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Natriuretic peptides (NP) play an essential role in heart failure (HF) regulation, and their measurement has improved diagnostic and prognostic accuracy. Clinical symptoms and objective measurements, such as NP levels, should be included in the HF definition to render it more reliable and consistent among observers, hospitals, and healthcare systems. BNP and NT-proBNP are reasonable surrogates for cardiac disease, and their measurement is critical to early diagnosis and risk stratification of HF patients. NPs should be measured in all patients presenting with dyspnea or other symptoms suggestive of HF to facilitate early diagnosis and risk stratification. Both BNP and NT-proBNP are currently used for guided HF management and display comparable diagnostic and prognostic accuracy. Standardized cutoffs for each NP assay are essential for data comparison. The value of NP testing is recognized at various levels, including patient empowerment and education, analytical and operational issues, clinical HF management, and cost-effectiveness. [ABSTRACT FROM AUTHOR]

Pulmonary embolisms (PEs) are obstructions of the pulmonary arteries by thrombi, which are emboli and they most frequently originate from the deep venous system of the inferior limbs. Emboli can also come from the inferior vena cava, abdominal and pelvic veins, or the upper body venous system from the right atrium or ventricle of the heart. Thrombi can form in situ inside pulmonary arteries as well. A cancer patient is at a higher risk for thromboembolic phenomena given both the oncological pathological context and also due to the associated medical or surgical treatment they receive. PE is a high-risk medical emergency that is associated with an increased risk of early mortality, with sudden death occurring in 25% of patients. The long-term presence of this condition can result in thromboembolic pulmonary hypertension. The risk of mortality, both in the acute and long-term, is dependent on the severity of the acute form, the recurrence of the embolism and the associated conditions. The majority of deaths associated with PE can be prevented by early diagnosis. The aim of the present review was to describe the various biological and cellular parameters, together with known paraclinical investigations, to assist in the rapid diagnosis of PE. Mortality in patients with PE and neoplastic conditions may be reduced by initiating anticoagulant treatment as soon as possible. PE may be the first manifestation of an underlying silent malignancy or may represent a complication of an already diagnosed malignancy. Exclusion or confirmation of the diagnosis is of utmost importance to avoid unnecessary anticoagulant treatment associated with a high risk of bleeding or to start immediate anticoagulant treatment if required. [ABSTRACT FROM AUTHOR]

BACKGROUND: Hs-cTnT (cardiac troponin T measured with a highly sensitive assay) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) may identify adults with hypertension who derive greater cognitive benefits from lower systolic blood pressure targets. METHODS: In the SPRINT (Systolic Blood Pressure Intervention Trial) MIND study, participants were categorized as having both hs-cTnT and NT-proBNP in the lower 2 tertiles (n=4226), one in the highest tertile (n=2379), and both in the highest tertile (n=1506). We assessed the effect of intensive versus standard treatment on the composite of mild cognitive impairment (MCI) or probable dementia (PD) across biomarker categories. RESULTS: Over a median follow-up of 5.1 years, 830 of 8111 participants (10.2%) developed MCI or PD. Participants in the highest biomarker category were at higher risk of MCI or PD compared with those in the lowest category (hazard ratio, 1.34 [95% CI, 1.00-1.56]). The effect of intensive treatment on reducing the risk of MCI or PD was greater among participants in the lowest biomarker category (hazard ratio, 0.64 [95% CI, 0.50-0.81]) than those in the intermediate (hazard ratio, 1.01 [95% CI, 0.80-1.28]) or highest categories (hazard ratio, 0.90 [95% CI, 0.72-1.13]; Pinteraction=0.02). The 5-year absolute risk differences in MCI or PD with intensive treatment were -2.9% (-4.4%, -1.3%), -0.2% (-3.0%, 2.6%), and -1.9% (-6.2%, 2.4%) in the lowest, intermediate, and highest biomarker categories, respectively. CONCLUSIONS: In SPRINT, the relative effect of intensive systolic blood pressure lowering on preventing cognitive impairment appears to be stronger among participants with lower compared with higher cardiac biomarker levels, though the absolute risk reductions were similar. [ABSTRACT FROM AUTHOR]

Aims Lung ultrasound (LUS) is often used to assess congestion in heart failure (HF). In this study, we assessed the prognostic role of LUS in patients with HF at admission and hospital discharge, and in an outpatient setting, and explored whether clinical factors [age, sex, left ventricular ejection fraction (LVEF), and atrial fibrillation] impact the prognostic value of LUS findings. Further, we assessed the incremental prognostic value of LUS on top of the following two clinical risk scores: (i) the atrial fibrillation, haemoglobin, elderly, abnormal renal parameters, diabetes mellitus (AHEAD) and (ii) the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) clinical risk scores. Methods and results We pooled data on patients hospitalized for HF or followed up in outpatient clinics from international cohorts. We enrolled 1947 patients at admission (n = 578), discharge (n = 389), and in outpatient clinics (n = 980). The total LUS B-line count was calculated for the eight-zone scanning protocol. The primary outcome was a composite of rehospitalization for HF and all-cause death. Compared with those in the lower tertiles of B lines, patients in the highest tertiles were older, more likely to have signs of HF and had higher N-terminal pro b-type natriuretic peptide (NT-proBNP) levels. A higher number of B lines was associated with increased risk of primary outcome at discharge [Tertile 3 vs. Tertile 1: adjusted hazard ratio (HR): 5.74 (3.26–10.12), P < 0.0001] and in outpatients [Tertile 3 vs. Tertile 1: adjusted HR: 2.66 (1.08–6.54), P = 0.033]. Age and LVEF did not influence the prognostic capacity of LUS in different clinical settings. Adding B-line count to the MAGGIC and AHEAD scores improved net reclassification significantly in all three clinical settings. Conclusion A higher number of B lines in patients with HF was associated with an increased risk of morbidity and mortality, regardless of the clinical setting. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusions Non‐ischaemic cardiomyopathy (NICMP), an incurable disease terminating in systolic heart failure (heart failure with reduced ejection fraction [HFrEF]), causes immune activation, however anti‐inflammatory treatment strategies so far have failed to alter the course of this disease. Myeloperoxidase (MPO), the principal enzyme in neutrophils, has cytotoxic, pro‐fibrotic and nitric oxide oxidizing effects. Whether MPO inhibition ameliorates the phenotype in NICMP remains elusive.Prognostic information from MPO was derived from proteomic data of a large human cardiovascular health cohort (n = 3289). In a murine model of NICMP, we studied the mechanisms of MPO in this disease. In a case series, the MPO inhibitor was also evaluated in NICMP patients. Individuals with increased MPO revealed higher long‐term mortality and worsening of heart failure, with impaired prognosis when MPO increased during follow‐up. MPO infusion attenuated left ventricular ejection fraction (LVEF) in mice with NICMP, whereas genetic ablation or inhibition of MPO decreased systemic vascular resistance (SVR, 9.4 ± 0.7 mmHg*min/ml in NICMP vs. 6.7 ± 0.8 mmHg*min/ml in NICMP/Mpo−/−mice, n = 8, p = 0.006, data expressed as mean ± standard error of the mean) and improved left ventricular function (LVEF 30.3 ± 2.2% in NICMP vs. 40.7 ± 1.1% in NICMP/Mpo−/− mice, n = 16, p < 0.0001). Four patients diagnosed with NICMP and treated with an MPO inhibitor over 12 weeks showed increase in LVEF, decline in natriuretic peptides and improved 6‐min walking distance. MPO inhibitor‐related changes in the proteome of NICMP patients predicted reduced mortality when related to the changes in the proteome of the above referenced cardiovascular health cohort.Myeloperoxidase predicts long‐term outcome in HFrEF and its inhibition elicits systemic anti‐inflammatory and vasodilating effects which translate into improved left ventricular function. MPO inhibition deserves further evaluation as a novel, complementary treatment strategy for HFrEF. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusion Heart failure (HF) with preserved ejection fraction (HFpEF) is characterized by growing incidence and poor outcomes. A large majority of HFpEF patients are cared by non‐cardiologists. The availability of sodium–glucose cotransporter 2 inhibitors (SGLT2i) as recommended therapy raises the importance of prompt and accurate identification and treatment of HFpEF across diverse healthcare settings. We evaluated HFpEF management across specialties through a survey targeting cardiologists, HF specialists, and non‐cardiologists.An independent web‐based survey was distributed globally between May and July 2023. We performed a post‐hoc analysis, comparing cardiologists, HF specialists, and non‐cardiologists. A total of 1460 physicians (61% male, median age 41[34–49]) from 95 countries completed the survey; 20% were HF specialists, 65% cardiologists, and 15% non‐cardiologists. Compared with HF specialists, non‐cardiologists and cardiologists were less likely to use natriuretic peptides (p = 0.003) and HFpEF scores (p = 0.004) for diagnosis, and were also less likely to have access to or consider specific echocardiographic parameters (p < 0.001) for identifying HFpEF. Diastolic stress tests were used in less than 30% of the cases, regardless of the specialty (p = 1.12). Multidrug treatment strategies were similar across different specialties. While SGLT2i and diuretics were the preferred drugs, angiotensin receptor blockers and angiotensin receptor–neprilysin inhibitors were the least frequently prescribed in all three groups. However, when constrained to choose one drug, the proportion of physicians favoring SGLT2i varied significantly among specialties (66% HF specialists, 52% cardiologists, 51% non‐cardiologists). Additionally, 10% of non‐cardiologists and 8% of cardiologists considered beta blocker the drug of choice for HFpEF.Significant differences among specialty groups were observed in HFpEF management, particularly in the diagnostic work‐up. Our results highlight a substantial risk of underdiagnosis and undertreatment of HFpEF patients, especially among non‐HF specialists. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusion Although body mass index (BMI) is the most commonly used anthropometric measure to assess adiposity, alternative indices such as the waist‐to‐height ratio may better reflect the location and amount of ectopic fat as well as the weight of the skeleton.The prognostic value of several alternative anthropometric measures was compared with that of BMI in 1116 patients with non‐ischaemic heart failure with reduced ejection fraction (HFrEF) enrolled in DANISH. The association between anthropometric measures and all‐cause death was adjusted for prognostic variables, including natriuretic peptides. Median follow‐up was 9.5 years (25th–75th percentile, 7.9–10.9). Compared to patients with a BMI 18.5–24.9 kg/m2 (n = 363), those with a BMI ≥25 kg/m2 had a higher risk of all‐cause and cardiovascular death, although this association was only statistically significant for a BMI ≥35 kg/m2 (n = 91) (all‐cause death: hazard ratio [HR] 1.78, 95% confidence interval [CI] 1.28–2.48; cardiovascular death: HR 2.46, 95% CI 1.69–3.58). Compared to a BMI 18.5–24.9 kg/m2, a BMI <18.5 kg/m2 (n = 24) was associated with a numerically, but not a significantly, higher risk of all‐cause and cardiovascular death. Greater waist‐to‐height ratio (as an exemplar of indices not incorporating weight) was also associated with a higher risk of all‐cause and cardiovascular death (HR for the highest vs. the lowest quintile: all‐cause death: HR 2.11, 95% CI 1.53–2.92; cardiovascular death: HR 2.17, 95% CI 1.49–3.15).In patients with non‐ischaemic HFrEF, there was a clear association between greater adiposity and higher long‐term mortality.Clinical Trial Registration: ClinicalTrials.gov NCT00542945. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) represents a complex clinical syndrome, often very difficult to diagnose using the available tools. As the global burden of this disease is constantly growing, surpassing the prevalence of heart failure with reduced ejection fraction, during the last few years, efforts have focused on optimizing the diagnostic and prognostic pathways using an immense panel of circulating biomarkers. After the paradigm of HFpEF development emerged more than 10 years ago, suggesting the impact of multiple comorbidities on myocardial structure and function, several phenotypes of HFpEF have been characterized, with an attempt to find an ideal biomarker for each distinct pathophysiological pathway. Acknowledging the limitations of natriuretic peptides, hundreds of potential biomarkers have been evaluated, some of them demonstrating encouraging results. Among these, soluble suppression of tumorigenesis-2 reflecting myocardial remodeling, growth differentiation factor 15 as a marker of inflammation and albuminuria as a result of kidney dysfunction or, more recently, several circulating microRNAs have proved their incremental value. As the number of emerging biomarkers in HFpEF is rapidly expanding, in this review, we aim to explore the most promising available biomarkers linked to key pathophysiological mechanisms in HFpEF, outlining their utility for diagnosis, risk stratification and population screening, as well as their limitations. [ABSTRACT FROM AUTHOR]

