Natriuretic Peptide Release Research Articles

Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone

Heart failure is a leading cause of morbidity and mortality1,2. Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which act through their receptor (NPR1) to affect vasodilation, diuresis and natriuresis, lowering venous pressures and relieving venous congestion3–8. Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect9,10. Here we report that in a human genetic analysis of over 700,000 individuals, lifelong exposure to coding variants of the NPR1 gene is associated with changes in blood pressure and risk of heart failure. We describe the development of REGN5381, an investigational monoclonal agonist antibody that targets the membrane-bound guanylate cyclase receptor NPR1. REGN5381, an allosteric agonist of NPR1, induces an active-like receptor conformation that results in haemodynamic effects preferentially on venous vasculature, including reductions in systolic blood pressure and venous pressure in animal models. In healthy human volunteers, REGN5381 produced the expected haemodynamic effects, reflecting reductions in venous pressures, without obvious changes in diuresis and natriuresis. These data support the development of REGN5381 for long-lasting and selective lowering of venous pressures that drive symptomatology in patients with heart failure.

Novel Biomarkers in Early Detection of Heart Failure: A Narrative Review.

Heart failure (HF) represents a significant global health challenge, characterized by a variety of symptoms resulting from cardiac dysfunction. This dysfunction often leads to systemic and pulmonary congestion. The pathophysiology of HF is complex, involving stimulation of the sympathetic nervous system, which is insufficiently balanced by the release of natriuretic peptide. This imbalance leads to progressive hypertrophy and dilatation of the heart's chambers, impairing its pumping efficiency and increasing the risk of arrhythmias and conduction disorders. The prevalence of HF is exceptionally high in industrialized nations and is expected to increase owing to an aging population and advancements in diagnostic methods. This study emphasizes the critical role of early diagnosis in reducing morbidity and mortality associated with HF, focusing specifically on the evolving importance of biomarkers in managing this condition. Biomarkers have played a key role in transforming the diagnosis and treatment of HF. Traditional biomarkers such as b-type natriuretic peptide and N-terminal pro-b-type natriuretic peptide have been widely adopted for their cost-effectiveness and ease of access. However, the rise of novel biomarkers such as growth differentiation factor 15 and adrenomedullin has shown promising results, offering superior sensitivity and specificity. These new biomarkers enhance diagnostic accuracy, risk stratification, and prognostic evaluation in HF patients. Despite these advancements, challenges remain, such as limited availability, high costs, and the need for further validation in diverse patient populations. Through a comprehensive literature review across databases such as PubMed, Google Scholar, and the Cochrane Library, this study compiles and analyzes data from 18 relevant studies, offering a detailed understanding of the current state of HF biomarkers.The study examines both traditional and emerging biomarkers such as galectin-3 and soluble suppression of tumorigenicity 2 in HF, exploring their clinical roles and impact on patient outcomes.

Hypoxia-Inducible Factor mediates the Release of Natriuretic Peptides

Background: The physiology of natriuretic peptides is insufficiently known. The function of mechanical heart alone, mediated by large and rapid volume overloads, has been suggested to be the key operator in the synthesis and release of natriuretic peptides from the endocrine heart. Researchers have concluded that terrestrial mammals, including humans, have a powerful endocrine system that responds to the mechanical stress of the heart by causing instantaneous diuresis and natriuresis. Although one of the most important and valid paradigms in cardiology is that mechanical load increases the oxygen consumption of heart, the investigation of the relationship between mechanical load and oxygen metabolism has been neglected in the studies on circulating natriuretic peptides. Purpose: To develop a comprehensive conceptual model explaining how the oxygen metabolism plays a central role in the biology of natriuretic peptides. Conclusions: All cells including cardiac myocytes, share an oxygen sensing pathway which is regulated through a nuclear transcription factor, the Hypoxia-Inducible Factor. When the oxygen concentration is normal Hypoxia-Inducible Factor is rapidly oxidized, whereas in hypoxic conditions, Hypoxia-Inducible Factor starts to accumulate and trigger downhill the expression of hundreds of genes such as the genes for A-type and B-type natriuretic peptide. As a result of diuresis, natriuresis, and plasma shift from intravascular space to extravascular space, circulating natriuretic peptides cause volume contraction and hemoconcentration contributing to the transport of oxygen into tissues and organs. Implications: Understanding the biology of natriuretic peptides in cardiac diseases would increase the usefulness of plasma measurement of natriuretic peptides.

