF score, respectively). A lower perfusion response to SNP was associated with higher pulmonary arterial systolic pressure in men while a lower perfusion response to acetylcholine associated with higher LV mass index in women and with worse LV longitudinal strain in the total population. No significant associations were found between perfusion responses and conventional LVDD markers.ConclusionsImpaired microvascular responses to insulin and acetylcholine in skin confers a higher risk of HFpEF in women with type 2 diabetes. In vivo measures of systemic MVD could represent novel risk markers for HFpEF, opening new avenues for the prevention of HFpEF in type 2 diabetes.

Secondary leaflet tethering in patients with severe degenerative mitral regurgitation and its association with the severity of mitral regurgitation.

The purpose of the study was to determine the association between vena contracta area (VCA) and secondary leaflet tethering among mitral valve prolapse (MVP) patients, and thus to further identify and characterize an MVP with pathological leaflet tethering (MVPt+) phenotype. We prospectively evaluated 94 consecutive MVP patients with significant mitral regurgitation (MR) and 21 healthy controls. MVPt+ group was defined as tenting volume index (TVi)>.7mL/m2 . The three-dimensional (3D) geometry of mitral valve apparatus and VCA was measured with dedicated quantification software. Of the 94 patients with MVP and significant MR, 31 patients showed a TVi>.7mL/m2 and entered the MVP with leaflet tethering (MVPt+) group. In stepwise multivariate analysis, only prolapse volume index and TVi were independently associated with 3D VCA. 3D VCA, annular area index, and plasma levels of NT-proBNP were independently correlated with the severity of leaflet tethering. ROC curve revealed that a 3D VCA ≥ .55 cm2 is the optimal cutoff point to predict MVPt+ phenotype. Secondary leaflet tethering is a significant mechanism behind severe degenerative MR, resulting in an MVPt+ phenotype featuring more advanced morphological and hemodynamical characteristics.

DECREASED SERUM LEVELS OF IRISIN PREDICTED HEART FAILURE IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Objective: Type 2 diabetes mellitus (T2DM) is a powerful risk factor for heart failure (HF) contributing to untoward clinical course of the condition. Although natriuretic peptides are validated biomarkers to rule out HF, the accuracy of them in prediction of HF in T2DM is not optimal. The aim of the study was to investigate whether serum irisin has additional discriminative capacity for HF in patients with T2DM. Design and method: We prospectively included 183 T2DM patients with aged 41 to 65 years (153 patients with any phenotypes of HF and 30 patients without HF) in the study. The following criteria such as age &gt; 18 years, established T2DM regardless of HF, and the levels of HbAc1 less 6.9% were used as inclusion ones. All patients underwent general examination, echocardiography and Doppler. The plasma levels of NT-proBNP and irisin were measured using ELISA Results: The Receive Operation Characteristics curve analysis showed that the well-balanced cut-off point for serum concentration of irisin (HF vs non-HF) were 10.4 ng/mL (area under curve [AUC] = 0.96 (95% CI = 0.88 – 1.00), sensitivity = 81.0%, specificity = 88.0%; P = 0.0001). Cutoff point of NT-proBNP (HF vs non-HF) was 750 pmol/L (AUC = 0.96; 95% CI = 0.59 - 0.98; sensitivity = 72.7%, specificity 76.5%, p = 0.0001). Multivariate logistic model yielded that the serum levels of irisin &lt; 10.4 ng/mL (OR = 1.30; P = 0.001) and NT-proBNP &gt; 750 pmol/mL (OR = 1.17; P = 0.042), left atrial volume index (LAVI) &gt; 34 mL/m2 (OR = 1.06; P = 0.042) remained to be strong predictors for HF, whereas LAVI did not. Add-on of irisin levels &lt; 10.4 ng/mL to the predictive model constructed from NT-proBNP (&gt; 750 pg/mL) significantly improved discriminatory potency of the whole model for HF. Conclusions: We found that decreased serum levels of irisin significantly predicted HF in T2DM patients. This finding may open a new approach for HF risk stratification in T2DM patients.

Mitral Valve Repair in Advanced Age Groups: Does Cardiac Age Differ from Chronological Age?

Advanced age is a risk factor in cardiac surgery contributing significantly to a worse outcome. The reasons are frailty and multimorbidity. In this study, we asked: Is there an aging of the heart which differs from chronological age? Propensity score matching was performed between 115 seniors ≥ 80 years and 345 juniors < 80 years. After the patients were found to be comparable in terms of cardiac and noncardiac disease and risk profiles, they were further analyzed for cardiac parameters. In addition, the seniors and juniors were compared in terms of cardiac health and postoperative outcome. Furthermore, the patients were subdivided into several age groups (<60 years, 60-69 years, 70-79 years, and >80 years) and compared regarding outcome. The seniors demonstrated significantly lower tricuspid annular plane systolic excursion (TAPSE), significantly more frequent diastolic dysfunction, significantly higher plasma levels of NT-proBNP, and significantly larger left ventricular end-diastolic and end-systolic diameters and left atrial diameters (p < 0.001, respectively). Furthermore, in-hospital mortality and most postoperative complications were significantly higher in seniors compared with juniors. While old cardiac healthy patients showed better outcome than old cardiac aged patients, the outcome from young cardiac aged patients was better than old cardiac aged patients. The outcome and survival deteriorated with increasing life decades. The elderly suffer significantly more from cardiac deterioration, i.e., cardiac aging, and show higher multimorbidity. Mortality risk is significantly higher and they suffer more often from a complicated postoperative course compared to younger patients. Further approaches to prevention and treatment of cardiac aging are needed to address the needs of an aging society.