Acute Heart Failure Syndromes Mihai Gheorghiade, and Peter S. Pang J. Am. Coll. Cardiol. 2009;53;557-573 doi:10.

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EKR Therapeutics. AstraZeneca.* Peter S. Pang is a consultant for Astellas. Johnson & Johnson. is over 34 billion dollars per year. Irrespective of the underlying cause (e. MD† Chicago. Improving post-discharge outcomes is the single most important goal in the management of acute heart failure syndromes. (J Am Coll Cardiol 2009. anemia. Debiopharm. Chicago. pathophysiology. 2008.S. revised manuscript received October 21. Merck. Bayer. and Solvay Pharmaceuticals. myocardial injury and/or renal impairment occurring in AHFS may contribute to this grim prognosis. composed of cardiologists. they should no longer be considered acute but chronic HF (11).041 STATE-OF-THE-ART PAPER Acute Heart Failure Syndromes Mihai Gheorghiade. after initial management resulting in stabilization. Otsuka. Scios Inc. Dr. however. 7. Manuscript received July 2. respectively.. Although this may reflect the severity of HF. Northwestern University Feinberg School of Medicine. and has received research support from Corthera and PDL BioPharma. 2008. GlaxoSmithKline. valvular heart disease. incomplete understanding of its pathophysiology. Dr. Over 1 million hospitalizations with a primary diagnosis of HF occur each year in the U. The vast majority of patients symptomatically improve during hospitalization. the Medicines Company. and governmental agencies (5). However. Coronary artery disease (CAD). and Palatin Technologies.e. severe hypertension). Medtronic. Illinois Heart failure resulting in hospitalization represents a significant and growing health care burden. and Sigma-Tau.g. As a diagnosis at hospital discharge.53:557–73) © 2009 by the American College of Cardiology Foundation Hospitalization for acute heart failure syndromes (AHFS) is 1 of the most important predictors of post-discharge mortality and readmission in patients with chronic HF (1..S. absence of a universally accepted definition. Solvay Pharmaceuticals.11–13).8). HF has tripled over the last 3 decades. This review reflects concepts developed by the International Working Group on AHFS that met annually for the last 5 years. and medications (i. and lack of robust evidence-based guidelines.Journal of the American College of Cardiology © 2009 by the American College of Cardiology Foundation Published by Elsevier Inc. Novartis. accepted October 26. Further investigation into pathophysiologic targets and novel approaches to clinical trial design are needed. and prognosis. MD.jacc.S. emergency physicians. with similar financial burdens for many European countries (3. Gheorghiade is or has been a consultant for and/or received honoraria from Abbott. PDL BioPharma. Management of AHFS is challenging given the heterogeneity of the patient population. Nile. and/or atrial fibrillation.1016/j. Illinois. Downloaded from content. improved survival after myocardial infarction (MI). PeriCor Therapeutics. Over 1 million hospital discharges for HF occurred in 2005 in the U. PDL BioPharma. Corthera. This trend will likely continue due to an aging population. Bayer.4). ischemic event) or precipitant (e. Pang. FACC.onlinejacc. Nile. 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. has received honoraria from Biogen Idec. Worsening signs and symptoms. The majority of patients appear to respond well to initial therapies consisting of loop diuretics and vasoactive agents (5–7). 53. hospitalists. 2010 . their early post-discharge rehospitalization and mortality rates continue to be high. 2008. (3). nonsteroidal anti-inflammatory drugs. as well as noncardiac conditions such as renal dysfunction. Vol. 2009 ISSN 0735-1097/09/$36.. Heterogeneity characterizes this group in terms of mode of presentation. EKR Therapeutics. within 3 to 6 months (6.2008. hypertension. may also contribute to these abnormalities (5. glitazones).10. 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).g. and better prevention of sudden cardiac death (3. mainly related to hospitalizations. Definitions AHFS can be defined as new onset or gradual or rapidly worsening HF signs and symptoms requiring urgent therapy (5). No.9 –11). Otsuka.org by on April 18. Errekappa Terapeutici.11–13).. an increase of 171% compared with discharges in From the *Division of Cardiology. The majority of AHFS patients have worsening chronic HF.00 doi:10. industry. Astellas.2). Corthera. post-discharge mortality and rehospitalization rates reach 10% to 20% and 20% to 30%. The cost in the U. PeriCor. Improving post- discharge mortality and prevention of readmissions are the most important goals in AHFS.. Department of Medicine. Patient Characteristics Heart failure afflicts over 5 million Americans and 15 million Europeans (3. diabetes. neurohormonal. and †Department of Emergency Medicine.

and 20% to 30% take digoxin (9.. They are older and more likely to be female. many do not have a decrease in BW during hospitalization and are often discharged with HF signs and/or symptoms (7. and/or an increase in body weight (BW) (clinical congestion). In-hospital mortality ( 2% to 4%) may reach 20% for those patients with severe renal impairment and low SBP. approximately 40% will die from progressive HF and 30% will die suddenly and unexpectedly post-discharge (31). such as CAD. However.21). and/or signs and symptoms refractory to standard therapy characterize Downloaded from content.28. renal impairment.9. 2010 . peripheral edema. hypertension in 70%.18.18). This may result in underutilization of evidence-based therapies (5.S.35). IV intravenous Patient characteristics. is 1 of the most important predictors for rehospitalization (1. assessment for viable. Among patients admitted with chronic HF and low ejection fraction (EF).9. renal function.15–20).onlinejacc. Between 1992 ACE angiotensinand 2001.12–14). the presence and extent of CAD may determine the initial. 1). they are often discharged on the same pre-admission medications (8. uncontrolled hypertension.21). Often a comprehensive assessment is not performed (e. In patients presenting Abbreviations and Acronyms with de novo HF. arrhythmias. Early post-discharge events in PSF patients appear similar to those with reduced EF.S. is 6 days (median: 4 days) (9. provided us disease with an accurate characterization CRT chronic and prognosis of these patients resynchronization therapy (6.7. hypertension. They are also more likely to have a history of hypertension and atrial arrhythmias. 