In patients with type 2 diabetes mellitus (T2DM), asymptomatic adverse cardiac remodeling plays a pivotal role in the development of heart failure (HF). Patients with T2DM often have low or near-normal levels of natriuretic peptides, including N-terminal brain natriuretic peptide (NT-proBNP), which have been inconclusive in predicting the transition from asymptomatic adverse cardiac remodeling to HF with preserved ejection fraction (HFpEF). The aim of this study was to elucidate the predictive ability of adropin for HFpEF depending on the circulating levels of NT-proBNP. We prospectively enrolled 561 T2DM patients (glycated hemoglobin < 6.9%) with echocardiographic evidence of structural cardiac abnormalities and left ventricular ejection fractions >50%. All patients underwent B-mode transthoracic echocardiographic and Doppler examinations. Circulating biomarkers, i.e., NT-proBNP and adropin, were assessed at baseline. All individuals were divided into two groups according to the presence of low levels (<125 pmol/mL; n = 162) or elevated levels (≥125 pmol/mL; n = 399) of NT-proBNP. Patients with known asymptomatic adverse cardiac remodeling and elevated NT-proBNP were classified as having asymptomatic HFpEF. A multivariate logistic regression showed that low serum levels of adropin (<3.5 ng/mL), its combination with any level of NT-proBNP, and use of SGLT2 inhibitors were independent predictors of HFpEF. However, low levels of adropin significantly increased the predictive ability of NT-proBNP for asymptomatic HFpEF in patients with T2DM, even though the concentrations of NT-proBNP were low, while adropin added discriminatory value to all concentrations of NT-proBNP. In conclusion, low levels of adropin significantly increase the predictive ability of NT-proBNP for asymptomatic HFpEF in patients with T2DM. [ABSTRACT FROM AUTHOR]

Background Heart failure with preserved ejection fraction (HFpEF) often coexists with chronic kidney disease (CKD). Exercise intolerance is a major determinant of quality of life and morbidity in both scenarios. We aimed to evaluate the associations between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and carbohydrate antigen 125 (CA125) with maximal aerobic capacity (peak VO2) in ambulatory HFpEF and whether these associations were influenced by kidney function. Methods This single-centre study prospectively enrolled 133 patients with HFpEF who performed maximal cardiopulmonary exercise testing. Patients were stratified across estimated glomerular filtration rate (eGFR) categories (<60 ml/min/1.73 m2 versus ≥60 ml/min/1.73 m2). Results The mean age of the sample was 73.2 ± 10.5 years and 56.4% were female. The median of peak VO2 was 11.0 ml/kg/min (interquartile range 9.0–13.0). A total of 67 (50.4%) patients had an eGFR <60 ml/min/1.73 m2. Those patients had higher levels of NT-proBNP and lower peak VO2, without differences in CA125. In the whole sample, NT-proBNP and CA125 were inversely correlated with peak VO2 (r  = −0.43, P  < .001 and r  = −0.22, P  = .010, respectively). After multivariate analysis, we found a differential association between NT-proBNP and peak VO2 across eGFR strata (P for interaction = .045). In patients with an eGFR ≥60 ml/min/1.73 m2, higher NT-proBNP identified patients with poorer maximal functional capacity. In individuals with eGFR <60 ml/min/1.73 m2, NT-proBNP was not significantly associated with peak VO2 [β = 0.02 (95% confidence interval −0.19–0.23), P  = .834]. Higher CA125 was linear and significantly associated with worse functional capacity without evidence of heterogeneity across eGFR strata (P for interaction = .620). Conclusions In patients with stable HFpEF, NT-proBNP was not associated with maximal functional capacity when CKD was present. CA125 emerged as a useful biomarker for estimating effort intolerance in HFpEF irrespective of the presence of CKD. [ABSTRACT FROM AUTHOR]

The article discusses the need for reliable biomarkers to detect pulmonary congestion in patients with heart failure (HF) in order to prevent hospitalizations and improve patient outcomes. The current biomarkers used in clinical practice, B-type natriuretic peptides (NPs), have limitations such as being affected by comorbidities and having inconsistent measurement intervals. The article presents the BioMEMS study, which aims to identify alternative biomarkers that accurately reflect worsening congestion and can be easily measured. The study collects blood samples from HF patients and analyzes them using the Olink Cardiovascular III panel to evaluate the relationship between biomarkers and pulmonary artery pressures. The ultimate goal is to develop a biomarker-based management strategy for HF patients that is decentralized, manageable, and economically sustainable. [Extracted from the article]

