Potential Mechanisms of the Protective Effects of the Cardiometabolic Drugs Type-2 Sodium-Glucose Transporter Inhibitors and Glucagon-like Peptide-1 Receptor Agonists in Heart Failure.

Different multifactorial pathophysiological processes are involved in the development of heart failure (HF), including neurohormonal dysfunction, the hypertrophy of cardiomyocytes, interstitial fibrosis, microvascular endothelial inflammation, pro-thrombotic states, oxidative stress, decreased nitric oxide (NO) bioavailability, energetic dysfunction, epicardial coronary artery lesions, coronary microvascular rarefaction and, finally, cardiac remodeling. While different pharmacological strategies have shown significant cardiovascular benefits in HF with reduced ejection fraction (HFrEF), there is a residual unmet need to fill the gap in terms of knowledge of mechanisms and efficacy in the outcomes of neurohormonal agents in HF with preserved ejection fraction (HFpEF). Recently, type-2 sodium-glucose transporter inhibitors (SGLT2i) have been shown to contribute to a significant reduction in the composite outcome of HF hospitalizations and cardiovascular mortality across the entire spectrum of ejection fraction. Moreover, glucagon-like peptide-1 receptor agonists (GLP1-RA) have demonstrated significant benefits in patients with high cardiovascular risk, excess body weight or obesity and HF, in particular HFpEF. In this review, we will discuss the biological pathways potentially involved in the action of SGLT2i and GLP1-RA, which may explain their effective roles in the treatment of HF, as well as the potential implications of the use of these agents, also in combination therapies with neurohormonal agents, in the clinical practice.

Mitochondrial Dysfunction in Heart Failure: From Pathophysiological Mechanisms to Therapeutic Opportunities.

Mitochondrial dysfunction, a feature of heart failure, leads to a progressive decline in bioenergetic reserve capacity, consisting in a shift of energy production from mitochondrial fatty acid oxidation to glycolytic pathways. This adaptive process of cardiomyocytes does not represent an effective strategy to increase the energy supply and to restore the energy homeostasis in heart failure, thus contributing to a vicious circle and to disease progression. The increased oxidative stress causes cardiomyocyte apoptosis, dysregulation of calcium homeostasis, damage of proteins and lipids, leakage of mitochondrial DNA, and inflammatory responses, finally stimulating different signaling pathways which lead to cardiac remodeling and failure. Furthermore, the parallel neurohormonal dysregulation with angiotensin II, endothelin-1, and sympatho-adrenergic overactivation, which occurs in heart failure, stimulates ventricular cardiomyocyte hypertrophy and aggravates the cellular damage. In this review, we will discuss the pathophysiological mechanisms related to mitochondrial dysfunction, which are mainly dependent on increased oxidative stress and perturbation of the dynamics of membrane potential and are associated with heart failure development and progression. We will also provide an overview of the potential implication of mitochondria as an attractive therapeutic target in the management and recovery process in heart failure.

New Insights into Endothelial Dysfunction in Cardiometabolic Diseases: Potential Mechanisms and Clinical Implications.

The endothelium is a monocellular layer covering the inner surface of blood vessels. It maintains vascular homeostasis regulating vascular tone and permeability and exerts anti-inflammatory, antioxidant, anti-proliferative, and anti-thrombotic functions. When the endothelium is exposed to detrimental stimuli including hyperglycemia, hyperlipidemia, and neurohormonal imbalance, different biological pathways are activated leading to oxidative stress, endothelial dysfunction, increased secretion of adipokines, cytokines, endothelin-1, and fibroblast growth factor, and reduced nitric oxide production, leading eventually to a loss of integrity. Endothelial dysfunction has emerged as a hallmark of dysmetabolic vascular impairment and contributes to detrimental effects on cardiac metabolism and diastolic dysfunction, and to the development of cardiovascular diseases including heart failure. Different biomarkers of endothelial dysfunction have been proposed to predict cardiovascular diseases in order to identify microvascular and macrovascular damage and the development of atherosclerosis, particularly in metabolic disorders. Endothelial dysfunction also plays an important role in the development of severe COVID-19 and cardiovascular complications in dysmetabolic patients after SARS-CoV-2 infection. In this review, we will discuss the biological mechanisms involved in endothelial dysregulation in the context of cardiometabolic diseases as well as the available and promising biomarkers of endothelial dysfunction in clinical practice.