53. Dyspnea and signs of SBP systolic blood congestion manifested by jugular pressure venous distention and edema are common (9.31).24). 5% to 10% have advanced HF. 40% take angiotensin-converting enzyme (ACE) inhibitors. and Europe. 10% are hypotensive. diabetes in 40%. the most BP blood pressure expensive (3.9. In fact. AHFS registries from CAD coronary artery Europe and the U. although the mode of death and reason for rehospitalization has not been studied in these patients (6). Approximately 50% of AHFS patients have a relatively preserved systolic function (PSF) (6.7. this group represents 2% to 5% of the overall AHFS population (6).15. At presentation. the lower the mortality). and noncompliance (dietary and/or medication) are major precipitants for admission (27). independent of SBP at presentation (21). atrial fibrillation in 30%. cardiac catheterization. 2009 February 17. Of the approximately 80% of AHFS patients with chronic HF resulting in hospitalization. a significant number are diagnosed with acute coronary syndrome (19). in itself.500 visits each year ARB angiotensin (4). AHFS resulting in hospitalreceptor blocker ization is the most common BNP B-type natriuretic peptide diagnosis-related group for Medicare patients and in total. and post-discharge management (36). In patients admitted with worsening chronic HF. less EF ejection fraction is known from other geographiHF heart failure cal regions.26).g.10.5 million converting enzyme U. Only reBW body weight cently.2). Clinical course. renal insufficiency. Approximately 3.23) (Table 1). Clinical Classification Patients may be classified into HF presenting for the first time (de novo) or worsening chronic HF (5) (Fig.28.29). or stroke (34.. No.18).558 Gheorghiade and Pang Acute HF Syndromes JACC Vol.30. atrial fibrillation. This often starts days if not weeks before admission (25. in-hospital. Although systemic and pulmonary congestion is the main reason for hospitalization. The mean length of stay in the U.7. Precipitants for admission.g. In both groups. there were 10. ischemia. with the remainPCWP pulmonary ing 15% to 20% diagnosed with capillary wedge pressure HF for the first time. The readmission rate is approximately 30%. but dysfunctional myocardium). most are taking diuretics.S. with an average insyndromes crease of 18. Hospitalization commonly results from congestion or fluid overload and not a low cardiac output (9.32). 50% take beta-blockers. Hospitalization for HF. introduction of new or up-titration of evidence-based therapies (e. which should be based on the presenting clinical profile. A history of CAD is present in 60%.23). and present with severe hypertension (6. Risk for these events is highest in the first few months following discharge (2.org by on April 18. except for diuretic dose escalation. Recent data suggests an association between early events and worsening symptoms. Most patients have rapid symptomatic improvement with loop diuretics and have a relatively short hospital stay (4.15. However.8 million hospital diagnoses of HF occurred in 2004 (3).15. Low blood pressure. due to an increase in left ventricular filling pressure (LVFP) (hemodynamic congestion) often results in jugular venous distention. emergency department visits AHFS acute heart failure for AHFS. exacerbation of chronic obstructive pulmonary disease with or without pneumonia. Post-discharge mortality varies at 60 to 90 days from 5% to 15% depending on BP at presentation (the higher the BP. The mean PSF preserved systolic age is 75 years and over one-half function are women. The maLVFP left ventricular jority of AHFS patients have filling pressure worsening chronic HF resulting in MI myocardial infarction hospitalization. Approximately 50% of readmissions are not related to HF. The EF may influence post-discharge rather than initial management. 10% take angiotensin-receptor blockers. beta-blockers) is 5% to 10%. and moderate to severe renal impairment in 20% to 30% (22). ACE inhibitors.15. Congestion.S.31). and neurohormonal profile during the first few weeks after discharge (33). It is possible that a significant number of morbid events in the AHFS/PSF population are related to coexisting cardiac or noncardiac comorbidities. 7. approximately 25% of patients are hypertensive (systolic blood pressure [SBP] 160 mm Hg). 2009:557–73 1979 (12). Both in the U.

8 1.0.0] 89 135 77 22 31 19 78. hyperlipidemia. mean SD. g/dl BNP. or peripheral vascular disease.9 4.3 [1. kg Heart rate. cerebrovascular disease/transient ischemic attack. 2009:557–73 Preserved Versus Reduced Systolic Function Patient Characteristics Table 1 Preserved Versus Reduced Systolic Function Patient Characteristics Patients With LVSD (n 20. *Statin use among patients with coronary artery disease.5] 85 149 76 21 33 19 54% 17% 18% 38% 28% 21% 3% 23% 9% 44% 63% 63% 62% 33% 24.0 1. 1. mm Hg DBP.7 4.0] 0.118) Gheorghiade and Pang Acute HF Syndromes 559 Characteristics at Admission Demographics Age. No. or median [25th.9 2.org by on April 18. Downloaded from content.2 137. ARB angiotensin receptor blocker.onlinejacc.7 10. mg/dl Serum hemoglobin. 2.5 2. pg/ml Troponin I. SBP systolic blood pressure.0.1 62% 71% 21% 38% 77% 15% 15% 24% 66% 34% 28% 17% 26% 76% 32% 33% 78.9 [64.190. mEq/l Serum creatinine.6 137.170. ng/ml Medications on admission ACE inhibitor ARB Amlodipine Aldosterone antagonist Beta-blocker Loop diuretic Digoxin Aspirin Antiarrhythmic Hydralazine Nitrate Statin* Patients With PSF (n 21.0 1. 53. 2010 .280.8] 11.4 14. % Laboratory values Serum sodium. Adapted and reproduced.3 7. 94.0. LVSD left ventricular systolic dysfunction. 2009 February 17.5 [320. mm Hg Etiology Ischemic Hypertensive Idiopathic Findings on admission Acute pulmonary edema Chest pain Uncontrolled hypertension Dyspnea at rest Dyspnea on exertion Rales Lower extremity edema Jugular venous distention Left ventricular EF.1. 7.4 [1.3 75.149) 70.0.0 [603.1.1 [0.9] 12. (6). 75th percentiles]. 97. noninsulin-treated Hypertension Hyperlipidemia Atrial arrhythmia Vital signs on admission Body weight.3] 601. 0. 1. 1. EF ejection fraction. diabetes. PSF preserved systolic function. 0.0] 0. insulin-treated Diabetes.3] 45% 11% 5% 10% 56% 63% 30% 42% 13% 3% 22% 40% 36% 13% 10% 5% 52% 58% 17% 38% 8% 3% 21% 39% Data presented as percent.JACC Vol. ACE angiotensin-converting enzyme. DBP diastolic blood pressure. BNP B-type natriuretic peptide. yrs Male Caucasian African American Medical history Diabetes. from Fonarow et al. with permission.5 [65.1 [0.7 2% 24% 12% 44% 62% 65% 68% 26% 54.0.8.1 13. beats/min SBP.

