Prediction of adverse cardiovascular events in children using artificial intelligence-based electrocardiogram.

BACKGROUND: Convolutional neural networks (CNNs) have emerged as a novel method for evaluating heart failure (HF) in adult electrocardiograms (ECGs). However, such CNNs are not applicable to pediatric HF, where abnormal anatomy of congenital heart defects plays an important role. ECG-based CNNs reflecting neurohormonal activation (NHA) may be a useful marker of pediatric HF. This study aimed to develop and validate an ECG-derived marker of pediatric HF that reflects the risk of future cardiovascular events. METHODS: Based on 21,378 ECGs from 8324 children, a CNN was trained using B-type natriuretic peptide (BNP) and the occurrence of major adverse cardiovascular events (MACEs). The output of the model, or the electrical heart failure indicator (EHFI), was compared with the BNP regarding its ability to predict MACEs in 813 ECGs from 295 children. RESULTS: EHFI achieved a better area under the curve than BNP in predicting MACEs within 180 days (0.826 versus 0.691, p = 0.03). On Cox univariable analyses, both EHFI and BNP were significantly associated with MACE (log10 EHFI: hazard ratio [HR] = 16.5, p < 0.005 and log10 BNP: HR = 4.4, p < 0.005). The time-dependent average precisions of EHFI in predicting MACEs were 32.4%-67.9% and 1.6-7.5-fold higher than those of BNP in the early period. Additionally, the MACE rate increased monotonically with EHFI, whereas the rate peaked at approximately 100 pg/mL of BNP and decreased in the higher range. CONCLUSIONS: ECG-derived CNN is a novel marker of HF with different prognostic potential from BNP. CNN-based ECG analysis may provide a new guide for assessing pediatric HF.

Current experimental and early investigational agents for cardiac fibrosis: where are we at?

INTRODUCTION: Myocardial fibrosis (MF) is induced by factors activating pro-fibrotic pathways such as acute and prolonged inflammation, myocardial ischemic events, hypertension, aging process, and genetically-linked cardiomyopathies. Dynamics and characteristics of myocardial fibrosis development are very different. The broad range of myocardial fibrosis presentations suggests the presence of multiple potential targets. AREA COVERED: Heart failure treatment involves medications primarily aimed at counteracting neurohormonal activation. While these drugs have demonstrated efficacy against MF, not all specifically target inflammation or fibrosis progression with some exceptions such as RAAS inhibitors. Consequently, new therapies are being developed to address this issue. This article is aimed to describe anti-fibrotic drugs currently employed in clinical practice and emerging agents that target specific pathways, supported by evidence from both preclinical and clinical studies. EXPERT OPINION: Despite various preclinical findings suggesting the potential utility of new drugs and molecules for treating cardiac fibrosis in animal models, there is a notable scarcity of clinical trials investigating these effects. However, the pathology of damage and repair in the heart muscle involves a complex network of interconnected inflammatory pathways and various types of immune cells. Our comprehension of the positive and negative roles played by specific immune cells and cytokines is an emerging area of research.

Sodium loading in ambulatory patients with heart failure with reduced ejection fraction: Mechanistic insights into sodium handling.

AIMS: Sodium restriction was not associated with improved outcomes in heart failure patients in recent trials. The skin might act as a sodium buffer, potentially explaining tolerance to fluctuations in sodium intake without volume overload, but this is insufficiently understood. Therefore, we studied the handling of an increased sodium load in patients with heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Twenty-one ambulatory, stable HFrEF patients and 10 healthy controls underwent a 2-week run-in phase, followed by a 4-week period of daily 1.2 g (51 mmol) sodium intake increment. Clinical, echocardiographic, 24-h urine collection, and bioelectrical impedance data were collected every 2 weeks. Blood volume, skin sodium content, and skin glycosaminoglycan content were assessed before and after sodium loading. Sodium loading did not significantly affect weight, blood pressure, congestion score, N-terminal pro-brain natriuretic peptide, echocardiographic indices of congestion, or total body water in HFrEF (all p > 0.09). There was no change in total blood volume (4748 ml vs. 4885 ml; p = 0.327). Natriuresis increased from 150 mmol/24 h to 173 mmol/24 h (p = 0.024), while plasma renin decreased from 286 to 88 µU/L (p = 0.002). There were no significant changes in skin sodium content, total glycosaminoglycan content, or sulfated glycosaminoglycan content (all p > 0.265). Healthy controls had no change in volume status, but a higher increase in natriuresis without any change in renin. CONCLUSIONS: Selected HFrEF patients can tolerate sodium loading, with increased renal sodium excretion and decreased neurohormonal activation.

