Activation Of Neurohormonal Systems Research Articles

Markers of Vascular Dysfunction in Hypertension.

Hypertension is a modifiable cardiovascular risk factor and displays a rapidly growing incidence due to aging and the acquisition of an unhealthy lifestyle. Hypertension is linked to the development of target organ damage in several vascular beds such as coronary arteries, peripheral, cerebral, and renal arteries. Besides, along with the presence of other cardiovascular risk factors, it aggravates vascular dysfunction due to the aging process. The mechanisms of vascular dysfunction in hypertension are complex and involve excessive salt intake and water retention, activation of neurohormonal systems, induction of endothelial dysfunction of large arteries and microcirculation, development of arterial stiffness, and complex interactions with cellular pathways of inflammation, oxidative stress, and thrombosis. The extent of vascular dysfunction in patients with hypertension can be assessed by evaluating endothelial function, measuring arterial stiffness, and testing the levels of circulating biomarkers of oxidative stress, pro-inflammatory cytokines, and thrombosis. Assessing these markers in subjects with and without hypertension could aid in identifying those at risk of vascular damage and improving risk prediction for future cardiovascular events. While several lifestyle and pharmacological therapies have shown promise in addressing vascular dysfunction in hypertension, none of these biomarkers have been established as an independent risk factor or treatment target. Therefore, in this article, we review the literature on the evidence that exists regarding the role of vascular dysfunction in the pathophysiology, diagnosis, progression, and treatment of hypertension, highlighting the lack of conclusive evidence in this field.

Molecular Mechanisms and Therapeutic Implications of Endothelial Dysfunction in Patients with Heart Failure

Heart failure is a complex medical syndrome that is attributed to a number of risk factors; nevertheless, its clinical presentation is quite similar among the different etiologies. Heart failure displays a rapidly increasing prevalence due to the aging of the population and the success of medical treatment and devices. The pathophysiology of heart failure comprises several mechanisms, such as activation of neurohormonal systems, oxidative stress, dysfunctional calcium handling, impaired energy utilization, mitochondrial dysfunction, and inflammation, which are also implicated in the development of endothelial dysfunction. Heart failure with reduced ejection fraction is usually the result of myocardial loss, which progressively ends in myocardial remodeling. On the other hand, heart failure with preserved ejection fraction is common in patients with comorbidities such as diabetes mellitus, obesity, and hypertension, which trigger the creation of a micro-environment of chronic, ongoing inflammation. Interestingly, endothelial dysfunction of both peripheral vessels and coronary epicardial vessels and microcirculation is a common characteristic of both categories of heart failure and has been associated with worse cardiovascular outcomes. Indeed, exercise training and several heart failure drug categories display favorable effects against endothelial dysfunction apart from their established direct myocardial benefit.

Edema formation in congestive heart failure and the underlying mechanisms.

Congestive heart failure (HF) is a complex disease state characterized by impaired ventricular function and insufficient peripheral blood supply. The resultant reduced blood flow characterizing HF promotes activation of neurohormonal systems which leads to fluid retention, often exhibited as pulmonary congestion, peripheral edema, dyspnea, and fatigue. Despite intensive research, the exact mechanisms underlying edema formation in HF are poorly characterized. However, the unique relationship between the heart and the kidneys plays a central role in this phenomenon. Specifically, the interplay between the heart and the kidneys in HF involves multiple interdependent mechanisms, including hemodynamic alterations resulting in insufficient peripheral and renal perfusion which can lead to renal tubule hypoxia. Furthermore, HF is characterized by activation of neurohormonal factors including renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system (SNS), endothelin-1 (ET-1), and anti-diuretic hormone (ADH) due to reduced cardiac output (CO) and renal perfusion. Persistent activation of these systems results in deleterious effects on both the kidneys and the heart, including sodium and water retention, vasoconstriction, increased central venous pressure (CVP), which is associated with renal venous hypertension/congestion along with increased intra-abdominal pressure (IAP). The latter was shown to reduce renal blood flow (RBF), leading to a decline in the glomerular filtration rate (GFR). Besides the activation of the above-mentioned vasoconstrictor/anti-natriuretic neurohormonal systems, HF is associated with exceptionally elevated levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). However, the supremacy of the deleterious neurohormonal systems over the beneficial natriuretic peptides (NP) in HF is evident by persistent sodium and water retention and cardiac remodeling. Many mechanisms have been suggested to explain this phenomenon which seems to be multifactorial and play a major role in the development of renal hyporesponsiveness to NPs and cardiac remodeling. This review focuses on the mechanisms underlying the development of edema in HF with reduced ejection fraction and refers to the therapeutic maneuvers applied today to overcome abnormal salt/water balance characterizing HF.