severe neurohormonal or endothelial abnormalities. Pulmonary congestion may be defined as pulmonary venous hypertension (increased pulmonary capillary wedge pressure [PCWP]) often resulting in pulmonary interstitial and alveolar edema. indicates right-sided failure that is usually associated with left-sided HF. However. 7.37. most commonly caused Assessment of Congestion Table 2 BW Assessment of Congestion Increase in BW predicts hospitalization (26.onlinejacc. this position may be tolerated in spite of a relatively high filling pressure. BP blood pressure. pleural effusions) may be absent in spite of a very high PCWP in patients with severe but chronic HF. 2009:557–73 De novo HF No CAD Preserved EF Worsening Chronic HF * Reduced EF Figure 1 General Clinical Classification Broad general classification proposed for AHFS patients representing key factors that may influence management. Increased systemic venous pressure (high right atrial pressure). Renal impairment. Systemic congestion manifests clinically by jugular venous distention with or without peripheral edema and gradual increases in BW are often seen (11) (Table 2). it indicates a high PCWP.38). RA right atrium.27. JVD. LVDP left ventricular diastolic pressure. and first generation calcium-channel blockers.. the RA pressure correlates with PCWP/LVDP. hypertension. subendocardial ischemia. However.org by on April 18.g.g. In a chronic state. a reduction in BW in response to different therapies may not necessarily result in decreased hospitalization or mortality.. reduced EF) (13).37. advanced HF. renal insufficiency). 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. Both bradyarrhythmias and tachyarrhythmias can contribute to congestion. severe pulmonary congestion develops abruptly when precipitated by a rapid increase in BP (afterload). Downloaded from content. atrial fibrillation. Figure illustration by Rob Flewell. may contribute to the progression of HF by further causing activation of neurohormones. particularly in patients with diastolic dysfunction (45– 48). and/or changes in LV size and shape (remodeling) that often results in mitral insufficiency (24. BW body weight. Associated with increase in PCWP when present with other signs of elevated filling pressure (e.33). CAD coronary artery disease.39 – 42). Heart rate and rhythm BP Jugular venous pressure Rales Edema Orthopnea test BNP/NT-proBNP Chest X-ray Exercise testing to assess functional classification might aid in assessment of residual congestion. hypertension. LV left ventricle. These abnormalities may be caused or precipitated by ischemia. Pathophysiology AHFS are characterized by severe hemodynamic and neurohormonal abnormalities that may cause myocardial injury and/or renal dysfunction or may be a result of it (11. Occasionally. Congestion.24. PCWP pulmonary capillary wedge pressure. 53.53–55). No.44). may also contribute to fluid overload (5. Marker of increased LV filling pressures. when present. High LV diastolic pressure. only when associated with JVD. Peripheral edema. in a chronic state. However. Equals RA pressure. Patients often do not tolerate lying flat when there is a rapid increase in filling pressure. Either no change in BP or an increase in BP from supine to the upright position or during Valsalva maneuver usually reflects a relatively high LV filling pressure (113).g. alveolar edema. S3).. by itself. 2010 . other noncardiac conditions (e. but is nonspecific by itself. glitazones. may move from dependent periphery to the sacral area. During hospitalization. interstitial edema. †With or without acute coronary syndromes. and certain medications such as nonsteroidal anti-inflammatory drugs. *Advanced HF is a subset of chronic HF. EF ejection fraction. or untoward drug effects (11. NT-proBNP N-terminal pro-brain natriuretic peptide.g.. De novo HF represents the remainder of AHFS and may be further divided into those with pre-existing risk for HF (e. CAD) without evidence of prior LV dysfunction or structural abnormalities and those with pre-existing cardiac structural abnormalities (e. 2009 February 17.9.49 –52). dietary indiscretion. HF heart failure. HF heart failure. JVD jugular venous distention. Pulmonary congestion (cephalization. BNP B-type natriuretic peptide.43.560 Gheorghiade and Pang Acute HF Syndromes JACC Vol.

66. congestion. 2009 February 17. particularly in patients with CAD. which may be aggravated by high-dose loop diuretics (56 –59. Non–potassium-sparing intravenous (IV) loop diuretics are first-line agents to alleviate congestive symptoms. However.68) (Fig. These conditions may precipitate injury. however.JACC Vol. and arteriosclerosis. Untoward drug effects. Structural renal dysfunction due to diabetes.onlinejacc. High-dose administration of IV loop diuretics has been associated with worse outcomes in HF patients. recent data suggest a more complex relationship among BW.org by on April 18. hypertension. Figure illustration by Rob Flewell.63). 2). further activation of neurohormones. 53. resulting in a supply and demand mismatch (increased myocardial oxygen demand and decreased coronary perfusion) (38). vasopressin antagonists and non–potassium-sparing diuretics appear to decrease BW effectively. In AHFS. 7. However. Recent data suggests that approximately 20% of patients have worsening renal function soon after discharge (67). and/or inotropic stimulation.66). 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. This worsening during or after discharge may result from further neurohormonal and hemodynamic abnormalities (low cardiac output and/or high venous pressure). This is supported by experimental data in dogs where stimulation of hibernating myocardium with low-dose dobutamine resulted in myocardial necrosis (64). who often have hibernating and/or ischemic myocardium (36). 2009:557–73 Gheorghiade and Pang Acute HF Syndromes 561 “Vasomotor” Nephropathy Intrinsic Renal Disease • Diabetes • Hypertension • Arteriosclerosis • Decreased cardiac output and/or systemic vasodilation • High renal venous pressures • Neurohormonal activation • High dose loop diuretic therapy Cardio-renal Syndrome Worsening renal function during hospitalization. distinguishing between vasomotor nephropathy from abnormalities related to intrinsic kidney disease is often difficult and remains an important area for research. further activation of neurohormones. Worsening renal function occurs in 20% to 30% of patients during hospitalization (65. This likely reflects myocardial injury. those beneficial effects may be associated with electrolyte abnormalities. by high left-sided pressures (PCWP). which may be related to hemodynamic and/or neurohormonal abnormalities or the result of an ischemic event (MI). particularly in patients with CAD (14.61). Renal impairment. are common. Troponin release often occurs in AHFS.69). renal abnormalities promote sodium and water retention (59). The importance of myocardial injury in AHFS has not been well studied and remains an area of investigation. in spite of clinical improvement in response to therapy for HF and adequate intravascular volume 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.62. For example. In a given patient. Body weight is often used as a marker of congestion in both inpatient and outpatient settings. 2010 . their use has not always been associated with an improvement in mortality or rehospitalization (60. No.33). Myocardial injury. Injury may also be the consequence of a high LV diastolic pressure. a reduction in BW in response to different therapies may not necessarily result in decreased hospitalization or mortality. Although an increase in BW predicts hospitalization (26. and worsening renal function (68. may contribute to the development of the cardio-renal syndrome (56 –59). and outcomes. Downloaded from content.