Abstract 15078: Atrial and Brain Natriuretic Peptides Expression and Release in Pulmonary Hypertension

Introduction: Precapillary pulmonary hypertension (PH) is characterized by progressive overload for the right ventricle and right heart failure (RHF). N-terminal Brain Natriuretic Peptides (NTproBNP) and Atrial Natriuretic Peptides (ANP) are secreted from cardiomyocytes upon stretch. NTproBNP is used as biomarker for RHF. Aim: To study the association between ANP and NTproBNP and pressure overload in blood, right heart tissue and induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) from PH-patients. Methods: We analyzed NTproBNP in 344 PH-patients, 9 controls, and in 9 PH-patients before and 6-months after pulmonary endarterectomy (PEA). We measured NPPA and NPPB gene expression on end-stage human right ventricular (RV) and right atrial (RA) samples from 8 PH-patients and 5 controls. In addition, we performed immunofluoresence staining for ANP and BNP on RA tissue (N=4) and RV tissue (N=10) in PH and controls (N=5). iPSC-CMs from 1 male and 1 female PH-patients were stretched for 24h at 1Hz and 10% on the Flexcell FX-6000 system, and NTproBNP release was measured on static and stretched iPSC-CMs. NTproBNP levels were measured through ECLIA. Results: NTproBNP serum levels were elevated in PH-patients versus controls (918 vs 25 pg/mL, Fig1A). Pressure unloading in CTEPH patients did not result in a decrease in NTproBNP (Fig1B). In RV tissue of PH-patients NPPA expression was upregulated, but NPPB was not (Fig1C). ANP and BNP content was higher in RA and RV tissue of PH-patients (Fig1D-E). Finally, ~5x higher NTproBNP was released from male vs female iPSC-CMs under static conditions and after mechanical stretch (Fig1F). Conclusions: ANP and BNP showed important differences at gene and protein levels in relation to pressure overload. To confirm current results, further analyses on atrial and ventricular iPSC-CMs will be performed, in addition to mid-range proANP measurements in patients’ blood and iPSC-CMs conditioned medium.

Abstract P2045: Regulation Of Atrial Natriuretic Peptide Secretion By Palmitoylation And Modulation Of The Rab3a GTPase Cycle In Cardiac Myocytes

Despite the clinical relevance to cardiovascular disease, molecular regulation of atrial natriuretic peptide (ANP) release by cardiomyocytes remains ill-defined. We uncovered novel functions for Rab3gap1 and modulation of Rab3a nucleotide cycling in membrane fusion and atrial natriuretic peptide (ANP) release in cardiomyocytes. We generated transgenic mice overexpressing the Golgi-localized S-acyltransferase, zDHHC9, and identified Rab3gap1 as a novel cardiac substrate of zDHHC9 by S-acyl proteomics. Rab3gap1 palmitoylation and retention at the cardiomyocyte Golgi, Rab3a-GTP levels, and formation of Rab3a-positive post-Golgi vesicles were all enhanced in zDHHC9 overexpressing hearts as were Rab3gap1, Rab3a, and ANP atrial protein levels but circulating ANP levels were reduced, suggesting a defect in ANP secretion. Notably, treatment of cardiomyocytes with the secretagogue phenylephrine (PE) promoted substantial ANP release as expected, but also enhanced Rab3gap1 palmitoylation and Rab3a GTP-loading and peripheral vesicle formation, whereas knockdown of zDHHC9 repressed these PE-induced effects on Rab3gap1 and Rab3a but further enhanced PE-stimulated ANP secretion, suggesting zDHHC9-mediated palmitoylation of Rab3gap1 serves as an intrinsic mechanism to limit ANP release. Consistent with a role for Rab3a nucleotide exchange in modulation of ANP release, overexpression of Rab3gap1 in cardiomyocytes promoted a profound increase in ANP release whereas a GAP-deficient mutant of Rab3gap1 (Rab3gap1 R728A ) was resistant to this effect. Collectively, these data suggest disruption of Rab3a nucleotide cycling perturbs secretory vesicle membrane fusion and ANP release in cardiac myocytes and establish critical roles for Rab3a activity and its modulation by zDHHC9-mediated palmitoylation of Rab3gap1 in governing cardiac homeostasis and endocrine signaling.