Aims: The optimal echocardiographic predictors of cardiovascular outcome in heart failure (HF) with preserved ejection fraction (HFpEF) are unknown. We aimed to identify independent echocardiographic predictors of cardiovascular outcome in patients with HFpEF. Methods and results: Systematic literature search of three electronic databases was conducted from date of inception until November 2022. Hazard ratios (HRs) and their 95% confidence intervals (CIs) for echocardiographic variables from multivariate prediction models for the composite primary endpoint of cardiovascular death and HF hospitalization were pooled using a random effects meta‐analysis. Specific subgroup analyses were conducted for studies that enrolled patients with acute versus chronic HF, and for those studies that included E/e′, pulmonary artery systolic pressure (PASP), renal function, natriuretic peptides and diuretic use in multivariate models. Forty‐six studies totalling 20 056 patients with HFpEF were included. Three echocardiographic parameters emerged as independent predictors in all subgroup analyses: decreased left ventricular (LV) global longitudinal strain (HR 1.24, 95% CI 1.10–1.39 per 5% decrease), decreased left atrial (LA) reservoir strain (HR 1.30, 95% CI 1.13–1.1.50 per 5% decrease) and lower tricuspid annular plane systolic excursion (TAPSE) to PASP ratio (HR 1.17, 95% CI 1.07–1.25 per 0.1 unit decrease). Other independent echocardiographic predictors of the primary endpoint were a higher E/e′, moderate to severe tricuspid regurgitation, LV mass index and LA ejection fraction, although these variables were less robust. Conclusions: Impaired LV global longitudinal strain, lower LA reservoir strain and lower TAPSE/PASP ratio predict cardiovascular death and HF hospitalization in HFpEF and are independent of filling pressures, clinical characteristics and natriuretic peptides. These echocardiographic parameters reflect key functional changes in HFpEF, and should be incorporated in future prospective risk prediction models. [ABSTRACT FROM AUTHOR]

Osteocrin (OSTN) is an endogenous protein sharing structural similarities with the natriuretic peptides [NPs; atrial (ANP), B‐type (BNP) and C‐type (CNP) NP], which are hormones known for their crucial role in maintaining pressure/volume homeostasis. Osteocrin competes with the NPs for binding to the receptor involved in their clearance (NPR‐C). In the present study, having identified, for the first time, the major circulating form of OSTN in human and ovine plasma, we examined the integrated haemodynamic, endocrine and renal effects of vehicle‐controlled incremental infusions of ovine proOSTN (83–133) and its metabolism in eight conscious normal sheep. Incremental i.v. doses of OSTN produced stepwise increases in circulating concentrations of the peptide, and its metabolic clearance rate was inversely proportional to the dose. Osteocrin increased plasma levels of ANP, BNP and CNP in a dose‐dependent manner, together with concentrations of their intracellular second messenger, cGMP. Increases in plasma cGMP were associated with progressive reductions in arterial pressure and central venous pressure. Plasma cAMP, renin and aldosterone were unchanged. Despite significant increases in urinary cGMP levels, OSTN administration was not associated with natriuresis or diuresis in normal sheep. These results support OSTN as an endogenous ligand for NPR‐C in regulating plasma concentrations of NPs and associated cGMP‐mediated bioactivity. Collectively, our findings support a role for OSTN in maintaining cardiovascular homeostasis. What is the central question of this study?What role does osteocrin (OSTN) have in integrated cardiovascular, renal and neurohumoral function in normal health?What is the main finding and its importance?Osteocrin is structurally similar to natriuretic peptides (NPs) that play a crucial role in cardiovascular homeostasis and binds to the NP receptor‐C (NPR‐C). Stepped doses of OSTN raised plasma atrial NP, B‐type NP, C‐type NP and cGMP and reduced arterial and venous pressures. Collectively, these findings provide strong evidence that increased NP levels result from competitive displacement from NPR‐C, not from increased NP secretion, suggesting that OSTN might play a role in maintaining cardiovascular homeostasis. [ABSTRACT FROM AUTHOR]

Obesity condition causes morphological and functional alterations involving the cardiovascular system. These can represent the substrates for different cardiovascular diseases, such as atrial fibrillation, coronary artery disease, sudden cardiac death, and heart failure (HF) with both preserved ejection fraction (EF) and reduced EF. Different pathogenetic mechanisms may help to explain the association between obesity and HF including left ventricular remodelling and epicardial fat accumulation, endothelial dysfunction, and coronary microvascular dysfunction. Multi‐imaging modalities are required for appropriate recognition of subclinical systolic dysfunction typically associated with obesity, with echocardiography being the most cost‐effective technique. Therapeutic approach in patients with obesity and HF is challenging, particularly regarding patients with preserved EF in which few strategies with high level of evidence are available. Weight loss is of extreme importance in patients with obesity and HF, being a primary therapeutic intervention. Sodium–glucose co‐transporter‐2 inhibitors have been recently introduced as a novel tool in the management of HF patients. The present review aims at analysing the most recent studies supporting pathogenesis, diagnosis, and management in patients with obesity and HF. [ABSTRACT FROM AUTHOR]

Aims Residual congestion in acute heart failure (AHF) is associated with poor prognosis. However, there is a lack of data on the prognostic value of changes in a combined assessment of in-hospital congestion. The present study sought to assess the association between in-hospital congestion changes and subsequent prognosis according to left ventricular ejection fraction (LVEF) classification. Methods and results Patients (N = 244, 80.3 ± 7.6 years, 50.8% male) admitted for acute HF in two European tertiary care centres underwent clinical assessment (congestion score included dyspnoea at rest, rales, third heart sound, jugular venous distention, peripheral oedema, and hepatomegaly; simplified congestion score included rales and peripheral oedema), echocardiography, lung ultrasound, and natriuretic peptides (NP) measurement at admission and discharge. The primary outcome was a composite of all-cause mortality and/or HF re-hospitalization. In the 244 considered patients (95 HF with reduced EF, 57 HF with mildly reduced EF, and 92 HF with preserved EF), patients with limited improvement in clinical congestion score (hazard ratio 2.33, 95% CI 1.51–3.61, P = 0.0001), NP levels (2.29, 95% CI 1.55–3.38, P < 0.0001), and the number of B-lines (6.44, 95% CI 4.19–9.89, P < 0.001) had a significantly higher risk of outcome compared with patients experiencing more sizeable decongestion. The same pattern of association was observed when adjusting for confounding factors. A limited improvement in clinical congestion score and in the number of B-lines was related to poor prognosis for all LVEF categories. Conclusion In AHF, the degree of congestion reduction assessed over the in-hospital stay period can stratify the subsequent event risk. Limited reduction in both clinical congestion and B-lines number are related to poor prognosis, irrespective of HF subtype. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a syndrome characterized by signs and symptoms resulting from structural or functional cardiac abnormalities, confirmed by elevated natriuretic peptides or evidence of congestion. HF patients are classified according to left ventricular ejection fraction (LVEF). Worsening HF (WHF) is associated with increased short- and long-term mortality, re-hospitalization, and healthcare costs. The standard treatment of HF includes angiotensin-converting enzyme inhibitors, angiotensin receptor–neprilysin inhibitors, mineralocorticoid-receptor antagonists, beta-blockers, and sodium-glucose-co-transporter 2 inhibitors. To manage systolic HF by reducing mortality and hospitalizations in patients experiencing WHF, treatment with vericiguat, a direct stimulator of soluble guanylate cyclase (sGC), is indicated. This drug acts by stimulating sGC enzymes, part of the nitric oxide (NO)–sGC–cyclic guanosine monophosphate (cGMP) signaling pathway, regulating the cardiovascular system by catalyzing cGMP synthesis in response to NO. cGMP acts as a second messenger, triggering various cellular effects. Deficiencies in cGMP production, often due to low NO availability, are implicated in cardiovascular diseases. Vericiguat stimulates sGC directly, bypassing the need for a functional NO-sGC-cGMP axis, thus preventing myocardial and vascular dysfunction associated with decreased sGC activity in heart failure. Approved by the FDA in 2021, vericiguat administration should be considered, in addition to the four pillars of reduced EF (HFrEF) therapy, in symptomatic patients with LVEF < 45% following a worsening event. Cardiac rehabilitation represents an ideal setting where there is more time to implement therapy with vericiguat and incorporate a greater number of medications for the management of these patients. This review covers vericiguat's metabolism, molecular mechanisms, and drug–drug interactions. [ABSTRACT FROM AUTHOR]

