Search

Despite significant improvements in diagnosis, understanding the pathophysiology and management of the patients with acute decompensated heart failure (ADHF), diuretic resistance, yet to be clearly defined, is a major hurdle. Secondary hyperaldosteronism is a pivotal factor in pathogenesis of sodium retention, refractory congestion in heart failure (HF) as well as diuretic resistance. In patients with decompensated cirrhosis who suffer from ascites, similar pathophysiological complications have been recognized. Administration of natriuretic doses of mineralocorticoid receptor antagonists (MRAs) has been well established in management of cirrhotic patients. However, this strategy in patients with ADHF has not been well studied. This article will discuss the potential use of natriuretic doses of MRAs to overcome the secondary hyperaldosteronism as an alternative diuretic regimen in patients with HF.

Background: Hyponatremia at hospital admission is a well-known risk factor of morbidity and mortality in patients with heart failure (HF). However, there are few data about hyponatremia developing during hospitalization in patients with HF. The present study compares hospital-acquired hyponatremia (HAH) with community-acquired hyponatremia (CAH) in HF patients with respect to outcome., Methods and Results: A total of 5347 consecutive hospitalized patients with a diagnosis of HF were analyzed. CAH was defined as a serum sodium value of ≤135 mEq/L at the time of hospital admission. HAH was defined as development of a serum sodium level of ≤135 mEq/L during hospitalization in the setting of a serum sodium value >135 mEq/L on admission. In-hospital mortality, length of stay, worsening kidney function, and discharge to short-/long-term care facilities were analyzed. CAH and HAH were identified in 1039 patients (19.4%) and in 1302 patients (24.4%) of the 5347 patients admitted, respectively. Both types of hyponatremia were associated with increased mortality, length of stay, rate of discharge to short-/long-term care facilities, and worsening kidney function. In-hospital mortality did not differ between CAH and HAH, but differences in demographics and comorbidities were present., Conclusions: The present results identified HAH as a risk factor for increased mortality in HF as has been previously described for CAH. HAH was associated with increased length of stay, discharge to short-/long-term care facilities, and development of cardio-renal failure. Thus, hyponatremia in hospitalized patients with a diagnosis of HF, either on admission or during hospitalization, is a prognostic marker for poor outcomes.

Sodium and water retention in cardiac failure and cirrhosis is pivotal in the morbidity and mortality of patients with these disorders. Moreover, the pathophysiology of these edematous disorders is quite similar. Both disorders have activation of the renin-angiotensin-aldosterone system, increased sympathetic activity, and nonosmotic stimulation of arginine vasopressin, which is initiated by unloading of the arterial baroreceptors; this occurs secondary to diminished cardiac output with heart failure and primary systemic arterial vasodilation with cirrhosis. With this common pathophysiology causing pulmonary congestion, ascites, and peripheral edema, diuretics are pivotal in the therapy of patients with heart failure and cirrhosis. Advanced cardiac failure and cirrhosis both show secondary hyperaldosteronism and impaired renal escape from the sodium-retaining effect of aldosterone. However, currently there are contradictory uses of mineralocorticoid-receptor antagonists in cardiac failure (non-natriuretic doses) versus cirrhosis (natriuretic doses). This disparity relates to the greater potential of hyperkalemia in cardiac failure patients receiving inhibitors of the renin-angiotensin-aldosterone system. This review discusses the beneficial and potentially deleterious effects of diuretic use in patients with cardiac failure and cirrhosis., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Renal dysfunction is highly prevalent in patients with heart failure. Furthermore, worsening renal function in patients with acute decompensated heart failure (ADHF), the so-called cardiorenal syndrome, impacts short and long-term morbidity and mortality. In recent years, more evidence has surfaced from clinical trials and heart failure registries that a complex cross-talk between the kidney and heart in patients with ADHF exists. Meanwhile, management of patients presenting with ADHF and concomitant renal dysfunction continues to be challenging. Therefore, understanding the interaction of the heart and kidneys is pivotal in tailoring therapy of these patients. We have extensively reviewed the pathophysiology of ADHF, the role of neurohoromones as well as other biomarkers and predictors of mortality in these patients based on the current evidence. Moreover, we have discussed the current and future pharmacologic and non-pharmacologic therapies for treatment of this deadly disease. The strength of the evidence is limited, however, due to a paucity of randomized controlled trials in this patient population. What is evident from current national statistics; however, are the poor results in treating the congestion of ADHF. In this regard, the role of secondary hyperaldosteronism is discussed in the diuretic section as well as diuretic resistance in ADHF. In conclusion, since renal function is the single most important prognostic factor in the outcome of patients with ADHF, a better understanding of the pathophysiology of the cardiorenal syndrome is needed to target therapy and ultimately improve the mortality of patients with ADHF.

