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Abstract

  1. Top of page
  2. Abstract
  3. The Arterial Underfilling Hypothesis For Chronic HF
  4. The Role of Renal Impairment
  5. Neurohormonal Basis for Volume Overload in AHFS
  6. Acute Vascular Failure vs Decompensated Cardiac Failure
  7. The Continuum of Congestion: Hemodynamic to Clinical Congestion
  8. Lessons Learned From Recent AHFS Studies
  9. Conclusions
  10. References

Signs and symptoms of volume overload is a common feature in patients presenting with acute heart failure syndromes. Management of volume overload, or congestion, is an important goal of therapy. Despite the importance of volume overload management, the precise causes have not been fully elucidated. The authors review possible explanatory models of volume overload and reflect on recent insights from acute heart failure syndromes clinical trials and registries. Congest Heart Fail. 2010;16(4)( suppl 1):S1–S6. ©2010 Wiley Periodicals, Inc.

Volume overload or congestion is a characteristic feature for patients who present with acute heart failure syndromes (AHFS).1 This results from elevated left and/or right ventricular filling pressures and manifests itself clinically by symptoms such as dyspnea and orthopnea and signs such as elevated jugular venous pressure, rales, hepatomegaly, and peripheral edema.1

Volume overload is a leading cause of admission and readmission and may be associated with progression of heart failure (HF).2 Such admissions are not benign events, with an increased (and independent) risk of mortality following the initial and each subsequent hospitalization for HF.3–5 Achieving euvolemia (both clinically and hemodynamically) safely is an important goal of therapy. In fact, the overwhelming majority of patients receive diuretic therapy as their primary intervention, as seen in observational data from the United States and Europe.6–8

Despite the importance of volume overload management in AHFS, the precise causes have not been fully elucidated. In this review, we discuss potential explanatory models such as the arterial underfilling hypothesis for chronic HF, highlight mechanisms related to and resulting from volume overload in AHFS, and reflect on recent insights derived from AHFS trials and registries.

The Arterial Underfilling Hypothesis For Chronic HF

  1. Top of page
  2. Abstract
  3. The Arterial Underfilling Hypothesis For Chronic HF
  4. The Role of Renal Impairment
  5. Neurohormonal Basis for Volume Overload in AHFS
  6. Acute Vascular Failure vs Decompensated Cardiac Failure
  7. The Continuum of Congestion: Hemodynamic to Clinical Congestion
  8. Lessons Learned From Recent AHFS Studies
  9. Conclusions
  10. References

More than 2 decades ago, Schrier and colleagues proposed a unifying hypothesis of body fluid regulation (see Figure 1 and Figure 2), which encompassed HF as well as other potentially edematous states.9–11 This hypothesis summarizes the complex interplay among the heart, kidneys, sympathetic nervous system (SNS), renin-angiotensin-aldosterone system (RAAS), and other cellular and inflammatory modulators that function to regulate intravascular volume in the human body in any low-output state.12 Although not intended to explain the mechanisms leading to volume overload seen specifically in AHFS, its principles remain relevant and important. Briefly, the body functions to maintain homeostasis of the arterial circulation, driven primarily by cardiac output and peripheral vascular resistance. If a decrease in arterial pressure is seen, either by decreased cardiac output and/or vasodilation, the body acts via neurohormonal responses to retain sodium and water to ensure arterial circulatory integrity.9–11 In patients with reduced cardiac output, irrespective of cause, what begins as an adaptive response eventually becomes maladaptive, resulting in excess fluid accumulation and the HF syndrome.13,14 While these factors clearly play a role in the pathophysiology of volume overload in AHFS, the degree to which each contributes and the varying susceptibility of certain hospitalized HF patient subgroups to specific components is not completely understood.

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Figure 1.  Arterial underfilling hypothesis by Schrier. Reproduced with permission from Cadnapaphornchai et al.46

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image

Figure 2.  Decreased cardiac output as primary driver for sodium and water retention. Reproduced with permission from Cadnapaphornchai et al.46

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The Role of Renal Impairment

  1. Top of page
  2. Abstract
  3. The Arterial Underfilling Hypothesis For Chronic HF
  4. The Role of Renal Impairment
  5. Neurohormonal Basis for Volume Overload in AHFS
  6. Acute Vascular Failure vs Decompensated Cardiac Failure
  7. The Continuum of Congestion: Hemodynamic to Clinical Congestion
  8. Lessons Learned From Recent AHFS Studies
  9. Conclusions
  10. References