Aim: The role of malnutrition among patients with severe heart failure (HF) is not well established. We evaluated the incidence, predictors, and prognostic impact of malnutrition in patients with severe HF. Methods and results: Nutritional status was measured using the geriatric nutritional risk index (GNRI), based on body weight, height and serum albumin concentration, with malnutrition defined as GNRI ≤98. It was assessed in consecutive patients with severe HF, defined by at least one high‐risk 'I NEED HELP' marker, enrolled at four Italian centres between January 2020 and November 2021. The primary endpoint was all‐cause mortality. A total of 510 patients with data regarding nutritional status were included in the study (mean age 74 ± 12 years, 66.5% male). Among them, 179 (35.1%) had GNRI ≤98 (malnutrition). At multivariable logistic regression, lower body mass index (BMI) and higher levels of natriuretic peptides (B‐type natriuretic peptide [BNP] > median value [685 pg/ml] or N‐terminal proBNP > median value [5775 pg/ml]) were independently associated with a higher likelihood of malnutrition. Estimated rates of all‐cause death at 1 year were 22.4% and 41.1% in patients without and with malnutrition, respectively (log‐rank p < 0.001). The impact of malnutrition on all‐cause mortality was confirmed after multivariable adjustment for relevant covariates (adjusted hazard ratio 2.03, 95% confidence interval 1.43–2.89, p < 0.001). Conclusion: In a contemporary, real‐world, multicentre cohort of patients with severe HF, malnutrition (defined as GNRI ≤98) was common and independently associated with an increased risk of mortality. Lower BMI and higher natriuretic peptides were identified as predictors of malnutrition in these patients. [ABSTRACT FROM AUTHOR]

The central role of natriuretic peptides (NPs) in the complex cardio‐renal integrated physiology and organ failure has been revealed over the last four decades. Atrial natriuretic peptide (ANP), the oldest representative of the NPs family, is produced through conversion of proANP to the mature peptide by corin, a trans‐membrane protease localized to the cardiac myocyte membrane. Similarly, brain natriuretic peptide (BNP) is generated by furin, which cleaves proBNP to BNP in myocytes. Though the components of NPs system, their synthesis and target organs are well established, understanding their role in the interplay between the heart and the kidney is steadily evolving. In this context, Feldman et al. (New England Journal of Medicine, 389, 1685) recently described patients with hypertension, cardiomyopathy, atrial arrhythmia and left atrial fibrosis, associated with a homozygous loss‐of‐function variant of the gene encoding corin (Cor−/−). Notably, reduced baseline urinary electrolyte and creatinine excretion have been observed in one of the studied patients. This renal excretory functional impairment could be attributed to the lack of cardiac‐derived ANP in these patients, as implied by Feldman et al. Yet, in this mini‐review we suggest that this aberrant renal manifestation may principally stem from lack of local ANP production at renal tissue, as corin is normally expressed in proximal tubules, Henle's loop and collecting ducts, with locally produced ANP provoking Na+ and water exertion. Collectively, it seems that beside the classic well‐established cardio‐renal axis, the renal NPs system functions as local endocrine machinery in the regulation of sodium excretion. [ABSTRACT FROM AUTHOR]

Background: European Society of Cardiology (ESC) guidelines recommend measuring natriuretic peptides (BNP or NT-proBNP) in patients with suspected heart failure (HF) as a first-line tool. HF should be ruled-out if concentrations of NT-proBNP are below 300 ng/L and 125 ng/L for acute HF and chronic HF, respectively. Methods: Patients with suspected HF referred for transthoracic echocardiography (TTE) were enrolled; NT-proBNP concentrations were obtained from medical charts (measurement < 48 hours) or prospectively measured on the day of TTE. Results: Out of 109 patients, NT-proBNP was measured by the referring department before TTE in 40 patients (36.7%), and 37.5% of these patients had NT-proBNP concentration below the rule-out threshold. NT-proBNP was measured in additional 38 patients on the day of TTE. Overall, 38.5% of the patients had a NT-proBNP concentration below the threshold value. Conclusions: Natriuretic peptides are not routinely measured in patients with suspected HF; systematic measurement would reduce unnecessary TTE by at least 38.5% [ABSTRACT FROM AUTHOR]

Background: Achondroplasia, the most prevalent skeletal dysplasia, stems from a functional mutation in the fibroblast growth factor receptor 3 gene, leading to growth impairment. This condition presents multifaceted medical, functional and psychosocial challenges throughout childhood, adolescence and adulthood. Current management strategies aim to minimise medical complications, optimise functional capabilities and provide comprehensive supportive care. Vosoritide (trade name: VOXZOGO®, BioMarin Pharmaceuticals) is the first disease-modifying pharmaceutical treatment approved for the management of patients with achondroplasia and became available in Australia in May 2023. Methods: Standardised clinical guidelines for its optimal use are not yet widely available. To address this gap, a multidisciplinary Australian Vosoritide Working Group, comprising 12 experts with experience in achondroplasia management from across Australia, developed recommendations to guide the use of vosoritide in clinical practice. Results: The recommendations, which are expert opinions of the Australian Vosoritide Working Group, aim to (i) standardise the use of vosoritide across Australia, (ii) support the safe clinical rollout of vosoritide and (iii) support universal access. Conclusions: These recommendations have been developed for healthcare professionals and institutions that are engaged in using vosoritide in the management of achondroplasia and will be revised using a formal framework for clinical guideline development once more evidence is available. [ABSTRACT FROM AUTHOR]

Abstract Osteocrin (OSTN) is an endogenous protein sharing structural similarities with the natriuretic peptides [NPs; atrial (ANP), B‐type (BNP) and C‐type (CNP) NP], which are hormones known for their crucial role in maintaining pressure/volume homeostasis. Osteocrin competes with the NPs for binding to the receptor involved in their clearance (NPR‐C). In the present study, having identified, for the first time, the major circulating form of OSTN in human and ovine plasma, we examined the integrated haemodynamic, endocrine and renal effects of vehicle‐controlled incremental infusions of ovine proOSTN (83–133) and its metabolism in eight conscious normal sheep. Incremental i.v. doses of OSTN produced stepwise increases in circulating concentrations of the peptide, and its metabolic clearance rate was inversely proportional to the dose. Osteocrin increased plasma levels of ANP, BNP and CNP in a dose‐dependent manner, together with concentrations of their intracellular second messenger, cGMP. Increases in plasma cGMP were associated with progressive reductions in arterial pressure and central venous pressure. Plasma cAMP, renin and aldosterone were unchanged. Despite significant increases in urinary cGMP levels, OSTN administration was not associated with natriuresis or diuresis in normal sheep. These results support OSTN as an endogenous ligand for NPR‐C in regulating plasma concentrations of NPs and associated cGMP‐mediated bioactivity. Collectively, our findings support a role for OSTN in maintaining cardiovascular homeostasis.

Abstract Obesity condition causes morphological and functional alterations involving the cardiovascular system. These can represent the substrates for different cardiovascular diseases, such as atrial fibrillation, coronary artery disease, sudden cardiac death, and heart failure (HF) with both preserved ejection fraction (EF) and reduced EF. Different pathogenetic mechanisms may help to explain the association between obesity and HF including left ventricular remodelling and epicardial fat accumulation, endothelial dysfunction, and coronary microvascular dysfunction. Multi‐imaging modalities are required for appropriate recognition of subclinical systolic dysfunction typically associated with obesity, with echocardiography being the most cost‐effective technique. Therapeutic approach in patients with obesity and HF is challenging, particularly regarding patients with preserved EF in which few strategies with high level of evidence are available. Weight loss is of extreme importance in patients with obesity and HF, being a primary therapeutic intervention. Sodium–glucose co‐transporter‐2 inhibitors have been recently introduced as a novel tool in the management of HF patients. The present review aims at analysing the most recent studies supporting pathogenesis, diagnosis, and management in patients with obesity and HF.

Abstract Plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) level is primarily used as a biomarker for left ventricular (LV) dysfunction. It is influenced by various conditions, such as myocardial strain and situations affecting the clearance of NT-proBNP, including sepsis and shock. In this study, we investigated the appropriateness of NT-proBNP as a prognostic factor for septic shock. Patients with septic shock who visited the emergency department of the Ewha Womans’ University Mokdong Hospital between January 1, 2018, and December 31, 2020, were classified into the survival group (those who survived in the hospital and were discharged) and the death group (those who died in the hospital). The effectiveness of NT-proBNP, lactate, and blood urea nitrogen as predictive factors of in-hospital mortality was evaluated using the area under the receiver operating characteristic (AUROC) curve. The AUROC curve was 0.678 and 0.648 for lactate and NT-proBNP, respectively, with lactate showing the highest value. However, there was no significant difference between lactate and NT-proBNP levels in the comparison of their AUROC curve (p = 0.6278). NT-proBNP could be a useful predictor of in-hospital mortality in patients with septic shock who present to the emergency department.