CAD. Recently. BP. Hyponatremia.74.72). Dobutamine. Other prognostic factors. these effects may be associated with increased myocardial oxygen consumption (tachycardia and increased contractility) and hypotension due to their vasodilatory effects (71. *This is not an all-inclusive list. a marker of ventricular dyssynchrony. and ACE inhibitors is associated with an improved prognosis (6). Defined as serum sodium 135 mmol/l. either blood urea nitrogen.67). high SBP at time of admission is associated with a substantially lower in-hospital and post-discharge mortality (21). this was not studied in AHFS (31. Prognostic Factors Recent clinical trials and observational studies have identified emerging prognostic factors in patients admitted with AHFS (74 – 83) (Table 3).to 3-fold increase in post-discharge mortality (30. Unstable angina appears to be an important cause for hospitalization in patients with chronic HF and PSF (84).60.94.70.40 – 42. and/or cystatin C all have important prognostic significance (22. from Gheorghiade et al.68. this association may be a marker of the severity of HF. Although vasopressin antagonists (e. and increased heart rate appear to be markers of increased post-discharge mortality risk (62. Although chronic resynchronization therapy (CRT) appears to be beneficial in patients with chronic HF and reduced systolic function with a prolonged QRS. their use has not been associated with improved outcomes (43. Results in a 3-fold increase in in-hospital mortality. CAD Troponin release Ventricular dyssynchrony Renal impairment Hyponatremia Clinical congestion at time of discharge EF BNP/NT-proBNP Functional capacity at time of discharge Adapted and modified. however. and usually remains uncorrected during hospitalization (30.g.79). Downloaded from content. and is associated with a 2. Extent and severity of CAD appears to be a predictor of poor prognosis (36). blood urea nitrogen/Cr ratio.96). when present. 2009:557–73 Potential Targets of Therapy in AHFS* Prognostic Indicators and Table 3 SBP Prognostic Indicators and Potential Targets of Therapy in AHFS* Admission and early post-discharge SBP inversely correlates with post-discharge mortality. This is associated with an increase in early and late post-discharge mortality and hospitalization (31).org by on April 18. Hibernating and/or ischemic myocardium is a therapeutic target for medical therapy and/or revascularization (36) (Fig.to 3-fold increase in postdischarge mortality. Similar early post-discharge event rates and mortality between reduced and preserved EF (6). However.66. elevated natriuretic peptide levels.66. 7. is emerging as an important predictor of post-discharge outcomes (82.562 Gheorghiade and Pang Acute HF Syndromes JACC Vol. Associated with a 2. yet demonstrate a significantly greater risk of death post-discharge (95). In contrast. Markers of renal impairment.88). 3). they predict an increase in postdischarge mortality (86). No. The higher the BP. irrespective of systolic function. the readmission rate of approximately 30% is independent of the SBP at time of admission (21). elevated PCWP.87–93). other abbreviations as in Tables 1 and 2. An important predictor of post-discharge mortality and morbidity (24. a 2-fold increase in post-discharge mortality.63. This improvement was related to implementation of evidence-based therapy for CAD during hospitalization (105). Cr. older age. Increase in QRS duration occurs in approximately 40% of patients with reduced systolic function and is a strong predictor of early and late post-discharge mortality and rehospitalization (31). It correlates inversely with mortality. cardiac catheterization has been associated with improvement in post-discharge outcomes. Decreasing coronary perfusion due to hypotension in the presence of increased myocardial oxygen demand may result in myocardial injury. the 60.onlinejacc. However. anemia. Renal impairment.33). Renal impairment is often present at time of admission (22).44). 2010 . Arrhythmias. 2009 February 17. Troponin release. and levosimendan improve hemodynamics.73).95). liver disease. (5). the use of betablockers. A prolonged QRS complex. rather than a cause of increased mortality (61. Pre-discharge functional capacity. aldosterone antagonists. Elevated natriuretic peptides associated with increased resource utilization and mortality (81). CAD coronary artery disease. defined by the 6min walk test. However. Hypotension associated with the use of vasodilators may also result in myocardial and renal hypoperfusion and possibly injury (38.97–103). These hyponatremic patients have the same hemodynamic and clinical response as those with normonatremia.94. particularly in patients with CAD who often have ischemic or hibernating myocardium (38). tolvaptan and conivaptan) effectively correct hyponatremia. however.95). Approximately 30% of patients with AHFS have worsening renal function during hospitalization (87. Mild hyponatremia occurs in 25% of patients with AHFS.. is present in approximately 40% of patients with reduced systolic function hospitalized for worsening HF. 53. the lower both in-hospital and postdischarge mortality.80). Worsening renal function during hospitalization or soon after discharge is also associated with an increase in in-hospital and post-discharge mortality (33. Ventricular dyssynchrony. milrinone. Patients with AHFS and CAD often have a worse prognosis than other patients. and a 3-fold increase in the rehospitalization rate (14. 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. New sustained ventricular or atrial arrhythmias developing during hospitalization are uncommon. occurs in approximately 25% of patients. severe symptoms. with permission.to 90-day readmission rate remains high and appears independent of presenting BP (21).85).70). estimated glomerular filtration rate.83). The prognostic value of QRS duration in patients with AHFS and PSF has not been studied. Systolic BP on admission and early post-discharge is emerging as an important predictor of in-hospital and post-discharge mortality (21. 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).