Patients with cirrhosis and heart failure (HF) share the pathophysiology of decreased effective arterial blood volume because of splanchnic vasodilatation in cirrhosis and decreased cardiac output in HF, with resultant stimulation of the renin-angiotensin-aldosterone system. Hyperaldosteronism plays a major role in the pathogenesis of ascites and contributes to resistance to loop diuretics. Therefore, the use of high doses of aldosterone antagonist (spironolactone up to 400 mg/day) is the main therapy to produce a negative sodium balance in cirrhotic patients with ascites. Hyperaldosteronism also has increasingly been recognized as a risk factor for myocardial and vascular fibrosis. Therefore, low-dose aldosterone antagonists are being used in patients with HF for cardioprotective action. However, the doses (25 to 50 mg/day) at which they are being used in cardiac patients as reported in the Randomized Aldactone Evaluation Study are not natriuretic. It is likely, therefore, that the mortality benefit relates primarily from their effect on cardiac and vascular fibrosis. Resistance to commonly used loop diuretics is frequently present in patients with advanced HF. In patients with decompensated HF with volume overload who are loop diuretic resistant, ultrafiltration may be the only available option. This is, however, an invasive procedure. For these patients, natriuretic doses of aldosterone antagonists (spironolactone >50 mg/day) may be a potential option. The competitive natriuretic response of aldosterone antagonists is related to activity of the renin-angiotensin-aldosterone system: the higher the renin-angiotensin-aldosterone system activity, the higher the dose of aldosterone antagonist required to produce natriuresis. This article will discuss the potential use of natriuretic doses of aldosterone antagonists in patients with HF, including the potential side effect of hyperkalemia.

The pathogenesis of cardiac failure involves activation of the neurohumoral axis including stimulation of the sympathetic nervous system, the renin-angiotensin-aldosterone, and nonosmotic vasopressin systems. While these responses are critical in maintaining arterial pressure, they are associated with renal vasoconstriction, as well as sodium and water retention. In advanced circumstances, renal dysfunction and hyponatremia occur with cardiac failure. Even a modest rise in serum creatinine related to diminished renal function in heart failure patients is associated with increased risk for cardiovascular morbidity and mortality. Similarly, increased thirst and the nonosmotic stimulation of vasopressin in advanced cardiac failure leads to hyponatremia, which is also a major risk factor for mortality. Currently, V2 vasopressin receptor antagonists have been shown to correct hyponatremia in cardiac failure. One such agent, conivaptan, also is a V1 receptor antagonist which could theoretically benefit heart failure patients by decreasing cardiac afterload and remodeling. The effect of V2 receptor antagonists to correct hyponatremia in heart failure patients appears to be quite safe. However, to date no effect on mortality has been demonstrated.

In this article, the pathophysiology of left ventricular failure is reviewed. By contrast, the paucity of information about pulmonary arterial hypertension and right ventricular failure is acknowledged. The potential mechanisms whereby renal sodium and water retention in right ventricular failure secondary to pulmonary arterial hypertension can occur, despite normal left ventricular function, are discussed. With right ventricular failure as the primary cause of death in patients with pulmonary hypertension, more information about the mechanisms of renal sodium and water retention in these patients is direly needed. Specifically, studies to examine the activation of the neurohumoral axis at various stages of pulmonary arterial hypertension and right ventricular failure, including inhibition of mineralocorticoid and V2 vasopressin receptors, are indicated.

