Elevated B-Type Natriuretic Peptide Level as a Residual Risk Factor for Ventricular Arrhythmias Among Patients Undergoing Cardiac Resynchronization Therapy With Improved Left Ventricular Ejection Fraction.

Background: Patients who achieve improved left ventricular ejection fraction (LVEF >35%) with cardiac resynchronization therapy (CRT) are at a lower risk of ventricular arrhythmia (VA). Little is known about the significance of the B-type natriuretic peptide (BNP) level for the risk of VA. This study investigated the risk factors for VA in CRT and the risk stratification of VA with BNP in CRT with improved LVEF. Methods and Results: This study evaluated 352 CRT patients from 2012 to 2020. Patients were categorized into 2 groups: improved LVEF (impEF; LVEF >35%), and low LVEF (lowEF; LVEF ≤35%). The serum BNP levels 6 months after CRT device implantation were measured. The primary endpoint was defined as VA requiring treatment with anti-tachycardia pacing or shock or persisting for ≥30 s. Overall, 102 patients had improved LVEF. The impEF group had a significantly lower VA risk than the lowEF group. Patients with low BNP had a lower VA risk than those with high BNP; however, no significant difference was observed between patients with high BNP and those in the lowEF group. Univariate analysis revealed that high BNP was a predictor of VA in the impEF group. Conclusions: The VA risk is reduced with improved LVEF after CRT but not with high BNP levels. The post-BNP level after CRT implantation is a useful marker for predicting VA in patients with improved LVEF.

Atrial natriuretic peptide (ANP) modulates stress-induced autophagy in endothelial cells.

Atrial natriuretic peptide (ANP), a cardiac hormone involved in the regulation of water/sodium balance and blood pressure, is also secreted by endothelial cells, where it exerts protective effects in response to stress. Autophagy is an intracellular self-renewal process involved in the degradation of dysfunctional cytoplasmic elements. ANP was recently reported to act as an extracellular regulator of cardiac autophagy. However, its role in the regulation of endothelial autophagy has never been investigated. Here, we tested the effects of ANP in the regulation of autophagy in human umbilical vein endothelial cells (HUVECs). We found that ANP rapidly increases autophagy and autophagic flux at physiological concentrations through its predominant pathway, mediated by natriuretic peptide receptor type A (NPR-A) and protein kinase G (PKG). We further observed that ANP is rapidly secreted by HUVEC under stress conditions, where it mediates stress-induced autophagy through autocrine and paracrine mechanisms. Finally, we found that the protective effects of ANP in response to high-salt loading or tumor necrosis factor (TNF)-α are blunted by concomitant inhibition of autophagy. Overall, our results suggest that ANP acts as an endogenous autophagy activator in endothelial cells. The autophagy mechanism mediates the protective endothelial effects exerted by ANP.

Cardiomyocyte-derived C-type natriuretic peptide diminishes myocardial ischaemic injury by promoting revascularisation and limiting fibrotic burden.

BACKGROUND: C-type natriuretic peptide (CNP) is a significant player in the maintenance of cardiac and vascular homeostasis regulating local blood flow, platelet and leukocyte activation, heart structure and function, angiogenesis and metabolic balance. Since such processes are perturbed in myocardial infarction (MI), we explored the role of cardiomyocyte-derived CNP, and pharmacological administration of the peptide, in offsetting the pathological consequences of MI. METHODS: Wild type (WT) and cardiomyocyte-restricted CNP null (cmCNP-/-) mice were subjected to left anterior descending coronary artery (LADCA) ligation and acute effects on infarct size and longer-term outcomes of cardiac repair explored. Heart structure and function were assessed by combined echocardiographic and molecular analyses. Pharmacological administration of CNP (0.2mg/kg/day; s.c.) was utilized to assess therapeutic potential. RESULTS: Compared to WT littermates, cmCNP-/- mice had a modestly increased infarct size following LADCA ligation but without significant deterioration of cardiac structural and functional indices. However, cmCNP-/- animals exhibited overtly worse heart morphology and contractility 6 weeks following MI, with particularly deleterious reductions in left ventricular ejection fraction, dilatation, fibrosis and revascularization. This phenotype was largely recapitulated in animals with global deletion of natriuretic peptide receptor (NPR)-C (NPR-C-/-). Pharmacological administration of CNP rescued the deleterious pathology in WT and cmCNP-/-, but not NPR-C-/-, animals. CONCLUSIONS AND IMPLICATIONS: Cardiomyocytes synthesize and release CNP as an intrinsic protective mechanism in response to MI that reduces cardiac structural and functional deficits; these salutary actions are primarily NPR-C-dependent. Pharmacological targeting of CNP may represent a new therapeutic option for MI.