Décompensation aiguë d’une insuffisance cardiaque chronique chez une personne âgée

AbstractHeart failure is defined by an inability of the heart pump to ensure adequate cardiac output under normal conditions, it is very resistant in the geriatric population. The diagnosis is suggested by clinical examination, confirmed by chest x-ray, echocardiography, and plasma values of natriuretic peptides. The treatment of chronic heart failure includes patient education and stable pharmacological therapy aimed at effectively combating the activation of neurohormonal systems.

Relationships between the activity of neurohormonal systems and intracardiac hemodynamics in patients with heart failure: focus on galectin-3

The introduction of novel biomarkers necessitates their detailed study in patients with different heart failure (HF) phenotypes as part of a personalized approach to assessing the disease severity and predicting outcomes.Aim. To assessthe activity of following neurohormonal systems: N-terminal probrain natriuretic peptide (NT-proBNP) and galectin-3 in HF with preserved, mildly reduced and reduced ejection fraction (EF).Material and methods. In 69 patients with NYHA class II-IV HF, along with a general clinical examination, the level of NT-proBNP and serum galectin-3 was determined by enzyme immunoassay.Results. Patients included in the study were divided into 3 groups: preserved EF (HFpEF) — 23 patients, mildly reduced EF (HFmrEF) — 26 patients, and reduced EF (HFrEF) — 20 patients. In patients with HF, the level of galectin-3 did not directly depend on EF, but was associated with NT-proBNP level as follows: there was a tendency to increase the concentration of galectin-3 in the tertile groups of NT-proBNP. Correlation analysis revealed significant feedback (r=-0,41, p<0,05) between galectin-3 and left ventricular EF only in patients with preserved systolic function. In the same group of HFpEF patients, the maximum values of serum galectin-3 indices were noted, reaching 10,5 [6,5; 14,5] ng/ml.Conclusion. Analysis of neurohormonal activity demonstrated a unidirectional increase in NT-proBNP and galectin-3 in patients with HF, regardless of left ventricular EF, while the maximum values of galetin-3 were observed in patients with HFpEF.

Relationships between the activity of neurohormonal systems and intracardiac hemodynamics in patients with heart failure: focus on galectin-3

The introduction of novel biomarkers necessitates their detailed study in patients with different heart failure (HF) phenotypes as part of a personalized approach to assessing the disease severity and predicting outcomes.Aim. To assessthe activity of following neurohormonal systems: N-terminal probrain natriuretic peptide (NT-proBNP) and galectin-3 in HF with preserved, mildly reduced and reduced ejection fraction (EF).Material and methods. In 69 patients with NYHA class II-IV HF, along with a general clinical examination, the level of NT-proBNP and serum galectin-3 was determined by enzyme immunoassay.Results. Patients included in the study were divided into 3 groups: preserved EF (HFpEF) — 23 patients, mildly reduced EF (HFmrEF) — 26 patients, and reduced EF (HFrEF) — 20 patients. In patients with HF, the level of galectin-3 did not directly depend on EF, but was associated with NT-proBNP level as follows: there was a tendency to increase the concentration of galectin-3 in the tertile groups of NT-proBNP. Correlation analysis revealed significant feedback (r=-0,41, p<0,05) between galectin-3 and left ventricular EF only in patients with preserved systolic function. In the same group of HFpEF patients, the maximum values of serum galectin-3 indices were noted, reaching 10,5 [6,5; 14,5] ng/ml.Conclusion. Analysis of neurohormonal activity demonstrated a unidirectional increase in NT-proBNP and galectin-3 in patients with HF, regardless of left ventricular EF, while the maximum values of galetin-3 were observed in patients with HFpEF.

Prognostic value of copeptin in patients with acute myocardial infarction treated with percutaneous coronary intervention: a prospective cohort study.

