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STATE-OF-THE-ART PAPER

Acute Heart Failure Syndromes

Mihai Gheorghiade, MD, FACC^_*,_* and Peter S. Pang, MD

^_* Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
Department of Emergency Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois

Manuscript received July 2, 2008; revised manuscript received October 21, 2008, accepted October 26, 2008.

^_* Reprint requests and correspondence: Dr. Mihai Gheorghiade, Professor of Medicine and Surgery, Northwestern University Feinberg School of Medicine, Division of Cardiology, 676 N. St. Clair, Suite 600, Chicago, Illinois 60611 (Email: m-gheorghiade{at}northwestern.edu).

	Abstract

Top Abstract Definitions Patient Characteristics Clinical Classification Pathophysiology Prognostic Factors Evaluation Phases of AHFS... Transitioning From Acute to... Early Pharmacologic Management Clinical Trials in AHFS Conclusions References

 
Heart failure resulting in hospitalization represents a significant and growing health care burden. Heterogeneity characterizes this group in terms of mode of presentation, pathophysiology, and prognosis. The vast majority of patients symptomatically improve during hospitalization; however, their early post-discharge rehospitalization and mortality rates continue to be high. Worsening signs and symptoms, neurohormonal, and renal abnormalities occurring soon after discharge may contribute to these high post-discharge event rates. Currently available assessment modalities combined with recent advances in cardiovascular therapies provide present-day opportunities to improve post-discharge outcomes. Further investigation into pathophysiologic targets and novel approaches to clinical trial design are needed. Improving post-discharge outcomes is the single most important goal in the management of acute heart failure syndromes.

Key Words: heart • failure • decompensated • acute • syndromes

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   AHFS = acute heart failure syndromes   ARB = angiotensin receptor blocker   BNP = B-type natriuretic peptide   BP = blood pressure   BW = body weight   CAD = coronary artery disease   CRT = chronic resynchronization therapy   EF = ejection fraction   HF = heart failure   IV = intravenous   LVFP = left ventricular filling pressure   MI = myocardial infarction   PCWP = pulmonary capillary wedge pressure   PSF = preserved systolic function   SBP = systolic blood pressure

Management of AHFS is challenging given the heterogeneity of the patient population, absence of a universally accepted definition, incomplete understanding of its pathophysiology, and lack of robust evidence-based guidelines. The majority of patients appear to respond well to initial therapies consisting of loop diuretics and vasoactive agents (5–7). However, post-discharge mortality and rehospitalization rates reach 10% to 20% and 20% to 30%, respectively, within 3 to 6 months (6,8). Although this may reflect the severity of HF, myocardial injury and/or renal impairment occurring in AHFS may contribute to this grim prognosis. Improving post-discharge mortality and prevention of readmissions are the most important goals in AHFS.

This review reflects concepts developed by the International Working Group on AHFS that met annually for the last 5 years, composed of cardiologists, hospitalists, emergency physicians, industry, and governmental agencies (5).

	Definitions

Top Abstract Definitions Patient Characteristics Clinical Classification Pathophysiology Prognostic Factors Evaluation Phases of AHFS... Transitioning From Acute to... Early Pharmacologic Management Clinical Trials in AHFS Conclusions References

 
AHFS can be defined as new onset or gradual or rapidly worsening HF signs and symptoms requiring urgent therapy (5). Irrespective of the underlying cause (e.g., ischemic event) or precipitant (e.g., severe hypertension), pulmonary and systemic congestion due to elevated ventricular filling pressures with or without a decrease in cardiac output is a nearly universal finding in AHFS (5). Coronary artery disease (CAD), hypertension, valvular heart disease, and/or atrial fibrillation, as well as noncardiac conditions such as renal dysfunction, diabetes, anemia, and medications (i.e., nonsteroidal anti-inflammatory drugs, glitazones), may also contribute to these abnormalities (5,9–11). The majority of AHFS patients have worsening chronic HF; after initial management resulting in stabilization, they should no longer be considered acute but chronic HF (11).

	Patient Characteristics

Top Abstract Definitions Patient Characteristics Clinical Classification Pathophysiology Prognostic Factors Evaluation Phases of AHFS... Transitioning From Acute to... Early Pharmacologic Management Clinical Trials in AHFS Conclusions References

 
Heart failure afflicts over 5 million Americans and 15 million Europeans (3,11–13). The cost in the U.S. is over 34 billion dollars per year, mainly related to hospitalizations, with similar financial burdens for many European countries (3,11–13). Over 1 million hospital discharges for HF occurred in 2005 in the U.S., an increase of 171% compared with discharges in 1979 (12). Approximately 3.8 million hospital diagnoses of HF occurred in 2004 (3). Between 1992 and 2001, there were 10.5 million U.S. emergency department visits for AHFS, with an average increase of 18,500 visits each year (4). AHFS resulting in hospitalization is the most common diagnosis-related group for Medicare patients and in total, the most expensive (3,12–14). Only recently, AHFS registries from Europe and the U.S. provided us with an accurate characterization and prognosis of these patients (6,7,9,10,15–20). However, less is known from other geographical regions.

Patient characteristics.   The majority of AHFS patients have worsening chronic HF resulting in hospitalization, with the remaining 15% to 20% diagnosed with HF for the first time. The mean age is 75 years and over one-half are women. Dyspnea and signs of congestion manifested by jugular venous distention and edema are common (9,15,21). At presentation, approximately 25% of patients are hypertensive (systolic blood pressure [SBP] >160 mm Hg), <10% are hypotensive, most are taking diuretics, 40% take angiotensin-converting enzyme (ACE) inhibitors, 10% take angiotensin-receptor blockers, 50% take beta-blockers, and 20% to 30% take digoxin (9,18,21). A history of CAD is present in 60%, hypertension in 70%, diabetes in 40%, atrial fibrillation in 30%, and moderate to severe renal impairment in 20% to 30% (22).

Approximately 50% of AHFS patients have a relatively preserved systolic function (PSF) (6,7,9,15,23). They are older and more likely to be female. They are also more likely to have a history of hypertension and atrial arrhythmias, and present with severe hypertension (6,7,23) (Table 1).

Clinical course.   Most patients have rapid symptomatic improvement with loop diuretics and have a relatively short hospital stay (4,9,15,18). Although systemic and pulmonary congestion is the main reason for hospitalization, many do not have a decrease in BW during hospitalization and are often discharged with HF signs and/or symptoms (7,28,29). Often a comprehensive assessment is not performed (e.g., cardiac catheterization, assessment for viable, but dysfunctional myocardium). This may result in underutilization of evidence-based therapies (5,28,30,31). In patients admitted with worsening chronic HF, except for diuretic dose escalation, introduction of new or up-titration of evidence-based therapies (e.g., ACE inhibitors, beta-blockers) is <5% to 10%. In fact, they are often discharged on the same pre-admission medications (8,15,32).

The mean length of stay in the U.S. is 6 days (median: 4 days) (9,18). In-hospital mortality (2% to 4%) may reach 20% for those patients with severe renal impairment and low SBP. However, this group represents <2% to 5% of the overall AHFS population (6). Post-discharge mortality varies at 60 to 90 days from 5% to 15% depending on BP at presentation (the higher the BP, the lower the mortality). The readmission rate is approximately 30%, independent of SBP at presentation (21). Risk for these events is highest in the first few months following discharge (2,31). Recent data suggests an association between early events and worsening symptoms, renal function, and neurohormonal profile during the first few weeks after discharge (33). Among patients admitted with chronic HF and low ejection fraction (EF), approximately 40% will die from progressive HF and 30% will die suddenly and unexpectedly post-discharge (31). Approximately 50% of readmissions are not related to HF. Early post-discharge events in PSF patients appear similar to those with reduced EF, although the mode of death and reason for rehospitalization has not been studied in these patients (6). It is possible that a significant number of morbid events in the AHFS/PSF population are related to coexisting cardiac or noncardiac comorbidities, such as CAD, hypertension, atrial fibrillation, renal insufficiency, or stroke (34,35).

	Clinical Classification

Top Abstract Definitions Patient Characteristics Clinical Classification Pathophysiology Prognostic Factors Evaluation Phases of AHFS... Transitioning From Acute to... Early Pharmacologic Management Clinical Trials in AHFS Conclusions References

 
Patients may be classified into HF presenting for the first time (de novo) or worsening chronic HF (5) (Fig. 1). In both groups, the presence and extent of CAD may determine the initial, in-hospital, and post-discharge management (36). The EF may influence post-discharge rather than initial management, which should be based on the presenting clinical profile. Of the approximately 80% of AHFS patients with chronic HF resulting in hospitalization, <5% to 10% have advanced HF. Low blood pressure, renal impairment, and/or signs and symptoms refractory to standard therapy characterize advanced HF. De novo HF represents the remainder of AHFS and may be further divided into those with pre-existing risk for HF (e.g., hypertension, CAD) without evidence of prior LV dysfunction or structural abnormalities and those with pre-existing cardiac structural abnormalities (e.g., reduced EF) (13).