Introduction: Rheumatic Heart Disease (RHD) remains the primary cause of acquired Valvular Heart Disease (VHD) in developing countries. The role of Tissue Doppler Indices (TDI) in RHD is understudied. This study aims to fill evidence gaps identified by the American College of Cardiology/American Heart Association in the management of Valvular Heart Disease (VHD) by analysing newer echocardiographic techniques {Tissue Doppler Imaging (TDI)} and biochemical markers (NT-proBNP) against clinical parameters {New York Heart Association (NYHA)} in an understudied patient group. Aim: To evaluate the role of TDI and its association with the functional class of dyspnoea and serum NT-proBNP levels in RHD. Materials and Methods: This cross-sectional study was conducted in the Cardiology and Medicine departments, Central Gujarat, Western India, from January 2021 to June 2022. Fifty-seven consenting adult patients with RHD who underwent echocardiography with Standard Echocardiographic Techniques (SET) to stratify VHD severity were included. Patients were divided into three sub-groups: a) Isolated MR and MR with mild/moderate MS (n=23); b) Isolated MS and MS with mild MR (n=29); and c) Isolated MS and MS with mild or moderate MR (n=48). TDI parameters (e’, a’, e’/a’, and E/e’) at medial mitral, lateral mitral, and tricuspid annuli, NYHA classification, and serum NT-proBNP levels were analysed. The Analysis of Variance (ANOVA) was used to assess the association between NYHA class and clinical and NT-proBNP parameters. The Pearson correlation coefficient was employed to determine linear relationships between NT-proBNP and TDI parameters. Results: The mean age was 45.4±16 years, with the age groups 20-40 years (n=20) and 40-60 years (n=22) having a nearly equal distribution. The female-to-male ratio was 1.48 (34/23). In subgroup C, the a’ velocity decreased from 13.74±3.92 cm/s in NYHA I to 5.17±1.98 cm/s in NYHA IV (p=0.0312), and the e’/a’ ratio increased from 0.96±0.40 in NYHA I to 2.41±1.00 in NYHA IV (p=0.0210). These changes paralleled trends in a’ value (p=0.0306) and e’/a’ ratio (p=0.0157) with increasing NT-proBNP levels. Conclusion: At the tricuspid annulus, the e’/a’ ratio and a’ velocity can complement NT-proBNP in cases where there is a discrepancy between the clinical status of the patient and the severity of the valve lesion as determined by SET. Larger-scale studies are needed to further evaluate the association between TDI parameters and long-term clinical outcomes, as well as to identify the optimal timing for surgical intervention in RHD patients.

Abstract Aims Natriuretic peptide (NP) uptake varies in Emergency Departments (EDs) across Europe. The ‘Peptide for Life’ (P4L) initiative, led by Heart Failure Association, aims to enhance NP utilization for early diagnosis of heart failure (HF). We tested the hypothesis that implementing an educational campaign in Western Balkan countries would significantly increase NP adoption rates in the ED. Methods and results This registry examined NP adoption before and after implementing the P4L‐ED study across 10 centres in five countries: Bosnia and Herzegovina, Croatia, Montenegro, North Macedonia, and Serbia. A train‐the‐trainer programme was implemented to enhance awareness of NP testing in the ED, and centres without access received point‐of‐care instruments. Differences in NP testing between the pre‐P4L‐ED and post‐P4L‐ED phases were evaluated. A total of 2519 patients were enrolled in the study: 1224 (48.6%) in the pre‐P4L‐ED phase and 1295 (51.4%) in the post‐P4L‐ED phase. NP testing was performed in the ED on 684 patients (55.9%) during the pre‐P4L‐ED phase and on 1039 patients (80.3%) during the post‐P4L‐ED phase, indicating a significant absolute difference of 24.4% (95% CI: 20.8% to 27.9%, P

Background: General practitioners (GPs) specialized in cardiovascular disease (GPSI-CVD) may suspect heart failure (HF) more easily than GPs not specialized in CVD. We assessed whether GPSI-CVD consider investigations aimed at detecting HF more often than other GPs in two clinical scenarios of an older male person with respiratory and suggestive HF symptoms. Methods: In this vignette study, Dutch GPs evaluated two vignettes. The first involved a 72-year-old man with hypertension and a 30 pack-year smoking history who presented himself with symptoms of a common cold, but also shortness of breath, reduced exercise tolerance, and signs of fluid overload. The second vignette was similar but now the 72-year-old man was known with chronic obstructive pulmonary disease (COPD). GPs could select diagnostic tests from a multiple-choice list with answer options targeted at HF, COPD or exacerbation of COPD, or lower respiratory tract infection. With Pearson Chi-square or Fisher's exact test differences between the two GP groups were assessed regarding the chosen diagnostic tests. Results: Of the 148 participating GPs, 25 were GPSI-CVD and 123 were other GPs. In the first vignette, GPSI-CVD more often considered performing electrocardiography (ECG) than other GPs (64.0% vs. 32.5%, p = 0.003). In the second vignette, GPSI-CVD were more inclined to perform both ECG (36.0% vs. 12.2%, p = 0.003) and natriuretic peptide testing (56.0% vs. 32.5%, p = 0.006). Conclusions: Most GPs seemed to consider multiple diagnoses, including HF, with GPSI-CVD more likely performing ECG and natriuretic peptide testing in an older male person with both respiratory and suggestive HF symptoms. [ABSTRACT FROM AUTHOR]

Background and Aims Many adult patients with congenital heart disease (ACHD) are still afflicted by premature death. Previous reports suggested natriuretic peptides may identify ACHD patients with adverse outcome. The study investigated prognostic power of B-type natriuretic peptide (BNP) across the spectrum of ACHD in a large contemporary cohort. Methods The cohort included 3392 consecutive ACHD patients under long-term follow-up at a tertiary ACHD centre between 2006 and 2019. The primary study endpoint was all-cause mortality. Results A total of 11 974 BNP measurements were analysed. The median BNP at baseline was 47 (24–107) ng/L. During a median follow-up of 8.6 years (29 115 patient-years), 615 (18.1%) patients died. On univariable and multivariable analysis, baseline BNP [hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.15–1.18 and HR 1.13, 95% CI 1.08–1.18, respectively] and temporal changes in BNP levels (HR 1.22, 95% CI 1.19–1.26 and HR 1.19, 95% CI 1.12–1.26, respectively) were predictive of mortality (P <.001 for both) independently of congenital heart disease diagnosis, complexity, anatomic/haemodynamic features, and/or systolic systemic ventricular function. Patients within the highest quartile of baseline BNP (>107 ng/L) and those within the highest quartile of temporal BNP change (>35 ng/L) had significantly increased risk of death (HR 5.8, 95% CI 4.91–6.79, P <.001, and HR 3.6, 95% CI 2.93–4.40, P <.001, respectively). Conclusions Baseline BNP and temporal BNP changes are both significantly associated with all-cause mortality in ACHD independent of congenital heart disease diagnosis, complexity, anatomic/haemodynamic features, and/or systolic systemic ventricular function. B-type natriuretic peptide levels represent an easy to obtain and inexpensive marker conveying prognostic information and should be used for the routine surveillance of patients with ACHD. [ABSTRACT FROM AUTHOR]

Aim: Sacubitril/valsartan treatment reduces mortality and hospitalizations in heart failure with reduced ejection fraction but has limited application in hypertrophic cardiomyopathy (HCM). The aim of this study was to evaluate the effect of sacubitril/valsartan on peak oxygen consumption (VO2) in patients with non‐obstructive HCM. Methods and results: This is a phase II, randomized, open‐label multicentre study that enrolled adult patients with symptomatic non‐obstructive HCM (New York Heart Association class I–III) who were randomly assigned (2:1) to receive sacubitril/valsartan (target dose 97/103 mg) or control for 16 weeks. The primary endpoint was a change in peak VO2. Secondary endpoints included echocardiographic measures of cardiac structure and function, natriuretic peptides and other cardiac biomarkers, and Minnesota Living with Heart Failure quality of life. Between May 2018 and October 2021, 354 patients were screened for eligibility, 115 patients (mean age 58 years, 37% female) met the study inclusion criteria and were randomly assigned to sacubitril/valsartan (n = 79) or control (n = 36). At 16 weeks, there was no significant change in peak VO2 from baseline in the sacubitril/valsartan (15.3 [4.3] vs. 15.9 [4.3] ml/kg/min, p = 0.13) or control group (p = 0.47). No clinically significant changes were found in blood pressure, cardiac structure and function, plasma biomarkers, or quality of life. Conclusion: In patients with HCM, a 16‐week treatment with sacubitril/valsartan was well tolerated but had no effect on exercise capacity, cardiac structure, or function. [ABSTRACT FROM AUTHOR]