Novel Biomarkers and Their Role in the Diagnosis and Prognosis of Acute Coronary Syndrome.

The burden of cardiovascular diseases and the critical role of acute coronary syndrome (ACS) in their progression underscore the need for effective diagnostic and prognostic tools. Biomarkers have emerged as crucial instruments for ACS diagnosis, risk stratification, and prognosis assessment. Among these, high-sensitivity troponin (hs-cTn) has revolutionized ACS diagnosis due to its superior sensitivity and negative predictive value. However, challenges regarding specificity, standardization, and interpretation persist. Beyond troponins, various biomarkers reflecting myocardial injury, neurohormonal activation, inflammation, thrombosis, and other pathways are being explored to refine ACS management. This review article comprehensively explores the landscape of clinically used biomarkers intricately involved in the pathophysiology, diagnosis, and prognosis of ACS (i.e., troponins, creatine kinase MB (CK-MB), B-type natriuretic peptides (BNP), copeptin, C-reactive protein (CRP), interleukin-6 (IL-6), d-dimers, fibrinogen), especially focusing on the prognostic role of natriuretic peptides and of inflammatory indices. Research data on novel biomarkers (i.e., endocan, galectin, soluble suppression of tumorigenicity (sST2), microRNAs (miRNAs), soluble oxidized low-density lipoprotein receptor-1 (sLOX-1), F2 isoprostanes, and growth differentiation factor 15 (GDF-15)) are further analyzed, aiming to shed light on the multiplicity of pathophysiologic mechanisms implicated in the evolution of ACS. By elucidating the complex interplay of these biomarkers in ACS pathophysiology, diagnosis, and outcomes, this review aims to enhance our understanding of the evolving trajectory and advancements in ACS management. However, further research is necessary to establish the clinical utility and integration of these biomarkers into routine practice to improve patient outcomes.

Could Endothelin-1 Be a Promising Neurohormonal Biomarker in Acute Heart Failure?

Acute heart failure (AHF) is a life-threatening condition with high morbidity and mortality. Even though this pathology has been extensively researched, there are still challenges in establishing an accurate and early diagnosis, determining the long- and short-term prognosis and choosing a targeted therapeutic strategy. The use of reliable biomarkers to support clinical judgment has been shown to improve the management of AHF patients. Despite a large pool of interesting candidate biomarkers, endothelin-1 (ET-1) appears to be involved in multiple aspects of AHF pathogenesis that include neurohormonal activation, cardiac remodeling, endothelial dysfunction, inflammation, atherosclerosis and alteration of the renal function. Since its discovery, numerous studies have shown that the level of ET-1 is associated with the severity of symptoms and cardiac dysfunction in this pathology. The purpose of this paper is to review the existing information on ET-1 and answer the question of whether this neurohormone could be a promising biomarker in AHF.

Updates in Cardiorenal Syndrome.

Cardiorenal syndrome is a term that refers to a collection of disorders involving both the heart and kidneys, encompassing multi-directional pathways between the 2 organs mediated through low arterial perfusion, venous congestion, and neurohormonal activation. The pathophysiology is complex and includes hemodynamic and neurohormonal changes, but inconsistent findings from recent studies suggest this is very heterogenous disorder. Management for ADHF remains focused on decongestion and neurohormonal blockade to overcome the intense sodium and fluid avidity of the CRS.

Left Ventricular Remodeling after Myocardial Infarction: From Physiopathology to Treatment.