The discovery of four major water channels in the kidney, namely aquaporins (AQP) 1, 2, 3 and 4, has allowed a substantial increase in our understanding of renal water regulation in health and disease. This review discusses the renal aquaporin water channels in the urinary dilution and concentrating defects in cardiac failure, cirrhosis, syndrome of inappropriate hormone secretion, pregnancy, hypothyroidism, isolated glucocorticoid deficiency, isolated mineralocorticoid deficiency, primary polydipsia, acquired and genetic nephrogenic diabetes insipidus.

There are several markers of poor prognosis in heart failure (HF). The most established markers of poor prognosis in HF include neurohormonal (NH) imbalance, low ejection fraction (EF), ventricular arrhythmias, intraventricular conduction delays, low functional capacity, low SBP, and renal failure. The relative importance of these factors is unknown, as they have never been studied together. We present a 74-year-old female with nonischemic cardiomyopathy and an EF<20% who over 24 years since diagnosis, never developed clinical or hemodynamic congestion, was never hospitalized for HF, and never required a loop diuretic. She had all of the clinical indicators of poor prognosis in HF except for severe NH imbalance and renal failure, illustrating their importance in HF prognosis. While NH activation in HF is initially an adaptive mechanism, an imbalance of NH effectors causes congestion leading to a vicious cycle of congestion, renal dysfunction, and worsening of HF. The combination of NH activation and renal failure in HF is a vasomotor nephropathy known as the cardiorenal syndrome (CRS) and portends a poor prognosis. Pharmacological disruption of NH pathways early in HF may prevent CRS and, therefore, improve outcomes.

The inability to effectively regulate volume status is a major consequence of acute heart failure syndromes (AHFS). A variety of pathophysiologic processes contribute to this impairment, most notably neurohormonal activation of the renin-angiotensin-aldosterone system, arginine vasopressin, and the sympathetic nervous system. As a result, addressing volume overload is one of the most challenging aspects of AHFS management. Neurohormonal activation leads to substantial changes in hemodynamics and myocardial remodeling, which further contribute to the severity of heart failure (HF) disease and thereby cyclically increase the risk of further neurohormonal activation. Pulmonary capillary wedge pressure is a dependable reflection of volume status and has been used as a surrogate marker in recent studies to assess disease progression in response to innovative HF treatment strategies. Future approaches to HF treatment should focus on the more accurate assessment and management of volume status in an effort to improve patient care.

This article discusses the pathophysiology of sodium and water retention in edematous disorders with a particular focus on cardiac failure, cirrhosis, and pregnancy. The body fluid volume hypothesis, which emphasizes the dominant role of arterial baroreceptors in renal sodium and water excretion, is reviewed. With arterial underfilling, either due to a decrease in cardiac output or peripheral arterial vasodilation, the normal central inhibition of the sympathetic nervous system activity and baroreceptor-mediated, nonosmotic arginine vasopressin (AVP) release is attenuated. The resultant increase in renal adrenergic activity stimulates the renin-angiotensin-aldosterone system. Although the resultant increase in systemic vascular resistance compensates for the primary arterial underfilling, this activation of the neurohumoral axis results in diminished sodium and water delivery to the renal collecting duct sites of aldosterone, AVP, and natriuretic peptide action. This diminished distal sodium and water delivery will be discussed as an important factor in the failure to escape from the sodium-retaining effects of aldosterone, the resistance to the natriuretic and diuretic effects of natriuretic peptides, and the diminished maximal solute-free water excretion in patients with edema. The role of the nonosmotic AVP release in water retention and hypo-osmolality/hyponatremia has been demonstrated in patients and experimental animals by administering nonpeptide, orally active vasopressin V2 receptor antagonists. These agents have been found to increase solute-free water excretion in patients with water-retaining, hyponatremic edema as well as in experimental animals.

The interactions between the heart and the kidney recently have been the focus of intense interest because of epidemiological evidence indicating that even mild deterioration of renal function is an important risk factor for poor outcome in patients with congestive heart failure, myocardial infarction, and cardiovascular surgery. Kidney function deterioration may be a consequence of cardiac and baroreceptor dysfunction or may be primarily caused by intrinsic kidney disease. This review provides a comprehensive analysis of the role of the kidney not only as a marker but also as a pathogenic factor in cardiorenal syndromes, whether primary heart or primary kidney disease or both are the initiators of the subsequent pathophysiological events.