During mammalian heart development, the clustered genes encoding peptide hormones, Natriuretic Peptide A (NPPA; ANP) and B (NPPB; BNP), are transcriptionally co-regulated and co-expressed predominately in the atrial and ventricular trabecular cardiomyocytes. After birth, expression of NPPA and a natural antisense transcript NPPA-AS1 becomes restricted to the atrial cardiomyocytes. Both NPPA and NPPB are induced by cardiac stress and serve as markers for cardiovascular dysfunction or injury. NPPB gene products are extensively used as diagnostic and prognostic biomarkers for various cardiovascular disorders. Membrane-localized guanylyl cyclase receptors on many cell types throughout the body mediate the signaling of the natriuretic peptide ligands through the generation of intracellular cGMP, which interacts with and modulates the activity of cGMP-activated kinase and other enzymes and ion channels. The natriuretic peptide system plays a fundamental role in cardio-renal homeostasis, and its potent diuretic and vasodilatory effects provide compensatory mechanisms in cardiac pathophysiological conditions and heart failure. In addition, both peptides, but also CNP, have important intracardiac actions during heart development and homeostasis independent of the systemic functions. Exploration of the intracardiac functions may provide new leads for the therapeutic utility of natriuretic peptide-mediated signaling in heart diseases and rhythm disorders. Here, we review recent insights into the regulation of expression and intracardiac functions of NPPA and NPPB during heart development, homeostasis, and disease. [ABSTRACT FROM AUTHOR]

Aims: The use of large medical or healthcare claims databases is very useful for population‐based studies on the burden of heart failure (HF). Clinical characteristics and management of HF patients differ according to categories of left ventricular ejection fraction (LVEF), but this information is often missing in such databases. We aimed to develop and validate algorithms to identify LVEF in healthcare databases where the information is lacking. Methods and results: Algorithms were built by machine learning with a random forest approach. Algorithms were trained and reinforced using the French national claims database [Système National des Données de Santé (SNDS)] and a French HF registry. Variables were age, gender, and comorbidities, which could be identified by medico‐administrative code‐based proxies, Anatomical Therapeutic Chemical codes for drug delivery, International Classification of Diseases (Tenth Revision) coding for hospitalizations, and administrative codes for any other type of reimbursed care. The algorithms were validated by cross‐validation and against a subset of the SNDS that includes LVEF information. The areas under the receiver operating characteristic curve were 0.84 for the algorithm identifying LVEF ≤ 40% and 0.79 for the algorithms identifying LVEF < 50% and ≥50%. For LVEF ≤ 40%, the reinforced algorithm identified 50% of patients in the validation dataset with a positive predictive value of 0.88 and a specificity of 0.96. The most important predictive variables were delivery of HF medication, sex, age, hospitalization, and testing for natriuretic peptides with different orders of positive or negative importance according to the LVEF category. Conclusions: The algorithms identify reduced or preserved LVEF in HF patients within a nationwide healthcare claims database with high positive predictive value and low rates of false positives. [ABSTRACT FROM AUTHOR]

Aims: Hypertonic saline solution (HSS) plus intravenous (IV) loop diuretic appears to enhance the diuretic response in patients hospitalized for heart failure (HF). The efficacy and safety of this therapy in the ambulatory setting have not been evaluated. We aimed to describe the design and baseline characteristics of the SALT‐HF trial participants. Methods and results: 'Efficacy of Saline Hypertonic Therapy in Ambulatory Patients with HF' (SALT‐HF) trial was a multicenter, double‐blinded, and randomized study involving ambulatory patients who experienced worsening heart failure (WHF) without criteria for hospitalization. Enrolled patients had to present at least two signs of volume overload, use ≥ 80 mg of oral furosemide daily, and have elevated natriuretic peptides. Patients were randomized 1:1 to treatment with a 1‐h infusion of IV furosemide plus HSS (2.6–3.4% NaCl depending on plasmatic sodium levels) versus a 1‐h infusion of IV furosemide at the same dose (125–250 mg, depending on basal loop diuretic dose). Clinical, laboratory, and imaging parameters were collected at baseline and after 7 days, and a telephone visit was planned after 30 days. The primary endpoint was 3‐h diuresis after treatment started. Secondary endpoints included (a) 7‐day changes in congestion data, (b) 7‐day changes in kidney function and electrolytes, (c) 30‐day clinical events (need of IV diuretic, HF hospitalization, cardiovascular mortality, all‐cause mortality or HF‐hospitalization). Results: A total of 167 participants [median age, 81 years; interquartile range (IQR), 73–87, 30.5% females] were randomized across 13 sites between December 2020 and March 2023. Half of the participants (n = 82) had an ejection fraction >50%. Most patients showed a high burden of comorbidities, with a median Charlson index of 3 (IQR: 2–4). Common co‐morbidities included diabetes mellitus (41%, n = 69), atrial fibrillation (80%, n = 134), and chronic kidney disease (64%, n = 107). Patients exhibited a poor functional NYHA class (69% presenting NYHA III) and several signs of congestion. The mean composite congestion score was 4.3 (standard deviation: 1.7). Ninety per cent of the patients (n = 151) presented oedema and jugular engorgement, and 71% (n = 118) showed lung B lines assessed by ultrasound. Median inferior vena cava diameter was 23 mm, (IQR: 21–25), and plasmatic levels of N‐terminal‐pro‐B‐type natriuretic peptide (NTproBNP) and antigen carbohydrate 125 (CA125) were increased (median NT‐proBNP 4969 pg/mL, IQR: 2508–9328; median CA125 46 U/L, IQR: 20–114). Conclusions: SALT‐HF trial randomized 167 ambulatory patients with WHF and will determine whether an infusion of hypertonic saline therapy plus furosemide increases diuresis and improves decongestion compared to equivalent furosemide administration alone. [ABSTRACT FROM AUTHOR]

Aims: We assessed eligibility for omecamtiv mecarbil (OM) in a real-world cohort with heart failure with reduced ejection fraction (HFrEF) according to the selection criteria of the GALACTIC-HF trial (trial scenario) and selected trial´s criteria more likely to impact real-world use (pragmatic scenario). Methods and results: We included 31,015 patients with HFrEF lasting ≥3 months and registered in the Swedish HF registry between 2000–2021. Trial eligibility was calculated by applying all the GALACTIC-HF selection criteria. The pragmatic scenario considered only the New York Heart Association class, history of worsening HF, N-terminal pro-B-type natriuretic peptides (NT-proBNP), blood pressure and renal failure criteria defined as in the trial. Eligibility for OM in chronic HFrEF was 21% and 36% in the trial and pragmatic scenarios, respectively. Eligibility was higher in those with EF<30% (trial: 27%, pragmatic: 44%), in-patients (trial:30%, pragmatic:57%), severe HF (trial: 35%, pragmatic: 60%), NYHA class III-IV (trial: 26%, pragmatic: 45%), and NT-proBNP≥5,000pg/mL (trial: 30%, pragmatic: 51%). The criteria that most limited eligibility were history of a recent worsening HF event (60% eligible in chronic HFrEF), elevated NT-proBNP (82% eligible), and deviating blood pressure (82% eligible). Overall, eligible patients were characterized by more severe HF and higher CV event-rates in both scenarios, and higher comorbidity burden in the pragmatic scenario. Conclusion: Approximately 21% of real-world chronic HFrEF patients would be eligible for OM according to the GALACTIC-HF selection criteria, and 36% according to the criteria more likely to affect OM use in clinical practice. Criteria in both scenarios identified a patient-group with severe HF and high CV event-rates. [ABSTRACT FROM AUTHOR]

Plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) level is primarily used as a biomarker for left ventricular (LV) dysfunction. It is influenced by various conditions, such as myocardial strain and situations affecting the clearance of NT-proBNP, including sepsis and shock. In this study, we investigated the appropriateness of NT-proBNP as a prognostic factor for septic shock. Patients with septic shock who visited the emergency department of the Ewha Womans' University Mokdong Hospital between January 1, 2018, and December 31, 2020, were classified into the survival group (those who survived in the hospital and were discharged) and the death group (those who died in the hospital). The effectiveness of NT-proBNP, lactate, and blood urea nitrogen as predictive factors of in-hospital mortality was evaluated using the area under the receiver operating characteristic (AUROC) curve. The AUROC curve was 0.678 and 0.648 for lactate and NT-proBNP, respectively, with lactate showing the highest value. However, there was no significant difference between lactate and NT-proBNP levels in the comparison of their AUROC curve (p = 0.6278). NT-proBNP could be a useful predictor of in-hospital mortality in patients with septic shock who present to the emergency department. [ABSTRACT FROM AUTHOR]