Myocardial infarction (MI) is the leading cause of death and morbidity worldwide, with an incidence relatively high in developed countries and rapidly growing in developing countries. The most common cause of MI is the rupture of an atherosclerotic plaque with subsequent thrombotic occlusion in the coronary circulation. This causes cardiomyocyte death and myocardial necrosis, with subsequent inflammation and fibrosis. Current therapies aim to restore coronary flow by thrombus dissolution with pharmaceutical treatment and/or intravascular stent implantation and to counteract neurohormonal activation. Despite these therapies, the injury caused by myocardial ischemia leads to left ventricular remodeling; this process involves changes in cardiac geometry, dimension and function and eventually progression to heart failure (HF). This review describes the pathophysiological mechanism that leads to cardiac remodeling and the therapeutic strategies with a role in slowing the progression of remodeling and improving cardiac structure and function.

Biomarkers in Patients with Left Ventricular Assist Device: An Insight on Current Evidence.

Left ventricular assist devices (LVADs) have been representing a cornerstone therapy for patients with end-stage heart failure during the last decades. However, their use induces several pathophysiological modifications which are partially responsible for the complications that typically characterize these patients, such as right ventricular failure, thromboembolic events, as well as bleedings. During the last years, biomarkers involved in the pathways of neurohormonal activation, myocardial injury, adverse remodeling, oxidative stress and systemic inflammation have raised attention. The search and analysis of potential biomarkers in LVAD patients could lead to the identification of a subset of patients with an increased risk of developing these adverse events. This could then promote a closer follow-up as well as therapeutic modifications. Furthermore, it might highlight some new therapeutic pharmacological targets that could lead to improved long-term survival. The aim of this review is to provide current evidence on the role of different biomarkers in patients with LVAD, in particular highlighting their possible implications in clinical practice.

Pathophysiology of Advanced Heart Failure: What Knowledge Is Needed for Clinical Management?

Understanding of heart failure (HF) has evolved from a simple hemodynamic problem through a neurohormonally and proinflammatory-driven syndrome to a complex multiorgan dysfunction accompanied by inadequate energy handling. This article discusses the most important clinical aspects of advanced HF pathophysiology. It presents the concept of neurohormonal activation and its deleterious effect on cardiovascular system and reflex control. The current theories regarding the role of inflammation, cytokine activation, and myocardial remodeling in HF progression are presented. Advanced HF is a multiorgan syndrome with interplay between cardiovascular system and other organs. The role of iron deficiency is also discussed.

Neurohormonal activation induces intracellular iron deficiency and mitochondrial dysfunction in cardiac cells.

BACKGROUND: Iron deficiency (ID) is common in patients with heart failure (HF) and is associated with poor outcomes, yet its role in the pathophysiology of HF is not well-defined. We sought to determine the consequences of HF neurohormonal activation in iron homeostasis and mitochondrial function in cardiac cells. METHODS: HF was induced in C57BL/6 mice by using isoproterenol osmotic pumps and embryonic rat heart-derived H9c2 cells were subsequently challenged with Angiotensin II and/or Norepinephrine. The expression of several genes and proteins related to intracellular iron metabolism were assessed by Real time-PCR and immunoblotting, respectively. The intracellular iron levels were also determined. Mitochondrial function was analyzed by studying the mitochondrial membrane potential, the accumulation of radical oxygen species (ROS) and the adenosine triphosphate (ATP) production. RESULTS: Hearts from isoproterenol-stimulated mice showed a decreased in both mRNA and protein levels of iron regulatory proteins, transferrin receptor 1, ferroportin 1 and hepcidin compared to control mice. Furthermore, mitoferrin 2 and mitochondrial ferritin were also downregulated in the hearts from HF mice. Similar data regarding these key iron regulatory molecules were found in the H9c2 cells challenged with neurohormonal stimuli. Accordingly, a depletion of intracellular iron levels was found in the stimulated cells compared to non-stimulated cells, as well as in the hearts from the isoproterenol-induced HF mice. Finally, neurohormonal activation impaired mitochondrial function as indicated by the accumulation of ROS, the impaired mitochondrial membrane potential and the decrease in the ATP levels in the cardiac cells. CONCLUSIONS: HF characteristic neurohormonal activation induced changes in the regulation of key molecules involved in iron homeostasis, reduced intracellular iron levels and impaired mitochondrial function. The current results suggest that iron could be involved in the pathophysiology of HF.

Metabolic syndrome and heart failure: mechanism and management.

