During the past half-century, the advances in the prevention, diagnosis, and management of cardiovascular disease (CVD) have been nothing short of spectacular. Age-adjusted CVD related deaths have declined by about two-thirds in industrialized nations
Survival after a diagnosis of HF has improved during the past 30 years; the age-adjusted death rate has declined, and the mean age at death from HF has risen. However, despite these modest improvements, the 5-year mortality is still approximately 50% worse than that of many cancers. Among Medicare patients, 30-day mortality is 10% to 12%, and the 30-day readmission rate after hospital discharge is 20% to 25%
Cardiorenal syndrome (CRS) is the umbrella term used to describe clinical conditions in which cardiac and renal dysfunctions coexist. Much has been written on this subject, but underlying pathophysiological mechanisms continue to be unraveled and implications for management continue to be debated. Mortality is increased in patients with heart failure (HF) who have a reduced glomerular filtration rate (GFR).Patients with chronic kidney disease have an increased risk of both atherosclerotic cardiovascular disease and HF, and cardiovascular disease is responsible for up to 50 percent of deaths in patients with renal failure
Heart failure (HF) is a condition in which the heart pump is unable to provide blood supply suitable to various organs and tissues, as well as to eliminate harmful residual products. Thus HF, with its mosaic of signs and symptoms is really defined as a syndrome. In this sense, two pathognomonic symptoms are shortness of breath and fatigue, with secondary congestion, renal retention of sodium and water with elevated venous pressure favoring the transudation of intravascular fluid in the interstitial space.
Most often, older people who have HF have many risk factors that contribute to the development of this syndrome, such as hypertension, diabetes mellitus, kidney disease, obesity, COPD and sleep apnea
The severity of the clinical manifestations of HF is variable; however, the progressive condition that can have recurrent exacerbations and requires constant therapeutic interventions is defined as chronic heart failure (CHF), while a gradual or sudden quick start requiring urgent treatment is acute HF (AHF)
We consider that a concept more contemporary and emerging for HF which goes beyond the concept of retention of sodium and water, and congestion is the real justification for this review. What is emerging is a concept of a systemic syndrome in which multiple deleterious cellular pathways are activated by mechanical and humoral mediators known and unknown.
Similarly, renal failure is clearly linked with increased adverse cardiovascular outcomes. Almost 44% of deaths in patients with end-stage renal failure (ESRF) are due to cardiovascular diseases, and a 2006 meta-analysis indicated that patients with ESRF are more likely to die from cardiovascular causes than from renal failure itself
In this sense, several cascade mechanisms result in remodeling of tissue in the heart and kidney, and probably in other systems of the body, leading inexorably to pro-fibrotic and mechanisms of apoptosis in the final phase of HF. In fact, it is in this context circulating biomarkers that can be valuable diagnostic and prognostic tools of disease as well as serve as biochemical factors of protection or deleterious enhancers of HF.
Heart failure with preserved ejection fraction (HFpEF) and with reduced ejection fraction (HFrEF)
Although each cell type and heart Chamber can potentially be involved in the beginning of the HF, there is often to top left ventricular (LV) dysfunction linked to a lifting of the pressures of filling of the LV
Thus, a bad secondary adaptation to the loss of the muscle due to myocardial infarction, the reduction of an increase in afterload or contractility due to idiopathic cardiomyopathy as result of hypertension they generate at the time a low heart beat volume and increased tension of the LV wall with performance altered preload.
In the last decade it has been described that when the LV ejection fraction (EF) is reduced (≤40%), is a condition called "systolic dysfunction", what defines the IC as "IC with reduced ejection fraction" (HFrEF). When LVEF is ≥50%, but have concomitant impaired relaxation of the left ventricle, a condition called "diastolic dysfunction", along with the presence of pathognomonic signs and symptoms of IC, is classified as "IC with preserved ejection fraction" (HFpEF).
Individuals with heart failure and a faith between 40% and 50% are considered as part of an intermediate group (gray area), situation which we have also known as HF with systolic dysfunction in transit
The mortality rate may be higher in patients with HFrEF, however, the high prevalence of HFpEF leads the largest absolute number of deaths, then still numerically greater epidemiological impact HFpEF as cause of death
HFpEF, LV cavity typically has a normal volume and the walls are hypertrophic. See
Comorbidities HFpEF-associated lead to endothelial dysfunction, a condition characterized by the alteration of the "Endothelial Activation" and endothelium-dependent vasodilation, referring to a state where the endothelium loses its physiological properties and moves to a state pro-inflammatory, pro-coagulator and vasoconstrictor.