inotropes) (39). *Select patients. and variables measured during the Downloaded from content. The presence and severity of underlying CAD may affect early management decisions. Dor procedure ventricular reconstructive surgery to restore aneurysmal left ventricle to its normal. MAZE Cox maze procedure to eliminate atrial fibrillation.relppoD OHCE( gnitset esicrexe ro cigolocamrahP tnemrusaem erusserp doolB amede .noitcnuf VL noisnetrepyH noitsegnoC **stsinogatna enisonedA **stsinogatna nisserposaV *noitartlifartlU sciteruiD noitcirtser tlaS )erudecorp roD . other abbreviations as in Figure 1. 53.. LV left ventricle. risk stratification should consider baseline variables.e. emergency department). 2) in-hospital phase. The downstream impact of early therapy on outcomes for AHFS has not been well studied (106). After stabilization/treatment of life-threatening conditions.org by on April 18.16. MRI magnetic resonance imaging. 2009 February 17. improving hemodynamics and symptoms are key goals.raluvlav . 2009:557–73 Gheorghiade and Pang Acute HF Syndromes 563 In-Hospital Assessment Potential Targets Methods of Assessment Implementation of Evidence Based Therapy Figure 3 Assessment and Targeted Implementation of Evidence-Based Therapy in AHFS Chart recommends assessment methods and ways to implement therapy. Determining if injury to key organs such as the heart or kidney occurs early or begins prior to presentation may shift the therapeutic window upstream. ACE-I angiotensin-converting enzyme inhibitor. Evaluation and management often proceeds concomitantly (Table 4). should be treated for optimal results. because these patients may require additional therapies or may be adversely affected by other therapies (e. IV inotropes and vasodilators that initially improve signs and symptoms may adversely affect post-discharge outcomes (39. These conditions. ISDN isosorbide dinitrate. if any. 3) pre-discharge phase.109. Early phase. The potential deleterious effects of these therapies. Evaluation Phases of AHFS Patients Four phases of hospital evaluation and management of AHFS are proposed: 1) initial or early phase (i. and/or arrhythmias.18). AF atrial fibrillation. Abnormal hemodynamics often results from conditions such as hypertension. Initial management should be based on clinical profiles (Table 5). CRT chronic resynchronization therapy. A universally accepted risk-stratification method applicable at the time of admission and a classification similar to the Killip scoring system for acute MI is needed. on the myocardium and kidney have not been well studied (5). ECHO echocardiography. 7. ischemia. elliptical shape. Intravenous loop diuretics with or without vasoactive agents (inotropes and/or vasodilators) improve symptoms in most patients (106 –109).JACC Vol.42. 2010 smargorp tnemevorpmi ecnamofrep ¥ tnemeganam esaesiD noitacudE senilediug AHA/CCA rep rehtO sciteruiD srekcolb-ateB BRA ro I-ECA **erudecorp EZAM *lortnoc mhtyhR nirafraW srekcolb-ateB ¥ nixogiD ¥ lortnoc etaR Therapies for LV Dysfunction Therapy for Congestion CAD Therapies Atrial Fibrillation margoidracortcelE yhpargoigna dna noitaziretehtac caidraC )IRM . MR mitral valve regurgitation..71.onlinejacc.e( *yregrus caidraC *nixogiD *NDSI/enizalardyH *DCI -/+ TRC *DCI *tsinogatna enoretsodlA srekcolb-ateB BRA ro I-ECA .WB relppoD OHCE Hypertension Enhance Adherence noitneverp yradnoces rof ypareht dednemmocer enilediug AHA/CCA rehtO ¥ *noitaziralucsav-eR ¥ *snitatS ¥ *teletalp-itnA ¥ )SRQ ediw( ynorhcnyssyd ralucirtneV DAC muidracoym lanoitcnufsyd tub elbaiv ro/dna aimehcsI )msyruena( seitilamronba noitom llaW RM . as well as any other precipitants of HF. ICD implantable cardiac-defibrillator. Clinical profiles at presentation. ARB angiotensin receptor blocker. This phase of AHFS management typically takes place in the emergency department.110).g.gnigami raelcun . where 80% of all hospitalized patients initially present (15. **investigational agents.g. AHA American Heart Association.41. ACC American College of Cardiology. and 4) early post-discharge phase (5). In general. clinical course. No.

acute valvular pathologies. NIV noninvasive ventilation. Morphine may also be used for pulmonary edema† Avoid hypotension or increase in HR. nesiritide..13. hypertension. levosimendan). Determine clinical profile and begin initial treatment 4. plaque HF signs/symptoms symptoms of HF that resolve after resolution of ischemia.76.48.onlinejacc. JVP jugular venous pressure. often related to worsening diastolic function and performance (output) volume overload immediately after surgery and the Therapy: diuretic or fluid administration subsequent early post-operative interval. correction of ischemia Therapy: reperfusion (e. valve surgery Isolated right HF from pulmonary HTN or intrinsic RV failure (e. inotropic support. Further improvement of signs and symptoms. 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. JVP. arrhythmia. *Of all AHFS admissions. ACS. ECG electrocardiogram. Make disposition *These steps usually occur in parallel. VAD) Adapted and modified. BNP) and CXR Key components include HR.g.. ¶Avoid if retaining CO2.564 Gheorghiade and Pang Acute HF Syndromes JACC Vol.77. nitrates. unstable arrhythmia.. RV right ventricle. Mostly related to low cardiac output and often associated with decreased renal function. VAD ventricular assist device. The role of serial B-type natriuretic peptide (BNP)/N-terminal Clinical Presentation Elevated BP (above 160 mm Hg) Characteristics Targets† and Therapies‡ Predominantly pulmonary (radiographic/clinical) with or without Target: BP and volume management systemic congestion. ECG. nitrates§. epoprostenol.org by on April 18.g. dyspnea) 6. §Probably preferred in patients with ACS or history of CAD. BNP. diuretics. early post-discharge period. (5). pulse oximetry. 2. Clinical Profiles Table 5 Clinical Profiles Incidence* 25% In-hospital phase. Determine and manage the cause or precipitant 5. endothelinblocking agents. coronary reperfusion for RV infarcts. flash pulmonary edema. tricuspid valve endocarditis) Post-cardiac surgery HF ? Occurring in patients with or without previous ventricular Target: volume management. RV infarct). IABP) Target: improve cardiac pump function Therapy: inotropes vasoactive medications mechanical assist devices. symptoms (dyspnea). uncontrolled diabetes. MI myocardial infarction. infection). other abbreviations as in Tables 1.g. acute valvular disease. CXR chest X-ray. mechanical in cardiac injury. Monitoring for potential cardiac injury and renal function is important. Radiographic pulmonary congestion may be minimal in patients with advanced HF.. renal function. Primarily complicating acute MI. Not well characterized with little epidemiological data. Many patients have preserved EF. 2009 February 17.. Flash pulmonary edema 3% ACS and AHFS 25% of ACS have Rapid or gradual onset. ‡Represents initial therapies for early management and should be tailored to each patient’s unique presentation.. Abrupt onset. Patients respond readily to vasodilators and diuretics. history of CAD Such as ischemia. Target: PA pressure Therapy: nitrates. presence of pulmonary congestion. Can also be caused (directed by filling pressures and cardiac by inadequate intra-operative myocardial protection resulting index). Protect/preserve myocardium and renal function 7. AHFS acute heart failure syndromes.. worsening renal function. assistance (IABP. Alleviate symptoms (e. nitroprusside) and loop diuretics Develop gradually (days or weeks) and are associated with systemic congestion. BP.g. Its incidence may be related to the definition used (clinical versus radiographic). S3..g.g. Establish the diagnosis 3.g. Target: volume management Therapy: loop diuretics vasodilators Target: cardiac output Therapy: inotropes with vasodilatory properties (e. 53. Downloaded from content.. infarct) or valvular abnormalities (e. 2010 . biomarkers (e. Severity of initial signs and symptoms may not always correlate with outcomes (33. HR heart rate. milrinone. Many such patients may have signs and Target: coronary thrombosis.g.. PCI. from Gheorghiade et al. Robust evidence to support risk stratification and disposition identifying the low-risk patient for safe discharge with close outpatient follow-up is lacking 1. not series. arrhythmias. ACS acute coronary syndromes. †Retrospective data suggests morphine is associated with worse outcomes. lytics. fulminant myocarditis. volume management Therapy: vasodilators. Treat immediate life-threatening conditions/stabilize patient 2. HTN hypertension. STEMI ST-segment elevation myocardial infarction. corrective surgery Target: BP. signs (JVD. phosphodiesterase inhibitors. and 3.102). antiplatelet agents) ? Rapid or gradual onset due to primary or secondary PA hypertension or RV pathology (e. consider digoxin (intravenous and/or orally) vasopressor medications mechanical assist devices (e. CXR. with permission. Use of inotropes should be restricted to those with low-output state (low BP with organ hypoperfusion) Majority are admitted to telemetry. PA pulmonary artery. Patients with severe signs of HF (pulmonary edema) as a result of severe systemic hypertension may have better post-discharge outcomes than advanced HF patients with low EF who may present with less severe symptoms (11). Therapy: vasodilators (e. stabilization. Often precipitated by severe systemic hypertension.e. with a small number discharged home. troponin. No. STEMI) Based on medical history. †Treating etiology or precipitant is of equal of greater importance (e. particularly in patients with CAD. and/or infectious etiologies is critical to ensure maximal benefits from HF management Usually a diuretic with or without other vasoactive agents. 7.111).g. invasive or NIV.g. improve cardiac dysfunction. IABP intra-aortic balloon pump.. achieving euvolemia. edema). morphine¶ Normal or moderately elevated BP 50% Low BP ( 90 mm Hg) 8% Cardiogenic shock 1% Rapid onset. dobutamine. 2009:557–73 Initial Management for AHFS* Table 4 Initial Management for AHFS* Life-saving measures may precede or parallel diagnostic evaluation (i.

In addition. Pre-discharge phase. and often aldosterone-blocking agents (33). and this may not be feasible or specific in many older patients. and electrical devices (5. 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 (6.13. 3). only ACE inhibitor/ARB has been shown to improve outcomes in AHFS (8. CRT). This important hypothesis remains to be tested. Goals at discharge: 1) improve signs and symptoms.8. 2) appropriate management of precipitants.123–125. smoking cessation.119).onlinejacc. This is particularly important because high right atrial pressure is a sign of elevated left-sided pressure.120.g.116). with clear instruction regarding weight monitoring. the use of novel intravenous therapies (126. CAD.131). Appropriate management of comorbidities (e. Currently. No. interventional. and adequate discharge instructions). hydralazine/nitrates. 6-min walk test) before discharge has not been well studied. should be developed.g. neurohormonal profile. electrical devices. 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). Refractory or advanced HF should be managed according to published guidelines (13. anticoagulant at discharge for HF patients with atrial fibrillation. and renal function during the first few weeks after discharge in patients who die or are rehospitalized within 60 to 90 days (33). Hospitalization presents opportunities to optimize management. or ARB. 4) implementation or planned implementation of current HF guidelines. assessment of EF. 3). Implementation of evidence-based therapies (pharmacological. Measurement of jugular venous pressure. The level of BNP/N-terminal pro-BNP has also been proposed as a “measure” of congestion. medications. hypertension. rather than optimization of therapies known to improve outcomes in patients (37.111. which account for the heterogeneity of the patient population and incorporate different strategies of care.113). 2009:557–73 Gheorghiade and Pang Acute HF Syndromes 565 pro-BNP measurements in this setting remains to be determined.111. including beta-blockers. such as beta-blockers. improving symptoms and decreased BW).128 –130). is an important bedside measurement of right atrial pressure (112. race.. ARB. 2009 February 17. given the resources available in-hospital versus outpatient. 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. particularly in the presence of worsening renal function. It is doubtful that those measures alone will have a significant impact on post-discharge outcomes. 53. Of current HF quality measures (ACE inhibitor/ angiotensin receptor blocker [ARB]. 7.17. and 5) post-discharge planning and education involving patients and family have been established. diabetes mellitus) based on evidence-based guidelines may also improve post-discharge outcomes (35). ACE inhibitors. geographic region. 2010 .g. The traditional focus during hospitalization has been on alleviating congestion (e. Thromboembolic events and myocardial ischemia should be considered in patients not responding to standard therapy. Recent analysis from the GWTG-HF (Get With the Guidelines–Heart Failure) database showed variations by age. Orthostatic BP changes and the response during Valsalva maneuver or sublingual nitroglycerin may aid in assessment of LVFP (24.120 –125) (Fig. edema) and hemodynamic congestion (high LVFP) may be present after initial therapy.28). evidence and/or guidelines to assess congestion during hospitalization or pre-discharge are not well established. This deterioration occurs despite standard therapy. atrial fibrillation. Because dissociation between clinical (dyspnea. and comorbidities on CRT uptake as well as differences between clinical trials and guideline recommendations (131). Formal assessment of functional capacity (e. A thorough assessment to ensure implementation of evidence-based guidelines (pharmacological.118. and telephone and clinic follow-up.JACC Vol.org by on April 18. Discharge criteria.116. and surgical) based on comprehensive assessment may improve outcomes (13.11. ACE inhibitors. and implantable cardiac-defibrillator/CRT) should occur during this phase or soon after discharge (Fig. Available data highlight gaps in utilization/optimization of evidence-based therapies. Initiation or up-titration of evidence-based chronic HF therapies during hospitalization or soon after.. a pulmonary artery line may be considered for refractory signs and symptoms. Transitioning From Acute to Chronic HF Approximately 80% of patients hospitalized with worsening HF have chronic HF. surgical. 3) euvolemia with successful transition to oral diuretics. assessment of filling pressures is important.48. if done properly. aldosterone-blocking agents. Early post-discharge phase (“vulnerable” phase).128.. However.g. Routine pulmonary artery line-guided therapy in patients with severe HF does not result in improved outcomes (114). This approach remains to be investigated in AHFS.113).28. absent Downloaded from content. Recent data demonstrates deterioration in signs and symptoms.. For the vast majority who stabilize after initial management. aldosterone-blocking agents. given the complex pathophysiol- ogy and heterogeneity of this patient population. they should be considered as chronic HF and be treated according to published guidelines (11. 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.127) that are known to improve hemodynamics or to preserve myocardial and renal function should be studied in this vulnerable period.117).