Impact of first-line antihypertensive drug class and intensity on NT-proBNP improvement and cardiovascular outcomes among hypertensive patients with pre-heart failure: findings from SPRINT trial.

Five first-line classes of antihypertensive drugs are recommended for hypertension treatment. However, it is unclear which class should be chosen for hypertensive patients with pre-heart failure (pre-HF). The study aimed to investigate the association between antihypertensive drug classes and intensity with probability of NT-proBNP (N-terminal pro-B-type natriuretic peptide) improvement and risk of cardiovascular events among pre-HF hypertensive patients. Utilizing the data from SPRINT, we included pre-HF hypertensive patients, identified by NT-proBNP ≥125 pg/mL at baseline. NT-proBNP improvement is defined as a reduction of ≥50% to a level below 125 pg/mL. A total of 3293 patients (mean age: 71.9 years; female: 43.8%) were included. NT-proBNP improvement was observed in 415 patients (12.6%) over 1-year follow up. Thiazide-type diuretics users were associated with a higher likelihood of NT-proBNP improvement (odds ratio [OR], 1.33; 95% confidence interval [CI], 1.05-1.70), a lower risk of HF (hazard ratio [HR], 0.54; 95% CI, 0.37-0.78) and primary composite outcome (HR, 0.72; 95% CI, 0.57-0.89). ACEI/ARB users were only associated with a lower risk of primary composite outcome (HR, 0.80; 95% CI, 0.63-0.99). In contrast, beta-blockers users were associated with a lower likelihood of NT-proBNP improvement (OR, 0.43; 95% CI, 0.34-0.55), while a higher risk of HF (HR, 1.79; 95% CI, 1.21-2.64) and primary composite outcome (HR, 1.48; 95% CI, 1.18-1.87). These associations varied across subgroups of different drug intensities. This post hoc analysis supports the use of thiazide-type diuretics and ACEI/ARB for prevention of cardiovascular events. The use of beta-blockers is associated with an increased risk of HF and primary outcomes, which requires further validation. Association between antihypertensive drug classes and intensity with NT-proBNP improvement and long-term clinical outcome.

Relationship between initial B-type natriuretic peptide levels and detection of atrial fibrillation with an insertable cardiac monitor in cryptogenic stroke: CRYPTON-ICM registry.

High B-type natriuretic peptide (BNP) levels are associated with new atrial fibrillation (AF). This study investigated the distribution of AF detection rates according to BNP levels in patients with cryptogenic stroke (CS) using an insertable cardiac monitor (ICM). We enrolled consecutive patients with CS who underwent ICM implantation between October 2016 and September 2020 at eight stroke centers in Japan. Those with BNP levels were divided into three groups by tertiles. We evaluated the association of BNP levels with AF detection. Youden's index was calculated to identify the optimal cutoff for BNP. Of 417 patients, we analyzed 266 patients with BNP data. The tertile range of BNP level was 19.0 to 48.5 pg/mL. AF detection rate was 13.3%/year, 12.8%/year, and 53.7%/year in the low-BNP (≤19.0), mid-BNP (19.1-48.4), and high-BNP (≥48.5) groups, respectively (log-rank trend p < 0.01). Compared with low-BNP group, the adjusted hazard ratios for AF detection in mid-and high-BNP groups were 0.91 [95% confidence interval (CI) 0.46-1.78] and 2.17 (95% CI 1.14-4.13), respectively. Receiver operating characteristic curve analysis showed the optimal cutoff value was 43.4 pg/mL. The area under curve using BNP to predict AF detection was 0.69. The BNP level was associated with AF detection in patients with CS. This relationship changed around the BNP levels of 40-50 pg/mL.

Deletion of AT1a receptors selectively in the proximal tubules alters the hypotensive and natriuretic response to ANP via NPRA/cGMP/NO Signaling.