The natriuretic peptide (NP) family consists of cardiac NPs (ANP, BNP, and VNP) and brain NPs (CNPs) in teleosts. In addition to CNP1-4, a paralogue of CNP4 (named CNP4b) was recently discovered in basal teleosts including Japanese eel. Mammals have lost most Cnps during the evolution, but teleost cnps were conserved and diversified, suggesting that CNPs are important hormones for maintaining brain functions in teleost. The present study evaluated the potency of each Japanese eel CNP to their NP receptors (NPR-A, NPR-B, NPR-C, and NPR-D) overexpressed in CHO cells. A comprehensive brain map of cnps- and nprs-expressing neurons in Japanese eel was constructed by integrating the localization results obtained by in situ hybridization. The result showed that CHO cells expressing NPR-A and NPR-B induced strong cGMP productions after stimulation by cardiac and brain NPs, respectively. Regarding brain distribution of cnps, cnp1 is engaged in the ventral telencephalic area and periventricular area including the parvocellular preoptic nucleus (Pp), anterior/posterior tuberal nuclei, and periventricular gray zone of the optic tectum. cnp3 is found in the habenular nucleus and prolactin cells in the pituitary. cnp4 is expressed in the ventral telencephalic area, while cnp4b is expressed in the motoneurons in the medullary area. Such CNP isoform-specific localizations suggest that function of each CNP has diverged in the eel brain. Furthermore, the Pp lacking the blood-brain barrier expressed both npra and nprb, suggesting that endocrine and paracrine NPs interplay for regulating the Pp functions in Japanese eels. [ABSTRACT FROM AUTHOR]

The pathophysiology behind sodium retention in heart failure with preserved ejection fraction (HFpEF) remains poorly understood. We hypothesized that patients with HFpEF have impaired natriuresis and diuresis in response to volume expansion and diuretic challenge, which is associated with renal hypo‐responsiveness to endogenous natriuretic peptides. Nine HFpEF patients and five controls received saline infusion (0.25 mL/kg/min for 60 min) followed by intravenous furosemide (20 mg or home dose) 2 h after the infusion. Blood and urine samples were collected at baseline, 2 h after saline infusion, and 2 h after furosemide administration; urinary volumes were recorded. The urinary cyclic guanosine monophosphate (ucGMP)/plasma B‐type NP (BNP) ratio was calculated as a measure of renal response to endogenous BNP. Wilcoxon rank‐sum test was used to compare the groups. Compared to controls, HFpEF patients had reduced urine output (2480 vs.3541 mL; p = 0.028), lower urinary sodium excretion over 2 h after saline infusion (the percentage of infused sodium excreted 12% vs. 47%; p = 0.003), and a lower baseline ucGMP/plasma BNP ratio (0.7 vs. 7.3 (pmol/mL)/(mg/dL)/(pg/mL); p = 0.014). Patients with HFpEF had impaired natriuretic response to intravenous saline and furosemide administration and lower baseline ucGMP/plasma BNP ratios indicating renal hypo‐responsiveness to NPs. [ABSTRACT FROM AUTHOR]

Introduction: Rheumatic Heart Disease (RHD) remains the primary cause of acquired Valvular Heart Disease (VHD) in developing countries. The role of Tissue Doppler Indices (TDI) in RHD is understudied. This study aims to fill evidence gaps identified by the American College of Cardiology/American Heart Association in the management of Valvular Heart Disease (VHD) by analysing newer echocardiographic techniques {Tissue Doppler Imaging (TDI)} and biochemical markers (NT-proBNP) against clinical parameters {New York Heart Association (NYHA)} in an understudied patient group. Aim: To evaluate the role of TDI and its association with the functional class of dyspnoea and serum NT-proBNP levels in RHD. Materials and Methods: This cross-sectional study was conducted in the Cardiology and Medicine departments, Central Gujarat, Western India, from January 2021 to June 2022. Fifty-seven consenting adult patients with RHD who underwent echocardiography with Standard Echocardiographic Techniques (SET) to stratify VHD severity were included. Patients were divided into three sub-groups: a) Isolated MR and MR with mild/moderate MS (n=23); b) Isolated MS and MS with mild MR (n=29); and c) Isolated MS and MS with mild or moderate MR (n=48). TDI parameters (e', a', e'/a', and E/e') at medial mitral, lateral mitral, and tricuspid annuli, NYHA classification, and serum NT-proBNP levels were analysed. The Analysis of Variance (ANOVA) was used to assess the association between NYHA class and clinical and NT-proBNP parameters. The Pearson correlation coefficient was employed to determine linear relationships between NT-proBNP and TDI parameters. Results: The mean age was 45.4±16 years, with the age groups 20-40 years (n=20) and 40-60 years (n=22) having a nearly equal distribution. The female-to-male ratio was 1.48 (34/23). In subgroup C, the a' velocity decreased from 13.74±3.92 cm/s in NYHA I to 5.17±1.98 cm/s in NYHA IV (p=0.0312), and the e'/a' ratio increased from 0.96±0.40 in NYHA I to 2.41±1.00 in NYHA IV (p=0.0210). These changes paralleled trends in a' value (p=0.0306) and e'/a' ratio (p=0.0157) with increasing NTproBNP levels. Conclusion: At the tricuspid annulus, the e'/a' ratio and a' velocity can complement NT-proBNP in cases where there is a discrepancy between the clinical status of the patient and the severity of the valve lesion as determined by SET. Larger-scale studies are needed to further evaluate the association between TDI parameters and long-term clinical outcomes, as well as to identify the optimal timing for surgical intervention in RHD patients. [ABSTRACT FROM AUTHOR]

Many recent studies have validated the internal jugular vein ultrasound (IJV-US) for estimating volemic status in critical patients. If research confirms its accuracy in detecting intravascular volume, congestion, and prognosis, this method could help manage heart failure (HF) because it is simple, fast, and applicable in several settings. This review examines the IJV-US's reliability, diagnostic accuracy, and ability to predict poor outcomes for HF, as well as its correlation with surrogate congestion tests like natriuretic peptides and elevated central venous pressure (CVP). Our systematic review followed the PRISMA statement for systematic reviews and meta-analyses. Eleven studies examined the reliability and validity of IJV-US measures in predicting congestion, volume status, and prognosis in adult spontaneously breathing HF patients. We searched PubMed, Cochrane Library, and EMBASE. IJV-US measurements using Valsalva and sniffing seem more accurate for predicting congestion, volume status, high CVP, and poor prognosis. The IJV ratio in chronic HF and out-hospital patients and the absence of IJV area [cross-sectional area (CSA)] changes in acute HF (AHF) and in-hospital patients are the most validated measurements. No evidence suggests the method is reliable between and within raters. AHF patients' IJV ratio and CSA absence appear to correlate with CVP and atrial natriuretic peptides. In conclusion, the IJV-US may be useful for managing HF patients, but more research is needed to confirm its reliability and prognostic accuracy. Develop a standard US protocol lastly. [ABSTRACT FROM AUTHOR]

A common flame-retardant and plasticizer, triphenyl phosphate (TPhP) is an aryl phosphate ester found in many aquatic environments at nM concentrations. Yet, most studies interrogating its toxicity have used µM concentrations. In this study, we used the model organism zebrafish (Danio rerio) to uncover the developmental impact of nM exposures to TPhP at the phenotypic and molecular levels. At concentrations of 1.5–15 nM (0.5 µg/L–5 µg/L), chronically dosed 5dpf larvae were shorter in length and had pericardial edema phenotypes that had been previously reported for exposures in the µM range. Cardiotoxicity was observed but did not present as cardiac looping defects as previously reported for µM concentrations. The RXR pathway does not seem to be involved at nM concentrations, but the tbx5a transcription factor cascade including natriuretic peptides (nppa and nppb) and bone morphogenetic protein 4 (bmp4) were dysregulated and could be contributing to the cardiac phenotypes. We also demonstrate that TPhP is a weak pro-oxidant, as it increases the oxidative stress response within hours of exposure. Overall, our data indicate that TPhP can affect animal development at environmentally relevant concentrations and its mode of action involves multiple pathways. [ABSTRACT FROM AUTHOR]