A Mobile App-based Approach in Cardiovascular Disease Prevention: A Prospective Randomized Study.

Cardiovascular risk factors are prevalent in the Italian population, and cardiovascular diseases remain a leading cause of mortality in the Western world. As the incidence of risk factors and cardiovascular diseases increases with age, effective and early prevention and management strategies are crucial. This study aims to evaluate the feasibility and potential benefits of using the Heartaway® mobile application as an additional intervention to standard clinical care for patients with hypertension. The study will explore improvements in blood pressure control, medication adherence, cardiovascular risk factors, lifestyle habits, and cardiovascular outcomes. The results of this study may contribute to a broader integration of telemedicine into cardiovascular disease prevention in the clinical practice.

Atrial Fibrillation in Patients with Hypertrophic Cardiomyopathy and Cardiac Amyloidosis: From Clinical Management to Catheter Ablation Indication.

Atrial fibrillation (AF) is the most common arrhythmia in patients affected by cardiomyopathies. Reports estimate a prevalence of 27% in patients with hypertrophic cardiomyopathy (HCM) and 40% in patients with cardiac amyloidosis (CA). The presence of AF typically results in progressive functional decline, an increased frequency of hospitalizations for heart failure, and a higher thromboembolic risk. Medical management using mainly beta-blockers or amiodarone has produced variable outcomes and a high rate of recurrence. Catheter ablation reduces symptom burden and complications despite a moderate rate of recurrence. Recent evidence suggests that an early rhythm control strategy may lead to more favorable short- and long-term outcomes. In this review, we summarize contemporary data on the management of AF in patients with cardiomyopathy (HCM and CA) with particular reference to the timing and outcomes of ablation procedures.

What about chronotropic incompetence in heart failure with mildly reduced ejection fraction? Clinical and prognostic implications from the Metabolic Exercise combined with Cardiac and Kidney Indexes score dataset.

AIMS: Chronotropic incompetence (CI) is a strong predictor of outcome in heart failure with reduced ejection fraction, however no data on its clinical and prognostic impacts in heart failure with mildly reduced ejection fraction (HFmrEF) are available. Therefore, the study aims to investigate, in a large multicentre HFmrEF cohort, the prevalence of CI as well as its relationship with exercise capacity and its prognostic role over the cardiopulmonary exercise testing (CPET) parameters. METHODS AND RESULTS: Within the Metabolic Exercise combined with Cardiac and Kidney Indexes (MECKI) database, we analysed data of 864 HFmrEF out of 1164 stable outpatients who performed a maximal CPET at the cycle ergometer and who had no significant rhythm disorders or comorbidities. The primary study endpoint was cardiovascular (CV) death. All-cause death was also explored. Chronotropic incompetence prevalence differed depending on the method (peak heart rate, pHR% vs. pHR reserve, pHRR%) and the cut-off adopted (pHR% from ≤75% to ≤60% and pHRR% ≤ 65% to ≤50%), ranging from 11% to 62%. A total of 84 (9.7%) CV deaths were collected, with 39 (4.5%) occurring within 5 years. At multivariate analysis, both pHR% [hazard ratio 0.97 (0.95-0.99), P < 0.05] and pHRR% [hazard ratio 0.977 (0.961-0.993), P < 0.01] were associated with the primary endpoint. A pHR% ≤ 75% and a pHRR% ≤ 50% represented the most accurate cut-off values in predicting the outcome. CONCLUSION: The study suggests an association between blunted exercise-HR response, functional capacity, and CV death risk among patients with HFmrEF. Whether the CI presence might be adopted in daily HFmrEF management needs to be addressed in larger prospective studies.