Heart failure (HF) and metabolic syndrome (MetS) are syndromes that affect a large proportion of the world population. MetS is known to be one of the risk factors of HF, and it can also act as comorbidity in HF. This review aims to further discuss the mechanism of MetS in causing HF, the management of MetS in order to prevent HF, and the management of MetS in HF patients. Visceral adiposity is the primary trigger of MetS which is followed by chronic inflammation, insulin resistance, and neurohormonal activation. All the mechanisms causing MetS play also an important role in the progression of HF. The MetS approach can be achieved by managing its components according to the current guidelines and careful management of MetS should be done in patients with HF. MetS is closely related to the progression of HF so that comprehensive management which involves a multidisciplinary team is necessary for managing patients with metabolic syndrome and heart failure.

Post-Myocardial Infarction Ventricular Remodeling Biomarkers-The Key Link between Pathophysiology and Clinic.

Studies in recent years have shown increased interest in developing new methods of evaluation, but also in limiting post infarction ventricular remodeling, hoping to improve ventricular function and the further evolution of the patient. This is the point where biomarkers have proven effective in early detection of remodeling phenomena. There are six main processes that promote the remodeling and each of them has specific biomarkers that can be used in predicting the evolution (myocardial necrosis, neurohormonal activation, inflammatory reaction, hypertrophy and fibrosis, apoptosis, mixed processes). Some of the biomarkers such as creatine kinase-myocardial band (CK-MB), troponin, and N-terminal-pro type B natriuretic peptide (NT-proBNP) were so convincing that they immediately found their place in the post infarction patient evaluation protocol. Others that are related to more complex processes such as inflammatory biomarkers, atheroma plaque destabilization biomarkers, and microRNA are still being studied, but the results so far are promising. This article aims to review the markers used so far, but also the existing data on new markers that could be considered, taking into consideration the most important studies that have been conducted so far.

Mortality in cardiogenic shock is stronger associated to clinical factors than contemporary biomarkers reflecting neurohormonal stress and inflammatory activation.

PURPOSE: To validate the IABP-SHOCK II risk score in a Danish cohort and assess the association between the IABP-SHOCK II risk score and admission concentration of biomarkers reflecting neurohormonal - (Copeptin, Pro-atrial natriuretic peptide (proANP), Mid-regional pro-adrenomedullin (MRproADM)) and inflammatory (ST2) activation in patients with CS complicating ST segment elevation myocardial infarction (STEMI). METHODS: A total of 137 consecutive patients admitted with STEMI and CS at two tertiary heart centres were stratified according to the IABP-SHOCK II risk score (0-2; 3/4; 5-9), and had blood sampled upon admission. RESULTS: Plasma concentrations of Copeptin (median (pmol/L) score 0-2: 313; score 3/4: 682; score 5-9: 632 p < 0.0001), proANP (pmol/L) (1459; 2225; 2876 p = 0.0009) and MRproADM (nmol/L) (0.86; 1.2; 1.4 p = 0.04) were significantly associated with the risk score, whereas ST2 (ng/mL) was not (44; 60; 45 p = 0.23). The IABP-SHOCK II risk score predicted 30-day mortality (score 0-2: 22%; score 4/3: 51%; score 5-9: 72%, area under the curve (AUC): 0.73, plogrank < 0.0001), while the tested biomarkers did not (AUC: 0.51

Early Stages of Obesity-related Heart Failure Are Associated with Natriuretic Peptide Deficiency and an Overall Lack of Neurohormonal Activation: The Copenhagen Heart Failure Risk Study.