BW. even when hemodynamics were monitored with a pulmonary artery catheter (40). Intravenous enalaprilat may adversely affect outcomes when used early in patients with acute MI (73). has been approved by the Food and Drug Administration only for treatment of hyponatremia. but its effects on clinical outcomes have not been well studied. Nitroprusside is a powerful systemic vasodilator. and symptoms (e.. retrospective analysis demonstrated increased mortality when used early in patients with acute MI complicated by severe HF. No. require urgent attention upon presentation. and is associated with a decrease in readmission rates (137). NITROGLYCERIN. dietary indiscretion. 53. and/or adenosineblocking agents. ACE inhibitor) (33). Conivaptan.140 –144).149). The clinical value of new or emerging therapies for fluid removal.132. on Symptoms. along with other symptoms and signs of AHFS. such as ultrafiltration.. 7.127. in spite of a reduction in BW when compared with standard therapies (60. vasopressin antagonists. as well as the optimal dose and duration.107). as many patients are left with signs of HF despite symptomatic improvement. however.g. Retrospective data raised the hypothesis that it may worsen renal function and increase post-discharge mortality (41. It may be particularly useful in patients with AHFS and underlying CAD or acute coronary syndrome complicated by HF. NITROPRUSSIDE. often resulting in liver congestion. a vasopressin-1 and -2 antagonist. However.107. Loop diuretics are the mainstay of therapy in AHFS and effectively relieve symptoms. may improve symptoms and post-discharge outcomes. use of aldosterone-blocking agents in AHFS has not been studied.org by on April 18.566 Gheorghiade and Pang Acute HF Syndromes JACC Vol.134). It improves hemodynamics and dyspnea (109). valvular disease). Adenosine antagonists induce diuresis via inhibition of sodium absorption in the proximal tubule. Pre-load and afterload reducers. will likely improve post-discharge event rates (128).127. INTRAVENOUS ACE INHIBITORS. pulmonary embolism) may aggravate or worsen the clinical profile and need to be taken into consideration and treated. NESIRITIDE. The role of IV ACE inhibitors remains to be determined.48. but not in Europe. remains to be determined. The potential negative effects of non– potassium-sparing diuretics. ischemia. dyspnea is related to high PCWP. Combination therapy with thiazide diuretics may also be considered (11. usually requires hemodynamic monitoring. Early Pharmacologic Management Pharmacologic therapies have been reviewed extensively elsewhere (126. The American College of Emergency Physicians guidelines support the use of intravenous ACE inhibitors for initial AHFS therapy. and Outcomes in Patients With Acute Heart Failure) pilot trial suggested that rolofylline. reduces BW without improving dyspnea. not to rely totally on diuretics for fluid removal. VASOPRESSIN ANTAGONISTS. Nesiritide was approved for the treatment of AHFS in the U.42). ULTRAFILTRATION. Lung. although small studies suggest benefit (106. arrhythmias. Aldosterone-blocking agents may be particularly useful in patients with AHFS. and Blood Institutes trial (DOSE-AHF [Diuretic Optimal Strategy Evaluation in Acute Heart Failure] study) (136). 2009 February 17. However. These promising results need to be confirmed in a larger clinical trial. In spite of their clinical benefits.. 2009:557–73 contraindications. non–potassium-sparing diuretics may cause further neurohormonal and renal abnormalities (61. and appears useful in patients with advanced HF (147). pneumonia. Placebo-Controlled. dyspnea) and normalizes serum sodium in hyponatremic patients (43. In this setting. Multicenter Acute Study of Clinical Effectiveness of Nesiritide in Subjects With Decompensated Heart Failure] trial) (148). Precipitants (e. The addition of vasodilators and/or digoxin should be considered (46. Renal Function.onlinejacc.. block tubuloglomerular feedback.146). have not been well studied and are currently being investigated in a large National Heart. and therefore preserve or increase glomerular filtration rate in HF (126. Fluid removal. The PROTECT (Effects of Rolofylline.g.68). Continuation of fixed doses of Downloaded from content. it does not improve signs and symptoms in patients admitted with HF (138.S.139). a vasopressin-2 antagonist. and is now being tested in a large outcome trial (145).138). signs. a selective A1 receptor antagonist. when added to standard therapy in patients admitted with worsening chronic HF and reduced EF modestly improves hemodynamics.g. Continuous infusion has been recommended for improved efficacy and for diuretic-resistant patients (11). The safety and efficacy of nitroprusside in AHFS has not been well studied. a New Adenosine A1 Receptor Antagonist.135). both their neurohormonal and diuretic effects (with higher doses) may be of benefit. which often require specific therapies.g. however. Tolvaptan. although as a Level C recommendation. Accordingly. The increase of PCWP may be the result of different pathophysiological processes (e. This is often associated with increased serum concentrations of aldosterone despite standard therapies (e. Dyspnea. in 2001. ADENOSINE ANTAGONISTS. Although it has a similar hemodynamic profile when compared with tolvaptan. Ultrafiltration effectively removes fluid. hypertension. because the majority of patients have evidence of right-sided failure. The safety and efficacy of nesiritide is being tested in a large international trial (ASCEND-HF [Double-Blind. tolvaptan after discharge decreased neither mortality nor readmission rates. The role of vasopressin antagonists in the management of AHFS remains to be determined. Nitroglycerin reduces LVFP.133). 2010 . It is prudent. while European Society of Cardiology guidelines do not support their use (11.