In the kidney, vasoactive peptide hormones angiotensin II (Ang II), via AT1a receptors, and atrial natriuretic peptide (ANP), via NPRA receptors, reportedly play counteracting roles to regulate proximal tubule Na+ reabsorption and maintain blood pressure homeostasis. However, how AT1a and NPRA receptors interact in the proximal tubules and whether deletion of AT1 (AT1a) receptors selectively in the proximal tubules alters the hypotensive and natriuretic effects of ANP) have not been studied previously. The present study used a novel mouse model with proximal tubule-specific knockout of AT1a receptors to test the hypothesis that deletion of AT1a receptors selectively in the proximal tubules augments the hypotensive and natriuretic responses to ANP. Basal blood pressure was about 16 ± 3 mmHg lower, fractional proximal tubule Na+ reabsorption was significantly lower, whereas 24 h urinary Na+ excretion was significantly higher in PT-Agtr1a-/- than in wild-type mice (P<0.01). Infusion of ANP for 2 weeks (0.5 mg/kg/day, i.p.) further significantly decreased blood pressure and increased the natriuretic response in PT-Agtr1a-/- mice by inhibiting proximal tubule Na+ reabsorption (P<0.01). These augmented hypotensive and natriuretic responses to ANP in PT-Agtr1a-/- mice were associated with increased plasma and kidney cGMP levels (P<0.01), kidney cortical NPRA and NPRC mRNA expression (P<0.01), total and phosphorylated endothelial nitric oxide synthase (eNOS) (P<0.01), and urinary nitric oxide (NO) excretion (P<0.01). Taken together, the results of the present study support important physiological roles of Ang II/AT1a and ANP/NPRA signaling pathways in the proximal tubules to regulate proximal tubule reabsorption and maintain blood pressure homeostasis.

Natriuretic Peptides, Kidney Function, and Clinical Outcomes in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: N-terminal pro-B-type natriuretic peptides (NT-proBNPs) are guideline-recommended biomarkers for risk stratification in patients with heart failure. However, NT-proBNP levels are often elevated in chronic kidney disease, introducing uncertainty about their prognostic relevance in persons across a broad range of estimated glomerular filtration rate (eGFR). OBJECTIVES: The aim of this study was to assess the association of NT-proBNP with cardiovascular and mortality outcomes in patients with heart failure and mildly reduced or preserved ejection fraction, stratified by baseline kidney function. METHODS: A pooled analysis was conducted of participants with NT-proBNP and eGFR measured at baseline in the I-PRESERVE (Irbesartan in Heart Failure and Preserved Ejection Fraction), TOPCAT (Americas region) (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function), PARAGON (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction), and DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure) trials. The relationship between NT-proBNP and eGFR was assessed using piecewise linear regression. Using multivariable Cox and Poisson regression models, the association of NT-proBNP with outcomes across a range of eGFR was evaluated. The primary outcome was hospitalization for heart failure or cardiovascular death. RESULTS: Among 14,831 participants (mean age: 72.1 years; 50.3% female; mean eGFR: 63.3 mL/min/1.73 m2, and median NT-proBNP: 840 pg/mL) followed up for a median 33.5 months, there were 3,092 primary outcomes. NT-proBNP levels increased by 9%, 8%, and 23% per 10 mL/min/1.73 m2 lower eGFR in patients with baseline eGFR ≥60, 45-<60, and <45 mL/min/1.73 m2, respectively (P for nonlinearity < 0.001). Each doubling in NT-proBNP was associated with a 37% relative increase in the primary outcome (HR: 1.37; 95% CI: 1.34-1.41), consistent across different eGFR categories (P for interaction = 0.42). For the same incidence of the primary outcome, NT-proBNP levels were approximately 2.5- to 3.5-fold lower in patients with eGFR <45 mL/min/1.73 m2, compared with patients with eGFR ≥60 mL/min/1.73 m2. Similar patterns were observed across all outcomes studied, including cardiovascular and noncardiovascular death. CONCLUSIONS: The same NT-proBNP concentration predicts a substantially higher absolute risk of adverse outcomes for people with heart failure and reduced kidney function, compared with those with preserved kidney function. These data call into question proposals for higher NT-proBNP references ranges in people with CKD, and suggest that reduced kidney function per se should not be a reason to disregard higher NT-proBNP levels.