ZDHHC9 Regulates Cardiomyocyte Rab3a Activity and Atrial Natriuretic Peptide Secretion Through Palmitoylation of Rab3gap1

Production and release of natriuretic peptides by the stressed heart reduce cardiac workload by promoting vasodilation, natriuresis, and diuresis, which has been leveraged in the recent development of novel heart-failure pharmacotherapies, yet the mechanisms regulating cardiomyocyte exocytosis and natriuretic peptide release remain ill defined. We found that the Golgi S-acyltransferase zDHHC9 palmitoylates Rab3gap1 resulting in its spatial segregation from Rab3a, elevation of Rab3a-GTP levels, formation of Rab3a-positive peripheral vesicles, and impairment of exocytosis that limits atrial natriuretic peptide release. This novel pathway potentially can be exploited for targeting natriuretic peptide signaling in the treatment of heart failure.

MORPHOLOGICAL CHARACTERISTICS OF THE ENDOCRINE FUNCTION OF THE HEART IN COMORBID PATHOLOGY.

Aim: To study the ultrastructural remodeling of atrial myoendocrine cells (AMC) of the atrial myocardium in streptozotocin-induced diabetes (SID) under chronic immobilization stress (CIS). Materials and methods: 40 sexually mature white male rats (body weight 150-180 g) were included in the study. Four groups were formed: group 1 - animals with comorbid pathology (SID and CIS), group 2 - animals with SID, group 3 - animals with CIS, group 4 - intact animals. Results: On the 14th day of the development of SID and CIS, an increase in the functional activity of AMC is noted, which is confirmed by hyperplasia and hypertrophy of the protein-synthesizing apparatus, an increase in the volume density of secretory granules (SG), especially diffusing ones, and indicates enhanced release of atrial natriuretic peptide (ANP) from cells during the experiment. On the 56th day of the experiment, in groups 1 and 2 of , destructive changes in AMC were noted, such as vacuolar and balloon dystrophy, colliquative and partial necrosis. At the same time, the functional activity of AMC of different regions of the myocardium significantly. In animals with CIS, the volume density of young and diffusing SG in AMC is decreased. Conclusions: Therefore, in the early stages of the development of SID and CIS, an increase in the morpho-functional activity of AMC is noted. The long course of SID and its combination with CIS lead to destructive changes in AMC and to decrease in their secretory activity.

Parkia speciosa Hassk. Empty Pod Extract Prevents Cardiomyocyte Hypertrophy by Inhibiting MAPK and Calcineurin-NFATC3 Signaling Pathways.

Cardiac hypertrophy is an early hallmark during the clinical course of heart failure. Therapeutic strategies aiming to alleviate cardiac hypertrophy via the mitogen-activated protein kinase (MAPK)/calcineurin-nuclear factor of activated T-cells (NFAT) signaling pathway may help prevent cardiac dysfunction. Previously, empty pod ethanol crude extract of Parkia speciosa Hassk was shown to demonstrate protective effects against cardiomyocyte hypertrophy. Therefore, the current study aimed to investigate the effects of various fractions of the plant ethanol extract on the MAPK/NFAT signaling pathway in angiotensin II (Ang II)-induced cardiomyocyte hypertrophy. Simultaneous treatment with ethyl acetate (EA) fraction produced the most potent antihypertrophic effect evidenced by the reduced release of B-type natriuretic peptide (BNP). Subsequently, treatment with the EA fraction (6.25, 12.5, and 25 μg/mL) prevented an Ang II-induced increase in cell surface area, hypertrophic factors (atrial natriuretic peptide and BNP), reactive oxygen species, protein content, and NADPH oxidase 4 expression in the cells. Furthermore, EA treatment attenuated the activation of the MAPK pathway and calcineurin-related pathway (GATA-binding protein 4 and NFATC3), which was similar to the effects of valsartan (positive control). Our findings indicate that the EA fraction prevents Ang II-induced cardiac hypertrophy by regulating the MAPK/calcineurin-NFAT signaling pathway.