Chronotropic incompetence is an easy-to-obtain additive parameter for cardiovascular death risk stratification in heart failure with mildly reduced ejection fraction (HFmrEF). Peak heart rate and peak heart rate reserve are associated with exercise capacity in HFmrEF. Peak heart rate and peak heart rate reserve are associated with cardiovascular death in HFmrEF.

The effect of mindfulness on decision-making, inhibitory control, and impulsivity of substance use disorder in-treatment patients: A randomized clinical trial.

This study aimed to investigate the effects of Mindfulness-Based Relapse Prevention (MBRP) in decision-making, inhibitory control and impulsivity compared to Treatment as Usual (TAU) for individuals with Substance Use Disorders (SUD's) in Brazil. A randomized clinical trial was conducted with participants from a therapeutic community (n = 122). Decision-making (Iowa Gambling Task), impulsivity dimensions (UPPS-P Scale), and inhibitory control (Stroop Color-Word Test) were assessed before and after the MBRP 8-week intervention. GLM Multivariate analysis was used to evaluate the effects of MBRP on different impulsivity measures. The results showed that MBRP+TAU improved the general decision-making score (p = 0,008) compared to TAU. However, no significant effects were found in impulsivity dimensions and inhibitory control in individuals with SUDs in the therapeutic community. This study found improvement in decision-making in the total IGT score; however, no effect for self-reported impulsivity and inhibitory control among middle-aged patients after an 8-weeks intervention of MBRP protocol in an inpatient setting. It adds information to the subject, with implications and possible directions to be followed by the next clinical trials with patients with SUDs in treatment. Trial registration: EnsaiosClinicos.gov.br: RBR-6c9njc.

From cardiovascular system to brain, the potential protective role of Mas Receptors in COVID-19 infection.

Coronavirus disease 2019 (COVID-19) has been declared a new pandemic in March 2020. Although most patients are asymptomatic, those with underlying cardiovascular comorbidities may develop a more severe systemic infection which is often associated with fatal pneumonia. Nonetheless, neurological and cardiovascular manifestations could be present even without respiratory symptoms. To date, no COVID-19-specific drugs are able for preventing or treating the infection and generally, the symptoms are relieved with general anti-inflammatory drugs. Angiotensin-converting-enzyme 2 (ACE2) may function as the receptor for virus entry within the cells favoring the progression of infection in the organism. On the other hand, ACE2 is a relevant enzyme in renin angiotensin system (RAS) cascade fostering Ang1-7/Mas receptor activation which promotes protective effects in neurological and cardiovascular systems. It is known that RAS is composed by two functional countervailing axes the ACE/AngII/AT1 receptor and the ACE/AngII/AT2 receptor which counteracts the actions mediated by AngII/AT1 receptor by inducing anti-inflammatory, antioxidant and anti-growth functions. Subsequently an "alternative" ACE2/Ang1-7/Mas receptor axis has been described with functions similar to the latter protective arm. Here, we discuss the neurological and cardiovascular effects of COVID-19 highlighting the role of the stimulation of the RAS "alternative" protective arm in attenuating pulmonary, cerebral and cardiovascular damages. In conclusion, only two clinical trials are running for Mas receptor agonists but few other molecules are in preclinical phase and if successful these drugs might represent a successful strategy for the treatment of the acute phase of COVID-19 infection.

Nuclease Activity of the Junín Virus Nucleoprotein C-Terminal Domain.