It is possible that HFpEF can evolve to HFrEF and, therefore, both conditions can be considered "the ends of a single disease"
More recently, the PARAMOUNT Study
This new drug is added to the basal therapy in n = 301 patients HFpEF compared with subjects with initial treatment only valsartan. The results of this study showed a greater reduction in the levels of NT-proBNP in the group treated with LCZ696 compared with controls; however, this difference was not present after 36 weeks of observation. Moreover, this reduction in the levels of NT-proBNP appears to translate into better clinical results. LCZ696 has recently been added to standard therapy in chronic HFrEF patients symptomatic: PARADIGM-IC
These impressive results have been obtained using a drug that targets at the same time for RAAS and the NP system supporting a favorable effect and increase of the combination of the two molecules. LCZ696 may change the therapeutic strategy and survival to long-term HFrEF patients
Another essential essay is TOPCAT that tested the efficacy of spironolactone in patients with HFpEF
In conclusion, the treatment of the HF and, particularly, HFpEF remains a challenge that certainly warrants new therapeutic approaches to alternative and innovative, in the acute setting, as well as in CHF.
Key element in the pathogenesis of HFpEF: Endothelial dysfunction
The cardiac endothelium comprises the endothelial cells of the coronary microvasculature, endocardium, and the capillary intramyocardial. Cardiomyocytes are within the coronary microvascular network to maximum 3 microns in endothelial cells. This specific anatomical layout allows not only the adequate blood supplies, but also facilitates two-way communication between cells. The relevance of the cardiac endothelium in cardiac function follows from the work pioneers who demonstrated in vitro that the cardiac endocardial surface modulates cardiac muscle performance.
By coronary infusion of the substance P which leads to acute modulation of left ventricular function (LV), provided evidence later that the cardiac endothelium is important for cardiac contractile function in human beings potentially through the release of paracrine factors including ON, endothelin-1, natriuretic peptides, cytokines, and others.
Thus, emphasizes the importance of the cardiac endothelium function of cardiomyocytes, i.e. the cardiac endothelium and consequently Endothelial dysfunction or damage affects cardiomyocytes as well as cardiac fibroblasts and the intracardiac neurohormonal activation. The impact of the cardiac endothelium at these different heart cells along with complex interactions (bi-directional) emphasizes the relevance of the Endothelial dysfunction in the pathogenesis of HFPEF.
A very relevant aspect is remember deprivation nitric oxide helps transition endothelial-mesenchymal, a process whereby endothelial cells become a type of cell mesenchymal, which can give rise to fibroblasts. EndMT is induced by inflammatory factors (TGF-ss and TNF-α), oxidized LDL and by age. Also the EndMT contributes to cardiac fibrosis during chronic pressure overload.
Recently, specific endothelial expression of endothelin-1 and NOX2 (NADPH oxidase-2) have shown that they induce EndMT in experimental models of diabetes mellitus and cardiac hypertrophy and fibrosis induced by Ang II, respectively. Interestingly, the activation Ang II-induced endothelial NOX2 is associated with isolated in the absence of systolic dysfunction, diastolic dysfunction.
In summary, these findings suggest that activation by endothelial dysfunction and inflammation not only, also induce the much less appreciated EndMT, as important mechanisms that contribute to cardiac fibrosis and the development of HFPEF. Cardiac fibroblasts in turn may trigger more cardiac inflammation in a multimodal way. This complex interaction between them cells endothelial, cells inflammatory and fibroblasts heart could explain why those strategies unidirectional of counter inflammation or fibrosis have failed until now to block the process fibrotic e indicates the need of new strategies with effects immunomodulatory more spacious. In addition, emphasis is on the need to diagnose and treat HFPEF in an early stage of its pathogenesis, where the vicious cycle of inflammation and fibrosis, which leads to chronic inflammation, might even be repealed.
Despite different pathophysiology, HFrEF and HFpEF share the activation of three main systems neurohormonales: NP system, the sympathetic nervous system (SNS) and RAAS. Neurohormonal activation has laid the foundations in the field of biomarkers of IC. The initial phase of HF is usually asymptomatic. Cardiomyocytes that distended in the heart failure secrete natriuretic peptides mainly from the Atria
More specifically, the SNS increases inotropic function and peripheral vasoconstriction
There is a third receiver for the natriopeptides receptor C (NPR-C), which can also have proliferative action on cardiomyocytes and anti-fibrotic actions in cardiac fibroblasts
The PNs are not the only contributors to the increased levels of cGMP. The nitric oxide (no) to act through guanylate Cyclase soluble, another receptor guanylate Cyclase, through the production of cGMP can modulate inflammation
Directly or indirectly, there are greater renal involvement, with an increase of angiotensin II (Ang II) and finally the levels of aldosterone. It is important that the kidney plays a crucial role during the IC, ultimately leading to the retention of sodium and water through the activation of the Mineralocorticoid receptors in the distal nephron
It is important to underline that these complex interactions are present in both heart failure, acute and chronic, although with different levels of severity. On the other hand, after a myocardial infarction, aldosterone is also in its maximum plasma concentration
Therefore, the role of aldosterone in the pathogenesis of cardiovascular diseases clearly goes beyond heart failure and hypertension.