Background: Heart failure (HF) occurs more frequently and is a significant cause of mortality in diabetic patients. The purpose of the current study is to ascertain risk factors that are predictive of HF hospitalizations in type 2 diabetic patients., Methods: Longitudinal observational study of type 2 diabetic patients with baseline diastolic blood pressures > or =80 mm Hg and no history of New York Heart Association class III-IV HF or a serum creatinine > or =2.5 mg/dL nested within a randomized clinical trial. The outcome measure of this study was the first occurrence of HF hospitalization over a 5-year follow-up period., Results: Patients with overt albuminuria at baseline had a higher and earlier occurrence of HF hospitalizations than those with micro- or normoalbuminuria (13.6% versus 3.3%, odds ratio [OR]=3.1, 95% confidence interval [CI]=2.15-4.60, P<.0001). In the multiple logistic regression analyses, the presence of overt albuminuria (OR 5.4, 95% CI=2.3-12.5, P<.001), history of myocardial infarction (OR 4.6, 95% CI=1.6-13.1, P=.004) and a history of New York Heart Association Class I or II HF (OR 8.0, 95% CI=2.2-28.6, P=.0014) at baseline were independently associated with HF hospitalizations., Conclusions: Overt albuminuria predicts the occurrence of HF hospitalizations in type 2 diabetic patients. Thus early aggressive treatment of diabetic nephropathy should be investigated as a means of preventing of HF.

Hyponatraemia--the most common serum electrolyte disorder--has also emerged as an important marker of the severity and prognosis of important diseases such as heart failure and cirrhosis. Acute hyponatraemia can cause severe encephalopathy, but the rapid correction of chronic hyponatraemia can also profoundly impair brain function and even cause death. With the expanding elderly population and the increased prevalence of hyponatraemia in this segment of society, prospective studies are needed to examine whether correcting hyponatraemia in the elderly will diminish cognitive impairment, improve balance and reduce the incidence of falls and fractures. Given that polypharmacy is also common in the elderly population, the various medications that may stimulate arginine vasopressin release and/or enhance the hormone's action to increase water absorption must also be taken into consideration. Whether hyponatraemia in a patient with cancer is merely a marker of poor prognosis or whether its presence may alter the patient's quality of life remains to be examined. In any case, hyponatraemia can no longer be considered as just a biochemical bystander in the ill patient. A systematic diagnostic approach is necessary to determine the specific aetiology of a patient's hyponatraemia. Therapy must then be dictated not only by recognized reversible causes such as advanced hypothyroidism, adrenal insufficiency, diuretics or other medicines, but also by whether the hyponatraemia occurred acutely or chronically. Information is emerging that the vast majority of cases of hyponatraemia are caused by the nonosmotic release of arginine vasopressin. Now that vasopressin V2-receptor blockers are available, a new era of clinical investigation is necessary to examine whether hyponatraemia is just a marker of severe disease or whether correction of hyponatraemia could improve a patient's quality of life. Such an approach must involve prospective randomized studies in different groups of patients with hyponatraemia, including those with advanced heart failure, those with cirrhosis, patients with cancer, and the elderly. [ABSTRACT FROM AUTHOR]