BackgroundIschemic myocardial injury leads to neurohormonal system activation and increased release of copeptin. Although diagnostic value of copeptin has been widely described, data on its prognostic performance in patients with myocardial infarction is inconclusive. The aim of this study was to asses if elevated copeptin concentration provides prognostic information for long-term adverse cardiac events in a cohort of first acute myocardial infarction patients treated with percutaneous coronary intervention.MethodsCopeptin concentration was assessed in a cohort of 100 consecutive patients (39% women; mean age 63±7 years) presenting with first acute myocardial infarction and subjected to percutaneous coronary intervention. Samples were collected at the time of admission and on the 4th/5th day of hospitalisation. All patients were followed-up prospectively for 12 months for the occurrence of major adverse cardiovascular events defined as reinfarction, unscheduled coronary revascularisation and all-cause death.ResultsElevated copeptin concentration on the 4th/5th day of hospitalisation was identified as a predictor of major adverse cardiovascular events (P=0.0445). The increase between copeptin level on admission and on day 4th/5th was associated with the requirement for unscheduled coronary revascularisation in receiver operating characteristics (ROC) analysis (AUC =0.639; 95% CI: 0.504–0.773; P=0.0430). In a multivariate analysis, copeptin concentration on the 4th/5th day of hospitalisation and left ventricular ejection fraction assessed by transthoracic echocardiography, were the only predictors for major adverse cardiac events during follow-up (P=0.024 and P=0.001, respectively).ConclusionsCopeptin seems to be a prognostic marker in patients with first myocardial infarction treated with percutaneous coronary intervention.

Angiotensin Receptor-Neprilysin Inhibition (ARNI) in Heart Failure.

Recognition that neurohormonal activation plays a central role in the pathogenesis of heart failure (HF) led to the development of angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers, mineralocorticoid receptor antagonists and beta blockers. While there has been substantial success with these neurohormonal blocking drugs in patients with HF with reduced ejection fraction (HFrEF), persistently high rates of morbidity and mortality in this population underscore the need for more effective therapies. As part of the systemic neurohormonal activation that takes place in patients with HF, systems that counteract the adverse effect of the renin angiotensin aldosterone system (RAAS) and sympathetic nervous system (SNS) are also activated. Evidence that neprilysin metabolizes many of the effector molecules produced by these counter-regulatory systems raised the possibility that inhibition of this enzyme might be beneficial. However, since angiotensin II is a substrate of neprilysin, inhibition of the enzyme alone would increase levels of this peptide. Thus, treatment strategies that combine RAAS blockade with neprilysin inhibition were sought. Recent large scale randomized clinical trials (RCTs) have provided compelling evidence that sacubitril-valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is superior to an ACEI in reducing mortality and HF hospitalization and in improving quality of life in patients with stage C HFrEF. In these trials, sacubitril-valsartan was found to be safe and well tolerated. This review presents the rationale for using ARNIs, describes the RCTs showing their efficacy, summarizes updated recommendations from recent guidelines, and provides practical points about ARNI initiation and up-titration.

Síndrome cardiorrenal em cães: a busca por medidas de controle

A relação fisiopatológica entre os rins e o coração na doença, conhecida como síndrome cardiorrenal (SCR), envolve distúrbios do coração e dos rins, pois a disfunção aguda ou crônica em um órgão pode induzir a disfunção aguda ou crônica do outro. Em Medicina Veterinária são descritos 5 subtipos de síndrome cardiorrenal: cardiorrenal aguda, cardiorrenal crônica, renocárdica aguda, renocárdica crônica e secundária. A anemia é um achado comum em cães com disfunção cardíaca e renal, caracterizando a chamada síndrome da anemia cardiorrenal. Os mecanismos envolvidos na fisiopatologia da síndrome cardiorrenal envolvem, não somente alterações hemodinâmicas e ativação de sistemas neuro-hormonais, como também a ativação de mecanismos compensatórios do próprio organismo, que acabam contribuindo para a piora da função cardíaca e renal, levando ao desenvolvimento da SCR. O grande desafio encontrado em Medicina Veterinária está relacionado ao diagnóstico precoce dessa síndrome e, principalmente, ao correto manejo terapêutico, uma vez que que a terapia da cardiopatia pode deteriorar a função renal, e vice-versa. Portanto, é importante compreender como a fisiopatologia de uma doença pode impactar a função do outro órgão. O presente trabalho tem como objetivo trazer uma completa abordagem da fisiopatologia, diagnóstico e tratamento da síndrome cardiorrenal em cães.