Background: The characterization of the different pathophysiological mechanisms involved in normotensive versus hypertensive acute heart failure (AHF) might help to develop individualized treatments. Methods: The extent of hemodynamic cardiac stress and cardiomyocyte injury was quantified by measuring the B-type natriuretic peptide (BNP), N-terminal proBNP (NT-proBNP), and high-sensitivity cardiac troponin T (hs-cTnT) concentrations in 1152 patients presenting with centrally adjudicated AHF to the emergency department (ED) (derivation cohort). AHF was classified as normotensive with a systolic blood pressure (SBP) of 90–140 mmHg and hypertensive with SBP > 140 mmHg at presentation to the ED. Findings were externally validated in an independent AHF cohort (n = 324). Results: In the derivation cohort, with a median age of 79 years, 43% being women, 667 (58%) patients had normotensive and 485 (42%) patients hypertensive AHF. Hemodynamic cardiac stress, as quantified by the BNP and NT-proBNP, was significantly higher in normotensive as compared to hypertensive AHF [1105 (611–1956) versus 827 (448–1419) pg/mL, and 5890 (2959–12,162) versus 4068 (1986–8118) pg/mL, both p < 0.001, respectively]. Similarly, the extent of cardiomyocyte injury, as quantified by hs-cTnT, was significantly higher in normotensive AHF as compared to hypertensive AHF [41 (24–71) versus 33 (19–59) ng/L, p < 0.001]. A total of 313 (28%) patients died during 360 days of follow-up. All-cause mortality was higher in patients with normotensive AHF vs. patients with hypertensive AHF (hazard ratio 1.66, 95%CI 1.31–2.10; p < 0.001). Normotensive patients with a high BNP, NT-proBNP, or hs-cTnT had the highest mortality. The findings were confirmed in the validation cohort. Conclusion: Biomarker profiling revealed a higher extent of hemodynamic stress and cardiomyocyte injury in patients with normotensive versus hypertensive AHF. [ABSTRACT FROM AUTHOR]

Hypertension (HT) is a disease that poses a serious threat to human health, mediating organ damage such as the cardiovascular (CV) system, kidneys, central nervous system (CNS), and retinae, ultimately increasing the risk of death due to damage to the entire vascular system. Thus, the widespread prevalence of hypertension brings enormous health problems and socioeconomic burdens worldwide. The goal of hypertension management is to prevent the risk of hypertension-mediated organ damage and excess mortality of cardiovascular diseases. To achieve this goal, hypertension guidelines recommend accurate monitoring of blood pressure and assessment of associated target organ damage. Early identification of organ damage mediated by hypertension is therefore crucial. Plasma biomarkers as a non-invasive test can help identify patients with organ damage mediated by hypertension who will benefit from antihypertensive treatment optimization and improved prognosis. In this review, we provide an overview of some currently available, under-researched, potential plasma biomarkers of organ damage mediated by hypertension, looking for biomarkers that can be detected by simple testing to identify hypertensive patients with organ damage, which is of great significance in clinical work. Natriuretic peptides (NPs) can be utilized as a traditional biomarker to detect hypertension-mediated organ damage, especially for heart failure. Nevertheless, we additionally may need to combine two or more plasma biomarkers to monitor organ damage in the early stages of hypertension. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is one of the leading causes of cardiovascular disease and powerful predictor for new-onset heart failure (HF). We focus on the relevant literature covering evidence of risk stratification based on imaging predictors and circulating biomarkers to optimize approaches to preventing HF in DM patients. Multiple diagnostic algorithms based on echocardiographic parameters of cardiac remodeling including global longitudinal strain/strain rate are likely to be promising approach to justify individuals at higher risk of incident HF. Signature of cardiometabolic status may justify HF risk among T2DM individuals with low levels of natriuretic peptides, which preserve their significance in HF with clinical presentation. However, diagnostic and predictive values of conventional guideline-directed biomarker HF strategy may be non-optimal in patients with obesity and T2DM. Alternative biomarkers affecting cardiac fibrosis, inflammation, myopathy, and adipose tissue dysfunction are plausible tools for improving accuracy natriuretic peptides among T2DM patients at higher HF risk. In summary, risk identification and management of the patients with T2DM with established HF require conventional biomarkers monitoring, while the role of alternative biomarker approach among patients with multiple CV and metabolic risk factors appears to be plausible tool for improving clinical outcomes. [ABSTRACT FROM AUTHOR]

Heart failure (HF) remains a major medical and social problem. The NT-pro-brain natriuretic peptide (NT-proBNP) and its active form, brain-type natriuretic peptide (BNP), in a simple blood test are the gold-standard biomarkers for HF diagnosis. However, even good biomarkers such as natriuretic peptides fail to predict all the risks associated with HF due to the diversity of the mechanisms involved. The pathophysiology of HF is determined by numerous factors, including oxidative stress, inflammation, neuroendocrine activation, pathological angiogenesis, changes in apoptotic pathways, fibrosis and vascular remodeling. High readmission and mortality rates prompt a search for new markers for the diagnosis, prognosis and treatment of HF. Oxidative-stress-mediated inflammation plays a crucial role in the development of subsequent changes in the failing heart and provides a new insight into this complex mechanism. Oxidative stress and inflammatory biomarkers appear to be a promising diagnostic and prognostic tool in patients with HF. This systematic review provides an overview of the current knowledge about oxidative stress and inflammation parameters as markers of HF. [ABSTRACT FROM AUTHOR]

Natriuretic peptides (NP) have multiple actions benefitting cardiovascular and metabolic health. Although many of these are mediated by Guanylyl Cyclase (GC) receptors NPR1 and NPR2, their role and relative importance in vivo is unclear. The intracellular mediator of NPR1 and NPR2, cGMP, circulates in plasma and can be used to examine relationships between receptor activity and tissue responses targeted by NPs. Plasma cGMP was measured in 348 participants previously recruited in a multidisciplinary community study (CHALICE) at age 50 years at a single centre. Associations between bio-active NPs and bio-inactive aminoterminal products with cGMP, and of cGMP with tissue response, were analysed using linear regression. Mediation of associations by NPs was assessed by Causal Mediation Analysis (CMA). ANP's contribution to cGMP far exceed those of other NPs. Modelling across three components (demographics, NPs and cardiovascular function) shows that ANP and CNP are independent and positive predictors of cGMP. Counter intuitively, findings from CMA imply that in specific tissues, NPR1 responds more to BNP stimulation than ANP. Collectively these findings align with longer tissue half-life of BNP, and direct further therapeutic interventions towards extending tissue activity of ANP and CNP. [ABSTRACT FROM AUTHOR]

Aims: The safety and effectiveness of the MitraClip device to treat functional mitral regurgitation (FMR) has been tested in previous clinical trials yielding somewhat heterogeneous results in heart failure (HF) patients. Over time, the MitraClip device system has been modified and clinical practice evolved to consider also less severely diseased HF patients with FMR for this therapeutic option. The RESHAPE‐HF2 trial aims to assess the safety and effectiveness of the MitraClip device system on top of medical therapy considered optimal in the treatment of clinically significant FMR in symptomatic patients with chronic HF. Methods: The RESHAPE‐HF2 is an investigator‐initiated, prospective, randomized, parallel‐controlled, multicentre trial designed to evaluate the use of the MitraClip device (used in the most up‐to‐date version as available at sites) plus optimal standard of care therapy (device group) compared to optimal standard of care therapy alone (control group). Eligible subjects have signs and symptoms of HF (New York Heart Association [NYHA] class II–IV despite optimal therapy), and have moderate‐to‐severe or severe FMR, as confirmed by a central echocardiography core laboratory; have an ejection fraction between ≥20% and ≤50% (initially 15–35% for NYHA class II patients, and 15–45% for NYHA class III/IV patients); have been adequately treated per applicable standards, and have received appropriate revascularization and cardiac resynchronization therapy, if eligible; had a HF hospitalization or elevated natriuretic peptides (B‐type natriuretic peptide [BNP] ≥300 pg/ml or N‐terminal proBNP ≥1000 pg/ml) in the last 90 days; and in whom isolated mitral valve surgery is not a recommended treatment option. The trial has three primary endpoints, which are these: (i) the composite rate of total (first and recurrent) HF hospitalizations and cardiovascular death during 24 months of follow‐up, (ii) the rate of total (i.e. first and recurrent) HF hospitalizations within 24 months, and (iii) the change from baseline to 12 months in the Kansas City Cardiomyopathy Questionnaire overall score. The three primary endpoints will be analysed using the Hochberg procedure to control the familywise type I error rate across the three hypotheses. Conclusions: The RESHAPE‐HF2 trial will provide sound evidence on the MitraClip device and its effects in HF patients with FMR. The recruitment was recently completed with 506 randomized patients. [ABSTRACT FROM AUTHOR]