View larger version (31K): [in this window] [in a new window] [Download PPT slide]   Figure 1 General Clinical Classification Broad general classification proposed for AHFS patients representing key factors that may influence management. *Advanced HF is a subset of chronic HF. With or without acute coronary syndromes. Figure illustration by Rob Flewell. CAD = coronary artery disease; EF = ejection fraction; HF = heart failure.

	Pathophysiology

Top Abstract Definitions Patient Characteristics Clinical Classification Pathophysiology Prognostic Factors Evaluation Phases of AHFS... Transitioning From Acute to... Early Pharmacologic Management Clinical Trials in AHFS Conclusions References

Congestion.   High LV diastolic pressure resulting in pulmonary and systemic congestion with or without low cardiac output is the main reason for presentation in the majority of patients (5,9,24,37,43,44). Pulmonary congestion may be defined as pulmonary venous hypertension (increased pulmonary capillary wedge pressure [PCWP]) often resulting in pulmonary interstitial and alveolar edema. Systemic congestion manifests clinically by jugular venous distention with or without peripheral edema and gradual increases in BW are often seen (11) (Table 2). Occasionally, severe pulmonary congestion develops abruptly when precipitated by a rapid increase in BP (afterload), particularly in patients with diastolic dysfunction (45–48). Renal impairment, severe neurohormonal or endothelial abnormalities, dietary indiscretion, and certain medications such as nonsteroidal anti-inflammatory drugs, glitazones, and first generation calcium-channel blockers, may also contribute to fluid overload (5,27,49–52).

Body weight is often used as a marker of congestion in both inpatient and outpatient settings. However, recent data suggest a more complex relationship among BW, congestion, and outcomes. Although an increase in BW predicts hospitalization (26,33), a reduction in BW in response to different therapies may not necessarily result in decreased hospitalization or mortality. For example, vasopressin antagonists and non–potassium-sparing diuretics appear to decrease BW effectively, however, their use has not always been associated with an improvement in mortality or rehospitalization (60,61).

Myocardial injury.   Troponin release often occurs in AHFS, particularly in patients with CAD (14,62,63). This likely reflects myocardial injury, which may be related to hemodynamic and/or neurohormonal abnormalities or the result of an ischemic event (MI). Injury may also be the consequence of a high LV diastolic pressure, further activation of neurohormones, and/or inotropic stimulation, resulting in a supply and demand mismatch (increased myocardial oxygen demand and decreased coronary perfusion) (38). These conditions may precipitate injury, particularly in patients with CAD, who often have hibernating and/or ischemic myocardium (36). This is supported by experimental data in dogs where stimulation of hibernating myocardium with low-dose dobutamine resulted in myocardial necrosis (64). The importance of myocardial injury in AHFS has not been well studied and remains an area of investigation.

Renal impairment.   In AHFS, renal abnormalities promote sodium and water retention (59). Structural renal dysfunction due to diabetes, hypertension, and arteriosclerosis, are common. Worsening renal function occurs in 20% to 30% of patients during hospitalization (65,66). Recent data suggests that approximately 20% of patients have worsening renal function soon after discharge (67). This worsening during or after discharge may result from further neurohormonal and hemodynamic abnormalities (low cardiac output and/or high venous pressure), which may be aggravated by high-dose loop diuretics (56–59,66,68) (Fig. 2). Renal dysfunction resulting from neurohormonal or hemodynamic abnormalities (vasomotor nephropathy) may be preventable or reversible and it is often referred as the cardio-renal syndrome. In a given patient, distinguishing between vasomotor nephropathy from abnormalities related to intrinsic kidney disease is often difficult and remains an important area for research.

View larger version (36K): [in this window] [in a new window] [Download PPT slide]   Figure 2 The Cardio-Renal Syndrome Both intrinsic/pre-existing structural kidney disease and potential contributors to renal injury from acute heart failure (HF) syndromes characterize the cardio-renal syndrome. Figure illustration by Rob Flewell.

Dobutamine, milrinone, and levosimendan improve hemodynamics; however, these effects may be associated with increased myocardial oxygen consumption (tachycardia and increased contractility) and hypotension due to their vasodilatory effects (71,72). Decreasing coronary perfusion due to hypotension in the presence of increased myocardial oxygen demand may result in myocardial injury, particularly in patients with CAD who often have ischemic or hibernating myocardium (38).

Hypotension associated with the use of vasodilators may also result in myocardial and renal hypoperfusion and possibly injury (38,40–42,73).

	Prognostic Factors

Top Abstract Definitions Patient Characteristics Clinical Classification Pathophysiology Prognostic Factors Evaluation Phases of AHFS... Transitioning From Acute to... Early Pharmacologic Management Clinical Trials in AHFS Conclusions References

 
Recent clinical trials and observational studies have identified emerging prognostic factors in patients admitted with AHFS (74–83) (Table 3).

CAD.   Patients with AHFS and CAD often have a worse prognosis than other patients. This may be related to the extent and severity of CAD but also to the presence of other comorbidities that are more common in these patients (36). Hibernating and/or ischemic myocardium is a therapeutic target for medical therapy and/or revascularization (36) (Fig. 3). Unstable angina appears to be an important cause for hospitalization in patients with chronic HF and PSF (84).

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 3 Assessment and Targeted Implementation of Evidence-Based Therapy in AHFS Chart recommends assessment methods and ways to implement therapy. *Select patients; **investigational agents. ACC = American College of Cardiology; ACE-I = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; AHA = American Heart Association; ARB = angiotensin receptor blocker; CRT = chronic resynchronization therapy; Dor procedure = ventricular reconstructive surgery to restore aneurysmal left ventricle to its normal, elliptical shape; ECHO = echocardiography; ICD = implantable cardiac-defibrillator; ISDN = isosorbide dinitrate; LV = left ventricle; MAZE = Cox maze procedure to eliminate atrial fibrillation; MR = mitral valve regurgitation; MRI = magnetic resonance imaging; other abbreviations as in Figure 1.

Arrhythmias.   New sustained ventricular or atrial arrhythmias developing during hospitalization are uncommon; however, when present, they predict an increase in post-discharge mortality (86).

Renal impairment.   Renal impairment is often present at time of admission (22). Approximately 30% of patients with AHFS have worsening renal function during hospitalization (87,88). Markers of renal impairment, either blood urea nitrogen, Cr, blood urea nitrogen/Cr ratio, estimated glomerular filtration rate, and/or cystatin C all have important prognostic significance (22,66,87–93). Emerging data suggests that an increase in blood urea nitrogen during the early post-discharge period is 1 of the most important predictors of early mortality (33,67).

Hyponatremia.   Mild hyponatremia occurs in 25% of patients with AHFS, irrespective of systolic function, and usually remains uncorrected during hospitalization (30,94,95). These hyponatremic patients have the same hemodynamic and clinical response as those with normonatremia, yet demonstrate a significantly greater risk of death post-discharge (95). Although vasopressin antagonists (e.g., tolvaptan and conivaptan) effectively correct hyponatremia, their use has not been associated with improved outcomes (43,60,96).

Other prognostic factors.   Troponin release, elevated natriuretic peptide levels, elevated PCWP, liver disease, anemia, severe symptoms, older age, and increased heart rate appear to be markers of increased post-discharge mortality risk (62,63,74,97–103). In contrast, the use of beta-blockers, aldosterone antagonists, and ACE inhibitors is associated with an improved prognosis (6). Recently, cardiac catheterization has been associated with improvement in post-discharge outcomes. This improvement was related to implementation of evidence-based therapy for CAD during hospitalization (105).

	Evaluation Phases of AHFS Patients

Top Abstract Definitions Patient Characteristics Clinical Classification Pathophysiology Prognostic Factors Evaluation Phases of AHFS... Transitioning From Acute to... Early Pharmacologic Management Clinical Trials in AHFS Conclusions References

 
Four phases of hospital evaluation and management of AHFS are proposed: 1) initial or early phase (i.e., emergency department); 2) in-hospital phase; 3) pre-discharge phase; and 4) early post-discharge phase (5).

Early phase.   This phase of AHFS management typically takes place in the emergency department, where 80% of all hospitalized patients initially present (15,16,18). Evaluation and management often proceeds concomitantly (Table 4). After stabilization/treatment of life-threatening conditions, improving hemodynamics and symptoms are key goals. Abnormal hemodynamics often results from conditions such as hypertension, ischemia, and/or arrhythmias. These conditions, as well as any other precipitants of HF, should be treated for optimal results.

Clinical profiles at presentation.   Initial management should be based on clinical profiles (Table 5). The presence and severity of underlying CAD may affect early management decisions, because these patients may require additional therapies or may be adversely affected by other therapies (e.g., inotropes) (39).

In-hospital phase.   Further improvement of signs and symptoms, achieving euvolemia, and targeted initiation and/or up-titration of evidence-based therapies for chronic HF based on a comprehensive assessment are the goals of this phase (11,13,48,111). Monitoring for potential cardiac injury and renal function is important. The role of serial B-type natriuretic peptide (BNP)/N-terminal pro-BNP measurements in this setting remains to be determined.