Cardiopulmonary Baroreflex Control of Renal Sympathetic Nerve Activity Is Impaired in Dogs With Left Ventricular Dysfunction

Activation of neurohormonal systems contributes to the progression of heart failure (HF). The mechanism(s) whereby these systems become activated is(are) not fully explained. We determined whether vagal cardiopulmonary baroreflex control of renal sympathetic nerve activity is abnormal in dogs with left ventricular (LV) dysfunction in the absence of clinical HF, and the relationship of abnormalities in baroreflexes to the development of the neurohumoral excitatory state. LV end-systolic and end-diastolic dimensions (echocardiography), arterial baroreflex sensitivity (slope of ΔRR/Δsystolic BP during phenylephrine or nitroglycerin bolus), and neurohumoral profiles (plasma norepinephrine, renin activity, and arginine vasopressin) were measured serially in conscious dogs (n=24) with progressive LV dysfunction due to rapid ventricular pacing. LV dimensions were used to define groups with mild, moderate, and marked LV dilatation (LVD; increase in LV end-diastolic volume <15%, 15-30%, and >30% of control, respectively). Changes in renal nerve activity (RNA) were recorded in response to increases in pulmonary capillary wedge pressure (PCWP) induced by volume infusion in anesthetized, sinoaortic-denervated dogs. Cardiopulmonary baroreflex sensitivity (slope of %ΔRNA/ΔPCWP) for mild LVD (-17.8%/mmHg) was the same as controls (-17.7%/mmHg). However, the slopes of moderate (-5.8%/mmHg) and severe LVD (-1.9%/mmHg) were decreased significantly compared with controls (P < .05). Arterial baroreflex sensitivity was preserved at all stages of LVD. Plasma norepinephrine, renin activity, and arginine vasopressin remained unchanged after 4, 7, and 11 days of pacing. Vagal cardiopulmonary baroreflex control of renal sympathetic nerve activity is blunted early in the development of LVD. These abnormalities precede neurohumoral excitation and abnormal arterial baroreflexes and become apparent when LV end-diastolic volume starts to increase.

Pathogenesis and pathophysiology of heart failure with reduced ejection fraction: translation to human studies.

Heart failure represents the end result of different pathophysiologic processes, which culminate in functional impairment. Regardless of its aetiology, the presentation of heart failure usually involves symptoms of pump failure and congestion, which forms the basis for clinical diagnosis. Pathophysiologic descriptions of heart failure with reduced ejection fraction (HFrEF) are being established. Most commonly, HFrEF is centred on a reactive model where a significant initial insult leads to reduced cardiac output, further triggering a cascade of maladaptive processes. Predisposing factors include myocardial injury of any cause, chronically abnormal loading due to hypertension, valvular disease, or tachyarrhythmias. The pathophysiologic processes behind remodelling in heart failure are complex and reflect systemic neurohormonal activation, peripheral vascular effects and localised changes affecting the cardiac substrate. These abnormalities have been the subject of intense research. Much of the translational successes in HFrEF have come from targeting neurohormonal responses to reduced cardiac output, with blockade of the renin-angiotensin-aldosterone system (RAAS) and beta-adrenergic blockade being particularly fruitful. However, mortality and morbidity associated with heart failure remains high. Although systemic neurohormonal blockade slows disease progression, localised ventricular remodelling still adversely affects contractile function. Novel therapy targeted at improving cardiac contractile mechanics in HFrEF hold the promise of alleviating heart failure at its source, yet so far none has found success. Nevertheless, there are increasing calls for a proximal, 'cardiocentric' approach to therapy. In this review, we examine HFrEF therapy aimed at improving cardiac function with a focus on recent trials and emerging targets.

The Role of Renal Vascular Reactivity in the Development of Renal Dysfunction in Compensated and Decompensated Congestive Heart Failure

Background/Aims: Reduction of renal blood flow (RBF) is commonly thought to be a causative factor of renal dysfunction in congestive heart failure (CHF), but the exact mechanism of the renal hypoperfusion is not clear. Apart from the activation of neurohormonal systems controlling intrarenal vascular tone, the cause might be altered reactivity of the renal vasculature to endogenous vasoactive agents. Methods: To evaluate the role of this mechanism, we assessed by an ultrasonic transient-time flow probe maximum RBF responses to renal artery infusion of angiotensin II (ANG II), norepinephrine (NE) and acetylcholine (Ach) in healthy male rats and animals with compensated and decompensated CHF. CHF was induced by volume overload achieved by the creation of the aorto-caval fistula (ACF) in Hannover Sprague-Dawley rats. Results: Maximum responses in RBF to ANG II were similar in rats studied five weeks (compensated phase) and 20 weeks (decompensated phase) after ACF creation when compared to sham-operated rats. On the other hand, NE elicited larger maximum decreases in RBF in rats with CHF (five and 20 weeks post-ACF) than in sham-operated controls. We observed greater maximum vasodilatory responses to Ach only in rats with a compensated stage of CHF (five weeks post-ACF). Conclusion: Greater renal vasoconstrictor responsiveness to ANG II or reduced renal vasodilatation in response to Ach do not play a decisive role in the development of renal dysfunction in ACF rats with compensated and decompensated CHF. On the other hand, exaggerated renal vascular responsiveness to NE may be here a contributing causative factor, active in either CHF phase.