N-terminal pro-brain natriuretic peptide is associated with pulmonary hypertension or diastolic dysfunction in patients with systemic sclerosis: An Australian prospective cross-sectional study.

Introduction: Pulmonary arterial hypertension and left ventricular diastolic dysfunction are associated with significant morbidity and mortality in systemic sclerosis. N-terminal pro-brain natriuretic peptide has been proposed as part of composite screening algorithms for pulmonary arterial hypertension. Our aim was to assess the prevalence of pulmonary hypertension and diastolic dysfunction, and evaluate their association with serum N-terminal pro-brain natriuretic peptide in systemic sclerosis patients. Methods: Patients with systemic sclerosis were prospectively enrolled to undergo N-terminal pro-brain natriuretic peptide testing and transthoracic echocardiography at a tertiary Australian centre from January to October 2022. We collected demographic and transthoracic echocardiography variables including pulmonary hypertension estimated by tricuspid regurgitant velocity and diastolic dysfunction assessed by the ASE/EACVI 2016 guidelines. Pearson's correlation coefficient was used to evaluate association between N-terminal pro-brain natriuretic peptide and echocardiographic parameters. Results: Sixty-one patients were enrolled (median age = 62 years (interquartile range = 55-69 years); 84% female). Two-thirds of patients had limited systemic sclerosis (40/61). Five patients (8%) had high likelihood of pulmonary hypertension by transthoracic echocardiography. Seven patients (11%) had diastolic dysfunction; however, seven patients (11%) had indeterminate diastology. Six patients underwent right heart catheterisation, with five patients diagnosed with pulmonary hypertension. N-terminal pro-brain natriuretic peptide in patients with pulmonary hypertension or diastolic dysfunction was significantly higher (median = 207 and 226 pg/mL, respectively) compared to patients without either condition (median = 69 pg/mL, p = 0.01). N-terminal pro-brain natriuretic peptide showed a statistically significant although limited correlation with estimated pulmonary pressures measured by tricuspid regurgitant velocity (r = 0.44, p = 0.002) and left ventricular filling pressures (r = 0.27, p = 0.04). Conclusion: Pulmonary hypertension and diastolic dysfunction are both observed in systemic sclerosis. N-terminal pro-brain natriuretic peptide is associated with both conditions; however, it cannot distinguish between the two disease processes. Right heart catheterisation may be required to make this distinction.

Association between physical activity and the N-terminal pro-brain natriuretic peptide in a middle-aged Japanese population: The interaction with alcohol consumption, 2005-2006.

OBJECTIVE: Higher N-terminal pro-brain natriuretic peptide (NT-proBNP) levels are a strong risk factor for cardiovascular disease. The current study aimed to clarify the cross-sectional association of physical activity (PA) with NT-proBNP and to identify the interaction of PA with alcohol consumption or cigarette smoking in middle-aged individuals. METHODS: The study included 4613 individuals (1824 men and 2789 women) (November 2005-November 2006). Total PA, steps, light-intensity PA (LPA), and moderate-to-vigorous-intensity PA (MVPA) were assessed using accelerometer. Serum NT-proBNP levels were measured. Cross-sectional associations of total PA and steps with NT-proBNP were analyzed using multiple regression with adjustment for potential confounders. The isotemporal substitution model was used to assess activity intensity-specific association. The interaction between PA and alcohol consumption or smoking was also examined. RESULTS: Total PA was independently and inversely associated with NT-proBNP in the entire sample (P = 0.04). The inverse association of substituting LPA with MVPA for NT-proBNP was clearer in men than in women (Pinteraction = 0.04). Inverse associations of total PA or steps with NT-proBNP were clearer in heavy drinkers than in moderate drinkers and non-drinkers in the entire sample (Pinteraction < 0.05). In men, the inverse association of substituting LPA with MVPA for NT-proBNP was also clearer in heavy drinkers (Pinteraction = 0.02). No interactions of PA with smoking were detected. CONCLUSIONS: Higher total PA was associated with better NT-proBNP in middle-aged individuals. Additionally, the effect of substituting LPA with MVPA on NT-proBNP was greater in men than in women. Furthermore, the association between PA and NT-proBNP may be modified by alcohol consumption.