While the arterial underfilling hypothesis provides much insight, an important distinction in AHFS is that the majority of patients do not present with low cardiac output and instead have a phenotype dominated by vasoconstriction with elevated blood pressure. Whether long-standing or acute, such vasoconstriction contributes to systemic hypertension, which itself can cause damage to the renal microvasculature and, especially among those with diabetes mellitus, impairment of afferent arteriolar autoregulation in the kidney.15 The latter removes what in effect functions as a vasomotor (ie, myogenic) buffer that protects the glomerulus from excessive capillary pressure, leading to glomerular injury. This effect on autoregulation, which may be compounded (especially in HF patients) by loop diuretic–mediated inhibition of the tubuloglomerular feedback mechanism, alters the renal blood flow response to typical stimuli (ie, RAAS, SNS, atrial and brain-type natriuretic peptides [NPs], and urine sodium concentration) and results in progressive kidney dysfunction. The latter may have particular implications on volume status for those individuals with salt-sensitive hypertension.16

In AHFS, a relationship between the heart and kidneys exists, communicating through homeostatic and even maladaptive mechanisms in HF.17,18 Furthermore, the majority of patients admitted with AHFS have some degree of baseline renal impairment, as defined by the National Kidney Foundation, with no substantive differences based on the presence of preserved or reduced systolic function.19 This baseline renal impairment reflects the confluence of comorbid conditions (eg, diabetes, hypertension) and the AHFS state itself.20 The collective pathophysiologic milieu of AHFS may result in a worsening of chronic kidney disease through 1 or more of the following mechanisms: altered renal perfusion from progression of HF, untoward medication effects (possibly loop diuretics), continued renovascular damage caused by fluctuations in blood pressure, neurohormonal activation, and increased venous congestion.17,21,22 Venous congestion, which can be estimated clinically by central venous pressure, may be a particularly important modulator of glomerular filtration (and hence fluid balance), especially in individuals with increased right heart pressures.23,24

Neurohormonal Basis for Volume Overload in AHFS

  1. Top of page
  2. Abstract
  3. The Arterial Underfilling Hypothesis For Chronic HF
  4. The Role of Renal Impairment
  5. Neurohormonal Basis for Volume Overload in AHFS
  6. Acute Vascular Failure vs Decompensated Cardiac Failure
  7. The Continuum of Congestion: Hemodynamic to Clinical Congestion
  8. Lessons Learned From Recent AHFS Studies
  9. Conclusions
  10. References

Neurohormonal activation (particularly the RAAS system, arginine vasopressin [AVP], and the NP system), renal perfusion and intrinsic function, venous congestion, vascular compliance, extent and severity of coronary artery disease, extent and severity of cardiac dysfunction, as well as other comorbid cardiac and noncardiac conditions, are all involved in the pathogenesis of volume overload in AHFS. Dietary indiscretion (especially sodium intake) and medication noncompliance may also trigger or contribute to the development of acute or progressive volume overload. In addition, seemingly innocuous medications such as thiazolidinediones can increase fluid retention or, in the case of nonsteroidal anti-inflammatory drugs (NSAIDs), interfere with renal blood flow and offset the known beneficial effects of RAAS antagonist therapy.2

Once a volume-overloaded state occurs, this congestion further activates neurohormones, impairs myocardial performance, affects ventricular chamber geometry leading to functional mitral regurgitation,25 and increases wall stress, which may cause subendocardial ischemia.2 This exacerbates already elevated filling pressures, resulting in worsening pulmonary congestion. The degree to which this occurs is determined by the components of Starling’s equation regarding filtration of fluid.26 Regardless, volume overload both initiates and potentiates decompensation in patients with AHFS.

Neurohormonal Activation: Role of RAAS and AVP

In patients with worsening chronic HF, RAAS activation maintains perfusion by actions on the vasculature as well as the kidneys to ensure adequate volume for circulation. Of note, this activation persists well beyond the initial episode of decompensation, which may be one contributor to the high post-discharge event rate.27 Initially, such RAAS activation is helpful; however, over time, it becomes increasingly deleterious and leads to a worsening of HF.

Angiotensin II plays a particularly important role, acting as a direct vasoconstrictor as well as a mediator of both AVP and aldosterone release, leading to further retention of sodium and water. Higher levels of serum angiotensin II are associated with worse prognosis, presumably due to its consequential adverse effects on peripheral and central components of the circulatory system.28

In addition to stimulation by angiotensin II, release of vasopressin from the posterior pituitary gland is driven by receptors for both serum osmolality and blood pressure.29 Elevated AVP (also called antidiuretic hormone [ADH]) levels are seen in patients with HF, even in patients who are total body volume–overloaded.30,31 In HF, therefore, other nonosmotic mechanisms may play a greater role in AVP secretion, explaining why further retention of free water occurs despite an overall volume-overloaded state.32