Heart Failure: The Most Important, Preventable, and Treatable Cardiovascular Complication of Type 2 Diabetes.

Concerns about cardiovascular disease in type 2 diabetes have traditionally focused on atherosclerotic vasculo-occlusive events, such as myocardial infarction, stroke, and limb ischemia. However, one of the earliest, most common, and most serious cardiovascular disorders in patients with diabetes is heart failure (1). Following its onset, patients experience a striking deterioration in their clinical course, which is marked by frequent hospitalizations and eventually death. Many sudden deaths in diabetes are related to underlying ventricular dysfunction rather than a new ischemic event. As effective treatments for heart failure have emerged, the risk of sudden death has declined, even in the absence of an implantable cardioverter-defibrillator (2). Heart failure and diabetes are linked pathophysiologically. Type 2 diabetes and heart failure are each characterized by insulin resistance and are accompanied by the activation of neurohormonal systems (norepinephrine, angiotensin II, aldosterone, and neprilysin) (3). The two disorders overlap; diabetes is present in 35–45% of patients with chronic heart failure, whether they have a reduced or preserved ejection fraction. A similar prevalence of diabetes in acute heart failure is reported in this issue of Diabetes Care by van den Berge et al. (4). The interplay between diabetes and heart failure is particularly striking among those with heart failure and preserved ejection fraction, who typically have features of metabolic syndrome. As noted by Sandesara et al. (5) in this issue, the presence of diabetes markedly increases the risk of morbidity and mortality of patients with heart failure and preserved ejection fraction, particularly if the microvascular complications of diabetes are also present. There exists a relationship between the severity of type 2 diabetes and the risk of heart failure, but this …

PP.16.21] HEART RATE VARIABILITY IN PATIENTS WITH RESISTANTS WITH ARTERIAL HYPERTENSION

Objective: Study heart rate variability(HRV) as an indicator on the development of complications of arterial hypertension(HT). It is proven that the increase in heart rate(HR) is associated with both the level of blood pressure and the degree of activity of the autonomic nervous system, and requires improvement. Design and method: 42patients with hypertension were divided into 2groups: 1group comprising 20patients (average age: 51,4 ± 2,6 y.) with resistant hypertension, and 2group comprising 22patients (average age 45,3 ± 3,7 y.) with controlled hypertension disease. They had 14,4 ± 2,1 year-long history of hypertension. All these patients were subject to physical examination, biochemical investigation for cortisol, aldosterone-renin ratio, metanephric in urine, echocardiography, doppler echocardiography, ultrasound investigation of the kidneys and adrenal glands, 24-hour blood pressure monitoring, 24-hour ECG monitoring, conducted with the account of heart rate variability(HRV). Results: HRV is determined by the impact of autonomic nervous system on heart. In 1group, lack of blood pressure lowering (type «non-dipper») was registered in 50% of patients, while 22.7% of the patients had higher blood pressure at night than during the day (type «night-peaker»). In 1group, 50% of patients had reduced SDANN rate (less than 100 ms). Their SDNN indexes correlated with the thickness of LV rear wall (r = 0,652; P < 0,05), LV interventricular septum thickness (r = 0,651; P < 0,05), the LVMI(r = 0,661; P < 0,05) and the RMSSD rates, respectively. In patients of 1group, the reduced SDANN and RMSSD rates indicated the reduced HRV and correlated with higher systolic blood pressure, contributing to hypertrophy of LV, and was accompanied by the deterioration of LV diastolic function, increasing the content of aldosterone and metanephrine in daily urine (P < 0.05), compared to patients in group 2. Conclusions: we found that that in 1group patients, the peculiar type of BP characteristic («non-dipper»), the concentric left ventricular hypertrophy (CLVH), the increased functional activity of the sympathetic division of the autonomic nervous system, the content of aldosterone in blood and the content of metanephrines in daily urine indicate that activation of neurohormonal systems is essential for the formation of resistance to drug therapy.