Relationship between oxytocin receptor gene polymorphism and hypertension in Turkish population

Introduction and objectivesKnown to play a key role in uterine contraction and milk ejection, the neuropeptide, oxytocin, has cardiovascular effects. To date, the known cardiovascular effects of oxytocin are blood pressure lowering (caused by natriuresis and atrial natriuretic peptide release), negative inotropic and chronotropic effect caused by parasympathetic neuromodulation, anti-stress effect and vasodilation mediated by activation of the nitric oxide pathway. The clinical significance of the rs2268498 polymorphism in oxytocin receptors in these effects is controversial. Based on the known genetic inheritance of hypertension, our research aimed to determine whether the presence of the rs2268498 oxytocin receptor (OXTR) allele C affects hypertension in our region. MethodsThis article is a case-control study conducted in the Turkish population. About 140 normotensive and 140 isolated hypertensive volunteers included in the research and genotyped with real-time PCR hybridization method via melt curve analysis. ResultsOxytocin receptor rs2268498 polymorphism was assessed in terms of the risk of hypertension and hypertensive individuals were compared to the control group. OXTR rs2268498 polymorphism was not found to be a significant risk factor for dominant, recessive and additive modeled hypertension (ORdominant: 0.966, 95% CI: 0.57-1.61, p: 0.9; ORrecessive: 1, 95% CI: 0.58-1.71, p: 1.0 and ORoverall: 0.98, chi2=0.01). ConclusionWe concluded that rs2268498 single nucleotide polymorphism is not a risk factor for hypertension in our region.

Thrombin receptor protease-activated receptor 1 (PAR1) related cytotoxic CD8+ T cell activity is associated with atrial myopathy and pro-inflammatory immune response in early atrial fibrillation

Abstract Background and aims Cytotoxic CD8+ T cells mediate myocardial damage in patients with virus induced myocarditis, plaque erosion during acute coronary syndrome, and promote adverse post-ischemic cardiac remodeling. There is emerging evidence to support a link between inflammation and atrial fibrillation (AF). Protease-activated receptor 1 (PAR1) is the thrombin receptor expressed on platelets, but it is also expressed in endothelial cells, vascular smooth muscle cells, cardiac fibroblasts, and CD8+ T cells. The role of CD8+ T cells and PAR1 in atrial myopathy and early AF have not been studied. Methods In 80 non-anticoagulated patients with a first documented episode of AF, and 20 control subjects without AF but with a comparable cardiovascular risk profile (e.g. SCORE2, CHA2DS2-VASc, p>0.05), we studied PAR1-related cytotoxic T cell activity in the first hours (up to 24 h) of AF clinical manifestation. The Apolipoprotein E–knock out (ApoEko) mouse is a commonly used model of metabolic syndrome that develops atrial myopathy (structural correlate of AF). ApoEko male mice (Apoetm1Unc with a C57BL/6 genetic background) were fed for six weeks with a standard chew, western-type diet (high fat and high sucrose = WD) ± the specific PAR1 inhibitor vorapaxar. Results High levels of circulating, activated CD8+ T cells (CD8+CD57+ T cells with pro-inflammatory and high cytotoxic properties) were present in patients with early AF (flow cytometry). Stimulation of cytotoxic T cells, that expressed the thrombin receptor PAR1, that were isolated from patients with new onset of AF, released pro-inflammatory cytokines (e.g. IFN-γ, TNF-α). Enhanced cytotoxic activity of CD8+ T cells was suggested by elevated plasma levels of effector molecules (e.g. granulysin and granzyme). In ApoEko mice fed a WD, atrial myopathy as the structural correlate for AF, was paralleled by increased expression of effector molecules that were associated with CD8+ T cell activity (like perforin, granzyme A, granzyme B, IFN-γ). Cytotoxic T cell activity disrupted the release of the potective atrial natriuretic peptide, ANP, and increased signaling pathways associated with atrial fibrosis (e.g. TGF-β, cTGF, TGF-β receptor). The specific PAR1 inhibitor, vorapaxar, reduced inflammatory T cell activity, transcription of fibrotic mediators, and reconstituted ANP secretion in atria of ApoEko mice. Conclusions Targeting the FXa/FIIa-PAR1-CD8+ axis might be a promising approach to reduce atrial fibrosis and inflammation. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): BIH Charité Clinician Scientist Program

Exogenous ketosis suppresses diuresis and atrial natriuretic peptide during exercise.