Because dissociation between clinical (dyspnea, edema) and hemodynamic congestion (high LVFP) may be present after initial therapy, assessment of filling pressures is important. Measurement of jugular venous pressure, if done properly, is an important bedside measurement of right atrial pressure (112,113). This is particularly important because high right atrial pressure is a sign of elevated left-sided pressure. Orthostatic BP changes and the response during Valsalva maneuver or sublingual nitroglycerin may aid in assessment of LVFP (24,113). Routine pulmonary artery line-guided therapy in patients with severe HF does not result in improved outcomes (114). However, a pulmonary artery line may be considered for refractory signs and symptoms, particularly in the presence of worsening renal function. The level of BNP/N-terminal pro-BNP has also been proposed as a "measure" of congestion. A tailored approach with evidence-based therapy in response to BNP levels in chronic HF was associated with better outcomes in the outpatient setting (115). This approach remains to be investigated in AHFS. Currently, evidence and/or guidelines to assess congestion during hospitalization or pre-discharge are not well established.

Refractory or advanced HF should be managed according to published guidelines (13,111,116). Thromboembolic events and myocardial ischemia should be considered in patients not responding to standard therapy.

A thorough assessment to ensure implementation of evidence-based guidelines (pharmacological, surgical, interventional, and implantable cardiac-defibrillator/CRT) should occur during this phase or soon after discharge (Fig. 3). The ADHERE (Acute Decompensated National Heart Failure Registry) and OPTIMIZE-HF (Organized Program to Initiate Life-Saving Treatment in Hospitalized Patients with Heart Failure) registries demonstrated the relative paucity of comprehensive assessment (6,28). Hospitalization presents opportunities to optimize management, given the resources available in-hospital versus outpatient. The traditional focus during hospitalization has been on alleviating congestion (e.g., improving symptoms and decreased BW), rather than optimization of therapies known to improve outcomes in patients (37,117). Appropriate management of comorbidities (e.g., CAD, atrial fibrillation, hypertension, diabetes mellitus) based on evidence-based guidelines may also improve post-discharge outcomes (35).

Of current HF quality measures (ACE inhibitor/angiotensin receptor blocker [ARB], anticoagulant at discharge for HF patients with atrial fibrillation, assessment of EF, smoking cessation, and adequate discharge instructions), only ACE inhibitor/ARB has been shown to improve outcomes in AHFS (8,118,119). It is doubtful that those measures alone will have a significant impact on post-discharge outcomes, given the complex pathophysiology and heterogeneity of this patient population. Implementation of evidence-based therapies (pharmacological, electrical devices, and surgical) based on comprehensive assessment may improve outcomes (13,120–125) (Fig. 3). This important hypothesis remains to be tested.

Pre-discharge phase.   Goals at discharge: 1) improve signs and symptoms; 2) appropriate management of precipitants; 3) euvolemia with successful transition to oral diuretics; 4) implementation or planned implementation of current HF guidelines; and 5) post-discharge planning and education involving patients and family have been established, with clear instruction regarding weight monitoring, medications, and telephone and clinic follow-up. Formal assessment of functional capacity (e.g., 6-min walk test) before discharge has not been well studied, and this may not be feasible or specific in many older patients.

Discharge criteria, which account for the heterogeneity of the patient population and incorporate different strategies of care, should be developed. Strategies for discharge after complete resolution of signs and symptoms compared with earlier discharge with residual symptoms and close follow-up for further optimization should be studied.

Early post-discharge phase ("vulnerable" phase).   Recent data demonstrates deterioration in signs and symptoms, neurohormonal profile, and renal function during the first few weeks after discharge in patients who die or are rehospitalized within 60 to 90 days (33). This deterioration occurs despite standard therapy, including beta-blockers, ACE inhibitors, or ARB, and often aldosterone-blocking agents (33). Assessment of these variables in the early post-discharge period may provide unique opportunities to further optimize standard therapy (up-titration) and/or introduce additional therapy known to improve outcomes (e.g., hydralazine/nitrates, aldosterone-blocking agents, CRT). In addition, the use of novel intravenous therapies (126,127) that are known to improve hemodynamics or to preserve myocardial and renal function should be studied in this vulnerable period.

	Transitioning From Acute to Chronic HF

Top Abstract Definitions Patient Characteristics Clinical Classification Pathophysiology Prognostic Factors Evaluation Phases of AHFS... Transitioning From Acute to... Early Pharmacologic Management Clinical Trials in AHFS Conclusions References

 
Approximately 80% of patients hospitalized with worsening HF have chronic HF. For the vast majority who stabilize after initial management, they should be considered as chronic HF and be treated according to published guidelines (11,13,48,111,116,120,123–125,128–130).

Available data highlight gaps in utilization/optimization of evidence-based therapies, such as beta-blockers, ACE inhibitors, aldosterone-blocking agents, ARB, and electrical devices (5,8,11,17,28,128,131). Recent analysis from the GWTG-HF (Get With the Guidelines–Heart Failure) database showed variations by age, race, geographic region, and comorbidities on CRT uptake as well as differences between clinical trials and guideline recommendations (131). Initiation or up-titration of evidence-based chronic HF therapies during hospitalization or soon after, absent contraindications, will likely improve post-discharge event rates (128).

	Early Pharmacologic Management

Top Abstract Definitions Patient Characteristics Clinical Classification Pathophysiology Prognostic Factors Evaluation Phases of AHFS... Transitioning From Acute to... Early Pharmacologic Management Clinical Trials in AHFS Conclusions References

 
Pharmacologic therapies have been reviewed extensively elsewhere (126,127,132,133). Dyspnea, along with other symptoms and signs of AHFS, require urgent attention upon presentation. In this setting, dyspnea is related to high PCWP. The increase of PCWP may be the result of different pathophysiological processes (e.g., hypertension, ischemia, arrhythmias, valvular disease), which often require specific therapies. Precipitants (e.g., dietary indiscretion, pneumonia, pulmonary embolism) may aggravate or worsen the clinical profile and need to be taken into consideration and treated.

Fluid removal.   Loop diuretics are the mainstay of therapy in AHFS and effectively relieve symptoms. Continuous infusion has been recommended for improved efficacy and for diuretic-resistant patients (11). Combination therapy with thiazide diuretics may also be considered (11,134). It is prudent, however, not to rely totally on diuretics for fluid removal, as many patients are left with signs of HF despite symptomatic improvement. The addition of vasodilators and/or digoxin should be considered (46,135). The clinical value of new or emerging therapies for fluid removal, such as ultrafiltration, vasopressin antagonists, and/or adenosine-blocking agents, remains to be determined.

In spite of their clinical benefits, non–potassium-sparing diuretics may cause further neurohormonal and renal abnormalities (61,68). The potential negative effects of non–potassium-sparing diuretics, as well as the optimal dose and duration, however, have not been well studied and are currently being investigated in a large National Heart, Lung, and Blood Institutes trial (DOSE-AHF [Diuretic Optimal Strategy Evaluation in Acute Heart Failure] study) (136).

Aldosterone-blocking agents may be particularly useful in patients with AHFS, because the majority of patients have evidence of right-sided failure, often resulting in liver congestion. This is often associated with increased serum concentrations of aldosterone despite standard therapies (e.g., ACE inhibitor) (33). Accordingly, both their neurohormonal and diuretic effects (with higher doses) may be of benefit. However, use of aldosterone-blocking agents in AHFS has not been studied.

Ultrafiltration
Ultrafiltration effectively removes fluid, reduces BW without improving dyspnea, and is associated with a decrease in readmission rates (137). These promising results need to be confirmed in a larger clinical trial.

Vasopressin Antagonists
Tolvaptan, a vasopressin-2 antagonist, when added to standard therapy in patients admitted with worsening chronic HF and reduced EF modestly improves hemodynamics, signs, and symptoms (e.g., BW, dyspnea) and normalizes serum sodium in hyponatremic patients (43,107,138). Continuation of fixed doses of tolvaptan after discharge decreased neither mortality nor readmission rates, in spite of a reduction in BW when compared with standard therapies (60,107). Conivaptan, a vasopressin-1 and -2 antagonist, has been approved by the Food and Drug Administration only for treatment of hyponatremia. Although it has a similar hemodynamic profile when compared with tolvaptan, it does not improve signs and symptoms in patients admitted with HF (138,139). The role of vasopressin antagonists in the management of AHFS remains to be determined.

Adenosine Antagonists
Adenosine antagonists induce diuresis via inhibition of sodium absorption in the proximal tubule, block tubuloglomerular feedback, and therefore preserve or increase glomerular filtration rate in HF (126,127,140–144). The PROTECT (Effects of Rolofylline, a New Adenosine A1 Receptor Antagonist, on Symptoms, Renal Function, and Outcomes in Patients With Acute Heart Failure) pilot trial suggested that rolofylline, a selective A1 receptor antagonist, may improve symptoms and post-discharge outcomes, and is now being tested in a large outcome trial (145).

Pre-load and afterload reducers.   Nitroglycerin
Nitroglycerin reduces LVFP, but its effects on clinical outcomes have not been well studied, although small studies suggest benefit (106,146). It may be particularly useful in patients with AHFS and underlying CAD or acute coronary syndrome complicated by HF.