Vasopressin has multiple functions, affecting fluid and osmolality regulation through its affects on free water absorption. AVP acts on the collecting ducts of the kidney via V2 receptors, leading to increased free water reabsorption. It also acts as a vasoconstrictor and has been implicated in ventricular remodeling.29 Similar to other neurohormones, elevated levels in HF are associated with worse outcomes.32

Attempting to Restore Balance: The NPs

The NPs are released in response to increasing atrial (ANP) or ventricular (BNP) wall tension associated with increased left ventricular end-diastolic pressure.33 The NPs work to offset this by decreasing peripheral vascular resistance (thus reducing excessive impedance to forward flow) and promoting sodium excretion from the kidney. In HF patients, however, a diminished response to increasing levels of ANP and BNP has been reported,34,35 and it is thought that this may be an important contributor to chronic volume overload. Why this develops is not entirely clear but may be related to NP receptor down-regulation in the kidney, increased activity of neutral endopeptidase (NEP), diminished activity of NEP inhibitors, secretion of inactive BNP caused by reduced functioning of corin (the enzyme required to cleave BNP from an inactive prohormone to an active hormone), and enhanced sodium reabsorption in the proximal tubule leading to decreased sodium delivery to the distal nephron, where NP receptors are located.

Acute Vascular Failure vs Decompensated Cardiac Failure

  1. Top of page
  2. Abstract
  3. The Arterial Underfilling Hypothesis For Chronic HF
  4. The Role of Renal Impairment
  5. Neurohormonal Basis for Volume Overload in AHFS
  6. Acute Vascular Failure vs Decompensated Cardiac Failure
  7. The Continuum of Congestion: Hemodynamic to Clinical Congestion
  8. Lessons Learned From Recent AHFS Studies
  9. Conclusions
  10. References

Traditionally, volume overload in HF has generally been viewed as in increase in total body fluid. This is evidenced by the importance of body weight to practicing clinicians, which is often viewed as a surrogate for total volume status. In conjunction with a careful physical examination, its measurement is recommended in HF management guidelines.8 However, as a result of insights from large AHFS registries, recent reviews have suggested that not all pulmonary congestion is due to total body fluid gain. In a proportion of patients (especially those with hypertensive HF), the pathophysiologic trigger may be fluid redistribution rather than accumulation.8,34,35

This dichotomy was summarized by Cotter and colleagues in recent reviews that describe 2 divergent but overlapping AHFS phenotypes: (1) acute cardiovascular (hypertensive or vascular) failure and (2) acute decompensated (cardiac) failure.34,35 The latter is the traditionally held view of volume overload in HF, while the “flash” pulmonary edema patient is the prototypical “vascular” failure patient. Such vascular failure patients tend not to exhibit slowly progressive clinical signs/symptoms of HF, such as worsening lower extremity edema but instead typically experience a sudden increase in afterload by as yet undefined mechanisms, leading to substantial, acute increases in ventricular wall tension with rapidly elevated filling pressures and precipitous onset of pulmonary congestion. Thus, in theory, therapy for such patients might be primarily directed toward afterload reduction rather than diuresis, but the optimal approach for such differing phenotypes has yet to be defined.35

The Acute Decompensated Heart Failure National Registry (ADHERE) and the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) highlight an AHFS population that is older than that seen from clinical trials (mean age in ADHERE, 72 years), over half are women, nearly 50% have preserved ejection fraction (EF), and approximately 50% of patients present with relatively high systolic blood pressure (SBP; >140 mm Hg).1,36 This suggests that decompensation in these patients, who likely have relatively stiffer vasculature or greater vascular resistance combined with a less compliant ventricle, is predominantly of the “vascular” failure type.34,35 Although a greater proportion of patients in OPTIMIZE-HF with higher SBP had evidence of pulmonary congestion by rales, edema was seen in equal proportions across a range of SBPs. This latter finding would be inconsistent with the rapid fluid redistribution prototype. It is likely that both prototypes are seen in a continuum in AHFS, with redistribution more likely to be seen in AHFS patients with preserved systolic function. Further research regarding these prototypes is needed.

The Continuum of Congestion: Hemodynamic to Clinical Congestion

  1. Top of page
  2. Abstract
  3. The Arterial Underfilling Hypothesis For Chronic HF
  4. The Role of Renal Impairment
  5. Neurohormonal Basis for Volume Overload in AHFS
  6. Acute Vascular Failure vs Decompensated Cardiac Failure
  7. The Continuum of Congestion: Hemodynamic to Clinical Congestion
  8. Lessons Learned From Recent AHFS Studies
  9. Conclusions
  10. References

Clinical congestion prompts presentation to the hospital due to symptoms and signs of HF, such as dyspnea, orthopnea, and lower extremity edema. However, prior to clinical evidence of congestion, patients initially experience a clinically quiescent phase of congestion, where ventricular filling pressures begin to rise prior to the onset of symptoms. This phase of congestion has been termed hemodynamic congestion.2 Thus, patients may initially develop volume overload, without the appearance of clinical manifestations until a certain severity or threshold is reached.