Cholecystokinin regulates atrial natriuretic peptide secretion through activation of NOX4-Sirt1-LEF1 signaling in beating rat hypoxic atria.

The mammalian cardiac myocytes not only synthesize and secrete atrial natriuretic peptide (ANP), but also express cholecystokinin (CCK) and its receptors (CCK1R and CCK2R). However, atrial CCK expression patterns and its effects on ANP secretion during hypoxia are unclear. Therefore, this study is aimed to investigate the effect of hypoxia on the expression levels of CCK and its receptors, as well as the underlying mechanisms involved in regulating hypoxia-induced ANP secretion in isolated beating atria. The results of this study showed that acute hypoxia significantly upregulated expression of CCK and CCK1R as well as CCK2R through activation of hypoxia-inducible factor 1α-apelin signaling. Endogenous CCK induced by hypoxia markedly upregulated the expression of silent information regulator factor 2-related enzyme 1 (Sirt1) and its downstream nuclear factor erythroid­2­related factor 2 (Nrf2) via the activation of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), leading to increase of activating T cell factor (TCF) 3 and TCF4/ lymphoid enhancer factor (LEF) 1, ultimately promoting hypoxia-induced ANP secretion. In addition, siRNA-mediated knockdown of LEF1 dramatically attenuated hypoxia-induced increase of ANP expression in HL-1 atrial myocytes. These results indicated endogenous CCK induced by hypoxia promoted hypoxia-induced ANP secretion by activation of NOX4-Sirt1-TCF3/4-LEF1 signaling pathway.

Plasma renin activity as a marker for predicting the antihypertensive effect of switching to sacubitril/valsartan in treated hypertensive patients: Usefulness in daily clinical practice.

The authors investigated the antihypertensive effect of sacubitril/valsartan (Sac/Val) when switching from other drugs and assessed whether brain natriuretic peptide (BNP) or plasma renin activity (PRA) before drug switching was a predictor of blood pressure lowering after switching to Sac/Val. In 92 patients with treated hypertension, clinic blood pressure, plasma BNP, and PRA were examined before and after switching to Sac/Val. Clinic systolic and diastolic blood pressures significantly decreased after drug switching to Sac/Val (p < .0001, respectively). The level before drug switching of BNP had no correlation with the change in systolic blood pressure (Δ-SBP) before and after switching to Sac/Val, but that of PRA was significantly correlated with Δ-SBP (r = .3807, p = .0002). A multiple regression analysis revealed that PRA before drug switching was an independent determinant of Δ-SBP. Our findings suggest that low PRA may become a useful marker to predict the antihypertensive effect of switching to Sac/Val in treated hypertensive patients.

Natriuretic peptides and soluble ST2 improves echocardiographic diagnosis of elevated left ventricular filling pressures.

Elevated filling pressure of the left ventricle (LV) defines diastolic dysfunction. The gold standard for diagnosis is represented by the measurement of LV end-diastolic pressure (LVEDP) during cardiac catheterization, but it has the disadvantage of being an invasive procedure. This study aimed to investigate the correlation between LVEDP and cardiac serum biomarkers such as natriuretic peptides (mid-regional pro-atrial natriuretic peptide [MR-proANP], B-type natriuretic peptide [BNP], and N-terminal prohormone BNP [NT-proBNP]), soluble ST2 (sST2), galectin-3 and mid-regional pro-adrenomedullin (MR-proAMD). Consecutive patients hospitalized in a tertiary center and undergoing left cardiac catheterization were included in the study. Diastolic dysfunction was considered present if the end-expiratory LVEDP was ≥ 15 mmHg. Cardiac biomarkers were determined from pre-procedural peripheral venous blood samples. A total of 110 patients were included, of whom 76 (69.0%) were males, with a median age of 65 (55-71) years. Median LVEDP was 13.5 (8-19) mmHg and diastolic dysfunction was present in 50 (45.4%) of the patients. LVEDP correlated with BNP (p < 0.0001, r = 0.39 [0.20-0.53]), NT-proBNP (p < 0.0001, r = 0.40 [0.22-0.55]), MR-proANP (p = 0.001, r = 0.30 [0.11-0.46]), sST2 (p < 0.0001, r = 0.47 [0.30-0.60]), but not with MR-proAMD (p = 0.77) or galectin-3 (p = 0.76). In the final stepwise multivariable binary logistic regression model, diastolic dysfunction was predicted by NT-proBNP, mitral average E/e', sST2, atrial fibrillation, and left atrium reservoir strain. BNP, NT-proBNP, MR-proANP, and sST2 had predictive value for diastolic dysfunction. In contrast, galectin-3 and MR-proAMD were not associated with increased filling pressures. Furthermore, NT-proBNP and sST2 significantly improved diastolic dysfunction prediction in the final multivariable model.