The mammarenavirus Junín (JUNV) is the causative agent of Argentine hemorrhagic fever, a severe disease of public health concern. The most abundant viral protein is the nucleoprotein (NP), a multifunctional, two-domain protein with the primary role as structural component of the viral nucleocapsids, used as template for viral polymerase RNA synthesis activities. Here, we report that the C-terminal domain (CTD) of the attenuated Candid#1 strain of the JUNV NP can be purified as a stable soluble form with a secondary structure in line with known NP structures from other mammarenaviruses. We show that the JUNV NP CTD interacts with the viral matrix protein Z in vitro, and that the full-length NP and Z interact with each other in cellulo, suggesting that the NP CTD is responsible for this interaction. This domain comprises an arrangement of four acidic residues and a histidine residue conserved in the active site of exoribonucleases belonging to the DEDDh family. We show that the JUNV NP CTD displays metal-ion-dependent nuclease activity against DNA and single- and double-stranded RNA, and that this activity is impaired by the mutation of a catalytic residue within the DEDDh motif. These results further support this activity, not previously observed in the JUNV NP, which could impact the mechanism of the cellular immune response modulation of this important pathogen.

Hypertension, coronary artery disease and myocardial ischemic syndromes.

Hypertension represents a major contributor to the development of coronary artery disease. The pathophysiological mechanisms underlying the link between hypertension and CAD are complex and include overactivation of neurohormones, accelerated development of the atherosclerotic plaque, endothelial dysfunction, altered intramyocardial coronary circulation, hypertension-mediated cardiac and vascular damage and the relationship between arterial stiffness and coronary perfusion. Blood pressure (BP) reduction is associated with a significant decrease of the risk of coronary events. Therapeutic interventions targeted to reduce BP and to improve endothelial function and coronary microvascular dysfunction, as well as to prevent left ventricular hypertrophy and dysfunction, contribute to reduce the burden of coronary disease and its acute ischemic manifestations.

Effects of two-month treatment with a mixture of natural activators of autophagy on oxidative stress and arterial stiffness in patients with essential hypertension: A pilot study.

BACKGROUND AND AIMS: Trehalose, spermidine, nicotinamide, and polyphenols are natural substances that exert pro-autophagic and antioxidant properties. Their role in blood pressure (BP) regulation and preservation of vascular function in essential hypertension is unknown. The aim of this study was to evaluate the effect of a mixture of these agents on BP level, markers of oxidative stress, autophagy, endothelial function, and vascular stiffness in outpatients with grade 1 uncomplicated essential hypertension. METHODS AND RESULTS: A single-centre, open-label, case-control, pilot study was conducted in adult outpatients (aged ≥18 years) receiving or not the mixture for two months along with the standard therapies. Both at baseline and at the end of the treatment the following clinical parameters were evaluated: brachial seated office BP level, central aortic pressure, pulse wave velocity, augmentation index (AI@75). Both at baseline and at the end of the treatment, a blood sample was drawn for the measurement of: H2O2, HBA%, levels of sNOX2-dp, Atg 5, P62, endothelin 1, and NO bioavailability. The mixture of nutraceuticals did not influence BP levels. Patients receiving the mixture showed a significant decrease of oxidative stress, stimulation of autophagy, increased NO bioavailability and no increase of the AI@75, in contrast to what observed in hypertensive patients not receiving the mixture. CONCLUSIONS: The supplementation of the trehalose, spermidine, nicotinamide, and polyphenols mixture counteracted hypertension-related arterial stiffness through mechanisms likely dependent on oxidative stress downregulation and autophagy stimulation. These natural activators of autophagy may represent favourable adjuvants for prevention of the hypertensive cardiovascular damage.

Polymorphic variants at NDUFC2, encoding a mitochondrial complex I subunit, associate with cardiac hypertrophy in human hypertension.