Studies with implantable monitoring devices have yielded data to support this concept. Yu and colleagues37 evaluated an implantable impedance monitoring device in 33 patients with New York Heart Association (NYHA) class III/IV HF. They found evidence for a reduction in thoracic impedance (which is indicative of increased lung water content) on average 18 days prior to admission for HF and an average of 15 days prior to symptom onset, suggesting that subclinical pulmonary congestion occurs prior to symptom manifestation. Adamson and colleagues38 examined data derived from an implantable hemodynamic monitor in 32 patients with NYHA class II/III HF and found evidence of worsening pressures in the majority of patients requiring hospitalization for an average of 4 days prior to presentation with decompensation. Moreover, they noted a significant decrease in hospitalizations after use of the data generated from the device, suggesting that a full-blown AHFS episode could be averted by detection and early treatment of this subclinical phase of congestion.

From a clinician’s perspective, insight that volume overload leading to abnormal hemodynamics can occur in the absence of overt symptoms and signs of HF symptoms may be important to increase awareness for subtle evidence of worsening HF.

Lessons Learned From Recent AHFS Studies

  1. Top of page
  2. Abstract
  3. The Arterial Underfilling Hypothesis For Chronic HF
  4. The Role of Renal Impairment
  5. Neurohormonal Basis for Volume Overload in AHFS
  6. Acute Vascular Failure vs Decompensated Cardiac Failure
  7. The Continuum of Congestion: Hemodynamic to Clinical Congestion
  8. Lessons Learned From Recent AHFS Studies
  9. Conclusions
  10. References

In an observational study by Chaudhry and colleagues,39 268 patients, predominantly with NYHA class III disease, were enrolled in a home-monitoring study. Increases in body weight were seen as early as 30 days prior to hospitalization for HF, with clinically important weight gains seen 7 days prior to admission (see Figure 3). In the 7 days prior to hospitalization for HF, the odds ratio for hospitalization was 1.07 (95% confidence interval [CI], 1.02–1.11) for every single pound of additional weight.39 More than 25% of patients gained more than 5 pounds, and half of those saw their weight increase by at least 10 pounds.39 Importantly, no changes in weight were seen between groups in regard to non-HF related hospitalizations. These findings suggest that despite clinically silent hemodynamic congestion, a noninvasive method of assessment such as body weight measurement may identify patients with slowly progressive volume overload at risk for hospitalization.

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Figure 3.  Daily weight change before heart failure hospitalization: cases vs controls (N=268). “Days” on the x-axis denotes days before hospital admission in case patients. The difference in daily weight changes between case and control patients within 30 days before (case) hospitalization was statistically significant (P<.001) on the basis of a generalized linear model with daily weight change as the dependent variable. Reproduced with permission from Chaudhry et al.39

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In a prospective study of 146 patients (mean EF, 20%) by Lucas and colleagues, the authors studied whether freedom from congestion was associated with improved outcomes, despite previous NYHA class IV symptoms. Management began during hospitalization by HF specialists and included pulmonary artery catheterization with tailored therapy if necessary. Outpatient management continued for the next 4 weeks, typically at 1-week intervals, by attending HF cardiologists. Four to 6 weeks post-discharge, congestion was assessed on a 0 to 5 score. In patients with a congestion score of 0, 87% were alive at 2 years vs 67% of patients with mild congestion vs only 41% in patients with moderate to severe congestion.40 This study highlights the importance of volume management but also raises the question of whether management by an HF specialist would have led to different outcomes vs a non-HF specialist. Furthermore, whether these improved outcomes were truly due to an absence of congestion or merely a reflection of patients at lower risk who were more able to respond to therapy was not able to be clearly differentiated.

Results from the Efficacy of Vasopressin Antagonism in HF: Outcome Study with Tolvaptan (EVEREST) trials, which enrolled 4133 patients with a history of chronic HF and EF <40%, demonstrated significantly greater weight loss as well as greater improvement in signs and symptoms (dyspnea) during hospitalization, without serious adverse events with tolvaptan when added to standard therapy vs standard therapy alone.41 Despite these short-term benefits, as well as the continuation of tolvaptan through 60 days post-discharge, no long-term benefits in terms of mortality or HF morbidity were seen.42 Importantly, however, no serious adverse safety signals were seen.