NT-proBNP and Cardiac Troponin I, but Not Cardiac Troponin T, Are Associated With 7-Year Changes in Cardiac Structure and Function in Older Adults: The ARIC Study.

BACKGROUND: Higher circulating concentrations of NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI) are associated with left ventricular remodeling and with incident heart failure. The associations of these cardiac biomarkers with changes in cardiac structure and function over time are uncharacterized. METHODS: Among 2006 participants in the ARIC prospective cohort study (Atherosclerosis Risk in Communities) who were free of overt cardiovascular disease and underwent echocardiography at study visits 5 (2011- 2013) and 7 (2018-2019), we assessed the associations of NT-proBNP, hs-cTnT, and hs-cTnI concentrations at visit 5 with changes in left ventricular structure and function between visits 5 and 7 (≈7-year change) using multivariable linear regression with the biomarkers modeled as restricted cubic splines. Models were adjusted for age, sex, race, body mass index, smoking, diabetes, hypertension, and renal function at visit 5; blood pressure and heart rate at both visits; and the baseline value of the echocardiographic parameter of interest. RESULTS: Mean±SD age was 74±4 years at visit 5; 61% were women; and 23% were Black adults. Median (25th-75th percentile) concentrations at visit 5 of NT-proBNP, hs-cTnT, and hs-cTnI were 87 ng/L (50-157 ng/L), 9 ng/L (6-12 ng/L), and 2.6 ng/L (1.9-3.9 ng/L). In adjusted models, elevated baseline concentrations of NT-proBNP and hs-cTnI were significantly associated with 7-year decline in left ventricular systolic function (ejection fraction, longitudinal and circumferential strain) and worsening diastolic indices. In contrast, elevated baseline concentrations of hs-cTnT were not significantly associated with 7-year changes in cardiac structure, systolic function, or diastolic function (all P>0.05). CONCLUSIONS: Higher concentrations of NT-proBNP and hs-cTnI, but not hs-cTnT, were associated with greater declines in left ventricular function over ≈7 years in late life independently of traditional cardiovascular risk factors.AQ.

Clinical effect of recombinant human brain natriuretic peptide in the treatment of heart failure in elderly patients.

BACKGROUND: Heart failure in elderly individuals poses significant challenges due to the decline in cardiac function associated with aging. This study aimed to investigate the clinical efficacy of recombinant human brain natriuretic peptide (rhBNP) for the treatment of heart failure, especially in elderly patients. METHODS: This was a retrospective case control study of the medical records of 60 elderly patients with heart failure admitted to our hospital between December 2020 and December 2023. Patients were divided into two groups based on treatment. The control group (n = 30) received diuretics, digitalis, and ß receptor blockers, while the observation group (n = 30) received lyophilized rhBNP in addition to the control group treatment. Changes in BNP levels and clinical outcomes were compared between the two groups. RESULTS: Posttreatment BNP levels were significantly lower in the observation group than in the control group (p < 0.05), and the total clinical effective rate was greater in the observation group (p < 0.05). Additionally, the left ventricular diameter, left atrial diameter, left ventricular shortening fraction, diastolic flow signal and cardiac output in the observation group were lower than those in the control group (p < 0.05), while the thickness of the aortic root diameter in the observation group was greater than that in the control group (p < 0.05). CONCLUSION: RhBNP demonstrated ideal clinical efficacy in elderly patients with heart failure, improving symptoms and indicating potential for widespread use in the future.

Diabetes mellitus in stable chronic heart failure and the combination with humoral activation, their association, and prediction of 2-year adverse outcomes. Data from the FAR NHL registry.