Aim To provide an in-depth clinical characterization and analysis of outcomes of the patients hospitalized for heart failure (HF) who subsequently develop worsening renal function (WRF) during hospitalization or soon after discharge. Methods and results Of the 4133 patients hospitalized with worsening HF and reduced left ventricular ejection fraction (LVEF) (≤40%) in the EVEREST trial, 2072 were randomized to tolvaptan, a selective vasopressin-2 receptor antagonist, and 2061 were randomized to placebo, both in addition to standard therapy. This analysis included the 2021 (98%) patients in the placebo group with a complete set of renal function parameters. Renal function parameters and clinical variables were measured prospectively during hospitalization and after discharge. Worsening renal function was defined as an increase in sCr ≥0.3 mg/dL during the in-hospital (randomization to discharge or Day 7) and post-discharge (discharge or Day 7 to 4 weeks post-discharge) periods. Blood pressure (BP), body weight (BW), natriuretic peptides (NPs), and congestion score were correlated with WRF. The prognostic value of baseline renal function at admission and WRF during hospitalization and post-discharge on long-term outcomes were assessed using a Cox proportional hazards model adjusted for other baseline covariates. At randomization, 53.2% of patients had moderately or severely reduced estimated glomerular filtration rate (eGFR) (<60.0 mL/min/1.73 m2). Worsening renal function was observed in 13.8% in-hospital and 11.9% post-discharge. Worsening renal function during hospitalization and post-discharge was associated with greater reductions in BP, BW, and NPs. Baseline renal dysfunction as well as in-hospital and post-discharge WRF were predictive of a composite endpoint of cardiovascular (CV) mortality/HF rehospitalization. Conclusion The prevalence of renal dysfunction is high in patients hospitalized for HF with reduced LVEF. Worsening renal function may occur not only during hospitalization, but also in the early post-discharge period. Since worsening renal function during hospitalization is associated with a significant decrease in signs and symptoms of congestion, body weight and natriuretic peptides, which are good prognostic indicators, worsening renal function during hospitalization as an endpoint in clinical trials should be re-evaluated. [ABSTRACT FROM PUBLISHER]

Body sodium, water, and extracellular fluid volume are tightly regulated by neural, humoral, and renal mechanisms to maintain osmolality in extracellular fluid and to maintain normal intravascular volume. This is accomplished by controlling sodium content in extracellular fluid. In the normal physiologic state, total body water (which accounts for ∼60% of body weight) is distributed among three compartments: intracellular, interstitial, and intravascular spaces. About two thirds of total body water is intracellular fluid. Potassium is the major intracellular cation, and sodium is the major extracellular cation. Body water content and plasma osmolality are tightly regulated by the action of arginine vasopressin on renal tubules. A wide variety of disease states are associated with a nonosmotic response of arginine vasopressin, also known as the antidiuretic hormone. Determination of the serum sodium concentration is the most direct measure of hyponatremia. The vasopressin V2-receptor antagonists are effective aquaretic agents and correct hyponatremia in several hyponatremic disorders. [ABSTRACT FROM AUTHOR]

Summary: Impaired urinary dilution leading to water retention and hyponatremia may occur in patients with cardiac failure, cirrhosis, pregnancy, oxytocin administration, hypothyroidism, glucocorticoid, and mineralocorticoid deficiency. The mechanisms for these defects predominantly involve the nonosmotic stimulation of arginine vasopressin release with up-regulation of aquaporin 2 water channel expression and trafficking to the apical membrane of the principal cells of the collecting duct. These perturbations are reversed by V2 vasopressin receptor antagonists. In contrast, urinary concentration defects leading to polyuria are vasopressin resistant. They may involve several factors, such as impaired countercurrent concentration secondary to down-regulation of Na-K-2Cl cotransporter. Vasopressin-resistant down-regulation of aquaporin 2 expression has also been described as a factor in impaired urinary concentration. [Copyright &y& Elsevier]

Heart failure is a leading cause of morbidity and mortality. In the United States, there are more than 5 million patients with heart failure and over 500,000 newly diagnosed cases each year. Numerous advances have been made in our understanding of the pathophysiologic mechanisms contributing to sodium and water retention in this condition. Important alterations in the sympathetic nervous system and the renin-angiotensin-aldosterone system have been described in heart failure, allowing the use of mechanism-specific treatments such as beta-adrenergic receptor antagonism and angiotensin-converting enzyme inhibition. As our understanding of the roles of the natriuretic peptides and the arginine vasopressin-aquaporin-2 system in the pathophysiology of heart failure evolves, treatments directed toward the alterations in these systems in heart failure can be further developed.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article examines the water retention and aquaporins in heart failure, liver disease and pregnancy. According to the authors, water retention in excess of total body sodium oftentimes occurs in patients with cardiac failure and in pregnancy. On their investigation, they proposed that water retention can be inferred in the context of unifying hypothesis of body fluid volume expansion. Other significant information and analyses relative to the matter are presented.