this trial was not stratified by severity of presenting illness (161).154). Although its use has been associated with decreased resource utilization and mortality. Inotropes with vasodilatory properties. emergency department).. However. an investigational vasodilator identical to the native human neurohormone. and/or quality of life. occurred at higher doses (151. including ACE inhibitors (135. Clinical Trials in AHFS Overall. gaps in our knowledge exist (Table 6).72. particularly in patients with CAD who may have ischemic and/or hibernating myocardium (38). Expecting therapies used for 48 h to improve outcomes at 2 to 6 months in a complex. BP.72. it increases SBP and decreases heart rate in AHFS (156). Cardiac myosin activators. has been evaluated in an early clinical trial (151. in the largest noninvasive ventilation trial to date. heterogeneous substrate such as HF may set the bar too high.JACC Vol. A number of other treatments are commonly given. and/or end points chosen. 2009 February 17. Dividing trials into stages has been proposed: Stage A is early intervention (i.152). 2009:557–73 RELAXIN. ISTAROXIME. improves hemodynamics. In retrospect. Ularitide. an investigational inotrope with lusitropic properties. and was associated with severe hypotension and arrhythmias (71). A reassessment of how to conduct clinical trials in AHFS is being investigated (5.162). the short-term use of levosimendan improved symptoms and reduced the need for cointervention for worsening HF. In addition.107–109). defined as low BP with sign of organ hypoperfusion. a natriuretic peptide composed of 32 amino acid residues originally isolated from human urine. These findings raised the hypothesis that short-term administration of drugs may affect post-discharge outcomes. In general. These disappointing results may have been related to the drug itself. such as dobutamine.42. assuming an acceptable safety profile. Improving post-discharge outcomes is the most important goal in AHFS.g. This agent appears promising for patients presenting in a low-output state. 2010 . clinical trial results have disappointed in terms of efficacy and/or safety (41. This may negatively affect research of therapies that may safely improve patient reported outcomes (e. post-approval questions of safety arose (41. Soluble guanylate cyclase activators represent another emerging therapy. In patients admitted with very severe HF. manifested by a low BP (157). Another consideration Downloaded from content. milrinone. and levosimendan (available in Europe) are known to improve hemodynamics (71. Stage B involves in-hospital management. It is currently being investigated in AHFS patients.110). symptoms. only nesiritide has been approved for the treatment of AHFS. it was associated with significant side effects (hypotension.. although randomized clinical trial data are lacking.159). when added to standard therapy. CARDIAC MYOSIN ACTIVATORS.127). It is currently being tested in a larger clinical trial. Digoxin improves hemodynamics in HF without activating neurohormones or negatively affecting heart rate. target myocardial myosin adenosine triphosphatase. both patients and physicians desire therapies that improve signs. inotropes with vasodilator properties should be reserved for those patients with a low output state.org by on April 18. At the same time. DIGOXIN (IV). appears in animal and pilot clinical studies to be a potent vasodilator (150). early data suggest beneficial arterial and venous vasodilatory effects (164).onlinejacc.111.116). It improves hemodynamics and signs and symptoms. and Stage C is before or soon after discharge (5).60. who do not respond to other therapies (13.42). Istaroxime. possibly by causing myocardial injury due to decreased perfusion and/or increased myocardial oxygen demand. Short-term use of IV milrinone without a bolus. 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. future clinical trials should address this issue. This molecule is currently undergoing further investigation in clinical trials (158. ventricular tachycardia) and a trend toward increased early mortality (110). patient selection. These therapies include morphine and oxygen supplementation. or renal function (135. Adenosine-regulating agents are an emerging therapy aimed to enhance endogenous adenosine-mediated cardioprotective mechanisms (163). levosimendan was not superior to dobutamine in terms of post-discharge mortality that was very high in both groups (72).153). ULARITIDE.71. as such. demonstration of early symptomatic benefit beyond that of standard therapy alone is difficult given the significant beneficial response to available therapies (107–109). These effects are seen when used alone or in combination with other vasoactive agents. Other therapies.e. in the early stages of clinical investigation. Severe hypotension. In contrast to current inotropes. dyspnea). however. In the last 15 years.165). Noninvasive ventilation relieves dyspnea in AHFS (161). however. or reduce the total number of hospital days. 53. without worsening renal function when compared with placebo treatment.152). does not improve signs and symptoms. 7. For the majority of agents being studied in AHFS. it appeared to increase post-discharge mortality in patients with CAD (39). Direct renin inhibitors will be explored in AHFS in the ASTRONAUT (Aliskerin Trial on Acute Heart Failure Outcomes) trial. No. its effects in AHFS in patients with or without AF have not been studied (135). generating force to improve contractility without changing intracellular concentrations of calcium (126. Inotropes. Gheorghiade and Pang Acute HF Syndromes 567 Relaxin. no mortality benefit was seen over oxygen for either continuous or bilevel noninvasive ventilation (161. however. In AHFS.153. failure to target the appropriate pathophysiologic process. The use of morphine in the ADHERE registry retrospectively points toward an association between morphine and worse outcomes (160).

†Elevates vasopressin levels. with permission. 2010 K-sparing diuretics Fluid removal—experimental Vasopressin antagonists (orally) Adenosine antagonists (IV) Vasodilators Nitroglycerin (IV) Nitroprusside (IV) Nesiritide (BNP) (IV) Enalaprilat (IV) Vasodilators—experimental Ularitide (urodilatin) Relaxin (IV) Inotropes Digoxin (IV) Dopamine (IV) Dobutamine (IV) Levosimendan (IV) Enoximone Milrinone (IV) Inotropes—experimental Cardiac myosin activators Istaroxime Endothelin antagonists Tezosentan Yes ?1 No ? 2 ? N ? No ? ? ? ? ? ? ? N ?1 ?† ? Yes Yes Yes ? Poss Yes Poss Poss 2 2 2 2 2 2 2 Dose dependent 2 2 2 2 ? 2 2 No Var No No No No No No ?1 ?2 ? ? ? ? ? ? ? ? ? ? ? ? ?2 ?2 ?1 ? ? 2 ? ? ? ? ?1 ? Poss ? Poss Poss ?1 ? ? ? ? ? ? ? ? ? ?N ? ? ? ? ? ? Yes Yes Poss N ? ? 2 1 ?1 1 1 1 ? 2 N No No Poss Poss Poss Poss 1 Dose dependent 1 1 1 1 1 1 1 No‡ Dose dependent 1 1 1 1 ? May ? ? ? ? ? ? ? ? ? 2 (may cause injury) ? ? ? ? ? Poss ? ? ? N ? ? ? ? ? 2 ? ? ? ? ? 2 ? ?1 ?1 ? ? 1 in CAD ? ? ? No ? ? ? ? ? ? ? N N ? No N Yes No ? ? ? ? N Adapted and reproduced. (127). 2009:557–73 possible. LVFP left ventricular filling pressure. N no change or neutral. Var variable response. other abbreviations as in Tables . May may worsen or improve. No. IV intravenous. 1 increase.onlinejacc.org by on April 18. 2009 February 17. ‡At proper therapeutic levels. TN troponin. JACC Vol. K potassium. 53. *Aldosterone antagonists only. Poss 1 and 5. ? unknown. 2 decrease. from Shin et al. 7.568 Gheorghiade and Pang Acute HF Syndromes Therapies for AHFS Table 6 Therapies for AHFS Effect on Viable But Dysfunctional Myocardium Effects on Mortality and/or Rehospitalization Symptomatic Improvement Fluid removal Diuretics (IV) Yes Poss HR Hypotension LVFP Cardiac Output Arrhythmia Coronary Perfusion Myocardial Injury (Tn) Renal Function Neurohormonal Activation Var N N N Var Var Var N N ? Poss No 2 ? Var ? ? No ? ? ? ? ? ? ?2 ? Yes ? No ? 2* N ?2 Downloaded from content.

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