BACKGROUND/AIM: The study aims to describe the role of diabetes in patients with heart failure. METHODS: In all, 1052 chronic heart failure patients were included in the FARmacology and NeuroHumoral Activation (FAR NHL) multicenter prospective registry. They had ejection fraction below 50% and were on stable medication for at least 1 month. RESULTS: More than one-third (38.9%) of the patients had diabetes mellitus (DM). Diabetic patients (N = 409) were older (median 67 vs. 64, p < 0.001), had higher body mass index (BMI) (30 vs. 28 kg/m2, p < 0.001), much more frequently had ischemic heart disease (71 vs. 47%, p < 0.001), hypertension (80 vs. 67%, p < 0.001), dyslipidemia (89 vs. 69%, p < 0.001), worse renal function (estimated glomerular filtration rate [eGFR] median 63 vs. 73 mL/min/1.73 m2, p < 0.001), and higher N-terminal pro-brain natriuretic peptide (NT-proBNP) (median 681 vs. 463 pg/mL, p = 0.003). All-cause death, left ventricle assist device implantation, and orthotopic heart transplantation were set as the combined primary end point, which was present in 15.5% (163 patients) within the 2-year follow-up. In the 2-year follow-up, 81.0% of patients with diabetes survived without a primary end point, while 85.4% of the patients without diabetes survived, the difference being on the verge of statistical significance (p = 0.089). DM is a statistically significant predictor of NT-proBNP value in univariate analysis, but it is not an independent predictor in a multivariate analysis. When the NT-proBNP level was high, the presence of DM did not influence the prognosis. CONCLUSION: The combination of diabetes and NT-proBNP levels may better stratify the prognosis of patients with chronic heart failure.

Genophenotypic correlates and long-term outcome prognosticators of left ventricular non-compaction in children.

BACKGROUND: To investigate the outcomes, clinical prognosticators, and genetic profiles of pediatric left ventricular non-compaction (LVNC). METHODS: All subjects were <18 years old, diagnosed with LVNC between January 2008 and December 2020. Whole-exome sequencing was undertaken. The primary endpoint was composite outcome, including death, heart transplant, and left ventricular assist device implantation. RESULTS: Thirty-three patients were enrolled, males predominating (57.6%). Median age at diagnosis was 0.33 (0.1-7.2) years. Family history was documented in four (12.1%). Five (15.2%) had sustained arrhythmias. Mean follow-up period was 9.5 years, and 5- and 10-year event-free survival were 84.8% and 66.9%, respectively. Seven died of heart failure, four received heart transplants, and one required left ventricular assist device placement. Log of baseline NT-proBNP (adjusted odds ratio [aOR] = 4.4, p = 0.012) and lack of improvement in NT-proBNP (aOR = 41.2, p = 0.033) impacted the primary outcome most significantly. Eighteen out of 25 genetic testing (72%) revealed chromosomal anomalies, or pathogenic or likely pathogenic variants. Three genetic variants (PLEKHM2 p.G419R, RYR2 p.V2571A, and SCN5A p.M1676I) were significantly associated with the primary outcome (p = 1.52 × 10-6). CONCLUSIONS: Pediatric LVNC is a rare disorder with variable genetic underpinnings. Baseline NT-proBNP values and lack of improvement in NT-proBNP levels were important predictors of poor long-term outcomes. Pathogenic genetic variants or chromosomal anomalies are not unusual.

Computational Biology in the Discovery of Biomarkers in the Diagnosis, Treatment and Management of Cardiovascular Diseases.