We have previously demonstrated that exogenous ketosis reduces urine production during exercise. However, the underlying physiological mechanism of this antidiuretic effect remained unclear. Therefore, we investigated whether acute exogenous ketosis by oral ingestion of ketone ester (KE) during a simulated cycling race (RACE) affects the hormonal pathways implicated in fluid balance regulation during exercise. In a double-blind crossover design, 11 well-trained male cyclists participated in RACE consisting of a 3-h submaximal intermittent cycling (IMT180') bout followed by a 15-min time trial (TT15') in an environmental chamber set at 28°C and 60% relative humidity. Fluid intake was adjusted to maintain euhydration. Before and during RACE, the subjects received either a control drink (CON) or the ketone ester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KE), which elevated blood β-hydroxybutyrate to ∼2-4 mM. Urine output during IMT180' was ∼20% lower in KE (1,172 ± 557 mL) than in CON (1,431 ± 548 mL, P < 0.05). Compared with CON, N-terminal proatrial natriuretic peptide (NT-pro ANP) concentration during RACE was ∼20% lower in KE (P < 0.05). KE also raised plasma noradrenaline concentrations during RACE. Performance in TT15' was similar between CON and KE. In conclusion, exogenous ketosis suppresses diuresis and downregulates NT-pro ANP secretion during exercise.NEW & NOTEWORTHY We previously demonstrated that exogenous ketosis reduces urine production during exercise, however, the underlying physiological mechanism remained unclear. Here, we, for the first time demonstrate that exogenous ketosis suppresses the exercise-induced release of atrial natriuretic peptide (ANP). However, given the limited effects of ANP on renal haemodynamics during exercise, the underlying physiological mechanism remains unknown. But downregulation of ANP might explain a new physiological mechanism by which exogenous ketosis lowers blood-free fatty acid levels.

Biochemistry of the Endocrine Heart.

Simple SummaryBesides being a muscle and an electrochemically active organ, the heart is a true endocrine organ. As endocrine cells, cardiac myocytes possess all the needed chemical necessities for translation, post-translational modifications, and complex peptide proteolysis. In addition, intracellular granules in the cells contain not only peptides destined for secretion but also important granin molecules involved in maintaining a regulated secretory pathway. In this review, we highlight the biochemical phenotype of the endocrine heart, recapitulating that the cardiac myocytes are truly and fully capable endocrine cells.Production and release of natriuretic peptides and other vasoactive peptides are tightly regulated in mammalian physiology and involved in cardiovascular homeostasis. As endocrine cells, the cardiac myocytes seem to possess almost all known chemical necessities for translation, post-translational modifications, and complex peptide proteolysis. In several ways, intracellular granules in the cells contain not only peptides destined for secretion but also important granin molecules involved in maintaining a regulated secretory pathway. In this review, we will highlight the biochemical phenotype of the endocrine heart recapitulating that the cardiac myocytes are capable endocrine cells. Understanding the basal biochemistry of the endocrine heart in producing and secreting peptides to circulation could lead to new discoveries concerning known peptide products as well as hitherto unidentified cardiac peptide products. In perspective, studies on natriuretic peptides in the heart have shown that the post-translational phase of gene expression is not only relevant for human physiology but may prove implicated also in the development and, perhaps one day, cure of human cardiovascular disease.