Therapy of heart failure. The incidence and prevalence of heart failure is on the rise. It has become the single most expensive health care item in the United States and the number one discharge diagnosis in the elderly. The goals of therapy include both prevention and treatment of heart failure. In recent years research studies and randomized clinical trials have revolutionized the understanding of the pathophysiology and treatment of this disease. This article focuses on the medical management of chronic systolic heart failure based on the pathophysiology of the disease. Systolic heart failure is characterized by a decrease in left ventricular function and cardiac output, which results in activation of several neurohormonal compensatory systems. The long term effects of this neurohormonal activation leads to further deterioration of cardiac function. The use of hydralazine and nitrates to reduce the systemic vascular resistance was the first to show an improvement in mortality and morbidity. Then angiotensin converting enzyme inhibitors, by inhibiting the renin angiotensin system, demonstrated a greater improvement in mortality and morbidity. More recently the inhibition of the sympathetic stimulation with beta-blockers has been shown to have an additive effect on morbidity and mortality in combination with angiotensin-converting enzyme inhibitors. Digoxin and diuretics remain important for improving symptoms and decreasing hospitalizations but have not been shown to decrease mortality. The most recent advance in the treatment of cardiac failure is the demonstration that the aldosterone antagonists, spironolactone decreases morbidity and mortality. [ABSTRACT FROM AUTHOR]

Background: Hyponatremia (serum sodium concentration, <135 mmol per liter) is a predictor of death among patients with chronic heart failure and cirrhosis. At present, therapy for acute and chronic hyponatremia is often ineffective and poorly tolerated. We investigated whether tolvaptan, an orally active vasopressin V2-receptor antagonist that promotes aquaresis — excretion of electrolyte-free water — might be of benefit in hyponatremia. Methods: In two multicenter, randomized, double-blind, placebo-controlled trials, the efficacy of tolvaptan was evaluated in patients with euvolemic or hypervolemic hyponatremia. Patients were randomly assigned to oral placebo (223 patients) or oral tolvaptan (225) at a dose of 15 mg daily. The dose of tolvaptan was increased to 30 mg daily and then to 60 mg daily, if necessary, on the basis of serum sodium concentrations. The two primary end points for all patients were the change in the average daily area under the curve for the serum sodium concentration from baseline to day 4 and the change from baseline to day 30. Results: Serum sodium concentrations increased more in the tolvaptan group than in the placebo group during the first 4 days (P<0.001) and after the full 30 days of therapy (P<0.001). The condition of patients with mild or marked hyponatremia improved (P<0.001 for all comparisons). During the week after discontinuation of tolvaptan on day 30, hyponatremia recurred. Side effects associated with tolvaptan included increased thirst, dry mouth, and increased urination. A planned analysis that combined the two trials showed significant improvement from baseline to day 30 in the tolvaptan group according to scores on the Mental Component of the Medical Outcomes Study 12-item Short-Form General Health Survey. Conclusions: In patients with euvolemic or hypervolemic hyponatremia, tolvaptan, an oral vasopressin V2-receptor antagonist, was effective in increasing serum sodium concentrations at day 4 and day 30. (ClinicalTrials.gov numbers, NCT00072683 [SALT-1] and NCT00201994 [SALT-2].) N Engl J Med 2006;355:2099-112. [ABSTRACT FROM AUTHOR]

A letter to the editor on patients with type 2 diabetes and hypertension is presented.

Discusses a hypothesis which deals with the integrity of the arterial circulation as the primary determinant of renal sodium and water excretion in health and disease. Health effects of renal retention in patients with heart failure; Symptoms which the hypothesis explains; Arterial underfilling; Sympathetic nervous system; Conclusions.

Abstract: Much has been learned about the pathophysiological state that underlies the development of increased total body volume and edema in left ventricular failure. Very little, however, is known about the mechanism underlying systemic hypervolemia in patients with isolated right ventricular dysfunction. In this manuscript, we describe our randomized clinical trial to assess the relationship between severity of pulmonary arterial hypertension and neurohormonal activation, total plasma volume and renal function. We assess the role of aldosterone and vasopressin in volume retention in patients with pulmonary arterial hypertension with right ventricular failure. As understanding of the pathogenesis of left ventricular failure has been associated with improved therapies, the better understanding of the mechanisms of isolated right ventricular cardiac failure will also lead to improved patient care. [Copyright &y& Elsevier]