BACKGROUND: A dysfunction of NADH dehydrogenase, the mitochondrial Complex I (CI), associated with the development of left ventricular hypertrophy (LVH) in previous experimental studies. A deficiency of Ndufc2 (subunit of CI) impairs CI activity causing severe mitochondrial dysfunction. The T allele at NDUFC2/rs11237379 variant associates with reduced gene expression and impaired mitochondrial function. The present study tested the association of both NDUFC2/rs11237379 and NDUFC2/rs641836 variants with LVH in hypertensive patients. In vitro studies explored the impact of reduced Ndufc2 expression in isolated cardiomyocytes. METHODS: Two-hundred-forty-six subjects (147 male, 59.7%), with a mean age of 59 ± 15 years, were included for the genetic association analysis. Ndufc2 silencing was performed in both H9c2 and rat primary cardiomyocytes to explore the hypertrophy development and the underlying signaling pathway. RESULTS: The TT genotype at NDUFC2/rs11237379 associated with significantly reduced gene expression. Multivariate analysis revealed that patients carrying this genotype showed significant differences for septal thickness (p = 0.07), posterior wall thickness (p = 0.008), RWT (p = 0.021), LV mass/BSA (p = 0.03), compared to subjects carrying either CC or CT genotypes. Patients carrying the A allele at NDUFC2/rs641836 showed significant differences for septal thickness (p = 0.017), posterior wall thickness (p = 0.011), LV mass (p = 0.003), LV mass/BSA (p = 0.002) and LV mass/height2.7(p = 0.010) after adjustment for covariates. In-vitro, the Ndufc2 deficiency-dependent mitochondrial dysfunction caused cardiomyocyte hypertrophy, pointing to SIRT3-AMPK-AKT-MnSOD as a major underlying signaling pathway. CONCLUSIONS: We demonstrated for the first time a significant association of NDUFC2 variants with LVH in human hypertension and highlight a key role of Ndufc2 deficiency-dependent CI mitochondrial dysfunction on increased susceptibility to cardiac hypertrophy development.

Influence of exertional oscillatory breathing and its temporal behavior in patients with heart failure and reduced ejection fraction.

BACKGROUND: Exertional oscillatory breathing (EOV) represents an emerging prognostic marker in heart failure (HF) patients, however little is known about EOV meaning with respect to its disappearance/persistence during cardiopulmonary exercise test (CPET). The present single-center study evaluated EOV clinical and prognostic impact in a large cohort of reduced ejection fraction HF patients (HFrEF) and, contextually, if a specific EOV temporal behavior might be an addictive risk predictor. METHODS AND RESULTS: Data from 1.866 HFrEF patients on optimized medical therapy were analysed. The primary cardiovascular (CV) study end-point was cardiovascular death, heart transplantation or LV assistance device (LVAD) implantation at 5-years. For completeness a secondary end-point of total mortality at 5- years was also explored. EOV presence was identified in 251 patients (13%): 142 characterized by EOV early cessation (Group A) and 109 by EOV persistence during the whole CPET (Group B). The entire EOV Group showed worse clinical and functional status than NoEOV Group (n = 1.615) and, within the EOV Group, Group B was characterized by a more severe HF. At CV survival analysis, EOV patients showed a poorer outcome than the NoEOV Group (events 27.1% versus 13.1%, p < 0.001) both unpolished and after matching for main confounders. Instead, no significant differences were found between EOV Group A and B with respect to CV outcome. Conversely the analysis for total mortality failed to be significant. CONCLUSIONS: Our analysis, albeit retrospective, supports the inclusion of EOV into a CPET-centered clinical and prognostic evaluation of the HFrEF patients. EOV characterizes per se a more advanced HFrEF stage with an unfavorable CV outcome. However, the EOV persistence, albeit suggestive of a more severe HF, does not emerge as a further prognostic marker.

Contribution of Genetic Test to Early Diagnosis of Methylenetetrahydrofolate Reductase (MTHFR) Deficiency: The Experience of a Reference Center in Southern Italy.