Inflammation and Cardio-Renal Interactions in Heart Failure: A Potential Role for Interleukin-6

Introduction: Inflammation is considered a key driver of cardio-renal dysfunction in patients with heart failure (HF). Of the myriad of pro-inflammatory cytokines, interleukin 6 (IL-6) is of particular interest; it is a multifunctional effector with a central role in several chronic inflammatory conditions via its influence on ubiquitous cellular pathways. Accordingly, IL-6 has emerged as a promising therapeutic target for several chronic inflammatory states. Whereas IL-6 causes adverse cardio-renal effects in rodent models, its effects on these pathways in humans are less clear. Hypothesis: Plasma and urine IL-6 levels would associate with key parameters of cardio-renal dysfunction such as diuretic resistance, renal filtration, and neurohormonal activation. Methods: We enrolled 98 consecutive patients receiving high-dose loop diuretics in an ambulatory HF unit. IL-6 levels in plasma were used to query systemic inflammation and IL-6 in urine to quantify inflammation at the renal tissue level. Results: Plasma and urine IL-6 levels were modestly correlated (r = 0.40, P < .001), and levels showed varied association with key parameters of cardiorenal syndrome (Fig. 1). Plasma IL-6, a measure of systemic inflammation, showed the strongest relationship with systemic neurohormonal activation (OR for high plasma renin = 1.9 per SD increase, 95% CI 1.2–3.0, P = .008) and risk of mortality (adjusted HR = 2.3 per SD increase, 95% CI = 1.5–3.7, P < .001). Conversely, levels of urine IL-6, which reported on tissue specific inflammation, were closely associated with measures of cardio-renal dysfunction such as diuretic resistance (OR = 2.3 per SD increase, 95% CI 1.4–3.8, P = .001), lower eGFR (OR = 1.9 per SD increase, 95% CI = 1.2–3.1, P = .01) and increased renal tissue-level neurohormonal activation (OR for high urine renin = 2.1 per SD increase, 95% CI 1.3–3.4, P = .002). Conclusion: IL-6 was strongly and independently associated with parameters of cardio-renal dysfunction, neurohormonal activation, and mortality. In the context of existing mechanistic data suggesting a causal role for IL-6 in cardio-renal dysfunction, this pathway represents a potential therapeutic target.

Rationale of chloride hypothesis for explanation of the activity of neurohormonal systems in heart failure pathophysiology: Literature review

Rationale of chloride hypothesis for explanation of the activity of neurohormonal systems in heart failure pathophysiology: Literature review

Lipids, Statins and Heart Failure: An Update.

Heart failure (HF) is characterized by cardiac functional and structural alterations, progressively leading to clinical symptoms and signs. Certain neurohormonal systems (i.e. the sympathetic nervous system, the reninangiotensin-aldosterone system and the natriuretic peptide system) as well as interactions between endothelial, monocytes/macrophages and myocardial cells are involved in the process. The present narrative review discusses the relationships between lipids, statins and HF. Lipid metabolism is involved in cardiac function. Inflammation, oxidative stress, endothelial and platelet dysfunction, activation of neurohormonal systems, adverse cardiac remodeling, haemodynamic disorders and arrhythmogenesis predispose to HF development and progression. Statins have been shown to reduce HF incidence possibly via their pleiotropic actions on the above mentioned mechanisms. Other cardiovascular (CV) risk factors affecting HF prevalence and outcomes include metabolic syndrome, non-alcoholic fatty liver disease, chronic kidney disease, hyperuricaemia, epicardial fat and increased arterial stiffness that are improved following statin therapy. Lipid disorders are involved in HF development and progression. Statins may beneficially affect these disorders as well as other CV risk factors linked to HF. However, the impact of statins in patients with established HF has yet to be determined. Further studies are needed to unveil potential benefits of statin therapy (or some statins) in specific groups of HF patients.

Angiotensin II Receptor Blocker Neprilysin Inhibitor (ARNI): New Avenues in Cardiovascular Therapy.