This lack of association with weight loss and post-discharge events was also seen in a retrospective analysis from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial, which included 383 of the 433 enrolled patients hospitalized for worsening HF, EF <30%, SBP <125 mm Hg, with signs and symptoms of HF who were randomized to pulmonary artery catheter–guided therapy vs clinical assessment alone. Despite a substantial decrease in weight, (the mean weight loss during hospitalization was 3.6 kg), no association was seen with days well, 180-day death, or death or rehospitalization at 180 days.43 Although the data were not specifically presented, the authors also reported no association between weight loss and quality of life measures at 1, 3, or 6 months.43

The Ultrafiltration vs Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure (UNLOAD) trial, however, did find an association between volume removal and outcomes. UNLOAD randomized 200 patients with worsening HF in a 1:1 fashion to receive, after an initial dose of furosemide, venovenous ultrafilration (UF) vs continued intravenous diuretic therapy. Significantly greater weight loss was seen in the UF arm, and this was associated with fewer HF rehospitalizations or unscheduled emergency department visits (without an effect on mortality) when compared to standard intravenous diuretic therapy.44

In a secondary analysis from the EVEREST trial, Blair and colleagues45 examined the association between weight changes after discharge to rehospitalization and all-cause mortality. In this trial population, increases in weight of 1.96, 2.07, and 1.97 kg at 60-, 120-, and 180-day follow-up, respectively, were associated with HF rehospitalization as well as rehospitalization for cardiovascular causes. Interestingly, no association was seen with weight gain and all-cause mortality.

This suggests the possibility that drivers of rehospitalization, such as weight gain, may be distinct from the pathophysiologic mechanisms leading to mortality, although this hypothesis requires further testing. Given the conflicting evidence in regard to the efficacy of fluid removal during hospitalization and post-discharge events, it may be that the manner by which fluid is removed, the type of fluid (isotonic, hypotonic), the timing of removal (early, late, post-discharge), speed, potential untoward effects of therapies, as well as patient characteristics may all be important factors to consider when designing volume removal strategies. This further highlights our growing but still incomplete understanding of the pathophysiology of volume overload in AHFS.

Conclusions

  1. Top of page
  2. Abstract
  3. The Arterial Underfilling Hypothesis For Chronic HF
  4. The Role of Renal Impairment
  5. Neurohormonal Basis for Volume Overload in AHFS
  6. Acute Vascular Failure vs Decompensated Cardiac Failure
  7. The Continuum of Congestion: Hemodynamic to Clinical Congestion
  8. Lessons Learned From Recent AHFS Studies
  9. Conclusions
  10. References

Volume overload or congestion is a defining characteristic of patients who present with AHFS. Its pathophysiology is complex, involving neurohormonal and other cellular modulators as well as an interaction between cardiac and kidney function. Alleviating congestion to ensure symptomatic relief is a fundamental goal of therapy. Despite a well-established association between congestion and hospitalization for HF, whether alleviating congestion leads to reductions in mortality has yet to be definitively established. Safely treating volume overload in AHFS without further activation of neurohormones or inciting cardiac and/or renal injury is an important target of therapy and may lead to improved outcomes.

Disclosure:  Dr. Pang received research support from Merck and PDL Biopharma; serves as a consultant to Astellas, Bayer, Johnson & Johnson, The Medicines Company, Palatin Technologies, Pericor Therapeutics, and Solvay Pharmaceuticals; and has received honoraria from the Society of Chest Pain Centers, Biogenidec, Corthera, Ikaria, and Nile Therapeutics. He received an honorarium funded by Abbott Laboratories and Otsuka America Pharmaceuticals for time and expertise spent in the compilation of this article. Dr. Levy received an honorarium from the Society of Chest Pain Centers; served as a consultant for The Medicines Company, Corthera, and Bayer Schering A.G. He received grant funding from the Robert Wood Johnson Foundation Physician Faculty Scholars Program, NIH, Cleveland Clinic Foundation, Nile Therapeutics, Astellas Pharma, Corthera, Solvay Pharmaceuticals, and Bayer Schering A.G.

References

  1. Top of page
  2. Abstract
  3. The Arterial Underfilling Hypothesis For Chronic HF
  4. The Role of Renal Impairment
  5. Neurohormonal Basis for Volume Overload in AHFS
  6. Acute Vascular Failure vs Decompensated Cardiac Failure
  7. The Continuum of Congestion: Hemodynamic to Clinical Congestion
  8. Lessons Learned From Recent AHFS Studies
  9. Conclusions
  10. References