BACKGROUND: the deficiency of 5,10-Methylenetetrahydrofolate reductase (MTHFR) constitutes a rare and severe metabolic disease and is included in most expanded newborn screening (NBS) programs worldwide. Patients with severe MTHFR deficiency develop neurological disorders and premature vascular disease. Timely diagnosis through NBS allows early treatment, resulting in improved outcomes. METHODS: we report the diagnostic yield of genetic testing for MTHFR deficiency diagnosis, in a reference Centre of Southern Italy between 2017 and 2022. MTHFR deficiency was suspected in four newborns showing hypomethioninemia and hyperhomocysteinemia; otherwise, one patient born in pre-screening era showed clinical symptoms and laboratory signs that prompted to perform genetic testing for MTHFR deficiency. RESULTS: molecular analysis of the MTHFR gene revealed a genotype compatible with MTHFR deficiency in two NBS-positive newborns and in the symptomatic patient. This allowed for promptly beginning the adequate metabolic therapy. CONCLUSIONS: our results strongly support the need for genetic testing to quickly support the definitive diagnosis of MTHFR deficiency and start therapy. Furthermore, our study extends knowledge of the molecular epidemiology of MTHFR deficiency by identifying a novel mutation in the MTHFR gene.

An Expert Opinion on the Role of the Rosuvastatin/Amlodipine Single Pill Fixed Dose Combination in Cardiovascular Prevention.

Current cardiovascular disease prevention strategies are based on the management of cardiovascular risk as a continuum, redefining the therapeutic goals for each individual based on the estimated global risk profile. Given the frequent clustering of the principal cardiovascular risk factors, such as hypertension, diabetes and dyslipidaemia, in the same individual, patients are required to take multiple drugs to achieve therapeutic targets. The adoption of single pill fixed dose combinations may contribute to achieve better control of blood pressure and cholesterol compared to the separate administration of the individual drugs, mostly due to better adherence related to therapeutic simplicities. This paper reports the outcomes of an Expert multidisciplinary Roundtable. In particular, the rational and potential clinical use of the single pill fixed dose combination "Rosuvastatin-Amlodipine" for the management of concomitant hypertension/hypercholesterolemia in different clinical fields are discussed. This Expert Opinion also illustrates the importance of an early and effective management of total cardiovascular risk, highlights the substantial benefits of combining blood pressure and lipid-lowering treatments in a single-pill fixed dose combination and attempts to identify and overcome the barriers to the implementation in clinical practice of the fixed dose combinations with dual targets. This Expert Panel identifies and proposes the categories of patients who may benefit the most from this fixed dose combination.

Atrial natriuretic peptide stimulates autophagy/mitophagy and improves mitochondrial function in chronic heart failure.

Mitochondrial dysfunction, causing increased reactive oxygen species (ROS) production, is a molecular feature of heart failure (HF). A defective antioxidant response and mitophagic flux were reported in circulating leucocytes of patients with chronic HF and reduced ejection fraction (HFrEF). Atrial natriuretic peptide (ANP) exerts many cardiac beneficial effects, including the ability to protect cardiomyocytes by promoting autophagy. We tested the impact of ANP on autophagy/mitophagy, altered mitochondrial structure and function and increased oxidative stress in HFrEF patients by both ex vivo and in vivo approaches. The ex vivo study included thirteen HFrEF patients whose peripheral blood mononuclear cells (PBMCs) were isolated and treated with αANP (10-11 M) for 4 h. The in vivo study included six HFrEF patients who received sacubitril/valsartan for two months. PBMCs were characterized before and after treatment. Both approaches analyzed mitochondrial structure and functionality. We found that levels of αANP increased upon sacubitril/valsartan, whereas levels of NT-proBNP decreased. Both the ex vivo direct exposure to αANP and the higher αANP level upon in vivo treatment with sacubitril/valsartan caused: (i) improvement of mitochondrial membrane potential; (ii) stimulation of the autophagic process; (iii) significant reduction of mitochondrial mass-index of mitophagy stimulation-and upregulation of mitophagy-related genes; (iv) reduction of mitochondrial damage with increased inner mitochondrial membrane (IMM)/outer mitochondrial membrane (OMM) index and reduced ROS generation. Herein we demonstrate that αANP stimulates both autophagy and mitophagy responses, counteracts mitochondrial dysfunction, and damages ultimately reducing mitochondrial oxidative stress generation in PBMCs from chronic HF patients. These properties were confirmed upon sacubitril/valsartan administration, a pivotal drug in HFrEF treatment.