Nitroprusside
Nitroprusside is a powerful systemic vasodilator, usually requires hemodynamic monitoring, and appears useful in patients with advanced HF (147). However, retrospective analysis demonstrated increased mortality when used early in patients with acute MI complicated by severe HF, even when hemodynamics were monitored with a pulmonary artery catheter (40). The safety and efficacy of nitroprusside in AHFS has not been well studied.

Nesiritide
Nesiritide was approved for the treatment of AHFS in the U.S. in 2001, but not in Europe. It improves hemodynamics and dyspnea (109). Retrospective data raised the hypothesis that it may worsen renal function and increase post-discharge mortality (41,42). The safety and efficacy of nesiritide is being tested in a large international trial (ASCEND-HF [Double-Blind, Placebo-Controlled, Multicenter Acute Study of Clinical Effectiveness of Nesiritide in Subjects With Decompensated Heart Failure] trial) (148).

Intravenous Ace Inhibitors
The American College of Emergency Physicians guidelines support the use of intravenous ACE inhibitors for initial AHFS therapy, although as a Level C recommendation, while European Society of Cardiology guidelines do not support their use (11,48,149). Intravenous enalaprilat may adversely affect outcomes when used early in patients with acute MI (73). The role of IV ACE inhibitors remains to be determined.

Relaxin
Relaxin, an investigational vasodilator identical to the native human neurohormone, appears in animal and pilot clinical studies to be a potent vasodilator (150). It is currently being investigated in AHFS patients.

Ularitide
Ularitide, a natriuretic peptide composed of 32 amino acid residues originally isolated from human urine, has been evaluated in an early clinical trial (151,152). It improves hemodynamics and signs and symptoms, without worsening renal function when compared with placebo treatment. Severe hypotension, however, occurred at higher doses (151,152).

Inotropes.   Inotropes with vasodilatory properties, such as dobutamine, milrinone, and levosimendan (available in Europe) are known to improve hemodynamics (71,72,110). Short-term use of IV milrinone without a bolus, when added to standard therapy, does not improve signs and symptoms, or reduce the total number of hospital days, and was associated with severe hypotension and arrhythmias (71). In retrospect, it appeared to increase post-discharge mortality in patients with CAD (39). These findings raised the hypothesis that short-term administration of drugs may affect post-discharge outcomes, possibly by causing myocardial injury due to decreased perfusion and/or increased myocardial oxygen demand, particularly in patients with CAD who may have ischemic and/or hibernating myocardium (38).

In AHFS, the short-term use of levosimendan improved symptoms and reduced the need for cointervention for worsening HF; however, it was associated with significant side effects (hypotension, ventricular tachycardia) and a trend toward increased early mortality (110). In patients admitted with very severe HF, levosimendan was not superior to dobutamine in terms of post-discharge mortality that was very high in both groups (72). In general, inotropes with vasodilator properties should be reserved for those patients with a low output state, defined as low BP with sign of organ hypoperfusion, who do not respond to other therapies (13,111,116).

Digoxin (IV)
Digoxin improves hemodynamics in HF without activating neurohormones or negatively affecting heart rate, BP, or renal function (135,153,154). These effects are seen when used alone or in combination with other vasoactive agents, including ACE inhibitors (135,153). Its chronic use has been shown to decrease hospitalization when added to a diuretic and ACE inhibitor (155). Although IV digoxin has all the properties of an ideal agent in AHFS, its effects in AHFS in patients with or without AF have not been studied (135).

Istaroxime
Istaroxime, an investigational inotrope with lusitropic properties, improves hemodynamics. In contrast to current inotropes, it increases SBP and decreases heart rate in AHFS (156). This agent appears promising for patients presenting in a low-output state, manifested by a low BP (157). It is currently being tested in a larger clinical trial.

Cardiac Myosin Activators
Cardiac myosin activators, in the early stages of clinical investigation, target myocardial myosin adenosine triphosphatase, generating force to improve contractility without changing intracellular concentrations of calcium (126,127). This molecule is currently undergoing further investigation in clinical trials (158,159).

Other therapies.   A number of other treatments are commonly given, although randomized clinical trial data are lacking. These therapies include morphine and oxygen supplementation. The use of morphine in the ADHERE registry retrospectively points toward an association between morphine and worse outcomes (160). Noninvasive ventilation relieves dyspnea in AHFS (161). Although its use has been associated with decreased resource utilization and mortality, in the largest noninvasive ventilation trial to date, no mortality benefit was seen over oxygen for either continuous or bilevel noninvasive ventilation (161,162). However, this trial was not stratified by severity of presenting illness (161). Adenosine-regulating agents are an emerging therapy aimed to enhance endogenous adenosine-mediated cardioprotective mechanisms (163). Soluble guanylate cyclase activators represent another emerging therapy; early data suggest beneficial arterial and venous vasodilatory effects (164). Direct renin inhibitors will be explored in AHFS in the ASTRONAUT (Aliskerin Trial on Acute Heart Failure Outcomes) trial.

	Clinical Trials in AHFS

Top Abstract Definitions Patient Characteristics Clinical Classification Pathophysiology Prognostic Factors Evaluation Phases of AHFS... Transitioning From Acute to... Early Pharmacologic Management Clinical Trials in AHFS Conclusions References

 
Overall, clinical trial results have disappointed in terms of efficacy and/or safety (41,42,60,71,72,107–109). In the last 15 years, only nesiritide has been approved for the treatment of AHFS; however, post-approval questions of safety arose (41,42). These disappointing results may have been related to the drug itself, failure to target the appropriate pathophysiologic process, patient selection, and/or end points chosen. For the majority of agents being studied in AHFS, gaps in our knowledge exist (Table 6). In addition, demonstration of early symptomatic benefit beyond that of standard therapy alone is difficult given the significant beneficial response to available therapies (107–109). A reassessment of how to conduct clinical trials in AHFS is being investigated (5,165).

Improving post-discharge outcomes is the most important goal in AHFS; as such, future clinical trials should address this issue. At the same time, both patients and physicians desire therapies that improve signs, symptoms, and/or quality of life, assuming an acceptable safety profile. Expecting therapies used for 48 h to improve outcomes at 2 to 6 months in a complex, heterogeneous substrate such as HF may set the bar too high. This may negatively affect research of therapies that may safely improve patient reported outcomes (e.g., dyspnea). Another consideration would be to create a novel end point, emphasizing the importance of bridging to evidence-based therapies. For example, in-hospital therapy with an investigational agent, which improves hemodynamics and symptoms, protects or preserves the heart and/or kidneys, has a strong safety profile, and improves uptake of known life-saving therapies (e.g., ACE inhibitors, beta-blockers), might represent an excellent short-term goal. Subsequently, this may result in improved post-discharge outcomes.

A significant number of patients with early events have worsening hemodynamics and neurohormonal and renal abnormalities in the first few weeks after discharge. Accordingly, early intervention during this vulnerable phase with intravenous (e.g., adenosine-blocking agents, guanylate cyclase activators, natriuretic peptides) or oral (e.g., vasopressin antagonists, renin inhibitors) and/or other therapeutic interventions (e.g., CRT, ultrafiltration) should be explored in future clinical trials. Novel applications of existing therapies (e.g., aldosterone-blocking agents, digoxin) should also be explored during this phase.

The present model of clinical development programs follows a stepwise progression, from in vitro to animal modeling to first-in-human into clinical trials. Given the still-limited understanding of the pathophysiology of AHFS, a "bidirectional" research approach may be in order. For example, during early clinical studies, new hypotheses may emerge; in partnership with scientists, novel therapies would go back to animal models to try to answer these questions for both efficacy and safety, which would then lay the foundation for clinical studies.

	Conclusions

Top Abstract Definitions Patient Characteristics Clinical Classification Pathophysiology Prognostic Factors Evaluation Phases of AHFS... Transitioning From Acute to... Early Pharmacologic Management Clinical Trials in AHFS Conclusions References

 
Hospitalization for AHFS represents a significant and growing health care burden. Heterogeneity characterizes this group in terms of mode of presentation, pathophysiology, and prognosis. The vast majority of patients symptomatically improve during hospitalization; however, their early post-discharge rehospitalization and mortality rates continue to be extremely high. Worsening signs and symptoms and neurohormonal and renal abnormalities occurring soon after discharge may contribute to these high post-discharge event rates. Currently available assessment modalities combined with recent advances in cardiovascular therapies provide present-day opportunities to improve post-discharge outcomes. Further investigation into pathophysiologic targets and novel approaches to clinical trial design are needed. Improving post-discharge outcomes is the most important goal in the management of AHFS.

	Footnotes

 
Dr. Gheorghiade is or has been a consultant for and/or received honoraria from Abbott, Astellas, Bayer, AstraZeneca, Corthera, Debiopharm, Errekappa Terapeutici, EKR Therapeutics, GlaxoSmithKline, Johnson & Johnson, Medtronic, Merck, Nile, Novartis, Otsuka, PeriCor, PDL BioPharma, Scios Inc., Solvay Pharmaceuticals, and Sigma-Tau. Dr. Pang is a consultant for Astellas, Bayer, the Medicines Company, Otsuka, Nile, PDL BioPharma, PeriCor Therapeutics, and Solvay Pharmaceuticals; has received honoraria from Biogen Idec, Corthera, EKR Therapeutics, and Palatin Technologies; and has received research support from Corthera and PDL BioPharma.