Objective: This study evaluated the associations between the natriuretic peptide activity and the neurohormonal response in non-obese and obese outpatients with and without heart failure (HF). Background: Obesity-related HF may be a distinct subtype of HF. Obesity is associated with lower plasma concentrations of natriuretic peptides. The associations between obesity and neurohormonal activation estimated by mid-regional pro-adrenomedullin (MR-proADM) and copeptin in patients with HF is not elucidated. Methods: This prospective cohort-study included 392 outpatients ≥60years, plus ≥1 risk-factor(-s) for HF (hypertension, ischemic heart disease, atrial fibrillation, diabetes, chronic kidney disease), and without known HF. Patients were categorized 'non-obese' BMI = 18.5-29.9 kg/m2 (n = 273) and 'obese' BMI ≥ 30 kg/m2 (n = 119). The diagnosis of HF required signs, symptoms, and abnormal echocardiography. NT-proBNP, MR-proANP, MR-proADM, and copeptin were analyzed. Results: Obese patients were younger, had a higher prevalence of diabetes and chronic kidney disease, but a lower prevalence of atrial fibrillation. A total of 39 (14.3%) non-obese and 26 (21.8%) obese patients were diagnosed with HF. In obese patients, HF was not associated with higher plasma concentrations of NT-proBNP (Estimate: 0.063; 95%CI: -0.037-1.300; P = 0.064), MR-proANP (Estimate: 0.207; 95%CI: -0.101-0.515; P = 0.187), MR-proADM (Estimate: 0.112; 95%CI: -0.047-0.271; P = 0.168), or copeptin (Estimate: 0.093; 95%CI: -0.333-0.518; P = 0.669). Additionally, obese patients with HF had lower plasma concentrations of NT-proBNP (Estimate: -0.998; 95%CI: -1.778-0.218; P = 0.012), and MR-proANP (Estimate: -0.488; 95%CI: -0.845-0.132; P = 0.007) compared to non-obese patients with HF, whereas plasma concentrations of MR-proADM (Estimate: 0.066; 95%CI: -0.119-0.250; P = 0.484) and copeptin (Estimate: 0.140; 95%CI: -0.354-0.633; P = 0.578) were comparable. Conclusions: Patients with obesity-related HF have natriuretic peptide deficiency and lack of increased plasma concentrations of MR-proADM and copeptin suggesting that patients with obesity-related HF have a blunted overall neurohormonal activity.

A normal sodium diet preserves serum sodium levels during treatment of acute decompensated heart failure: A prospective, blind and randomized trial.

BACKGROUND: We tested the hypothesis that a normal sodium diet could be associated with preservation of serum sodium during treatment of acute decompensated heart failure (ADHF). METHODS AND RESULTS: Forty-four patients hospitalized for ADHF were blindly randomized by using block method to a low sodium diet (LS: 3 g/day of dietary sodium chloride; n = 22, 59.5 ± 11.9 y.o., 50% males. LVEF = 30.0 ± 13.6%); and a normal sodium diet (NS: 7 g/day; n = 22, 56.4 ± 10.3 y.o., 68% males; LVEF = 27.8 ± 11.7%), and both groups were submitted to fluid restriction of 1.000 mL/day. At the 7th day of intervention 16 patients of LS group and 15 patients of NS group were assessed for difference in serum sodium. Both groups had equivalent decongestion, reflected by similar percent reduction of body weight (LS: -5.0 ± 4.7% vs NS: -4.5 ± 5.2%. p = 0.41). Reduction of the N terminal fragment of type B natriuretic peptide (NT-proBNP) was significant only in the NS (-1497.0 [-18843.0 - 1191.0]. p = 0.04). The LS group showed lower levels of serum sodium (135.4 ± 3.5 mmol/L) compared to the NS group (137.5 ± 1.9 mmol/L; p = 0.04). Four cases of hyponatremia were observed only in the LS group (22%). The NS group exhibited higher mean blood pressure values (79.4 ± 2.4 mmHg vs 75.5 ± 3.0 mmHg. p = 0.03), and lower heart rate (73.2 ± 1.6 bpm vs 75.5 ± 2.1 bpm. p = 0.02). CONCLUSIONS: These results suggest that a normal sodium diet, when compared to a low sodium diet, is associated with similar degrees of decongestion, but with higher levels of natremia, blood pressure and lower neurohormonal activation during ADHF treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier no. NCT03722069.

Bidirectional Relationship Between Cancer and Heart Failure: Old and New Issues in Cardio-oncology.