The effect of subclinical thyroid dysfunction on B- type natriuretic peptide level

Thyroid hormones (THs) have a significant effect on the cardiovascular system. THs increase myocardium stretch, leading to the release of B-type Natriuretic Peptide (BNP), which is considered a diagnostic biomarker of heart failure (HF). Thyroid dysfunctions (subclinical hypothyroidism; SCH and subclinical hyperthyroidism; SCHyper) stimulate several changes in the heart by causing either diastolic or systolic left ventricular dysfunctions leading to HF. This study aims to measure the changes of B- type NP levels in cases of subclinical hypo and hyperthyroidism. The present study aims to measure the changes in B-type Natriuretic Peptide (BNP) levels in subclinical hypo and hyperthyroidism (SCH and SCHyper). A theoretical study was also conducted using a docking program to find the effectiveness of some drugs in inhibiting or promoting B-type Natriuretic Peptide (BNP). A case study was conducted in a private clinic, Mosul- Iraq, from (April 1st – Sep 1) 2021, with 25 healthy participants with normal functioning thyroids as a control group (EU). A newly diagnosed 25 SCH and 17 SCHyper patients participated in this study, considering that none of them have thyroid dysfunctions taking medicine, hypertension, heart diseases, renal failure, and pregnant women. They all were checked for Thyroid Function Tests (TFTs), Free Triiodothyronine (FT3), Free Thyroxin (FT4) and Thyroid Stimulating Hormone (TSH). The plasma level of BNP was measured in all participants of the three groups. The results showed that the plasma level of BNP was higher in SCHyper patients (10.97 pg/ml) as compared to that of SCH patients (8.09 pg/ml) and EU subjects (8.27 pg/ml). Hereby, we could state that subclinical hyperthyroidism, SCHyper, triggers BNP release. Therefore, it should be kept in mind that any high BNP levels due to SCHyper should be considered a reliable diagnostic biomarker of heart failure (HF). Keywords. Thyroid hormone(TH), Subclinical hypothyroidism(SCH), Subclinical hyperthyroidism(SCHyper), Chronic heart disease(CHD), Heart failure(HF), B-type natriuretic peptide(BNP), Docking Study.

Cardiovascular Biomarkers

The value of circulating biomarkers to care for patients with cardiovascular disease has grown significantly over the last few decades. The majority of clinical data focus on the use of natriuretic peptides (NPs) for the diagnosis, prognosis, and management of patients with heart failure (HF) and troponin measurements in patients with suspected or proven acute coronary syndrome (ACS). Part of the reason for the slow adoption of biomarkers beyond these two classes has been limitation in the optimal modes of application of new assays. Future studies are needed to clarify the use of biomarkers, with the ultimate goal of simplifying the diagnosis, prognosis, and patient care of complex cardiovascular conditions. This chapter reviews the use of established biomarkers for HF, ACS, and atrial fibrillation (AF). Tables include a summary of emerging and established cardiovascular biomarkers, characteristics of B-type natriuretic peptide and amino-terminal pro-B-type natriuretic peptide, cutoff points for NP measurement, differential diagnosis of elevated NP concentrations, biomarkers in HF with preserved ejection fraction, summary of NP management trials, third universal definition of myocardial infarction, and guidelines for recommendations of biomarkers in HF. Figures depict the various causes of NP release, the complex mechanism of troponin release in patients with HF, the ischemic and nonischemic etiologies of troponin release, timing of biomarker release during myocardial infarction, and the biomarkers involved in the pathogenesis of AF. Algorithms demonstrate evaluating outpatients with dyspnea in the clinic using NPs in their workup and the use of troponin to assist with determining an appropriate management strategy for a patient with ACS. This review contains 7 highly rendered figures, 8 tables, and 202 references.

Cardiovascular Biomarkers

The value of circulating biomarkers to care for patients with cardiovascular disease has grown significantly over the last few decades. The majority of clinical data focus on the use of natriuretic peptides (NPs) for the diagnosis, prognosis, and management of patients with heart failure (HF) and troponin measurements in patients with suspected or proven acute coronary syndrome (ACS). Part of the reason for the slow adoption of biomarkers beyond these two classes has been limitation in the optimal modes of application of new assays. Future studies are needed to clarify the use of biomarkers, with the ultimate goal of simplifying the diagnosis, prognosis, and patient care of complex cardiovascular conditions. This chapter reviews the use of established biomarkers for HF, ACS, and atrial fibrillation (AF). Tables include a summary of emerging and established cardiovascular biomarkers, characteristics of B-type natriuretic peptide and amino-terminal pro-B-type natriuretic peptide, cutoff points for NP measurement, differential diagnosis of elevated NP concentrations, biomarkers in HF with preserved ejection fraction, summary of NP management trials, third universal definition of myocardial infarction, and guidelines for recommendations of biomarkers in HF. Figures depict the various causes of NP release, the complex mechanism of troponin release in patients with HF, the ischemic and nonischemic etiologies of troponin release, timing of biomarker release during myocardial infarction, and the biomarkers involved in the pathogenesis of AF. Algorithms demonstrate evaluating outpatients with dyspnea in the clinic using NPs in their workup and the use of troponin to assist with determining an appropriate management strategy for a patient with ACS. This review contains 7 highly rendered figures, 8 tables, and 202 references.