	References

Top Abstract Definitions Patient Characteristics Clinical Classification Pathophysiology Prognostic Factors Evaluation Phases of AHFS... Transitioning From Acute to... Early Pharmacologic Management Clinical Trials in AHFS Conclusions References

 
1. Ahmed A, Allman RM, Fonarow GC, et al. Incident heart failure hospitalization and subsequent mortality in chronic heart failure: a propensity-matched study J Card Fail 2008;14:211-218.[CrossRef][Web of Science][Medline]

2. Solomon SD, Dobson J, Pocock S, et al. Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure Circulation 2007;116:1482-1487.[Abstract/Free Full Text]

3. Fang J, Mensah GA, Croft JB, Keenan NL. Heart failure-related hospitalization in the U.S., 1979 to 2004 J Am Coll Cardiol 2008;52:428-434.[Abstract/Free Full Text]

4. Hugli O, Braun JE, Kim S, Pelletier AJ, Camargo Jr CA. United States emergency department visits for acute decompensated heart failure, 1992 to 2001 Am J Cardiol 2005;96:1537-1542.[CrossRef][Web of Science][Medline]

5. Gheorghiade M, Zannad F, Sopko G, et al. Acute heart failure syndromes: current state and framework for future research Circulation 2005;112:3958-3968.[Free Full Text]

6. Fonarow GC, Stough WG, Abraham WT, et al. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry J Am Coll Cardiol 2007;50:768-777.[Abstract/Free Full Text]

7. Yancy CW, Lopatin M, Stevenson LW, De Marco T, Fonarow GC. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) database J Am Coll Cardiol 2006;47:76-84.[Abstract/Free Full Text]

8. Fonarow GC, Abraham WT, Albert NM, et al. Association between performance measures and clinical outcomes for patients hospitalized with heart failure JAMA 2007;297:61-70.[Abstract/Free Full Text]

9. Adams Jr. KF, Fonarow GC, Emerman CL, et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE) Am Heart J 2005;149:209-216.[CrossRef][Web of Science][Medline]

10. Cleland JG, Swedberg K, Follath F, et al. The EuroHeart Failure survey programme—a survey on the quality of care among patients with heart failure in Europe. Part 1: patient characteristics and diagnosis. Eur Heart J 2003;24:442-463.[Abstract/Free Full Text]

11. Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J 2008;29:2388-2442.[Free Full Text]

12. Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee Circulation 2008;117:e25-e146.[Free Full Text]

13. Hunt SA. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure) J Am Coll Cardiol 2005;46:e1-e82.[Free Full Text]

14. Peacock 4th WF, De Marco T, Fonarow GC, et al. Cardiac troponin and outcome in acute heart failure N Engl J Med 2008;358:2117-2126.[CrossRef][Medline]

15. ADHERE Scientific Advisory Committee Acute Decompensated Heart Failure National Registry (ADHERE) Core Module Q1 2006 Final Cumulative National Benchmark ReportScios, Inc; 2006.

16. Fonarow GC. The Acute Decompensated Heart Failure National Registry (ADHERE): opportunities to improve care of patients hospitalized with acute decompensated heart failure Rev Cardiovasc Med 2003;4(Suppl 7):S21-S30.

17. Fonarow GC, Abraham WT, Albert NM, et al. Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF): rationale and design Am Heart J 2004;148:43-51.[CrossRef][Web of Science][Medline]

18. Fonarow GC, Heywood JT, Heidenreich PA, Lopatin M, Yancy CW. Temporal trends in clinical characteristics, treatments, and outcomes for heart failure hospitalizations, 2002 to 2004: findings from Acute Decompensated Heart Failure National Registry (ADHERE) Am Heart J 2007;153:1021-1028.[CrossRef][Web of Science][Medline]

19. Nieminen MS, Brutsaert D, Dickstein K, et al. EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population Eur Heart J 2006;27:2725-2736.[Abstract/Free Full Text]

20. Siirila-Waris K, Lassus J, Melin J, Peuhkurinen K, Nieminen MS, Harjola VP. Characteristics, outcomes, and predictors of 1-year mortality in patients hospitalized for acute heart failure Eur Heart J 2006;27:3011-3017.[Abstract/Free Full Text]

21. Gheorghiade M, Abraham WT, Albert NM, et al. Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure JAMA 2006;296:2217-2226.[Abstract/Free Full Text]

22. Heywood JT, Fonarow GC, Costanzo MR, Mathur VS, Wigneswaran JR, Wynne J. High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database J Card Fail 2007;13:422-430.[CrossRef][Medline]

23. Sweitzer NK, Lopatin M, Yancy CW, Mills RM, Stevenson LW. Comparison of clinical features and outcomes of patients hospitalized with heart failure and normal ejection fraction (> or =55%) versus those with mildly reduced (40% to 55%) and moderately to severely reduced (<40%) fractions Am J Cardiol 2008;101:1151-1156.[CrossRef][Web of Science][Medline]

24. Gheorghiade M, Filippatos G, De Luca L, Burnett J. Congestion in acute heart failure syndromes: an essential target of evaluation and treatment Am J Med 2006;119:S3-S10.[Medline]

25. Adamson PB, Magalski A, Braunschweig F, et al. Ongoing right ventricular hemodynamics in heart failure: clinical value of measurements derived from an implantable monitoring system J Am Coll Cardiol 2003;41:565-571.[Abstract/Free Full Text]

26. Chaudhry SI, Wang Y, Concato J, Gill TM, Krumholz HM. Patterns of weight change preceding hospitalization for heart failure Circulation 2007;116:1549-1554.[Abstract/Free Full Text]

27. Fonarow GC, Abraham WT, Albert NM, et al. Factors identified as precipitating hospital admissions for heart failure and clinical outcomes: findings from OPTIMIZE-HF Arch Intern Med 2008;168:847-854.[Abstract/Free Full Text]

28. Gheorghiade M, Filippatos G. Reassessing treatment of acute heart failure syndromes: the ADHERE registry Eur Heart J 2005;7(Suppl):B13-B19.[CrossRef]

29. Gattis WA, O'Connor CM, Gallup DS, Hasselblad V, Gheorghiade M. Predischarge initiation of carvedilol in patients hospitalized for decompensated heart failure: results of the Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF) trial J Am Coll Cardiol 2004;43:1534-1541.[Abstract/Free Full Text]

30. Gheorghiade M, Abraham WT, Albert NM, et al. Relationship between admission serum sodium concentration and clinical outcomes in patients hospitalized for heart failure: an analysis from the OPTIMIZE-HF registry Eur Heart J 2007;28:980-988.[Abstract/Free Full Text]

31. Wang NC, Maggioni AP, Konstam MA, et al. Clinical implications of QRS duration in patients hospitalized with worsening heart failure and reduced left ventricular ejection fraction JAMA 2008;2992656–6.

32. Blair JA, Zannad F, Konstam MA, et al. Continental differences in clinical characteristics, management and outcomes in patients hospitalized with worsening heart failure: results from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) program J Am Coll Cardiol 2008;52:1640-1648.[Abstract/Free Full Text]

33. Gheorghiade M, Filippatos G, Pang PS, et al. Changes in clinical, neurohormonal, electrolyte, renal, and hepatic profiles during and after hospitalization for acute decompensated heart failure: analysis from the EVEREST trial (late breaking clinical trial). Paper presented at: European Society of Cardiology; September 2, 2008; Munich, Germany.

34. Ahmed A, Rich MW, Fleg JL, et al. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial Circulation 2006;114:397-403.[Abstract/Free Full Text]

35. Shah SJ, Gheorghiade M. Heart failure with preserved ejection fraction: treat now by treating comorbidities JAMA 2008;300:431-433.[Free Full Text]

36. Flaherty JD, Bax JJ, DeLuca L, et al. Acute heart failure syndromes in patients with coronary artery disease: early assessment and treatment J Am Coll Cardiol 2009;53:254-263.[Abstract/Free Full Text]

37. Gheorghiade M, De Luca L, Fonarow GC, Filippatos G, Metra M, Francis GS. Pathophysiologic targets in the early phase of acute heart failure syndromes Am J Cardiol 2005;96:11G-17G.[Web of Science][Medline]

38. Beohar N, Erdogan AK, Lee DC, et al. Acute heart failure syndromes and coronary perfusion J Am Coll Cardiol 2008;52:13-16.[Abstract/Free Full Text]

39. Felker GM, Benza RL, Chandler AB, et al. Heart failure etiology and response to milrinone in decompensated heart failure: results from the OPTIME-CHF study J Am Coll Cardiol 2003;41:997-1003.[Abstract/Free Full Text]

40. Cohn JN, Franciosa JA, Francis GS, et al. Effect of short-term infusion of sodium nitroprusside on mortality rate in acute myocardial infarction complicated by left ventricular failure: results of a Veterans Administration cooperative study N Engl J Med 1982;306:1129-1135.[Web of Science][Medline]

41. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials JAMA 2005;293:1900-1905.[Abstract/Free Full Text]

42. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure Circulation 2005;111:1487-1491.[Abstract/Free Full Text]

43. Gheorghiade M, Gattis WA, O'Connor CM, et al. Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial JAMA 2004;291:1963-1971.[Abstract/Free Full Text]

44. Lucas C, Johnson W, Hamilton MA, et al. Freedom from congestion predicts good survival despite previous class IV symptoms of heart failure Am Heart J 2000;140:840-847.[CrossRef][Web of Science][Medline]

45. Cotter G, Metra M, Milo-Cotter O, Dittrich HC, Gheorghiade M. Fluid overload in acute heart failure—re-distribution and other mechanisms beyond fluid accumulation Eur J Heart Fail 2008;10:165-169.[Abstract/Free Full Text]

46. Cotter G, Felker GM, Adams KF, Milo-Cotter O, O'Connor CM. The pathophysiology of acute heart failure—is it all about fluid accumulation? Am Heart J 2008;155:9-18.[CrossRef][Web of Science][Medline]

47. Cotter G, Moshkovitz Y, Milovanov O, et al. Acute heart failure: a novel approach to its pathogenesis and treatment Eur J Heart Fail 2002;4:227-234.[Abstract/Free Full Text]

48. Nieminen MS, Bohm M, Cowie MR, et al. ESC Committee for Practice Guideline Executive summary of the guidelines on the diagnosis and treatment of acute heart failure: the Task Force on Acute Heart Failure of the European Society of Cardiology Eur Heart J 2005;26:384-416.[Free Full Text]

49. Felker GM, Cotter G. Unraveling the pathophysiology of acute heart failure: an inflammatory proposal Am Heart J 2006;151:765-767.[CrossRef][Web of Science][Medline]

50. Mueller C, Laule-Kilian K, Christ A, Brunner-La Rocca HP, Perruchoud AP. Inflammation and long-term mortality in acute congestive heart failure Am Heart J 2006;151:845-850.[CrossRef][Web of Science][Medline]

51. Colombo PC, Banchs JE, Celaj S, et al. Endothelial cell activation in patients with decompensated heart failure Circulation 2005;111:58-62.[Abstract/Free Full Text]

52. Milo O, Cotter G, Kaluski E, et al. Comparison of inflammatory and neurohormonal activation in cardiogenic pulmonary edema secondary to ischemic versus nonischemic causes Am J Cardiol 2003;92:222-226.[Web of Science][Medline]

53. Kono T, Sabbah HN, Rosman H, Alam M, Jafri S, Goldstein S. Left ventricular shape is the primary determinant of functional mitral regurgitation in heart failure J Am Coll Cardiol 1992;20:1594-1598.[Abstract]

54. Kono T, Sabbah HN, Stein PD, Brymer JF, Khaja F. Left ventricular shape as a determinant of functional mitral regurgitation in patients with severe heart failure secondary to either coronary artery disease or idiopathic dilated cardiomyopathy Am J Cardiol 1991;68:355-359.[CrossRef][Web of Science][Medline]

55. Steimle AE, Stevenson LW, Chelimsky-Fallick C, et al. Sustained hemodynamic efficacy of therapy tailored to reduce filling pressures in survivors with advanced heart failure Circulation 1997;96:1165-1172.[Abstract/Free Full Text]

56. Damman K, Navis G, Smilde TD, et al. Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction Eur J Heart Fail 2007;9:872-878.[Abstract/Free Full Text]

57. Firth JD, Raine AE, Ledingham JG. Raised venous pressure: a direct cause of renal sodium retention in oedema? Lancet 1988;1:1033-1035.[Web of Science][Medline]

58. Mullens W, Abrahams Z, Skouri HN, et al. Elevated intra-abdominal pressure in acute decompensated heart failure: a potential contributor to worsening renal function? J Am Coll Cardiol 2008;51:300-306.[Abstract/Free Full Text]

59. Schrier RW. Blood urea nitrogen and serum creatinine: not married in heart failure Circulation: Heart Fail 2008;1:2-5.[CrossRef]

60. Konstam MA, Gheorghiade M, Burnett Jr. JC, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST outcome trial JAMA 2007;297:1319-1331.[Abstract/Free Full Text]

61. Domanski M, Norman J, Pitt B, Haigney M, Hanlon S, Peyster E. Diuretic use, progressive heart failure, and death in patients in the Studies Of Left Ventricular Dysfunction (SOLVD) J Am Coll Cardiol 2003;42:705-708.[Abstract/Free Full Text]

62. Gheorghiade M, Gattis Stough W, Adams Jr. KF, Jaffe AS, Hasselblad V, O'Connor CM. The Pilot Randomized Study of Nesiritide Versus Dobutamine in Heart Failure (PRESERVD-HF) Am J Cardiol 2005;96:18G-25G.[CrossRef][Web of Science][Medline]

63. Metra M, Nodari S, Parrinello G, et al. The role of plasma biomarkers in acute heart failure. Serial changes and independent prognostic value of NT-proBNP and cardiac troponin-T. Eur J Heart Fail 2007;9:776-786.[Abstract/Free Full Text]

64. Schulz R, Rose J, Martin C, Brodde OE, Heusch G. Development of short-term myocardial hibernation. Its limitation by the severity of ischemia and inotropic stimulation. Circulation 1993;88:684-695.[Abstract/Free Full Text]

65. Nohria A, Hasselblad V, Stebbins A, et al. Cardiorenal interactions: insights from the ESCAPE trial J Am Coll Cardiol 2008;51:1268-1274.[Abstract/Free Full Text]

66. Klein L, Massie BM, Leimberger JD, et al. Admission or changes in renal function during hospitalization for worsening heart failure predict postdischarge survival: results from the Outcomes of a Prospective Trial of Intravenous Milrinione for Exacerbation of Chronic Heart Failure (OPTIME-CHF) Circulation: Heart Fail 2008;1:25-33.[CrossRef]

67. Blair JE, Burnett J, Konstam MA, et al. Prognostic value and changes in renal function in patients admitted with acute heart failure—results from the EVEREST program (abstr) Eur J Heart Fail Suppl 2008;7:204.[Free Full Text]

68. Hasselblad V, Gattis Stough W, Shah MR, et al. Relation between dose of loop diuretics and outcomes in a heart failure population: results of the ESCAPE trial Eur J Heart Fail 2007;9:1064-1069.[Abstract/Free Full Text]

69. Francis GS, Siegel RM, Goldsmith SR, Olivari MT, Levine TB, Cohn JN. Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure. Activation of the neurohumoral axis. Ann Intern Med 1985;103:1-6.[Abstract/Free Full Text]

70. Metra M, Nodari S, Parrinello G, et al. Worsening renal function in patients hospitalised for acute heart failure: clinical implications and prognostic significance Eur J Heart Fail 2008;10:188-195.[Abstract/Free Full Text]

71. Cuffe MS, Califf RM, Adams Jr. KF, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial JAMA 2002;287:1541-1547.[Abstract/Free Full Text]

72. Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE randomized trial JAMA 2007;297:1883-1891.[Abstract/Free Full Text]

73. Swedberg K, Held P, Kjekshus J, Rasmussen K, Ryden L, Wedel H. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction. Results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). N Engl J Med 1992;327:678-684.[Web of Science][Medline]

74. Felker GM, Leimberger JD, Califf RM, et al. Risk stratification after hospitalization for decompensated heart failure J Card Fail 2004;10:460-466.[CrossRef][Web of Science][Medline]

75. Fonarow GC. Epidemiology and risk stratification in acute heart failure Am Heart J 2008;155:200-207.[CrossRef][Web of Science][Medline]

76. Fonarow GC, Adams Jr. KF, Abraham WT, Yancy CW, Boscardin WJ. Risk stratification for in-hospital mortality in acutely decompensated heart failure: classification and regression tree analysis JAMA 2005;293:572-580.[Abstract/Free Full Text]

77. Lee DS, Austin PC, Rouleau JL, Liu PP, Naimark D, Tu JV. Predicting mortality among patients hospitalized for heart failure: derivation and validation of a clinical model JAMA 2003;290:2581-2587.[Abstract/Free Full Text]

78. Collins S, Storrow AB, Kirk JD, Pang PS, Diercks DB, Gheorghiade M. Beyond pulmonary edema: diagnostic, risk stratification, and treatment challenges of acute heart failure management in the emergency department Ann Emerg Med 2008;51:45-57.[CrossRef][Web of Science][Medline]

79. Horwich TB, Patel J, MacLellan WR, Fonarow GC. Cardiac troponin I is associated with impaired hemodynamics, progressive left ventricular dysfunction, and increased mortality rates in advanced heart failure Circulation 2003;108:833-838.[Abstract/Free Full Text]

80. Smith GL, Vaccarino V, Kosiborod M, et al. Worsening renal function: what is a clinically meaningful change in creatinine during hospitalization with heart failure? J Card Fail 2003;9:13-25.[CrossRef][Web of Science][Medline]