Cardiovascular diseases are the leading cause of mortality worldwide, with a disproportionately high burden in low- and middle-income countries. Biomarkers play a crucial role in the early detection, diagnosis, and treatment of cardiovascular diseases by providing valuable insights into the normal and abnormal conditions of the heart and vascular system. The biomarkers derived from the cells and tissues can be identified and quantified in the blood and other body fluids and in tissues. Changes in their expression level under a pathological condition provide clinical information on the underlying pathophysiology that could have predictive, diagnostic, and prognostic value in the treatment of a disease process, and therefore incorporated in clinical guidelines. This enhances the effectiveness of biomarkers in risk stratification and therapeutic decisions in personalized medicine and improvement in patient outcomes. Biomarkers could be protein, carbohydrate, or genome-based and may also be derived from lipids and nucleic acids. Computational biology has emerged as a powerful discipline in biomarker discovery, leveraging computational techniques to identify and validate biological markers for disease diagnosis, prognosis, and drug response prediction. The convergence of advanced technologies, such as artificial intelligence, multi-omics profiling, liquid biopsies, and imaging, has led to a significant shift in the discovery and development of biomarkers, enabling the integration of data from multiple biological scales and providing a more comprehensive understanding of the complex signaling and transcriptional networks underlying disease pathogenesis. In this article, we reviewed the role of computational biology integrated with genomics, proteomics, and metabolomics, together with machine learning techniques and predictive modeling and data integration in the discovery of biomarkers in cardiovascular diseases. We discussed specific biomarkers, including epigenetic, metabolic, and emerging biomarkers, such as extracellular vesicles, miRNAs, and circular RNAs, and their role in the pathophysiology of the heart and vascular diseases.

Insights into the Neutrophil-to-Lymphocyte Ratio and the Platelet-to-Lymphocyte Ratio as Predictors for the Length of Stay and Readmission in Chronic Heart Failure Patients.

Background/Objectives: Chronic heart failure (CHF) is characterized by complex pathophysiology, leading to increased hospitalizations and mortality. Inflammatory biomarkers such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) provide valuable diagnostic insights. METHODS: This study evaluates the prognostic relationship between NLR, PLR, and, in a specific subcohort, N-terminal pro B-type natriuretic peptide (NT-proBNP), alongside length of stay (LOS) and 90-day readmission rates in CHF patients, irrespective of heart failure phenotype. A retrospective analysis of 427 CHF admissions (males = 57.84%) was conducted. RESULTS: The mean age of the entire population was 68.48 ± 11.53 years. The average LOS was 8.33 ± 5.26 days, with a readmission rate of 73 visits (17.09%) for 56 patients. The NLR (3.79 ± 3.32) showed a low but positive correlation with the LOS (r = 0.222, p < 0.001). Conversely, the PLR (144.84 ± 83.08) did not demonstrate a significant association with the LOS. The NLR presented a low negative correlation for days until the next admission (r = -0.023, p = 0.048). In a prespecified subanalysis of 323 admissions, the NT-proBNP exhibited a low positive Pearson correlation with the NLR (r = 0.241, p < 0.001) and PLR (r = 0.151, p = 0.006). CONCLUSIONS: The impact of the NLR across heart failure phenotypes may suggest the role of systemic inflammation in understanding and managing CHF.

Galectin-3 Predicts Long-Term Risk of Cerebral Disability and Mortality in Out-of-Hospital Cardiac Arrest Survivors.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is associated with high mortality and cerebral disability in survivors. Current models of risk prediction and survival are mainly based on resuscitation duration. We examined the prognostic value of circulating biomarkers in predicting mortality and severe cerebral disability for OHCA survivors, alongside traditional clinical risk indicators. METHODS: Biomarkers including BNP, troponin I, and galectin-3 were measured at hospital admission in resuscitated OHCA patients. Prognostic significance for mortality and cerebral disability involving circulating biomarkers, resuscitation duration, demographics, and laboratory and clinical characteristics was examined via univariate and multivariate Cox proportional hazards regression models. The incremental prognostic value of the index covariates was examined through model diagnostics, focusing on the Akaike information criterion (AIC) and Harrell's concordance statistic (c-statistic). RESULTS: In a combinatorial analysis of 144 OHCA survivors (median follow-up 5.7 years (IQR 2.9-6.6)), BNP, galectin-3, arterial pH, and resuscitation time were significant predictors of all-cause death and severe cerebral disability, whereas troponin I levels were not. Multivariate regression, adjusting for BNP, arterial pH, and resuscitation time, identified galectin-3 as an independent predictor of long-term mortality. Multiple linear regression models also confirmed galectin-3 as the strongest predictor of cerebral disability. The incorporation of galectin-3 into models for predicting mortality and cerebral disability enhanced fit and discrimination, demonstrating the incremental value of galectin-3 beyond traditional risk predictors. CONCLUSIONS: Galectin-3 is a significant, independent long-term risk predictor of cerebral disability and mortality in OHCA survivors. Incorporating galectin-3 into current risk stratification models may enhance early prognostication and guide targeted clinical interventions.