Cardiovascular Biomarkers

The value of circulating biomarkers to care for patients with cardiovascular disease has grown significantly over the last few decades. The majority of clinical data focus on the use of natriuretic peptides (NPs) for the diagnosis, prognosis, and management of patients with heart failure (HF) and troponin measurements in patients with suspected or proven acute coronary syndrome (ACS). Part of the reason for the slow adoption of biomarkers beyond these two classes has been limitation in the optimal modes of application of new assays. Future studies are needed to clarify the use of biomarkers, with the ultimate goal of simplifying the diagnosis, prognosis, and patient care of complex cardiovascular conditions. This chapter reviews the use of established biomarkers for HF, ACS, and atrial fibrillation (AF). Tables include a summary of emerging and established cardiovascular biomarkers, characteristics of B-type natriuretic peptide and amino-terminal pro-B-type natriuretic peptide, cutoff points for NP measurement, differential diagnosis of elevated NP concentrations, biomarkers in HF with preserved ejection fraction, summary of NP management trials, third universal definition of myocardial infarction, and guidelines for recommendations of biomarkers in HF. Figures depict the various causes of NP release, the complex mechanism of troponin release in patients with HF, the ischemic and nonischemic etiologies of troponin release, timing of biomarker release during myocardial infarction, and the biomarkers involved in the pathogenesis of AF. Algorithms demonstrate evaluating outpatients with dyspnea in the clinic using NPs in their workup and the use of troponin to assist with determining an appropriate management strategy for a patient with ACS. This review contains 7 highly rendered figures, 8 tables, and 202 references.

T1 and T2 Mapping in Uremic Cardiomyopathy: An Update.

Uremic cardiomyopathy (UC) is the cardiac remodelling that occurs in patients with chronic kidney disease (CKD). It is characterised by a left ventricular (LV) hypertrophy phenotype, diastolic dysfunction and generally preserved LV ejection fraction. UC has a major role mediating the increased rate of cardiovascular events, especially heart failure related, observed in patients with CKD. Recently, the use of T1 and T2 mapping techniques on cardiac MRI has expanded the ability to characterise cardiac involvement in CKD. Native T1 mapping effectively tracks the progression of interstitial fibrosis in UC, whereas T2 mapping analysis suggests the contribution of myocardial oedema, at least in a subgroup of patients. Both T1 and T2 increased values were related to worsening clinical status, myocardial injury and B-type natriuretic peptide release. Studies investigating the prognostic relevance and histology validation of mapping techniques in CKD are awaited.

A Contemporary View of Natriuretic Peptides in the SARS-CoV-2 Era.

The heart releases natriuretic peptides (NPs) which represent an important hormonal axis with cardiorenal protective effects. In view of their properties, NPs have pathophysiologic, diagnostic and prognostic implications in several cardiovascular diseases (CVDs). Severe pulmonary inflammation, as induced by the SARS-COV2, may increase pulmonary pressure with potential influence on NPs release, whereby normal cardiovascular integrity becomes impaired. Moreover, pre-existing CVDs are strong negative prognostic factors since they exacerbate the effects of the viral infection and lead to worse outcomes. In this context, it may be expected that NPs exert a key protective role toward the virus infection whereas an impairment of NPs release contributes to the virus deleterious effects. In this review article we explore the potential involvement of NPs in the COVID-19 disease. To this aim, we will first focus on the interactions between NPs and the Ang II/ATIR arm of the renin-angiotensin-aldosterone system (RAAS) as well as with the protective ACE2/Ang (1-7) arm of the RAAS. Subsequently, we will review evidence that strongly supports the role of increased NT-proBNP level as a marker of cardiac damage and of worse prognosis in the COVID-19 affected patients. Finally, we will discuss the potential therapeutic benefits of these protective hormones toward the viral infection through their endothelial protective function, anti-inflammatory and anti-thrombotic effects. In conclusion, the potential implications of NPs in the SARS-CoV-2 infection, as discussed in our article, represent an important issue that deserves to be fully investigated.