Originally specified by Dr. Eugene Braunwald, the key symptoms of CHF (dyspnea and fatigue) are consequence of the retention of salt and water
Renin cleaves to angiotensinogen,
This action is counter-regulated by the natriuretic effect of cardiac ANP and BNP that is at least at the beginning, effective. However, with the evolution of the HF, the actions of protection of PNs/cGMP are lost, leading to the progression of the disease. The volume overload induces more loss of cardiomyocytes by stress and cell apoptosis. Also, start with the accumulation of extracellular matrix pro-fibrotic and inflammatory processes. The remodeling, hypertrophy, fibrosis and death with regeneration reduced myocardial
Renal blood flow is reduced, and/or the reduced venous return can result in renal congestion
As in the heart, renal perfusion impaired long-term induces local routes in fibrosis and consequent reduction in the glomerular function and tubular with eventual damage to the parenchyma (chronic kidney disease, CKD).
This is the picture of the cardiorenal syndrome with high risk of death and rehospitalization. This syndrome has been classified by the Working Group of the initiative for the quality of dialysis, which proposes a 5 subtypes classification scheme academic way. This classification of 5 items is based on: a) if the principal organ of the dysfunction is the heart, kidney, or a third independent process that affects both the bodies and b) the acute or chronic nature of the disease.
This strong and complex intercommunication between the heart and the kidney is bidirectional. Therefore, the kidney may even be the first body to start the IC. This concept is supported by earlier clinical studies that have shown even mild renal impairment as a factor that contributes to an increased cardiovascular risk
| CRS types | Hallmarks | Clinical sceneries |
| CRS type 1(acute CRS) | The rapid deterioration of heart function that leads to AKI | Acute Decompensated HF, AMI with cardiogenic shock, acute valvular insufficiency |
| CRS type 2 (chronic CRS) | Chronic alterations in cardiac function leading to chronic progressive renal disease | Chronic HF (activation of the RAAS and SNS long-term, chronic hypoperfusion) |
| CRS type 3 (acute renocardiac syndrome) | Primary worsening of renal function leading to acute cardiac dysfunction. Overload of fluids, electrolyte disturbances, the accumulation of myocardial depressants factors, neurohormonal activation, and systemic inflammation have been postulated to lead to cardiac dysfunction | Acute kidney injury (uremia causing deterioration of contractility, hyperkalaemia cause arrhythmias, the volume overload causing pulmonary edema)) |
| CRS type 4 (chronic renocardiac syndrome) | Chronic kidney disease primary contributing to decreased cardiac function and an increased risk of cardiovascular events | The chronic kidney disease that leads to the HVI, coronary artery disease, and diastolic dysfunction |
| CRS type 5 (secondary CRS) | Whether the presence of concomitant cardiac and renal dysfunction due to acute or chronic systemic disorders | Diabetes mellitus, vasculitis, amyloidosis, sepsis, cardiogenic shock |
The consensus report: Acute Dialysis Quality Initiative. European Heart Journal (2010) 31, 703-711. CRS, Cardiorenal syndrome; AKI, acute Kidney injury; AMI, acute myocardial infarction; RAAS, Renin-angiotensin-aldosterone system; LVH, Left ventricular hypertrophy
These results were independent of blood pressure, sodium, water retention or the activity of aldosterone. In addition, this connection of the kidney - heart in early CKD could involve at least two pathways of genes in the heart: pathways of TGF-β and apoptosis. These important findings support the hypothesis that impaired renal function is associated with release of renal cellular or humoral factors that contribute to changes in the structure and function of the myocardium.
Arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), is synthesized by the hypothalamus and stored in the neurohypophysis. This hormone induces the reabsorption of water by the nephron, ultimately increases the intravascular volume
Adrenomedullin (ADM) is a peptide vasodilator first found in cells of pheochromocytoma, but has subsequently been found in various organs such as the heart, kidney, lung, smooth muscle cells, and endothelium
Cortisol is produced in the zona fasciculata of the adrenal cortex. This hormone glucocorticoid, locally not completely inactivated the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11 βHSD2), can induce sodium and water retention during IC, using the link to the RM in the kidney
The activation of the endothelium, the extracellular matrix, cells of the immune system and the reaction of oxidative stress also contribute to the deadly progression of a phase offset to a lopsided and symptomatic stage IC. Specifically, Endothelins, released by endothelial cells, induces vasoconstriction and release of aldosterone
More recently, in the systemic circulation of the IC holder, it is also possible to detect matrix proteinases, the enzymes involved in the metabolism of collagen. Its presence indicates extracellular matrix remodeling and active processes fibrotic
Therefore, both ST2 soluble and galectin-3 together with the peptidases of collagen, are currently widely used, demarcating the important concept of the volume control in interaction with extracellular collagen during IC.
The ischemic injury could characterize the progression of IC, causing release of peptides specific cardiac, such as troponins in the bloodstream
Inflammation and Endothelial dysfunction, participate directly in the activation of fibroblasts responsible for excess remodeling and fibrosis of the extracellular matrix.
In the IC has been also reported that there may be a secondary hyperparathyroidism. Specifically, parathyroid hormone (PTH) is released from the parathyroid glands when there is hypocalcemia. Therefore, calcium homeostasis may be impaired in IC, as well as ERC. In addition, PTH has shown direct pleiotropic effects in cardiomyocytes
The growth of fibroblasts, FGF 23, factor has direct actions on myocardial hypertrophy. In short, all of these factors are considered valid biomarkers of IC. However, to date, BNP and N-terminal of the Pro-hormone (NT-proBNP) are the only ones recommended by the American Heart Association for the diagnosis of IC. Besides BNP, biomarkers of damage (troponin) myocardial and cardiac fibrosis (ST2 soluble and galectin-3) may be considered for the risk stratification of additive in ICA
An ideal biomarker should then allow the diagnosis, to help in the monitoring of the treatment and prognosis of a specific disease, in addition to being highly sensitive, specific, reliable and standardized, regardless of age, sex, and anthropometric parameters of the subject
Then one could speculate that the use of biomarkers to track the disease might not totally be an optimal strategy
Nevertheless endothelial dysfunction and increased oxidative stress seem to be important pathophysiologic processes associated with the pro-inflammatory state of HFpEF and HFrEF
In a study comparing HFpEF patients with age- and sex-matched hypertensives without symptoms as well as age- and sex-matched healthy controls, global vascular function (Ea and SVRI) was not significantly different between groups, but endothelial function was impaired in both HFpEF and hypertensive subjects compared to the controls
Nitric oxide (NO) is considered a key player in endothelial dysfunction. NO promotes LV relaxation through cyclic guanosine monophosphate (cGMP)–protein kinase G (PKG) dependent and independent mechanisms. Myocardial samples from HFpEF patients displayed reduced levels of PKG activity and lower cGMP concentration, which was related to increased cardiomyocyte stiffness, demonstrated by measurement of passive tension
High diastolic stiffness was correlated to relative hypophosphorylation of the stiff N2B titin isoform, and in HFpEF the N2BA:N2B expression ratio was decreased compared to HFrEF patients
Endothelial dysfunction is not just confined to the systemic or the coronary arteries, but also includes the pulmonary arteries. Pulmonary hypertension (PH) is a common feature in HFpEF. In a community-based study, PH was present in 83% of HFpEF patients
The above data suggest an important role for inflammation and inflammation-induced endothelial dysfunction in the pathophysiology of HFpEF. Targeting these processes and the pathways involved, such as cGMP–PKG, could be potentially beneficial to HFpEF patients.
Despite advances in science and medicine of the cardiovascular diseases, IC is still a huge burden as a public health problem. The need for new effective drugs should involve returning to the study of the pathophysiology of HFrEF and HFpEF and redefine new and different paths and biomarkers to aim with new therapies. Recognizing the activation of several hormonal systems in IC and the imbalance between PNs and RAAS, the use of natriuretic peptide receptor agonists, could be justified to increase the beneficial effects of PNs/cGMP and counteract the negative actions of Ang II and the activation of the Mineralocorticoid receptor.
However, any disease in which the majority of risk factors are modifiable, HF prevention is the first step. In addition some reports emphasize the importance of the monitoring of blood pressure, central obesity and peptide N-terminal procollagen-III to identify the first structural and functional changes in the heart, before HF stage B-C or D