81. Maisel AS, Peacock WF, McMullin N, et al. Timing of immunoreactive B-type natriuretic peptide levels and treatment delay in acute decompensated heart failure: an ADHERE (Acute Decompensated Heart Failure National Registry) analysis J Am Coll Cardiol 2008;52:534-540.[Abstract/Free Full Text]

82. Stevenson LW, Steimle AE, Fonarow G, et al. Improvement in exercise capacity of candidates awaiting heart transplantation J Am Coll Cardiol 1995;25:163-170.[Abstract]

83. Shah MR, Hasselblad V, Gheorghiade M, et al. Prognostic usefulness of the six-minute walk in patients with advanced congestive heart failure secondary to ischemic or nonischemic cardiomyopathy Am J Cardiol 2001;88:987-993.[CrossRef][Web of Science][Medline]

84. Ahmed A, Zile MR, Rich MW, et al. Hospitalizations due to unstable angina pectoris in diastolic and systolic heart failure Am J Cardiol 2007;99:460-464.[CrossRef][Web of Science][Medline]

85. Cleland JG, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure N Engl J Med 2005;352:1539-1549.[CrossRef][Web of Science][Medline]

86. Benza RL, Tallaj JA, Felker GM, et al. The impact of arrhythmias in acute heart failure J Card Fail 2004;10:279-284.[CrossRef][Web of Science][Medline]

87. Krumholz HM, Chen YT, Vaccarino V, et al. Correlates and impact on outcomes of worsening renal function in patients > or =65 years of age with heart failure Am J Cardiol 2000;85:1110-1113.[CrossRef][Web of Science][Medline]

88. Smith GL, Lichtman JH, Bracken MB, et al. Renal impairment and outcomes in heart failure: systematic review and meta-analysis J Am Coll Cardiol 2006;47:1987-1996.[Abstract/Free Full Text]

89. Cowie MR, Komajda M, Murray-Thomas T, Underwood J, Ticho B. Prevalence and impact of worsening renal function in patients hospitalized with decompensated heart failure: results of the prospective outcomes study in heart failure (POSH) Eur Heart J 2006;27:1216-1222.[Abstract/Free Full Text]

90. Damman K, Navis G, Voors AA, et al. Worsening renal function and prognosis in heart failure: systematic review and meta-analysis J Card Fail 2007;13:599-608.[CrossRef][Web of Science][Medline]

91. Gottlieb SS, Abraham W, Butler J, et al. The prognostic importance of different definitions of worsening renal function in congestive heart failure J Card Fail 2002;8:136-141.[CrossRef][Web of Science][Medline]

92. Lassus J, Harjola VP, Sund R, et al. Prognostic value of cystatin C in acute heart failure in relation to other markers of renal function and NT-proBNP Eur Heart J 2007;28:1841-1847.[Abstract/Free Full Text]

93. Filippatos G, Rossi J, Lloyd-Jones DM, et al. Prognostic value of blood urea nitrogen in patients hospitalized with worsening heart failure: insights from the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Chronic Heart Failure (ACTIV in CHF) study J Card Fail 2007;13:360-364.[CrossRef][Medline]

94. Klein L, O'Connor CM, Leimberger JD, et al. Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure: results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study Circulation 2005;111:2454-2460.[Abstract/Free Full Text]

95. Gheorghiade M, Rossi JS, Cotts W, et al. Characterization and prognostic value of persistent hyponatremia in patients with severe heart failure in the ESCAPE Trial Arch Intern Med 2007;167:1998-2005.[Abstract/Free Full Text]

96. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia N Engl J Med 2006;355:2099-2112.[CrossRef][Medline]

97. Perna ER, Macin SM, Cimbaro Canella JP, et al. Minor myocardial damage detected by troponin T is a powerful predictor of long-term prognosis in patients with acute decompensated heart failure Int J Cardiol 2005;99:253-261.[CrossRef][Web of Science][Medline]

98. Fonarow GC, Peacock WF, Horwich TB, et al. Usefulness of B-type natriuretic peptide and cardiac troponin levels to predict in-hospital mortality from ADHERE Am J Cardiol 2008;101:231-237.[CrossRef][Web of Science][Medline]

99. Januzzi Jr. JL, Sakhuja R, O'Donoghue M, et al. Utility of amino-terminal pro-brain natriuretic peptide testing for prediction of 1-year mortality in patients with dyspnea treated in the emergency department Arch Intern Med 2006;166:315-320.[Abstract/Free Full Text]

100. Januzzi JL, van Kimmenade R, Lainchbury J, et al. NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1,256 patients: the International Collaborative of NT-proBNP Study Eur Heart J 2006;27:330-337.[Abstract/Free Full Text]

101. Mueller C, Scholer A, Laule-Kilian K, et al. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea N Engl J Med 2004;350:647-654.[CrossRef][Web of Science][Medline]

102. Abraham WT, Fonarow GC, Albert NM, et al. Predictors of in-hospital mortality in patients hospitalized for heart failure: insights from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) J Am Coll Cardiol 2008;52:347-356.[Abstract/Free Full Text]

103. O'Connor CM, Abraham WT, Albert NM, et al. Predictors of mortality after discharge in patients hospitalized with heart failure: an analysis from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) Am Heart J 2008;156:662-673.[CrossRef][Web of Science][Medline]

104. Deleted in proof.

105. Flaherty JD, Rossi J, Fonarow G, et al. Influence of coronary angiography on the utilization of therapies in patients with acute heart failure syndromes: a report from OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) (abstr) Am J Cardiol 2008;102(Suppl):48i.

106. Levy P, Compton S, Welch R, et al. Treatment of severe decompensated heart failure with high-dose intravenous nitroglycerin: a feasibility and outcome analysis Ann Emerg Med 2007;50:144-152.[CrossRef][Web of Science][Medline]

107. Gheorghiade M, Konstam MA, Burnett Jr. JC, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST clinical status trials JAMA 2007;297:1332-1343.[Abstract/Free Full Text]

108. McMurray JJ, Teerlink JR, Cotter G, et al. Effects of tezosentan on symptoms and clinical outcomes in patients with acute heart failure: the VERITAS randomized controlled trials JAMA 2007;298:2009-2019.[Abstract/Free Full Text]

109. VMAC Investigators Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial JAMA 2002;287:1531-1540.[Abstract/Free Full Text]

110. Cleland JG, Freemantle N, Coletta AP, Clark AL. Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVIVE-II, SURVIVE, and PROACTIVE Eur J Heart Fail 2006;8:105-110.[Abstract/Free Full Text]

111. Heart Failure Society of America Executive summary: HFSA 2006 comprehensive heart failure practice guideline J Card Fail 2006;12:10-38.[CrossRef][Web of Science][Medline]

112. Drazner MH, Rame JE, Stevenson LW, Dries DL. Prognostic importance of elevated jugular venous pressure and a third heart sound in patients with heart failure N Engl J Med 2001;345:574-581.[CrossRef][Web of Science][Medline]

113. Felker GM, Cuculich PS, Gheorghiade M. The Valsalva maneuver: a bedside "biomarker" for heart failure Am J Med 2006;119:117-122.[CrossRef][Web of Science][Medline]

114. Binanay C, Califf RM, Hasselblad V, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial JAMA 2005;294:1625-1633.[Abstract/Free Full Text]

115. Jourdain P, Jondeau G, Funck F, et al. Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure: the STARS-BNP multicenter study J Am Coll Cardiol 2007;49:1733-1739.[Abstract/Free Full Text]

116. Metra M, Ponikowski P, Dickstein K, et al. Heart Failure Association of the European Society of Cardiology Advanced chronic heart failure: a position statement from the Study Group on Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology Eur J Heart Fail 2007;9:684-694.[Abstract/Free Full Text]

117. Gheorghiade M, Shin DD, Thomas TO, Brandimarte F, Fonarow GC, Abraham WT. Congestion is an important diagnostic and therapeutic target in heart failure Rev Cardiovasc Med 2006;7(Suppl 1):12-24.[CrossRef]

118. Fonarow GC, Yancy CW, Heywood JT. Adherence to heart failure quality-of-care indicators in US hospitals: analysis of the ADHERE registry Arch Intern Med 2005;165:1469-1477.[Abstract/Free Full Text]

119. Bonow RO, Bennett S, Casey Jr. DE, et al. ACC/AHA clinical performance measures for adults with chronic heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Performance Measures (Writing Committee to Develop Heart Failure Clinical Performance Measures): endorsed by the Heart Failure Society of America J Am Coll Cardiol 2005;46:1144-1178.[Free Full Text]

120. Bonow RO, Carabello BA, Chatterjee K, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients with Valvular Heart Disease) J Am Coll Cardiol 2006;48:e1-e148.[Free Full Text]

121. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) J Am Coll Cardiol 2007;50:e1-e157.[Free Full Text]

122. Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery) J Am Coll Cardiol 2007;50:1707-1732.[Free Full Text]

123. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J Am Coll Cardiol 2006;48:e247-e346.[Free Full Text]

124. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation) J Am Coll Cardiol 2006;48:854-906.[Free Full Text]

125. Epstein AE, Dimarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices): developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons J Am Coll Cardiol 2008;51:2085-2105.[Free Full Text]

126. deGoma EM, Vagelos RH, Fowler MB, Ashley EA. Emerging therapies for the management of decompensated heart failure: from bench to bedside J Am Coll Cardiol 2006;48:2397-2409.[Abstract/Free Full Text]

127. Shin DD, Brandimarte F, De Luca L, et al. Review of current and investigational pharmacologic agents for acute heart failure syndromes Am J Cardiol 2007;99:S4-S23.