Obesity and cardiovascular disease: An executive document on pathophysiological and clinical links promoted by the Italian Society of Cardiovascular Prevention (SIPREC).

The prevalence of obesity worldwide has increased in recent decades not only among adults, but also in children and adolescents. This phenomenon contributes to an increased risk of cardiovascular diseases (CVD), also after the adjustment for conventional risk factors such as hypertension, diabetes and dyslipidemia. Indeed, obesity contributes to the development of insulin resistance, endothelial dysfunction, sympathetic nervous system activation, increased vascular resistance and inflammatory and prothrombotic state which promote the incidence of major cardiovascular events. On the basis of this evidence, in 2021 obesity has been acknowledged as a definite pathological identity and identified as a recurrent, chronic non-communicable disease. Therapeutic strategies for the pharmacological treatment of obesity include the combination of naltrexone and bupropione and the lipase inhibitor orlistat and they have been recently implemented with the glucagon like peptide-1 receptor agonists semaglutide and liraglutide, which have produced positive and sustained effects on body weight reduction. If drug interventions are not effective, bariatric surgery may be considered, representing an efficacious treatment option for extreme obesity or obesity with comorbidities. The present executive paper is aimed to increase knowledge on the relationships between obesity and CVD, to raise the perception of this condition which is currently insufficient and to support the clinical practice management.

New Insight in Cardiorenal Syndrome: From Biomarkers to Therapy.

Cardiorenal syndrome consists in the coexistence of acute or chronic dysfunction of heart and kidneys resulting in a cascade of feedback mechanisms and causing damage to both organs associated with high morbidity and mortality. In the last few years, different biomarkers have been investigated with the aim to achieve an early and accurate diagnosis of cardiorenal syndrome, to provide a prognostic role and to guide the development of targeted pharmacological and non-pharmacological therapies. In such a context, sodium-glucose cotransporter 2 (SGLT2) inhibitors, recommended as the first-line choice in the management of heart failure, might represent a promising strategy in the management of cardiorenal syndrome due to their efficacy in reducing both cardiac and renal outcomes. In this review, we will discuss the current knowledge on the pathophysiology of cardiorenal syndrome in adults, as well as the utility of biomarkers in cardiac and kidney dysfunction and potential insights into novel therapeutics.

Natriuretic Peptides: It Is Time for Guided Therapeutic Strategies Based on Their Molecular Mechanisms.

Natriuretic peptides (NPs) are the principal expression products of the endocrine function of the heart. They exert several beneficial effects, mostly mediated through guanylate cyclase-A coupled receptors, including natriuresis, diuresis, vasorelaxation, blood volume and blood pressure reduction, and regulation of electrolyte homeostasis. As a result of their biological functions, NPs counterbalance neurohormonal dysregulation in heart failure and other cardiovascular diseases. NPs have been also validated as diagnostic and prognostic biomarkers in cardiovascular diseases such as atrial fibrillation, coronary artery disease, and valvular heart disease, as well as in the presence of left ventricular hypertrophy and severe cardiac remodeling. Serial measurements of their levels may be used to contribute to more accurate risk stratification by identifying patients who are more likely to experience death from cardiovascular causes, heart failure, and cardiac hospitalizations and to guide tailored pharmacological and non-pharmacological strategies with the aim to improve clinical outcomes. On these premises, multiple therapeutic strategies based on the biological properties of NPs have been attempted to develop new targeted cardiovascular therapies. Apart from the introduction of the class of angiotensin receptor/neprilysin inhibitors to the current management of heart failure, novel promising molecules including M-atrial natriuretic peptide (a novel atrial NP-based compound) have been tested for the treatment of human hypertension with promising results. Moreover, different therapeutic strategies based on the molecular mechanisms involved in NP regulation and function are under development for the management of heart failure, hypertension, and other cardiovascular conditions.