The burden of cardiovascular disease (CVD) is continuously and progressively raising worldwide. Essential hypertension is a major driver of cardiovascular events, including coronary artery disease, myocardial infarction, ischemic stroke and congestive heart failure. This latter may represent the final common pathway of different cardiovascular diseases, and it is often mediated by progressive uncontrolled hypertension. Despite solid advantages derived from effective and sustained blood pressure control, and the widespread availability of effective antihypertensive medications, the vast majority of the more than 1 billion hypertensive patients worldwide continue to have uncontrolled hypertension. Among various factors that may be involved, the abnormal activation of neurohormonal systems is one consistent feature throughout the continuum of cardiovascular diseases. These systems may initiate biologically meaningful "injury responses". However, their sustained chronic overactivity often may induce and maintain the progression from hypertension towards congestive heart failure. The renin-angiotensin-aldosteron system, the sympathetic nervous system and the endothelin system are major neurohormonal stressor systems that are not only able to elevate blood pressure levels by retaining water and sodium, but also to play a role in the pathophysiology of cardiovascular diseases. More recently, the angiotensin receptor neprilysin inhibitor (ARNI) represents a favourable approach to inhibit neutral endopeptidase (NEP) and suppress the RAAS via blockade of the AT1 receptors, without the increased risk of angioedema. LCZ696, the first-in-class ARNI, has already demonstrated BP lowering efficacy in patients with hypertension, in particular with respect to systolic blood pressure levels, improved cardiac biomarkers, cardiac remodelling and prognosis in patients with heart failure. This manuscript will briefly overview the main pathophysiological and therapeutic aspects of ARNI in the clinical management of hypertension and heart failure.

Cardiorenal syndrome: pathophysiological mechanism, preclinical models, novel contributors and potential therapies.

To review the current knowledge about the pathophysiological mechanisms, preclinical models, novel contributors and potential therapies of cardiorenal syndrome. The literature concerning cardiorenal syndrome in this review was collected from PubMed published in English up to January 2014. Original articles and critical reviews related to cardiorenal syndrome were selected and carefully analyzed. Cardiorenal syndrome is a condition characterized by kidney and heart failure where failure of one organ worsens the function of the other thus further accelerating the progressive failure of both organs. The pathophysiology of cardiorenal syndrome is not fully understood, but may be caused by a complex combination of neurohormonal system activation, endothelial dysfunction, proteinuria, oxidative stress, uremic toxins and other factors. Managing cardiorenal syndrome is still a major therapeutic challenge in clinical practice because many of the drugs used to control heart failure can worsen renal function, and vice versa. Non-dialyzable uremic toxins, such as indoxyl sulfate, causing detrimental effects on the heart and kidney as well as stimulation of inflammatory responses, may be an effective therapeutic target for cardiorenal syndrome. Suitable disease models of cardiorenal syndrome are urgently needed to investigate the pathophysiology and effective therapeutic approaches to the condition. Non-dialyzable protein-bound uremic toxins that may have cardiac and renal effects may provide therapeutic benefit to cardiorenal syndrome patients.

The pathophysiology of heart failure

Heart failure is a clinical syndrome that results when the heart is unable to provide sufficient blood flow to meet metabolic requirements or accommodate systemic venous return. This common condition affects over 5 million people in the United States at a cost of $10-38 billion per year. Heart failure results from injury to the myocardium from a variety of causes including ischemic heart disease, hypertension, and diabetes. Less common etiologies include cardiomyopathies, valvular disease, myocarditis, infections, systemic toxins, and cardiotoxic drugs. As the heart fails, patients develop symptoms which include dyspnea from pulmonary congestion, and peripheral edema and ascites from impaired venous return. Constitutional symptoms such as nausea, lack of appetite, and fatigue are also common. There are several compensatory mechanisms that occur as the failing heart attempts to maintain adequate function. These include increasing cardiac output via the Frank-Starling mechanism, increasing ventricular volume and wall thickness through ventricular remodeling, and maintaining tissue perfusion with augmented mean arterial pressure through activation of neurohormonal systems. Although initially beneficial in the early stages of heart failure, all of these compensatory mechanisms eventually lead to a vicious cycle of worsening heart failure. Treatment strategies have been developed based upon the understanding of these compensatory mechanisms. Medical therapy includes diuresis, suppression of the overactive neurohormonal systems, and augmentation of contractility. Surgical options include ventricular resynchronization therapy, surgical ventricular remodeling, ventricular assist device implantation, and heart transplantation. Despite significant understanding of the underlying pathophysiological mechanisms in heart failure, this disease causes significant morbidity and carries a 50% 5-year mortality.