128. Fonarow GC, Gheorghiade M, Abraham WT. Importance of in-hospital initiation of evidence-based medical therapies for heart failure-a review Am J Cardiol 2004;94:1155-1160.[CrossRef][Web of Science][Medline]

129. King 3rd SB, Smith Jr. SC, Hirshfeld Jr. JW, et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines J Am Coll Cardiol 2008;51:172-209.[Free Full Text]

130. Heart Failure Society of America Evaluation of patients for ventricular dysfunction and heart failure J Card Fail 2006;12:e16-e25.[CrossRef][Medline]

131. Piccini JP, Hernandez AF, Dai D, et al. Use of cardiac resynchronization therapy in patients hospitalized with heart failure Circulation 2008;118:901-903.[Free Full Text]

132. De Luca L, Fonarow GC, Mebazaa A, et al. Early pharmacological treatment of acute heart failure syndromes: a systematic review of clinical trials Acute Card Care 2007;9:10-21.[CrossRef][Medline]

133. Stough WG, O'Connor CM, Gheorghiade M. Overview of current noninodilator therapies for acute heart failure syndromes Am J Cardiol 2005;96:41G-46G.[Web of Science][Medline]

134. Gheorghiade M, Cody RJ, Francis GS, McKenna WJ, Young JB, Bonow RO. Current medical therapy for advanced heart failure Heart Lung 2000;29:16-32.[CrossRef][Web of Science][Medline]

135. Gheorghiade M, van Veldhuisen DJ, Colucci WS. Contemporary use of digoxin in the management of cardiovascular disorders Circulation 2006;113:2556-2564.[Free Full Text]

136. National, Heart, Lung, and Blood Institute Determining Optimal Dose and Duration of Diuretic Treatment in People with Acute Heart Failure (The DOSE-AHF Study) http://www.clinicaltrials.gov 2006Accessed September 14, 2008.

137. Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure J Am Coll Cardiol 2007;49:675-683.[Abstract/Free Full Text]

138. Finley 4th JJ, Konstam MA, Udelson JE. Arginine vasopressin antagonists for the treatment of heart failure and hyponatremia Circulation 2008;118:410-421.[Free Full Text]

139. Goldsmith SR, Elkayam U, Haught WH, Barve A, He W. Efficacy and safety of the vasopressin V1A/V2-receptor antagonist conivaptan in acute decompensated heart failure: a dose-ranging pilot study J Card Fail 2008;14:641-647.[CrossRef][Web of Science][Medline]

140. Dittrich HC, Gupta DK, Hack TC, Dowling T, Callahan J, Thomson S. The effect of KW-3902, an adenosine A1 receptor antagonist, on renal function and renal plasma flow in ambulatory patients with heart failure and renal impairment J Card Fail 2007;13:609-617.[CrossRef][Web of Science][Medline]

141. Givertz MM, Massie BM, Fields TK, Pearson LL, Dittrich HC. The effects of KW-3902, an adenosine A1-receptor antagonist, on diuresis and renal function in patients with acute decompensated heart failure and renal impairment or diuretic resistance J Am Coll Cardiol 2007;50:1551-1560.[Abstract/Free Full Text]

142. Gottlieb SS, Brater DC, Thomas I, et al. BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy Circulation 2002;105:1348-1353.[Abstract/Free Full Text]

143. Vallon V, Miracle C, Thomson S. Adenosine and kidney function: potential implications in patients with heart failure Eur J Heart Fail 2008;10:176-187.[Abstract/Free Full Text]

144. Vallon V, Muhlbauer B, Osswald H. Adenosine and kidney function Physiol Rev 2006;86:901-940.[Abstract/Free Full Text]

145. Cotter G, Dittrich HC, Weatherley BD, et al. The PROTECT pilot study: a randomized, placebo-controlled, dose-finding study of the adenosine A1 receptor antagonist rolofylline in patients with acute heart failure and renal impairment J Card Fail 2008;14:631-640.[CrossRef][Web of Science][Medline]

146. Cotter G, Metzkor E, Kaluski E, et al. Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema Lancet 1998;351:389-393.[CrossRef][Web of Science][Medline]

147. Mullens W, Abrahams Z, Francis GS, et al. Sodium nitroprusside for advanced low-output heart failure J Am Coll Cardiol 2008;52:200-207.[Abstract/Free Full Text]

148. Scios Inc A Study Testing the Effectiveness of Nesiritide in Patients with Decompensated Heart Failure (ASCEND-HF) http://www. clinicaltrials.gov 2008Accessed September 14, 2008.

149. Silvers SM, Howell JM, Kosowsky JM, Rokos IC, Jagoda AS. Clinical policy: critical issues in the evaluation and management of adult patients presenting to the emergency department with acute heart failure syndromes Ann Emerg Med 2007;49:627-669.[CrossRef][Web of Science][Medline]

150. Conrad KP, Novak J. Emerging role of relaxin in renal and cardiovascular function Am J Physiol Regul Integr Comp Physiol 2004;287:R250-R261.[Abstract/Free Full Text]

151. Mitrovic V, Seferovic PM, Simeunovic D, et al. Haemodynamic and clinical effects of ularitide in decompensated heart failure Eur Heart J 2006;27:2823-2832.[Abstract/Free Full Text]

152. Luss H, Mitrovic V, Seferovic PM, et al. Renal effects of ularitide in patients with decompensated heart failure Am Heart J 2008;155:1012.e1-1012.e8.

153. Ahmed A, Rich MW, Love TE, et al. Digoxin and reduction in mortality and hospitalization in heart failure: a comprehensive post hoc analysis of the DIG trial Eur Heart J 2006;27:178-186.[Abstract/Free Full Text]

154. Antonello A, Cargnielli G, Ferrari M, Melacini P, Montanaro D. Effect of digoxin on plasma-renin-activity in man Lancet 1976;2:850.[Web of Science][Medline]

155. Gheorghiade M, Adams Jr. KF, Colucci WS. Digoxin in the management of cardiovascular disorders Circulation 2004;109:2959-2964.[Free Full Text]

156. Gheorghiade M, Blair JE, Filippatos GS, et al. Hemodynamic, echocardiographic, and neurohormonal effects of istaroxime, a novel intravenous inotropic and lusitropic agent: a randomized controlled trial in patients hospitalized with heart failure J Am Coll Cardiol 2008;51:2276-2285.[Abstract/Free Full Text]

157. Dec GW. Istaroxime in heart failure new hope or more hype J Am Coll Cardiol 2008;51:2286-2288.[Free Full Text]

158. Coletta AP, Cleland JG, Cullington D, Clark AL. Clinical trials update from Heart Rhythm 2008 and Heart Failure 2008: ATHENA, URGENT, INH study, HEART and CK-1827452 Eur J Heart Fail 2008;10:917-920.[CrossRef][Web of Science][Medline]

159. Cleland JGF. The selective cardiac myosin activator CK-1827452 increases systolic function in a concentration-dependent manner in patients with stable heart failure (late breaking clinical trial). Paper presented at: Heart Failure Society of America Annual Meeting; September 24, 2008; Toronto, Canada.

160. Peacock WF, Hollander JE, Diercks DB, Lopatin M, Fonarow G, Emerman CL. Morphine and outcomes in acute decompensated heart failure: an ADHERE analysis Emerg Med J 2008;25:205-209.[Abstract/Free Full Text]

161. Gray A, Goodacre S, Newby DE, Masson M, Sampson F, Nicholl J. Noninvasive ventilation in acute cardiogenic pulmonary edema N Engl J Med 2008;359:142-151.[CrossRef][Medline]

162. Masip J, Roque M, Sanchez B, Fernandez R, Subirana M, Exposito JA. Noninvasive ventilation in acute cardiogenic pulmonary edema: systematic review and meta-analysis JAMA 2005;294:3124-3130.[Abstract/Free Full Text]

163. Drew BG, Kingwell BA. Acadesine, an adenosine-regulating agent with the potential for widespread indications Expert Opin Pharmacother 2008;9:2137-2144.[CrossRef][Web of Science][Medline]

164. Boerrigter G, Costello-Boerrigter LC, Cataliotti A, Lapp H, Stasch JP, Burnett Jr JC. Targeting heme-oxidized soluble guanylate cyclase in experimental heart failure Hypertension 2007;49:1128-1133.[Abstract/Free Full Text]

165. International Working Group on Acute Heart Failure Syndromes Conference on Clinical Trial Endpoints in Acute Heart Failure SyndromesDecember 1Silver Springs, MD: Food and Drug Administration; 2008.

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