Adiponectin and cardiometabolic trait and mortality: where do we go?

Adiponectin is an adipocyte-derived cytokine known for its cardioprotective effects in preclinical studies. Early epidemiologic studies replicated these findings and drew great interest. Subsequent large-scale prospective cohorts, however, showed that adiponectin levels seemed not to relate to incident coronary artery disease (CAD). Even more surprisingly, a paradoxical increase of all-cause and cardiovascular (CV) mortality with increased adiponectin levels was reported. The adiponectin-mortality paradox has been explained by some groups asserting that adiponectin secretion is promoted by elevated natriuretic peptides (NP). Other groups have proposed that adiponectin is elevated due to adiponectin resistance in subjects with metabolic syndrome or heart failure (HF). However, there is no unifying theory that can clearly explain this paradox. In patients with HF with reduced ejection fraction (HFrEF), stretched cardiomyocytes secrete NPs, which further promote release of adiponectin from adipose tissue, leading to adiponectin resistance. On the other hand, adiponectin biology may differ in patients with heart failure with preserved ejection fraction (HFpEF), which constitutes 50% of all of HF. Most HFpEF patients are obese, which exerts inflammation and myocardial stiffness, i.e. likely to prevent myocardial stretch and subsequent NP release. This segment of the patient population may display different adiponectin biology from its HFrEF counterpart. Dissecting the adiponectin-mortality relationship in terms of different HF subtypes may help to comprehensively understand this paradox. Mendelian randomization (MR) analyses claimed that adiponectin levels are not causally related to CAD or metabolic syndrome. Results from MR studies, however, should be interpreted with great caution because the underlying history of CAD or CHF was not taken into account in these analyses, an issue that may substantially confound the results. Here, we discuss many aspects of adiponectin; cardiometabolic traits, therapeutic interventions, and the ongoing debate about the adiponectin paradox, which were recently described in basic, epidemiologic, and clinical studies.

GPER mediates estrogen cardioprotection against epinephrine-induced stress.

Currently, there are no conventional treatments for stress-induced cardiomyopathy (SCM, also known as Takotsubo syndrome), and the existing therapies are not effective. The recently discovered G protein-coupled estrogen receptor (GPER) executes the rapid effects of estrogen (E2). In this study, we investigated the effects and mechanism of GPER on epinephrine (Epi)-induced cardiac stress. SCM was developed with a high dose of Epi in adult rats and human-induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs). (1) GPER activation with agonist G1/E2 prevented an increase in left ventricular internal diameter at end-systole, the decrease both in ejection fraction and cardiomyocyte shortening amplitude elicited by Epi. (2) G1/E2 mitigated heart injury induced by Epi, as revealed by reduced plasma brain natriuretic peptide and lactate dehydrogenase release into culture supernatant. (3) G1/E2 prevented the raised phosphorylation and internalization of β2-adrenergic receptors (β2AR). (4) Blocking Gαi abolished the cardiomyocyte contractile inhibition by Epi. G1/E2 downregulated Gαi activity of cardiomyocytes and further upregulated cAMP concentration in culture supernatant treated with Epi. (5) G1/E2 rescued decreased Ca2+ amplitude and Ca2+ channel current (ICa-L) in rat cardiomyocytes. Notably, the above effects of E2 were blocked by the GPER antagonist, G15. In hiPSC-CM (which expressed GPER, β1AR and β2ARs), knockdown of GPER by siRNA abolished E2 effects on increasing ICa-L and action potential duration in the stress state. In conclusion, GPER played a protective role against SCM. Mechanistically, this effect was mediated by balancing the coupling of β2AR to the Gαs and Gαi signaling pathways.