The main focus of cardio-oncology has been the prevention and treatment of the cardiac toxicity of chemotherapy and radiotherapy. Furthermore, several targeted therapies have been associated with unexpected cardiotoxic side-effects. Recently, epidemiological studies reported a higher incidence of cancer in patients with heart failure (HF) compared with individuals without HF. On this basis, it has been proposed that HF might represent an oncogenic condition. This hypothesis is supported by preclinical studies demonstrating that hyperactivation of the sympathetic nervous system and renin-angiotensin-aldosterone system, which is a hallmark of HF, promotes cancer growth and dissemination. Another intriguing possibility is that the co-occurrence of HF and cancer is promoted by a common pathological milieu characterised by a state of chronic low-grade inflammation, which predisposes to both diseases. In this review, we provide an overview of the mechanisms underlying the bidirectional relationship between HF and cancer.

Relationship between non-osmotic arginine vasopressin secretion and hemoglobin A1c levels in adult patients with congenital heart disease.

Arginine vasopressin (AVP), which induces vasoconstriction and conserves solute-free water when released during high plasma osmolality, is secreted through 2 mechanisms: osmoregulation and baroregulation. This study aims to clarify the mechanisms and influencing factors for non-osmotic AVP secretion in adult patients with congenital heart disease (CHD). AVP levels were measured in 74 adults with CHD. Non-osmotic AVP secretion was defined as excessive AVP secretion relative to the AVP level inferred from plasma osmolality. Accordingly, 10 patients (13.5%) demonstrated non-osmotic AVP secretion, with AVP levels higher than those in patients without non-osmotic AVP secretion (6.4 ± 3.1 vs. 1.6 ± 0.9 pg/ml; p < 0.0001). Non-osmotic AVP secretion was significantly correlated with diuretic use [odds ratio (OR) 7.227; confidence interval (CI) 1.743-29.962; p = 0.0006], HbA1c level (OR 11.812; CI 1.732-80.548; p = 0.012), and B-type natriuretic peptide (BNP) level (OR 1.007; CI 1.001-1.012; p = 0.022). Multiple logistic regression analysis revealed that there was a significant association between non-osmotic AVP secretion and HbA1c level (OR 9.958; 1.127-87.979; p = 0.0039), and a nearly significant relationship between non-osmotic AVP secretion and BNP (OR 1.006; CI 1.000-1.012; p = 0.056). In conclusion, this study showed that 13.5% of adult patients with CHD demonstrated non-osmotic AVP secretion, which could be correlated with heart failure and insulin resistance. The AVP system might be one of the mechanisms linking heart failure and the onset of type 2 diabetes mellitus in adults with CHD.

Heart-Kidney Interactions in Cardiorenal Syndrome Type 1.

The exact significance of kidney function deterioration during acute decompensated heart failure (ADHF) episodes is still under debate. Several studies reported a wide percentage of worsening renal function (WRF) in ADHF patients ranging from 20% to 40%. This is probably because of different populations enrolled with different baseline kidney and cardiac function, varying definition of acute kidney injury (AKI), etiology of kidney dysfunction (KD), and occurrence of transient or permanent KD over the observational period. Current cardiorenal syndrome classification does not distinguish among the mechanisms leading to cardiac and renal deterioration. Cardiorenal syndrome type 1 (CRS-1) is the result of a combination of neurohormonal activation, fluid imbalance, arterial underfilling, increased renal and abdominal pressure, and aggressive decongestive treatment. A more complete mechanistic approach to CRS-1 should include evaluation of baseline kidney function, timing, course and magnitude of KD, and introduction of specific biomarkers able to identify early kidney damage. Therefore, clinical and laboratory parameters may yield a different combination among predisposing, precipitating, and amplifying factors that may influence cardiorenal syndrome development. Thus, CRS-1 is a heterogeneous syndrome that needs to be better defined and categorized taking into account clinical status, renal condition, and treatment. The application of universal definitions for WRF/AKI definition would be the first step to achieve a clear classification.

Hypothalamic dysfunction in heart failure: pathogenetic mechanisms and therapeutic implications.

Neurohumoral activation is an important feature of heart failure. Recent advances in molecular biology and imaging techniques permitted a better understanding of the central role that hypothalamus plays in the modulation of dysfunctional mechanisms, as well as the occurrence of comorbidities, such as depression, in heart failure patients. This review summarizes the commonly reported neural reflexes and molecular signaling pathways at the level of the hypothalamus along with the dysfunctional mechanisms within the paraventricular nucleus and other areas of the hypothalamus in heart failure and describes some relevant therapeutic implications.